MXPA96000386A - Nitric oxide donating composition and method for the treatment of ana disorders - Google Patents

Abstract

The present invention relates to: A pharmaceutical composition contains a nitric oxide donor and advantageously an optional topical corticosteroid and / or anesthetic. The composition is useful in a method for treating anal disorders such as anal fissure, anal ulcer, hemorrhoidal disease, elevating spasm and so on, by topical application affected area, or close to

Description

"COMPOSITION DONOR OF NITRIC OXIDE AND METHOD FOR THE TREATMENT OF ANAL DISORDERS" Inventor (s): STEPHEN R. GORFINE, North American, domiciled at 1215 FIFTH STREET, New York, New York 10029, E.U.A ..

Causaire: NEPTUNE PHARMACEUTICAL CORPORATION, Missouri State Corporation, E.U.A., domiciled at One Kansas City Place, Suite 3000, 1200 Main Street, Kansas City, Missouri 64105, E.U.A.

DONOR COMPOSITION OF NITRIC ORD AND METHOD FOR THE TREATMENT OF ANAL DISORDERS BACKGROUND OF THE INVENTION This invention relates to a composition and method for treating anal disorders such as anal fissure, anal ulcer, hemorrhoidal disease and levator spasm, by the application Topical composition of the affected Area, or close to it. In general, anal fissure (fissure in the anus), anal ulcer, acute hemorrhoidal disease and levator spasm (proctalgia fuga?) Are r '* t benign, common conditions of the anal canal that affect humans of all ages, races and sexes. However, these conditions can be problematic to deal with and drawbacks if pain is not supported. A fissure or anal ulcer is a tear or ulcer of the mucosa or lining tissue of the anal canal, distant. Anal fissure can be associated with other systemic or local diseases, but more often it is present as a finding isolated. The typical idiopathic fissure or ulcer is confined to the anal mucosa, and is usually located in the posterior midline, distant from the dentate line. The person with a fissure or anal ulcer frequently experiences anal pain and anal bleeding, the pain that is most pronounced during and after bowel movements. Hemorrhoids are specialized vascular areas that are located underlying the anal mucosa. Symptomatic hemorrhoidal disease is manifested by hemorrhage, thrombosis and / or prolapse of the hemorrhoidal tissues. Commonly, internal hemorrhoidal tissue swells in the anal canal during defecation causing hemorrhage and pain. As the tissue enlarges, bleeding and additional pain, prolapse, and thrombosis may result. Thrombosis of hemorrhoids is another cause, of hemorrhage and pain. Lifting spasm is a condition that affects women more often than men. This syndrome is characterized by spasticity of the levator ani muscle, a portion of the anal sphincter complex. The patient suffering from the lifting spasm may experience episodic, severe rectal pain. The physical examination can reveal the spasm of the pubiorectal muscle and the pain can be reproduced by direct pressure on this muscle. Bleeding is not always associated with this condition. The causes dependent on these anal disorders are misunderstood, but all these conditions are associated with a relative or absolute degree of the hypertonicity of the anal sphincter. In the case of fissure / anal ulcer, the abnormality seems to be a problem so far unidentified of the internal anal sphincter muscle. The internal sphincter is an involuntary, specialized muscle that originates from the circular, inner muscular layer of the rectum. Measurements of intra-anal pressure, obtained from people suffering from the typical anal fissure / ulcer disease, show an exaggerated response of the pressure to a variety of stimuli. Abnormally high intra-anal pressure is generated by the internal sphincter muscle and is responsible for the non-healing of the fissure or ulcer and associated pain. An abnormal response of pressure in the anal canal has also been observed in people suffering from hemorrhoidal disease, symptomatic.

High intra- nal pressures may be a major factor in the development of this condition. It has been postulated that the pain associated with acute hemorrhoidal disease is caused in 5 part by the spasm of the internal anal sphincter muscle. Similarly, the pain associated with the lifting spasm is induced by the spasm of the muscle itself. Several therapies have been devised to treat I LOVE these anal disorders. Typical non-surgical therapy includes body laxatives and sitz baths. Sitz baths are useful because they induce relaxation of the anal sphincter mechanism. See for example, Shafik, "Role r ~ * of warm-water bath in anorectal conditionss The 'thermosphincteric reflex,' "J_. Cl in.

Bastroenterol .. Ié »s304-30ß, 1 * 993. Anal, topical therapy is also used in an effort to promote healing, alleviate the pain, and reduce swelling and inflammation. Many preparations have been tried, including those containing local anesthetics, corticosteroids, astringents, and other agents. However, none of these preparations has been used. shown that conclusively reduces the healing time or reliably relieves the associated pain. In certain cases, surgery may be used to treat anal disorders. The 5 cases of fissure / anal ulcer or hemorrhoids that are opposed to medical therapy are frequently assigned to surgical therapy. According to the proposed etiology of the fissure / anal ulcer, the normal surgical procedure, current for The same is the anal sphincterotomy, internal, lateral. In this procedure, the internal anal sphincter muscle is partially cut, thereby reducing intra-nal pressure. Decreased pressure allows the fissure / ulcer '* • ** > heal and also relieves the associated pain. Surgical hemorrhoidectomy removes redundant hemorrhoidal tissue, and many surgeons will perform the internal, limited, concomitant, anal, internal anal sphincter to decrease the pressure or in the anal canal. There is no successful surgical treatment for the lifting spasm. Recently, a third has been described and clarified. component of the autonomic nervous system, known as the ßl enteric nervous system (ENS, for its acronym in English). This neural network enervates the entrails in a continuous way from the esophagus to the anus. It is composed of enteric neurons, and the processes of efferent and afferent neurons, extrinsic, of the traditional autonomous system. This system regulates the motor and secretory functions of the bowels. A remarkable feature of the ENS is the diversity of the chemical messengers that are contained and se. released by enteric neurons. In addition to acetylcholine and neropinephrine, several peptidic and non-peptidic substances have been identified that appear to work with neurotransmitters in the ENS. The non-cholinergic, non-adrenergic, inhibitory nerves (NANC) are thought to be important in it. More recently, nitric oxide (NO) has been identified as an inhibitory transmitter for muscle. It has been shown that NO mediates the inhibitory anorectal reflex in animals and man. See, for example, "Rattan et al.," Nitric inhibitory ref lex af sphincter ", Gastroentero1oav. 103" 43-50, 1992; Chakder et al., "Relase of nitric oxide by activation of nonchol and nergic neurons of internal anal sphincter", Am. J. Physiol .. 2 £ > 4: G7-G12, 1993; O'Kelley et al., "Nerve mediated relaxation of the internal anal ßphincters The role of nitric oxide", Gut. 34: 689-693, 1993 See also, Gillespie et al., "Influence of haemoglobin and erythrocytes on the effects of EDRF, on smooth muscle inhibitory factor, and nitric oxide on vascular and non-vascular smooth muscle", Br. J. Pharmacol .. 95 s 1151- 115a, 1988, Ignarro et al., "Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muse" Biochem Biochem. Res. Commun. 170s843-850, 1990; Bult et al., " Nitric oxide as an inhibitory non-adrenergic non-cho1 inergic neurotrans itter ", Nature. 345? 346-347 1990. It has been proposed that the formation of NO, based on the non-enzymatic release of NO from various organic nitrates when catalyzed in the presence of cysteine, causes the direct or indirect activation of guaní lato cyclase, soluble, which finally results in smooth, vascular muscle relaxation, in vivo.

See, Feelisch et al., "Correlation betuieen nitric oxide farmatian during degradation of organic nitrates and activation of guanylate cyclase", Eur. J. Pharmacol .. 139: 19-30, 1987. See also Fung et al., "Biochemical mechanism of organic nitrate action, "Am. J. Cardiol .. 70: 4B-10B, 1992. Organic nitrates such as ni roglycerin (GTN), issorbide d-rnitrate (ISDN), isosorbide mononitrate (ISMN), erythrityl tetranitrate (ETN), pentaeri tetranitrate tri ti what < PETN) is known to cause vasodilation and has been used for decades in the treatment of angina. See for example, Huff et al. (Eds.), "Physicians' Desk Reference," 41st Edition, Medical Economics Company, Oradßll, N.J., 1987 on pages 780, 1176-78, 1533 and 1984-85; Rubin, U.S. Patent No. 5,059,603 (Oct. 1991); Budavari et al. (Eds.), "The Merck Index," 11 th Edition, Merck & Co., Rahway, N.J., 1989, p. 821 -.CN isopropyl treatment); Fung et al. "Biochemical mechanism of organic nitrate action," A. J. Cardiol .. 70? 4B-10B, 1992.

IO Corticosteroids such as h idrscort isone have been used for the treatment of several benign anal disorders for many years. Studies of this treatment have shown some benefit for it, but not in a reproducible or significant way. Topical anesthetics such as dibucal na, lidocaine, pramoxine, and others have been used for the treatment of anal pain. Nevertheless,. any relief has been of a relatively short duration. Other different preparations are known.

See for example, Suzuki et al., Patent North American No. 4,292,299 (Sep. 1981), note column 5 lines 18-20 and 26-28; Rubin '603, note column 7, lines 61-65 and example 1; Greiner, North American Patent No. ' 5,183,663 (Feb. 1993). See also, Williams, Patent North American No. 4,118,480 (Oct. 1978); Huff et al. (Eds.), "The Merck Index," llth.

Edition, page 198. - ^ BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention to provide an effective treatment for anal diseases such as anal fissure, anal ulcer, hemorrhoidal disease, and lifting spasm, which treatment includes the rapid relief of pain associated with these diseases. It is another object of the invention to provide a composition containing an organic nitric oxide donor compound that can be employed in the treatment of this anal disease (s). It is also another object of the invention to provide a method for treating this anal disease (s) by contacting the affected area with an effective amount of nitric oxide supplied by the release from an organic nitrate. It is a further object of this invention to provide a "composition containing". an organic, nitric oxide donor compound in combination with a corticosteroid and / or topical anesthetic that can be used in the treatment of this anal disease (s).

It is yet another additional object thereof to provide a method for treating this anal disease (s) by contacting the affected area with an effective amount of nitric oxide supplied by the release from an organic nitrate plus a corticosteroid and / or topical anesthetic. To achieve these and other related objects of the invention, the present invention provides, in one aspect, a pharmaceutical composition useful for treating anal diseases without weakening side effects comprising an organic nitric oxide donor in combination with a carrier, optionally with a corticosteroid and / or topical anesthetic. In one embodiment, if the organic nitric oxide donor is solely nitroglycerin and the composition is a petrolatum-based or soft paraffin-based ointment then the nitroglycerin is present in an amount that excludes O.5 percent by weight, and optionally also. Exc e O.2, 1 and / or 2 weight percent. All percents by weight, expressed herein, are based on the total weight of the composition. In another aspect, the invention relates to a method for treating anal disease comprising contacting an appropriate anal area with an effective amount of nitric oxide, preferably delivered by an organic nitric oxide donor. The method may also include the additional application of a corticosteroid and / or topical anesthetic to the anal area. The present invention is useful in the treatment of anal disease, especially an anal fissure, anal ulcer, hemorrhoids and levator spasm. In many patients, treatment can be obtained without weakening side effects. Notably, and perhaps more significantly, anal pain can be controlled rapidly and effectively with the composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION All references cited in the present specification are incorporated herein by reference. Generally in the present, the term "anal" includes the tissue of the musculature and vasculature of the anus and / or lower bowels, or those that are close to these. The term "anal disease" means a disorder of the tissue that may include the muscle and / or vasculature of the anus and / or lower bowels, or close to these. The term "organic nitric oxide donor" means an organic compound or mixture of compounds with at least one of this (these) compound (s) capable of releasing nitric oxide under the physiological conditions of the treatment of anal disease. The present invention is related to the treatment directed to the cause dependent on anal diseases including, for example, anal fissure, anal ulcer, hemorrhoids and / or lifting spasm. In general, the cause of these diseases is that it is an unidentified abnormality of the anal sphincter muscles. The compositions useful for the treatment according to the present invention may be in the * .J§g »^ f5 *} .,, tópiga. adequate, physiologically acceptable, appropriate, to contain the organic nitric oxide donor, optionally with another agent (s), such as a corticosteroid and / or a topical anesthetic. Methods for treating anal diseases according to the present invention can employ nitric oxide from any suitable source. The invention can be used in therapeutic medicine with human patients. Preferably, the organic nitric oxide donor includes at least one organic nitrate, which includes nitric acid esters and can be an acyl or cyclic compound, as represented by the following general formula: R (-CR 'R "-O-NOa)" wherein: R is an organic portion or H "(h * dro) or covalent bond, preferably a hydrocarbon having from 2 to about 12 0 carbon atoms or hydrocarbon substituted with oxygen, especially having 2 to 6 carbon atoms and 0 to 2 oxygen (s); R 'is an organic or hydro or covalent bond, and preferably methyl, lower alkyl, including ethyl, propyl. butyl, pentyl, and hexyl; methoxy; lower alkoxy; or hydro; R "is an organic or hydro or covalent bond, preferably methyl, lower alkyl, methoxy, lower alkoxy, or hydro, and especially hydro; and x is an integer from 1 to about 12, and preferably from 2 to 6.

For example, the organic nitrate may be ethylene glycol dinitrate, isopropyl nitrate; gl iceri 1-1-mononi deal; gl iceri 1-1, 2-dini treatment; 1-1 gly, 1-1-dinitrate; nitroglycerin (GTN); butane-1, 2,4-triol-trini treatment; Erythrityl tetranitrate (ETN); pentaeri tetranitrate tri t i lo (PETN); isosorbide mononitrate (ISMN), which may include i sosorb i da-2-mononi treatment (IS2N) and / or isosorbide - ß-mononitrate (ISSN); and / or isosorbide dinitrate (ISDN), and so on and the like. An advantageous organic nitrate is GTN, and the different advantageous organic nitrates include ISDN, ETN, PETN, etc., to which they could have been given legal approval for use in treatments in other fields of medicine or in human individuals.

In general, the organic nitric oxide donor, to include organic nitrate, is present in any amount that is effective in the practice of treating anal disease. In typical practice of the invention, the organic nitric oxide donor can be present in a concentration from about 0.O.sub.l to about 10 percent by weight. All percentages by weight herein are based on the total weight of the composition. If the GTN is organic nitrate, the preferred concentrations lie in the range of from about O.Ol to about 5 weight percent. The following table lists some more particular general ranges for other organic nitrates in compositions of the invention: Composed by hundreds in weight. Approximate ISDN from O.Ol to 7.5, to include O.3 to 3 ETN from O.Ol to 4, to include O.l to 1.5 PETN from O.Ol to 4, to include O.l to 1.5 Optionally, a corticosteroid may be present in the compositions of the present invention. For example, the corticosteroid may include h idrocort isone, i.e., 11-17-21-trihydroxipegn--eno-3,20-dione or cortisol, cortisol acetate, hydrocortisone phosphate, hydrocort-isone succinate-21- sodium, hydrocort isone tebutate, corticosterone, corticosterone acetate, cortisone, cortisone acetate, corticosone 21B- c iclopeptanopropionate, triame inolone-hexacetonide, dexamethasone phosphate, desonide, betamethasone dipropionate, mometasone furate, and so on and so on. In general, the corticosteroid can be present in any amount that is effective in the practice of treating anal disease. In the typical practice of the invention, the corticosteroid may be present in a concentration of approximately O.OOl up to or. • about 10 percent by weight, and preferably from about 0.1 to about 5 percent by weight. If the cortisol is the corticosteroid, the preferred concentrations lie in the range from about 0.5 to about 2. 5 percent by weight. If the hydrocort isone is *** - * < The preferred corticosteroid concentrations are in the range from about 0.5 to about 5 weight percent, if the dexamethasone phosphate is the corticosteroid. The preferred concentrates reside in the range from about 0.005 to about 0.03 weight percent Optionally, a topical anesthetic may be present in the composition of the invention For example, the topical anesthetic may include dibucalna, lidocaine, pramoxine , benzocal, tetracal, and so on, etc. In general, the topical anesthetic may be present in any amount that is effective in the treatment of anal disease.In typical practice of the invention, the topical anesthetic may be present in a concentration from about Ol to about 5 percent by weight and preferably from about 0.5 to about 4 percent by weight based on total weight to the composition. If the dibucalna is the topical anesthetic, the preferred concentrations lie in the range from about 0.25 to about 2 percent in-weight. If the benzscal is the topical anesthetic, the preferred concentrations are in the range of about 10 to about 20 weight percent. If the tetracalm is the topical anesthetic, the preferred concentrations reside in a range from about 1 to about 2 weight percent. The corticosteroid and topical anesthetic can be used with ease in the practice of the invention. As will be appreciated by those skilled in the art, the composition of the invention can be formulated in any pharmaceutical state suitable for topical application, examples of which include liquid, aerosol, thickened liquid, semi-solid emulsion, powder, and a tablet or capsule, which can be lubricated for insertion into the anus. The method of the invention may employ any of these formulations as may be appropriate for treatment in particular cases. Advantageously, the composition can be formulated in the form of highly convenient doses with thickening agents to include solutions or lotions, thickened, ointments to include creams and gels, and so on.

Thickened solutions and lotions and ointments can be formed by incorporating with the active ingredients various gel-forming agents and other thickeners (viscosity enhancers) that allow the release of the active ingredients to the skin or to the tissue on or after the application. These forms are used salefully to decrease runoff from the skin or tissue, which can occur with IO more fluid formulations (less viscous). Importantly, they also allow a more sustained contact of the active ingredient (s) and any penetration improver with the treated surfaces, thereby allowing a • * v increase in the delivery rate of the active ingredient (s) subcutaneously, and providing a more accurate and controllable dosage. Accidental spillage and unwanted contact with the composition can also be minimized with these types of formulations. It may be advantageous to employ agents which are dispersible in water, that is to say, water dispersible thickeners to form a homogeneous distribution or uniform solution, such as 5 polyethylene glycols and similar agents, since they are easily compatible with water or water. other diluents that can be formulated in the composition. Alternatively, an emulsion base can be used to impart the desired thickener effect, together with the emollient effect of the lipoid phase of the base of the emulsion. The bases or thickening substances, dispersible in water or soluble in water, can employ polyethylene glycols and the like of different viscosities depending on the consistency and desired concentration of the active ingredient (s) (s) that can be used. ) incorporate in the composition. Other thickening agents which may be suitable for use therein include, but are not limited to, water-dispersible gums, carboxy-vinyl polymers, methylcelluloses, carbohydrate, sodiumcellulose, and the like. Lotions and ointments incorporating emulsion bases may contain the usual ingredients to provide the base, including fatty alcohols such as acetyl alcohol, an emulsifier such as, for example, lauryl sulfate and water. Also, the remainder of a topical preparation may contain one or more conventional components of the ointments, such as for example white petrolatum, lanolin, distilled water and mineral oil in conventional amounts. The remainder of a suppository may contain conventional amounts of the known components of the suppositories such as, for example, zinc oxide and / or cocoa butter. Pourable pharmaceutical doses can be provided and distributed in graduated containers, or in containers containing a given volume, i.e., for example 5 or 10, and so on. Containers with larger volume, ie, for example, 20 cc and greater, can provide multiple, convenient dosage forms. Containers containing a single, typical dose, for example, from about 0.5 g to about 10 g of the active ingredient (s), can provide convenient dosage forms. Tubes that are tightened for lotions and ointments and cotton bar applicators can be employed for topical application of the composition for liquids ranging from those of viscosity similar to water to the more viscous formulation of thickened compositions, and for powders and the like . Powders can be used. It can be used in an inert powder such as, for example, starch and / or talc to dilute the active ingredient (s) in the powder form. The composition of the invention and the active ingredient (s) in a method can also be administered by dusting, spraying or nebulising such as from walkers, dusting devices, fogging devices and spray bottles. . The containers of the composition can be loaded with any suitable amount and concentration of the ingredient (s). As an administration, a container may be loaded with a fluid formulation containing at least about 10 percent by weight of a combination of active ingredients, together with an aqueous diluent, optionally with thickening agent (s), salt ( is) physiological (s) and so on. Liquid compositions, for example, can be administered as substances of, ba, ja_, viscosity to semi-solid gels or foams, depending on any amount of the gelling agent (s) and / or surfactant (s), included therein. These compositions may be sufficiently fluid to allow their administration upon spraying or nebulization from the container and may also satisfy the criteria for penetration. In the treatment according to the invention, an amount of the active ingredient (s) or composition of the invention is put on.

IO contact with the affected anal area, or applied to it or close to it, such that an effective amount of nitric oxide, preferably supplied by the release of an organic nitric oxide donor, is administered. * 5 The amount of the active ingredient (s) or composition used may be effective for the improvement, control and / or cure of anal disease and the early or dramatic control or relief of the resulting pain. from the disease, or is associated with it. For example, an ointment composition of the invention can be applied topically in each application to the external anus and to the distant anal canal with the finger or # * & r an applicator. As an illustrative alternative, The medicine can be delivered intra-rectally as a suppository. The medicine or medication can be applied in this manner, for example, three or more times daily in the case of ointment or one or more times daily in the case of suppository. The use of the corticosteroid and / or topical anesthetic, optional in the practice of the invention can provide decidedly advantageous results. In cases where treatment with an organic nitrate alone as the active treatment agent fails to provide pain relief and / or healing, most notably, the use of corticosteroid and / or topical anesthetic in combination with nitrate Organic, it can often provide significant relief if not complete pain and also provide significant healing if not total. Pain relief from the invention is rapid and often dramatic. The following examples further illustrate the present invention. All parts and percentages (percent or * A) herein are by weight, unless otherwise specified.

EXAMPLE 1 An ointment was prepared by mixing 12.5 g of 2 percent nitroglycerin in white petralate, lanolin and distilled water (nitroglycerin ointment, USP 2 *, E. Fougera &Co. Melville, NY) with 37.5 g of white petrolatum, USP (VASELINE; Chesebrough-Pond® USA Co., Greenwich, Conn.) In a mixing vessel, laboratory, at room temperature. The resulting mixture was 50 g of 0.5 percent nitroglycerin ointment.

EXAMPLE 2 An ointment of 12.5 g of 2 percent nitroglycerin in white petrolatum, lanolin and distilled water (nitroglycerin ointment, USP 2.5%, E. Faugera Se Co., Melville, NY) was mixed with 20 g of 2.5% hydrocortisone. percent in white petrolatum and light mineral oil (hidrocort isone ointment, USP 2.5%; Clay-Park Labs, Inc., Bronx, N.Y.) and with 17.5 g of white petrolatum, USP (VASELINE; Chesebrough-Ponds USA Co., Greenwich, Conn.) In a laboratory mixing vessel, at room temperature. The resulting mixture was 50 g of a nitroglycerin ointment at 0.5% and 1% hydrocortisone.

EXAMPLE 3 An ointment of 12.5 g of nitroglycerin at 2 percent in white petrolatum, lanolin and distilled water (nitroglycerin ointment, USP 2.5%, E. Fougera SE Co., Melville, NY) was mixed with 25 g of 1 percent dibucalna , USP in white petrolatum and light mineral oil, sodium acetone disulfite, lanolin and purified water (NUPERCAINAL; Ciba Consumer Pharmaceut ic ls, Edison, NJ) and with 12.5 g of USP white petrolatum (VASELINE; Chesebrough-Ponds USA Co. , Greenwich, Conn.) In a laboratory mixing vessel, at room temperature. The resulting mixture was SO g of a nitroglycerin ointment at O.5 percent and drastically at 1 * f O.5 percent.

EXAMPLE 4 An ointment of 2.5 g of 2 percent nitroglycerin was mixed in white petrolatum, lanolin and distilled water (nitro licerine ointment, USP 2%? E. Fougera Se Co., Melville, NY) with 20 g of hydrocort isone 2.5 percent in white petrolatum and light mineral oil (hydrocortisone ointment, USP 2.5% Clay-Park Labs, Inc., Bron, NY) with 25 g of 1 percent dibucalna, USP, in white petrolatum, light mineral oil, disulfite of acetone-sodium, lanolin and purified water (NUPERCAINAL, Ciba Consumer Pharmaceutica ls, Edison, N.J.) and with 2.5 g of white petrolatum, USP (VASELINE; Chesebrough-Ponds USA Co., Greenwich, Conn.) In a laboratory mixing container, at room temperature. The resulting mixture was 50 g of nitroglycerin ointment at 0.5%, hydrocarbon isone at 1 percent, and dibucalna at 0.5%.

EXAMPLE 5 A 29-year-old woman had a 7-day history of bleeding and anal pain with bowel movements. The physical examination showed anal fissure in the posterior midline. The patient assessed her pain before treatment as 7/10. The patient applied approximately 500 g of the ointment as prepared in Example 1, three times daily and after bowel movements, the patient reported that her pain was decreasing after the initial application. After two weeks of treatment, the fissure had healed completely.

EXAMPLE 6 A 40-year-old woman had a 3-month history of bleeding and anal pain with bowel movements. The physical examination showed an anal fissure in the posterior midline, superficial. The patient assessed her pain before treatment as 7/10. The patient applied approximately 500 mg of the ointment as prepared in Example 1, three times daily and after bowel movements. After one week of treatment, the patient noticed persistent hemorrhage, but her pain was assessed as 2/10. After three weeks of treatment, the fissure was healed, and the pain went away.

EXAMPLE 7 A 36-year-old man had a 2-year history of bleeding and anal pain with anal movements. The examination showed an anal ulcer in the midline, posterior. The pain before the treatment was evaluated as 9/10. The patient was treated with hydrocort isone / pramoxin cream (ANALPRAM-HC, 2.5%, Ferndale laboratories, Inc., Ferndale, Mich.) Three times daily and after bowel movements. After a week of treatment, the patient rated his pain as 6/10, and the physical condition was essentially unchanged. The patient was then treated with approximately 500 mg of the ointment as prepared in Example 2, three times daily and after bowel movements. He reported "immediate" pain relief with each application. After a week of this therapy, the ulcer was smaller, but still not completely healed.

EXAMPLE 8 A 23-year-old woman had a 1-month history of bleeding and anal pain with bowel movements. The examination showed an anal fissure in the posterior midline, superficial. He had previously failed a hydrocort isone therapy procedure. The pain before the treatment was evaluated as 9/10. The patient was treated with approximately SOO mg of the preparation of Example 1, three times daily and after bowel movements. After a week of treatment, the fissure was still present, and the pain was 8/10. The patient was then treated with approximately 500 mg of the preparation of Example 2, three times daily and after bowel movements. After a week of therapy with the ointment of Example 2, the patient reported no pain or bleeding. Subsequent examination showed that the fissure had healed.

EXAMPLE 9 A 27-year-old woman had a 3-day history of bleeding and anal pain with bowel movements. The physical examination showed an anal fissure in the anterior midline, superficial. Pain before treatment was rated as 4/10. The patient was treated with the ointment of Example 2, approximately 50O mg three times daily and after bowel movements. After one week of therapy, the patient reported that his pain had decreased, and was rated as 2/10. The exam showed improvement. After fifteen days of therapy, the patient was free of pain, and the fissure had healed.

EXAMPLE IO A 27-year-old man presented with a 5-day history of anal pain. The physical examination revealed an external hemorrhoid, with thrombi, of 1 centimeter in the anal quadrant, anterolateral, left. The patient was treated with the ointment of Example 3, approximately 500 mg three times daily and after bowel movements. He reported a significant reduction in anal pain and his digestive system worked three days later.

EXAMPLE 11 A 57-year-old man was referred for the treatment of the documented elevating spasm that he developed after lower spinal surgery, two years earlier. The patient was treated with the ointment of Example 1, approximately 500 mg intra-anally three times daily and after bowel movements. He reported improvement of ano-rectal spasm in the space of one day. The treatment was then changed to the preparation of Example 3, approximately 500 mg intra-anally three times daily and after bowel movements. The pain relief was not so great, and thus, the treatment was restarted with the preparation of Example 1.

EXAMPLE 12-GROUP STUDY METHODS TEH Group: Five patients (three women and two men) were recruited to participate in a trial of topical treatment of nitroglycerin for acutely trsmbosade external hemorrhoids (DEH, for its acronym in English). Their ages ranged from 23 to 51 years of age. The duration of their symptoms varied from 2 to 4 days. The anorectal examination of all these patients revealed TEH in an anal quadrant (three patients) and in two anal quadrants (two patients). None of these patients had evidence of thrombosis of hemorrhoids, internal, fissure, abscess or fistula. All patients had used one or more topical preparations (ANUSOL or ANUSOL-HC, Parke-Davis, Morris Plains, N.J; PREPARATION H, Whi had 11 Laboratories, Madison, N.J .; PROCTOCREAM-HC, Reed Se Carnrick, Jersey City, N.J.) without symptomatic relief. Fissure Group: Fifteen patients (ten women and five men) were recruited to participate in a trial of topical treatment of nitroglycerin for fissure or anal ulcer. Their ages varied from 23 to 61 years of age. The duration of their symptoms varied from 2 days to 2 years. Three patients had anal ulcers in the posterior midline; eleven had fissures in the midline, posterior, acute; one had an anal fissure in the anterior, acute midline. Two patients had a history of Crohn's ileitis. None of these patients had a history of anal surgery, recent. After obtaining the informed consent of each participant, a therapy program was initiated. The treatment included psyllium seeds (12 g daily) and sitz baths as needed. Approximately 500 to 500 mg of nitroglycerin ointment was applied at 0.5 percent as in Example 1 with the finger to the external anus and the distant anal canal, four or more times daily and after bowel movements. All patients were interviewed and examined one week after starting therapy. The patients in the cleft group were re-examined three weeks after the start of therapy, and every week or every two weeks - later until the fissure had healed or until eight weeks of therapy had passed.

RESULTS TEH Group: All patients reported total or almost total relief of anal pain in the space of 2 to 3 minutes after the application of nitroglycerin. Nitroglycerin was especially useful in relieving pain that typically occurred after defecation. Each application of nitroglycerin ointment IO relieved anal pain from 4 to 6 hours in all patients. All patients reported the need for a few sitz baths. The nitroglycerin ointment was used for an average of three days (range of two to six days). The resolution of the thrombi seemed to follow the usual course of time. Side effects were limited to passing headache in two patients (40 percent of the group's population). Fissure Group: All patients reported dramatic relief of anal pain in the space of 3 to 4 minutes after the application of nitroglycerin ointment, and the effect of pain relief was maintained for 2 to 6 hours. The majority of patients reported that the ointment nitroglycerin was especially useful in alleviating the pain that occurred after defecation. Fourteen patients applied the ointment every 4 to 6 hours while they were awake. One patient required the application every 2 to 3 hours to achieve satisfactory pain control. Of the twelve with superficial anal fissures, IO (83 percent of this group) healed within two weeks, and this group included patients with Crohn's disease. Two patients who had discontinued the treatment after complete healing at two weeks had recurrence of their fissures. Both responded to another two weeks of therapy with no further recurrence of symptoms. The remaining two patients with anal fissures healed after four weeks of continuous treatment. A patient with a posterior anal ulcer was improved but not fully cured after two weeks of therapy. She asked for the spherical approach that resulted in complete healing in the space of another month. Two patients with posterior anal ulcers improved but did not fully heal after two months of therapy, and the interotomy in both cases was refused. Lateral effects were limited to passing, mild headaches in five patients (33 percent of the group's population). The twenty patients in this study experienced dramatic pain relief after the first dose of nitroglycerin ointment, applied topically, and healing was significant. The nitroglycerin ointment applied topically to the anal and rectal area was well tolerated by the majority of patients in this study. Seven of the twenty human subjects (35 percent of the population of the groups) experienced headaches after the topical application of nitroglycerin ointment. The headaches were self-limited in general and abated after approximately fifteen minutes.

EXAMPLE 13 An ointment is prepared by mixing 8.75 g of 2 percent nitroglycerin in white petrolatum, lanolin, and distilled water (nitroglycerin ointment, USP 2 X, E. Fougera Se Co., Melville NY) with 41.25 g of white petrolatum, USP (VASELINE; Chesebrough-Ponds USA Co., Greenwich, Conn.) In a laboratory mixing vessel at room temperature. The resulting mixture is 50 g of a nitroglycerin ointment at O.35 percent. The ointment is effective in the treatment of anal disease when it is applied topically to the affected area or close to it. With this, pain relief and healing are significant, and side effects such as headache are few and / or mild. The ointment can be used with humans.

CONCLUSION From the foregoing, it will be seen that this invention is well adapted to achieve all the terms and objects set forth hereinbefore. It will be understood that certain characteristics and subcountries are useful and can be used without reference to other characteristics and sub-groups. This is contemplated and is within the scope of the claims. Since many possible embodiments of the invention can be made without departing from the scope thereof, it should be understood that all of the subject matter disclosed herein should be construed as illustrative and not in an imitative sense.

It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property:

Claims (36)

1. A pharmaceutical composition useful for the topical treatment of an anal disease, the composition is characterized in that it comprises an organic nitric oxide donor in combination with a carrier, in a form selected from the group consisting of a powder, an aerosol, a liquid to include a thickened liquid, an ointment and a suppository; wherein if the organic nitric oxide donor is solely nitroglycerin and the composition is a petrolatum-based or soft paraffin-based ointment then nitroglycerin is present in an amount that excludes 2.0 *? in weigh.

2. The composition according to claim 1, characterized in that the organic nitric oxide donor is nitroglycerin.

3. The composition according to claim 2, characterized in that it is an ointment.

4. The composition according to the rei indication 1, characterized in that the nitroglycerin is the organic nitric oxide donor, present in an amount from about 0.25 to about 0.45 weight percent, in an ointment.

5. The composition according to claim 1, characterized in that the nitroglycerin is the organic nitric oxide donor, present in an amount from about 0.07 to about 0.15 weight percent, in an ointment.

6. The composition according to claim 1, characterized in that it is a suppository.

7. The composition according to claim 1, characterized in that the organic nitric oxide donor includes at least one organic nitrate represented by the following general formula: R (-CR'R "-Q-NOa)" wherein: R, R 'and R "are, independently whenever they occur, organic or hydro or covalent bond portions, and x is an integer from 1 to about 12.

8. The composition according to claim 7, characterized in that R is a hydrocarbon of 2 to about 12 carbon atoms, or a hydrocarbon substituted with oxygen; R 'is from 2 to 6 carbon atoms and from O to 2 oxygen (s), a hydro portion or a cova-lens bond; R "is a hydro portion, and x is from 2 to 6.

9. The composition according to claim 8, which excludes nitroglycerin; ethylene glycol dinitrate; isopropyl nitrate; gl iceri 1-1 mononitrate; gl iceri 1-1, 2-dini trata, gl iceri 1-1, 3-di ni trata; butane-1, 2,4-triol trinitrate; Erythrityl tetranitrate; pentae tetranitrate i tr i t i lo; isosorbide mononitrate; and isosorbide dinitrate. ÍO.

The composition according to claim 1, characterized in that the organic nitric oxide donor includes at least one organic nitrate selected from the group consisting of ethylene glycol dinitrate; isopropy nitrate; gl iceri 1-1-manonitrate; glyceryl-1,2-dinitrate; gl iceri 1-1, 3-d ini trata; butane- 1, 2,4-triol-trini treatment; Erythritil tetranitrate; pentaeri tetranitrate tr i t i lo, isosorbide mononitrate and isosorbide dinitrate; in a form of ointment or suppository.

11. The composition according to claim 1, characterized in that the organic nitrate donor is selected from the group consisting of one or more of erythrityl tetranitrile; pentaeri tri-thiol tri-nitrate; and isosorbide dinitrate.

12. A pharmaceutical composition useful for treating anal disease, characterized in that it comprises an organic nitric oxide donor in combination with a corticosteroid and a pharmaceutically acceptable topical carrier.

13. The composition according to claim 12, characterized in that the organic nitric oxide donor is nitroglycerin.

14. The composition according to claim 13, characterized in that the corticosteroid is h icrocort isone.

15. The composition according to claim 12, characterized in that a topical anesthetic is also present.

16. A pharmaceutical composition useful for treating anal disease, characterized in that it comprises an organic nitric oxide donor in combination with a topical anesthetic and a carrier.

17. The composition according to the rei indication 16, characterized in that the organic nitric oxide donor is nitroglycerin.

18. The composition according to claim 17, characterized in that the topical anesthetic is dibucalna.

19. A method for treating anal disease, characterized in that it comprises contacting an appropriate anal area with an effective amount of nitric oxide.

20. The method according to claim 19, characterized in that the nitric oxide is supplied by the release from an organic donor of nitric oxide.

21. The method according to claim 20, characterized in that the organic nitric oxide donor is an organic nitrate represented by the following general formula: R (-CR 'R "-O-NOa > ~ where: R, R 'and R "are, independently whenever they occur, an organic or hydro or covalent bond, and x is an integer from 1 to 5 approximately 12.

22. The method according to claim 21, characterized in that R is a hydrocarbon of 2 to 10 approximately 12 carbon atoms or a hydrocarbon substituted with oxygen; R 'is from 2 to 6 carbon atoms and from O to 2 oxygen (s), a hydro portion or a cova lens bond; - •• 5 R "eß a hydro portion, and x is from 2 to 6.

23. The method according to claim 20, characterized in that the organic nitric oxide donor is nitroglycerin.

24. The method according to claim 20, characterized in that at least one agent selected from the group consisting of a corticosteroid and a topical anesthetic is used in conjunction with the nitric oxide donor.

25. The method according to claim 21, characterized in that at least one agent selected from the group consisting of a corticosteroid and a topical anesthetic is used in conjunction with the nitric oxide donor. IO

26. The method according to claim 25, characterized in that the corticosteroid is hydrocortisone, and the topical anesthetic is dibucalna. * > 5

27. The method of * copformity with claim 19, characterized in that the pain is controlled by the same method. ?

28. The method according to claim 19, characterized in that the anal disease is a fissure or ulcer ana 1.

29. The method of conformance with rei indication 19, characterized in that anal disease is a disease of hemorrhoids.

30. The method according to claim 19, characterized in that the anal disease is the lifting spasm.

31. The method according to claim 28, characterized in that neither t rag 1 iceri na is used.

32. The method according to claim 29, characterized in that neither trogl icerin is used.

33. The method according to claim 30, characterized in that nitro-licerine is used. *** "*" '

34. The method according to claim 31, characterized in that anal pain is controlled by the same method.

35. The method according to claim 32, characterized in that anal pain is controlled by the same method.

36. The method according to claim 33, characterized in that anal pain is controlled by the same method. In testimony of which I sign the present in this City of Mexico, D.F., on January 26, 1996. By: NEPTÜNE PHARMACEUTICAL CORPORATION