WO2013070236A1 - Méthodes et compositions de traitement des hémorroïdes à effets anesthésiques et anti-inflammatoires locaux - Google Patents

Méthodes et compositions de traitement des hémorroïdes à effets anesthésiques et anti-inflammatoires locaux Download PDF

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Publication number
WO2013070236A1
WO2013070236A1 PCT/US2011/060343 US2011060343W WO2013070236A1 WO 2013070236 A1 WO2013070236 A1 WO 2013070236A1 US 2011060343 W US2011060343 W US 2011060343W WO 2013070236 A1 WO2013070236 A1 WO 2013070236A1
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ethyl
piperidyl
methyl
composition
hemorrhoids
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PCT/US2011/060343
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English (en)
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Moh Samir Amer
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Ventrus Biosciences, Inc.
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Priority to PCT/US2011/060343 priority Critical patent/WO2013070236A1/fr
Publication of WO2013070236A1 publication Critical patent/WO2013070236A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates generally to the treatment of hemorrhoids, and more particularly, to compositions and methods for treatment of internal and/or external hemorrhoids, wherein the treatment includes a reduced, yet surprisingly effective, amount of iferanserin that not only treats the condition but includes a local anesthetic and anti-inflammatory effects to cause a reduction in itching, irritation and edema at the site of application.
  • the treatment includes a reduced, yet surprisingly effective, amount of iferanserin that not only treats the condition but includes a local anesthetic and anti-inflammatory effects to cause a reduction in itching, irritation and edema at the site of application.
  • Hemorrhoids are an annoying and uncomfortable disorder. They are characterized by the signs and symptoms of itching, burning, pain, bleeding, seepage, protrusion, inflammation, irritation, swelling general discomfort and changes in bowel pattern or any combination thereof. Many remedies have been suggested and tied for the alleviation of these symptoms with varying degrees of success. Hemorrhoids, though rare in animals, are common in humans.
  • Hemorrhoids are a common ailment of the anorectal area and may be either or both internal and external.
  • the causes of hemorrhoids include predisposing causes such as erect posture, heredity, occupation and diet. Precipitating causes are constipation, diarrhea, pregnancy, anal infection, rectal carcinoma, pelvic tumors, cardiac failure, portal hypertension, coughing, sneezing, vomiting and physical exertion.
  • Hemorrhoids are abnormally large or symptomatic conglomerates of blood vessels, supporting tissues and overlying mucous membrane or skin of the anorectal area. About 9% of the people in Western countries suffer from some hemorrhoidal symptoms. The percentage increases with age and reaches 50% after age 50.
  • Hemorrhoid disease is more prevalent in men than in women and is generally associated with bleeding, hence the term “hemorrhoid.”
  • the disease is aggravated by straining during defecation, heavy lifting and during pregnancy. Such conditions exert physical pressure on the exit veins interfering with the escape of the blood from the hemorrhoid plexus and thus contributing to blood congestion. This is particularly true during defecation of hardened and compact stools.
  • Hemorrhoid disease is a varicose dilatation of the blood vessels in the superior or inferior hemorrhoidal plexus, resulting from persistent increase in pressure brought about by the constriction of downstream colonic veins.
  • Occlusion brought about by platelet aggregation and thrombus formation also contributes to the symptoms of hemorrhoids by increasing blood stasis and tissue congestion. This results in masses of dilated vessels situated near the anal sphincter, usually above the dentate line. Such masses underlie the uncomfortable feeling of fullness and throbbing and result in difficulty and pain while defecating.
  • hemorrhoids There are two main types of hemorrhoids, that being, internal and external. Internal hemorrhoids originate above the dentate line and are characterized by bleeding and irritation but usually do not cause pain since the area above the dentate line does not contain sensory nerves. By contrast, external hemorrhoids originate below the dentate line (usually at the anal verge) and are very painful. External hemorrhoids do not generally bleed since the dermis at the verge is thicker.
  • vaso-constrictive and platelet aggregating agents the platelet release reaction
  • serotonin 5-hydroxytryptamine, 5-HT
  • the resultant increased platelet aggregation and vaso-constriction cause greater elevation of venous pressure that further decreases blood flow. This establishes a vasoconstrictive cycle resulting in diminished blood perfusion in the affected tissues associated with swelling, irritation and pain. These symptoms are the hallmarks of hemorrhoids.
  • 5-HT 2 A receptors are located in the vasculature and mediate both the vasoconstrictive and platelet aggregatory effects of 5-HT.
  • the hemorrhoids can further deteriorate or rupture when subjected to the additional pressure during bouts of constipation and straining or from external pressure resulting from sitting for any length of time.
  • Ruptured and bleeding piles are susceptible to infection because fecal mass contains numerous infectious organisms which can enter damaged tissue and hamper healing. Further, the swelling caused by inflammation can also exacerbate the hemorrhoids by pressing on the exit veins.
  • compositions comprise an effective amount of S-2'- [2-(l- methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride having the following structural formula:
  • the effective amount treats the hemorrhoids, while providing a local anesthetic effect and an anti-inflammatory effect to reduce edema at the site of application.
  • the present invention provides for a composition comprising from about 0.3% to about 0.7% concentration of S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride, and preferably a concentration of about 0.5%, wherein the S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride is substantially free or devoid of the (R) enantiomer.
  • the S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride may be mixed with a pharmaceutically acceptable cream, gel, paste, lotion, ointment, emulsion, foam, liquid or a combination thereof.
  • the present invention provides for a method for controlling pain and inflammation associated therewith, the method comprising topically contacting an appropriate anal area with a therapeutically effective amount of a composition that consists essentially from 0.3% to 0.7% of S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride, wherein the S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride is substantially free or devoid of the (R) enantiomer.
  • the present invention provides for a homogenous composition for providing a local anesthetic effect and reduction of edema at the site of topical application, the composition comprising:
  • liquid paraffin in an amount form about 5% to 20%
  • cetanol in an amount from about 2% to about 10%
  • the present invention provides for a method of treating internal and/or external hemorrhoids while inducing a local anesthetic effect and reducing edema, the method comprising:
  • composition comprises from about 0.3% to 0.7 % concentration of S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride, wherein the S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride is substantially free or devoid of the (R) enantiomer; ; and
  • step (a) for a period ranging from one (l)day to thirty (30) days, more preferably from three (3) days to fourteen (14) days, and most preferably, from seven (7) days to fourteen (14) days.
  • the present invention relates to a method of treating internal and/or external hemorrhoids in a subject in need thereof, the method comprising: administering a topical composition to the anorectal region of a subject in need of such treatment, wherein the composition comprises from about 0.3% to about 0.7% concentration of S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride, wherein the composition has a local anesthetic effect on contact with the subject and reduces edema in areas of treatment.
  • the present invention provides for a single dose applicator device comprising an ointment, wherein the ointment comprises from about 0.3% to 0.7% concentration of S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide.
  • the amount is 0.5% and effective to delay or inhibit the recurrence of symptoms due to hemorrhoids while inducing a local anesthetic effect with reduced edema at the site of application.
  • the present invention provides for molecules having therapeutic effects on hemorrhoidal symptoms, wherein the molecules have the following structural formulas:
  • the present invention provides for a composition comprising S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride and a synthesized metabolite as described in Figure 1.
  • the present invention provides for a kit comprising a sufficient amount of single use applicators to treat hemorrhoidal symptoms, wherein each applicator comprises a composition comprising from about 0.3% to about 0.7% concentration of S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride, wherein the S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride is substantially free or devoid of the (R) enantiomer.
  • the kit includes a sufficient number of the single use applicators to treat the hemorrhoidal symptoms over a period from 1 to 14 days.
  • Figure 1 shows a metabolic scheme for the metabolism of the (S) enantiomer of 2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride.
  • Figure 2 is a graph showing that the 0.5%> dose group provided the most consistent improvement in hemorrhoidal symptoms including: bleeding, pain, ease of defecation, swelling and size.
  • Figure 3 is a bar graph shows the percentage of change in specific symptoms relative to the % percent concentration, wherein the 0.5% concentration showed the greatest reduction in all the symptoms.
  • Figure 4 is a graph showing that symptoms in the group using the 0.5% concentration started improving on day one (1), peaked on day seven (7) and were maintained until day fourteen (14).
  • Figure 5 is a bar graph showing the reduction in hemorrhoid size at day 28 relative to the different concentrations. Again, the 0.5% dose level was the most effective on the primary efficacy parameters.
  • Figure 6 is a bar graph showing the number of patients experiencing return of hemorrhoidal symptoms within forty-five (45) days after completion of a fourteen (14) day study.
  • Figure 7 is a bar graph showing the number of patients ceasing bleeding for a minimum of three (3) consecutive days on the specific days of the study.
  • Figure 8 is a bar graph showing the number of patients ceasing itching for a minimum of three (3) consecutive days on the specific days of the study.
  • Figure 9 is a bar graph showing the number of patients ceasing pain for a minimum of four (4) consecutive days on the specific days of the study.
  • Figure 10 shows the surface anesthetic activities of S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride (S-MPEC), lidocaine and kentanserin in guinea pig cornea.
  • Figure 11 shows the stimulated points of guinea pigs skin.
  • Figure 12 shows the results of different levels of inhibition of inflammatory edema for the testing compounds using the recto-anus coefficient (RAC).
  • Figure 13 shows the Evans Blue Permeability % of the different compounds into the tissues.
  • Figure 14 shows the RAC (a) and permeability % (b) of S-MPEC at different concentrations and indomethacin.
  • Hemorrhoids which are characterized by the inflammation and swelling of tissues around the anus or lower rectum, can cause bleeding, itching, pain and difficulty defecating.
  • Iferanserin is a powerful and selective 5-HT 2 A receptor antagonist. Since it does not cross the blood/brain barrier (except at extremely high doses in animal studies), iferanserin represents the first of a class of 5-HT 2 A receptor antagonists that acts primarily in the periphery. Iferanserin is particularly selective to human colonic venous 5-HT 2 A receptors, although there is data supporting activity at both 5-HT 2B and 5-HT 2 c. In all systems studied, iferanserin selectively blocked 5-HT 2 A receptors with little effect on 5-HT-l, dopamine or adrenergic receptors. More importantly, iferanserin effectively antagonized the constrictive effects of 5-HT on human colon veins.
  • 5-HT platelet aggregation effects of 5-HT on human platelets. Since 5-HT is released by the blood platelets in static and pooled blood, selective peripheral 5-HT 2A receptor antagonists would be expected to have built-in tissue selectivity, i.e., will act only where there is vaso-constriction and platelet aggregation mediated by 5-HT. Therefore, the effects of iferanserin should be limited only to those areas where there is stasis and pooled blood caused by serotonin.
  • the present invention comprising iferanserin as the active agent, is believed to be more efficacious and/or less invasive than conventional hemorrhoid therapies.
  • Iferanserin has the ability to significantly reduce bleeding, pain and itchiness with minimal adverse effects.
  • other effects of iferanserin include a local anesthetic effect that is equivalent to that of lidocaine and also exhibits an antiinflammatory effect, thereby reducing edema in areas experiencing the effects of hemorrhoids.
  • This invention comprises therapeutic compositions comprising S-2'- [2-(l-methyl-2- piperidyl) ethyl] cinnamanilide (S-MPEC) or a pharmaceutically acceptable acid salt thereof, wherein the S-MPEC is substantially free of the R isomer.
  • substantially free is intended to cover mixtures containing from about 0.0001% to about 10% of the R isomer (stereoisomer).
  • the substantially free molecule contains no more than about 4%, and more preferably, no more than about 1% of the R-MPEC impurity.
  • the S-MPEC is 100% pure and devoid of the (R) enantiomer.
  • the present invention also provides other active ingredients that may be combined with S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide for treatment of internal and/or external hemorrhoids.
  • the S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide compound can be combined with antibiotics, antifungals, antivirals, corticosteroids (e.g., hydrocortisone or triamcinolone), non-steroidal antiinflammatory drugs (including specifically diclofenac or COX-2 inhibitors such as nimesulide or piroxicam), or salicylates (e.g., salsalate or sulfasalazine).
  • antibiotics e.g., antifungals, antivirals, corticosteroids (e.g., hydrocortisone or triamcinolone), non-steroidal antiinflammatory drugs (including specifically diclofenac or COX-2 inhibitors such
  • any composition described herein is administered at effective and non-toxic dosages, such that the subject experiences relief from symptoms in the absence of any undesirable side effects.
  • compositions in the form of ointments, creams, gels, pastes, suppositories, liquids, emulsions, foams, aerosols, semisolid powders, or any other form suitable for topical administration are acceptable compositions for the topical treatment of the anorectal pain.
  • suitable carriers can be chosen depending on the dosage forms and include, but are not limited to, hydrocarbons such as vaseline, liquid paraffin, and plasticized hydrocarbon gel (plastibase); animal and vegetable oils such as medium-chain fatty acid triglyceride, lard, hard fat, and cacao oil; higher fatty acid and alcohols and esters thereof such as stearic acid, cetanol, stearyl alcohol, and palmitic acid isopropyl; water-soluble bases such as Macrogol (polyethylene glycol), 1,3-butylene glycol, glycerol, gelatine, white sugar, and sugar alcohol; emulsifiers such as glycerine fatty acid ester, stearic acid polyoxyl, and polyoxyethylene/or curing castor oils; thickeners such as water-dispersible gums, carboxyvinyl polymers, methyl cellulose, sodium carboxymethyl cellulose, and alginates; and preservatives such as paraoxybenzoic acid esters, stearic acid
  • the preparation of the present invention can be prepared with the aforementioned carriers by methods well-known to those skilled in the art.
  • additives such as stabilizers, pH adjusting agents, diluents, surfactants, neutralizers, antiseptics, germicides, and antioxidants are, if necessary, used.
  • the external preparation of the present invention can be applied to the tropical wound site by conventional methods.
  • compositions listed above may be used in the inventive compositions as thickening agents to create highly convenient dosage forms. Thickened solutions permit release of the active compound to the skin or tissue upon or following application. These forms are advantageously employed to lessen the runoff from the skin or tissue that can occur with more fluid (less viscous) formulations. Importantly, they also permit more sustained contact of the active compound(s) and any penetration enhancer with the treated surfaces, thus permitting an enhancement of the speed of delivery of the active compound(s) to the inflamed tissues and providing more accurate and controllable dosing.
  • the base cream for use as an ointment may include components such as petrolatum album, liquid petrolatum, beeswax, liquid paraffin, Cetanol, and/or water, wherein the components are mixed until homogenous. More preferably, the base cream of the present invention includes the active agent S-MEPC, liquid paraffin, cetanol and white vaseline, wherein the active agent is in an amount from about 0.3% to 0.7%, the liquid paraffin is in an amount form about 5% to 20%, the cetanol is in an amount from about 2% to about 10% and the white vaseline makes up the remainder to 100%.
  • the active agent is in an amount from about 0.3% to 0.7%
  • the liquid paraffin is in an amount form about 5% to 20%
  • cetanol is in an amount from about 2% to about 10%
  • the white vaseline makes up the remainder to 100%.
  • a base cream or ointment comprises or consists of 0.5% of S-MEPC, 10% of liquid paraffin, 6% of cetanol and the remaining amount of 83.5% of white vaseline.
  • Dosage may include a single dose applicator wherein approximately 6 to 14 mg of iferanserin (S-MEPC) in the form of two (2) grams of 0.3% to about 0.7 % ointment is placed within the applicator.
  • the amount of iferanserin is 10 mg thereby providing a 0.5% concentration.
  • Applicators, such as dispensing tubes, syringes, etc., containing a single dose can provide convenient dosage forms.
  • Squeeze tubes for lotions and ointments may be employed for topical application of the composition for liquids ranging from those of water-like viscosity or the more viscous formulations of thickened compositions and the like.
  • an amount of the composition of the invention is contacted with or applied to the affected anal area or proximate thereto such that an effective amount of the antagonist is administered.
  • 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.
  • the medication can be delivered rectally as a suppository. The medication can be applied in this fashion, for example, twice daily in the form of an ointment or one or more times daily in the case of the suppository.
  • Metabolism of iferanserin was investigated in the rat bile, urine and plasma following administration of [ 14 C] iferanserin using spectroscopic means. Based on the profile in the rat urine and bile, it is evident that iferanserin is extensively metabolized prior to excretion. An overall metabolic scheme is shown in Figure 1, based on what has been characterized in the urine from rat and human, and in the bile from rat. It appears that the primary reaction is oxidation on the aromatic rings. This may be followed by O- methylation and/or conjugation with glucuronic acid, sulfate or glutathione. The main metabolites are MP-KW109, MP-KW110 and MP-MA5. Importantly, both MP- KW109 and MP-KW110 were found to have 5-HT 2 A antagonistic activity in vitro.
  • AUC and C max of the parent compound showed extensive fluctuation, thus a clear dose- proportionality could not be established.
  • the mean values were approximately linearly related to the dose, except for subject S-03, who was identified as a CYP2D6 poor metabolizer (type D, CYP2D6*5).
  • Apparent terminal half-life of iferanserin was 1.9-3.0 h, and that of metabolites MP-KW 109 and MP-1 10 was 5.4-8.4 h.
  • the values for MA5 were below the limit of quantitation.
  • exposure to metabolites KW109 and KWl 10 showed a half-life that is 3-4 fold that of iferanserin, except in subject S-03.
  • the metabolites provide extended activity providing for extended timing between dosages.
  • Subject S-03 showed a higher C max (3-fold) and AUC (17-fold), a delayed t max (5.0 h), and a prolonged half-life (16.7 h).
  • Simulation for a twice-a-day (b.i.d) multiple dose regime (10 mg) showed that steady state is likely reached in 4-5 days with a projected C max , ss of 90 ng/m.
  • Plasma levels of the three metabolites analyzed for the S-03 subject were below the limit of quantitation in this particular subject.
  • hemorrhoids become symptomatic when the supporting structures become disrupted and the vascular anal cushions prolapse. Hemorrhoids occur more frequently in people with constipation who have hard, infrequent stools. Symptoms attributed to hemorrhoids include bleeding, protrusion, itching and pain. Most hemorrhoidal symptoms arise from enlarged internal hemorrhoids. Bleeding is the most common presenting symptom. Abnormal swelling of the anal cushions, stretching of the suspensory muscles, and dilation of the submucosal arteriovenous plexus result in the prolapse of upper anal and lower rectal tissue through the anal canal. This tissue is easily traumatized, leading to bleeding.
  • the blood is typically bright red due to the arterial oxygen tension caused by arteriovenous communications within the anal cushions. Painless bleeding is usually seen on the toilet tissue or dripping into the toilet at the end of defecation. Sometimes the bleeding can be more substantial, and the blood can accumulate in the rectum with the passage of dark blood or clots. When hemorrhoids prolapse, blood or mucus may stain a patient's underwear, and the mucus against the anal skin may lead to itching. The aforementioned mass of dilated vessels near the anal sphincter underlie the uncomfortable feeling of fullness and throbbing, may bleed, and result in difficulty and pain while defecating. These symptoms were evaluated in this testing regime.
  • a randomized, double-blind dose study of iferanserin (S-MPEC) was conducted using 0.25%, 0.5%, 1.0 % concentrations, wherein the respective dose was applied intra- rectally twice a day (b.i.d) for 2 weeks in patients with hemorrhoids.
  • the primary endpoint of this trial was the improvement in hemorrhoidal symptoms and objective findings including swelling and hemorrhoidal size. Secondary endpoints were subjective symptoms of bleeding, pain, anal discomfort, difficulty in defecation and prolapse rated on a visual analog scale.
  • the completed study demonstrates that most of the drug effects observed were complete, or essentially complete, within seven days of drug application, hence a seven day endpoint appears optimal.
  • the adverse events reported were gastro-intestinal system disorders such as "abdominal discomfort” and "diarrhea,” all of them were mild and the patients recovered without any treatment.
  • the S isomer of MPEC in doses of 0.25%>, 0.5%> and 1.0% cream was used for symptomatic internal and mixed internal/external hemorrhoids and administered twice a day for 14 days. Seventy two patients were enrolled; 68 evaluable for analysis: 0.25% (23pts), 0.5% (24pts), 1.0% (21pts).
  • a randomized, double-blinded, placebo controlled dose study of S-MPEC was conducted using 0.25%>, 0.5%> and 1% concentrations, wherein a 5, 10 or 20 mg dose in the form of two (2) grams was administered in a single dose. .
  • the dosage was applied intra-rectally twice a day (b.i.d) for 4 weeks in patients with hemorrhoids.
  • the primary endpoint of this trial was the reduction in hemorrhoidal area (size) at 4 weeks compared to baseline. Secondary endpoints were subjective symptoms of bleeding, pain, anal discomfort, difficulty in defecation and prolapse rated on a visual analog scale.
  • a double-blind placebo-controlled study was conducted to assess the effects of topical iferanserin (S-MPEC) cream (0.5%), applied intra-rectally twice a day for two weeks, on bleeding and other symptoms of patients with internal hemorrhoids (stages 1-3).
  • the 0.5% dose was selected based on previous performance, such as shown in Examples 3, 4 and 5 wherein 0.5% concentration consistently performed better then 0.25% and 1% in both patient reported symptoms and in physician rated symptoms at day 7 in a patient population similar to the planned study population.
  • Investigator examinations occurred on days 0 and 14 which included evaluation of hemorrhoidal size, bleeding frequency and intensity, soiling, pruritis, pain, prolapse and incontinence to gas.
  • Tenderness The effects of iferanserin in ameliorating tenderness were statistically significant from the second day of treatment and were maintained throughout the trial period. Ease of Defecation: Iferanserin improved the ease of defecation and was statistically significantly better than baseline from day three to the end of the study. Safety Results:
  • iferanserin decrease the major symptoms of hemorrhoids during treatment but it also delayed the time for these symptoms to reappear after termination of treatment.
  • This prolonged symptom-free period, following treatment with iferanserin provides for less frequent hemorrhoidal episodes, or at least less frequent episodes of hemorrhoidal symptoms in patients who experience chronic hemorrhoids, thereby translating into less frequent treatment.
  • bleeding, itching and pain were analyzed for recurrence during the 14-day dosing period.
  • cessation of a symptom was defined as the absence of the symptom for as little as one day; in a posthoc analysis cessation was defined as three consecutive days without the specific symptom.
  • cessation of bleeding was defined as one day without the symptom, 71% of placebo patients reported that bleeding stopped; 60% of those that stopped for one day had a recurrence of bleeding while still on treatment.
  • S-MPEC surface anesthetic action of iferanserin
  • Guinea pigs were purchased at 4 weeks of age and acclimatized for one week to be used in the study. Cilia of the right and left eyes were cut off, and the cornea of the guinea pigs was stimulated with the stimulating hair (porcine fur) five times. The eyes which developed the normal corneal reflex on all the five pokes were used in the study. The test substance S-MPEC (0.03 mL) was instilled and then removed at 1 minute after instillation. The same test substance was not instilled to right and left eyes. The cornea was stimulated five times each before instillation and at 5, 10, 15, 20, 25 and 30 minutes thereafter, and the number of times of corneal reflex was determined.
  • the surface anesthetic action of S-MPEC was judged to be positive when the corneal reflex disappeared on three of five pokes.
  • the test substance was S MPEC (0.125, 0.25 and 0.5%).
  • Lidocaine (0.125, 0.25 and 0.5%) and Ketanserin (1.0 and 2.0%>) were used as control substances.
  • a sham group (saline) and vehicle group (saline solution equivalent to the 0.5%> S-MPEC solution) were served.
  • the x -test was used to test the significant difference.
  • S-MPEC As shown in Table 2, S-MPEC, at concentrations from 0.125%, inhibited the corneal reflex at 5 minutes after instillation.
  • the corneal reflex-inhibitory action of S-MPEC 9 peaked at a concentration of 0.5% and lasted up to 25 minutes after instillation.
  • lidocaine a local anesthetic drug
  • ketanserin a 5-HT 2 receptor antagonist
  • S-MPEC possesses surface anesthetic activity in the guinea pig corneal stimulation method; the activity was more potent than that of lidocaine, a local anesthetic drug, and was longer in duration.
  • Figure 10 shows that the surface anesthetic activity of S-MPEC was surprisingly more effective that lidocaine at the same concentration and was four times more effective than ketanserin because it required 2% concentration of Ketanserin to show the same effect of a mere 0.5% of S-MPEC.
  • the present invention provides a method of preventing or alleviating topical pain, that is, providing topical analgesia, in warm-blooded mammals, including humans, for example, by the topical administration of an effective local anesthetic amount of a compound of S-MPEC or a pharmaceutically-acceptable salt thereof in admixture with a pharmaceutical carrier.
  • S-MPEC improves the blood flow impairment at the local area of the anus through its 5-HT2 receptor antagonistic activity.
  • Most agents for external use as a hemorrhoid therapeutic drug are complex agents containing several kinds of drugs. Most of them are a composition that includes an extra compound that is used for a local anesthetic to alleviate the pain due to hemorrhoids. Therefore, the fact that S-MPEC alone has a local anesthetic activity in addition to its ability to improve the blood flow impairment in the anus area is a very useful characteristic for this drug as a hemorrhoid therapeutic agent. As shown in Example 7, S-MPEC has a surface anesthetic activity more powerful and longer lasting than that of lidocaine.
  • the guinea pig papule induction method was used to investigate the infiltration anesthetic activity.
  • 36 five week old guinea pigs were used in the papule induction method.
  • a magic marker is used to mark a colored number from 1-4 on the head part of the animal for each cage for identification.
  • Ten (10) mg of S-MPEC were weighed and completely dissolved in an equivalent amount of 0.1 mol/L HC1. The solution thus obtained was diluted with physiological saline to obtain 2 mL of 0.5% S-MPEC solution. This 0.5% S-MPEC solution was diluted to prepare a 0.25%> and 0.125%) S-MPEC solution. These solutions were prepared at the time of their use.
  • Lidocaine (commercial name: Xylocaine* injection solution 1 %) solutions were prepared with concentrations of 0.5%>, 0.25%> and 0.125%).
  • Ketanserin tartrate Ten mg of ketanserin tartrate were weighed and dissolved completely in 2.0 mL of distilled water by mixing alternately with a mixer and ultrasound irradiation to obtain 2.0 mL of 0.5% ketanserin solution 0.5 mL of the 0.5% ketanserin solution thus obtained was diluted with 0.5 mL of distilled water to obtain 1 mL of 0.25% ketanserin solution. As in the case of the test substance, the above solutions were prepared at the time of their use.
  • lidocaine 0.125%, 0.25%
  • the anterior area of the back of the guinea pig under pentobarbital (20 mg/kg i p ) anesthesia was depilated with the use of clippers on the day before the study.
  • the depilated area measured 5 x 12 cm with the midline as the center. Further depilation was achieved by coating the depilated area with a hair removing cream, followed by thorough wiping of the area with gauze soaked with warm water.
  • the animals were used for the study on the next day after confirming that they had recovered from the anesthesia. Two injection sites, one each on the right and left sides of the midline, were established in each animal. One site was used only for one stimulation study.
  • the area was irritated 5 times and the area of the skin that always responded to the irritation only was used in the study.
  • Administration of the test substance was carried out on a blind basis. During the administration, the head of the animal only was fixed with a fixing device 0.1 mL of the drug solution was injected subcutaneously to the two injection sites located symmetrically on each side of the midline. The induced papule was marked by circling it with the use of, e g , a ball pen. It was not allowed to inject the same drug to the two symmetrical sites.
  • the skin reflex was examined before the administration and 5, 10, 15, 20, 25 and 30 minutes after the administration.
  • the stimulation interval for each site was set to be 3-5 seconds and the presence or absence of the skin reflex was determined.
  • the papule area other than the area of edema was stimulated 5 times to carry out the measurement.
  • the infiltration anesthetic activity test was considered to be positive when the skin reflex was not detected in 3 out of the 5 measurement periods.
  • S-MPEC at a concentration of 0.125% had already suppressed the skin reflex 5 minutes after the administration.
  • the skin reflex suppressing activity of S-MPEC was strongest at a concentration of 0.5% and persisted until 15 minutes after the administration.
  • the local anesthetic lidocaine significantly suppressed the skin reflex at a concentration of 0.25%.
  • the 5-HT2 antagonist ketanserin failed to suppress the skin reflex even at a concentration of 0.25 %.
  • a test was conducted to compare the actions of S-MPEC against anti-serotonic, anti- histaminic and anti-inflammatory drugs on the inflammatory reaction at 2 hours after inflammation induction in a croton mixture oil-induced hemorrhoidal inflammation model.
  • Croton mixed oil-induced hemorrhoidal inflammation was induced according to the routine procedure. Generally, a swab immersed in an inflammation-inducing solution (croton oil in ether) was inserted in the anus of each animal thereby inducing inflammation. About one hour after inflammation induction, intrarectal administration of the following substances was conducted at a dose level of 3 mg/kg: S-MPEC, 5-HTi antagonist (S I Methiothepin), 5-HT 2 antagonist (S2 Ketanserin), 5-HT 3 antagonist (S3 metoclopramide), histaminei antagonist (HI clorpheniramine), histamine 2 antagonist (H2 famotidine), indomethacin, and prednisolone.
  • S-MPEC 5-HTi antagonist
  • 5-HT 2 antagonist S2 Ketanserin
  • 5-HT 3 antagonist S3 metoclopramide
  • histaminei antagonist HI clorpheniramine
  • histamine 2 antagonist H2 famotidine
  • the inhibitory effect of S-MPEC on inflammatory edema shows a reduced RAC when compared to the controls and all other testing compounds, as shown in Figure 12.
  • S-MPEC was examined to determine whether or not it was capable of inhibiting edema which developed at 6 hours after irritation.
  • the mixed croton oil- induced inflammation was provoked according to the description in Example 9.
  • S-MPEC (0.01, 0.1, 1.0, 10 and 30 mg/kg) was administered intrarectally to rats to evaluate the inflammatory response which developed at 6 hours after irritation in terms of edema (RAC) and vascular permeability (Evans Blue permeability, %).
  • Indomethacin (3 mg/kg), control drug, was similarly given by intrarectally route on three occasions. It was found that S-MPEC significantly inhibited the RAC values at dose levels exceeding 10 mg/kg., as shown in Figure 14a.
  • S-MPEC when administered at the maximal dose level of 30 mg/kg, inhibited inflammation by 43.8%, thus revealing that S-MPEC had potent inhibitory activity which was nearly equivalent to that of indomethacin (3 mg/kg), control drug, that showed an inhibition rate of 55.1 % when given by consecutive administration. Furthermore, S-MPEC clearly showed dose- dependent inhibitory activity on edema (RAC value) and vascular permeability (Evans Blue permeability), as shown in Figure 14b.
  • RAC value edema
  • vascular permeability Evans Blue permeability

Abstract

Cette invention concerne des compositions et des méthodes permettant de traiter les hémorroïdes internes et/ou externes, ledit traitement consistant à administrer par voie topique chez un sujet une composition comprenant de 0,3 % à 0,7 % de S-2'-[2-(1-méthyl-2-pipéridyl)éthyl] cinnamanilide. Le S-2'-[2-(1-méthyl-2-pipéridyl)éthyl] cinnamanilide, en plus de traiter les symptômes des hémorroïdes, présente également des effets anesthésiques locaux et des effets anti-inflammatoires dans la zone traitée.
PCT/US2011/060343 2011-11-11 2011-11-11 Méthodes et compositions de traitement des hémorroïdes à effets anesthésiques et anti-inflammatoires locaux WO2013070236A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56164112A (en) * 1980-05-23 1981-12-17 Shizuya Shiozu Preparation for treating hemorrhoids, bleeding pile and their pains
US5780487A (en) * 1995-08-07 1998-07-14 Amer Moh Samir S-2'- 2-(1-methyl-2-piperidyl) ethyl! cinnamanilide
US20060159711A1 (en) * 2003-02-21 2006-07-20 Yukiko Inamoto Therapeutic agent for hemorrhoidal disease
US20080300410A1 (en) * 2005-11-17 2008-12-04 Mahavir Prashad Organic Compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56164112A (en) * 1980-05-23 1981-12-17 Shizuya Shiozu Preparation for treating hemorrhoids, bleeding pile and their pains
US5780487A (en) * 1995-08-07 1998-07-14 Amer Moh Samir S-2'- 2-(1-methyl-2-piperidyl) ethyl! cinnamanilide
US20060159711A1 (en) * 2003-02-21 2006-07-20 Yukiko Inamoto Therapeutic agent for hemorrhoidal disease
US20080300410A1 (en) * 2005-11-17 2008-12-04 Mahavir Prashad Organic Compounds

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