Patent 6,627,632

Compositions and methods for the treatment of anorectal disorders are provided in which certain combinations of NO donors, PDE inhibitors, superoxide (O_2^-) scavengers, .beta.-adrenergic agonists, cAMP-dependent protein kinase activators, .alpha.₁ -adrenergic antagonists, L-type Ca²⁺ channel blockers, estrogens, ATP-sensitive K⁺ channel activators and smooth muscle relaxants are used.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provides compositions for the treatment of anorectal disorders comprising a nitric oxide donor in combination with a second agent (typically one which modulates levels of cAMP or cGMP). The second agent can be 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, a .beta.-adrenergic agonist, a cAMP-dependent protein kinase activator, an estrogen or estrogen-like compound, or an .alpha.₁ -adrenergic antagonist. The agent can also be a superoxide anion (O_2^-) scavenger, an ATP-sensitive K⁺ channel activator, a sympathetic nerve terminal destroyer, or a smooth muscle relaxant, although these agents do not directly modulate either cAMP or cGMP levels. The present invention further provides methods of using these compositions.

In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising a phosphodiesterase inhibitor, preferably a PDE II inhibitor, a PDE IV inhibitor or a PDE V inhibitor, either alone or in combination with another agent selected from .beta.-adrenergic receptor agonists, .alpha.₁ -adrenergic antagonists, estrogens, L-type Ca²⁺ channel blockers, ATP-sensitive K⁺ channel activators, or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier. The present invention also provides methods of using these compositions.

In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising a .beta.-adrenergic receptor agonist, preferably a .beta.₂ - or .beta.₃ -adrenergic receptor agonist, either alone or in combination with another agent selected from cAMP-hydrolyzing PDE inhibitors (e.g., a PDE IV inhibitor), nonspecific PDE inhibitors, .alpha.₁ -adrenergic antagonists, estrogens or estrogen-like compounds, L-type Ca²⁺ channel blockers, or ATP-sensitive K⁺ channel activators, and methods of using those compositions.

In yet another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising an ATP-sensitive K⁺ channel activator, either alone or in combination with another agent selected from cAMP-dependent protein kinase activators, .alpha.₁ -adrenergic antagonists, estrogens, L-type Ca²⁺ channel blockers, or smooth muscle relaxants, and methods of using those compositions.

In still another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising an .alpha.₁ -adrenergic antagonist, either alone or in combination with another agent selected from cAMP-hydrolyzing PDE inhibitors (preferably a PDE IV inhibitor) or smooth muscle relaxants, and methods of using those compositions.

In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising .beta.₂ -adrenergic agonists, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, the .beta.₂ -adrenergic agonists are used alone. In a preferred embodiment, the .beta.₂ -adrenergic agonists is combined with a phosphodiesterase inhibitor. In another embodiment, the .beta.₂ -adrenergic agonists are combined with one or more other IAS relaxing agents.

In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising adenosine receptor antagonists, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, adenosine receptor antagonists are used alone. In another group of embodiments, the adenosine receptor antagonists are combined with at least one other IAS relaxing agent.

In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising cyclic nucleotide-dependent protein kinase activators, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, cGMP-dependent protein kinase activators are used alone. In another group of embodiments, nonspecific cyclic nucleotide-dependent protein kinase activators are used alone. In yet another group of embodiments, nonspecific cyclic nucleotide-dependent protein kinase activators are used in combination with smooth muscle relaxants. In still another group of embodiments, cAMP-dependent protein kinase activators are provided in combination with L-type Ca²⁺ channel blockers.

In yet another aspect, the present invention provides a composition for the treatment of anorectal disorders comprising a methylxanthine compound. In preferred embodiments, the compound is theophylline or dyphylline. In still another embodiment, the methylxanthine compound is used alone. In still another embodiment, the methylxanthine compound is combined with another IAS relaxing agent.

In yet another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising an estrogen or other estrogenic compound, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, estrogenic compounds are used alone. In another group of embodiments, the estrogenic compounds are used in combination with a second agent selected from phosphodiesterase inhibitors, .beta.-adrenergic receptor agonists, .alpha.₁ -adrenergic antagonists, L-type Ca²⁺ channel blockers, ATP-sensitive K+ channel activators, or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier. The present invention further provides methods of using these compositions.

Where the compounds discussed above act through mechanisms distinctly different from nitroglycerin, they can be used to complement nitroglycerin therapy, or as stand alone products.

As noted above, methods of treating anorectal disorders are also provided herein. The methods of the invention comprise administering to a subject a suitable formulation of one or more of the compositions above. In related methods, treatment is carried out by administration of two or more agents in sequence, either by the same route of administration or by different routes of administration.

DETAILED DESCRIPTION OF THE INVENTION

General

A promising new approach for treating anal disorders is the topical application of a nitric oxide (NO) donor to an appropriate anal area. Nitric oxide has been shown to bring about a concentration-dependent reduction 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 (e.g., nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, and L-arginine) have been shown to reduce anal pressure in humans. Schouten, W. R. et al., "Pathophysiological aspects and clinical outcome of intra-anal application of isosorbide dinitrate in patients with chronic anal fissure," Gut 39:465-9 (1996); Farid, M., Br J Surg 84:1 (1997); and Hechtman, H. B. et al., Arch. Surg 131:775-778 (1996). NO has also been shown to mediate adaptive relaxation of other sphincters in the gastrointestinal tract including 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), sphincter of Oddi (Mourelle et al., Gastroenterology 105:1299-1305 (1993)), and the ileocolic sphincter (Ward et al., Br J Pharmacol 105:776-782 (1992)). It is thought that NO or NO-like substances serve as important control mechanisms for the general phenomenon of gastrointestinal adaptive relaxation.

Despite the initial promise of NO donors, tachyphylaxis has been observed for members of this class of agents. Surprisingly, the present invention provides compositions which are useful to overcome side effects and problems associated with the current therapies.

Description of the Embodiments

NO Donors in Combination with a Second Agent

In one aspect, the present invention provides compositions for the treatment of anal disorders comprising a nitric oxide donor in combination with a second agent which modulates levels 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 still another group of embodiments the second agent is a superoxide anion (O_2^-) scavenger. In yet another group of embodiments the second agent is a .beta.-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 .alpha.₁ -adrenergic antagonist. In another group of embodiments the second agent is an estrogen, estrogen analog, or estrogenic compound. In another group of embodiments the second agent is an L-type Ca²⁺ channel blocker. In still another group of embodiments the second agent is an ATP-sensitive K⁺ channel activator. The present invention further provides methods of using the compositions provided above. In a related aspect, the present invention provides compositions 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, organic NO donors, inorganic NO donors and prodrug forms of NO donors. Preferably, the NO donor includes at least one organic nitrate (including esters of nitric acid) and can be either a cyclic or acyclic compound. For example, suitable NO donors include nitroglycerin (NTG), L-arginine, isosorbide dinitrate (ISDN), isosorbide mononitrate (ISMN) which may include isosorbide-2-mononitrate (IS2MN) and/or isosorbide-5-mononitrate (IS5MN), erythrityl tetranitrate (ETN), pentaerythrityl tetranitrate (PETN), ethylene glycol dinitrate, isopropyl nitrate, glyceryl-1-mononitrate, 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 given regulatory approval for use in treatments in other fields of medicine on human subjects. Additional NO donors include sodium nitroprusside, N,O-diacetyl-N-hydroxy-4-chlorobenzenesulfonamide, N^G -hydroxy-L-arginine (NOHA), hydroxyguanidine sulfate, molsidomine, 3-morpholinosydnonimine (SIN-1), (+)-S-nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), (+)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), (+)-N-[(E)-4-ethyl-3-[(Z)-hydroxyimino]-5-nitro-3-hexen-1-yl]-3-pyridin ecarboxamide (FR144420), and 4-hydroxymethyl-3-furoxancarboxamide.

In general, the organic nitric oxide donor (e.g., the organic nitrate) is present in any amount less than that which is effective in the practice of the treatment of anal disease when used alone. In typical practice of the invention the organic nitric oxide donor can be present in a concentration from about 0.01 to about 10 percent by weight. All weight percentages herein are based on the total weight of the composition. For NTG, preferred concentrations are in the range of from about 0.01 to about 5 percent by weight.

In one group of embodiments, the composition contains an agent which is a phosphodiesterase (PDE) inhibitor. Inhibitors of phosphodiesterases (PDE), are agents which can block the breakdown of cAMP and cGMP in the tissue. PDE inhibitors include both non-specific PDE inhibitors and specific PDE inhibitors (those which inhibit a single type of phosphodiesterase with little, if any, effect on any other type of phosphodiesterase). Still other useful PDE inhibitors are the dual selective PDE inhibitors (e.g., PDE III/IV inhibitors).

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

In another group of embodiments, the composition contains an agent which is a phosphodiesterase type II (PDE II) inhibitor. Suitable phosphodiesterase type II inhibitors include EHNA.

In yet another group of embodiments, the composition contains an agent which is a phosphodiesterase type IV (PDE IV) inhibitor. Suitable phosphodiesterase type IV inhibitors include ariflo (SB207499), RP73401, Ro-201724, CDP840, rolipram and LAS31025.

In still another group of embodiments, the composition contains an agent which is a dual selective phosphodiesterase inhibitor, preferably a PDE III/IV inhibitor such as, for example, zardaverine.

In yet another group of embodiments, the composition contains an agent which is a nonspecific phosphodiesterase (nonspecific PDE) inhibitor. Suitable nonspecific phosphodiesterase inhibitors include IBMX, theophylline, dyphylline theobromine, aminophylline, pentoxifylline, papaverine, caffeine and other methyl xanthine and non-xanthine derivatives (Goodman & Gilman's "The Pharmacological Basis of Therapeutics" The McGraw-Hill Companies, 1996).

In still another group of embodiments, the composition contains an agent which is a superoxide anion (O_2^-) scavenger. Superoxide can react with NO and dramatically reduce its biological effects. Accordingly, agents that scavenge superoxide anion (e.g., exogenous Mn- or Cu/Zn superoxide dismutase (SOD) or small molecule SOD mimetics, e.g. Mn(III) tetra(4-benzoic acid) porphyrin chloride (MnTBAP) and M40403, see Salvemini, et al., Science 286(5438):304-306 (1999)) can enhance the effects of NO. SODs are relatively stable enzymes and can be used in topical formulations with NO donors such as, for example, NTG, to boost the local potency of NO generated from NTG. The nitric oxide formed from NTG acts only locally due to its short half-life. However, NTG itself is stable enough to exert systemic effects following mucosal absorption. By enhancing the local efficacy of NTG with SOD or a SOD mimetic, less NTG is required to produce the same degree of internal anal sphincter relaxation, and less NTG is absorbed, leading to a reduction in systemic side effects.

In yet another group of embodiments, the composition contains an agent which is a .beta.-adrenergic agonist, preferably a .beta.₂ - or .beta.₃ -adrenergic receptor agonist. A variety of .beta.-adrenergic agonists have been described in the literature and are useful in the present invention. Suitable .beta.₃ -adrenergic agonists are described in, for example, Bristol, et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 33, Chap 19, pp 193-202, Academic Press (1998). Preferred .beta.-adrenergic agonists include salbutamol, terbutaline, procaterol, clenbuterol, isoproterenol, zinterol, 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. A variety of cyclic nucleotide-dependent protein kinase activators are useful in the present invention including, for example, cAMP mimetics and dual cGMP/cAMP-dependent protein kinase activators. cAMP mimetics are well known to those of skill 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 yet another group of embodiments, the composition contains an agent which is an estrogen or estrogen analog or mimetic. As used herein, the term "estrogens" is meant to include all forms of estrogen and estrogen-like compounds such as those compounds having estrogen like activity (e.g., those which bind to the estrogen receptor in a competitive binding assay). The estrogens can be either steroidal or nonsteroidal (see, for example, Bristol, et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 31, Chap. 19, pp 181-190, Academic Press (1996), and references cited therein). Estrogen-like compounds include but are not limited to 17-beta-estrodiol, estrone, mestranol, estradiol valerate, estrodiol dypionate, ethinyl estrodiol, quinestrol, estrone sulfate, phytoestrogens such as flavones, isoflavones (e.g. genistein), resveratrol, coumestan derivatives, other synthetic estrogenic compounds including pesticides (e.g. p,p'-DDT), plasticizers (e.g. bisphenol A), and a variety of other industrial chemicals (e.g. polychlorinated biphenyls).

In yet another group of embodiments, the composition contains an agent which is an .alpha.₁ -adrenergic antagonist. The sympathetic neurotransmitter norepinephrine contracts sphincter smooth muscle via .alpha.₁ -adrenergic receptors. Pharmacological interference with norepinephrine release or binding to .alpha.₁ -adrenergic receptors by administering sympatholytic agents to the appropriate anal area of a subject can also lead to anal sphincter relaxation, reduction of anal sphincter pressure, maintenance of reduced anal sphincter pressure, and improvement of the signs and symptoms of anorectal disorders. Such sympatholytic agents include .alpha.₁ -adrenergic receptor antagonists (e.g. prazosin, doxazosin, phentolamine, tolazoline, and the like as described in Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G Hardman, et al., McGraw-Hill 1996), .alpha.₂ -adrenergic agonists which block norepinephrine release (e.g. clonidine), nerve terminal norepinephrine depleting agents (e.g. guanethidine, bretylium, reserpine), norepinephrine synthesis inhibitors (e.g. .alpha.-methyl tyrosine), and agents which destroy sympathetic nerve terminals (e.g. 6-hydroxy dopamine). Accordingly, in a related embodiment, the composition contains an alternative sympatholytic agent, such as an .alpha.₂ -adrenergic receptor agonist, a nerve terminal norepinephrine depleting agent, a norepinephrine synthesis inhibitor or another agent which destroys sympathetic nerve terminals.

In still another group of embodiments the agent is an ATP-sensitive K⁺ channel activator. ATP, along with NO, is thought to serve as an inhibitory neurotransmitter released from the enteric non-adrenergic, non-cholinergic nerves that mediate adaptive relaxation of gastrointestinal smooth muscle (Burnstock, Pharmacol Rev. 24:509-81 (1972)). ATP appears to act primarily by opening ATP-sensitive potassium (K_ATP) channels which hyperpolarize the cell membrane, reducing intracellular calcium concentrations, leading to smooth muscle relaxation. Synthetic compounds that activate ATP-sensitive K+ channels are smooth muscle relaxants, e.g. minoxidil, minoxidil sulfate, pinocidil, diazoxide, levcromokalim, cromakalim, etc. (see 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)). Accordingly, 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 the signs and symptoms of anorectal disorders. It should be noted that other K⁺ channels can also influence smooth muscle tone, including apamin-sensitive low conductance calcium-activated K⁺ channels and charybdotoxin-sensitive high conductance calcium-activated K⁺ channels.

In still other embodiments, the compositions will comprise NO donors and smooth muscle relaxants. Preferred smooth muscle relaxants include, for example, hydralazine, papaverine, tiropramide, cyclandelate, isoxsuprine or nylidrin.

In yet other embodiments, the compositions will comprise NO donors and a second agent which is a methyl xanthine or adenosine receptor antagonist. Preferred second agents include theophylline, dyphylline, aminophylline, caffeine, and theobromine.

In a preferred embodiment, a second agent is a K⁺ ATP channel opener, an adenosine receptor antagonist, or a .beta.2-adrenergic receptor agonist. In yet further embodiments, a second agent is preferably selected from the group consisting of theophylline, dyphylline, minoxidil, diazoxide, terbutaline, and salbutamol.

Phosphodiesterase Inhibitor Compositions

In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising a phosphodiesterase inhibitor, preferably a PDE II inhibitor, a PDE IV inhibitor or a PDE V inhibitor, either alone or in combination with another agent selected from .beta.-adrenergic receptor agonists, .alpha.₁ -adrenergic antagonists, estrogens, L-type Ca²⁺ channel blockers, ATP-sensitive K⁺ channel activators, or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier. In other embodiments, the compositions will comprise a dual-selective PDE inhibitor (e.g., a PDE III/IV inhibitor such as zardaverine). The present invention also provides methods of using these compositions.

Phosphodiesterase inhibitors (PDE inhibitors) are agents which can block the breakdown of cAMP and cGMP in the tissue. PDE inhibitors include non-specific PDE inhibitors and specific PDE inhibitors. A non-specific PDE inhibitor inhibits more than one type of phosphodiesterase, while a specific PDE inhibitor inhibits only one type of phosphodiesterase with little, if any, effect on any other type of phosphodiesterase. Specific inhibitors of five cyclic nucleotide PDE isozyme families have been characterized: 8-methoxymethyl-IBMX (isobutyl methylxanthine) or vinpocetine (Ca²⁺, calmodulin-dependent PDE type I); EHNA(erythro-9-(2-hydroxy-3-nonyl)adenine HCl) (cGMP-stimulated PDE type II); milrinone (cGMP-inhibited PDE type III); rolipram (cAMP-specific PDE type IV); and zaprinast and DMPPO (1,3 dimethyl-6-(2-propoxy-5-methane sulphonylamidophenyl)-pyrazolo[3,4-d]pyrimidin-4-(5H)-one) (cGMP-specific PDE type V). Current knowledge suggests that there are at least nine classes of PDE isozymes with type 9A having been recently discovered (see, Fisher, et al., J Biol. Chem. 273(25):15559-15564 (1998)). Agents which are non-specific inhibitors of PDEs include, for example, IBMX, theophylline, aminophylline, theobromine, dyphylline caffeine, etc. (see, Vemulapalli, et al., J Cardiovasc. Pharmacol 28(6):862-9 (1996)).

Preferably, the compositions for treating anorectal disorders contain one or more compounds selected from the classes of PDE II, PDE IV and PDE V inhibitors, or a dual PDE II/IV inhibitor in a formulation suitable for local treatment. Members of each of these classes can be advantageously combined with a second agent selected from the group of .beta.-adrenergic receptor agonists, preferably a .beta.₂ - or .beta.₃ -adrenergic receptor agonists, .alpha.₁ -adrenergic antagonists, L-type Ca²⁺ channel blockers, estrogens, ATP-sensitive K⁺ channel activators, sympathetic nerve terminal destroyers, adenosine receptor antagonists, methylxanthines, or smooth muscle relaxants. Preferred members from each class of additional agent are those which have been described above for use with NO donors.

In embodiments comprising a second active agent with a PDE, a second agent is preferably a K⁺ ATP channel opener, an adenosine receptor antagonist, or a .beta.2-adrenergic receptor agonist. In yet further embodiments, a preferred second agent is a compound selected from the group consisting of theophylline, dyphylline, minoxidil, diazoxide, terbutaline, and salbutamol.

.beta.-adrenergic Receptor Agonist Compositions

In another aspect, the present invention provides pharmaceutical compositions for the treatment of anorectal disorders comprising a .beta.-adrenergic receptor agonist, preferably a .beta.₂ - or .beta.₃ -adrenergic receptor agonist, either alone or in combination with another agent selected from cAMP-hydrolyzing PDE inhibitors (e.g., a PDE IV inhibitor), nonspecific PDE inhibitors, .alpha.₁ -adrenergic antagonists, estrogens, L-type Ca²⁺ channel blockers, ATP-sensitive K⁺ channel activators, or smooth muscle relaxants, and a pharmaceutically acceptable carrier. The present invention further provides methods of using those compositions.

In this aspect of the invention, the .beta.-adrenergic receptor agonist can be essentially any of the .beta.-adrenergic receptor agonists provided above for use in combination with NO donors. Preferably, the .beta.-adrenergic agonist, is a .beta.₂ - or .beta.₃ -adrenergic receptor agonist. Particularly preferred .beta.-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 are selected from salbutamol, terbutaline, procaterol, clenbuterol, isoproterenol, zinterol, BRL 37344, CL316243, CGP-12177A, GS 332, L-757793, L-760087, L-764646, and L-766892.

Terbutaline and salbutamol (albuterol) are .beta.2-adrenergic agonists commonly used for the long-term treatment of obstructive airway diseases and acute bronchospasm in asthma. Beta-adrenergic agents, like VIP, potently relax smooth muscle, 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, T. J. et al., Gut 34(5): 689-93, (1993)); O'Kelly, T. J. et al., Br J Surg 80(10): 1337-41, (1993)). Cyclic AMP induces smooth muscle relaxation through phosphorylation of smooth muscle regulatory proteins (e.g., myosin light chain kinase) and by decreasing intracellular calcium concentrations (e.g., via K⁺ -ATP channel activation). Terbutaline and salbutamol have weaker cardiovascular effects than non-specific .beta.-receptor agonists, e.g., isoproterenol, because they do not stimulate cardiac .beta.₁ -adrenergic receptors at therapeutic doses. They are commonly administered by inhalation (i.e., topically). Tolerance is a potential downside effect of .beta.₂ -adrenergic agonists. Long-term systemic administration of .beta.-adrenergic agonists leads to down-regulation of .beta. receptors in some tissues and decreased pharmacological responses, and has been demonstrated in patients with asthma¹.

¹ Goodman & Gilman's "The Pharmacological Basis of Therapeutics" 9th edition. Chapter 10, Catecholamines, Sympathornimetic Drugs and Adrenergic Receptor Antagonists. Brian B. Hoffman and Robert J. Lefkowitz, 1996.

In one group of embodiments, the compositions comprise forskolin. Forskoline directly activates adenyl cyclase avoiding tolerance.

In one group of embodiments, the composition contains a suitable .beta.-adrenergic receptor agonist and a pharmaceutically acceptable carrier, preferably one formulated for local delivery to the site of the anorectal disease or disorder.

In another group of embodiments, the composition contains another agent selected from cAMP-hydrolyzing PDE inhibitors (e.g., a PDE IV inhibitor), nonspecific PDE inhibitors, .alpha.₁ -adrenergic antagonists, adenosine receptor antagonists including methyl xanthines, estrogens, L-type Ca²⁺ channel blockers, ATP-sensitive K⁺ channel activators or smooth muscle relaxants.

In one preferred group of embodiments, the agent is a cAMP-hydrolyzing PDE inhibitor, more preferably a phosphodiesterase type IV inhibitor. Preferred phosphodiesterase type IV (also referred to as PDE IV and PDE4) inhibitors are described in, for example, 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, dyphylline, lisophylline and papaverine.

In yet another group of preferred embodiments, the agent is an .alpha.₁ -adrenergic antagonist. Suitable .alpha.₁ -adrenergic receptor antagonists (e.g. prazosin, doxazosin, phentolamine, tolazoline, and the like) are described in Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G Hardman, et al., McGraw-Hill (1996). Preferred agents for use in these compositions are selected from prazosin, doxazosin, phentolamine, tolazoline and their derivatives.

In still other preferred embodiments, the adrenergic receptor agonist is combined with an L-type Ca²⁺ channel blocker, such as, for example, nifedipine, nimodipine, felopidine, nicardipine, isradipine, amlodipine, diltiazem, mentol, pinavarium bromide (a gastrointestinal tract selective calcium channel blocker; Awad R A et al., Acta Gastroent. Latinoamer. 27:247-251, 1997) and verapamil.

In yet other preferred embodiments, the .beta.-adrenergic receptor agonist is combined with an ATP-sensitive K⁺ channel activator. Preferred agents within this group are the same as those that have been provided above for use with NO donors.

Additional compositions are those in which a .beta.-adrenergic receptor agonist is combined with an estrogen or estrogen like compound, or with a smooth muscle relaxant. Suitable compounds within each of these classes have been described above for use with NO donors.

In embodiments comprising a second active agent with a .beta.₂ -adrenergic receptor agonist, a second agent is preferably a K⁺ ATP channel opener or an adenosine receptor antagonist. In yet further embodiments, a preferred second agent is a compound selected from the group consisting of theophylline, dyphylline, minoxidil, and diazoxide.

Potassium Channel Activator Compositions

In yet another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising an ATP-sensitive K⁺ channel activator, either alone or in combination with another agent selected from cAMP-dependent protein kinase activators, estrogens, .alpha.₁ -adrenergic antagonists, L-type Ca²⁺ channel blockers, sympathetic nerve terminal destroyers, or smooth muscle relaxants, and a pharmaceutically acceptable carrier. The present invention further provides methods of using those compositions.

In this aspect of the invention, the selected combinations are made from the components described in detail above for the NO donor compositions. Additional description of ATP-sensitive potassium ion channel activators can be found in, for example, Bristol, et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 29, Chap. 8, pp 73-82, Academic Press (1991). In preferred embodiments the potassium ion channel activator is diazoxide, minoxidil, PCO 400, pinocidil, levcromokalin, or cromokalim.

In some embodiments, the composition comprises an additional agent which is a cAMP-dependent protein kinase activator, an estrogen or estrogen like compound, an .alpha.₁ -adrenergic antagonist, an L-type Ca²⁺ channel blocker, a sympathetic nerve terminal destroyer, or a smooth muscle relaxant. Preferably, the cAMP-dependent protein kinase activator is a cAMP mimetic or a dual cGMP/cAMP-dependent protein kinase activator. More preferably, the cAMP mimetic is 8-bromo-cAMP, dibutyryl-cAMP, Rp-cAMPS, or Sp-cAMPS, and the dual activator is selected from Sp-8-pCPT-cGMPS, Sp-8-bromo-cGMPS and 8-CPT-cAMP.

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

In another group of embodiments, an L-type Ca²⁺ channel blocker is combined with an ATP-sensitive potassium ion channel activator. Preferably, the L-type Ca²⁺ channel blocker is nifedipine, nimodipine, felopidine, nicardipine, isradipine, amlodipine, diltiazem, menthol, pinavarium bromide (a gastrointestinal tract selective calcium channel blocker; Awad R A et al., Acta Gastroent. Latinoamer. 27:247-251, 1997) or verapamil.

Diazoxide and minoxidil have been used for the treatment of hypertension. 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 probably relaxes the 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 (Baird et al., Br J Pharmacol 100(2)329-35 (1990)) demonstrated that cromakalim, a K⁺ -ATP channel opener, inhibited spike discharge, hyperpolarized the membrane and relaxed the guinea pig IAS. In our studies, diazoxide and minoxidil relaxed the rat IAS in vivo. The adverse effects of these drugs are predictable and can be divided into three major categories: 1) fluid and salt retention, 2) cardiovascular effects, and 3) hypertrichosis. Topical minoxidil, inspired by the hypertrichosis side effect, is marketed for stimulating hair growth. This product has an excellent safety record and is now sold over the counter.

In still another group of embodiments, a smooth muscle relaxant is combined with an ATP-sensitive potassium ion channel activator. Preferably, the smooth muscle relaxant is hydralazine, papaverine, tiropramide, cyclandelate, isoxsuprine or nylidrin.

In embodiments comprising a second active agent with a K⁺ ATP channel opener, a second agent is preferably a K⁺ ATP channel opener, a .beta.₂ -adrenergic receptor agonist, or an adenosine receptor antagonist. In yet further embodiments, a preferred second agent is a compound selected from the group consisting of theophylline, dyphylline, terbutaline, and salbutamol.

.alpha.₁ -Adrenergic Antagonist Compositions

In still another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising an .alpha.₁ -adrenergic antagonist, either alone or in combination with another agent selected from cAMP-hydrolyzing PDE inhibitors (preferably a PDE IV inhibitor), estrogens, sympathetic nerve terminal destroyers, or smooth muscle relaxants, and a pharmaceutically acceptable carrier. The present invention further provides methods of using those compositions.

.alpha.₁ -Adrenergic antagonists which are useful in this aspect of the invention have been described above and can be found in, for example, Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G Hardman, et al., McGraw-Hill (1996). Preferred .alpha.₁ -adrenergic antagonists are prazosin, phentolamine and tolazoline.

For those embodiments in which an .alpha.₁ -adrenergic antagonist is combined with a cAMP-hydrolyzing PDE inhibitor (preferably a PDE IV inhibitor), an estrogen or estrogen like compound, a sympathetic nerve terminal destroyer, or a smooth muscle relaxant, the preferred members of each class are those which have been described above for use with NO donors.

In embodiments comprising a second active agent with a .alpha.₁ -adrenergic antagonist, a second agent is preferably a K⁺ ATP channel opener, a .beta.₂ -adrenergic receptor agonist or an adenosine receptor antagonist. In yet further embodiments, a preferred second agent is a compound selected from the group consisting of theophylline, dyphylline, minoxidil, diazoxide, terbutaline, and salbutamol.

Cyclic Nucleotide-Dependent Protein Kinase Activator Compositions

In another aspect, the present invention provides pharmaceutical compositions for the treatment of anorectal disorders comprising cyclic nucleotide-dependent protein kinase activators, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, cGMP-dependent protein kinase activators are used alone. In another group of embodiments, nonspecific cyclic nucleotide-dependent protein kinase activators are used alone. In yet another group of embodiments, nonspecific cyclic nucleotide-dependent protein kinase activators are used in combination with smooth muscle relaxants. In still another group of embodiments, cAMP-dependent protein kinase activators are provided in combination with L-type Ca²⁺ channel blockers.

In embodiments comprising a second active agent with the protein kinase activator, a second agent is preferably a K⁺ ATP channel opener, .beta.₂ -adrenergic receptor agonist or an adenosine receptor antagonist. In yet further embodiments, a preferred second agent is a compound selected from the group consisting of theophylline, dyphylline, terbutaline, minoxidil, diazoxide and salbutamol.

In each instance, preferred members of the recited classes of compounds are those that have been described above for use alone or in other combinations.

Estrogen and Estrogen Mimetic Compositions

In another aspect, the present invention provides pharmaceutical compositions for the treatment of anorectal disorders comprising estrogen or an estrogen mimetic, either alone or in combination with another agent from any of the classes of agents described above. Estrogen-like compounds include but are not limited to 17-beta-estrodiol, estrone, mestranol, estradiol valerate, estrodiol dypionate, ethinyl estrodil, quinestrol, estrone sulfate, phytoestrogens such as flavones, isoflavones (e.g. genistein), resveratrol, coumestan derivatives, other synthetic estrogenic compounds including pesticides (e.g. p,p'-DDT), plasticizers (e.g. bisphenol A), and a variety of other industrial chemicals (e.g. polychlorinated biphenyls) (Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G Hardman, et al., McGraw-Hill (1996). Preferred agents are selected from those described with reference to the compositions of single agents or combinations above. Methods for the use of these compositions are also provided.

In embodiments comprising a second active agent with the estrogenic agent, a second agent is preferably a K⁺ ATP channel opener, a .beta.₂ -adrenergic receptor agonist or an adenosine receptor antagonist. In yet further embodiments, a preferred second agent is a compound selected from the group consisting of theophylline, dyphylline, terbutaline, minoxidil, diazoxide and salbutamol.

Sympathetic Nerve Terminal Destroyer Compositions

In another aspect, the present invention provides pharmaceutical compositions for the treatment of anorectal disorders comprising a sympathetic nerve terminal destroyer, either alone or in combination with another agent from any of the classes of agents described above. The sympathetic nerve terminal destroyer compounds include but are not limited to 6-hydroxydopamine and its analogs See, Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G Hardman, et al., McGraw-Hill (1996). Preferred agents are selected from those described with reference to the compositions of single agents or combinations above. Methods for the use of these compositions are also provided.

Adenosine Receptor Antagonists/Methylxanthines

In another aspect, the present invention provides pharmaceutical compositions for the treatment of anorectal disorders comprising a adenosine receptor antagonist, either alone or in combination with another agent from any of the classes of agents described above. Examples of adenosine receptor antagonists include theophylline and dyphylline. See, Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G Hardman, et al., McGraw-Hill (1996). Preferred agents are selected from those described with reference to the compositions of single agents or combinations above. Methods for the use of these compositions are also provided.

Theophylline, a plant-derived methylxanthine, has been used for the treatment of bronchial asthma for decades. Theophylline relaxes smooth muscle, notably bronchial muscle, that has been contracted experimentally with a spasmogen, or clinically in asthma. We found that theophylline relaxed the rat IAS when instilled into the distal anal canal. Proposed mechanisms of methylxanthine-induced physiologic and pharmacological effects include: 1) inhibition of phosphodiesterases, thereby increasing intracellular cyclic AMP, 2) direct effects on intracellular calcium concentration, 3) indirect effects on intracellular calcium concentrations via cell membrane hyperpolarization, 4) uncoupling of intracellular calcium increases with muscle contractile elements, and 5) antagonism of adenosine receptors. Adenosine receptor antagonism is thought to be the most important factor responsible for most of the pharmacological effects of methylxanthines in therapeutically administered doses².

² Goodman & Gilman's "The Pharmacological Basis of Therapeutics" 9th edition. Chapter 28, Drugs Used in the Treatment of Asthma. William E. Serafin, 1996.

We have found the related compound, dyphylline, to also reduce IASP in tests. Dyphylline is not metabolized by the liver and is excreted unchanged by the kidneys, therefore its pharmacokinetics and plasma levels are independent of factors that effect liver enzymes such as smoking, age, congestive heart failure, or the use of other drugs that affect liver function.

In embodiments comprising a second active agent with the adenosine receptor antagonist, a second agent is preferably a K⁺ ATP channel opener or a .beta.₂ -adrenergic receptor agonist. In yet further embodiments, a preferred second agent is a compound selected from the group consisting of terbutaline, minoxidil, diazoxide and salbutamol.

Formulations for the Treatment of Anorectal Disorders

Many of the individual components of the compositions above have been described for use in a variety of disease states. However, certain classes and combinations of classes have now been found to be useful for the treatment of anorectal diseases and can be provided in formulations best suited for delivery to an appropriate anal area. Preferred formulations are those in which the components are combined in a topical formulation for local application to the external or internal anus, the external or internal anal sphincter, anal sphincter muscle, the external or internal anal canal and the lower rectum above the anal canal.

Accordingly, each of the compositions provided above will typically be presented in an appropriate pharmaceutical formulation comprising an effective amount of the noted agents (e.g., NO donors, .beta.₂ - or .beta.₃ -adrenergic receptor agonists, cAMP-hydrolyzing PDE inhibitors, nonspecific PDE inhibitors, .alpha.₁ -adrenergic antagonists, L-type Ca²⁺ channel blockers, ATP-sensitive K⁺ channel activators, adenosine receptor antagonists, and the like).

One of skill in the art will appreciate that suitable formulations are dependent on the form of delivery to be employed, and all such forms are contemplated by the present invention. Additionally, in some embodiments, combinations of agents are employed in a single formulation, while in other embodiments, agents are formulated separately, but administered in combination, or sequentially. In the discussion below, compositions of single agents will be understood to also include compositions of two or more agents. Still further, different formulations can be used for those embodiments in which agents are administered separately or sequentially, by different routes of administration.

Topical Compositions

In view of the above, the present invention provides topical compositions useful for treating anorectal disorders (including those related to hypertonicity and/or spasm of the internal anal sphincter muscle, e.g. hemorrhoidal pain) and for treating spasms of the mammal, including humans, which comprise an effective amount of an agent that reduces the contraction of anal sphincter muscle or maintains a reduced contraction of the anal sphincter muscle, 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 mimic, .beta.-adrenergic agonist, an estrogen or estrogen like compound, an .alpha.₁ -adrenergic antagonist or a potassium channel opener.

In related embodiments, the present invention provides topical pharmaceutical compositions in unit dosage form comprising per unit dosage an amount of the agent or combination provided above, which is effective for treating an anal disorder in a subject in need of such treatment. Typically the agents are in combination with a pharmaceutically acceptable carrier. Such compositions are useful in treating or reducing pain associated with anal disorders, such as hemorrhoidal pain, and for treating spasms and/or hypertonicity of the sphincters, including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, sphincter of Oddi, and the ileocolic sphincter. The topical composition is also useful in treating conditions resulting from spasms and/or hypertonicity of sphincters of the anorectal region including anal fissure, post-operative rectal pain, hypertrophic pyloric stenosis, and pancreatitis, as well as conditions resulting from general spasm of the muscles of the GI tract including Zenkers diverticulum, achalasia, esophageal spasm (nutcracker esophagus), irritable bowel disease, and Hirshprungs disease (bowel obstruction). In addition, the topical compositions are useful for relaxing the anal sphincter, reducing anal sphincter pressure or maintaining reduced anal sphincter pressure and reducing pain and discomfort before, during and after examinations of the anus, rectum and lower gastrointestinal system, insertion of instruments, and procedures such as colonoscopy, cystoscopy and surgery.

Dosage Forms

Topical Administration

Dosage forms for the topical administration of the anal sphincter relaxing agents of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, suppositories and liposomal preparations. The dosage forms may be formulated with mucoadhesive polymers for sustained release of the active compound(s) at the anal mucosa. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants, which may be required. Topical preparations can be prepared by combining the anal sphincter relaxing agent with conventional pharmaceutical diluents and carriers commonly used in topical dry, liquid, cream and aerosol formulations. Ointment and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Such bases may include water and/or an oil such as liquid paraffin or a vegetable oil such as peanut oil or castor oil. Thickening agents which may be used according to the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, woolfat, hydrogenated lanolin, beeswax, and the like. Lotions may be formulated with an aqueous or oily base and, in general, also include one or more of the following: stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes, and the like. Powders may be formed with the aid of any suitable powder base, e.g., talc, lactose, starch, and the like. Drops may be formulated with an aqueous base or non-aqueous base also comprising one or more dispersing agents, suspending agents, solubilizing agents, and the like.

The ointments, pastes, creams and gels also may contain excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Representative compositions include topical compositions comprising one or more of the following first pharmacologic agents: an NO donor, phosphodiesterase inhibitor, cyclic nucleotide mimetic, .beta.-adrenergic agonist, L-type calcium channel blocker, .alpha.-adrenergic antagonist, ATP-sensitive potassium channel activator, sympathetic nerve terminal destroyer, estrogen or estrogen-like compound or botulinum toxin in combination with a pharmaceutically acceptable carrier and at least one of the following second pharmacologic agents: a local anesthetic (e.g., lidocaine, prilocaine, etc.), local anti-inflammatory agent (e.g., naproxen, pramoxicam, etc.), corticosteroid (e.g., cortisone, hydrocortisone, etc.), anti-itch agent (e.g., loperamide diphylenoxalate, etc.), an agent that interferes with the activation of peripheral sensory neurons, including divalent and trivalent metal ions (e.g., manganese, calcium, strontium, nickel, lanthanum, cerium, zinc, etc.), analgesic agents, yeast-based product (e.g., lyophilized yeast, yeast extract, etc.), growth-promoting and/or wound healing-promoting agent known to promote re-epithelialization (e.g., platelet-derived growth factor PDGF, interleukin-11 (IL-11) etc.), anti-microbial agent (e.g., neosporin, polymyxin B sulfate, bacitracin zinc, etc.), mucoadhesive agent (e.g., cellulose derivatives, etc.), cytoprotectant agent (e.g., colloidal bismuth, misoprostol, etc., with the exception of sucralfate) as defined in GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, supra, an agent that promotes local tissue sclerosis (e.g., alum, etc.), or menthol. The first pharmacologic agent is typically present in the composition in unit dosage form effective for treatment of a first medical condition(s), such as an anal disease or pain associated with an anal disease. The second pharmacologic agent is typically present in the composition in unit dosage form effective for treatment of a second medical condition(s), or a condition(s), symptom(s) or effect(s) associated with or resulting from the first medical condition(s).

In one aspect, the invention provides compositions for treating anorectal disorders which comprise an active agent and a pharmaceutically acceptable carrier. The active agent comprises an agent that stimulates or causes an increase of either cGMP or cAMP through activation of guanylyl or adenylyl cyclase, respectively, a cyclic nucleotide mimetic, PDE inhibitor, .alpha.-adrenergic receptor antagonist, or .beta.-adrenergic receptor agonist, or potassium channel opener. In one aspect, the active agent is present in compositions of the invention in an amount of from about 0.001% to about 15% by weight of the composition. In another aspect, the active agent is present in an amount of from about 0.01% to about 7.5% by weight, more preferably from about 0.05% to about 2% by weight of the composition.

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

The topical pharmaceutical compositions can also include one or more preservatives or bacteriostatic agents, e.g., methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, and the like. The topical pharmaceutical compositions also can contain other active ingredients such as antimicrobial agents, particularly antibiotics, anesthetics, analgesics, and antipruritic agents.

One example of a topical formulation includes 75% (w/w) white petrolatum USP, 4% (w/w) paraffin wax USP/NF, lanolin 14% (w/w), 2% sorbitan sesquioleate NF, 4% propylene glycol USP, and 1% anal sphincter relaxing agent.

The dosage of a specific anal sphincter relaxing agent depends upon many factors that are well known to those skilled in the art, for example, the particular agent; the condition being treated; the age, weight, and clinical condition of the recipient patient; and the experience and judgment of the clinician or practitioner administering the therapy. An effective amount of the compound is that which provides either subjective relief of symptoms or an objectively identifiable improvement as noted by the clinician or other qualified observer. The dosing range varies with the compound used, the route of administration and the potency of the particular compound.

Transmucosal (i.e., sublingual, rectal, colonic, pulmonary, buccal and vaginal) drug delivery provides for an efficient entry of active substances to systemic circulation and reduces immediate metabolism by the liver and intestinal wall flora (See Chien Y. W., NOVEL DRUG DELIVERY SYSTEMS, Chapter 4 "Mucosal Drug Delivery," Marcel Dekker, Inc. (1992). Transmucosal drug dosage forms (e.g., tablet, suppository, ointment, gel, pessary, membrane, and powder) are typically held in contact with the mucosal membrane and disintegrate and/or dissolve rapidly to allow immediate local and systemic absorption. These formulations are used along with the anti-inflammatory agents of the present invention for reducing or eliminating inflammation of transmucosal membranes.

In order to enhance transmucosal absorption efficiency and bioavailability of the active agents, selected mucosal adhesive polymers or dosages can be employed. For example, a selected potassium channel opener, e.g. minoxidil can be formulated in a liquid suppository in which mucoadhesive polymers such as polyvinylpyrrolidone (PVP, BASF, Germany), polycarbophil (Goodrich, USA), or sodium alginate (Hayashi Pure Chemicals, Tokyo, Japan), etc. are incorporated. This type of liquid suppository has a gelation temperature between 30 to 36^oC. and has a mucoadhesive force of 430 to 5800 dyne/cm. As a result, the suppository remains as an easy to apply liquid at room temperature, gels at physiological temperature and remain adhered to the anal mucosal membrane for a sustained period of time (Rye J M 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 formulations are either as solutions or semi-solid preparations (gel, ointment, suspension, lotion, cream, etc.). Suitable excipients, depending on the agent, include petrolatum, lanolin, methylcellulose, sodium carboxymethylcellulose, hydroxpropylcellulose, sodium alginate, carbomers, glycerin, glycols, oils, glycerol, benzoates, parabens and surfactants. It will be apparent to those of skill in the art that the solubility of a particular compound will, in part, determine how the compound is formulated. An aqueous gel formulation will is suitable for soluble compounds. Where a compound is insoluble at the concentrations required for activity, a cream or ointment preparation will typically be preferable. In this case, oil phase, aqueous/organic phase and surfactant may be required to prepare the formulations. Thus, based on the solubility and excipient-active interaction information, the dosage forms can be designed and excipients can be chosen to formulate the prototype preparations. Particularly preferred preparations include those in a suppository or sustained release format.

Sustained or Controlled Delivery Formulations

In yet other embodiments, the invention provides topical sustained and prolonged release pharmaceutical compositions comprising one or more anal sphincter relaxant, including nitric oxide donors (such as nitroglycerin, isosorbide dinitrate, and L-arginine) or the pharmacological agents described above and a pharmaceutically acceptable carrier, to treat anorectal disorders. The compositions 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 comprise a unit dosage of one or more active agents (e.g., nitric oxide donor) which is effective in treating anal disorders and in controlling and alleviating pain associated therewith. Preferably, the compositions are administered in unit dosage form to a subject in need of such treatment. In other embodiments, the compositions contain an NO donor in an amount which is less than an effective amount when used alone, but which is effective when used in combination with a second agent which modulates levels of cAMP or cGMP in a subject. Topical sustained and prolonged release compositions are typically variants which include 1) an absorbent in a hydrophilic base; 2) an absorbent in a hydrophobic base; and 3) coated beads containing an absorbent matrix dispersed in a suitable vehicle. Also provided are methods of treating anal or GI tract disorders comprising topically administering an effective amount of such compositions (e.g., in unit dosage form) to the appropriate anal area of the subject in need of such treatment.

Such hydrophilic compositions and preparations of the invention comprise a nitric oxide donor (or other suitable agent or combination of agents) and a polymer, such as cellulose (methyl cellulose, ethyl cellulose, hydroxy propyl cellulose, etc.), higher molecular weight polyethylene glycol, methacrylic-acrylic acid emulsion, hydrogel, carbopol, ethyl vinyl acetate copolymer, or polyester, etc., to bind the nitric oxide donor to the polymer. The nitric oxide donor-polymer matrix or agent-polymer matrix is then dispersed in a hydrophilic vehicle to form a semi-solid. After administration of such hydrophilic composition into the appropriate anal area, such as the anal canal or anal sphincter, the water in the semi-solid preparation is adsorbed and the polymer matrix with the active ingredient--the nitric oxide donor or other agent--remains as a coating in the anal region or area to which it has been applied. The nitric oxide donor is then slowly released from this coating.

Hydrophobic compositions and preparations of the inventions employ similar polymers as used in the hydrophilic preparations, but the polymer/nitric oxide donor matrix is dispersed into a vehicle, such a plastibase, in the hydrophobic compositions and preparations. Plastibase is a mineral oil base that only partially dissolves the nitric oxide donor. The semi-solid composition forms a thin coating on the anal region to which the composition has been applied (such as the anal canal or anal sphincter area) and slowly releases the active. The prolonged action is controlled principally by the solubility of the active ingredient (nitric oxide donor) in the vehicle.

The present invention also provides coated beads which are produced by first absorbing the nitric oxide donor or other agent or combination of agents on a cellulosic material blended with polyethylene glycol, filler, binder and other excipients. The resulting matrix is then extruded and spheronized (e.g., the process of making into spheres) to create small beads. The beads are then coated to an appropriate thickness with one or more of a suitable material, such as a methacrylic-acrylic polymer, polyurethane, ethyl vinyl acetate copolymer, polyester, silastic, etc. The coating on the beads acts as a rate controlling membrane which regulates the release of the agent from the core beads.

Oral Formulations

In still another embodiment, the invention provides pharmaceutical compositions suitable for oral administration which are provided in unit dosage form comprising per unit dosage a phosphodiesterase inhibitor, cyclic nucleotide mimetic, or .beta.-adrenergic agonist, and a pharmaceutically acceptable carrier. Such compositions are useful for treating anorectal disorders, including those disorders and conditions provided above.

For delivery to the buccal membranes, typically an oral formulation, such as a lozenge, tablet, or capsule is used. The method of manufacture of these formulations are known in the art, including but not limited to, the addition of a pharmacological agent to a pre-manufactured tablet; cold compression of an inert filler, a binder, and either a pharmacological agent or a substance containing the agent (as described in U.S. Pat. No. 4,806,356); and encapsulation. Another oral formulation is one that can be applied with an adhesive, such as the cellulose derivative, hydroxypropyl cellulose, to the oral mucosa, for example as described in U.S. Pat. No. 4,940,587. This buccal adhesive formulation, when applied to the buccal mucosa, allows for controlled release of the pharmacological agent into the mouth and through the buccal mucosa. The anti-inflammatory agents of the present invention can be incorporated into these formulations as well.

Aerosol Formulations

For delivery to the nasal or bronchial membranes, typically an aerosol formulation is employed. The term "aerosol" includes any gas-borne suspended phase of the pharmacological agent which is capable of being inhaled into the bronchioles or nasal passages. Specifically, aerosol includes a gas-borne suspension of droplets of the compounds of the instant invention, as may be produced in a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol also includes a dry powder composition of a compound of the pharmacological agent suspended in air or other carrier gas, which may be delivered by insufflation from an inhaler device, for example. For solutions used in making aerosols, the preferred range of concentration of the pharmacological agent is 0.1-100 milligrams (mg)/milliliter (mL), more preferably 0.1-30 mg/mL, and most preferably, 1-10 mg/mL. Usually the solutions are buffered with a physiologically compatible buffer such as phosphate or bicarbonate. The usual pH range is 5 to 9, preferably 6.5 to 7.8, and more preferably 7.0 to 7.6. Typically, sodium chloride is added to adjust the osmolarity to the physiological range, preferably within 10% of isotonic. Formulation of such solutions for creating aerosol inhalants is discussed in Remington's Pharmaceutical Sciences, see also, Ganderton and Jones, DRUG DELIVERY TO THE RESPIRATORY TRACT, Ellis Horwood (1987); 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 the pharmacological agent may be converted into aerosols by any of the known means routinely used for making aerosol inhalant pharmaceuticals. In general, such methods comprise pressurizing or providing a means of pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice, thereby pulling droplets of the solution into the mouth and trachea of the animal to which the drug is to be administered. Typically, a mouthpiece is fitted to the outlet of the orifice to facilitate delivery into the mouth and trachea.

Parenteral Formulations

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

Methods of Treating Anorectal Disorders

In another aspect, the present invention provides methods for treating anorectal disorders which comprise administering to an appropriate anal area or affected anal tissue (e.g., external or internal anal tissue or anal canal) of a subject in need of such treatment an effective amount of any of the compositions provided above. By use of such methods of the invention, anorectal hypertonicity and/or spasms are relieved, anal sphincter pressure is reduced, reduced anal sphincter pressure is maintained, and signs and symptoms associated with anorectal disorders, e.g. anal fissures, anal ulcers and hemorrhoids, and pain are improved. The methods described herein are also applicable to the treatment of recurrent anal diseases, and are also useful for relaxing the anal sphincter and reducing pain during anorectal exams (in patients with and without disorders), particularly during procedures when instruments are inserted into the anus.

The present invention further provides methods of using the compositions above in combination with local anesthetic agents, for example lidocaine, prilocaine, etc. Each of the compositions will typically be in a pharmaceutically acceptable dosage form as an effective treatment for a medical condition such as hemorrhoidal pain and for treating spasms and/or hypertonicity of the sphincters including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, sphincter of Oddi, and the ileocolic sphincter. These pharmaceutical preparations are also useful in treating conditions resulting from spasms and/or hypertonicity of sphincters of the anorectal region including anal fissure, post-operative rectal pain, hypertrophic pyloric stenosis, and pancreatitis, as well as conditions resulting from general spasm of the muscles of the GI tract including Zenkers diverticulum, achalasia, esophageal spasm (nutcracker esophagus), irritable bowel disease, and Hirschsprung's disease (bowel obstruction). In another aspect, the present invention provides methods for treating anal disorders which comprise administering an effective amount of such composition along with a local anesthetic agent to a subject in need of such treatment. Such compositions can be administered orally, topically, or parenterally.

Similarly, the invention provides methods of using the compositions above in combinations with local anti-inflammatory agents, for example, naproxen, piroxicam, etc. in a pharmaceutically acceptable dosage form as an effective treatment for a medical condition such as hemorrhoidal pain and for treating hypertonicity and/or spasms of the sphincters including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, sphincter of Oddi, and the ileocolic sphincter. These pharmaceutical preparations are also useful in treating conditions resulting from spasms and/or hypertonicity of sphincters of the anorectal region including anal fissure, post-operative rectal pain, hypertrophic pyloric stenosis, and pancreatitis, as well as conditions resulting from general spasm of the muscles of the GI tract including Zenkers diverticulum, achalasia, esophageal spasm (nutcracker esophagus), irritable bowel disease, and Hirschsprung's disease (bowel obstruction). In another aspect, the present invention provides methods for treating anal disorders which comprise administering an effective amount of such composition along with a local anesthetic agent to a subject in need of such treatment. Such compositions can be administered orally, topically, or parenterally.

Additional methods provided by the present invention are those in which two or more agents selected from NO donors, phosphodiesterase type V (PDE V) inhibitor, a phosphodiesterase type II (PDE II) inhibitor, a nonspecific PDE inhibitor, a dual-selective PDE inhibitor, a .beta.-adrenergic agonist, a cAMP-dependent protein kinase activator, an .alpha.₁ -adrenergic antagonist, a superoxide anion (O_2^-) scavenger, an ATP-sensitive K⁺ channel activator, an estrogen or estrogen mimetic, a sympathetic nerve terminal destroyer, an adenosine receptor antagonist, or a smooth muscle relaxant, are administered either in combination or sequentially to provide an enhanced therapeutic benefit. In particular, the use of an NO donor and a second agent from those provided above can provide fewer and less severe side effects than equally effective doses of NO donors, if used alone. More particularly, the use of an NO donor in combination with a second agent allows for decreased amounts of the NO donor to be used to achieve the same benefit relative to use alone, while extending the period of reduction of anal sphincter pressure, and provides significantly reduced occurrence and duration of headaches.

Claim 1 of 10 Claims

What is claimed is:

1. A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition that consists essentially of an adenosine receptor antagonist.

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