KR100863758B1 - Compositions and methods for the treatment of anorectal disorders - Google Patents

Abstract

The present invention provides NO donors, PDE inhibitors, superoxide (O ₂ ⁻ ) scavengers, β-adrenergic agonists, cAMP dependent protein kinase activators, α ₁ -adrenergic antagonists, L type Ca ²⁺ channel blockers, Provided are compositions and methods for the treatment of anal rectal disorders, wherein certain combinations of estrogens, ATP-sensitive K ⁺ channel activators, and smooth muscle relaxants are used.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF ANORECTAL DISORDERS}

Reference to related application

This application claims 35 U.S.C. Priority application of US Patent Application No. 60 / 222.267, filed July 31, 2000, under 119 (e). In addition, this application is partly pending application claiming priority of US patent application Ser. No. 09 / 460,306, filed December 13, 1999 and US patent application Ser. No. 09 / 595,390, filed June 14,2000, both applications. Are both priority applications of US Provisional Application No. 60 / 112,325, filed December 14, 1998, 60 / 139,916, filed June 17, 1999, and 60 / 155,318, filed September 21, 1999. The disclosures of each of the above-claimed patent applications are incorporated herein by reference in their entirety.

A statement of the rights of the invention made under federally funded research or development

The present invention was made with government support under approval number 1 R43 DK 56563-01 granted by the National Institutes of Health, National Diabetes, Digestive Disease and Kidney Disease Research Institute. The government owns some of the rights concerning the invention.

Discussion of the "Sequence List", Table or List of Computer Program Lists submitted on a Compact Disc

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The present invention provides an agent or combination of agents that relaxes the internal anal sphincter in the anal region (eg, the internal anal canal) of a patient in need of treatment of anal rectal diseases such as anal laceration, anal ulcer, hemorrhoidal disease and big muscle spasm. A composition and method for treating anal disease by administration. More specifically, the present invention treats anorectal disease with an agent that causes an increase in the cyclic nucleotides in the anal sphincter, or an agent that mimics the action of the cyclic nucleotides or reduces intracellular calcium levels in the affected anal sphincter tissue. Thereby to compositions and methods for reducing anal sphincter tension and / or spasm in a patient suffering from such a disorder.

In general, anal lacerations (anal fissures), anal ulcers, hemorrhoidal disorders and big muscle spasms (transient rectal pain) are relatively common benign conditions of the rectal area that affect patients, including people of all ages, races and genders. . Hemorrhoids and anal lacerations are not given the attention given to life-threatening diseases, but these diseases affect more than 26 million people in the United States, Europe and Japan, causing significant pain and disability.

An anal laceration or anal ulcer is a rupture or ulcer of the mucous membrane or lining of the distal anal canal. Anal lacerations or anal ulcers may be associated with other systemic or local diseases, but are more commonly present as partial diseases. Typical idiopathic lacerations or ulcers are found in the anal mucosa, usually in the posterior midline distant from the tooth line. Individuals with anal laceration or anal ulcers often experience anal pain and bleeding, which is more pronounced during and after defecation.

Hemorrhoids are localized in areas of blood vessels below the anal mucosa. Indicative hemorrhoidal disease is manifested by bleeding, thrombus and / or prolapse of hemorrhagic tissue. Usually, hemorrhoidal tissues come out into the anal canal during defecation, leading to bleeding and pain. As this tissue grows, more bleeding, pain, prolapse and blood clots develop. Blood clots of hemorrhoids are another cause of bleeding and pain.

Big spasms are more common in women than in men. This symptom is characterized by spasm of the anal big muscles, which is part of the anal sphincter group. Patients with big spasms can experience severe and temporary rectal pain. Physical experiments can reveal spasms of the alveolar rectus muscles, and pain can be regenerated by directly pressing the muscles. Bleeding is largely unrelated to this condition.

Hemorrhoids are the most common anal rectal disorder and the most common cause of bloody excretion (ie, passage of bloody stool). Hemorrhoidal diseases, which generally play an important role in the ability to inhibit bowel movements, are the result of distal dislocation of anal shock relieving tissue. The cause of hemorrhoids is unknown. The most consistently described physiological abnormalities are increased resting anal pressures (Hancock BD, Br J Surg 64 (2): 92-5 (1975); Loder, PB, Br J Surg 81 (7): 946-54 ( 1994). Patients with non-extracting hemorrhoids appear to have higher anal pressure than patients with prolapsed hemorrhoids (Arabi, Y. et al., Am J Surg 134 (5): 608-10 (1977); Sun, WM et al., Br J Surg 77 (4): 458-62, (1990)), The therapeutic significance of this observation remains unclear. Treatment depends on the extent and symptoms of hemorrhoidal escape. In general, most cases (1st and 2nd degree hemorrhoids) follow conventional medical procedures (eg, dietary changes, sitz baths) or non-surgical procedures (eg, rubber band ligation). Usually, epilepsy with acute thrombosis is characterized by severe anal pain, and internal anal sphincter tension hypertension may play an important role in the pathogenesis of this pain (Gorfine, SR, Dis Colon Rectum 38 (5): 453-7). (1995)). Surgical resection of the cortex with symptomatic thrombosis is required within 48 to 72 hours after the onset of pain. Pain after hemorrhoidectomy is severe, disproportionate in the surgery itself and requires the use of anesthetic painkillers, which unfortunately exacerbate recovery by causing constipation. As a treatment to reduce anal sphincter pressure in hemorrhoids, anal dilatation and lateral sphincter resection have been successfully used independently or in combination with hemorrhoidectomy (Keighley, MR et al., Br Med J J2 (6196): 967-9 (1979). Schouten WR et al., Dis Colon Rectum 28 (12), 869-72 (1986); Galizia et al., Eur J Surg 166 (3): 223-8 (2000)).

Others have reported that adding lateral sphincter resection to conventional hemorrhoidectomy is unnecessary and carries an additional risk of incontinence (Mathai, V. et al., Br J Surg. 83 (3): 380-2 (1996) ).

Anal laceration is one of the most common causes of anal rectal pain. Anal lacerations usually rupture in the mucosa of the distal anal canal along the midline. The exact cause of anal laceration is unknown. These are often associated with trauma, such as the passage of cirrhosis, but can also occur during a period of diarrhea, childbirth or ulceration of hemorrhoids (Lund, JN et al., Br J Surg. 83 (10): 1335-44 (1996)). The most common symptom is pain in defecation, which is very severe and can last for hours. Pain only results from severe spasms of the internal anal sphincter. Most anal lacerations are adequately treated with left baths, debris and analgesics. Approximately 60% of acute anal lacerations can be cured within three weeks using this treatment regimen. Unhealed acute anal lacerations become chronic anal lacerations or anal ulcers. Tension hyperactivity of the internal anal sphincter and mucosal ischemia is thought to play an important role in the pathogenesis of chronic anal laceration (Schouten WR et al., Dis Colon Rectum 37 (7): 664-9 (1994); Lund, JN et al., Br J Surg 83 (10): 1335-44 (1996)). The anal canal blood flow in the posterior midline is less than in other parts of the anal canal, and the perfusion of the posterior mucosa is inversely related to anal pressure. Typically, chronic anal lacerations do not respond to conventional medical therapy. Therefore, current treatment focuses on relieving sphincter spasms and is anal dilatation (under anesthesia) or more generally lateral sphincter resection of the internal anal sphincter. Healing occurs after surgical sphinctomy in 95% of cases. Successful sphincter resection (or anal dilatation) is associated with significant decreases in anal pressure and increased coronary blood flow (Lund, JN et al., Br J Surg 83 (10): 1335-44, (1996); Schouten WR, etc.). , Scan J Gastroenterol.Suppl 218: 78-81 (1996)). Fecal incontinence and farting are embarrassing disorders with numerous social, medical and financial implications. Clearly, there is a largely unmet medical need to develop effective and non-surgical therapies for anal lacerations, acute hemorrhagic disease, hemorrhoidectomy pain, transient rectal pain and other colorectal conditions. Recently, understanding of rectal physiology and pharmacology has advanced significantly. These new insights provide important implications and opportunities for pharmacological management of colorectal disorders.

The sphincter is a circular group of smooth muscles that control the cavity of the hollow organs. They exist through the gastrointestinal tract and regulate the passage of matter through this system of the body. When contracted, it closes the hole resulting from or into the hollow organ, such as the stomach, intestines, rectum and the like. The sphincter must be relaxed to open this cavity. The sphincter closing the anus (anal sphincter) consists of two sphincter groups. The external anal sphincter is a thin plane of rhabdomyofiber attached to the sheath surrounding the margin of the anus. It is governed by motor neurons and is under the control of numbers. The internal anal sphincter (IAS) is a ring of smooth muscle that surrounds the anal canal and is formed by limited aggregation of involuntary circular smooth muscle fibers of the intestines. IAS is primarily responsible for resting anal sphincter pressure and endocrine suppression, which is maintained by endogenous myogen tension and is regulated by endogenous and exogenous nerve distribution from the autonomic nervous system (Penninckx, F. et al ., Baillieres Clin Gastroenterol 6 (1)). 193-214 (1992); Speakman, CT Eur J Gastroenterol Hepatol 9 (5): 442-6 (1997)).

ISA smooth muscle produces a rhythmic electrical slow, but no working potential. The slow wave is connected to calcium flux through voltage-dependent L-type calcium channels responsible for mechanical force generation and sphincter contraction. Thus, several calcium channel antagonists, including diltiazem and nifedipine, have been reported to reduce anal pressure in humans (Jonard et al., Lancet 1 (8535): 754 (1987); Chrysos, E. et al., Dis Colon Rectum 39). (2): 212-6 (1996); Antropoli, C. et al., Dis Colon Rectum 42 (8): 1011-5 (1999); Carapeti, EA et al., Gut 45 (5) 719-722 (1999); Carapeti , EA et al., Br J Surg 86 (2): 267-70 (1999)), several documents have been reported to cure chronic anal laceration (Cook, TA et al., Br J Surg 86 (10): 1269-73 (1999); Brisinda, G. et al., Br J Surg 87 (2): 251 (2000)),

The sympathetic distribution of IAS supplied by the gastric inferior nerve is primarily excitatory and functions to enhance myogenic tension through the action of norepinephrine on smooth muscle α ₁ -adrenergic receptors (Frenckner, B. et al., Gut 17 (4): 306-12 (1976); Speakman, CT et al., Dig Dis Sci 38 (11) 1961-9 (1993)). Fentolamine and indoramine, α ₁ -adrenergic receptor antagonists, reduce anal vascular pressure when administered to healthy volunteers or patients with chronic anal laceration (Speakman, CT, Eur J. Gastroenterology 9 (5): 442-6 (1997) Pitt, J. et al., Dis Colon Rectum 43 (6) 800-803 (2000)). In contrast, the α-receptor agonists methoxamine and phenylephrine increase anal pressure (see Speakman, CT 1997 supra; Carapeti, EA et al., Br J Surg 86 (2): 267-70 (1999)). Low anal pressure is associated with incontinence (Speakman, CT Gastroenterology 9 (5): 442-6 (1997)). Speakman, CT et al . , Dig. Dis Sci. 38 (11): 1961-9 (1993) report that IAS in incontinence patients shows reduced sensitivity to norepinephrine. Although the α-adrenergic receptor population predominates, β-adrenergic receptors also exist in human IAS and mediate relaxation (Parks, AG et al., Gut 10 (8): 674-7 (1969); Burleigh, DE et al., Gastroenterology 77 (3): 484-90 (1979)). The contractile response of IAS to norepinephrine can be converted to relaxation in vitro and in the presence of selective α-receptor blockade in normal human volunteers (Burleigh, DE et al., Gastroenterology 77 (3): 484-90 (1979)) Speakman, CT, Eur J Gastroenterology 9 (5): 442-6 (1997)). In Regadas, FS et al., Br J Surg 80 (6): 799-801 (1993), isolated IAS strips from chronic anal laceration patients have a relaxing effect of β-adrenergic agonist isoproterenol over control tissues. While significantly more sensitive to, it was explained that there was no difference in the contractile response to phenylephrene and potassium chloride (membrane depolarizer). However, it remains to be explained whether β-adrenergic agonists provide disease specific benefits for the treatment of chronic anal lacerations.

IAS relaxes in response to rectal expansion (rectal analgesia reflex). Nerve that mediates rectal analgesic reflexes are entirely within the intestinal wall (intestinal inhibitory nerves) and descend from the rectum to IAS. Electric field stimulation (EFS) mimics the effects of intrinsic nerve stimulation on isolated smooth muscle strips. The IAS strip is relaxed by EFS and its effect is abolished by the neurotoxin tetrodotoxin, but is not affected by acetylcholine or norepinephrine, which are antagonists of typical neurotransmitters. Thus, inhibitory nerves are classified as nondrenergic, noncholinergic (NANC) nerves. Adenosine triphosphate (ATP) and vasoactive intestinal peptide (VIP) were first proposed as NANC neurotransmitter candidates because they simulated relaxation induced by electrical stimulation of motor nerve fibers (Burnstock, G. et al., Br J Pharmacol. 46 (2): 234-42 (1972); Bitar, KN et al., Science 216 (4545): 531-3 (1982)). However, ATP and VIP, separately or together, cannot explain all inhibitory neurotransmissions in gastrointestinal smooth muscle, and their role has not been demonstrated in humans (Burleigh, DE et al., Gastroenterology 77 (3): 484-). 90 (1979); Burleigh, DE, J Pharmacol 35 (4): 258-60 (1983); Brookes, SJ, J Gastroenterol Hepatol 8 (6): 590-603 (1993).

Recent studies have shown that NO plays an important role in NANC nerve mediated relaxation of IAS. In animal models, Rattan, S. et al., Am J Physiol 262 (1 Pt 1): G107-12 (1992) include IAS relaxation associated with rectal anal reflex (induced by rectal balloon extension) or nerve stimulation. It is described that it is blocked by inhibiting NO synthase (NOS) with L-NNA [N ^5- (nitroamidino) -L-2,5-diaminopentanoic acid] rather than D-NNA. Blocking of rectal anal reflexes by L-NNR was reversed by L-arginine in a stereospecific manner, which includes NO or NO like substances as mediators of NANC neuron mediated IAS relaxation. NO has been shown to directly relax IAS in a concentration-dependent manner in vitro, simulating the effects of NANC nerve stimulation by EFS. NANC nerve mediated relaxation of the in vitro IAS strip was blocked by inhibiting NO synthase with L-NNA, which was reversed by L-arginine, not D-arginine (Rattan, S. et al., Am J Physiol 262). (1 Pt 1): G107-12, (1992) and Rattan, S. et al., Gastroenterology 103 (1): 43-50 (1992)). Similar observations were made using isolated muscle strips of human IAS (Burleigh, Gastroenterology 102 (2): 679-83 (1992); O'Kelly, TJ et al., Br J Surg 80 (10): 1337-41 ( 1993). Direct release of NO after NANC nerve stimulation of the pocket rat IAS strip was measured using specific chemiluminescence detection (Chakder, S. et al., Am J Physiol. , 264 (4 Pt 1) G702-7 (1993)). Recently, O'Kelly, TJ et al., Dis Colon Rectum 37 (4): 35-7 (1994) reported the presence of NOS in neurons of the myofascial plexus protruding through IAS and proximate to smooth muscle cells. It is explained. In Hirschsprung disease without rectal anal reflexes, neuronal NOS is not present in the non-relaxed segment but is present in the normal segment of the intestine (O'Kelly, TJ et al., J Pediatric Surgery 29 (2): 294-9 (1994)). This observation satisfies most of the entries for NO as inhibitors or neurotransmitters.

Many potent vasodilators and smooth muscle relaxants are known to chemically release NO on or in target cells and are therefore known as NO donors. Any NO donor, such as nitroglycerin, is widely used therapeutically as a coronary vasodilator for the treatment of heart disease. In maintaining NO's role as an inhibitory neurotransmitter that mediates relaxation of IAS, NO donors have begun to develop clinically as drugs to treat anal disorders associated with IAS hypertension. Significantly, nitroglycerin (Gorfine, SR, Dis Colon Rectum , 38 (5): 453-6 (1995); Watson, SJ et al., Br J Surgery 83 (6): 771-5, 1996; Lund, JN et al. , Lancet 349: 9044 (1997)) and isosorbide dinitrate have been used to perform reversible chemical sphincter resection for patients with chronic anal laceration. These drugs reduce maximal resting anal pressure, improve anal canal blood flow, reduce pain, and heal lacerations in most patients. Nitroglycerin has also been shown to reduce acute hemostatic thrombosis and pulsatile pain in transient rectal pain (Gorfine, SR, Dis Colon Rectum 38 (5): 453-6 (1995); Lowenstein, B. et al., Dis Colon Rectum 41 (5): 667-8 (1998).

US Pat. Nos. 5,504,117 and 5,693,676 describe the use of NO donors for the treatment of rectal conditions. However, the occurrence of side effects, such as the occurrence of headaches, limits the use of NO donors, especially in high dose monotherapy.

One problem associated with topical nitroglycerin therapy that can limit its efficacy is the increased headache, especially at high doses (Palazzo, FF et al., JR Coll Surg Edinb 45 (3): 168-70 (2000)). Headaches are presumed to be due to the systemic effects of nitroglycerin and are generally temporary, but can affect patient acceptance. There is a need for a strategy of treatment methodology that enhances the local effects of nitroglycerin and minimizes its systemic side effects. The second potential problem with nitrates is the development of drug resistance, which is well documented in the literature on nitrate treatment of cardiovascular disease (Fung, HL et al., Cardiovasc Drugs Ther 8 (3): 489-99, (1994)). . If resistance is present, this will in particular limit the ability of nitroglycerin to produce sustained relaxation of IAS, which may be necessary to heal refractive index chronic anal lacerations.

There is a clear need for anal rectal disorders, such as anal lacerations, and other anal rectal conditions caused by sphincter spasm and / or hypertension, such as acute hemorrhoidal disease and transient rectal pain. Do.

Thus, there is a need for alternative methods and compositions for reducing anal sphincter pressure that compensate or supplement nitroglycerin.                 

The use of topical or rectal medications that compensate or supplement nitroglycerin for the treatment of chronic anal lacerations and other anorectal disorders provide the first effective alternative to surgery for this painful disorder.

Summary of the Invention

In one embodiment, the present invention provides a composition for the treatment of anorectal disorders comprising a nitric oxide donor in combination with a second agent (typically regulating the level of cAMP or cGMP). The second agent is a phosphodiesterase type V (PDE V) inhibitor, a phosphodiesterase type II (PDE II) inhibitor, a phosphodiesterase type IV (PDE IV) inhibitor, a nonspecific PDE inhibitor, β -Adrenergic agonists, cAMP dependent protein kinase activators, estrogens or estrogen-like compounds or α ₁ -adrenergic antagonists. In addition, the agent may be a superoxide anion (O ₂ ⁻ ) scavenger, an ATP-sensitive K ⁺ channel activator, a sympathetic nerve terminal disruptor or a smooth muscle relaxant, but these agents directly regulate cAMP or cGMP levels. It is not. The present invention also provides a method of using such a composition.

In another embodiment, the present invention is directed to phosphodiesterase inhibitors, preferably PDE II inhibitors, PDE IV inhibitors or PDE V inhibitors alone, or β-adrenergic receptor agonists, α ₁ -adrenergic antagonists, estrogens, In combination with another agent selected from L-type Ca ²⁺ channel blocker, ATP sensitive K ⁺ channel activator or smooth muscle relaxant, the present invention provides a composition for the treatment of anorectal disorders comprising a pharmaceutically acceptable carrier. The present invention also provides a method of using such a composition.

In another embodiment, the present invention relates to β-adrenergic receptor agonists, preferably β ₂ -or β ₃ -adrenergic receptor agonists alone, or cAMP hydrolytic PDE inhibitors (eg, PDE IV inhibitors), Compositions for the treatment of anorectal disorders comprising in combination with other agents selected from nonspecific PDE inhibitors, α ₁ -adrenergic antagonists, estrogens or estrogen-like compounds, L-type Ca ²⁺ channel blockers or ATP-sensitive K ⁺ channel activators , And methods of using such compositions.

In another embodiment, the present invention is directed to an ATP sensitive K ⁺ channel activator alone or other selected from cAMP dependent protein kinase activators, α ₁ -adrenergic antagonists, estrogens, L-type Ca ²⁺ channel blockers or smooth muscle relaxants. Provided are compositions for the treatment of anal rectal disorders comprising in combination with agents, and methods of using such compositions.

In another embodiment, the present invention provides treatment of anorectal disorders comprising α ₁ -adrenergic antagonist alone or in combination with other agents selected from cAMP hydrolytic PDE inhibitors (preferably PDE IV inhibitors) or smooth muscle relaxants. Compositions for, and methods of using such compositions.

In another aspect, the present invention provides a composition for the treatment of anorectal disorders comprising β ₂ -adrenergic agonist alone or in combination with other agents. Also provided are methods of using such compositions. In one group of embodiments, the β ₂ -adrenergic agonist is used alone. In a preferred embodiment, the β ₂ -adrenergic agonist is combined with a phosphodiesterase inhibitor. In another embodiment, the β ₂ -adrenergic agonist is combined with one or more other IAS relaxants.

In another aspect, the present invention provides a composition for the treatment of anorectal disorders comprising adenosine receptor antagonists, alone or in combination with other agents. Also provided are methods of using such compositions. In a group of embodiments, adenosine receptor antagonists are used alone. In another group of embodiments, the adenosine receptor antagonist is combined with one or more other IAS relaxants.

In another aspect, the present invention provides a composition for the treatment of anorectal disorders comprising a cyclic nucleotide dependent protein kinase activator alone or in combination with other agents. Also provided are methods of using such compositions. In a group of embodiments, the cGMP dependent protein kinase activator is used alone. In another group of embodiments, nonspecific cyclic nucleotide dependent protein kinase activators are used alone. In another group of embodiments, the nonspecific cyclic nucleotide dependent protein kinase activator is used in combination with smooth muscle relaxant. In another group of embodiments, the cAMP dependent protein kinase activator is provided in combination with an L-type Ca ²⁺ channel blocker.

In another aspect, the present invention provides a composition for treating anorectal disorders comprising a methylxanthine compound. In a preferred embodiment, the compound is theophylline or diphylline. In another embodiment, the methylxanthine compound is used alone. In another embodiment, the methylxanthine compound is combined with other IAS relaxants.

In another aspect, the present invention provides a composition for the treatment of anorectal disorders comprising estrogen or other estrogenous compound, alone or in combination with other agents. Also provided are methods of using such compositions. In one group of embodiments, the estrogenic compound is used alone, in another group of embodiments, the estrogenic compound is a phosphodiesterase inhibitor, a β-adrenergic receptor agonist, α ₁ -adrenergic antagonist, type L Used in combination with a pharmaceutically acceptable carrier, in combination with a second agent selected from Ca ²⁺ channel blockers, ATP sensitive K ⁺ channel activators or smooth muscle relaxants. The present invention also provides a method of using such a composition.

If the compounds discussed above act through mechanisms distinctly different from nitroglycerin, they can be used to compensate for nitroglycerin therapy or as a single product.

As mentioned above, methods of treating anal rectal disorders are also provided herein. The method of the present invention comprises the step of administering to the patient an appropriate formulation of one or more of the above compositions. In a related method, the treatment is carried out by continuously administering two or more agents by the same or different routes of administration.

1 shows a typical waveform pattern for resting IASP of rats under the conditions of a control experiment.

2 shows the waveform pattern for IASP of rats after administration of 20 μl of a 1% solution of nitroglycerin in propylene glycol.

Figure 3 depicts the effect of cGMP analogues on endogenous sphincter pressure in rats. This figure shows the waveform pattern for IASP after 20 μl administration of a 10% solution of dibutyryl-cGMP in saline.

FIG. 4 shows the effect of type V phosphodiesterase inhibitors on rat internal sphincter pressure. This figure shows the waveform pattern for IASP for rats after administration of 20 μl of a 5% solution of japrinast in 1-methyl-2-pyrrolidinone.

5 depicts the effect of potassium channel openers on rat internal sphincter pressure. This figure shows the waveform pattern for IASP for rats after administration of 20 μl of a 4% solution of minoxidil in 62.5% propylene glycol.

6 depicts the effect of NTG administered to IAS as a monotherapy.

7 shows the effect of NTG administered to IAS by continuous infusion over 4 hours.

8 shows the effect of 8-bromo cAMP injected in IAS at 20 μg / hour for 3 hours.

9 shows the effect of dibutyryl cAMP injected in IAS at 20 μg / hour for 3 hours.

FIG. 10 shows the effect of NTG (200 μg) clot dosing within the same vehicle after SOD (200 μg) clot delivery to IAS.

FIG. 11 shows the effect of SOD (200 μg) clot dosing within the same vehicle after NTG (200 μg) clot delivery to IAS.

FIG. 12 shows the effect on IAS of a single dose of NTG 30 minutes after vehicle injection.

FIG. 13 shows the effect on IASP of the infusion dose of NTG topically applied to IAS following intraperitoneal injection of japrinat.

14 shows the effect on IASP of a monoclonal dose of NTG topically applied to IAS, where the first NTG dose is given at 2.75 hours after vehicle injection.

FIG. 15 shows the effect on IASP of the infusion dose of NTG after intraperitoneal injection of japrinat, wherein the first NTG dose is given at 2.75 hours after vehicle injection.

FIG. 16 depicts the effect on IAS of a single dose of NTG 50 minutes after vehicle injection.

Figure 17 depicts the effect on IAS of PDE V inhibitor dipyridamole injected intraperitoneally 50 minutes prior to the administration of NTG roundworm.

FIG. 18 depicts the effect on IASP of PDE V inhibitor MBCQ injected intraperitoneally 30 minutes prior to the administration of NTG roundworm.

FIG. 19 shows the effect on IASP of β-agonist isoproterenol delivered to IAS after 30 minutes of saline alone.

20 shows the effect on IASP of β ₂ -agonist terbutalin in saline injected continuously at 20 μg / hour.

21 shows the effect on IASP of β ₂ -agonist salbutamol in saline injected continuously at 20 μg / hour.

FIG. 22 shows the effect of PDE IV inhibitor rolifram on IASP in DMSO / acetone / olive oil injected continuously at 20 μg / hour.

FIG. 23 depicts a single monoclonal dosing of salbutamol and a PDE IV inhibitor etazolate following a monoclonal dosing of salbutamol.

FIG. 24 depicts single monoclonal dosing of salbutamol and etazolate after rounding dose of etazolate.

FIG. 25 depicts the effect of PDE IV inhibitor Ro 20-1724 on IASP in DMSO / acetone / olive oil injected continuously at 20 μg / hour.

FIG. 26 shows the vehicle control for the treatment provided in FIG. 27.

27 shows the effect on IASP of specific adenyl cyclase activator forskolin in DMSO / acetone / olive oil injected continuously at 20 μg / hour.

FIG. 28 shows the effect on IASP of α ₁ -blocker prazosin in DMSO / acetone / olive oil injected continuously at 20 μg / hour.

FIG. 29 depicts the effect on IASP of nonspecific PDE inhibitor IBMX in DMSO / acetone / olive oil injected continuously at 200 μg / hour.

30 shows the effect on IASP of nonspecific PDE inhibitor IBMX in DMSO / acetone / olive oil injected continuously at 20 μg / hour.

FIG. 31 shows the effect on IASP of a single rounded dose of K ⁺ -ATP channel opener minoxidil in propylene glycol / water.

FIG. 32 depicts the effect on IASP of K ⁺ -ATP channel opener diazooxide in DMSO / acetone / olive oil injected continuously at 20 μg / hour.

FIG. 33 depicts the effect of Ca ²⁺ channel blocker diltiazem on IASP in saline injected continuously at 20 μg / hour.

FIG. 34 shows the effect of Ca ²⁺ channel blocker verapamil on IASP in saline injected continuously at 20 μg / hour.

FIG. 35 depicts the effect of sympathetic nerve terminal disruptor 6-hydroxydopamine on IASP when administered to IAS at a dose of 200 μg / day for 5 days.

FIG. 36 depicts the effect on IASP of continuous infusion (0.2 μg / hour) of threshold dose of isoproterenol in saline 30 minutes after control vehicle intraperitoneal injection of 1-methyl-2-pyrrolidinone.                 

FIG. 37 shows the effect on IASP of continuous infusion of isoproterenol 30 minutes after PDE III / IV inhibitor zardaverin when injected intraperitoneally (10 mg in vehicle).

FIG. 38 shows the effect on IASP of continuous infusion of 5% dextrose 30 minutes after PDE III / IV inhibitor zardaverin when injected intraperitoneally (7.5 mg in vehicle).

FIG. 39 depicts the effect on IASP of continuous infusion of sub-threshold dosing of isoproterenol 30 minutes after PDE III / IV inhibitor zardaverin when injected intraperitoneally (7.5 mg in vehicle).

FIG. 40 depicts the effect of adenosine antagonist and nonspecific PDE inhibitor theophylline in IASP in 5% dextrose when administered at 200 μg / hour.

FIG. 41 shows the effect of theophylline on IASP in 5% dextrose at 20 μg / hour continuous infusion.

FIG. 42 depicts the effect of theophylline on IASP in 5% dextrose when continuous infusion at 2 μg / hour.

FIG. 43 shows the effect of depilin in IASP on 5% dextrose in continuous infusion at 20 μg / hour.

Detailed description of the invention

Acronyms and Definitions

cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; NO, nitric oxide; NTG, nitroglycerin; SOD, superoxide dismutase; PDE, phosphodiesterase; IASP, internal anal sphincter pressure; Rp-cAMPS, Rp-adenosine-3 ', 5'-cyclic monophosphorothioate; Sp-cAMPS, Sp-adenosine-3 ', 5'-cyclic monophosphorothioate; 8-CPT cAMP, 8- (4-chlorophenylthio) adenosine-3 ', 5'-cyclic monophosphate sodium salt; Sp-5,6-DCI-cBiMPS, Sp-5,6-dichloro-1-b-D-ribofuranosylbenzimidazole-3 ', 5'-monophosphorothioate; Dibutyryl-cAMP, N-6,2'-0-dibutyryladenosine-3 ', 5'-cyclic monophosphate, sodium salt monohydrate; Sp-8-pCPT-cGMPS, Sp-8- (4-chlorophenylthio) quaanosine-3 ', 5'-cyclic monophosphate sodium salt; 8-bromo-cGMP, 8-bromoguanosine-3 ', 5'-cyclic monophosphate sodium salt; Rp-8-Br-cGMPS, Rp-8-bromoguanosine-3 ', 5'-cyclic monophosphothioate sodium salt; Dibutyryl-cGMP, N2,2'-0-dibutyrylguanosine-3 ', 5'-cyclic monophosphate sodium salt; EHNA, erythro-9- (2-hydroxy-3-nonyl) adenine HCI; IBMX, 3-isobutyl-1-methylxanthine; MY-5445, 1- (3-chlorophenylamino) -4-phenylphthalazine; Ro 20-1724, 4- (3-butoxy-4-methoxybenzyl) -2-imidazolidinone; MBCQ, 4-((3,4- (methylenedioxy) benzyl) amino) -6-chloroquinazolin.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The following reference provides one of the techniques with a general definition of many terms used in the present invention: Singleton et al., DICTIONARY OF MIRCROBIOLOGY AND MOLECULA BIOLOGY (2d ed., 1994); THE CAMBRIDGE DICTIONARY OF SCIENCE AND TECHOLOGY (Walker ed., 1988); And Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY (1991). The following terms, as used herein, have the meanings set forth in these unless otherwise stated. Although any methods and materials similar or equivalent to those described herein can be used in the practice or teaching of the present invention, the preferred methods and materials are described. For the purposes of the present invention, the following terms are defined as follows.

The terms "treatment", "therapy" and the like include, but are not limited to, changes in the recipient's condition. This change may be objective or subjective and may be related to aspects such as symptoms or symptoms of the disease or condition to be treated. For example, if a patient is recorded with reduced itching, reduced bleeding, reduced discomfort, or reduced pain, successful treatment has been achieved. Similarly, if a clinician records subjective changes, eg, by histological analysis of a biopsy sample, the treatment is successful. Alternatively, the clinician may record the size reduction of the lesion or other abnormality at the time of examination of the patient. This also indicates an improvement or successful treatment. It is also included in this term to prevent deterioration of the recipient's condition. Therapeutic benefits include any of a number of objective or subjective factors indicative of the response of the condition to be treated as discussed herein.

"Drugs", "pharmacological agents", "pharmaceutical agents", "active agents" and "formulations" are used interchangeably and any treatment that is delivered to a living organism to produce a predetermined, usually beneficial effect. It is intended to have in their broadest interpretation of biologically active matter.

"Pharmaceutically acceptable" or "therapeutically acceptable" refers to a substance which does not interfere with the efficacy or biological activity of the active ingredient and which may be human or animal, which is not toxic to the host to which it is administered. A "therapeutically effective amount" refers to an amount of active agent that is sufficient to induce a given biological result. The result can be alleviation of the signs, symptoms or causes of the disease, or any other alteration of the biological system. The term “therapeutically effective amount” is used herein to refer to any amount of a preparation that, when applied repeatedly to the affected area over a period of time, results in substantial improvement of the disease state. The amount will vary depending on the condition being treated, the stage of development of the condition, and the type and concentration of preparation applied. In any given case, an appropriate amount will be readily apparent to those skilled in the art or may be determined by routine experimentation.

The term "anorectal site" is defined herein to include both the anal and rectal areas of a mammal. More specifically, the term includes the internal anal canal, the external anal canal, and the lower rectum.

"Tension hyperactivity" means being in a state of greater or incomplete relaxation than normal muscle tension.

The term "cyclic nucleotide" means cyclic adenosine monophosphate and cyclic guanosine monophosphate.

The term "regulation" refers to any systemic or gradual change in the nature of a variation (eg, frequency, concentration, amplitude, efficacy, etc.) that has lasted long enough to affect a biological function. The term "change" includes increasing or decreasing properties.

The term "patient" as used herein includes any animal, such as a mammal, including a human.                 

The term "anorectal disorder" refers to any disorder associated with anal rectal disease, such as acute or chronic anal laceration, thrombotic internal hemorrhoids or external hemorrhoids, hemorrhoidal disease, endoscopic hemorrhoidal ligation or pain associated with such ligation, muscle spasms , Constipation and other anal rectal disorders caused by hypertension or spasms of the anal sphincter. The term also refers to postoperative pain associated with hemorrhoidectomy or other anorectal surgery resulting in intense anal spasm. The term “anal laceration” is also referred to as “anal fissure” and the spasm of the anal sphincter is also referred to as “post-rectal weight.” The term is also meant to include pain that may be associated with any of the above disorders or conditions.

The terms "signs, symptoms and causes of anal rectal disease" and "signs and symptoms of anal rectal disease" include sphincter hypertension; Anal and rectal ischemia, itching, inflammation, pain or bleeding; Hemorrhoidal tissue with thrombosis affected or prolapsed; Stiffness of the anal big muscles, spasms of the alveolar rectus muscles or anal sphincter; And glandular or ischemic ulcers or fissure-like tracts on the anal canal or on the anal margins.

The term “desirable therapeutic effect” in the treatment of anorectal diseases and conditions includes anal sphincter relaxation; Reduction of anal sphincter pressure; Maintenance of reduced anal sphincter pressure; Reduction or elimination of ischemia, itching, inflammation, pain, bleeding or muscle spasms; Recovery or improvement of anal coronary blood flow; Dilation of blood vessels in the anus and rectum; And partial or complete healing of glandular or ischemic ulcers or crack-like tracts in the anal canal or on the anal margins.                 

In general, the terms “potassium channel opener” and “potassium channel activator” refer to a class of drugs that increase the flow of potassium ions from inside the electrically excited cell to the outside of the cell via the membrane of the cell with one or more potassium channels. Say. Potassium channel opener activity can be observed by measuring hyperpolarization of the cell membrane potential (ie, more negative membrane potential) caused by increased flow of potassium ions from inside the cell to outside the cell via the potassium channel in the cell membrane.

The term "pharmaceutical composition" means a composition suitable for pharmaceutical use in a patient, including an animal or human. Generally, the pharmaceutical composition comprises an effective amount of the active agent and a pharmaceutically acceptable carrier.

The term “pharmaceutically acceptable carrier” refers to any standard pharmaceutical carrier, buffer and excipient such as phosphate buffered saline solution, water and emulsions (eg oil / water or water / oil emulsions) and various types of wetting agents and / or Contains supplements. Suitable pharmaceutical carriers and their preparations are described in REMINGTON'S PHARMACEUTICAL SCIENCES, Mark Publishing Co., Easton, 19th ed. 1995. Preferred pharmaceutical carriers depend on the mode of administration of the active agent. Typical modes of administration are described below.

The term "effective amount" means a dosage sufficient to produce the desired result. Certain outcomes may include objective or subjective improvement in the recipient of that dose.

A “prophylactic treatment” is a treatment that is performed on a patient who shows signs of the disease or only shows early signs of the disease, where the treatment is performed for the purpose of reducing the risk of developing the etiology.                 

A "therapeutic treatment" is a treatment performed on a patient who exhibits signs of etiology, wherein the treatment is performed for the purpose of reducing or eliminating such pathological signs.

The term “appropriate anal region” means any site or tissue or sphincter in the anus that has or has developed an anal disorder or disease, including, for example, external or internal anal sphincter, anal sphincter or external or internal anal canal.

As used herein, the term “NO donor” means any organic or inorganic compound capable of delivering nitric oxide in a physiological setting. Also included are compounds that can be metabolized in vivo to a compound that delivers nitric oxide (eg, a prodrug form of a NO donor, or a bicomponent NO generation system).

Normal

A promising new approach to treating anal disorders is the topical application of nitric oxide (NO) donors to the appropriate anal area. Nitric oxide has been shown to result in a concentration dependent decrease in the resting tension of internal sphincter smooth muscle strips in vitro (Rattan, S. et al., Am J Physiol 262 : G107-112 (1992)), and NO donors (eg, nitro) Glycerin, isosorbide dinitrate, isosorbide mononitrate and L-arginine have been shown to reduce anal pressure in humans (Schouten, WR et al., "Pathophysiological aspects and clinical outcome of intra-anal application of isosorbide dinitrate in patients with chronic anal fussure ", Gut 39: 465-9 (1996); Farid, M., Br J Surg 84: 1 (1997); and Hechtmanb, HB et al . , Arch. Surg 131: 775-778 (1996) ). In addition, NO is expressed in the lower esophageal sphincter (Conklin et al., Gastroenterology 104: 1439-1444 (1993); Tottrup et al., Br J Pharmacol 104: 113-116 (1991)), pyloric sphincter (Bayguinov et al., Am J Physiol 264: G975- 983 (1993)), Audi sphincter (Mourelle et al., Gastroenterology 105: 1299-1305 (1993)), and the cognate sphincter (Ward et al., Br J Pharmacol 105: 776-782 (1992)). It has been shown to mediate relaxation. NO or NO-like substances are thought to act as important regulatory mechanisms for the general phenomenon of gastrointestinal adaptive relaxation.

Despite the initial outlook of NO donors, hypertension was observed in this class of formulation members. Surprisingly, the present invention provides compositions useful for overcoming the side effects and problems associated with existing therapies.

Description of Embodiment

NO donor in combination with the second agent

In one embodiment, the present invention provides a composition for the treatment of anal disorders comprising a nitric oxide donor in combination with a second agent that modulates the level of cAMP or cGMP. In one group of embodiments, the second agent is a phosphodiesterase type V (PDE V) inhibitor. In another group of embodiments, the second agent is a phosphodiesterase type IV (PDE IV) inhibitor. In another group of embodiments, the second agent is a phosphodiesterase type II (PDE II) inhibitor. In another group of embodiments, the second agent is a nonspecific PDE inhibitor. In another group of embodiments, the second agent is a superoxide anion (O ₂ ⁻ ) scavenger. In another group of embodiments, the second agent is a β-adrenergic agonist. In another group of embodiments, the second agent is a cAMP dependent protein kinase activator. In another group of embodiments, the second agent is an α ₁ -adrenergic antagonist. In another group of embodiments, the second agent is an estrogen, estrogen analog or estrogen compound. In another group of embodiments, the second agent is an L-type Ca ²⁺ channel blocker. In another group of embodiments, the second agent is an ATP sensitive K ⁺ channel activator. The present invention also provides a method of using the composition provided above. In a related aspect, the present invention provides a composition comprising a NO donor and a smooth muscle relaxant.

In each of the above embodiments, the nitric oxide donor can be any of a variety of NO donors, including, for example, prodrug forms of organic NO donors, inorganic NO donors, and NO donors. The NO donor preferably comprises one type of organic nitrate (including esters of nitric acid) and may be a cyclic or acyclic compound. For example, suitable NO donors include nitroglycerin (NTG), L-arginine, isosorbide dinitrate (ISDN), isosorbide-2-mononitrate (IS2MN) and / or isosorbide-5- Isosorbide mononitrate (ISMN), erythritol tetranitrate (ETN), pentaerythritol tetranitrate (PETN), ethylene glycol dinitrate, isopropyl, which may include mononitrate (IS5MN) Nitrate, glyceryl-1-monnitrate, glyceryl-1,2-dinitrate, glyceryl-1,3-dinitrate, butane-1,2,4-triol trinitrate, and the like. . More preferably, the NO donor is NTG. Nitroglycerin and other organic nitrates, including ISDN, ETN and PETN, have been approved for treatment in other fields of medicament for human patients. Additional NO donors include sodium nitroprusside, N, O-diacetyl-N-hydroxy-4-chlorobenzenesulfonamide, N ^G -hydroxy-L-arginine (NOHA), hydroxyguanidine sulfate, mol Sidomine, 3-morpholinosidoneimine (SIN-1), (±) -S-nitroso-N-acetylphenicylamine (SNAP), S-nitrosoglutathione (GSNO), (±)-(E ) -Ethyl-2-[(E) -hydroxyimino] -5-nitro-3-hexenamide (FK409), (±) -N-[(E) -4-ethyl-3-[(Z)- Hydroxyimino] -5-nitro-3-hexen-1-yl] -3-pyridinecarboxyamide (FR144420) and 4-hydroxymethyl-3-furoxanecarboxyamide.

In general, organic nitric oxide donors (eg, organic nitrates), when used alone, are present in any amount less than effective for the treatment of anal diseases. In common practice of the invention, the organic nitric oxide donor may be present at a concentration of about 0.01 to about 10 weight percent. All weight percents herein are based on the total weight of the composition. For NTG, preferred concentrations range from about 0.01 to about 5 weight percent.

In one group of embodiments, the compositions of the present invention contain an agent that is a phosphodiesterase (PDE) inhibitor. Inhibitors of phosphodiesterase (PDE) are agents that can block the degradation of cAMP and cGMP in tissues. PDE inhibitors include both non-specific PDE inhibitors and specific PDE inhibitors (which inhibit only a single type of phosphodiesterase if there is an effect on any other type of phosphodiesterase). Another useful PDE inhibitor is a biselective PDE inhibitor (such as a PDE III / IV inhibitor).                 

In a group of embodiments, the PDE inhibitor is a PDE V inhibitor. Useful phosphodiesterase type V inhibitors include japrinast, MBCQ, MY-5445, dipyridamole and sildenifil.

In another group of embodiments, the compositions of the present invention contain an agent that is a phosphodiesterase type II (PDE II) inhibitor. Suitable phosphodiesterase type II inhibitors are EHNAs.

In another group of embodiments, the compositions of the present invention contain an agent that is a phosphodiesterase type IV (PDE IV) inhibitor. Suitable phosphodiesterase type IV inhibitors include ariflo (SB207499), RP73401, Ro-201724, CDP840, rolipram and LAS31025.

In another group of embodiments, the compositions of the present invention contain a formulation which is a biselective phosphodiesterase inhibitor, preferably a PDE III / IV inhibitor such as zardaverine.

In another group of embodiments, the compositions of the present invention contain an agent that is a nonspecific phosphodiesterase (nonspecific PDE) inhibitor. Suitable nonspecific phosphodiesterase inhibitors include IBMX, theophylline, diphylline theobromine, aminophylline, pentoxifylline, papaverine, caffeine and other methyl xanthine and bixanthine derivatives (Goodman & Gilman's "The Pharmacological Basis of Therapeutics". '' The McGraw-Hill Compaies, 1996).

In another group of embodiments, the compositions of the present invention contain a formulation that is a superoxide anion (O ₂ ⁻ ) scavenger. Superoxides can react with NO and can significantly reduce their biological effects. Thus, agents scavenging superoxide anions (eg exogenous Mn- or Cu / Zn superoxide dismutase (SOD) or small molecule SOD analogs such as Mn (III) tetra (4-benzoic acid) porphyrin chloride (MnTBAP) and M40403, Salvemini et al., Science 286 (5438): 304-306 (1999)) can enhance the effect of NO. SOD is a relatively stable enzyme and can be used to promote the local efficacy of NO generated from NTG in topical formulations with NO donors such as, for example, NTG. Nitric oxide formed from NTG acts only locally because of its short half life. However, NTG itself is stable enough to exert systemic effects after mucosal absorption. By enhancing the local efficacy of NTG with SOD or SOD analogs, less NTG is required to produce the same degree of internal anal sphincter relaxation, and less NTG is absorbed, reducing systemic side effects.

In another group of embodiments, the compositions of the present invention contain an agent that is a β-adrenergic agonist, preferably a β ₂ -or β ₃ -adrenergic receptor agonist. Various β-adrenergic agonists are described in the literature and are useful in the present invention. Suitable β ₃ -adrenergic agonists are described, for example, in Bristol et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 33, Chap. 19, pp 193-202, Academic Press (1988). Preferred β-adrenergic agonists include salbutamol, terbutalin, procaterol, clenbuterol, isoproterenol, ginterol, BRL 37344, CL316243, CGP-12177A, GS 332, L-757793, L- 760087, L-764646 and L-766892.

In another group of embodiments, the agent is a cAMP dependent protein kinase activator. Various cyclic nucleotide dependent protein kinase activators are useful in the present invention, including, for example, cAMP analogs and dual cGMP / cAMP dependent protein kinase activators. cAMP analogs are well known to those skilled in the art and include 8-bromo-cAMP, dibutyryl-cAMP, Rp-cAMPS and Sp-cAMPS. Dual activators include Sp-8-pCPT-cGMPS, Sp-8-bromo-cGMPS and 8-CPT-cAMP.

In another group of embodiments, a composition of the present invention comprises an agent that is an estrogen or an estrogen analog or mimetic. As used herein, the term "estrogen" is meant to include all forms of estrogen and estrogen-like compounds, such as those with estrogen-like activity (eg, those that bind to the estrogen receptor in competitive binding assays). It may be steroidal or nonsteroidal (see, eg, Bristol et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 31, Chap. 19, pp 181-190, Academic Press (1996) and references cited therein). Similar compounds include 17-beta-estrodiol, estrone, mestranol, estradiol valerate, estradiol diionate, ethynyl estradiol, quinestrol, estrone sulfate, phytoestrogens such as flavone, Isoflavones (eg, genistein), resveratrol, cumestane derivatives, other synthetic estrogenous compounds, eg G. Anti-parasitic (e.g., p, p'-DDT), plasticizers (e.g., bisphenol A) and various other industrial chemicals (e. G., Poly chlorinated biphenyls), but, not limited to these.

In another group of embodiments, the compositions of the present invention contain an agent that is an α ₁ -adrenergic antagonist. Sympathetic neurotransmitter norepinephrine constricts sphincter smooth muscle via α ₁ -adrenergic receptors. In addition, pharmacological interference of norepinephrine release or binding to α ₁ -adrenergic receptors by administering sympathetic nerve blockers to the appropriate anal region of the patient may lead to anal sphincter relaxation, decreased anal sphincter pressure, maintenance of reduced anal sphincter pressure, anus May result in improvement of signs and symptoms of rectal disorders. Such sympathetic blockers include α ₁ -adrenergic receptor antagonists (eg, Goodman &Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 9th edition, ed. JG Hardman et al., Prazosin, doxazosin, phentolamine, as described in McGraw-Hill 1996, Tolazoline, etc.), α ₂ -adrenergic agonists (eg, clonidine) that block norepinephrine release, nerve endings norepinephrine depleting agents (eg guanetidine, bretillium, reserpin), norepinephrine synthesis inhibitors ( Such as α-methyl tyrosine), and agents that destroy sympathetic nerve endings (eg, 6-hydroxy dopamine). Thus, in related embodiments, the compositions of the invention contain alternative sympathetic nerve blockers, such as α ₂ -adrenergic receptor agonists, nerve endings norepinephrine depleting agents, norepinephrine synthesis inhibitors or other agents that destroy sympathetic nerve endings. do.

In another group of embodiments, the agent is an ATP sensitive K ⁺ channel activator. Along with NO, ATP is thought to act as an inhibitory neurotransmitter released from intestinal non-adrenergic, noncholinergic neurons that mediate adaptive relaxation of gastrointestinal smooth muscle (Burnstock, Pharmacol Rev. 24: 509-81 (1972) ). ATP appears to mainly act by opening up ATP-sensitive potassium (K _ATP ) channels that hyperpolarize the cell membranes, resulting in smooth muscle relaxation by reducing intracellular calcium concentrations. Synthetic compounds that activate ATP sensitive K ⁺ channels are smooth muscle relaxants such as minoxidil, minoxidil sulfate, pinosidyl, diazooxide, levomocalim, chromacalim and the like (White et al., Eur J Pharmacol. 357 (1): 41-51 (1998). ATP sensitive potassium channels are expressed in GI smooth muscle (Koh et al . , Biophys. J. 75: 1793-80 (1998)). Thus, specific potassium channel openers will be useful for relaxing internal anal sphincter smooth muscle, reducing anal sphincter pressure, maintaining reduced anal sphincter pressure, and improving signs and symptoms of anorectal disorders. It should be noted that other K ⁺ channels can also affect smooth muscle tension, including the apamin sensitive low conductivity calcium activated K ⁺ channel and the caribdotoxin sensitive high conductivity calcium activated K ⁺ channel.

In another embodiment, the composition of the present invention comprises a NO donor and a smooth muscle relaxant. Examples of preferred smooth muscle relaxants are hydralazine, papaverine, tyropramide, cyclandelate, isoxsuphyrin or nilidrin.

In another embodiment, a composition of the present invention comprises a NO donor and a second agent which is a methyl xanthine or adenosine receptor antagonist. Preferred second agents are theophylline, diphylline, aminophylline, caffeine and theobromine.

In a preferred embodiment, the second agent is a K ⁺ ATP channel opener, an adenosine receptor antagonist or β ₂ -adrenergic receptor agonist. In another embodiment, the second agent is preferably selected from the group consisting of theophylline, diphylline, minoxidil, diazooxide, terbutalin and salbutamol.

Phosphodiesterase inhibitor compositions

In another embodiment, the present invention is directed to phosphodiesterase inhibitors, preferably PED II inhibitors, PDE IV inhibitors or PDE V inhibitors alone, or β-adrenergic receptor agonists, α ₁ -adrenergic antagonists, estrogens, Provided is a composition for treating anorectal disorders comprising a pharmaceutically acceptable carrier in combination with an L-type Ca ²⁺ channel blocker, an ATP sensitive K ⁺ channel activator or a smooth muscle relaxant. In another embodiment, the compositions of the present invention comprise a biselective PDE inhibitor (eg, a PDE III / IV inhibitor, eg, zardaverin). The present invention also provides a method of using such a composition.

Phosphodiesterase inhibitors (PDE inhibitors) are agents that can block the degradation of cAMP and cGMP in tissues. PDE inhibitors include nonspecific PDE inhibitors and specific PDE inhibitors. Non-specific PDE inhibitors inhibit one or more phosphodiesterases, while specific PDE inhibitors have very little effect on any other type of phosphodiesterase, even though there is little to no single type of phosphodiesterase Only inhibits. Specific inhibitors of the five cyclic nucleotide PDE isoenzyme classes have been characterized: 8-methoxymethyl-IBMX (isobutyl methylxanthine) or vinpocetin (Ca ²⁺ , calmodulin dependent PDE type I); EHNA (erythro-9- (2-hydroxy-3-nonyl) adenine HCl) (cGMP stimulated PDE type II); Milon (cGMP inhibited PDE type III); Rolipram (cAMP specific PDE type IV); And japrinast and DMPPO (1,3-dimethyl-6- (2-propoxy-5-methane sulfonylamidophenyl) pyrazolo- [3,4-d] pyrimidin-4- (5H) -one (cGMP specific PDE Form V). Current knowledge suggests that there are more than nine classes of PDE isoenzymes with recently discovered type 9A (see Fisher et al. , J Biol. Chem. 273 (25): 15559-15564 (1998)). Examples of agents that are non-specific inhibitors of PDE include IBMX, theophylline, aminophylline, theobromine, depilin caffeine, and the like (see Vemupalli et al., J Cardiovasc. Pharmacol 28 (6): 862-9 (1996)).

Preferably, the composition for treating anorectal disorders contains at least one compound selected from the class of PDE II, PDE IV and PDE V inhibitors or dual PDE III / IV inhibitors in preparations suitable for topical treatment. Members of each of these classes are β-adrenergic receptor agonists, preferably β ₂ -or β ₃ -adrenergic receptor agonists, α ₁ -adrenergic antagonists, type L Ca ²⁺ channel blockers, estrogens, ATP sensitive K It is advantageous to combine with a second agent selected from a ⁺ channel activator, a sympathetic nerve terminal disruptor, an adenosine receptor antagonist, methylxanthine or smooth muscle relaxant. Preferred members from each class of additional agents are those described above for use with NO donors.

In embodiments comprising a second active agent in combination with PDE, the second agent is preferably a K ⁺ ATP channel opener, an adenosine receptor antagonist or a β ₂ -adrenergic receptor agonist. In another embodiment, the preferred second agent is a compound selected from the group consisting of theophylline, diphylline, minoxidil, diazooxide, terbutalin and salbutamol.

β-adrenergic receptor antagonist compositions

In another embodiment, the present invention is directed to a β-adrenergic receptor agonist, preferably a β ₂ -or β ₃ -adrenergic receptor agonist alone, or a cAMP hydrolytic PDE inhibitor (eg, a PDE IV inhibitor), nonspecific Anal rectum comprising in combination with a PDE inhibitor, α ₁ -adrenergic antagonist, estrogen, L-type Ca ²⁺ channel blocker, ATP-sensitive K ⁺ channel activator or smooth muscle relaxant, and a pharmaceutically acceptable carrier Provided are pharmaceutical compositions for the treatment of disorders. The present invention also provides a method of using such a composition.

In this aspect of the invention, the β-adrenergic receptor agonist may be essentially any of the β-adrenergic receptor agonists provided above for use in combination with a NO donor. The β-adrenergic agonist is preferably a β ₂ -or β ₃ -adrenergic receptor agonist. Particularly preferred β-adrenergic agonists are those described in Bristol et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 33, Chap. 19, pp 193-202, Academic Press (1998), or salbutamol, ter Butalin, procaterol, clenbuterol, isoproterenol, ginterol, BRL 37344, CL316243, CGP-12177A, GS 332, L-757793, L-760087, L-764646 and L-766892.

Terbutalin and salbutamol (albuterol) are β ₂ -adrenergic agonists commonly used for long-term treatment of obstructive airway disease and acute bronchial spasms of asthma. Beta-adrenergic agents, such as VIP, strongly relax smooth muscles including IAS smooth muscle by raising intracellular cyclic AMP levels (Parks et al., Gut 10 (8): 674-7 (1969); Chakder, S. et al. , Amer J Physiol. 264 (1 pt 1): G7-12, (1993); Chakder, S. et al., Amer J Physiol. 264 (4 pt 1): G702-7, (1993); O'Kelly, TJ Gut 34 (5): 689-93, (1993); O'Kelly, TJ et al., Br J Surg 80 (10): 1337-41, (1993)). Cyclic AMPs induce smooth muscle relaxation through phosphorylation of smooth muscle regulatory proteins (eg, myosin optical chain kinase) and by decreasing intracellular calcium concentrations (eg, by K ⁺ -ATP channel activation). Terbutalin and salbutamol have a weaker cardiovascular effect than nonspecific β-receptor agonists such as isoproterenol because they do not stimulate cardia β ₁ -adrenergic receptors at therapeutic doses. to be. They are usually administered inhaled topically. Resistance is a potential side effect of β ₂ -adrenergic agonists. Long-term systemic administration of β-adrenergic agonists leads to downregulation and reduced pharmacological response of β receptors in some tissues and has been described as asthmatic patients (Goodman &Gilman's"The Pharmacological Basis of Therapeutics" 9th edition. , Catecholamines, Sympathornimetic Drugs and Adrenergic Receptor Antagonists.Brian B. Hoffman and Robert J. Lefkowitz, 1996).

In one group of embodiments, the compositions of the present invention comprise forskolin. Forskolin avoids resistance by directly activating adenyl cyclase.

In one group of embodiments, the compositions of the present invention contain suitable β-adrenergic receptor agonists and pharmaceutically acceptable carriers, preferably those formulated for topical delivery to the site of anorectal disease or disorder.

In another group of embodiments, the compositions of the present invention comprise cAMP hydrolyzed PDE inhibitors (eg, PDE IV inhibitors), nonspecific PDE inhibitors, α ₁ -adrenergic antagonists, adenosine receptor antagonists such as methyl xanthine, estrogens, Other agents selected from L-type Ca ²⁺ channel blockers, ATP sensitive K ⁺ channel activators or smooth muscle relaxants.

In one preferred group of embodiments, the agent is a cAMP hydrolytic PDE inhibitor, more preferably a phosphodiesterase type IV inhibitor. Preferred phosphodiesterase type IV inhibitors (also called PDE IV and PDE4) inhibitors are described, for example, in Bristol et al., Annual Reports in Medicinal Chemistry, Vol. 33, Chap. 10, pp 91-109, Academic Press (1998). )). Most preferably the PDE IV inhibitor is rolipram, Ro 20-1724 or etazolate.                 

In another group of preferred embodiments, the agent is a nonspecific PDE inhibitor such as, for example, IBMX, aminophylline, theophylline, pentoxifylline, theobromine, diphylline, lysophylline and papaverine.

In another preferred embodiment, the agent is an α ₁ -adrenergic antagonist. Suitable α ₁ -adrenergic receptor antagonists (eg prazosin, doxazosin, phentolamine, tolazoline, etc.) are described in Goodman &Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 9th edition, ed. JG Hardman et al., McGraw-Hill (1996). It is described in. Preferred agents for use in such compositions are selected from prazosin, doxazosin, phentolamine, tolazoline and derivatives thereof.

In another preferred embodiment, the β-adrenergic receptor agonist is an L-type Ca ²⁺ channel blocker such as nifedipine, nimodipine, pelopidine, nicardipine, isradinine, amlodipine, diltiazem, menthol, Finavarium bromide (gastrointestinal selective calcium channel blocker; Awad RA et al . , Acta Gastroent. Latinoamer. 27: 247-251, 1997) and verapamil.

In another preferred embodiment, the β-adrenergic receptor agonist is combined with an ATP sensitive K ⁺ channel activator. Preferred agents in this group are as described above for use with NO donors.

Further compositions are those wherein the β-adrenerine is combined with an estrogen or an estrogen-like compound, or a smooth muscle relaxant. Suitable compounds in each of these classes are as described above for use with NO donors.

In embodiments comprising a second active agent in combination with a β ₂ -adrenergic receptor antagonist, the second agent is preferably a K ⁺ ATP channel opener or an adenosine receptor antagonist. In another embodiment, the preferred second agent is a compound selected from the group consisting of theophylline, diphylline, minoxidil, and diazooxide.

Potassium Channel Activator Composition

In another embodiment, the present invention provides an ATP sensitive K ⁺ channel activator alone, or a cAMP dependent protein kinase activator, estrogen, α ₁ -adrenergic antagonist, L type Ca ²⁺ channel blocker, sympathetic nerve terminal disruptor or It provides a composition for the treatment of anorectal disorders comprising a combination with other agents selected from smooth muscle relaxants, and pharmaceutically acceptable carriers. The present invention also provides a method of using such a composition.

In this aspect of the invention, the selected combination is prepared from the components described in detail above for the NO donor composition. Further description of ATP sensitive potassium ion channel activators can be found, for example, in Bristol et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 29, Chap. 8, pp 73-82, Academic Press (1991). . In a preferred embodiment, the potassium ion channel activator is diazotoxide, minoxidil, PCO 400, pinosidyl, levomocalin or chromocalin.

In some embodiments, the compositions of the present invention comprise additional agents that are cAMP dependent protein kinase activators, estrogens or estrogen-like compounds, α ₁ -adrenergic antagonists, type L Ca ²⁺ channel blockers, sympathetic nerve terminal disruptors or smooth muscle relaxants. Include. The cAMP dependent protein kinase activator is preferably a cAMP analog or a dual cGMP / cAMP dependent protein kinase activator. cAMP analogs are 8-bromo-cAMP, dibutyryl-cAMP, Rp-cAMPS or Sp-cAMPS, dual activators are Sp-8-pCPT-cGMPS, Sp-8-bromo-cGMPS and 8-CPT- More preferably, it is selected from cAMP.

In a group of embodiments, the α ₁ -adrenergic antagonist is combined with an ATP sensitive potassium ion channel activator. Preferably, the α ₁ -adrenergic antagonist is prazosin, phentolamine or tolazoline.

In another group of embodiments, the L-type Ca ²⁺ channel blocker is combined with an ATP sensitive potassium ion channel activator. L-type Ca ²⁺ channel blockers include nifedipine, nimodipine, pelopidine, nicardipine, isradipine, amlodipine, diltiazem, menthol, pinavarium bromide (gastrointestinal selective channel blockers; Awad RA et al . , Acta Gastroent.Latinoamer. 27: 247-251, 1997) or verapamil.

Diazooxide and minoxidil have been used to treat high blood pressure. These drugs are vasodilators that hyperpolarize arterial smooth muscle cells by activating ATP sensitive K ⁺ channels (Meisheri et al., J Pharmacol Exp Ther 245 (3): 751-60 (1988); Standen et al., Science 245: 177-80 ( 1989). Membrane hyperpolarization inactivates voltage-gated calcium channels, reduces intracellular calcium concentrations, and causes muscle relaxation. ATP released by NANC nerve stimulation is believed to relax IAS through this mechanism (Brookes J Gastroenterol Heaptol 8 (6): 590-603 (1993); Rae et al., J Physiol (London) 493 (Pt 2)). 517-27 (1996). (Baird and Muir, Br J Pharmacol 100 (2) 329-35 (1990)) describe that karmakalim, or K ⁺ -ATP channel opener, inhibits microwave release, hyperpolarizes the membrane, and relaxes guinea pig IAS. have. In our study, diazooxide and minoxidil relaxed rat IAS in vivo. The adverse effects of these drugs are predictable and can be divided into three main categories: 1) fluid and salt retention, 2) cardiovascular effects, and 3) hirsutism. Topical minoxidil developed by hirsutism side effects are commercially available to stimulate hair growth. This product has an excellent safety record and is sold at retail stores.

In another group of embodiments, the smooth muscle relaxant is combined with an ATP sensitive potassium ion channel activator. Smooth muscle relaxers are preferably hydralazine, papaverine, tyropramide, cyclandelate, isoxsuprine or nilidrin.

In an embodiment comprising a second active agent in combination with a K ⁺ ATP channel opener, the second agent is preferably a K ⁺ ATP channel opener, a β ₂ -adrenergic receptor agonist or an adenosine receptor antagonist. In another embodiment, the second preferred agent is a compound selected from the group consisting of theophylline, diphylline, terbutaline and salbutamol.

α _One Adrenergic antagonist compositions

In another embodiment, the present invention relates to an α ₁ -adrenergic antagonist alone or to other agents selected from cAMP hydrolytic PDE inhibitors (preferably PDE IV inhibitors), estrogens, sympathetic nerve terminal disruptors or smooth muscle relaxants, and It provides a composition for the treatment of anal rectal disorders comprising a combination with a pharmaceutically acceptable carrier. The present invention also provides a method of using such a composition.

Α ₁ -adrenergic antagonists useful in this aspect of the invention can be found, for example, in Goodman &Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 9th edition, ed. JG Hardman et al., McGraw-Hill (1996). . Preferred α ₁ -adrenergic antagonists are prazosin, phentolamine and tolazoline.

For these embodiments where the α ₁ -adrenergic antagonist is combined with a cAMP hydrolyzed PDE inhibitor (preferably PDE IV inhibitor), an estrogen or estrogen-like compound, a sympathetic nerve terminal disruptor or a smooth muscle relaxant, the preferred member of each class is NO Those described above for use with a donor.

In embodiments containing the second active agent in combination with an α ₁ -adrenergic antagonist, the second agent is preferably a K ⁺ ATP channel opener, a β ² -adrenergic receptor agonist or an adenosine receptor antagonist. In another embodiment, the preferred second agent is a compound selected from the group consisting of theophylline diphylline, minoxidil, diazooxide, terbutalin and salbutamol.

Cyclic Nucleotide-Dependent Protein Kinase Activator Compositions

In another aspect, the present invention provides a pharmaceutical composition for the treatment of anorectal disorders comprising a cyclic nucleotide dependent protein kinase activator alone or in combination with other agents. Also provided are methods of use of such compositions. In a group of embodiments, cGMP dependent protein kinase activators are used alone. In another group of embodiments, nonspecific cyclic nucleotide dependent protein activators are used alone. In another group of embodiments, the nonspecific cyclic nucleotide dependent protein kinase activator is used in combination with a smooth muscle relaxant. In another embodiment, the cAMP dependent protein kinase activator is provided in combination with an L-type Ca ²⁺ channel blocker.

In an embodiment comprising a second active agent in combination with a protein kinase activator, the second agent is preferably a K ⁺ ATP channel opener, a β ₂ -adrenergic receptor agonist or an adenosine receptor antagonist. In another embodiment, the preferred second agent is a compound selected from the group consisting of theophylline, diphylline, terbutalin, minoxidil, diazooxide and salbutamol.

In each case, preferred members of the listed classes of compounds are those described above for use alone or in other combinations.

Estrogen and Estrogen Analogue Compositions

In another aspect, the present invention provides a pharmaceutical composition for treating anorectal disorders comprising estrogens or estrogen analogs alone or in combination with other agents from any of the classes of agents described above. Estrogen-like compounds include 17-beta-estrodiol, estrone, mestranol, estradiol valerate, estradiol diionate, ethynyl estradiol, quinestol, estrone sulfate, phytoestrogens such as flavone, Isoflavones (e.g. Genistein), resveratrol, cumestane derivatives, other synthetic estrogenic compounds such as insect repellents (e.g. p, p'-DDT), plasticizers (e.g. bisphenol A) and various other industrial chemicals ( Polychlorinated bisphenols, for example, but are not limited to these (Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 9th ed. JG Hardman et al., McGraw-Hill (1996)). Preferred agents are selected from those described with reference to the compositions of the single agents or combinations above. Also provided are methods of use of such compositions.

In embodiments comprising a second active agent in combination with an estrogen agent, the second agent is preferably a K ⁺ ATP channel opener, a β ₂ -adrenergic receptor agonist or an adenosine receptor antagonist. In another embodiment, the preferred second agent is a compound selected from the group consisting of theophylline, diphylline, terbutalin, minoxidil, diazooxide and salbutamol.

Sympathetic nerve ending destroyer composition

In another aspect, the present invention provides a pharmaceutical composition for anorectal disorders comprising sympathetic nerve endings alone or in combination with other agents from any of the classes of agents described above. Sympathetic terminal disruptor compounds include, but are not limited to, 6-hydroxydopamine and analogs thereof (see Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 9th ed. JG Hardman et al., McGraw-Hill (1996)). Preferred formulations are selected from those described with reference to the compositions of a single formulation or a combination thereof. Also provided are methods of use of such compositions.

Adenosine Receptor Antagonists / Methylxanthine

In another aspect, the present invention provides a pharmaceutical composition for treating anorectal disorders comprising the adenosine receptor antagonist, alone or in combination with other agents from any of the aforementioned classes of agents. Examples of adenosine receptor antagonists are theophylline and diphylline (see Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 9th ed. JG Hardman et al., McGraw-Hill (1996)). Preferred formulations are selected from those described with reference to the compositions of a single formulation or a combination thereof. Also provided are methods of use of such compositions.

Theophylline, or plant derived methylxanthine, has been used for the treatment of bronchial asthma for decades. Theophylline relaxes convulsive material experimentally, or smooth muscles, notably bronchial muscles, which contract clinically in asthma. We have found that theophylline relaxes rat IAS when injected into the distal anal canal. The proposed mechanisms of methylxanthine-induced physiological and pharmacological effects include 1) increased intracellular cyclic AMP by inhibition of phosphodiesterases, 2) direct effects on intracellular calcium concentrations, and 3) cell membrane hyperpolarization. Indirect effects on intracellular calcium concentration, 4) decoupling of intracellular calcium increments and muscle contractile elements, and 5) antagonistic action of adenosine receptors. Adenosine receptor antagonism is thought to be the most important factor responsible for most of the pharmacological effects of methylxanthine at therapeutically administered doses (Goodman & Gilman's "The Pharmacological Basis of Therapeutics" 9th ed. Drugs Used in the Treatment of Asthma.William E. Serafin, 1996).

We found in the test also depilin, a related compound that reduces IASP. Since depilin is not metabolized by the liver and is secreted unchanged by the kidneys, its pharmacodynamics and plasma levels are factors that affect liver enzymes such as smoking, age, congestive heart failure or other effects on liver function. It is irrelevant to the use of the drug.

In an embodiment comprising a second active agent in combination with an adenosine receptor antagonist, the second agent is preferably a K ⁺ ATP channel opener or a β ₂ -adrenergic receptor agonist. In another embodiment, the preferred second agent is a compound selected from the group consisting of theophylline, diphylline, terbutalin, minoxidil, diazooxide and salbutamol.

Preparations for the Treatment of Anal Rectal Disorders

Many individual components of the compositions have been described with regard to their use for various disease states. However, certain classes and combinations of classes have now been found useful for the treatment of rectal diseases, and formulations best suited for delivery to the appropriate anal region can be provided. Preferred preparations are those in which the components are combined into topical preparations for topical application to the external or internal anal, external or internal anal sphincter, anal sphincter, external or internal anal canal and lower rectum above the anal canal.

Thus, typically, each of the above provided compositions is prepared by the preparations described (eg, NO donors, β ₂ -or β ₃ -adrenergic receptor agonists, cAMP hydrolytic PDE inhibitors, nonspecific PDE inhibitors, α ₁ -adrenergic receptors). Antagonists, L-type Ca ²⁺ channel blockers, ATP sensitive K ⁺ channel activators, adenosine receptor antagonists, etc.).

Those skilled in the art will appreciate that the preparations depend on the form of delivery desired to be employed and all such forms are contemplated herein. In addition, in some embodiments, a combination of agents is used as a single preparation, while in other embodiments, the agents are formulated separately, but administered in combination or continuously. In the discussion below, it should be understood that a composition of a single agent also includes a composition of two or more agents. In addition, different formulations may be used in embodiments in which the formulations are administered separately or sequentially by different routes.

Topical composition

In view of the above, the present invention provides topical compositions useful for the treatment of anal rectal disorders (including hypertension and / or spasms of the internal anal sphincter, including hemorrhoidal pain) and for the treatment of spasms in mammals, including humans. This includes an effective amount of an agent that reduces contraction of the anal sphincter, or maintains a reduced contraction of the anal sphincter, and a pharmaceutically acceptable carrier. In one embodiment, the agent is an ATP sensitive potassium channel opener. In another embodiment, the agent is a phosphodiesterase inhibitor, a cyclic nucleotide analogue, β-adrenergic agonist, estrogen or estrogen-like compound, α ₁ -adrenergic antagonist or potassium channel opener.

In a related embodiment, the present invention provides a topical pharmaceutical composition in unit dosage form comprising an amount of the agent or combination provided above, per unit dosage form, effective for the treatment of an anal disorder in a patient in need thereof. Typically, the agent is combined with a pharmaceutically acceptable carrier. Such compositions are useful for treating or reducing pain associated with anal disorders, such as hemorrhoidal pain, and for spasm and / or strain hypertension of the sphincter muscles, including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, Audi sphincter, and colonic sphincter. It is useful to treat. In addition, the topical composition may be a condition resulting from spasm of the sphincter of the rectum and / or hypertension, including anal laceration, postoperative rectal pain, hypertrophic pyloric stenosis and pancreatitis, as well as jenker diverticula, incomfort, esophageal spasms (nutcracker esophagus). ) Is useful for treating conditions resulting from general spasms of the gastrointestinal tract muscles, including irritable bowel disease and Hirschsprung disease (intestinal obstruction). In addition, the topical compositions can be used for, before, during and during procedures such as relaxation of the anal sphincter, reduction of anal sphincter pressure or maintenance of reduced anal sphincter pressure and examination of the anus, rectum and lower gastrointestinal system, insertion of instruments and colonoscopy, bladder and surgery, and It is useful for reducing pain and discomfort afterwards.

Formulation

Topical administration

Formulations for topical administration of anal sphincter relaxants of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, suppositories, and liposome preparations. The formulations may be formulated with a tacky polymer for sustained release of the active ingredient (s) in the anal mucosa. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants as necessary. Topical formulations can be prepared by combining anal sphincter relaxants with conventional pharmaceutical diluents and carriers commonly used in topical desiccants, liquids, creams, and aerosol formulations. Ointments and creams can be prepared, for example, with an aqueous or oily base with the addition of suitable thickening and gelling agents. Such substrates include water and / or oils such as liquid paraffin or vegetable oils such as peanut oil or castor oil. Thickeners that can be used depending on the nature of the substrate include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, beeswax and the like. The lotion may be prepared with an aqueous base or an oily base, and may generally contain one or more of stabilizers, emulsifiers, dispersants, suspending agents, thickening agents, coloring agents, flavoring agents, and the like. The powder may be formed with the aid of any suitable powder substrate, such as talc, lactose, starch and the like. Drops may also be formulated with an aqueous or non-aqueous base, including one or more dispersants, suspending agents, solubilizing agents, and the like.

Ointments, pastes, creams and gels may also contain excipients such as animal fats and vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide or mixtures thereof. It may contain. Powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials. The spray may further contain commercial propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Representative compositions include one or more of the following first pharmacological agents in combination with a pharmaceutically acceptable carrier: NO donor, phosphodiesterase inhibitor, cyclic nucleotide analogue, β-adrenergic agonist, type L calcium channel blocker , α-adrenergic antagonists, ATP sensitive potassium channel activators, sympathetic terminal disruptors, estrogens or estrogen-like compounds or botulinum toxins; And one or more of the following second pharmacological agents: local anesthetics (eg, lidocaine, prilocaine, etc.), topical anti-inflammatory agents (eg, naproxen, pramoxicam, etc.), corticosteroids (eg, cortisone, hydrocortisone, etc.) Peripheral sensory neurons, including anti-itch agents (eg, loperamide diphenyleneoxalate, etc.), divalent and trivalent metal ions (eg, manganese, calcium, strontium, nickel, lanthanum, cerium, zinc, etc.) Preparations that interfere with the activation of, analgesic, yeast-based products (eg, lyophilized yeast, yeast extracts, etc.), growth promoting and / or wound healing promoters known to promote re-epithelialization (eg, platelet-induced growth factor, PDGF) , Interleukin-11 (IL-11), etc.), antimicrobial agents (e.g. neosporin, polymyxin B sulfate, bacitracin zinc, etc.), adhesives (e.g., cellulose derivatives, etc.), cytoprotective agents (e.g., colloidal bismuth, Miso Stall, and the like; reference sucralfate was also negative) (GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, supra), it comprises a topical composition comprising an agent which promotes the local tissue sclerosis (e.g., alum) or menthol. Typically, the first pharmacological agent is present in the composition in unit dosage form effective to treat the first medical condition (s) such as anal disease or pain associated with anal disease. Typically, the second pharmacological agent is in unit dosage form effective for the second medical condition (s), or for the condition (s), symptom (s) or effect (s) associated with or resulting from the first medical condition (s). Present in the composition.

In one embodiment, the present invention provides a composition for the treatment of anorectal disorders comprising an active agent and a pharmaceutically acceptable carrier. The active agent stimulates an increase in cGMP or cAMP, cyclic nucleotide analogues, PDE inhibitors, α-adrenergic receptor antagonists or β-adrenergic receptor agonists, or potassium channel openers, respectively, through activation of guanylyl or adenylyl cyclases, respectively. Or triggering agents. In one embodiment, the active agent is present in the composition of the present invention in an amount from about 0.001% to about 15% by weight of the composition. In another embodiment, the active agent is present in about 0.01% to about 7.5%, more preferably about 0.05% to about 2% by weight of the composition.

For example, in one group of embodiments, the present invention provides a composition for treating anorectal disorders comprising a pharmaceutically acceptable carrier and sildenafil in an amount from about 0.001% to about 15% by weight. In another aspect, a composition is provided comprising a pharmaceutically acceptable carrier and sildenafil in an amount from about 0.01% to about 7.5% or from about 0.05% to about 2% by weight.

In addition, the topical pharmaceutical composition may comprise one or more preservatives or bacteriostatic agents such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride and the like. In addition, the topical pharmaceutical compositions may contain other active ingredients such as antimicrobial agents, in particular antibiotics, anesthetics, analgesics and antitussives.

Examples of topical preparations include 75% (w / w) white kerosene (US Pharmacopoeia), 4% (w / w) paraffin wax (US Pharmacopoeia) / NF, lanolin 14% (w / w), 2% sorbitan sesquiole Eight NF, 4% propylene glycol (US Pharmacopoeia) and 1% anal sphincter relaxant.

The dosage of specific anal sphincter relaxants can be determined by a number of factors well known to those skilled in the art, for example, certain agents; The condition to be treated; Age, weight and clinical condition of the recipient patient; And the experience and judgment of the clinician or physician performing the treatment. An effective amount of the composition is to provide an objective alleviation of symptoms or a subjectively identifiable improvement as recorded by a clinician or other validated observer. The dosage range depends on the compound used, the route of administration and the efficacy of the particular compound.

Transmucosal (ie sublingual, intestinal, colon, lung, buccal and vaginal) drug delivery provides efficient entry of active substances into the systemic circulation and reduces immediate metabolism by liver and barrier bacterial flora (Chien YW, NOVEL DRUG DELIVERY) See SYSTEMS, Chapter 4 "Mucosal Drug Delivery", Marcel Dekker, Inc. (1992). Typically, transmucosal drug formulations (e.g. tablets, suppositories, ointments, gels, pessaries, membranes and powders) maintain contact with the mucous membranes and disintegrate and / or dissolve quickly for immediate local and systemic absorption. do. Such preparations are used in conjunction with the anti-inflammatory agents of the invention to reduce or eliminate inflammation of the transmucosal membranes.

To improve transmucosal absorption efficiency and bioavailability of the active agent, selected tacky polymers or doses can be used. For example, selected potassium channel openers, such as minoxidil, can be formulated as liquid suppositories, adhesive polymers such as polyvinylpyrrolidone (PVP, BASF, Germany), polycarbophil (Goodrich, USA). ) Or sodium alginate (Hayashi Pure Chemicals, Tokyo, Japan). Liquid suppositories of this type have a gelation temperature of 30 to 36 ° C. and an adhesion of 430 to 5800 dyne / cm. As a result, suppositories are easy to add liquid at room temperature, gel at physiological temperature, and maintain adhesion to the anal mucosa for a prolonged time (Rye JM et al., Journal of Controlled Release , 59: 163-172, 1999; Chem Pharm Bull , 46 (2): 309-313, 1998; J Pharm Sci , 81 (11): 1119-1125, 1992; Chem Pharm Bull , 37 (3): 766-770, 1989; J Pharmacobiodyn , 9 ( 6): 526-531, 1986; J Pharm Sci . 84 (1): 15-20, 1995).

Preferred preparations are solutions or semisolid preparations (gels, ointments, suspensions, lotions, creams and the like). Depending on the formulation, suitable excipients include petrolatum, lanolin, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, glycerin, glycols, oils, glycerol, benzoates, parabens and surfactants. It will be apparent to those skilled in the art that the solubility of a particular compound is determined in part depending on how the compound is formulated. Aqueous gel formulations are suitable for soluble compounds. If the compound is insoluble at the concentration required for activity, cream or ointment preparations are usually preferred. In this case, an oil phase, an aqueous phase / organic phase and a surfactant may be necessary to prepare the preparation. Thus, based on solubility and excipient-active agent interaction information, formulations can be designed and excipients can be selected to prepare prototype formulations. Particularly preferred formulations are those in suppository or sustained release format.

Sustained or controlled release formulations

In another embodiment, the present invention provides one or more anal sphincter relaxers, including the nitric oxide donors (eg, nitroglycerin, isosorbide dinitrate and L-arginine), or the pharmacological agents described above, for the treatment of anal rectal disorders. Topical sustained release and delayed pharmaceutical compositions comprising an agent and a pharmaceutically acceptable carrier are provided. The compositions of the present invention are useful in the treatment of such disorders as reducing anal sphincter pressure, maintaining reduced anal sphincter pressure, and in controlling and reducing pain associated with such disorders. Such compositions may include unit dosage forms of one or more active agents (eg, nitric oxide donors) that are effective in treating and alleviating pain associated with anal disorders. The compositions of the invention are preferably administered in unit dosage form to patients in need of such treatment. In another embodiment, the compositions of the present invention contain less than an effective amount when used alone, but in an effective amount when used in combination with a second agent that modulates the level of cAMP or cGMP in a patient. Typically, topical sustained release and delayed compositions comprise 1) a hydrophilic based absorbent; 2) hydrophobic based absorbents; And 3) coated beads containing absorbent substrate dispersed in a suitable vehicle. Also provided is a method of treating an anal or gastrointestinal disorder comprising administering an effective amount of such a composition (eg, in unit dosage form) to an appropriate anal region of a patient in need thereof.

Such hydrophobic compositions and formulations of the present invention may be made of nitric oxide donors (or other suitable agents or combinations of agents) and polymers such as cellulose (methyl cellulose, ethyl cellulose, hydroxy propyl cellulose, etc.), high molecular weight polyethylene glycols, methacrylic acid- Nitric oxide donors are coupled to the polymer, including acrylic acid emulsions, hydrogels, carbopol, ethyl vinyl acetate copolymers or polyesters, and the like. The nitric oxide donor-polymer substrate or agent-polymer substrate is then dispersed in a hydrophilic vehicle to form a semisolid. After administering such a hydrophilic composition to a suitable anal area, such as the anal canal or anal sphincter, the polymer matrix with water adsorbed in the semisolid formulation and having the active ingredient-nitric oxide or other formulation-is applied as a coating to the anal region or site where it is applied. Remaining. Nitrogen oxide is then slowly released from this coating.

The hydrophobic compositions and formulations of the present invention use polymers similar to those used in hydrophilic formulations, but the polymer / nitric oxide donor substrate is dispersed in a hydrophobic composition and formulation in a vehicle such as a plastibase. Plastibase is a mineral oil base that only partially dissolves the nitric oxide donor. The semisolid composition forms a thin coating on the anal area where the composition is applied and slowly releases the active agent. The delaying action is in principle controlled by the solubility of the active ingredient (nitric oxide donor) in the vehicle.

The present invention also provides coated beads produced by first absorbing a nitric oxide donor or other agent or combination of agents on a cellulosic material mixed with polyethylene glycol, fillers, binders and other excipients. The resulting substrate is then extruded and embodied (eg, a process for making spheres) to produce small beads. The beads are then coated to a suitable thickness with a suitable material, such as methacrylic acid-acrylic acid polymer, polyurethane, ethyl vinyl acetate copolymer, polyester, silicone, and the like. The coating on the beads serves as a rate controlling membrane that controls the release of the formulation from the core beads.

Oral preparations

In another embodiment, the invention is directed to oral administration provided in unit dosage form, comprising a phosphodiesterase inhibitor, a cyclic nucleotide analog or β-adrenergic agonist, and a pharmaceutically acceptable carrier, per unit dosage form. Provide suitable pharmaceutical compositions. Such compositions are useful for treating anorectal disorders, including the disorders and conditions provided above.

For delivery to the buccal membrane, oral preparations are commonly used, such as lozenges, tablets or capsules. Methods for preparing such preparations include, but are not limited to, methods of adding pharmacological agents to preprepared tablets; Inert fillers, binders and pharmacological preparations or methods of cold compression of materials containing the preparations (as described in US Pat. No. 4,806,356); And encapsulation methods are known in the art. Another oral preparation is one that can be applied to oral mucosa with an adhesive such as cellulose derivative, hydroxypropyl cellulose, as described, for example, in US Pat. No. 4,940,587. The buccal adhesive composition is capable of controlled release of the pharmacological agent into the mouth and through the buccal mucosa when applied to the buccal mucosa. In addition, the anti-inflammatory agents of the present invention may be incorporated into such preparations.

Aerosol preparations

For delivery to the nasal or bronchial membranes, aerosol compositions are typically used. The term “aerosol” includes a phase in which any gas of the pharmacological agent can be inhaled into the bronchus or nasal passages. Specifically, aerosols comprise gaseous suspensions of droplets of the compounds of the invention, which can be produced in metered dose inhalers or nebulizers, or in mist nebulizers. Aerosols also include a dry powder composition of a compound of pharmacological agent suspended in air or other carrier gas, which may be delivered, for example, by aeration from an inhaler device. For solutions used to make aerosols, the preferred range of concentration of the pharmacological agent is 0.1 to 100 mg / ml, more preferably 0.1 to 30 mg / ml, most preferably 1 to 10 mg / ml. Typically, the solution is buffered with a pharmacologically compatible buffer such as phosphate or bicarbonate. Typical pH ranges are 5 to 9, preferably 6.5 to 7.8, more preferably 7.0 to 7.6. Typically, sodium chloride is added to adjust the osmolarity concentration within the physiological range, preferably within 10% of isotonicity. Preparation of such solutions for producing aerosol inhalers is discussed in Remington's Pharmaceutical Sciences and also described in Ganderton and Jones, DRUG DELIVERY TO THE RESPIRATORY TRACT, Ellis Horwood 91987; Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems 6: 273-313; And Raeburn et al., (1992) J Pharmacol Toxicol Methods 27: 143-159.

Solutions of pharmacological agents can be converted to aerosols by any of the known means commonly used to prepare aerosol inhalants. In general, such a method typically involves pressurizing a container of the solution in an inert carrier gas or providing a pressurizing means and passing the pressurized gas through a small orifice to the mouth and trachea of the animal to which the drug is administered. Pushing the droplets. Typically, the mouthpiece is mounted at the exit of the orifice to facilitate delivery to the mouth and trachea.

Parenteral preparations

In another embodiment, the invention provides a parenteral form in a unit dosage form comprising a phosphodiesterase inhibitor, a cyclic nucleotide analogue or β-adrenergic agonist, and a pharmaceutically acceptable carrier per unit dosage form. Provided are pharmaceutical compositions suitable for administration. Such compositions are useful for treating anorectal disorders and conditions as described above.                 

How to treat anal rectal disorders

In another aspect, the invention comprises administering an effective amount of any of the compositions provided above to an appropriate anal region or affected anal tissue (eg, external or internal anal tissue or anal canal) of a patient in need of treatment of an anorectal disorder. Provide a method for treating anorectal disorders. By using such methods of the present invention, anal rectal tension and / or spasms are alleviated, anal sphincter pressure is reduced, reduced anal sphincter pressure is maintained, and anal rectal disorders such as anal laceration, anal ulcers and hemorrhoids Associated signs and symptoms and pain are improved. In addition, the methods described herein can be applied to the treatment of recurrent anal disease, and also relax the anal sphincter during anal rectal experiments (patients with or without disorders), especially during procedures when the instrument is inserted into the anus, It is useful to reduce.

The present invention also provides a method of using the composition in combination with a local anesthetic such as lidocaine, prilocaine and the like. Typically, each composition is useful for treating medical conditions such as hemorrhoidal pain and spasms and / or strains of the sphincter, including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, Audi sphincter, and colonic sphincter. In addition, these pharmaceutical preparations may result from conditions such as anal lacerations, post-operative rectal pain, hypertrophic pyloric stenosis and spasticity and / or hypertension of the sphincter in the rectum site, including pancreatitis, as well as jenker diverticula, incomfort, esophageal spasms (nuts). Useful for treating conditions resulting from general spasms of the gastrointestinal tract muscles, including cracker esophagus), irritable bowel disease and Hirschsprung disease (intestinal obstruction). In another aspect, the present invention provides a method of treating an anal disorder comprising administering an effective amount of such a composition together with a local anesthetic to a patient in need thereof. Such compositions may be administered orally, topically or parenterally.

Similarly, the present invention is a topical anti-inflammatory agent as a treatment effective for treating medical conditions such as hemorrhoidal pain and spasticity and / or tension hyperactivity of the sphincter muscles, including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, Audi sphincter, and colonic sphincter. To provide a method of using the composition in a pharmaceutically acceptable formulation, for example in combination with naproxen, pyroxycam. In addition, these pharmaceutical preparations may result from conditions such as anal lacerations, post-operative rectal pain, hypertrophic pyloric stenosis and spasticity and / or hypertension of the sphincter in the rectum site, including pancreatitis, as well as jenker diverticula, incomfort, esophageal spasms (nuts). Useful for treating conditions resulting from general spasms of the gastrointestinal tract muscles, including cracker esophagus), irritable bowel disease and Hirschsprung disease (intestinal obstruction). In another aspect, the present invention provides a method of treating an anal disorder comprising administering an effective amount of such a composition together with a local anesthetic to a patient in need thereof. Such compositions may be administered orally, topically or parenterally.

Further methods provided by the present invention include NO donors, phosphodiesterase type V (PDE V) inhibitors, phosphodiesterase type II (PDE II) inhibitors, nonspecific PDE inhibitors, biselective PDE inhibitors, β- activate adrenergic agonists, cAMP-dependent protein kinase agents, α ₁ - adrenergic antagonists, super oxide anion (O ₂ ^-) scavenger, ATP-sensitive K ⁺ channel activators, estrogen, or estrogen analogs, sympathetic nerve terminal destruction of the Or combination of two or more agents selected from adenosine receptor antagonists or smooth muscle relaxants to provide improved therapeutic benefits. In particular, the use of a NO donor and a second agent selected from those provided above can provide fewer and less serious side effects than the same effective amount of the NO donor when used alone. More specifically, the use of a NO donor in combination with a second agent allows the reduction of the NO donor to be used to achieve the same benefits with respect to single use, while prolonging the reduction period of anal sphincter pressure, Frequency and duration are significantly reduced.

Example 1

This example illustrates the effect of a cGMP analogue alone or in combination with a NO donor in a rat endothelial sphincter (IAS) relaxation model.

Female Sprague-Dawley rats (300-400 g) were anesthetized by intramuscular injection of ketamine (90 mg / kg) and xylazine (9 mg / kg) and supplemented with 1/3 dose as needed. . Rats gently restrained their backs on a heated surgical table (Havard Apparatus) for the duration of the experiment. The diuretic effect of anesthesia was offset by rehydration with saline via an intraperitoneally injected 24 gauge vascular catheter (VWR, San Francisco, CA). The shrinkage / relaxation measurement assembly included a mill catheter / transducer (1.67 mm diameter) connected to a Digi-Med Low Pressure Analyzer (Micro-Med) that accurately measured pressures from -50 to 150 mmHg. Data was integrated using Digi-Med System Integrator software and converted to waveforms. Blood pressure changes were monitored using a Digi-Med Blood Pressure Analyzer with arterial catheter / transducer and DMSI software. Respiratory changes were monitored using a mercury stress gauge / transducer, wrapped around the rib cage of the rat, and collected on a Digi-Med Analog Signal Analyzer with DMSI software. Drug delivery was performed with a Hamilton syringe without dead space using PE 10 tubing adjacent the catheter sensor. Typically, the drug was applied immediately after a stable baseline reading was recorded. Unanesthetized, unconstrained rats may be used in other studies, but no differences were observed in resting anal pressure after anesthesia, so these studies were performed using anesthetized rats to avoid unnecessary animal abuse.

Typical resting mean anal sphincter pressure (IASP) in this model varied from 30 to 60 mmHg. The Mila catheter sensor enabled accurate and discrete recording of the IAS. 1 shows a typical waveform pattern for resting IASP in rats under control experimental conditions. Initial 10 minutes after nitroglycerin treatment is shown in FIG. 2.

Using the same experimental protocol, the effect of the cGMP analogue of dibutyryl-cGMP was studied. FIG. 3 shows that application of 20 μl of a 10% solution of dibutyryl-cGMP in saline to the anal canal reduced the mean IASP by 45% over 2.5 hours after treatment. The average IASP dropped to 60% over the last hour before the end of the experiment.

IASP was still reduced by 34% the next morning, indicating a potential long-term effect of the drug. Subsequent administration of 1% nitroglycerin lowered IASP by 24% for 30 minutes and dropped to 71% for the first 10 minutes after treatment. After IASP returned to pretreatment levels, dibutyryl-cGMP was further administered, which was found to drop IASP to 15% over 3 hours 10 minutes.

These results support the effect of cGMP analogues on relaxing anal sphincter tension and, more importantly, indicate the latent effect of a combination of NO donor and cGMP analogues, which is a rapid onset of NO donor action and produced by cGMP analogues. This is due to the long duration of relaxation.

Example 2

This example illustrates the effect of phosphodiesterase inhibitors in an rat inner sphincter relaxation model.

Using the same experimental protocol as described above, applying 20 μl of a 5% japrinast solution in 1-methyl-2-pyrrolidinone reduced IASP by 21% over 32 minutes compared to vehicle only treatment. . The effect of phosphodiesterase inhibitors can be further enhanced by minimal concentrations of NO donors, such as nitroglycerin, which provides more sphincter relaxation without the headache and other side effects observed when high concentrations of NO donors are administered alone. It started quickly and lasted longer.

Example 3

This example illustrates the effect of potassium channel opener (minoxidil) in the rat inner sphincter contraction / relaxation model.

According to the same experimental protocol as described above, a single dose of 20 μl of minoxidil 4% solution in 62.5% propylene glycol reduced 64% IASP over 2.5 hours after treatment. Vehicle alone had little effect on IASP (see FIG. 5).

Example 4

This example illustrates the use of various compositions of the present invention for the relaxation of IAS.

In this example, male Sprague-Dawley rats (250-300 g each) from the Higgs river were used. Rats were anesthetized by intramuscular injection of ketamine (90 mg / kg) and xylazine (9 mg / kg) and warmed on a heated surgical table. All internal anal sphincter pressures (IASPs) were measured with Milla catheter / transducer (MPC-500 microtip; Miller Instruments, Houston, USA) on low pressure and blood pressure analyzers, and at micro-met (Louisville, USA). Recorded with DMSI software provided. Rats were intraperitoneally infused with saline for rehydration due to the diuretic effect of anesthetics, and reesthetized at a dose of about one third of the initial dose as needed. In most experiments, IASPs were able to reach stable baseline levels prior to drug delivery. The drug was delivered to the anal sphincter primarily by PE 20 tubing attached to the catheter (s) around the sensor (s) by a manual infusion or programmable Harvard autoinfusion pump from a 100 μl or 250 μl Hamilton syringe.

Example 5

This example illustrates the effect of repeated or sustained administration of nitric oxide donor (NTG) on the reactivity of rat IAS.

One issue of chronic treatment or subchronic treatment with nitric oxide or nitric oxide donors such as NTG is the degree of any hypertension or resistance to the relaxing effects of nitric oxide. In clinical studies, the human cardiovascular system developed resistance to nitric oxide donors. The inventors have confirmed that in a rat model cardiovascular resistance can be generated by repeated administration of NTG, as measured by arterial blood pressure in vivo. At the biochemical level using in vitro assays, we found that NTG induced increases in cGMP levels were significantly attenuated in vascular smooth muscle. Thus, IAS appears to develop resistance to the effects of nitric oxide on repeated or sustained administration.

In FIG. 6, 1% propylene glycol with 0.1% NTG in 5% dextrose / water was directly administered to IAS at a rate of 20 μg / min every 30 minutes using a Hamilton syringe attached to a Harvard autoinfusion pump. Each successive dose was marked with * indicating a marked drop in resting IASP followed by a complete recovery to resting level; A slight decrease in resting pressure was observed over time in most experiments, probably due to the effects of anesthesia. Since each NTG administration could provide similar levels and duration of pressure reduction, nitrate related pressure resistance was not observed by repeated NTG administration.                 

As can be seen in FIG. 7, continuous infusion of NTG at 20 μg / hour resulted in a steady and sustained decrease in resting IASP, with signs of IASP recovery during the entire treatment period excluding the incidence of resistance even after 4 hours of perfusion. There was no; * Indicates time after initiation of NTG infusion. Similar results were obtained with experiments with 10 times higher doses of NTG. Since there was no adverse effect of pressure reduction with continuous NTG administration, no nitrate related pressure resistance was observed with continuous NTG administration.

Surprisingly, the inventors have found that hypertension of the relaxation effect of NTG on IAS is not caused by repeated or long-term administration in vivo. In addition, our in vitro tests confirmed that NTG-induced increase in cGMP levels in muscle of IAS was not attenuated as in vascular smooth muscle.

Example 6

This example illustrates the use of cyclic nucleotide analogues affecting IASP in the rat model.

8-bromo cAMP (0.1% in saline) was injected into IAS at 20 μg / hour for 3 hours. Minimal pressure drop was observed; This may be due to poor absorption of 8-bromo cAMP from saline into sphincter tissue (see FIG. 8).

Dibutyryl cAMP (0.1% in saline) was injected into IAS at 20 μg / hour for 3 hours. A slight decrease in IASP was observed (see FIG. 9). In addition, the cGMP analogs hardly lowered IASP, possibly due to poor bioavailability via topical formulations in vivo.                 

Since increasing the levels of cGMP and cAMP using NTG or ISO in IAS results in an expected decrease in IASP, the introduction of water soluble 8-bromo and dibutyryl analogues of cGMP and cAMP resulted in resting IASP in the rat model. It was expected to be enough to reduce. Surprisingly, cGMP analogs provided little effect on IASP, while dibutyryl cAMP proved to be more effective than 8-bromo derivatives in rat models, as demonstrated in the following figures. These results may reflect differences in the direct effect of the butyrate moiety on bioavailability and / or smooth muscle relaxation of the analog.

Example 7

This example illustrates the variable ability of a superoxide scavenger to enhance the effects of nitric oxide / nitric oxide donors in vivo.

The ability of superoxide dismutase (SOD), a superoxide scavenger to enhance the relaxation effect of NTG by extending the half-life of nitric oxide (NO), was investigated using a rat model. NO produced from enzymatic degradation of NTG in cells has only a few seconds half-life before being acted upon by oxygen radicals such as superoxide anions that form peroxynitrite (Weller, 1997). Perfusion of the anal sphincter using SOD prior to NTG treatment theoretically removes superoxide from the equilibrium, providing longer half-life for NO in the tissue, resulting in more persistent cGMP levels resulting in NTG- Enhance induced relaxation.

Deliver vehicle (20 μl 5% dextrose / water and 10% propylene glycol) to IAS, perform transfer of 200 μg of superoxide dismutase (SOD) in vehicle within 30 minutes, and after 15 minutes the same vehicle Infusion administration of 200 μg intra NTG was performed. Significant augmentation of the NTG effect, eg, an increase in the duration of action on decreasing anal sphincter, was observed (see FIG. 10). This result means that the activity of the NO donor is enhanced in the presence of a superoxide anion scavenger.

Vehicle (20 μl of 5% dextrose / water and 10% propylene glycol) was delivered to IAS, a mass transfer of 200 μg NTG in vehicle was performed within 30 minutes, and a 20 μg round mass administration of SOD was performed after 15 minutes. No significant enhancement of NTG was observed, which means that when administered prior to NTG, the enhancing effect of SOD is best seen (see FIG. 11). This result means that NTG-derived NO has already been released from the tissue.

Surprisingly, the synthetic superoxide scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) did not show significant NO enhancing activity in this model.

In addition, as demonstrated in FIGS. 10 and 11, SOD alone had little effect on IASP because resting IAS had a low internal level of NO acting on the superoxide anion.

Example 8

This example illustrates the enhancement of NTG by blocking PDE V inhibitors of cGMP specific PDE activity in a rat model.

Zaprinast:

Vehicle, 1-methyl 2-pyrrolidone (1M2P) was injected intraperitoneally (ip) (100 μl) 30 minutes prior to infusion of NTG (20 μg / min every 30 minutes). The duration of IASP degradation due to NTG was consistent with each dose (see Figure 12).

Japrinat (10 mg in 100 μl of 1M2P) was injected intraperitoneally 30 minutes prior to administration of NTG (20 μg / min every 30 minutes). The duration of IASP deterioration by continuous administration of NTG was increased, indicating enhanced NTG function by selective PDE V inhibitors (see FIG. 13).

Vehicle 1-methyl 2-pyrrolidone (1M2P) was injected intraperitoneally (ip) (100 μl), and 2.5 hours later, NTG (20 μg / min every 30 minutes) was initially administered. The duration of IASP reduction was consistent with each NTG administration (see Figure 14).

Japrinat (10 mg in 100 μl of 1M2P) was injected intraperitoneally before 2.75 hours of infusion of NTG (20 μg / min every 30 minutes). The duration of IASP reduction continued to increase with each NTG dose, peaked around 3.5-4 hours, and decreased with further dose of NTG. The study found that intraperitoneal administration of japrinat reached the highest level in 3.5 to 4 hours in IAS and induced augmentation with NTG (see FIG. 15).

These results indicate that enhancement of NTG activity can be achieved by agents that prevent PDE degradation of cGMP formed through NO activation of guanylyl cyclase.

Dipyridamole:

The vehicle 1-methyl 2-pyrrolidinone (1M2P) was intraperitoneally injected (100 μl) 50 minutes prior to the infusion of NTG (20 μg / min every 30 minutes). The duration of IASP reduction by NTG was consistent with each dose (see FIG. 16).

Dipyridamole (10 mg in 100 μl of 1M2P) was injected intraperitoneally 50 minutes prior to administration of NTG (20 μg / min every 30 minutes). The duration of IASP reduction by NTG was consistent with each dose and nearly doubled as compared to vehicle treated rats (see FIG. 17).

MBCQ:

MBCQ (10 mg in 100 μl of 1M2P) was injected intraperitoneally 30 minutes prior to administration of NTG (20 μg / min every 30 minutes). No augmentation of NTG recognizable using PDE V inhibitors was observed in this experiment (see FIG. 18). Bioavailability of MBCQ may be the cause of the minimal effects identified in the compound.

While dipyridamole showed less pronounced enhancement compared to NTG, the ability of MBCQ, the most potent PDE V inhibitor in vitro, did not show significant activity, presumably due to the reduced bioavailability of the drug in an in vivo model. (Data not shown).

Example 9

This example illustrates the effect of non-specific β-adrenergic agonists using isoproterenol. These agonists increase cAMP levels by activating adenyl cyclase and act on IASP through the direct smooth muscle relaxation activity of cAMP.

The administration of 200 μg of isoproterenol showed a significant drop in IASP, eliminating significant pressure readings by the catheter / transistor, in fact isoproterenol is a very powerful IAS relaxant, and 0.2 μg / hour through other experiments. Titration down to successive doses of IASP should be used to avoid significant drop in IASP (see FIG. 19).

Example 10

This example illustrates the effect of β ₂ -agonist on IASP.

The β ₂ -agonist terbutalin (in saline) was continuously injected at 20 μg / hour. Injection over 3 hours (FIGS. 4N, 20) resulted in a steady and sustained drop. Significant drops in IASP throughout the experiment reached steady state 1.5 to 2 hours after initiation of treatment.

A persistent but mild IASP drop is thought to be desirable for prolonging the increased blood flow to the anal canal epithelium needed to heal anal lacerations without inducing complete relaxation of IAS, which can cause temporary incontinence.

The β ₂ -agonist salbutamol (in saline) was continuously injected at 20 μg / hour, illustrating a significant drop in IASP throughout the terbutalin-like experiment (see FIG. 21).

Example 11

This example illustrates the effect of cAMP levels on IASP and the effect of blocking PDE IV inhibitors of cAMP specific PDE activity in the rat model.

Lolliphram has the following effects:

PDE IV inhibitor rolifram in 5% DMSO / acetone: olive oil 1: 1 was continuously injected at a rate of 20 μg / hour. The pattern, including a significant drop in IASP with a shorter recovery phase, occurred one hour before initiation of drug infusion (see FIG. 22).

Salbutamol etazolate enhancement:

Delivery of 200 μg salbutamol in saline to IAS did not show a short-term effect on IASP; Salbutamol and an eta sol rate (also 200 ㎍ in saline) subsequent administration of combined use of PDE IV inhibitors are eotneunde represent a significant and persistent lowering of IASP, which by using the PDE IV inhibitor for reducing pressure sphincter β ₂ - It means that the effect of the agonist is enhanced.

This experiment is similar to the experiment described in Example 23, but the order of drug delivery was reversed. The experimental results were similar (see FIG. 24).

Smooth muscle relaxation was induced by agents that elevate cAMP by phosphorylation of myosin light chain kinase by cAMP dependent protein kinase (PKA). PDE IV inhibitors prevented degradation of cAMP by cAMP specific PDEs. As confirmed in the enhancement by etazolate, the PDE IV inhibitor of the effect of salbutamol, a β ₂ -adrenergic agonist, the enhancement of the agent activating adenylyl cyclase can be achieved using a PDE type IV inhibitor. Can be.

Effect of RO-20-1724:

RO-20-1724, a PDE IV inhibitor, was injected at 20 μg / hour with the vehicle 5% DMSO / acetone: olive 1: 1. The drop in IASP was minimal, indicating that the drug's bioavailability is deficient by the current route of administration (see FIG. 25).                 

Forskolin's effect:

Forskolin, a specific adenyl cyclase activator, was injected at 20 μg / hour with the vehicle 5% DMSO / acetone: olive oil 1: 1. A significant and sustained drop in IASP was observed (see FIG. 26 (control) and FIG. 27). This experiment clearly demonstrates the contribution of cAMP to inducing relaxation of the internal anal sphincter.

Example 12

This example illustrates the use of an α-adrenergic antagonist to reduce IASP in the rat model.

Prazosin in 5% DMSO / acetone: olive oil 1: 1, α ₁ -blocker, was injected at 20 μg / hour. A significant and sustained drop in IASP, which reached steady state after 1 hour, was observed, indicating that an increase in cAMP levels caused relaxation of internal anal sphincter pressure (see FIG. 28).

Example 13

This example illustrates the effect of nonspecific PDE inhibitors on IASP in the rat model.

Isobutyl methylxanthine (IBMX) in 5% DMSO / acetone: olive oil 1: 1 was injected at 200 μg / hour. A significant and sustained drop in level reduced IASP 1 hour after initiation of infusion was observed (see FIG. 29).

Isobutyl methylxanthine (IBMX) in 5% DMSO / acetone: olive oil 1: 1 was injected at a lower dose, ie 20 μg / hour. The results were similar to those in the experiment described in FIG. 29 (see FIG. 30).

IBMX, a nonselective PDE inhibitor, is thought to act on smooth muscle by a number of mechanisms: 1) PDE inhibition and increased cAMP levels; 2) effect on intracellular calcium concentration; 3) effect on membrane hyperpolarization; 4) independent of increased calcium levels and muscle contractility; And 5) adenosine receptor antagonism (see Goodman & Gilman's "The Pharmacological Basis of Therapeutics" 9th ed., Section IV-Autocoids; Drug Therapy of Inflammation).

Example 14

This example illustrates the use of K ⁺ -ATP channel opener to relax IAS.

Minoxidil and diazooxide, K ⁺ -ATP channel openers, inactivated the voltage-gate Ca ²⁺ channel by inducing hyperpolarization of the cell membrane of smooth muscle.

Minoxidil (830 μg in 20 μl of 62.5% propylene glycol / water) was delivered to IAS. A significant and sustained drop in IASP was observed immediately after delivery of the drug (see FIG. 31).

Diazooxide in 5% DMSO / acetone: olive oil 1: 1 was injected at 20 μg / hour. Significant drop in IASP was observed during the experiment (see FIG. 32).

Example 15

This example illustrates the use of Ca ²⁺ channel blockers.

Diltiazem in saline was injected at 20 μg / hour. The drug showed a significant and sustained drop in IASP during the experiment (see FIG. 33).

Verapamil in saline was injected at 20 μg / hour. The drug showed a significant and sustained drop in IASP during the experiment (see FIG. 34).

Example 16

This example illustrates the use of sympathetic nerve terminal disruptors to achieve long term reduction of IASP in rat models involving short-term administration of the active agent.

Nervous tension in IAS is largely due to sympathetic adrenergic nerve distribution; Norepinephrine released by the nerve acts on α ₁ -adrenergic receptors that contract smooth muscle. Initial reports indicate that α-blockers reduce anal pressure in humans (Speakman, CT, Dig Dis Sci 38 (11): 1961-9 (1993); Parks, AG, Gut 10 (8) 674-7 (1969) Reference). One of the most powerful toxins known, and recent clinical trials with botulinum toxin produced by Clostridium botulinum have shown efficacy in treating anal laceration after multiple injections of toxin directly into IAS. It was. Botulinus toxin seems to relax IAS, possibly due to its ability to block acetylcholine (ACH) released from cholinergic pre-synthetic fibers (see Kao, I. et al., Science 193, 1256-8 (1976)). However, the choline distribution of IAS is not thought to contribute significantly to the IAS base. The present inventors decided to use drugs that can be applied locally to IAS and block the action of norepinephrine in maintaining sphincter tension by destroying parasympathetic nerve endings.

6-hydroxydopamine in saline was delivered to IAS in the same daily 5 day administration to rats at a dose of 200 μg roundfish. IASP was measured over three weeks. Continuous drop in IASP was observed until day 16, 11 days after treatment was terminated. Partial recovery of IASP was observed on day 19 and mean IASP was less than 36% of original reference pressure on day 22 (see FIG. 35).

Thus, treatment with 6-hydroxydopamine (6-OHDA) showed prolonged reduction of IASP over three weeks after 200 days of topical administration of 200 μg in saline to rat IAS.

Example 17

This example illustrates the effect of PDE III / IV inhibitors on IASP under various experimental conditions.

This experiment is a control experiment of the experiment described in FIG. Intraperitoneal injection of 100 μl of 1M2P was performed in 30 minutes with continuous infusion of isoproterenol in saline at 0.2 μg / hour. This threshold dose of isoproterenol had no significant effect on lowering IASP (see FIG. 36).

Intraperitoneal injection of PDE III / IV inhibitor, zadaberin (10 mg in 100 μl of 1M2P), was performed within 30 minutes of continuous infusion of isoproterenol in saline at 0.2 μg / hour. A rapid drop in IASP was observed immediately after intraperitoneal infusion of zardaverine, with a sustained decrease in mean IASP following isoproterenol infusion. Continuous slow wave patterns of decreasing IASP and increasing IASP were observed after isoproterenol injection (see FIG. 37).

Intraperitoneal injection of PDE III / IV inhibitor, zadaberin (7.5 mg in 100 μl of 1M2P), was performed in 30 minutes with a continuous infusion of 5% dextrose in saline at 20 μl / hour. Zardaverine injections produced a rapid but transient drop in IASP and soon returned to normal baseline levels. Subsequent infusion of 5% dextrose was ineffective at lowering IASP (see FIG. 38).

Intraperitoneal infusion of PDE III / IV inhibitor zardaverin (7.5 mg in 100 μl of 1M2P) was performed within 30 minutes with continuous infusion of isoproterenol in saline at 0.2 μg / hour. Zardaverin again induced a rapid and transient decrease in IASP. Isoproterenol injection further reduced IASP to nearly 0 mmHg (see FIG. 39). These experiments (FIGS. 36-39) imply an enhancement of sub-threshold levels of isoproterenol by zardaverin.

Example 18

This example illustrates the use of adenosine antagonists to relax IAS in a rat model.

Theophylline:

Theophylline, an adenosine antagonist, was continuously injected at 200 μg / hour in 5% dextrose. A significant and sustained drop in IASP was observed throughout the 4 hour experiment time (see FIG. 40).

Theophylline was injected continuously at 20 μg / hour in 5% dextrose. Mild drop in mean IASP was observed throughout the 3 hour test time (see FIG. 41).

Theophylline was continuously injected at a lower dose, ie 2 μg / hour, in 5% dextrose. The minimum drop in average IASP was observed throughout the 3 hour test time (see Figure 42).

Depilin:

Figure 43 shows the IAS relaxation effect of 20 μg / hour continuous administration of diphylline [7- (2,3-dihydroxypropyl) theophylline, theophylline derivative, which is not metabolized by the liver and is excreted unchanged by the kidneys. Indicates that the drug is a low toxicity latent drug.

Example 19

This example illustrates a method of treating anal disorders in an individual using phosphodiesterase inhibitors and other agents that reduce pain associated with diseases including acute anal lacerations and chronic anal lacerations.

Patients with severe anal pain, and especially those with severe anal pain during and after defecation, can be treated with the following therapies: 1 to 3 times a day or when it is necessary to effectively reduce anal rectal pain, japrinat, japrina Strepto nitroglycerin, minoxidil, nitroglycerin and cGMP analogues, isoproterenol, or sildenafil. Pain reduction (indicated by reduction of mean pain and / or bowel pain) will be assessed, and the time taken to reduce pain will also be assessed. Effective treatments for anal pain relief will substantially lead to effective resolution of these anal rectal disorders. In addition, drugs that effectively reduce anal sphincter pressure, maintain reduced sphincter pressure, or prevent the recurrence of disease, and which have no or minimal side effects such as headache, drowsiness, and high blood pressure, will be drugs of great therapeutic benefit.

Example 20

This example illustrates a method of treating anal disorders in an individual using phosphodiesterase inhibitors and other agents that promote healing of diseases including acute anal lacerations and chronic anal lacerations.

Anal laceration patients can be treated with the following therapies: japrinat, japrinast and nitroglycerin, minoxidil, nitroglycerin and cGMP analogues, isoproterenol 1 to 3 times a day or when it is necessary to effectively promote treatment , Or sildenafil. Treatment is indicated by improving re-epithelialization of the observed anal fissures and can be evaluated according to the time required for complete healing. Therapies effective in treating anal lacerations substantially lead to the complete resolution of these anal rectal disorders. In addition, drugs that effectively reduce anal sphincter pressure, maintain a reduced sphincter pressure, or prevent the recurrence of disease, and drugs that have no or minimal side effects such as headaches will provide significant medical benefits.

Example 21

This example illustrates a method of reducing bleeding in a patient with hemorrhoidal symptoms or disease.

Patients with hemorrhoidal symptoms or diseases can be treated with the following therapies: once or three times a day or when it is necessary to effectively reduce bleeding and promote healing, minoxidil, nitroglycerin, minoxidil, nitroglycerin And cGMP analogues, isoproterenol, or sildenafil. Disease resolution is manifested by a reduction in bleeding and / or pain and will be assessed according to healing time. Effective treatments to ameliorate hemorrhoidal symptoms will substantially lead to complete resolution of these anal rectal disorders. In addition, drugs that effectively reduce anal sphincter pressure, maintain a reduced sphincter pressure, or prevent the recurrence of disease, and drugs that have no or minimal side effects such as headaches will provide significant medical benefits.

Example 22

Salbutamol 1.0 g, Carbopol 1342 (US Pharmacopoeia) 0.6 g, Propylene glycol 35.44 g, Anhydrous ethanol (US Pharmacopoeia) 15.16 g, Isopropyl alcohol (US Pharmacopoeia) 15.16 g, 2.5% Oleic acid, Triethanolamine HCl 1 N ( pH 6.0 to 7.0), a composition of a base gel comprising 0.05 g of butylated hydroxytoluene NF and 29.72 g of purified water (US Pharmacopoeia). Different concentrations of salbutamol can be added to the same gel base to obtain an effective therapeutic dose; This can also be obtained by adjusting the concentration of other β-agonists using gel base excipients such as oleic acid.

Example 23

One example of a topical composition is 0.05-1% sildenafil, 75% (w / w) white kerosene (US Pharmacopoeia), 4% (w / w) paraffin wax (US Pharmacopoeia / NF), lanolin 14% (w / w) , 2% sorbitan sesquioleate NF and 4% propylene glycol (US Pharmacopoeia) and were applied to the rectal area in an effective therapeutic amount. Typically, 50 mg to 600 mg of sildenafil ointment can be applied to the rectal area to reduce signs and / or symptoms associated with anal rectal disorders such as anal laceration, anal ulcers and hemorrhoidal diseases. The concentration of sildenafil or other phosphodiesterase inhibitor can be varied by adjusting the ratio of sildenafil to an excipient that facilitates the attachment of sildenafil to local tissue, or to an agent that enhances absorption into affected tissue.

Other examples of topical compositions include 0.1% nitroglycerin and 0.1% sildenafil and can be incorporated into the same ointment base as described above. The composition can be applied topically from a metered dose device, wherein 50 mg to 1.5 g of the composition can be administered to the rectal affected tissue to achieve the desired therapeutic effect.

Another treatment regimen is to provide oral sildenafil tablets and topical nitroglycerin ointments to patients with anorectal disorders. These two formulations can be used in combination between these patients to provide optimal efficacy and compliance.

Example 24

The aminotiline topical spray composition is contained in a 2 oz pump spray bottle, containing 0.1 to 5.0% (w / w) aminotiline, acetylated lanolin alcohol, aloe vera, butane, cetyl acetate, hydrofluorocarbon, methyl paraben, PEG- 8 laurate and polysorbate 80. The concentration of aminophylline or other nonspecific phosphodiesterase inhibitor may be 0.5% to 5%. In addition, other nonhydrofluorocarbon propellants may be used in the compositions in place of hydrofluorocarbons. The composition can be sprayed directly to affected tissue once or four times per day to obtain the desired relieving effect of the signs and / or symptoms associated with anal rectal disorders. In addition, the compositions can provide direct local pain relief and sensory calming effects, including methanol and benzocaine, while aminophylline provides longer lasting relaxation of anal sphincter pressure.

Example 25

The base cream composition is 2 g of prazosin hydrochloride (2.0% w / w), 54.3 g of purified water (US Pharmacopoeia), 2 g of Cepigel 305, 4.5 g of Crodamol, 5.0 g of Glycerin, 6.0 g of Sesame oil, White Kerosene (US Pharmacopoeia) 15.0 g, Lanolin (US Pharmacopoeia) 2.0 g, 1,3-butylene glycol 7.0 g, 0.2 g methylparaben and 2.0 g silicone HL88.

Base creams may be prepared by separate mixing of the aqueous and non-aqueous, ie oily, ingredients of the cream first. Once the aqueous phase containing prazosin hydrochloride is well mixed, the molten oil phase is gently stirred into the aqueous phase to form a uniform cream base.

Example 26

Sildenafil, an inhibitor of the specificity of type V phosphodiesterase, can be administered orally, parenterally, or topically by tablets to patients diagnosed with anal lacerations or other anal rectal disorders such as acute anal lacerations or chronic anal lacerations. have. Sildenafil can be administered once to three times per day for eight weeks, particularly in patients with chronic anal laceration, to alleviate the signs and symptoms associated with anal rectal disorders.

For topical application, 50 mg to 900 mg of the cream (containing sildenafil at a concentration of 0.02% to 5%) measured by a metered dose device is applied to the affected area of the rectum by means of an applicator or finger 1 to 4 per day. Once applied, the desired therapeutic effect can be achieved. Alternatively, oral and topical treatments can be used in a limited regimen to achieve optimal therapeutic effects.

Example 27

Phosphodiesterase inhibitors, such as aminophylline, may be administered orally, parenterally, or topically in a dosage form, eg, to a patient diagnosed with anal laceration or other anal rectal disorders such as acute anal laceration or chronic anal laceration. For example, a cream can be applied. For topical application, 50 mg to 900 mg of the cream measured by a metered dose device can be applied to the affected rectum 1 to 4 times a day using an applicator or finger to achieve the desired therapeutic effect.

Example 28

β-adrenergic agonists such as salbutamol may be administered as suppositories to patients diagnosed with anal tears or other anal rectal disorders, such as acute anal lacerations or chronic anal lacerations, or as topical formulations such as creams. Can be. To apply suppositories, about 300 mg to 3 g of suppository units may be applied to the affected rectum affected area once to four times per day with an applicator or finger. Once the suppository is melted in the anus, salbutamol released from the formulation can be used to achieve the desired therapeutic effect.                 

Example 29

α-adrenergic antagonists, namely prazosin, are applied alone or in combination with local anesthetics, such as lidocaine, or mixed with β ₂ -and β ₃ -adrenergic agonists to patients diagnosed with hemorrhoidal disease For example, in combination with salbutamol or in combination with PDE IV inhibitors such as Ariflo (SB207499), RP73401, CDP840, rolipram and LAS31025. Prazosin can be applied directly to the affected area with a propellant from the spray, or can be used when local pain relief and anal sphincter stiffness relief are needed. Practically, applying prazosin will cure hemorrhoidal disease.

Example 30

This example illustrates the preparation of a theophylline topical formulation from a theophylline oral formulation.

Five theo-24 tablets (400 mg of theophylline per tablet; UCB Pharmaceuticals, Inc.) were combined and ground to a fine powder. To this powder, 50 ml of ethanol was added, and the solution was stirred at room temperature for 15 minutes. Then, 48 ml of propylene glycol and 100 ml of distilled water were added while stirring the ethanol mixture. The mixture was stirred for 15 minutes, at which time the powder was completely dissolved. Thereafter, a solution of carbopol in distilled water was added to the mixture while stirring to form a 1% topical theophylline gel. The resulting gel was then stirred for another 15 minutes.                 

Example 31

Methylxanthine derivatives such as diphylline or theophylline can be administered orally by tablets, parenterally or topically in patients diagnosed with anal laceration or other anal rectal disorders, such as acute or chronic anal laceration. For example, as a cream or rectal suppository.

In topical administration, 50 mg to 900 mg of the cream as measured by a metered dose device can be applied once or four times a day to the affected area of the rectum using an applicator or finger to achieve the desired therapeutic effect.

The examples and embodiments described herein have been described for purposes of illustration only, and various modifications and changes thereof will be apparent to those skilled in the art, which are also included within the scope of the invention as defined by the appended claims. will be. All documents, patents, and patent applications cited herein are incorporated by reference in their entirety.

Claims (36)

Acute or chronic anal lacerations, thrombotic internal hemorrhoids or external hemorrhoids, hemorrhagic diseases, endoscopic hemorrhoidal ligation disorders, anal big muscle spasm, constipation, or adenosine receptor antagonists selected from the group consisting of theophylline or diphylline Composition for the treatment of hypertension or spasms of the anal sphincter. The method of claim 1, wherein nitroglycerin, L-arginine, (±) -S-nitroso-N-acetylphenicylamine (SNAP), S-nitrosoglutathione (GSNO), 3-morpholinosidoneimine ( SIN-1), Isobutyl methylxanthine (IBMX), 8-methoxymethyl-isobutyl methylxanthine (8-methoxymethyl-IBMX), erythro-9- (2-hydroxy-3-nonyl) adenine (EHNA), Milinone, japriast, Zardaverin, Sildenafil, Aminophylline, 1,3-dimethyl-6- (2-propoxy-5-methane sulfonylamidophenyl) pyrazolo- [3,4-d ] Pyrimidin-4- (5H) -one (DMPPO), aminophylline, caffeine, theobromine, nifedipine, nimodipine, pelopidine, nicardipine, isradinine, amlodipine, diltiazem, menthol, pinavarium bromide, verapamil , Minoxidil, minoxidil sulfate, pinassidyl, diazooxide, revchromalim, (-)-(3S, 4R) -3,4-dihydro-3-hydroxy-2,2-dimethyl-4- ( 3-oxocyclopent-1-enyloxy) -2H-1benzopyran-6-carbonite (PCO400) and the composition further comprises a sphincter within relaxants least one member selected from the group consisting of chroma Kalim. The composition of claim 2, wherein the relaxant is japrinat. The composition of claim 2, wherein the relaxant is diltiazem. The composition of claim 2, wherein the relaxant is verapamil. The pharmaceutical composition according to any one of claims 1 to 5, wherein the carrier is formulated for topical application. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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