WO2012026914A1 - Procédés et compositions pour traitement d'hémorroïdes internes et externes - Google Patents

Procédés et compositions pour traitement d'hémorroïdes internes et externes Download PDF

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Publication number
WO2012026914A1
WO2012026914A1 PCT/US2010/046260 US2010046260W WO2012026914A1 WO 2012026914 A1 WO2012026914 A1 WO 2012026914A1 US 2010046260 W US2010046260 W US 2010046260W WO 2012026914 A1 WO2012026914 A1 WO 2012026914A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
piperidyl
methyl
composition
cinnamanilide
Prior art date
Application number
PCT/US2010/046260
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English (en)
Inventor
Moh Samir Amer
Original Assignee
Sam Amer & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sam Amer & Co., Inc. filed Critical Sam Amer & Co., Inc.
Priority to PCT/US2010/046260 priority Critical patent/WO2012026914A1/fr
Publication of WO2012026914A1 publication Critical patent/WO2012026914A1/fr

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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 delays or inhibits the recurrence of hemorrhoids and/or symptoms thereof.
  • 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, no pain generally accompanies internal hemorrhoids.
  • 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.
  • 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.
  • 5-HT 2 A receptors are located in the vasculature and mediate the vasoconstrictive and platelet aggregatory effects of 5-HT.
  • the present invention provides for a surprisingly effective composition for the treatment of both internal and external hemorrhoids, wherein the compositions have a reduced amount of S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride having the following structural formula:
  • 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.
  • a pharmaceutically acceptable cream, gel, paste, lotion, ointment, emulsion, foam, liquid or a combination thereof 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 homogenous composition for treating internal and/or external hemorrhoids, the composition comprising:
  • the present invention provides for a method of treating internal and/or external hemorrhoids, 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 (b) repeating 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 delaying or inhibiting recurrence of internal and/or external hemorrhoids, the method comprising:
  • composition comprises from about 0.3% to about 0.7% concentration of S-2'- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride for a sufficient period of time to reduce or inhibit recurrence of symptoms due to hemorrhoids.
  • the recurrence of symptoms is delayed at least three (3) days to about two (2) months. More preferably, there is total inhibition of any recurrence of hemorrhoidal symptoms.
  • 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.
  • the present invention provides for molecules having therapeutic effects on hemorrhoidal symptoms, wherein the molecules have the following structural formulas:
  • the compounds are formed in vivo due to the metabolism of iferanserin by a treated subject or in the alternative the compounds are synthesized ex vivo or in a laboratory and formulated for administering to a subject for the treatment of hemorrhoidal symptoms.
  • 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.
  • Hemorrhoids which are characterized by the inflammation and swelling of veins 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 2A 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 2C . In all systems studied, iferanserin selectively blocked 5-HT 2A 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, and preferably the (S) enantiomer, 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 anti-inflammatory effect, thereby reducing edema is 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.
  • S-MPEC S-2'- [2-(l- methyl-2-piperidyl) ethyl] cinnamanilide
  • R-MPEC pharmaceutically acceptable acid salt thereof
  • 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), nonsteroidal anti-inflammatory 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), nonsteroidal anti-inflammatory drugs (including specifically diclofenac or COX-2 inhibitors such as nimesulide or piroxicam), or salicylates (e.g., salsalate or sulfasalazine).
  • 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 paraoxybenz
  • 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.
  • 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%.
  • 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.
  • a solution of RS-APEMP.HI (516 g., 1.5 mole) ethyl acetate (5.5 g.) (or other low boiling water immiscible solvent such as benzene, toluene etc.) was extracted with 5% aqueous sodium hydroxide to liberate the free base (organic phase), washing the organic phase with water, drying over a suitable drying agent (such as anhydr. sodium sulfate, magnesium sulfate, potassium carbonate etc.).
  • a suitable drying agent such as anhydr. sodium sulfate, magnesium sulfate, potassium carbonate etc.
  • AUC and C max of the parent compound showed extensive fluctuation, thus a clear dose-proportionality could not be established. But 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. Interestingly, exposure to metabolites KW109 and KW1 10, at 0.5% concentration of Iferanserin, showed a half-life that is 3-4 fold that of iferanserin, except in subject S-03. It is possible that 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 tmax (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 maXiSS 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).
  • Tenderness The effects of iferanserin in ameliorating tenderness were statistically significant from the second day of treatment and were maintained throughout the trial period.
  • 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.

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Abstract

La présente invention concerne des compositions et des procédés pour le traitement d'hémorroïdes internes et/ou externes, le traitement comprenant l'administration topique à un sujet d'une composition comportant 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 non seulement traitant les symptômes hémorroïdaux mais retardant ou inhibant également la réapparition d'hémorroïdes et/ou de symptômes associés.
PCT/US2010/046260 2010-08-23 2010-08-23 Procédés et compositions pour traitement d'hémorroïdes internes et externes WO2012026914A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4064254A (en) * 1971-03-03 1977-12-20 Mead Johnson & Company Substituted piperidines therapeutic process and compositions
WO1994018958A1 (fr) * 1992-01-09 1994-09-01 Sam Amer & Co., Inc. Compositions antagonistes des recepteurs 5-ht2 utiles dans le traitement de pathologies veineuses
WO1995021819A1 (fr) * 1994-02-11 1995-08-17 Merck Sharp & Dohme Limited Composes azacycliques a substitution aralcoxy et aralkylthio utilises comme antagonistes de la tachykinine
US5780487A (en) * 1995-08-07 1998-07-14 Amer Moh Samir S-2'- 2-(1-methyl-2-piperidyl) ethyl! cinnamanilide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4064254A (en) * 1971-03-03 1977-12-20 Mead Johnson & Company Substituted piperidines therapeutic process and compositions
WO1994018958A1 (fr) * 1992-01-09 1994-09-01 Sam Amer & Co., Inc. Compositions antagonistes des recepteurs 5-ht2 utiles dans le traitement de pathologies veineuses
WO1995021819A1 (fr) * 1994-02-11 1995-08-17 Merck Sharp & Dohme Limited Composes azacycliques a substitution aralcoxy et aralkylthio utilises comme antagonistes de la tachykinine
US5780487A (en) * 1995-08-07 1998-07-14 Amer Moh Samir S-2'- 2-(1-methyl-2-piperidyl) ethyl! cinnamanilide

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