Pharmaceutical composition

Abstract

A topical composition comprises at least 5 wt % metronidazole or a pharmacologically acceptable derivative thereof in a non-aqueous vehicle. The composition may be used in the treatment of conditions of the colon, rectum, anorectum and perianal region, in particular inflammatory bowel disease and perianal Crohn's disease. The composition also relieves pain and inflammation and promotes healing of the colon, rectum, anorectum and perianal region following surgical operations. One advantage of the composition is that topical administration of metronidazole results in a primarily local effect and thus side effects observed from systemic administration are avoided.

Claims

1. A topical composition consisting of metronidazole and a pharmacologically acceptable non-aqueous vehicle selected from the group consisting of petrolatum and lanolin, wherein the metronidazole is present in a concentration of about 5 wt % to about 15 wt %, based on the total weight of the composition, and wherein the topical composition has a fluffy texture for direct application to the colon, rectum, anorectum, perianal region or anal canal.

2. The topical composition of claim 1 in the form of ointment, lotion, gel, foam or cream.

3. The topical composition of claim 1 in the form of an ointment.

4. The topical composition of claim 1, wherein the pharmacologically acceptable non-aqueous vehicle is petrolatum.

5. The topical composition of claim 1, wherein the metronidazole is present in a concentration of about 10 wt %, based on the total weight of the composition.

Description

DETAIL DESCRIPTION OF THE INVENTION

(1) The invention also encompasses methods of treatment of the above-mentioned conditions and indications using the topical composition of the first aspect of the present invention. The dose of metronidazole for each application is preferably between from about 125 mg to about 1250 mg, more preferably between from about 125 mg to about 375 mg and most preferably about 250 mg. The most preferred dose is based on a single application of 2.5 cm.sup.3 of a 10 wt % metronidazole ointment. The composition is usually applied between from 2 to 4 times daily and preferably 3 times daily.

(2) Without wishing to be bound by any particular theory, the inventor believes that the use of metronidazole in a topical form by direct application to the diseased or otherwise affected area results in a primarily local effect. Minimal systemic absorption is observed and therefore systemic side effects are effectively eliminated. In addition, a greater dose of metronidazole can be applied directly to the diseased or otherwise effected area, so increasing the efficacy of the medication.

(3) Compositions comprising metronidazole in the form of a gel, cream, ointment, lotion, foam or suppository may be used to treat conditions in the lower parts of the anorectum, such as perianal Crohn's disease, postoperative incisions, ulcers, abscess, fissures, or fistulas. In addition, metronidazole can be used in an enema form to treat conditions of the more proximal rectum and colon, such as inflammatory bowel disease, radiation proctitis, idiopathic proctocolitis or post-surgical pouchitis in a surgically constructed ileal J pouch.

(4) The following is a description of the present invention by way of example only and is not intended to limit the scope of the invention as defined in the claims.

EXAMPLE 1

(5) Method of Production of the Composition

(6) 100 g of metronidazole powder (USP) was mixed with 900 g of white petrolatum (USP) and the mixture passed through a mixer known as an ointment mill to produce a 10 wt % metronidazole composition having a fluffy texture.

EXAMPLE 2

(7) Post-Hemorrhoidectomy

(8) Twenty patients with grade 3 or 4 hemorrhoidal disease with significant external components and with or without a fissure in ano were studied. The presence of neurological deficit, chronic pain syndrome, and patients currently taking narcotic analgesics were excluded. All patients gave informed consent prior to involvement in the study. Patients underwent a closed three-quadrant Harmonic Scalpel hemorrhoidectomy under general anesthesia, with the patient in prone jack-knife position. All surgeries were performed by the same surgeon (DNA). In patients requiring fissurectomy and sphincterotomy, the flat blade of the Harmonic Scalpel was utilized to cauterize the fissure, and a left lateral internal sphincterotomy was performed, extending to the proximal extent of the fissure.

(9) Patients were prospectively randomized into one of two groups, before surgery was performed. Randomization was performed in a single blind manner, and determined by coin-toss. Identical tubes of metronidazole 10 wt % in an inert carrier (petrolatum) in accordance with Example 1 and tubes containing the inert carrier (petrolatum) alone, were obtained from a compounding pharmacy. Study patients applied approximately 2.5 cm.sup.3 of 10 wt % metronidazole composition to the surgical site three times daily, after a Sitz bath or warm soak. Control patients applied the same quantity of the inert carrier three times a day, after a Sitz bath or warm soak. All patients were supplied with a standard narcotic analgesic (hydrocodone, 10 mg po q 4-6 hrs prn; twenty five tablets dispensed), instructed to take a fiber supplement (Konsyl) twice daily, 30 cm.sup.3 mineral oil once daily, and maintain adequate oral hydration.

(10) Postoperative pain was evaluated using a visual analog score (VAS), which was recorded by the patient on days 1, 2, 7, 14, and 28. Patients in both groups ranked the level of pain from 0 (no pain) to 10 (very severe pain). The number of analgesics required (number of hydrocodone pills) per 24 hours, was also recorded by the patient on days 1, 2, 7, 14, and 28. Patients were evaluated at two and four weeks postoperatively, and the completed data sheets were collected at the four-week visit. The mean pain scores for each group were compared using Wilcoxin's Rank sum test. The number of narcotic analgesics required in each group was compared using a two-sample t-test.

(11) Wound healing was evaluated at two weeks, by taking a high quality color digital photograph of the surgical site. At the end of the study, three surgeons independently ranked the 20 surgical incisions in a blinded manner. Incisions were graded in three different categories: A, postoperative incisional edema: B, primary versus secondary wound healing; and C, overall wound healing. For each category (A, B and C), each of the three surgeons ranked the twenty photographs and a mean rank for each photograph was calculated. Thus all twenty photographs had three mean ranks for categories A, B and C. Mean ranking in categories A, B and C were then compared between metronidazole and control groups, using the Mann-Whitney U test.

(12) Twenty patients were prospectively enrolled in the study. Ten patients received 10% metronidazole composition and ten patients receiving the inert carrier. None of the patients were lost to follow-up. The two groups were comparable in terms of age, gender, hemorrhoidal grade and associated fissure in ano. Three patients in the metronidazole group and four patients in the control group had a fissure in ano, and underwent fissurectomy and sphincterotomy, in addition to hemorrhoidectomy.

(13) There was no significant difference in pre-operative pain scores, or pain scores on days 1 and 2, between the metronidazole and control groups. Metronidazole patients experienced significantly less pain on days 7 and 14, compared to patients in the control group (P<0.01 and P<0.05 respectively). There was no significant difference between groups on day 28. There was no significant difference in narcotic requirements between metronidazole and control groups on postoperative days 1 and 2. Metronidazole patients required significantly fewer narcotic analgesics on day 7, compared to control patients (P<0.05). There was no significant difference between groups on days 14 and 28.

(14) Wound healing in the metronidazole group was significantly better than controls, when ranked according to category A, postoperative edema (P<0.01) and category C, overall healing (P<0.05). There was no difference between groups when incisions were ranked according to category B, primary versus secondary healing (P>0.05).

EXAMPLE 3

(15) Refractory Anorectal Crohn's Disease

(16) A prospective pilot study of topical 10 wt % metronidazole according to Example 1 in the treatment of refractory anorectal Crohn's disease was undertaken. Three patients are described: one patient was suspected to have the disease on initial examination (Patient 1), and two unsuspected cases were diagnosed after undergoing routine anorectal surgery. Granulomata were identified histologically in all three patients.

(17) Patient 1, a 36 year-old male, presented with anorectal bleeding and mucous discharge, from a fissure-in-ano in the anterior midline. Anorectal Crohn's disease was suspected. Examination under anesthesia and intra-operative colonoscopy revealed a normal appearing colon and a granulomatous fissure, which was biopsied. No additional procedure was undertaken. Histopathology of the biopsy confirmed the presence of non-caseating granulomata. The patient was started immediately on topical 10% metronidazole according to Example 1.

(18) Patient 2, a 78 year-old female, presented with rectal bleeding from prolapsing internal hemorrhoids, with external components. The patient had had a normal barium enema approximately three years previously. The patient failed to respond to fiber supplements and increasing fluid intake, and therefore, surgical hemorrhoidectomy was recommended. Preoperative flexible sigmoidoscopy revealed no evidence of Crohn's disease in the rectum or distal sigmoid.

(19) The patient underwent a three-quadrant closed hemorrhoidectomy for innocuous-appearing hemorrhoidal disease. Histopathology of the hemorrhoidectomy specimens subsequently revealed the presence of non-caseating granulomata. Postoperatively, the patient experienced severe pain from her incisions, which appeared indurated, granulomatous, and failed to heal. The patient was started on topical 10% metronidazole according to Example 1 three times a day in an attempt to control her pain and heal her incisions.

(20) Patient 3, a 78 year-old female, presented with rectal bleeding and fissure-type symptoms. A posterior midline fissure was noted in association with a sentinel tag. The patient was treated with fiber supplements and copious liquids but failed to respond after two weeks. Intraoperative colonoscopy and examination under anesthesia were performed, which showed a normal appearing colon and a deep posterior midline fissure and a left postero-lateral trans-sphincteric fistula. The fissure was cauterized, the postero-lateral internal sphincter was divided, and a seton placed through the remaining fistula.

(21) Histopathology of the debrided tissue reported the presence of non-caseating granulomata, consistent with anorectal Crohn's disease. The patient experienced excessive postoperative pain associated with induration, bleeding, and non-healing of the surgical site. Topical 10 wt % metronidazole according to Example 1 was initiated in an attempt to promote healing and control pain.

(22) All three patients experienced dramatic relief of their anorectal pain, and the postoperative induration and granulation tissue resolved significantly within three weeks of starting topical metronidazole. Two patients (Patients 2 and 3) had been started on oral Flagyl for a brief period, but had developed nausea and failed to improve; the medication was discontinued before starting topical metronidazole. No patient was taking any additional antibiotic, anti-inflammatory or immunosuppressive medication.

(23) Patient 1 had anterior anal fissure. After two weeks of topical metronidazole, the patient reported a significant improvement in his pain and anorectal discharge. Repeat examination under anesthesia was performed three weeks later, and the tissue edema and granulomation tissue had resolved dramatically. In addition, the granulomata noted on the initial biopsy had resolved, and none was seen in the second biopsy specimen, performed after 3 weeks of topical metronidazole.

(24) Patient 2 reported dramatic pain relief and healing of her incisions had progressed significantly after 2 weeks of topical metronidazole treatment. Four weeks later, the patient was asymptomatic from her anorectal disease.

(25) Similarly, Patient 3 experienced dramatic pain relief within two weeks treatment with topical metronidazole and the incisions appeared much improved. At 4 weeks, the granulation tissue and induration had resolved and the seton was therefore removed. At 6 weeks, the incisions were healed, there was no evidence of a persistent fistula, and the patient had no anorectal symptoms.

(26) No patient experienced side effects from topical metronidazole. Two patients (Patients 2 and 3) developed a mildly reddened, shiny appearance of the perianal skin, which resulted in no adverse symptoms.

(27) It will be appreciated that the invention is not restricted to the details described above with reference to the preferred embodiments but that numerous modifications and variations can be made without departing from the spirit or scope of the invention as defined in the following claims.