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.
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.
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.
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).
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).
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
By haemorrhoids we mean to include both internal and external haemorrhoids and acute thrombosis of external haemorrhoid (TEM).
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.
Bethanechol and salts thereof is a particularly preferred cholinergic agent.
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.
Diltiazem and salts thereof is a particularly preferred calcium channel blocker.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 E2, adenosine triphosphate, nictotine, DMPP, bradykinin, caerulein, glucagon, and phentolamine.
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.
Further aspects of the invention are as follows:
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.
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.
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.
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.