U.S. patent application number 10/214333 was filed with the patent office on 2004-02-12 for topical pharmaceutical composition comprising a cholinergic agent or a calcium channel blocker.
This patent application is currently assigned to S.L.A. Pharma AG.. Invention is credited to Kamm, Michael A., Phillips, Robin K.S..
Application Number | 20040028752 10/214333 |
Document ID | / |
Family ID | 32475044 |
Filed Date | 2004-02-12 |
United States Patent
Application |
20040028752 |
Kind Code |
A1 |
Kamm, Michael A. ; et
al. |
February 12, 2004 |
Topical pharmaceutical composition comprising a cholinergic agent
or a calcium channel blocker
Abstract
A method and composition are provided for the treatment of an
anorectal disorder and for controlling the pain associated
therewith. The method comprises administering to a subject in need
of such treatment therapeutically effective amounts of a calcium
channel blocker either alone or together with a nitric oxide donor.
Amlodipine, anipamil, barnidipine, benidipine, bepridil,
darodipine, diltiazem, efonidipine, felodipine, isradipine,
lacidipine, lercanidipine, lidoflazine, manidipine, mepirodipine,
nicardipine, nifedipine, niludipine, nilvadipine, nimodipine,
nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil and
pharmaceutically acceptable salts thereof, are suitable calcium
channel blockers.
Inventors: |
Kamm, Michael A.; (London,
GB) ; Phillips, Robin K.S.; (Northwood, GB) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
S.L.A. Pharma AG.
|
Family ID: |
32475044 |
Appl. No.: |
10/214333 |
Filed: |
August 8, 2002 |
Current U.S.
Class: |
424/718 ;
514/355 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 31/55 20130101; A61K 31/55 20130101; A61K 31/573 20130101;
A61P 17/02 20180101; A61K 31/554 20130101; A61P 9/14 20180101; A61K
47/20 20130101; A61K 9/0031 20130101; A61P 43/00 20180101; A61P
1/00 20180101; A61K 31/55 20130101; A61K 31/573 20130101; A61K
31/27 20130101; A61P 9/00 20180101; A61K 31/27 20130101; A61K 47/14
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 31/27 20130101 |
Class at
Publication: |
424/718 ;
514/355 |
International
Class: |
A61K 033/00; A61K
031/455 |
Claims
What is claimed is:
1. A method of treating an anorectal disorder, and for controlling
the pain associated therewith, the method comprising administering
to a subject in need of such treatment a therapeutically effective
amount of a calcium channel blocker either alone or together with a
nitric oxide donor.
2. A method in accordance with claim 1, wherein both the calcium
channel blocker and nitric oxide donor are administered.
3. A method in accordance with claim 2, wherein said nitric oxide
donor and said calcium channel blocker are administered in
combination.
4. A method in accordance with claim 1, wherein said anorectal
disorder is an anal fissure.
5. A method in accordance with any one of claims 1, 2, 3 or 4,
wherein said administration is topical.
6. A method in accordance with claim 5, wherein said administration
is in the form of a gel, ointment, cream, emollient, lotion,
powder, solution, suspension, spray, paste, oil, foam, suppository
or enema.
7. A method in accordance with claim 6, wherein said calcium
channel blocker is administered in an amount within the range of
from 0.5% to 5% w/w.
8. A method of treating a benign anal disorder, the method
comprising administering to a subject in need of such treatment a
therapeutically effective amount of a calcium channel blocker
either alone or together with a nitric oxide donor.
9. A method in accordance with claim 8, wherein both the calcium
channel blocker and nitric oxide donor are administered.
10. A method in accordance with claim 9, wherein said nitric oxide
donor and calcium channel blocker are administered in
combination.
11. A method in accordance with claim 8, wherein said anorectal
disorder is an anal fissure.
12. A method in accordance with any one of claims 8, 9, 10 or 11,
wherein said administration is topical.
13. A method in accordance with claim 12, wherein said
administration is in the form of a gel, ointment, cream, emollient,
lotion, powder, solution, suspension, spray, paste, oil, foam,
suppository or enema.
14. A method in accordance with claim 13, wherein said calcium
channel blocker is administered in an amount within the range of
from 0.5% to 5% w/w.
15. A method of treating an anorectal disorder, and for controlling
the pain associated therewith, the method comprising administering
to a subject in need of such treatment a therapeutically effective
amount of an agent selected from the group consisting of diltiazem,
nifedipine and pharmaceutically acceptable salts thereof either
alone or together with a nitric oxide donor.
16. A method in accordance with claim 15, wherein both said agent
and the nitric oxide donor are administered.
17. A method in accordance with claim 16, wherein said agent and
said nitric oxide donor are administered in combination.
18. A method in accordance with claim 15, wherein said anorectal
disorder is an anal fissure.
19. A method in accordance with any one of claims 15, 16, 17 or 18,
wherein said administration is topical.
20. A method in accordance with claim 19, wherein said
administration is in the form of a gel, ointment, cream, emollient,
lotion, powder, solution, suspension, spray, paste, oil, foam,
suppository or enema.
21. A method in accordance with claim 20, wherein said calcium
channel blocker is administered in an amount within the range of
from 0.5% to 5% w/w.
22. A method of treating a benign anal disorder, the method
comprising administering to a subject in need of such treatment a
therapeutically effective amount of an agent selected from the
group consisting of diltiazem, nifedipine and pharmaceutically
acceptable salts thereof either alone or together with a nitric
oxide donor.
23. A method in accordance with claim 22, wherein both said agent
and said nitric oxide donor are administered.
24. A method in accordance with claim 23, wherein said agent and
said nitric oxide donor are administered in combination.
25. A method in accordance with claim 22, wherein said anorectal
disorder is an anal fissure.
26. A method in accordance with any one of claims 22, 23, 24 or 25,
wherein said administration is topical.
27. A method in accordance with claim 26, wherein said
administration is in the form of a gel, ointment, cream, emollient,
lotion, powder, solution, suspension, spray, paste, oil, foam,
suppository or enema.
28. A method in accordance with claim 27, wherein said calcium
channel blocker is administered in an amount within the range of
from 0.5% to 5% w/w.
29. A method of treating an anorectal disorder, and for controlling
the pain associated therewith, the method comprising administering
to a subject in need of such treatment a therapeutically effective
amount of a composition comprising a pharmaceutically acceptable
carrier and an agent which increases a level of cyclic guanidine
monophosphate or cyclic adenosine monophosphate in a tissue of an
anal sphincter muscle of the subject, thereby decreasing
hypertonicity of the anal sphincter muscle of the subject, which
composition comprises a calcium channel blocker either alone or
together with a nitric oxide donor.
30. A method according to claim 29, wherein both said calcium
channel blocker and said nitric oxide donor are administered.
31. A method for the treatment or prophylaxis of benign anal
disorders comprising local application to the anus of a patient a
therapeutically effective amount of a calcium channel blocker
either alone or in combination with a nitric oxide donor.
32. A method in accordance with claim 31, wherein both said calcium
oxide blocker and said nitric oxide donor are administered.
33. A method in accordance with claim 32, wherein said calcium
oxide blocker and said nitric oxide donor are administered in
combination.
34. A method in accordance with claim 31, wherein said
administration is in the form of a gel, ointment, cream, emollient,
lotion, powder, solution, suspension, spray, paste, oil, foam,
suppository or enema.
35. A method in accordance with claim 34, wherein said calcium
channel blocker is administered in an amount within the range of
from 0.5% to 5% w/w.
36. A method for the treatment or prophylaxis of benign anal
disorders associated with high anal pressure or anal sphincter
spasm, comprising local application to the anus of a patient a
therapeutically effective amount of a calcium channel blocker
either alone or in combination with a nitric oxide donor.
37. A method in accordance with claim 36, wherein both said calcium
oxide blocker and said nitric oxide donor are administered.
38. A method in accordance with claim 37, wherein said calcium
oxide blocker and said nitric oxide donor are administered in
combination.
39. A method in accordance with claim 36, wherein said
administration is in the form of a gel, ointment, cream, emollient,
lotion, powder, solution, suspension, spray, paste, oil, foam,
suppository or enema.
40. A method in accordance with claim 39, wherein said calcium
channel blocker is administered in an amount within the range of
from 0.5% to 5% w/w.
41. A method for the treatment or prophylaxis of benign anal
disorders associated with high anal pressure or anal sphincter
spasm, and the relief of symptoms associated therewith, comprising
local application to the internal anal sphincter of a patient a
therapeutically effective amount of a calcium channel blocker
either alone or together with a nitric oxide donor.
42. A method in accordance with claim 41, wherein both said calcium
oxide blocker and said nitric oxide donor are administered.
43. A method in accordance with claim 42, wherein said calcium
oxide blocker and said nitric oxide donor are administered in
combination.
44. A method according to any one of claims 1, 8,15, 29, 31, 36 or
41, wherein the calcium channel blocker is selected from the group
consisting of amlodipine, anipamil, barnidipine, benidipine,
bepridil, darodipine, diltiazem, efonidipine, felodipine,
isradipine, lacidipine, lercanidipine, lidoflazine, manidipine,
mepirodipine, nicardipine, nifedipine, niludipine, nilvadipine,
nimodipine, nisoldipine, nitrendipine, perhexiline, tiapamil,
verapamil, and pharmaceutically acceptable salts thereof.
45. A method according to any one of claims 1, 8, 15, 22, 29, 31,
36 or 41, wherein the nitric oxide donor is trinitroglycerine.
46. A method according to any one of claims 1, 8, 15, 22, 29, 31,
36 or 41, wherein the anal disorder is hemorrhoids.
47. A method in accordance with claim 41, wherein said
administration is in the form of a gel, ointment, cream, emollient,
lotion, powder, solution, suspension, spray, paste, oil, foam,
suppository or enema.
48. A method in accordance with claim 47, wherein said calcium
channel blocker is administered in an amount within the range of
from 0.5% to 5% w/w.
49. A composition adapted for topical application in and around the
anal canal comprising a calcium channel blocker and a nitric oxide
donor together with a pharmaceutically acceptable carrier.
50. A composition according to claim 49, wherein the calcium
channel blocker is selected from the group consisting of
amlodipine, anipamil, barnidipine, benidipine, bepridil,
darodipine, diltiazem, efonidipine, felodipine, isradipine,
lacidipine, lercanidipine, lidoflazine, manidipine, mepirodipine,
nicardipine, nifedipine, niludipine, nilvadipine, nimodipine,
nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil, and
pharmaceutically acceptable salts thereof.
51. A composition according to claim 50, wherein the calcium
channel blocker is selected from the group consisting of diltiazem,
nifedipine and pharmaceutically acceptable salts thereof.
52. A composition according to claim 49, wherein the nitric oxide
donor is trinitroglycerine or a pharmaceutically acceptable salt
thereof.
53. A composition according to claim 51, wherein said calcium
channel blocker is diltiazem.
54. A method in accordance with claim 49, wherein said composition
is in the form of a gel, ointment, cream, emollient, lotion,
powder, solution, suspension, spray, paste, oil, foam, suppository
or enema.
55. A method in accordance with claim 49, wherein said calcium
channel blocker is present in an amount within the range of from
0.5% to 5% w/w.
Description
[0001] This invention relates to the use of a calcium channel
blocker or a cholinegic agent, particularly diltiazem and
bethanechol, alone and in combination for the treatment of benign
anal diseases where there is an associated anal sphincter spasm.
The invention particularly relates to the treatment of anal
fissures and painful haemorrhoidal conditions.
[0002] A fissure is a split in the skin of the distal anal canal.
It is a common complaint in young adults with a roughly equal
incidence in both sexes. Acute fissures are very common and most
heal spontaneously, but a proportion progress to form a chronic
linear ulcer in the anal canal and show great reluctance to heal
without intervention.
[0003] Treatment has remained largely unchanged for over 150 years
and the pathogenesis of anal fissure is not fully understood. The
passage of a hard stool bolus has traditionally been thought to
cause anal fissure. Thus for acute fissures the avoidance of
constipation, such as involving a high bran diet, has been used as
treatment for many years.
[0004] Anal dilators have also been involved in treatment.
Typically a dilator of medium size was coated with anaesthetic
jelly and inserted into the anal canal before the passage of stool
to prevent exacerbation of the symptoms during defecation. The
procedure was inconvenient and success rate was low. The most
common treatment, for chronic anal fissures is a lateral internal
sphincterotomy, which involves surgery to the internal anal
sphincter. This procedure, however, requires hospitalisation and
leads in a sizeable number of patients to impairment of continence
(British Journal of Surgery 1996, 83, 1334-1344). As yet there is
no proven non-surgical treatment for chronic fissure, although
local injection of botulinum A toxin shows early promise
(Martindale, The Extra Pharmacopoeia 31st Edition p1516 and
1517).
[0005] A further potential non-surgical treatment that has recently
been reported for anal fissures and haemorrhoids is the topical use
of a nitric oxide donor, particularly glyceryl trinitrate. This
reduces the internal anal resting pressure (British Journal of
Surgery, 1994, 81, 1386-1389 and British Journal of Surgery, 1996,
83, 771-775 both by present inventors; Diseases of the Colon and
Rectum, May 1995, p453-457, The New England Journal of Medicine
Oct. 26, 1995, p1156 and 1157, WO 95/32715 and its equivalent U.S.
Pat. No. 5,504,117--all by Gorfine; British Journal of Surgery
1996, 83, 776-777).
[0006] At a meeting of the Royal Society of Medicine Coloproctology
Session on Nov. 27, 1996, a paper entitled "The effect of alpha
adrenoceptor blockade on the anal canal in patients with chronic
anal fissure" was presented showing that indoramin reduced maximum
resting pressures in the anal canal after 1 hour by 35.8% in
patients with anal fissures. The author suggested a clinical trial
to determine the efficacy of indoramin in the treatment of anal
fissures.
[0007] In Dis Colon Rectum, February 1996, vol 2, no.2, p212-216
nifedipine was reported as reducing the activity of the internal
anal sphincter in patients with high anal resting pressure, and was
proposed for use in relieving symptoms in patients with
haemorrhoids or anal fissures.
[0008] Haemorrhoids (`piles`) are venous swellings of the tissues
around the anus. Those above the dentate line (the point where the
modified skin of the outer anal canal becomes gut epithelium),
which usually protrude into the anal canal, are termed internal
haemorrhoids, while those below this point are called external
haemorrhoids. Due to internal pressure, internal haemorrhoids tend
to congest, bleed and eventually prolapse; with external
haemorrhoids painful thrombosis may develop.
[0009] Initial treatment of internal haemorrhoids involves a
high-fibre diet and avoidance of straining at stool, so bulk
laxatives and faecal softeners may be indicated. Small bleeding
haemorrhoids may be injected with a sclerosing agent such as oily
phenol injection, or they may be ligated with rubber bands. More
severe and prolonged prolapse generally requires surgery. Surgical
excision to remove the clot is used for thrombosed external
haemorrhoids.
[0010] A range of mainly topical drug treatments is available for
symptomatic relief, but in many cases their value is a best
unproven. Local anaesthetics may be included to relieve pain, and
corticosteroids may be used when infection is not present.
Preparations containing either group of drugs are intended only for
short-term use. Some preparations include heparinoids and other
agents frequently included for their soothing properties include
various bismuth salts, zinc oxide, hamamelis, resorcinol and peru
balsam.
[0011] In British Journal of Surgery 1994, 81, 946-954, Loder et al
reviewed the possible pathology, pathophysiology and aetiology of
haemorrhoids but came to no firm conclusions. The authors speculate
that the anal cushions surround the anal canal act as a seal to
prevent minor leakage from the anus and these cushions distend as a
consequence of haemorrhoidal disease. The authors also explored
whether haemorrhoids is more prevalent in certain racial groups,
whether it is a function of diet, habits or body habitus, whether
it is a genetic disorder or whether it is associated with other
conditions such as hernia. No firm conclusions were, however,
reached as to the aetiology of haemorrhoids or how to treat it
effectively.
[0012] Diltiazem is indicated orally for the treatment of angina
pectoris and hypertension, and may be given intravenously in the
treatment of arterial fibrillation or flutter and paroxysmal
supraventricular tachycardia. Bethanechol is used as an alternative
to catheterisation in the treatment of urinary retention, gastric
atony and retention, abdominal distension following surgery,
congenital megacolon, and oesophageal reflux. It is given in doses
of 5 mg subcutaneously or 10 to 50 mg by mouth (Martindale, The
Extra Pharmacopoeia, 31st Edition, p857 and p1417).
[0013] In a letter to the Lancet Jun. 28, 1986 at p1493 and Mar.
28, 1987 at p754 diltiazem given orally at 60 mg was found to
reduce internal anal resting pressure and to treat proctalgia
fugax. There was, however, no suggestion of diltiazem being used to
treat anal fissure or haemorrhoids.
[0014] It is an object of the present invention to provide a
non-surgical treatment for anal fissures and/or haemorrhoids, or
other benign anal disorders.
[0015] The inventors have now found that anal fissures and
haemorrhoids and other benign anal disorders can be treated by
local application to the anus of a cholinergic agent or a calcium
channel blocker or a mixture thereof. Other benign anal disorders
would be those conditions associated with a high anal pressure or
where there is an associated anal sphincter spasm.
[0016] Accordingly in a first aspect of the invention, there is
provided use of at least one of a cholinergic agent or a calcium
channel blocker in the preparation of a medicament for local
application to the anus for the treatment or prophylaxis of benign
anal disorders.
[0017] To the inventors knowledge the active agents are usually
administerd orally or intraveneously and have never before been
contemplated in topical form. Accordingly, a second aspect of the
invention provides a composition adapted for local application to
the anus comprising at least one of a cholinergic agent or a
calcium channel blocker together with a pharmaceutically acceptable
carrier.
[0018] By local application to the anus we mean to include local
injection into the anal sphincter, and administration in and around
the anal canal, preferably by topical application such as spreading
a topical composition in and around the anal canal.
[0019] Without being bound by theory, it is believed that the
cholinergic agents and calcium channel blockers are at least
partially effective (and there may be other mechanisms of action)
by lowering the anal resting pressure of the patient. This helps
the fissures to heal. This reduction in anal pressure should also
allow better venous drainage which will allow the haemorroidal
vascular cushions to heal.
[0020] In the case of haemorrhoids, it is also thought that the
cholinergic agents will act to contract the longitudinal muscle of
the anus, thereby pulling the haemorrhoidal cushions back into
place.
[0021] In any case the clinical results to date suggest the
inventors have made a major advance in the field by providing a
safe and efficacious non-surgical treatment for anal fissures and
haemorrhoids.
[0022] By anal fissures we mean to include both acute and chronic
fissures or ulcers. Any patient with persistent symptoms for more
than two weeks is taken to have a chronic fissure in accordance
with the invention.
[0023] By haemorrhoids we mean to include both internal and
external haemorrhoids and acute thrombosis of external haemorrhoid
(TEM).
[0024] Suitable cholinergic agents in accordance with the invention
are selected from a cholinergic agonist of acetylcholine,
bethanechol, carbachol, methacholine, and pilocarpine, or an
anticholinesterase of ambenonium, neostigmine, physostigmine,
pyridostigmine, dyflos, and ecothinopate, and pharmaceutically
acceptable salts of thereof.
[0025] Bethanechol and salts thereof is a particularly preferred
cholinergic agent.
[0026] Suitable calcium channel blockers in accordance with the
invention are selected from amlodipine, anipamil, barnidipine,
benidipine, bepridil, darodipine, diltiazem, efonidipine,
felodipine, isradipine, lacidipine, lercanidipine, lidoflazine,
manidipine, mepirodipine, nicardipine, nifedipine, niludipine,
nilvadipine, nimodipine, nisoldipine, nitrendipine, perhexiline,
tiapamil, verapamil, and pharmaceutically acceptable salts
thereof.
[0027] Diltiazem and salts thereof is a particularly preferred
calcium channel blocker.
[0028] A further preferred aspect of the invention provides a
composition for local application to the anus, particularly
topically acting composition, but not exclusively for topical
application in and around the anal canal comprising diltiazem or
bethanechol or a combination thereof or pharmaceutically acceptable
salts thereof, together with a pharmaceutically acceptable
carrier.
[0029] Accordingly in a preferred aspect of the invention there is
provided the use of diltiazem or bethanechol or a combination
thereof and pharmaceutically acceptable salts thereof in the
preparation of a topical medicament for the treatment or
prophylaxis of benign anal disorders, particularly in the treatment
of anal fissures and haemorrhoids.
[0030] Pharmaceutically acceptable salts of the aforementioned
agents, such as of diltiazem and bethanechol, include those formed
with both organic and inorganic acids. Such acid addition salts
will normally be pharmaceutically acceptable although salts of
non-pharmaceutically acceptable salts may be of utility in the
preparation and purification of the compound in question. Thus,
preferred salts include those formed from hydrochloric,
hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic,
pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic,
methanesulphonic, ethanesulphonic, benzenesulphonic, and isethionic
acids. Salts of the compounds of formula (1) can be made by
reacting the appropriate compound in the form of the free base with
the appropriate acid. Salts of halides are also suitable. Diltiazem
hydrochloride, diltiazem malate and diltiazem have CAS registry
numbers respectively as follows: 33286-22-5, 144604-00-2, and
42399-41-7. Bethanechol and bethanechol chloride have CAS registry
numbers respectively of 674-38-4 and 590-63-6.
[0031] Diltiazem and bethanechol are of great benefit when
topically administered separately, but are of particular benefit
and apparently exhibit a synergistic activity when administered
together.
[0032] A suitable proportion of calcium channel blocker, such as
diltiazem in a topical or local composition for a beneficial effect
is at least 0.5% w/w, such as 0.5% to 10% w/w, preferably 0.5% to
5% w/w, more preferably still 1% to 5% w/w, still more preferably
1% to 3%, and most preferably about 2% w/w. Preliminary dose
ranging studies suggest that the maximum effect of the invention is
obtained at about 2% and thereafter higher concentrations will not
produce a substantial additional effect.
[0033] The diltiazem composition is suitably applied 3 to 6 times,
preferably 3 to 4 times daily, which based on 8 mg per application,
gives a total daily dose of 24 mg to 48 mg.
[0034] A suitable proportion of cholinergic agent, such as
bethanechol in a topical or local composition is at least 0.01%
w/w, more preferably at least 0.05% such as 0.01% to 3% w/w,
preferably 0.01% to 1% w/w, more preferably 0.05% to 1% w/w, and
most preferably about 0.1% w/w. Preliminary dose ranging studies
suggest that 0.1% w/w produced the maximum effect of the invention,
and thereafter higher concentrations will not produce an additional
effect.
[0035] The bethanechol composition is suitably applied in the same
regimin as above which based on 0.4 mg per application, gives a
total daily dose of 1.2 mg to 2.4 mg.
[0036] Pharmaceutical compositions adapted for topical
administration in and/or around the anal canal may be formulated as
ointments, creams, suspensions, lotions, powders, solutions,
pastes, gels, sprays, foam, oils, aerosols, suppositories or
enemas.
[0037] The topical compositions can comprise emulsifiers,
preservatives, buffering agents and anti-oxidants. Preferably the
compositions also comprise steroids (e.g. present at 0.1 to 5% w/w)
such as prednisolone, busenonide or hydrocortisone, locally acting
anaesthetics such as lignocaine (e.g. at 0.1 to 5% w/w), and
soothants. Typical components used in existing fissure or
haemorrhoidal treatments which can also be used in topical
compositions of the invention include: zinc oxide, benzyl benzoate,
bismuth oxide, bismuth subgallate and Peru balsam.
[0038] In accordance with the invention, the cholinergic agent or
calcium channel blocker can be administered in combination with
trinitroglycerine or any other nitric oxide donor, isoprenaline,
histamine, prostaglandin E.sub.2, adenosine triphosphate,
nictotine, DMPP, bradykinin, caerulein, glucagon, and
phentolamine.
[0039] The topical composition may comprise skin penetrating
agents, particularly the sulphoxides, such as dimethyl sulphoxide
(DMSO) preferably at 25% to 50% w/w. Amides, (DMA, DMF)
pyrrolidones, organic solvents, laurocaprom (AZONE) and calcium
thioglycollate are suitable alternative penetrants. The composition
may also optionally contains a polyacrylic acid derivative, more
particularly a carbomer. This would both act as a skin hydrating
agent to aid penetration of the drug, but also an emulsifying
agent. The carbomer will help emulsify the DMSO, thereby mitigating
skin irritation and providing enhanced skin hydration. Propylene
glycol may also be present in the composition to soften the skin,
increase thermodynamic potential and aid skin penetration by the
DMSO and thus the drug. The final pH of the composition is
advantageously pH 3.5 to 4.5.
[0040] Further aspects of the invention are as follows:
[0041] A. A method for the treatment or prophylaxis of a benign
anal disorder comprising local application to the anus or the
internal anal sphincter at least one of a cholinergic agent or
calcium channel blocker.
[0042] B. An anal fissure and haemorroidal topical composition
comprising at least one of a cholinergic agent or calcium channel
blocker, together with a pharmaceutically acceptable carrier.
[0043] Early investigations suggest that the DMSO cream in the
clinical studies may also have a therapeutic effect independent of
the bethanechol or diltiazem. Thus a yet further aspect of the
invention provides use of DMSO as a therapeutically active agent in
the preparation of a topical medicament for the treatment of benign
anal disorders, particularly anal fissure or haemorrhoids.
[0044] Preferably the DMSO is present at 25% to 50% w/w, and is
advantageously present in combination with propylene glycol,
preferably in a ratio by w/w of 5:1 to 15:1. The DMSO composition
of this further aspect of the invention is also advantageously
present with a polyacrylic acid derivative, such as carbomer,
preferably at a ratio by w/w of 20:1 to 80:1. Preferably the pH of
the composition is pH 3.5 to 4.5.
[0045] The invention will now be described by way of example only
with reference to the accompanying drawings, in which:
[0046] FIG. 1 is a graph of the dose response of diltiazem gel
against mean anal resting pressure;
[0047] FIG. 2 is a graph of duration of action of 1% w/w diltiazem
gel against mean anal resting pressure;
[0048] FIG. 3 is a graph of the dose response of bethanechol gel
against mean anal resting pressure;
[0049] FIG. 4 is a graph of duration of action of 0.1% w/w
bethanechol gel against mean anal resting anal pressure; and
[0050] FIG. 5 is a graph comparing 2% diltiazem, 0.1% bethanechol,
and a combination of both over time against the reduction in mean
anal resting pressure.
EXAMPLE 1
[0051] A composition of base gel had the following composition:
carmellose sodium 6 g, polyethylene glycol 30 ml,
methylhydroxybenzoate 150 mg, propylhydroxybenzoate 15 mg, made up
to volume with distilled water (pH6-7).
[0052] Various amounts of diltiazem and bethanechol were added in
the amounts shown in examples 4 and 6 to form various compositions
for dose ranging studies.
EXAMPLE 2
[0053] A base cream of the invention had the following
composition:
1 Diltiazem hydrochloride (2% w/w) 10 g Dimethyl sulphoxide 250 g
Carbomer 974P 5 g White soft paraffin 15 g Cetomacrogel emulsifying
ointment* 115 g Propylene glycol 23 g Methylhydroxybenzoate
(preservative soln) to 500 g *composition: white soft paraffin 50
g, liquid paraffin 20 g, cetomacrogol emulsifying wax 30 g
(cetosteryl alcohol 24 g and cetomacrogol 1000, 6 g).
[0054] A base cream was formed by firstly separate mixing of the
aqueous and non-aqueous components of the cream. Weighed quantities
of propylene glycol and a proportion of the preservative solution
were placed in a beaker to which the weight quantity of carbomer
powder was added using an impeller type mixer to form a colloidal
suspension of the carbomer. Thereafter, the weighed quantity of
DMSO was added and rapid stirring continued at room temperature
until a translucent uniform gel had been formed.
[0055] In the meantime, the weighed quantities of white soft
paraffin and the cetamacrogol emulsifying ointment were placed in a
separate beaker, heated to melting point and gently stirred to give
a uniform base.
[0056] The drug is then added to the remainder of the preservative
solution , which in turn was then added to the gel and whilst
vigorously stirring, the uniform base (above) was added to form a
cream. The carbomer acted as a dual neutralisation agent and
primary emulsifier (of the oil and aqueous phases) to form the
uniform cream base.
EXAMPLE 3
[0057] A bethanechol cream composition was made up as above, but
using 0.5 g of bethanechol (0.1% w/w) instead of diltiazem.
EXAMPLE 4
Diltiazem Cream and Tablet--Dose Ranging Study on Healthy
Volunteers
[0058] Ten volunteers were used in a double blind study to
determine the concentration of diltiazem cream (of example 1) which
most effectively lowers resting anal sphincter pressure as measured
by an eight channel water perfused manometer. Concentrations of
diltiazem cream used were 0.1%, 0.5%, 1%, 2%, 5% and 10%. Results
showed a dose dependent reduction of the resting anal sphincter
pressure. The maximal effect, at which the mean resting anal
pressure was lowered by 28% (P<0.0001), was produced by 2% w/w
cream (See FIG. 1). Higher concentrations did not produce an
additional effect. A typical `one inch` application of the cream
from the tube is equivalent to 8 mg dose of diltiazem. Measurements
taken throughout the day showed the effect of a single application
to be sustained for 3 to 5 hours (see FIG. 2).
EXAMPLE 5
Open Study of Diltiazem Cream in Patients with Anal Fissures
[0059] 2% diltiazem cream from example 2 was applied to the anus
three times daily for 8 weeks to treat patients suffering from
chronic anal fissures (in an uncontrolled, open, pilot study). To
date, 7 patients were studied and followed up between 2 to 5 weeks.
5 patients have had complete resolution of symptoms, of whom 3 have
complete and 2 partial healing of the fissure. In four of these 5
patients there has been a reduction of the maximum resting anal
sphincter pressure to within normal limits. The last patient,
though symptom free, continues to have a high anal resting
pressure.
[0060] 2 patients have only had two weeks of treatment and one is
symptom free after this short period, whilst the other still has
occasional pain. It is too early to comment on healing of fissures
in these two patients.
EXAMPLE 6
Bethanechol Cream--Dose Ranging Study in Healthy Volunteers
[0061] Ten volunteers were used in a double blind study to
determine the concentration of bethanechol gel which most
effectively lowered resting anal sphincter pressure.
[0062] Bethanechol cream at concentrations of 0.05%, 0.1%, 0.5% and
1% w/w bethanechol were made up in accordance with example 1. The
compositions were studied following initial experimentation in an
open way to determine a clinically effective dose range. Results
showed a dose dependent reduction in the resting anal sphincter
pressure (see FIG. 3). Maximal effect was produced by application
of 0.1% bethanechol and higher concentrations of the cream produced
no additional effect. At 0.1% w/w bethanechol, the mean resting
pressure was reduced from about 110 cm to about 85 cm H.sub.2O
(about 25% decrease). A typical `one inch` application of this
cream from the tube is equivalent to 400 mcg of bethanechol.
Measurements taken throughout the day showed the effect of a single
application to be sustained from 3 to 5 hours (see FIG. 4).
EXAMPLE 7
Open Study of Bethanechol Cream in Patients with Chronic Anal
Fissures
[0063] The 0.1% bethanechol cream of example 3 was applied to the
anus three times daily for an eight week course to treat patients
suffering from chronic anal fissures (in an uncontrolled, open,
pilot study). To date, 6 patients have been treated and followed up
for 3 to 5 weeks. Four patients have had complete resolution of
symptoms, of whom 3 have complete and 1 partial healing of the
fissure. In all of these 4 patients there has been a reduction of
the maximum resting anal sphincter pressure to within normal
limits. One patient discovered she was pregnant and treatment was
discontinued. The last patient has had no relief and remains
symptomatic after 4 weeks' follow up.
[0064] These results shows that both bethanechol and diltiazem
(applied topically) reduce the resting anal sphincter pressure in
healthy and diseased patients. The preliminary open studies, albeit
in a small group of patients, has shown a significant healing rate
and symptom relief after only a few weeks application of both
agents. This is a major achievement for the non-surgical treatment
of fissures and offers hope to its many sufferers.
[0065] When the study of example 4 was repeated using 60 mg oral
diltiazem once a day, no notable effect was obtained. At 60 mg
twice a day, the mean anal resting pressure was reduced by 17%
(P=0.008), but two patients notices postural dizziness. Topical
diltiazem is surprisingly safer and more effective than oral
diltiazem.
EXAMPLE 8
[0066] In a combined bethanechol and diltiazem study, six healthy
volunteers had topically applied to their anus on different
days:
[0067] 1) diltiazem at 2% w/w alone;
[0068] 2) bethanechol at 0.1% w/w alone; and
[0069] 3) diltiazem and bethanechol combined.
[0070] Anal mamometry was carried out before and after each of the
three creams were applied and repeated at two hourly intervals. The
mean results are shown in FIG. 5.
[0071] These show that the combination of diltiazem and bethanechol
gives a larger reduction in the mean anal resting pressure than
either of diltiazem or bethanechol alone. This synergy may be due
to both agents working in different mechanistic pathways to effect
the pressure drop.
[0072] In summary, the results show that local application to the
anus of at least one of a cholinergic agent or calcium channel
provides a efficacious treatment for benign anal disorder,
particularly anal fissures and haemorrhoids. Furthermore since
efficacy can be obtained at surprisingly low doses, the treatment
of the invention is also substantially free of side effects
normally associated with the active agents.
* * * * *