HK1204553A1 - Extended-release formulation for reducing the frequency of urination and method of use thereof - Google Patents

Abstract

A method for reducing the frequency of urination is disclosed. The method comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising one or more analgesic agents and one or more a-b lockers. In one embodiment, the one or more analgesic agents are formulated for extended-release.

Description

Extended release formulations for reducing urinary frequency and methods of use thereof

This application claims priority to U.S. patent application serial No. 13/487,348 filed on 6/4/2012 and U.S. patent application serial No. 13/424,000 filed on 3/19/2012.

Technical Field

The present application relates generally to methods and compositions for inhibiting muscle contraction, and in particular, to methods and compositions for inhibiting bladder smooth muscle contraction.

Background

The detrusor is a layer of the bladder wall formed by smooth muscle fibers arranged in helical, longitudinal, and circular fiber bundles. When the bladder is stretched, this signals the parasympathetic nervous system to contract the detrusor muscle. This promotes urinary bladder urination through the urethra.

In order for urine to drain out of the bladder, both the voluntary control internal sphincter and the voluntary control external sphincter must be open. Problems with these muscles can lead to incontinence. If the urine volume reaches 100% of the absolute capacity of the bladder, the voluntary sphincter becomes involuntary and the urine is immediately excreted.

The adult bladder typically contains about 300-350ml of urine (working volume), but a full adult bladder may contain up to about 1000ml (absolute volume) depending on the individual. As urine accumulates, the ridges formed by the folds (folds) of the bladder wall flatten and the bladder wall thins as it stretches, allowing the bladder to store larger amounts of urine without a significant increase in internal pressure.

For most individuals, the need for urination typically begins when the volume of urine in the bladder reaches about 200 ml. At this stage, the individual can easily suppress the urge to urinate if he so desires. As the bladder continues to fill, the need to urinate becomes stronger and more difficult to ignore. Eventually, the bladder will fill to the point where the urge to urinate is overwhelmed and the individual will no longer be able to ignore it. In some individuals, this need for urination may arise when the bladder is less than 100% full compared to its working volume. This increased urinary demand may interfere with normal activities, including the ability to provide adequate uninterrupted sleep at rest. In some cases, this enhanced need for urination may be associated with a medical condition, such as benign prostatic hyperplasia or prostate cancer in men, or pregnancy in women. However, enhanced urinary demand also occurs in individuals (both male and female) who are not affected by other medical conditions.

Thus, there is a need for compositions and methods for treating male or female individuals suffering from the need for urination when the bladder is less than 100% full of urine compared to its working volume. The compositions and methods are needed for inhibiting muscle contraction, thereby allowing the individual's need to urinate to begin when the volume of urine in the bladder exceeds about 100% of the working volume.

Disclosure of Invention

One aspect of the present application relates to a method of reducing the frequency of urination in a subject. The method comprises administering to a subject in need thereof an effective amount of one or more analgesic agents and an effective amount of one or more additional active ingredients selected from the group consisting of alpha-blockers and 5 alpha-reductase inhibitors. The method may be used to treat nocturia or overactive bladder.

Another aspect of the present application relates to a pharmaceutical composition comprising: an active ingredient comprising one or more analgesic agents, an alpha-blocker, and a pharmaceutically acceptable carrier.

Another aspect of the present application relates to a pharmaceutical composition comprising: comprising one or more active ingredients of an analgesic agent, a 5 alpha-reductase inhibitor, and a pharmaceutically acceptable carrier.

Drawings

Fig. 1A and 1B are graphs showing that analgesics modulate the expression of co-stimulatory molecules of Raw264 macrophages in the absence (fig. 1A) or presence (fig. 1B) of LPS. The cells were cultured for 24 hours in the presence of an analgesic alone or in the presence of Salmonella typhimurium LPS (0.05. mu.g/ml). The results are the average relative percentage of CD40+ CD80+ cells.

Detailed Description

The following detailed description is presented to enable one skilled in the art to make and use the invention. For purposes of explanation, specific nomenclature is set forth below to provide a thorough understanding of the present invention. It will be apparent, however, to one skilled in the art that these specific details are not required in the practice of the present invention. Descriptions of specific applications are provided only as exemplary embodiments. The present invention is not intended to be limited to the embodiments shown, but is to be accorded the widest scope possible consistent with the principles and features disclosed herein.

The term "effective amount" as used herein refers to the amount necessary to achieve a selected result.

The term "analgesic" as used herein refers to an agent, compound or drug that is used to relieve pain and includes anti-inflammatory compounds. Exemplary analgesic and/or anti-inflammatory agents, compounds, or drugs include, but are not limited to, the following: non-steroidal anti-inflammatory drugs (NSAIDs), salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, p-aminophenol derivatives, acetanilide, acetaminophen, phenacetin, fenamate, mefenamic acid, meclofenamate sodium, heteroaryl acetic acid derivatives, tolmetin, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin; enolic acid, oxicam derivatives, piroxicam, meloxicam, tenoxicam, ampiroxicam, droxyxicam, pivoxicam, pyrazolone derivatives, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, analgin, coxib drugs (coxibss), celecoxib, rofecoxib, nabumetone, apazone, indomethacin, sulindac, etodolac, isobutylphenylpropionic acid, lumiracoxib (lumiracoxib), etoricoxib, parecoxib, valdecoxib, telacoxib (tiracoxib), etodol, dabrafenone, dexketoprofen, aceclofenac, lincofilone (licofelone), bromfenac, loxoprofen, pranoprofen, piroxicam, nimesulide, cizolirtine, 3-formylamino-7-methylsulfonylamino-6-phenoxy-4-H-1-benzopyran-4-one, meloxicam, lornoxicam, dexindobufen, moxezolidin, guaiamidine (amtolmetin), pranoprofen, tolfenamic acid, flurbiprofen, suprofen, oxaprozin, zaltoprofen, alminoprofen, tiaprofenic acid, pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof.

The terms "coxib (coxib)" and "COX inhibitor" as used herein refer to compositions containing compounds that inhibit the activity or expression of the COX2 enzyme or inhibit or ameliorate the severity of severe inflammatory reactions, including pain and swelling.

The term "derivative" as used herein refers to a chemically modified compound which is considered by the ordinarily skilled chemist to be a routine route, such as esters or amides of acids, protecting groups, such as benzyl for alcohols or thiols, and t-butoxycarbonyl for amines.

The term "analog" as used herein refers to a compound that includes a chemically modified form of a particular compound or class thereof that retains the pharmaceutically and/or pharmacologically active characteristics of the particular compound or class thereof.

As used herein, "subject" or "patient" includes mammals. In one aspect, the mammal is a human. In another aspect, the mammal is a non-human primate, such as an orangutan and other ape and monkey species. In one aspect, the mammal is a domestic animal, such as a rabbit, dog, or cat. In another aspect, the mammal is a farm animal, such as a cow, horse, sheep, goat, or pig. In another aspect, the mammal is an experimental animal, including rodents, such as rats, mice and guinea pigs, and the like.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, the parent compounds of which are modified by forming acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to: mineral or organic acid salts of basic residues (e.g., amines), basic or organic salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared with organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

The phrase "pharmaceutically acceptable" is employed herein in connection with compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The bladder has two important functions: store urine and empty. Storage of urine occurs at low pressure, which means that the detrusor muscle relaxes during the filling phase. Voiding of the bladder requires coordinated detrusor contraction and relaxation of the urethral sphincter. Disorders of storage function can lead to lower urinary tract symptoms such as urgency, frequency and urge incontinence, a component of overactive bladder syndrome. Overactive bladder syndrome, which may be due to involuntary contractions of the bladder smooth muscle (detrusor) during the storage phase, is a common and underestimated problem, the prevalence of which has only recently been assessed.

One aspect of the present application relates to a method of reducing urinary frequency. The method comprises administering to a subject in need thereof an effective amount of one or more analgesic agents and an effective amount of an alpha-blocker. In some embodiments, the one or more analgesic agents and the alpha-blocker are administered separately in different dosage forms. In other embodiments, the one or more analgesic agents and the alpha-blocker are administered simultaneously in a single dosage form (e.g., in a single pill or tablet). In some embodiments, the one or more analgesic agents and the alpha-blocker are both formulated for immediate release upon administration. In some further embodiments, the one or more analgesic agents and the alpha-blocker are both formulated for delayed release after administration. In other embodiments, the one or more analgesic agents and the alpha-blocker are both formulated for extended release upon administration. In other embodiments, the one or more analgesic agents and the alpha-blocker are both formulated for delayed-extended release after administration. In some further embodiments, the one or more analgesic agents are formulated for delayed-release, extended-release, or delayed-extended-release after administration, and the alpha-blocker is formulated for immediate-release. In still other embodiments, the one or more analgesic agents are formulated for immediate release and the alpha-blocker is formulated for delayed release, extended release, or delayed extended release. The method can be used to treat nocturia or overactive bladder. Another aspect of the present application relates to a pharmaceutical composition comprising: comprises one or more active ingredients of analgesic agent, alpha-retarder and pharmaceutically acceptable carrier.

Alpha blockers, also known as alpha-adrenergic antagonists or alpha-blockers, are a pharmaceutical formulation that act as receptor antagonists for alpha-adrenergic receptors, which are further divided into alpha 1-adrenergic receptors and alpha 2-adrenergic receptors. Alpha blockers can be classified into selective blockers acting selectively on alpha 1-adrenergic receptors or alpha 2-adrenergic receptors, and non-selective alpha blockers acting on both types of alpha-adrenergic receptors.

Examples of selective alpha 1-adrenergic blockers include, but are not limited to: alfuzosin, prazosin, doxazosin, tamsulosin, terazosin, carvedilol, labetadine and silodosin. Examples of selective alpha 2-adrenergic blockers include, but are not limited to: altimezole, idazoxan, and yohimbine. Examples of non-selective alpha adrenergic blockers include: phenoxybenzamine, phentermine, tolazoline, trazodone, typical and atypical antipsychotics.

In some embodiments, the one or more analgesics are used in an amount of 50-2000mg,50-1500mg,50-1200mg,50-1000mg,50-800mg,50-600mg,50-500mg,50-400mg,50-300mg,50-250mg,50-200mg,50-100mg,100-2000mg,100-1500mg,100-1200mg,100-1000mg,100-800mg,100-600mg,100-500mg,100-400mg,100-300mg,100-200mg,200-2000mg,200-1500mg,200-1200mg,200-1000mg,200-800mg,200-600mg,200-400mg,400-2000mg, 400-1500-1200 mg,400-1000mg, 800mg 400-; the one or more alpha-blockers are administered orally at a daily single or combined dose of 0.01-100mg,0.01-30mg,0.01-10mg,0.01-3mg,0.01-1mg,0.01-0.3mg,0.01-0.1mg,0.01-0.03mg,0.03-100mg,0.03-30mg,0.03-10mg,0.03-3mg,0.03-1mg,0.03-0.3mg,0.03-0.1mg,0.1-100mg,0.1-30mg,0.1-10mg,0.1-3mg,0.1-1mg,0.1-0.3mg,0.3-100mg,0.3-30mg,0.3-10mg,0.3-3mg,0.3-1mg and 0.2-1 mg.

In some embodiments, the alpha-blocker is a non-selective alpha-blocker. In other embodiments, the alpha-blocker is a selective alpha 1-adrenergic blocker. In other embodiments, the alpha-blocker is a selective alpha 2-adrenergic blocker. In other embodiments, the alpha-blocker is tamsulosin.

Another aspect of the present application relates to a pharmaceutical composition comprising: one or more analgesic agents; one or more alpha-blockers; and a pharmaceutically acceptable carrier. In some embodiments, the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen.

In some embodiments, the amount of the pharmaceutical composition used alone or in combination is 50-2000mg,50-1500mg,50-1200mg,50-1000mg,50-800mg,50-600mg,50-500mg,50-400mg,50-300mg,50-250mg,50-200mg,50-100mg,100-2000mg,100-1500mg,100-1200mg,100-1000mg,100-800mg,100-600mg,100-500mg,100-400mg,100-300mg,100-200mg,200-2000mg,200-1500mg,200-1200mg,200-1000mg,200-800mg,200-600mg,200-400mg,400-2000mg,400-1500mg, 400-1000-400-1000 mg,800 mg 400-; and one or more alpha-blockers in an amount of 0.01 to 100mg,0.01 to 30mg,0.01 to 10mg,0.01 to 3mg,0.01 to 1mg,0.01 to 0.3mg,0.01 to 0.1mg,0.01 to 0.03mg,0.03 to 100mg,0.03 to 30mg,0.03 to 10mg,0.03 to 3mg,0.03 to 1mg,0.03 to 0.3mg,0.03 to 0.1mg,0.1 to 100mg,0.1 to 30mg,0.1 to 10mg,0.1 to 3mg,0.1 to 1mg,0.1 to 0.3mg,0.3 to 100mg,0.3 to 30mg,0.3 to 10mg,0.3 to 3mg,0.3 to 1mg, and 0.2 to 1 mg.

In some embodiments, the alpha-blocker is a non-selective alpha-blocker. In other embodiments, the alpha-blocker is a selective alpha 1-adrenergic blocker. In other embodiments, the alpha-blocker is a selective alpha 2-adrenergic blocker. In other embodiments, the alpha-blocker is tamsulosin.

In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 100-200mg,200-400mg,400-600mg,600-800mg,800-1000mg or 1000-1200mg and tamsulosin in an amount of 0.1-0.3mg,0.3-0.6mg,0.6-0.9mg,0.9-1.2mg or 1.2-1.5 mg.

In other embodiments, the one or more analgesic agents and the one or more a-blockers are both formulated for immediate release. In some further embodiments, the one or more analgesic agents are formulated for immediate release and the one or more a-blockers are formulated for extended release.

In some further embodiments, the one or more analgesic agents are formulated for extended release and the one or more alpha-blockers are formulated for immediate release. In some embodiments, the one or more analgesic agents are released continuously or at a sustained rate over a period of time or 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours. In some embodiments, at least 90% of the one or more analgesic agents are released continuously or at a sustained rate over a period of time or 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

In still other embodiments, the one or more analgesic agents are released within 2 hours of administration, while the remainder are released continuously or at a sustained rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

In some further embodiments, the one or more analgesic agents and the one or more a-blockers are both formulated for extended release. In some embodiments, the one or more analgesic agents and the one or more alpha-blocker are both formulated for extended release such that the one or more analgesic agents and the one or more alpha-blocker are released continuously or at a sustained rate over a period of time or 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours. In still other embodiments, the one or more analgesic agents and the one or more alpha-blocker are both formulated for extended release with a biphasic release profile in which 20-60% of the one or more analgesic agents and the one or more alpha-blocker agents are released within 2 hours of administration and the remainder are released continuously or at a sustained rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 50-1000mg,50-250mg,250-400mg,400-600mg,600-800mg or 800-1000mg and tamsulosin in an amount of 0.1-1.2mg,0.1-0.3mg,0.3-0.6mg,0.6-0.9mg or 0.9-1.2mg in combination, wherein the composition is formulated for extended release of both acetaminophen and tamsulosin with a drug release profile in which at least 90% of the acetaminophen and tamsulosin are released continuously or at a steady rate over a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

In other embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 500-1000mg,50-200mg,50-400mg, 100-300mg,200-400mg,400-600mg,600-800mg,800-1000mg or 1000-1200mg and tamsulosin in an amount of 0.1-1.2mg,0.1-0.3mg,0.3-0.6mg,0.6-0.9mg or 0.9-1.2mg, wherein the composition is formulated for extended release having a two-stage release profile in which, 20-60% of the acetaminophen and tamsulosin are released within 2 hours of administration, while the remainder is released continuously or at a steady rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

"extended release", also known as sustained-release (SR), sustained-action (SA), time-release (TR), controlled-release (CR), modified-release (MR) or sustained-release (CR), is a mechanism used in pharmaceutical tablets or capsules to slowly dissolve and release the active ingredient over time. The advantage of extended release tablets or capsules is that they can generally be administered less frequently than immediate release formulations of the same drug and, moreover, they maintain a more stable level of drug in the bloodstream, thereby extending the duration of drug action and reducing the peak amount of drug in the bloodstream. For example, extended release analgesics can allow a person to sleep overnight without getting up to night.

In one embodiment, the pharmaceutical composition is formulated for extended release by embedding the active ingredient in a matrix of insoluble materials such as acrylates or chitin. The extended release form is designed to release the analgesic compound at a predetermined rate by maintaining a constant drug level over a specified period of time. This can be achieved by different formulations, including, but not limited to, liposomes and drug-polymer conjugates, such as hydrogels.

The extended release formulation can be designed to release the active agent at a predetermined rate to maintain a constant drug level over a particular extended period of time, e.g., up to about 24 hours, about 20 hours, about 16 hours, about 12 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour after administration or after a lag period associated with delayed release of the drug.

In certain preferred embodiments, the active agent is released over a time interval of about 2 hours to about 10 hours. Additionally, the active agent may also be released within about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, or about 24 hours. In other embodiments, the active agent is released over a period of about 3 hours to about 8 hours after administration.

In some embodiments, the extended release formulation includes an active core comprised of one or more inert particles each in the form of beads, pills, particulate particles, microcapsules, microspheres, microparticles, nanocapsules, or nanospheres having a drug coated on their surface (e.g., in the form of a drug-containing coating or film-forming composition (using, for example, fluidized bed techniques or other methods well known to those skilled in the art)). The inert particles may be of different sizes as long as they are large enough to remain insoluble. Alternatively, the active core may be prepared by granulation and milling and/or by extrusion and spheronization of a polymer composition containing the pharmaceutical ingredient.

The active agent may be incorporated into the inert carrier by techniques well known to those skilled in the art, such as drug layering, powder coating, extrusion/spheronization, rolling or granulation. The amount of drug in the core will depend on the required dosage and will generally vary from about 5 to 90 wt%. Typically, the polymer coating on the active core is about 1 to 50% based on the weight of the coated particle, depending on the desired lag time and/or the polymer and coating solvent selected. One skilled in the art will be able to select the appropriate amount of drug to coat or introduce into the core to achieve the desired dosage. In one embodiment, the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alters the microenvironment of the drug to facilitate its release.

Another aspect of the present application relates to a method of reducing frequency of urination. The method comprises administering to a subject in need thereof an effective amount of one or more analgesic agents, and an effective amount of a 5 α -reductase inhibitor. Examples of 5 α -reductase inhibitors include, but are not limited to: finasteride, beclomede, epristeride, epothilone, lapiostronide, and tolperiside. In some embodiments, the 5 α -reductase inhibitor is finasteride.

In some embodiments, the one or more analgesic agents and the 5 α -reductase inhibitor are administered separately in different dosage forms. In other embodiments, the one or more analgesic agents and the alpha-blocker are administered simultaneously in a single dosage form (e.g., in a single pill or tablet). In some embodiments, the one or more analgesic agents and the 5 α -reductase inhibitor are both formulated for immediate release upon administration. In other embodiments, the one or more analgesic agents and the 5 α -reductase inhibitor are both formulated for delayed release after administration. In other embodiments, the one or more analgesic agents and the 5 α -reductase inhibitor are both formulated for extended release upon administration. In other embodiments, the one or more analgesic agents and the 5 α -reductase inhibitor are both formulated for delayed-extended release after administration. In other embodiments, the one or more analgesic agents are formulated for delayed-release, extended-release, or delayed-extended-release, and the 5 α -reductase inhibitor is formulated for immediate-release. In still other embodiments, the one or more analgesic agents are formulated for immediate release and the 5 α -reductase inhibitor is formulated for delayed release, extended release, or delayed-extended release. The method can be used to treat nocturia or overactive bladder. Another aspect of the present application relates to a pharmaceutical composition comprising: comprises one or more active ingredients of analgesic, 5 alpha-reductase inhibitor and pharmaceutically acceptable carrier.

In some embodiments, the one or more analgesics are used in an amount of 50-2000mg,50-1500mg,50-1200mg,50-1000mg,50-800mg,50-600mg,50-500mg,50-400mg,50-300mg,50-250mg,50-200mg,50-100mg,100-2000mg,100-1500mg,100-1200mg,100-1000mg,100-800mg,100-600mg,100-500mg,100-400mg,100-300mg,100-200mg,200-2000mg,200-1500mg,200-1200mg,200-1000mg,200-800mg,200-600mg,200-400mg,400-2000mg, 400-1500-1200 mg,400-1000mg, 800mg 400-; and the 5 alpha-reductase inhibitor is orally administered in a daily single or combined dose of 0.1-250mg,0.1-100mg,0.1-30mg,0.1-10mg,0.1-3mg,0.1-1mg,0.3-250mg,0.3-100mg,0.3-30mg,0.3-10mg,0.3-3mg,0.3-1mg,1-100mg,1-30mg,1-10mg,1-3mg,3-7mg and 4-6 mg.

In some embodiments, the 5 α -reductase inhibitor is tamsulosin.

Another aspect of the present application relates to a pharmaceutical composition comprising: one or more analgesics, one or more 5 α -reductase inhibitors; and a pharmaceutically acceptable carrier. In some embodiments, the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen.

In some embodiments, the pharmaceutical composition comprises 50-2000mg,50-1500mg,50-1200mg,50-1000mg,50-800mg,50-600mg,50-500mg,50-400mg,50-300mg,50-250mg,50-200mg,50-100mg,100-2000mg,100-1500mg,100-1200mg,100-1000mg,100-800mg,100-600mg,100-500mg,100-400mg,100-300mg,100-200mg, 200-1500mg,200-1200mg,200-1000mg,200-800mg,200-600mg,200-400mg,400-2000mg, 400-1200mg,400-1000mg, 800mg 400-; and one or more 5 alpha-reductase inhibitors in an amount of 0.1-250mg,0.1-100mg,0.1-30mg,0.1-10mg,0.1-3mg,0.1-1mg,0.3-250mg,0.3-100mg,0.3-30mg,0.3-10mg,0.3-3mg,0.3-1mg,1-100mg,1-30mg,1-10mg,1-3mg,3-7mg and 4-6 mg.

In some embodiments, the alpha-blocker is a non-selective alpha-blocker. In other embodiments, the alpha-blocker is a selective alpha 1-adrenergic blocker. In other embodiments, the alpha-blocker is a selective alpha 2-adrenergic blocker. In other embodiments, the alpha-blocker is tamsulosin.

In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 100-200mg,200-400mg,400-600mg,600-800mg,800-1000mg or 1000-1200mg and finasteride in an amount of 0.1-0.3mg,0.3-0.6mg,0.6-0.9mg,0.9-1.2mg or 1.2-1.5 mg.

In other embodiments, the one or more analgesic agents and the one or more 5 α -reductase inhibitors are both formulated for immediate release. In some further embodiments, the one or more analgesic agents are formulated for immediate release and the one or more a-blockers are formulated for extended release.

In other embodiments, the one or more analgesic agents are formulated for extended release and the one or more 5 α -reductase inhibitors are formulated for immediate release. In some embodiments, the one or more analgesic agents are released continuously or at a steady rate over a period of time or 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours. In some embodiments, at least 90% of the one or more analgesic agents are released continuously or at a steady rate over a period of time or 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

In some further embodiments, the one or more analgesic agents are released within 2 hours of administration, while the remainder is released continuously or at a steady rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

In other embodiments, the one or more analgesic agents and the one or more 5 α -reductase inhibitors are both formulated for extended release. In some embodiments, the one or more analgesic agents and the one or more 5 a-reductase inhibitors are both formulated for extended release such that the one or more analgesic agents and the one or more 5 a-reductase inhibitors are released continuously or at a steady rate over a period of time or 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours. In some further embodiments, the one or more analgesic agents and the one or more 5 α -reductase inhibitors are both formulated to have an extended release with a biphasic release profile in which 20-60% of the one or more analgesic agents and the one or more 5 α -reductase inhibitors are released within 2 hours of administration and the remainder are released continuously or at a steady rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 50-1000mg,50-250mg,250-400mg,400-600mg,600-800mg or 800-1000mg and finasteride in a combined amount of 1-20mg,1-3mg,3-7mg,7-10mg,10-15mg or 15-20mg, wherein both acetaminophen and finasteride in the composition are formulated to have an extended release with a drug release profile in which at least 90% of acetaminophen and finasteride are released continuously or at a steady rate over a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

In other embodiments, the pharmaceutical composition comprises 50-1000mg,50-100mg,50-200mg,50-300mg,50-400mg,50-600mg,50-800mg,100-200mg,100-300mg,100-400mg, 100-800mg,100-1000mg,200-400mg,200-600mg,200-800mg,200-1000mg,400-600mg,400-800mg,400-1000mg,600-800mg,600-1000mg,800-1000mg, 1-3mg,1-7mg,1-10mg,1-15mg,3-7mg,3-10mg,3-15mg,3-20mg,7-10mg,7-15mg,7-20mg,10-15mg,10-20mg or 15-20mg finasteride, wherein the composition is formulated for extended release with a two-stage release profile in which 20-60% of the acetaminophen and finasteride are released within 2 hours of administration and the remainder is released continuously or at a steady rate over a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

"extended release", also known as sustained-release (SR), sustained-action (SA), time-limited release (TR), controlled-release (CR), modified-release (MR) or sustained-release (CR), is a mechanism used in pharmaceutical tablets or capsules to slowly dissolve and release the active ingredient over time. The advantage of extended release tablets or capsules is that they can generally be administered less frequently than immediate release formulations of the same drug and, moreover, they maintain a more stable level of drug in the bloodstream, thereby extending the duration of drug action and reducing the peak amount of drug in the bloodstream. For example, extended release analgesics can allow a person to sleep overnight without getting up to night.

In one embodiment, the pharmaceutical composition is formulated for extended release by embedding the active ingredient in a matrix of insoluble materials such as acrylates or chitin. The extended release form is designed to release the analgesic compound at a predetermined rate by maintaining a constant drug level over a specified period of time. This can be achieved by different formulations, including, but not limited to, liposomes and drug-polymer conjugate conjugates, such as hydrogels.

Extended release formulations can be designed to release the active ingredient at a predetermined rate to maintain a constant drug level for a particular extended period of time, e.g., up to about 24 hours, about 20 hours, about 16 hours, about 12 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour after administration, or after a lag period associated with delayed release of the drug.

In certain preferred embodiments, the active agent is released during a time interval of between about 2 hours and about 10 hours. Alternatively, the active agent is released within about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, or about 24 hours. In other embodiments, the active agent is released over a period of time between about three hours and about eight hours after administration.

In some embodiments, the extended release formulation includes an active core comprised of one or more inert particles each in the form of beads, pills, particulate particles, microcapsules, microspheres, microparticles, nanocapsules, or nanospheres having a drug coated on their surface (e.g., in the form of a drug-containing coating or film-forming composition (using, for example, fluidized bed techniques or other methods well known to those skilled in the art)). The inert particles may be of different sizes as long as they are large enough to remain insoluble. Alternatively, the active core may be prepared by granulation and milling and/or by extrusion and spheronization of a polymer composition containing the pharmaceutical ingredient.

The active agent may be incorporated into the inert carrier by techniques well known to those skilled in the art, such as drug layering, powder coating, extrusion/spheronization, rolling or granulation. The amount of drug in the core will depend on the required dosage and will generally vary from about 5 to 90 wt%. Typically, the polymer coating on the active core is about 1 to 50% based on the weight of the coated particle, depending on the desired lag time and/or the polymer and coating solvent selected. One skilled in the art will be able to select the appropriate amount of drug to coat or introduce into the core to achieve the desired dosage. In one embodiment, the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alters the microenvironment of the drug to facilitate its release.

The extended release formulations may employ various extended release coatings or mechanisms that facilitate the gradual release of the active agent over time. In some embodiments, the extended release formulation comprises a polymer that controls release by controlling dissolution release. In particular embodiments, the active agent is incorporated into a matrix containing an insoluble polymer and drug particles or granules coated with polymeric materials of varying thicknesses. The polymeric material may comprise a lipid barrier comprising a waxy material, such as carnauba wax, beeswax, spermaceti wax, candelilla wax, shellac wax (shellac wax), cocoa butter, cetostearyl alcohol, partially hydrogenated vegetable oils, ozokerite wax, paraffin wax, ozokerite wax, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid, together with a surfactant, such as polyoxyethylene sorbitan monooleate (polyoxyethylenesorbitan monolaurate). When contacted with an aqueous medium (e.g., biological fluids), the polymer coating is emulsified or eroded after a predetermined lag time, depending on the thickness of the polymer coating. The lag time is independent of gastrointestinal motility, pH or retention time in the stomach (gastrotic resistance).

In other embodiments, the extended release formulation comprises a polymeric matrix that achieves controlled diffusion release. The matrix may comprise one or more hydrophilic and/or water-swellable matrix-forming polymers, pH-dependent polymers and/or pH-independent polymers.

In one embodiment, the extended release formulation comprises a water-soluble or water-swellable matrix-forming polymer, optionally comprising one or more solubilizing excipients and/or release-promoting agents. With the solubilization of the water-soluble polymer, the active agent dissolves (if soluble) and gradually diffuses through the aqueous portion of the matrix. As more water penetrates into the matrix core, the gel layer grows over time, increasing the thickness of the gel layer and providing a diffusion barrier to drug release. As the outer layer becomes fully hydrated, the polymer chains are fully extended and can no longer maintain the integrity of the gel layer, resulting in disentanglement and erosion of the outer layer hydrated polymer on the surface of the substrate. Water continues to penetrate through the gel layer towards the core until it is completely eroded. Soluble drugs are released by this combined action of diffusion and erosion, while for insoluble drugs, erosion is the primary mechanism, regardless of dose.

Similarly, water-swellable polymers typically hydrate and swell in biological fluids to form a homogeneous matrix structure that retains its shape during drug release and acts as a carrier, solubilizer, and/or release enhancer for the drug. The initial matrix polymer hydration phase results in a slow release of the drug (lag phase). Once the water-swellable polymer is fully hydrated and swollen, the water in the matrix can likewise dissolve the drug substance and allow it to diffuse out through the matrix coating.

In addition, the porosity of the matrix can be increased due to leaching of the pH-dependent release enhancer, thereby releasing the drug at a faster rate. Subsequently, the drug release rate becomes constant and it becomes a function of drug diffusion through the hydrated polymer gel. The release rate from the matrix depends on different parameters including polymer type and grade; drug solubility and dosage; the ratio of polymer to drug; filler type and grade; the ratio of polymer to filler; particle size of drug and polymer; as well as the porosity and shape of the matrix.

Exemplary hydrophilic and/or water swellable matrix-forming polymers include, but are not limited to, cellulosic polymers, including hydroxyalkyl celluloses and carboxyalkyl celluloses, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), Methyl Cellulose (MC), carboxymethyl cellulose (CMC), powdered celluloses, such as microcrystalline cellulose, cellulose acetate, ethyl cellulose, salts thereof, and combinations thereof; alginates, gums including heteropolysaccharide gums and homopolysaccharide gums such as xanthan gum, tragacanth gum, pectin, acacia gum, karaya gum, alginates, agar, guar gum, hydroxypropyl guar, veegum, carrageenan, locust bean gum, guar gum,gellan gum, and derivatives thereof; acrylic resins, including polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate and methyl methacrylate, and crosslinked polyacrylic acid derivatives, such as carbomers (e.g.,such as, comprise71G NF, having different molecular weight grades, from Noveon, cincinnati, ohio); carrageen gum; the polyvinyl acetate (for example,SR); polyvinylpyrrolidone and its derivatives, such as crospovidone; polyethylene oxide; and polyvinyl alcohol. Preferred hydrophilic and water swellable polymers include cellulosic polymers, particularly HPMC.

The extended release formulation may further comprise at least one binder capable of crosslinking the hydrophilic compound to form a hydrophilic polymer matrix (i.e., a gel matrix) in an aqueous medium, including biological fluids.

Exemplary binders include homopolysaccharides such as galactomannan gum, guar gum, hydroxypropyl guar, hydroxypropyl cellulose (HPC; e.g., Klucel EXF), and locust bean gum. In other embodiments, the binder is an alginic acid derivative, HPC, or microcrystalline cellulose (MCC). Other binders include, but are not limited to, starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

In one embodiment, the method of introduction is drug layering by spraying a suspension of the active agent and binder onto an inert carrier.

The binder may be present in the bead formulation in an amount of about 0.1 wt% to about 15 wt%, and preferably about 0.2 wt% to about 10 wt%.

In some embodiments, the hydrophilic polymer matrix may further comprise ionic polymers, nonionic polymers, or water-insoluble hydrophobic polymers to provide a more robust gel layer and/or reduce the number and size of pores in the matrix, thereby slowing diffusion and erosion rates and concomitant release of active agents. This may additionally suppress the initial burst effect and result in a more stable "zero order release" of the active agent.

Exemplary ionic polymers for slowing the dissolution rate include anionic polymers and cationic polymers. Exemplary anionic polymers include, for example, polymers of sodium carboxymethylcellulose (Na CMC), sodium alginate, acrylic acid, or carbomer (e.g., carbopol)934. 940, 974P NF); enteric polymers, e.g. polyvinyl acetate phthalate (PVAP), methacrylic acid copolymers (e.g. polyethylene glycol terephthalate (PVA)), and the likeL100, L30D 55, a and FS 30D), hydroxypropylmethylcellulose acetate succinate (AQUAT HPMCAS); and xanthan gum. Exemplary cationic polymers include, for example, dimethylaminoethyl methacrylate copolymer (e.g.,E100) in that respect The incorporation of anionic polymers, especially enteric polymers, is useful for forming a pH independent release profile for weakly basic drugs, as compared to hydrophilic polymers alone.

Exemplary nonionic polymers for slowing dissolution rates include, for example, hydroxypropyl cellulose (HPC) and polyethylene oxide (PEO) (e.g., POLYOX)^TM)。

Exemplary hydrophobic polymers include ethyl cellulose (e.g., ETHOCEL)^TM,) Cellulose acetate, methacrylic acid copolymers (e.g.,NE30D), quaternary ammonium methacrylate copolymers (e.g.,RL 100 or ports 100), polyvinyl acetate, glycerol monostearate, fatty acids such as acetyl tributyl citrate, and combinations and derivatives thereof.

The swellable polymer may be incorporated into the formulation in a proportion of 1 to 50 wt%, preferably 5 to 40 wt%, most preferably 5 to 20 wt%. The swellable polymers and binders may be incorporated into the formulation either before or after granulation. The polymer may also be dispersed in an organic solvent or aqueous alcohol and sprayed during pelletization.

Exemplary release-enhancing agents include pH-dependent enteric polymers that remain intact at pH values below about 4.0 and dissolve at pH values above 4.0, preferably above 5.0, and most preferably above 6.0, and are believed to be useful as release-enhancing agents in the present invention. Exemplary pH-dependent polymers include, but are not limited to, methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (e.g., Rohm GmbH, Germany)L100 (type A),S100 (type B)); methacrylic acid-ethyl acrylate copolymers (e.g. Rohm GmbH, Germany)L100-55 (type C) andL30D-55 copolymer dispersion); copolymer of methacrylic acid-methyl methacrylate and methyl methacrylate(s) (ii)FS); a terpolymer of methacrylic acid, methacrylate ester and ethyl acrylate; cellulose Acetate Phthalate (CAP); hydroxypropylmethylcellulose phthalate (HPMCP) (e.g., HP-55, HP-50, HP-55S of Japan shin-Etsu chemical); polyvinyl acetate phthalate (PVAP) (e.g.,intestinal white (enteric white) OY-P-7171); polyvinyl acetate butyrate; cellulose Acetate Succinate (CAS); hydroxypropyl methylcellulose acetate succinate (HPMCAS), e.g. HPMCAS LF grade, MF grade, HF grade, includingLF andMF (japan shin-over chemistry); japanese shin-over chemistry); shellac (e.g. MARCOAT)^TM125 and marcomat 125N); vinyl acetate-maleic anhydride copolymers; styrene-maleic monoester copolymer (styrene-maleic monoester copolymer); carboxymethylethylcellulose (CMEC, Freund corporation, japan); cellulose Acetate Phthalate (CAP) (e.g.,) (ii) a Cellulose acetate-1, 2, 4-trimellitate (CAT); and mixtures of two or more thereof in a weight ratio of about 2: 1 to about 5: 1, e.g., such as in a weight ratio of about 3: 1 to about 2: 1L100-55 andmixtures of S100, or in a weight ratio of about 3: 1 to about 5: 1L30D-55 and(iii) a mixture of FS.

These polymers may be used alone or in combination, or together with polymers other than those mentioned above. The preferred pH-dependent enteric polymer is a pharmaceutically acceptable methacrylic acid copolymer. These copolymers are anionic polymers based on methacrylic acid and methyl methacrylate, and they preferably have an average molecular weight of about 135,000. In these copolymers, the ratio of free carboxyl groups to methyl esterified carboxyl groups ranges, for example, from 1: 1 to 1: 3, for example, about 1: 1 or 1: 2. The polymer is commercially available asTrade names are available commercially, e.g. the Eudragit L series, e.g. Eudragit LEudragit LEudragit LEudragit LEudragitEudragit L-30Series, e.g. Eudragit SEudragitSEudragitThe release promoter is not limited to pH-dependent polymers. Other hydrophilic molecules that dissolve rapidly and leach out of the dosage form rapidly leaving a porous structure may also be used for the same purpose.

The release-promoting agent may be incorporated in an amount of 10 wt% to 90 wt%, preferably 20 wt% to 80 wt%, and most preferably 30 wt% to 70 wt% of the dosage unit. The agents may be incorporated into the formulation either before or after granulation. The release-promoting agent may be added to the formulation as a dry material, or it may be dispersed or dissolved in a suitable solvent and dispersed during granulation.

In some embodiments, the matrix may include a combination of a release enhancer and a solubilizing agent. The solubilizing agent may be an ionic or non-ionic surfactant, a complexing agent, a hydrophilic polymer, a pH adjuster (such as an acidifying agent and an alkalifying agent), and a molecule that increases the solubility of a poorly soluble drug by molecular entrapment. Several solubilizers may be used simultaneously.

The solubilizing agent may include surfactants such as docusate sodium, lauryl sulfate sodium, stearyl alcohol sodium fumarate, tweensAnd Spans (Spans) (PEO-modified sorbitol monoesters and fatty acid sorbitol esters), poly (ethylene oxide) -polypropylene oxide-poly (ethylene oxide) block copolymers (also known as PLURONICS)^TM) (ii) a Complexing agents, such as low molecular weight polyvinylpyrrolidone and low molecular weight hydroxypropyl methylcellulose; molecules that aid solubility by molecular entrapment, such as cyclodextrins; and pH adjusting agents including acidulants such as citric acid, fumaric acid, tartaric acid, and hydrochloric acid; to be provided withAnd alkalizing agents such as meglumine and sodium hydroxide.

The solubilizer typically constitutes 1 wt% to 80 wt%, preferably 1 wt% to 60 wt%, more preferably 1 wt% to 50 wt% of the dosage form, and it may be incorporated in different ways. They may be incorporated into the formulation in a dry or wet manner prior to granulation. They may also be added to the formulation after granulation of other materials or other processes. During granulation, the solubilizer can be added in solution or sprayed without the addition of a binder.

In some embodiments, the extended release formulation comprises a polymer matrix that is capable of releasing the drug after a certain time independent of pH. For purposes of the present invention, "pH independent" is defined as having a characteristic (e.g., dissolution) that is not substantially affected by pH. pH-independent polymers are generally referred to in the context of "time-controlled" or "time-dependent" release profiles.

The pH-independent polymer may be used to coat the active agent and/or provide a polymer for the hydrophilic matrix in the extended release coating thereon. The pH independent polymer may be water insoluble or water soluble. Examples of pH independent polymers that are insoluble in water include, but are not limited to, neutral methacrylates with a small portion of trimethylammonium ethyl methacrylate chloride (e.g.,RS andRL; neutral ester dispersions without any functional groups, (e.g.,NE30D andNE 30); cellulosic polymers such as ethyl cellulose, hydroxyethyl cellulose, cellulose acetate or mixtures; and otherpH dependent coated products. Exemplary water-soluble pH independent polymers include hydroxyalkyl cellulose ethers such as hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC); polyvinylpyrrolidone (PVP), methylcellulose,amb, guar gum, xanthan gum, gum arabic, hydroxyethyl cellulose, and ethyl acrylate and methyl methacrylate copolymer dispersions, or combinations thereof.

In one embodiment, the extended release formulation comprises a water-insoluble water-permeable polymer coating or matrix comprising one or more water-insoluble water-permeable membranes formed on an active core. The coating may additionally comprise one or more water-soluble polymers and/or one or more plasticizers. The water-insoluble polymeric coating includes a release coating for releasing the active agent from the core, wherein lower molecular weight (viscosity) grades exhibit faster release rates than higher viscosity grades.

In a preferred embodiment, the water-insoluble film-forming polymer comprises one or more alkyl cellulose ethers, such as ethyl cellulose and mixtures thereof, (e.g., ethyl cellulose grades PR100, PR45, PR20, PR10, and PR 7;dow corporation).

Exemplary Water-soluble polymers, such as polyvinylpyrrolidoneHydroxypropyl methylcellulose, hydroxypropyl cellulose, and mixtures thereof.

In some embodiments, the water-insoluble polymer provides suitable properties (e.g., extended release characteristics, mechanical properties, and encapsulation properties) without the need for a plasticizer. For example, a coating containing the following may be used without a plasticizer: polyvinyl acetate (PVA), neutral copolymers of acrylate/methacrylate (e.g., eudragit ne30D commercially available from Evonik Industries), ethyl cellulose with hydroxypropyl cellulose, waxes, and the like.

In yet another embodiment, the water-insoluble polymer matrix may further comprise a plasticizer. The amount of plasticizer required depends on the plasticizer, the properties of the water-insoluble polymer and the properties of the final desired coating. Suitable levels of plasticizer are about 1 wt% to about 20 wt%, about 3 wt% to about 5 wt%, about 7 wt% to about 10 wt%, about 12 wt% to about 15 wt%, about 17 wt% to about 20 wt%, or about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 15 wt%, or about 20 wt%, including all ranges and subranges therein, relative to the total weight of the coating.

Exemplary plasticizers include, but are not limited to, triacetin, acetylated monoglyceride, oils (castor oil, hydrogenated castor oil, rapeseed oil, sesame oil, olive oil, etc.); citrate, triethyl citrate, acetyltriethyl citrate, acetyltributyl citrate, tributyl citrate, acetyltri-n-butyl citrate, diethyl phthalate, dibutyl phthalate, dioctyl phthalate, methyl paraben, propyl paraben, butyl paraben, diethyl sebacate, dibutyl sebacate, tributyrin, substituted triglycerides and glycerolipids, monoacetylated and diacylated glycerolipids (e.g., glycerol), glycerol9-45), glyceryl monostearate, glyceryl tributyrate, polysorbate 80, polyethylene glycol (e.g., PEG-4000, PEG-400), propylene glycol, 1, 2-propylene glycol, glycerin, sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, diethyl malonate, dibutyl succinate, fatty acid, glycerin, sorbitol, diethyl oxalate, diethyl malate, diethyl maleateDiethyl fumarate, diethyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate and mixtures thereof. The plasticizer may have the properties of a surfactant so that it can act as a release modifier. For example, nonionic detergents such as Brij 58 (polyoxyethylene (20) cetyl ether) and the like can be used.

The plasticizer may be a high boiling point organic solvent used to impart elasticity to other hard or brittle polymeric materials, and which can affect the release profile of the active agent. Plasticizers generally cause a decrease in cohesive intermolecular forces along the polymer chain, resulting in a change in various polymer properties, including a decrease in the tensile strength, an increase in elongation, and a decrease in the glass transition or softening temperature of the polymer. For example, the content and choice of plasticizer may affect the hardness of the tablet, and may even affect its dissolution or disintegration properties, as well as its physical and chemical stability. Some plasticizers may increase the elasticity and/or flexibility of the coating, thereby reducing the brittleness of the coating.

In another embodiment, the extended release formulation comprises a combination of at least two gel-forming polymers, including at least one non-ionic gel-forming polymer and/or at least one anionic gel-forming polymer. The gel formed by the combination of the gel-forming polymers provides controlled release such that when the formulation is ingested and comes into contact with gastrointestinal fluids, the polymer closest to the surface hydrates to form a viscous gel layer. Due to the high viscosity, the viscous layer can only gradually dissolve away, exposing the underlying material in the same process. Thus, the substance slowly dissolves away, thereby slowly releasing the active ingredient into the gastrointestinal fluids. The combination of at least two gel-forming polymers enables the properties (e.g., viscosity) of the resulting gel to be manipulated to provide a desired release profile.

In a particular embodiment, the formulation comprises at least one non-ionic gel-forming polymer and at least one anionic gel-forming polymer. In another embodiment, the formulation comprises two different non-ionic gel-forming polymers. In yet another embodiment, the formulation comprises a combination of non-ionic gel-forming polymers of the same chemistry but with different solubilities, viscosities, and/or molecular weights (e.g., a combination of hydroxypropylmethylcelluloses of different viscosity grades, such as HPMC K100 and HPMC K15M or HPMC K100M).

Exemplary anionic gel-forming polymers include, but are not limited to, sodium carboxymethylcellulose (Na CMC); carboxymethyl cellulose (CMC); anionic polysaccharides such as sodium alginate, alginic acid, pectin, polyglucuronic acid (poly alpha-and-beta-1, 4-glucuronic acid), polygalacturonic acid (pectic acid), chondroitin sulfate, carrageenan, furcellaran (furcellaran); anionic gums, such as xanthan gum; polymers of acrylic acid or carbomer (e.g. carbopol)934、940、974P NF)；A copolymer;a polymer; polycarbophil, and the like.

Exemplary non-ionic gel-forming polymers include, but are not limited to, povidone (PVP, polyvinylpyrrolidone), polyvinyl alcohol, copolymers of PVP and polyvinyl acetate, HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, gum arabic, dextrin, starch, Polyhydroxyethylmethacrylate (PHEMA), water-soluble non-ionic polymethacrylates and copolymers thereof, modified cellulose, modified polysaccharides, non-ionic gums, non-ionic polysaccharides, and/or mixtures thereof.

The formulation may optionally comprise an enteric polymer as described above, and/or at least one excipient, such as a filler, binder (as described above), disintegrant, and/or flow aid or glidant.

Exemplary fillers include, but are not limited to, lactose, glucose, fructose, sucrose, dicalcium phosphate, sugar alcohols, also known as "sugar polyols", such as sorbitol, mannitol, lactitol, xylitol, isomalt (isomalt), erythritol, and hydrogenated starch hydrolysates (a mixture of sugar alcohols), corn starch, potato starch, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, enteric polymers, or mixtures thereof.

Exemplary binders include, but are not limited to, water-soluble hydrophilic polymers such as povidone (PVP, polyvinylpyrrolidone), copovidone (a copolymer of polyvinylpyrrolidone and polyvinyl acetate), low molecular weight HPC (hydroxypropylcellulose), low molecular weight HPMC (hydroxypropylmethylcellulose), low molecular weight carboxymethylcellulose, ethylcellulose, gelatin, polyethylene oxide, gum arabic, dextrin, magnesium aluminum silicate, starches and polymethacrylates such as Eudragit NE30D, Eudragit RL, Eudragit RS, Eudragit E, polyvinyl acetate, and enteric polymers, or mixtures thereof.

Exemplary disintegrants include, but are not limited to, low substituted sodium carboxymethyl cellulose, crospovidone (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), croscarmellose sodium (croscarmellose), pregelatinized starch (starch 1500), microcrystalline cellulose, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, and magnesium or aluminum silicate.

Exemplary glidants include, but are not limited to, magnesium, silicon dioxide, talc, starch, titanium dioxide, and the like.

In yet another embodiment, the extended release formulation is formed by coating particles, such as beads or bead populations (as described above), containing a water-soluble/water-dispersible drug with a coating material and optionally a pore former and other excipients. The coating material is preferably selected from cellulosic polymers, such as ethyl cellulose (e.g.,) Methyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate and cellulose acetate phthalate; polyvinyl alcohol; acrylic polymers such as polyacrylates, polymethacrylates, and copolymers thereof; and other water-based or solvent-based coating materials. The controlled release coating for a given population of beads may be controlled by at least one parameter of the controlled release coating, such as the properties of the coating, the coating level, pore former type and concentration, process parameters, and combinations thereof. Thus, by varying parameters (such as pore former concentration) or curing conditions, the release of active agent from any given population of beads is allowed to vary, thereby allowing the formulation to be selectively tailored to a predetermined release profile.

Pore formers suitable for use in the controlled release coating herein can be organic or inorganic agents and include materials that are capable of being dissolved, extracted, or leached from the coating in an environment of use. Exemplary pore formers include, but are not limited to, organic compounds such as monosaccharides, oligosaccharides, and polysaccharides, including sucrose, glucose, fructose, mannitol, mannose, galactose, sorbitol, amylopectin, dextran; polymers soluble in the use environment, such as water-soluble hydrophilic polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, hydroxypropyl methylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyethylene oxide, carbon waxes (carbowax), carbopol, etc., glycols, polyols, polyalkylene glycols, polyethylene glycol, polypropylene glycol, or block polymers thereof, polyglycols, poly (α - Ω) alkylene glycols; inorganic compounds such as alkali metal salts, lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, suitable calcium salts, combinations thereof, and the like.

The controlled release coating may further comprise other additives known in the art, such as plasticizers, anti-tacking agents, glidants (or flow aids), and anti-foaming agents.

In some embodiments, the coated particles or beads may additionally include an "outer coating" to provide, for example, moisture protection, static reduction, taste masking, flavoring, coloring and/or buffing or other decorative effects on the beads. For such outer coatings, suitable coating materials are well known in the art and include, but are not limited to, cellulosic polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and microcrystalline cellulose or combinations thereof (e.g., a plurality ofA coating material).

The coated particles or beads may additionally comprise an enhancer, which may be exemplified by, but not limited to, a dissolution enhancing agent, an absorption enhancer, a penetration enhancer, a stabilizer, a complexing agent, an enzyme inhibitor, a P-glycoprotein inhibitor, and a multidrug resistance protein inhibitor. Alternatively, the formulation may also contain the enhancing agent separate from the coated particles, for example in a separate population of beads or as a powder. In yet another embodiment, the enhancing agent may be contained in a separate layer on the coated particle, either below or above the controlled release coating.

In other embodiments, the extended release formulation is formulated to release the active agent via an osmotic mechanism. For example, the capsule may be made as a single osmotic unit, or it may contain 2, 3, 4, 5 or 6 push-pull units encapsulated within a hard gelatin capsule, whereby each bi-layer push-pull unit contains an osmotic push layer and a drug layer, both surrounded by a semi-permeable membrane. One or more holes are drilled through the membrane adjacent to the drug layer. This film may additionally be covered with a pH-dependent enteric coating to prevent release until after gastric emptying. Gelatin capsules dissolve immediately after ingestion. As the push-pull unit enters the small intestine, the enteric coating disintegrates and fluid is then allowed to flow through the semipermeable membrane, swelling the osmotic push portion, thereby forcing the drug through the pores at a rate precisely controlled by the rate of water passage through the semipermeable membrane. The release of the drug may be carried out at a constant rate for up to 24 hours or more.

The osmotic push layer includes one or more osmotic agents that generate a driving force for water to pass through the semipermeable membrane into the core of the delivery vehicle. One class of osmotic agents includes water-swellable hydrophilic polymers, also known as "osmopolymers" and "hydrogels," which include, but are not limited to, hydrophilic vinyl and acrylic polymers, such as polysaccharides of calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic acid), poly (methacrylic acid), polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, crosslinked sodium carboxymethylcellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC), and carboxyethyl cellulose (CEC), Sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

Another class of osmotic agents includes zymogens that are capable of drawing water to achieve an osmotic pressure gradient across a semi-permeable membrane. Examples of the proenzyme include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose (dextrose), fructose, glucose (glucose), inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof.

Materials that may be useful in forming the semipermeable membrane include various grades of acrylic, vinyl, ethers, polyamides, polyesters, and cellulose derivatives that are water permeable and water insoluble at physiologically relevant pH values, or that are susceptible to exhibiting water insoluble properties through chemical changes, such as cross-linking.

In some embodiments, the extended release formulation may include a polysaccharide coating that resists erosion in the stomach and intestines. Such polymers can only be degraded in the colon containing a large number of microorganisms containing biodegradable enzymes that break down, for example, polysaccharide coatings, thereby releasing the drug content in a controlled time-dependent manner. Exemplary polysaccharide coatings may include, for example, amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin, xylan, and combinations or derivatives thereof.

In some embodiments, the pharmaceutical compositions of the present application are formulated as a delayed extended release. The term "delayed release" as used herein refers to a drug treatment that does not immediately disintegrate and release the active ingredient into the body. In some embodiments, the term "delayed extended release" is used with reference to a pharmaceutical formulation having a release profile such that: the release profile has a pre-set delay in the release of the drug after administration. In some embodiments, the delayed extended release formulation comprises an extended release formulation coated with an enteric coating, which is a barrier applied to the oral drug to prevent release before the drug reaches the small intestine. Delayed release formulations such as enteric coatings prevent gastric irritating drugs (e.g., aspirin) from dissolving in the stomach. Such coatings also serve to protect the acid-labile drug from exposure to the acidic environment of the stomach, but instead deliver it to an alkaline pH environment (pH of the intestinal tract above 5.5) where it does not degrade and give them the desired effect.

The term "pulsatile release" is one of the delayed releases, which is used herein with reference to: a drug formulation that provides rapid and transient drug release within a short period of time immediately following a predetermined lag period, thereby producing a "pulsed" plasma distribution of the drug following administration of the drug. The formulation may be designed to provide a single-pulse release or multiple-pulse release at predetermined time intervals after administration, or to provide a pulse release (e.g., 20-60% of the active ingredient) after a period of extended release (e.g., continuous release of the remainder of the active ingredient).

Delayed release or pulsatile release formulations typically include one or more elements covered by a barrier coating that dissolves, erodes or ruptures after a particular lag phase. In some embodiments, the pharmaceutical composition of the present application is formulated for extended release or delayed extended release and comprises 100% of the total dose of a given active agent administered in a single unit dose. In other embodiments, the pharmaceutical composition comprises an extended/delayed release component and an immediate release component. In some embodiments, the immediate release component and the extended/delayed release component contain the same active ingredient. In other embodiments, the immediate release component and the extended/delayed release component contain different active ingredients (e.g., an analgesic in one component and an alpha-blocker in the other component). In some embodiments, the first and second components each comprise an alpha-blocker and an analgesic agent selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen. In some further embodiments, the first and second components each comprise a 5 α -reductase inhibitor and an analgesic agent, the 5 α -reductase inhibitor being selected from finasteride, beclomethamide, epristeride, izontamide, lapoteramide, and tolperiside, and the analgesic agent being selected from aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen. In other embodiments, the extended/delayed release component is coated with an enteric coating. In still other embodiments, the immediate release component and/or the extended/delayed release component further comprises an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin, and atropine. In still other embodiments, the immediate release component and/or the extended/delayed release component further comprises an antidiuretic agent, an antimuscarinic agent, or a combination of both. In still other embodiments, the method of treatment comprises administering a diuretic to the subject at least 7 to 8 hours prior to a target time point (e.g., bedtime), and administering to the subject a pharmaceutical composition comprising an immediate release component and/or an extended/delayed release component within 2 hours prior to the target time point.

In other embodiments, the "immediate release" component provides about 5 to 50% of the total dose of active agent to be delivered by the pharmaceutical formulation, and the "extended release" component may provide about 50 to 95% of the total dose of active agent to be delivered by the pharmaceutical formulation. For example, the immediate release component provides about 20 to 60%, or about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% of the total dose of active agent to be delivered by the pharmaceutical formulation. The extended release component may provide about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the total dose of active agent to be delivered by the formulation. In some embodiments, the extended release component further comprises a barrier coating to delay the release of the active agent.

The barrier coating for delayed release may be composed of various materials according to purposes. In addition, the formulation may include multiple barrier coatings to facilitate release in a time-wise manner. The coating may be a sugar coating, a film coating (e.g., based on hydroxypropylmethyl cellulose, methyl cellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymers, polyethylene glycol, and/or polyvinylpyrrolidone), or a coating based on methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethyl cellulose. In addition, the formulation may additionally include a time delay material, for example, glyceryl monostearate or glyceryl distearate.

In some embodiments, the delayed extended release formulation includes an enteric coating comprising one or more polymers that facilitate release of the active agent in the proximal or distal regions of the gastrointestinal tract. The term "enteric polymer coating" as used herein refers to a coating comprising one or more polymers having a pH-dependent or pH-independent release profile. Typically, the coating resists dissolution in the acidic medium of the stomach, but dissolves or erodes in more distal regions of the gastrointestinal tract (e.g., the small intestine or colon). Enteric polymer coatings generally resist release of the active agent until some time after a lag period of gastric emptying of about 3-4 hours after administration.

The pH-dependent enteric coating comprises one or more pH-dependent or pH-sensitive polymers that retain their structural integrity under conditions of lower pH (e.g., in the stomach) and dissolve in the higher pH environment of the more distal regions of the gastrointestinal tract (e.g., the small intestine), thereby releasing the drug contents. For the purposes of the present invention, "pH dependent" is defined as having a characteristic (e.g., dissolution) that varies according to the pH of the environment. Exemplary pH-dependent polymers include, but are not limited to, methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (e.g., Rohm GmbH, Germany)L100 (type A),S100 (type B)); methacrylic acid-ethyl acrylate copolymers (e.g. Rohm GmbH, Germany)L100-55 (type C) andL30D-55 copolymer dispersion); copolymer of methacrylic acid-methyl methacrylate and methyl methacrylate(s) (ii)FS); a terpolymer of methacrylic acid, methacrylate ester and ethyl acrylate; cellulose Acetate Phthalate (CAP); hydroxypropyl methylcellulose ortho-cellulosePhthalic acid esters (HPMCP) (e.g., HP-55, HP-50, HP-55S of Japan shin-Etsu chemical); polyvinyl acetate phthalate (PVAP) (e.g.,intestinal white (enteric white) OY-P-7171); cellulose Acetate Succinate (CAS); hydroxypropyl methylcellulose acetate succinate (HPMCAS), e.g. HPMCAS LF grade, MF grade, HF grade, includingLF andMF (japan shin-over chemistry); japanese shin-over chemistry); shellac (e.g. Marcoat)^TM125 and Marcoat^TM125N); carboxymethylethylcellulose (CMEC, Freund corporation, japan), Cellulose Acetate Phthalate (CAP) (e.g.,) (ii) a Cellulose acetate-1, 2, 4-trimellitate (CAT); and mixtures of two or more thereof in a weight ratio of about 2: 1 to about 5: 1, e.g., in a weight ratio of about 3: 1 to about 2: 1L100-55 andmixtures of S100, or in a weight ratio of about 3: 1 to about 5: 1L30D-55 and(iii) a mixture of FS.

pH-dependent polymers generally exhibit a characteristic pH optimum for dissolution. In some embodiments, the pH dependent polymer exhibits a pH optimum between about 5.0 and 5.5, between about 5.5 and 6.0, between about 6.0 and 6.5, or between about 6.5 and 7.0. In other embodiments, the pH dependent polymer exhibits a pH optimum of 5.0 or more, 5.5 or more, 6.0 or more, 6.5 or more, or 7.0 or more.

In some embodiments, the coating process employs a blend of one or more pH-dependent and one or more pH-independent polymers. The mixing of pH-dependent and pH-independent polymers can reduce the release rate of the active ingredient once the soluble polymer has reached its optimum pH for dissolution.

In some embodiments, a "time-controlled" or "time-dependent" release profile may be obtained using a water-insoluble capsule body containing one or more active agents, wherein the capsule body is closed at one end with an insoluble, but permeable and swellable hydrogel plug. Upon contact with gastrointestinal fluids or dissolution media, the plug swells, pushing itself out of the capsule, and after a predetermined lag time (which can be controlled, for example, by the position and size of the plug), the drug is released. The capsule body may be further coated with an outer pH dependent enteric coating that keeps the capsule intact until it reaches the small intestine. Suitable plug materials include, for example, polymethacrylates, erodible compressed polymers (e.g., HPMC, polyvinyl alcohol), coagulated melted polymers (e.g., glycerol monooleate), and enzymatically controlled erodible polymers (e.g., polysaccharides such as amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin, and xylan).

In other embodiments, the capsule or bi-layer tablet may be formulated to include a drug-containing core covered by a swelling layer and an outer insoluble but semi-permeable polymer coating or film. The lag time before rupture can be controlled by the penetration and mechanical properties of the polymer coating and the swelling behavior of the swollen layer. Typically, the swelling layer comprises one or more swelling agents, such as swellable hydrophilic polymers that swell and retain moisture in their structure.

Exemplary water swellable materials for use in the delayed release coating include, but are not limited to, polyethylene oxide (e.g., having an average molecular weight of 1,000,000 to 7,000,000, e.g.,) Methyl cellulose, hydroxypropyl methyl cellulose; polyalkylene oxides having a weight average molecular weight of 100,000 to 6,000,000, including but not limited to polyoxymethylene (poly (ethylene oxide)), polybutylene oxide; poly (hydroxyalkyl methacrylates) having a molecular weight of 25,000 to 5,000,000; polyvinyl alcohol crosslinked with glyoxal, formaldehyde, or glutaraldehyde, having a lower acetal residue, and having a degree of polymerization of 200 to 30,000; a mixture of methylcellulose, cross-linked agar and carboxymethylcellulose; a hydrogel-forming copolymer prepared by: forming a dispersion of a finely divided copolymer of maleic anhydride and styrene, ethylene, propylene, butylene or isobutylene crosslinked in the copolymer with 0.001 to 0.5 moles of a saturated crosslinking agent per mole of maleic anhydride; having a molecular weight of 450,000 to 4,000,000An acidic carboxyl polymer;polyacrylamide; a crosslinked water-swellable indene maleic anhydride polymer; having a molecular weight of 80,000 to 200,000Polyacrylic acid; a starch graft copolymer; consisting of condensed glucose units, e.g. diester-crosslinked polyglucansAn acrylate polymer polysaccharide; carbomers having a viscosity of from 3,000 to 60,000mPa in water from 0.5% to 1% w/v; cellulose, process for producing the same, and process for producing the sameEthers, such as hydroxypropyl cellulose having a viscosity of about 1,000 to 7,000mPa in 1% w/w aqueous solution (25 ℃); hydroxypropyl methylcellulose having a viscosity of about 1000 or more, preferably 2,500 or more, up to 25,000mPa, in 2% w/v aqueous solution; polyvinylpyrrolidone having a viscosity of about 300 to 700mPa at 20 ℃, 10% w/v aqueous solution; and mixtures thereof.

Alternatively, the release time of the drug can be controlled by a disintegration delay time depending on the balance between the tolerance and thickness of a water-insoluble polymer film (e.g., ethylcellulose, EC) comprising predetermined micropores at the bottom of the body, and a certain amount of swellable auxiliary materials, such as low-substituted hydroxypropylcellulose (L-HPC) and sodium glycolate. Upon oral administration, gastrointestinal fluids permeate through the micropores, causing swelling of the swellable excipient, which generates internal pressure that disintegrates the capsule portion, which includes a first capsule body containing the swellable material, a second capsule body containing the drug, and an outer cover attached to the first capsule body.

The enteric layer may further comprise an anti-adherent, such as talc or glycerol monostearate and/or a plasticizer. The enteric layer may further comprise one or more plasticizers including, but not limited to, triethyl citrate, acetyltriethyl citrate, acetyltributyl citrate, acetylated monoglycerides of polyethylene glycol, glycerol, triacetin, propylene glycol, phthalates (e.g., diethyl phthalate, dibutyl phthalate), titanium dioxide, iron oxide, castor oil, sorbitol, and dibutyl sebacate.

In another embodiment, the delayed release formulation employs a water-permeable, but insoluble film coating to encapsulate the active ingredient as well as the osmotic agent. As water slowly diffuses from the intestine through the membrane into the core, the core swells until the membrane ruptures, thereby releasing the active ingredient. The membrane coating can be adjusted to achieve different rates of water penetration or release time.

In another embodiment, the delayed release formulation employs a water-impermeable sheet-like coating whereby water enters through controlled pores in the coating until the core bursts. When the tablet bursts, the drug content is released immediately, or over a longer period of time. These and other techniques may be modified to allow a predetermined lag period to develop before the drug begins to be released.

In another embodiment, the active agent is delivered in a formulation that provides delayed and extended release (delayed-sustained). The term "delayed-extended-release" is used herein with reference to: a pharmaceutical formulation that provides a pulsatile release of the active agent followed by an extended release of the active agent at a predetermined time or lag period after administration.

In some embodiments, an immediate release, extended release, delayed release, or delayed-extended-release formulation includes an active core comprised of one or more inert particles each in the form of beads, pills, pellets, particulate particles, microcapsules, microspheres, microparticles, nanocapsules, or nanospheres having a drug coated on their surface (e.g., in the form of a drug-containing film-forming composition (using, for example, fluidized bed techniques or other methods well known to those skilled in the art)). The inert particles may be of different sizes as long as they are large enough to remain insoluble. Alternatively, the active core may be prepared by granulation and milling and/or by extrusion and spheronization of a polymer composition containing the pharmaceutical ingredient.

The amount of drug in the core will depend on the required dosage and will typically vary from about 5 to 90 wt%. Typically, the polymer coating on the active core will be about 1 to 50% based on the weight of the coated particle, depending on the type of lag time and release profile desired and/or the polymer and coating solvent selected. One skilled in the art will be able to select the appropriate amount of drug to coat or incorporate the core to achieve the desired dosage. In one embodiment, the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alters the microenvironment of the drug to facilitate its release.

In some embodiments, for example, a delayed-release or delayed-extended release composition may be formed by coating water-soluble/dispersible drug-containing particles (e.g., beads) with a mixture of a water-insoluble polymer and an enteric polymer, wherein the water-insoluble polymer and the enteric polymer may be present in a weight ratio of 4: 1 to 1: 1, and the total weight of the coating is 10 to 60 wt%, based on the total weight of the coated beads. The drug layered beads may optionally include an ethylcellulose membrane to control the internal dissolution rate. The composition of the outer layer, as well as the individual weights of the inner and outer layers of the polymer film, are optimized to achieve the desired circadian release profile for a given activity, as would be expected based on in vitro/in vivo correlation.

In other embodiments, the formulation may comprise a mixture of particles containing immediate release drug (without a dissolution rate controlling polymer film) and delayed-extended release beads exhibiting, for example, a lag time of 2 to 4 hours following oral administration, thereby providing a bi-pulsatile release profile.

In some embodiments, the active core is coated with a layer of one or more dissolution rate controlling polymers to achieve a desired release profile (with or without lag time). The inner membrane can largely control the rate of drug release upon imbibing water or body fluid into the core, while the outer membrane can provide the desired lag time (the period during which no or little drug is released upon imbibing water or body fluid into the core). The inner film may comprise a water-insoluble polymer, or a mixture of a water-insoluble polymer and a water-soluble polymer.

As mentioned above, polymers suitable for the outer membrane which largely control the lag time up to 6 hours include enteric polymers, and 10 to 50 wt% of water-insoluble polymers. The ratio of water-insoluble polymer to enteric polymer may vary from 4: 1 to 1: 2, preferably the polymers are present in a ratio of about 1: 1. A commonly used water-insoluble polymer is ethyl cellulose.

Examples of water-insoluble polymers include ethyl cellulose, polyvinyl acetate (Kollicoat SR #0D from BASF), neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic esters with quaternary ammonium groups (e.g. copolymers of acrylic and methacrylic esters with quaternary ammonium groups)NE, RS and RS30D, RL or RL30D, etc.). Examples of water-soluble polymers include low molecular weight HPMC; HPC; methyl cellulose; polyethylene glycol (molecular weight)>3000 PEG), depending on the solubility of the activity in water and solvents, or based on the emulsion suspension of the coating formulation used, ranging from 1 wt% up to 10 wt%. The ratio of water-insoluble polymer to water-soluble polymer may vary generally from 95: 5 to 60: 40, preferably from 80: 20 to 65: 35.

In some embodiments, amberlite IRP69 resin is used as a carrier for extended release. AMBERLITE^TMIRP69 is an insoluble, strongly acidic sodium-type cation exchange resin suitable as a carrier for cationic (basic) species. In other embodiments, DUOLITE is used^TMAP143/1093 resin acts as a carrier for extended release. DUOLITE^TMAP143/1093 is an insoluble, strongly basic anion exchange resin that is suitable as a support for anionic (acidic) materials.

When used as a pharmaceutical carrier, AMBERLITE IRP69 or/and DUOLITE^TMThe AP143/1093 resin provides a means for adhering an agent to an insoluble polymer matrix. Extended release is achieved by forming a resin-drug complex (drug resinate). As the drug equilibrates with high electrolyte concentrations, the drug is released from the resin in vivo, which is typical of gastrointestinal drug release. Due to hydrophobic interactions with the aromatic structure of the cation exchange system, generally, more hydrophobic drugs will elute from the resin at a lower rate.

Most enteric coatings work by presenting a surface that is stable at higher acidic pH conditions (i.e., conditions in the stomach), but disintegrates at lower acidic pH conditions (relatively more basic). Thus, enteric coated pellets are insoluble in acidic gastric fluid (pH-3), but they are soluble in the alkaline environment present in the small intestine (pH 7-9). Examples of enteric coating materials include, but are not limited to, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, sodium alginate, and stearic acid. In some embodiments, the pharmaceutical composition is formulated for oral administration. Oral dosage forms include, for example, tablets, capsules, lozenges, and may also include a plurality of granules, beads, powders, or pills that may or may not be encapsulated. Tablets and capsules represent the most convenient oral dosage forms, in which case solid pharmaceutical carriers are employed.

In delayed release formulations, one or more barrier coatings may be applied to the pill, tablet or capsule to help slow the dissolution and concomitant release of the drug in the intestinal tract. Typically, the barrier coating comprises one or more polymers surrounding, surrounding or forming a layer or membrane around the pharmaceutical composition or active core.

In some embodiments, the active agent is delivered in a formulation that provides a delayed release at a predetermined time after administration. The delay may be up to about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or more.

Different coating techniques may be applied to granules, beads, powders or pills, tablets, capsules or combinations thereof containing the active agent to produce different and distinct release profiles. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule comprising a single coating layer. In other embodiments, the pharmaceutical composition is in the form of a tablet or capsule comprising multiple coating layers.

In some embodiments, the pharmaceutical composition comprises one or more analgesics, one or more alpha-blockers and one or more other active ingredients selected from antimuscarinic agents, antidiuretic agents and spasmolytics. In some embodiments, the pharmaceutical composition comprises one or more analgesic agents, one or more 5 α -reductase inhibitors, and one or more additional active ingredients selected from antimuscarinic agents, antidiuretic agents, α -blockers, and spasmolytics. Examples of antimuscarinic agents include, but are not limited to: oxybutynin, solifenacin, darifenacin, and atropine. Examples of antidiuretic agents include, but are not limited to, antidiuretic hormone (ADH), angiotensin ii, aldosterone, vasopressin analogs (e.g., desmopressin, lypressin, phenlyspressin, ornipressin, terlipressin); vasopressin receptor agonists, Atrial Natriuretic Peptide (ANP), and C-type natriuretic peptide (CNP) receptor (i.e., NPR1, NPR2, NPR3) antagonists (e.g., HS-142-1, isatin, [ Asu7, 23' ] b-ANP- (7-28) ], ansamitin (anantin), cyclic peptides from Streptomyces coerulescens, and the 3G12 monoclonal antibody); somatostatin type 2 receptor antagonists (e.g., somatostatin), and pharmaceutically acceptable derivatives, analogs, salts, hydrates, and solvates thereof. Examples of antispasmodics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine analogs, and dantrolene.

In some embodiments, the pharmaceutical composition comprises one or more analgesic agents and one or more alpha-blockers. In some further embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more alpha-blockers, and (3) one or more antimuscarinic agents. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more alpha-blockers and (3) one or more antidiuretic agents. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more alpha-blockers and (3) one or more spasmolytic agents. In other embodiments, the pharmaceutical composition comprises 1) one or two analgesic agents, (2) one or more alpha-blockers, (3) one or two antimuscarinic agents, and (4) one or two antidiuretic agents. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more alpha-blockers, (3) one or more spasmolytic agents, and (4) one or more antidiuretic agents.

In some embodiments, the pharmaceutical composition comprises one or more analgesic agents and one or more 5 α -reductase inhibitors. In some further embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more 5 α -reductase inhibitors, and (3) one or more antimuscarinic agents. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more 5 α -reductase inhibitors, and (3) one or more antidiuretic agents. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more 5 α -reductase inhibitors, and (3) one or more spasmolytic agents. In other embodiments, the pharmaceutical composition comprises (1) one or two analgesic agents, (2) one or more 5 α -reductase inhibitors, (3) one or two antimuscarinic agents, and (4) one or two antidiuretic agents. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more 5 α -reductase inhibitors, (3) one or more spasmolytic agents, and (4) one or more antidiuretic agents.

In other embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more 5 α -reductase inhibitors, and (3) one or more α -blockers. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5 α -reductase inhibitors, (3) one or more α -blockers, and (4) one or more antidiuretic agents. In other embodiments, the pharmaceutical compositions comprise (1) one or more analgesic agents, (2) one or more 5 α -reductase inhibitors, (3) one or more α -blockers, and (4) one or more spasmolytic agents. In other embodiments, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or more 5 α -reductase inhibitors, (3) one or two antimuscarinic agents, (4) one or two antidiuretic agents, and (5) one or more α -blockers. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more 5 α -reductase inhibitors, (3) one or more spasmolytic agents, (4) one or more antidiuretic agents, and (5) one or more α -blockers.

In one embodiment, the majority of the active ingredient is formulated for immediate release. In other embodiments, the majority of the active ingredient is formulated for extended release. In other embodiments, a majority of the active ingredients are formulated for immediate release and extended release (e.g., a first portion of each active ingredient is formulated for immediate release and a second portion of each active ingredient is formulated for extended release). In yet another embodiment, some of the majority of active ingredients are formulated for immediate release and some of the majority of active ingredients are formulated for extended release (e.g., active ingredients a, B, C are formulated for immediate release and active ingredients C and D are formulated for extended release). In other embodiments, the immediate release component and/or the extended release component are further coated with a delayed release coating (e.g., an enteric coating).

In certain embodiments, the pharmaceutical composition comprises an immediate release component and an extended release component. The immediate release component may comprise one or more active ingredients selected from the group consisting of analgesics, alpha-blockers, 5 alpha-reductase inhibitors, antimuscarinics, antidiuretic agents and spasmolytics. The extended release component may comprise one or more active ingredients selected from analgesics, alpha-blockers, antimuscarinics, antidiuretics and spasmolytics. In some embodiments, the immediate release component and the extended release component have exactly the same active ingredient. In other embodiments, the immediate release component and the extended release component have different active ingredients. In other embodiments, the immediate release component and the extended release component have one or more active ingredients in common. In some embodiments, the immediate release component and/or the extended release component is further coated with a delayed release coating (e.g., an enteric coating).

In one embodiment, the pharmaceutical composition comprises two or more active ingredients (e.g., a mixture of one or more analgesics and one or more α -blockers, one or more 5 α -reductase inhibitors, one or more antimuscarinics or antidiuretics or spasmolytics) formulated for immediate release at about the same time. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated for extended release over about the same time period. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated as two extended release components, each extended release component providing a different extended release profile. For example, a first extended release component releases a first active ingredient at a first release rate, while a second extended release component releases a second active ingredient at a second release rate. In another embodiment, the pharmaceutical composition comprises two or more active ingredients that are both formulated for delayed release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated for delayed release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated as two delayed release components, each providing a different delayed release profile. For example, a first delayed-release component releases a first active ingredient at a first point in time, while a second delayed-release component releases a second active ingredient at a second point in time. In another embodiment, the pharmaceutical composition comprises two or more active ingredients, one or more of which is formulated for immediate release and the remainder are formulated for extended release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients, wherein a portion is formulated for immediate release and the remaining portion is formulated for extended release.

In some embodiments, the pharmaceutical composition comprises one or more analgesics, and one or more alpha-blockers, 5 alpha-reductase inhibitors, antidiuretic agents, wherein the one or more analgesics and one or more alpha-blockers are formulated for delayed release, and wherein the antidiuretic agents are formulated for immediate release. In other embodiments, the pharmaceutical composition further comprises an additional agent selected from the group consisting of analgesics, α -blockers, 5 α -reductase inhibitors, antimuscarinic agents, antidiuretic agents, and spasmolytics, wherein the additional agent is formulated for delayed release. In some embodiments, the delayed release formulation delays release of the active ingredient for 1,2, 3, 4, or 5 hours.

The term "immediate release" as used herein refers to a pharmaceutical formulation that does not contain a dissolution rate controlling material. There is substantially no delay in the release of the active agent after administration of the immediate release formulation. Immediate release coatings may include suitable materials that dissolve immediately after administration, thereby releasing the drug contents therein. Examples of immediate release coating materials include gelatin, polyvinyl alcohol polyethylene glycol (PVA-PEG) copolymers (e.g., PVA-PEG)) And various other materials known to those skilled in the art.

An immediate release composition may comprise 100% of the total dose of a given active agent administered in a single unit dose. Alternatively, the immediate release component may be included as a component in a combined release profile formulation that may provide from about 1% to about 60% of the total dose of active agent to be delivered by the drug formulation. For example, the immediate release component may provide about 5% -60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 30%, about 30% to about 60%, about 30% to about 50%, about 40% to about 60%, about 40% to about 50%, about 45% to about 60%, or about 45% to about 50% of the total dose of active agent to be delivered by the formulation. In other embodiments, the immediate release component provides about 2,4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% of the total dose of active agent to be delivered by the formulation.

In some embodiments, the immediate release or delayed release formulation includes an active core comprised of one or more inert particles each in the form of beads, pills, particulate particles, microcapsules, microspheres, microparticles, nanocapsules or nanospheres having a drug coated on their surface (e.g., in the form of a drug-containing film-forming composition (using, for example, fluidized bed techniques or other methods well known to those skilled in the art)). The inert particles may be of different sizes as long as they are large enough to remain insoluble. Alternatively, the active core may be prepared by granulation and milling and/or by extrusion and spheronization of a polymer composition containing the pharmaceutical ingredient.

The amount of drug in the core will depend on the required dosage and will typically vary from about 5 to 90 wt%. Typically, the polymer coating on the active core will be about 1 to 50% based on the weight of the coated particle, depending on the type of lag time and release profile desired and/or the polymer and coating solvent selected. One skilled in the art will be able to select the appropriate amount of drug to be coated on or incorporated into the core to achieve the desired dosage. In one embodiment, the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alters the microenvironment of the drug to facilitate its release.

In some embodiments, the delayed release formulation is formed by coating water-soluble/dispersible drug-containing particles (e.g., beads) with a mixture of a water-insoluble polymer and an enteric polymer, wherein the water-insoluble polymer and the enteric polymer may be present in a weight ratio of 4: 1 to 1: 1, and the total weight of the coating is 10 to 60 wt%, based on the total weight of the coated beads. The drug layered beads may optionally include an ethylcellulose membrane to control the internal dissolution rate. The composition of the outer layer, as well as the individual weights of the inner and outer layers of the polymer film, are optimized to achieve the desired circadian release profile for a given activity, as would be expected based on in vitro/in vivo correlation.

In other embodiments, the formulation comprises a mixture of particles containing an immediate release drug (without a dissolution rate controlling polymer film) and delayed release beads exhibiting, for example, a lag time of 2 to 4 hours following oral administration, thereby providing a bi-pulsatile release profile. In other embodiments, the formulation comprises a mixture of two types of delayed release beads: a first type exhibiting a lag time of 1 to 3 hours and a second type exhibiting a lag time of 4 to 6 hours.

Preferably, the formulation is designed to have a release profile that: can limit its interference with quiet sleep, wherein the formulation releases the drug when the individual is typically awakened by a urinary urge. For example, consider an individual who typically begins sleeping at 11 pm and is typically awakened to urinate at 12:30 in the early morning, 3:00 in the early morning, and 6:00 in the early morning. The delayed extended release vehicle can be taken at 10 pm and deliver the drug beginning at 12 am and gradually release the drug over a period of 5-8 hours, thereby delaying or eliminating the need for urination. In other embodiments, the formulation is designed to have a release profile that: a portion (e.g., 20-60%) of the drug is released immediately or within 2 hours after administration, and the remainder is released over an extended period of time. The pharmaceutical composition may be administered daily or on demand. In certain embodiments, the pharmaceutical composition is administered to the subject before bedtime. In some embodiments, the pharmaceutical composition is administered immediately before bedtime. In some embodiments, the pharmaceutical composition is administered within about two hours before bedtime, preferably within about one hour before bedtime. In another embodiment, the pharmaceutical composition is administered about two hours before bedtime. In a further embodiment, the pharmaceutical composition is administered at least two hours before bedtime. In another embodiment, the pharmaceutical composition is administered about one hour before bedtime. In a further embodiment, the pharmaceutical composition is administered at least one hour before bedtime. In a further embodiment, the pharmaceutical composition is administered less than one hour before bedtime. In another still further embodiment, the pharmaceutical composition is administered immediately before bedtime. Preferably, the pharmaceutical composition is administered orally. Suitable orally administered compositions include, but are not limited to: tablets, coated tablets, lozenges, capsules, powders, granules and soluble tablets, and liquid forms (e.g., suspensions, dispersions or solutions).

The appropriate dosage ("therapeutically effective amount") of the active agent in the immediate release component or the extended release component will depend, for example, on the severity and course of the condition, the mode of administration, the bioavailability of the particular formulation, the age and weight of the patient, the clinical history and response to the active agent, the order of treatment, and the like.

It is generally recommended that a therapeutically effective amount of the active agent in the immediate-release component, the extended-release component, or the delayed-extended-release component be administered in a range of from about 100 μ g/kg body weight/day to about 100mg/kg body weight/day, whether administered in one or more administrations. In some embodiments, each active agent administered in a single or multiple doses per day ranges from about 100 μ g/kg body weight/day to about 50mg/kg body weight/day, 100 μ g/kg body weight/day to about 10mg/kg body weight/day, 100 μ g/kg body weight/day to about 1mg/kg body weight/day, 100 μ g/kg body weight/day to about 10mg/kg body weight/day, 500 μ g/kg body weight/day to about 100mg/kg body weight/day, 500 μ g/kg body weight/day to about 50mg/kg body weight/day, 500 μ g/kg body weight/day to about 5mg/kg body weight/day, 1mg/kg body weight/day to about 100mg/kg body weight/day, 1mg/kg body weight/day to about 50mg/kg body weight/day, 1mg/kg body weight/day to about 10mg/kg body weight/day, 5mg/kg body weight/day to about 100mg/kg body weight/day, 5mg/kg body weight/day to about 50mg/kg body weight/day, 10mg/kg body weight/day to about 100mg/kg body weight/day, and 10mg/kg body weight/day to about 50mg/kg body weight/day.

The active agents described herein may be contained in daily single or multiple doses of an immediate release component or an extended release component, a delayed-extended release component or a combination thereof for oral administration in the range of 1mg to 2000mg,5mg to 2000mg,10mg to 2000mg,50mg to 2000mg,100mg to 2000mg,200mg to 2000mg,500mg to 2000mg,5mg to 1800mg,10mg to 1600mg,50mg to 1600mg,100mg to 1500mg,150mg to 1200mg,200mg to 1000mg,300mg to 800mg,325mg to 500mg,1mg to 1000mg,1mg to 500mg,1mg to 200mg,5mg to 1000mg,5mg to 500mg,5mg to 200mg,10mg to 1000mg,10mg to 500mg,10mg to 200mg,50mg to 1000mg,50mg to 500mg,50mg to 200mg,250mg to 1000mg,250mg to 500mg, or a combination thereof. As expected, the dosage will depend on the condition, size, age and condition of the patient.

In some embodiments, the pharmaceutical composition comprises a single analgesic agent, and one or more alpha-blockers or one or more 5 alpha-reductase inhibitors. In one embodiment, the single analgesic is aspirin. In another embodiment, the single analgesic agent is ibuprofen. In another embodiment, the single analgesic agent is naproxen or naproxen sodium. In another embodiment, the single analgesic agent is indomethacin. In another embodiment, the single analgesic agent is nabumetone. In another embodiment, the single analgesic agent is acetaminophen. In another embodiment, said single analgesic agent is acetaminophen and said one or more α -blockers comprises tamsulosin. In another embodiment, the single analgesic agent is acetaminophen and the one or more 5 α -reductase inhibitors comprise finasteride.

In some embodiments, the single analgesic is administered at a dose of 1mg to 2000mg,5mg to 2000mg,20mg to 2000mg,5mg to 1000mg,20mg to 1000mg,50mg to 500mg,100mg to 500mg,250mg to 1000mg, or 500mg to 1000mg daily. In certain embodiments, the pharmaceutical composition comprises acetylsalicylic acid, ibuprofen, naproxen sodium, indomethacin, nabumetone, or acetaminophen as a single analgesic agent, and the analgesic agent is administered orally in a daily dosage range of 5mg to 2000mg,20mg to 2000mg,5mg to 1000mg,20mg to 1000mg,50mg to 500mg,100mg to 500mg,250mg to 1000mg, or 500mg to 1000 mg. In some embodiments, the second analgesic is administered at a daily dose of 1mg to 2000mg,5mg to 2000mg,20mg to 2000mg,5mg to 1000mg,20mg to 1000mg,50mg to 500mg,100mg to 500mg,250mg to 1000mg, or 500mg to 1000 mg.

In other embodiments, the pharmaceutical composition comprises a pair of analgesics and one or more alpha-blockers. Examples of such paired analgesics include, but are not limited to, acetylsalicylic acid and ibuprofen, acetylsalicylic acid and naproxen sodium, acetylsalicylic acid and nabumetone, acetylsalicylic acid and acetaminophen, acetylsalicylic acid and indomethacin, ibuprofen and naproxen sodium, ibuprofen and nabumetone, ibuprofen and acetaminophen, ibuprofen and indomethacin, naproxen sodium and nabumetone, naproxen sodium and acetaminophen, naproxen sodium and indomethacin, nabumetone and acetaminophen, nabumetone and indomethacin, and acetaminophen and indomethacin. The paired analgesics are mixed in a weight ratio of 0.1: 1 to 10: 1, 0.2: 1 to 5: 1, or 0.3: 1 to 3: 1, at a combined dose in the range of 5mg to 2000mg,20mg to 2000mg,100mg to 2000mg,200mg to 2000mg,500mg to 2000mg,5mg to 1500mg,20mg to 1500mg,100mg to 1500mg,200mg to 1500mg,500mg to 1500mg,5mg to 1000mg,20mg to 1000mg,100mg to 1000mg,250mg to 500mg,250mg to 1000mg,250mg to 1500mg,500mg to 1000mg,500mg to 1500mg,1000mg to 1500mg, and 1000mg to 2000 mg. In one embodiment, the paired analgesic agents are mixed in a 1: 1 weight ratio.

In other embodiments, the pharmaceutical compositions of the present application further comprise one or more antimuscarinic agents. Examples of the antimuscarinic agent include, but are not limited to oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, trospium chloride, and atropine. Daily dosages of the antimuscarinic agent range from 0.01mg to 100mg,0.1mg to 100mg,1mg to 100mg,10mg to 100mg,0.01mg to 25mg,0.1mg to 25mg,1mg to 25mg,10mg to 25mg,0.01mg to 10mg,0.1mg to 10mg,1mg to 10mg,10mg to 10mg, and 10mg to 25 mg.

In certain embodiments, the pharmaceutical composition comprises one or more alpha-blockers, an analgesic agent selected from acetylsalicylic acid, ibuprofen, naproxen sodium, nabumetone, acetaminophen, and indomethacin, and an antimuscarinic agent selected from oxybutynin, solifenacin, darifenacin, and atropine.

Another aspect of the present application relates to a method of reducing the frequency of urination by administering to a person in need thereof a pharmaceutical composition formulated in an immediate release formulation. The pharmaceutical composition comprises one or more analgesic agents and one or more additional active ingredients selected from the group consisting of 5 alpha-reductase inhibitors, alpha-blockers, antimuscarinic agents, antidiuretic agents and spasmolytics. The pharmaceutical composition may be formulated in the form of tablets, capsules, lozenges, powders, granules, liquids, gels, or emulsions. The liquid, gel or emulsion may be ingested by the subject either directly or contained in a capsule.

In some embodiments, the analgesic is selected from the group consisting of: salicylate, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, derivatives of p-aminophenol, acetanilide, acetaminophen, phenacetin, fenamate, mefenamic acid, mefenamate, meclofenamate sodium, heteroaryl acetic acid derivatives, tolmetin, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, olsalazine; enolic acid, oxicams (benzothiazines) derivatives, piroxicam, meloxicam, tenoxicam, ampiroxicam, droxicam, pivoxicam, pyrazolone derivatives, phenylbutazone, oxybuprazone, antipyrine, aminopyrine, analgin, colexides, celecoxib, rofecoxib, nabumetone, apazone, nimesulide, indomethacin, sulindac, etodolac, diflunisal and isobutylphenylpropionic acid. The antimuscarinic agent is selected from oxybutynin, solifenacin, darifenacin, and atropine.

In some embodiments, the pharmaceutical composition comprises a single analgesic agent, a single alpha-blocker, and a single antimuscarinic agent. In some embodiments, the pharmaceutical composition comprises a single analgesic agent, a single 5 α -reductase inhibitor, and a single antimuscarinic agent. In one embodiment, the single analgesic is aspirin. In another embodiment, the single analgesic agent is ibuprofen. In another embodiment, the single analgesic agent is naproxen or naproxen sodium. In another embodiment, the single analgesic agent is indomethacin. In another embodiment, the single analgesic agent is nabumetone. In another embodiment, the single analgesic agent is acetaminophen. In another embodiment, said single α -blocker is tamsulosin. The analgesic, alpha-blocker, 5 alpha-reductase inhibitor and antimuscarinic agent may be administered at dosages within the ranges set forth above. In some embodiments, the pharmaceutical composition further comprises an antidiuretic or spasmolytic.

In some embodiments, the pharmaceutical composition comprises one or more of 50-2000mg,50-1500mg,50-1200mg,50-1000mg,50-800mg,50-600mg,50-500mg,50-400mg,50-300mg,50-250mg,50-200mg,50-150mg,50-100mg,100-2000mg,100-1500mg,100-1200mg,100-1000mg,100-800mg,100-600mg,100-400mg,100-250mg,250-2000mg,250-1500mg,250-1200mg,250-1000mg,250-800mg,250-600mg,250-400mg,400-2000mg,400-1500mg,400-1200mg, 400-1000-400-800 mg,400-, 600-, 2000-, 600-, 1500-, 600-, 1200-, 600-, 1000-, 600-, 800-, 1500-, 800-, 1200-, 800-, 1000-, 2000-, 1000-, 1500-, 1200-or 1500-2000-mg analgesic, wherein the composition is formulated to have an extended release with a release profile in which the one or more analgesics are released continuously over a period of 5-24 hours, 5-8, 8-16 hours or 16-24 hours.

In some embodiments, the composition is formulated to have an extended release with a release profile in which at least 90% of the active ingredient is released continuously over a period of 5-24 hours, 5-8, 8-16 hours, or 16-24 hours.

In some embodiments, the composition is formulated to have an extended release with a release profile in which the active ingredient is released continuously over a period of 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours.

In other embodiments, the composition is formulated to have an extended release with a release profile in which the active ingredient is released at a steady rate over a period of 5-24 hours, 5-8, 8-16 hours, or 16-24 hours. In other embodiments, the composition is formulated to have an extended release with a release profile in which the active ingredient is released at a steady rate over a period of 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours. As used herein, "at a steady rate over a period of time" is defined as a release profile in which the release rate at any point over a given period of time is within 30% -300% of the average release rate over the given period of time. For example, if 80mg aspirin is released at a steady rate over an 8 hour period, with an average rate of 10mg/hr over the period, then the actual release rate at any time over this period is in the range of 3mg/hr to 30mg/hr (i.e., within 30% -300% of the average release rate of 10mg/hr over the 8 hour period).

In some embodiments, the analgesic agent is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, nabumetone, and acetaminophen. The pharmaceutical composition is formulated to provide a small, stable release of the analgesic agent, thereby maintaining an effective drug concentration in the blood such that the total amount of drug in a single administration is reduced compared to an immediate release formulation. The other active ingredients may be released immediately after administration or with the analgesic.

In some embodiments, the pharmaceutical composition comprises 50-400mg, 50-250mg,250-400mg or 400-600mg of an extended release analgesic formulated to have a release profile in which at least 90% of the analgesic is released continuously or at a steady rate over a period of 5-8, 8-16 hours, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In a particular embodiment, the pharmaceutical composition comprises 50-250mg of extended release acetaminophen formulated to have a release profile in which at least 90% of the acetaminophen is released continuously or at a steady rate over a period of 5-8, 8-16 hours, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another specific embodiment, the pharmaceutical composition comprises 250-400mg of extended release acetaminophen formulated to have a release profile in which 90% of the acetaminophen is released continuously or at a steady rate over a period of 5-8, 8-16 hours, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another specific embodiment, the pharmaceutical composition comprises 400-600mg of extended release acetaminophen formulated to have a release profile in which 90% of the acetaminophen is released continuously or at a steady rate over a period of 5-8, 8-16 hours, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another specific embodiment, the pharmaceutical composition comprises 600-800mg of extended release acetaminophen formulated to have a release profile in which 90% of the acetaminophen is released continuously or at a steady rate over a period of 5-8, 8-16 hours, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another specific embodiment, the pharmaceutical composition comprises 800-1000mg of extended release acetaminophen formulated to have a release profile in which at least 90% of the acetaminophen is released continuously or at a steady rate over a period of 5-8, 8-16 hours, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In some other embodiments, the pharmaceutical composition comprises one or more of 50-2000mg,50-1500mg,50-1200mg,50-1000mg,50-800mg,50-600mg,50-500mg,50-400mg,50-300mg,50-250mg,50-200mg,100-2000mg,100-1500mg,100-1200mg,100-1000mg,100-800mg,100-600mg,100-500mg,100-400mg,100-300mg,100-200mg, 200-1500mg,200-1200mg,200-1000mg,200-800mg,200-600mg,200-400mg,400-2000mg,400-1500mg, 400-1000mg,400-, 600-, 2000-, 600-, 1500-, 600-, 1200-, 600-, 800-, 1200-, 800-, 1000-, 2000-, 1200-or 1500-comprising an analgesic, wherein the analgesic is formulated for an extended release characterized by a two-stage release profile in which 20-50% of the analgesic is released within 2 hours of administration and the remainder is released continuously or at a steady rate within a period of 5-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another embodiment, the analgesic is formulated for extended release with a two-phase release profile in which 20, 30, 40 or 50% of the analgesic is released within 2 hours of administration and the remainder is released continuously or at a steady rate over a period of 5-8, 8-16 or 16-24 hours. In one embodiment, the analgesic agent is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, nabumetone, and acetaminophen. In another embodiment, the analgesic agent is acetaminophen. In some embodiments, the pharmaceutical composition further comprises an antimuscarinic agent, an antidiuretic agent, or a spasmolytic agent. The other active ingredients may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 50-400mg of extended release acetaminophen formulated to have a two-phase release profile in which 20, 30, 40, or 50% of the acetaminophen is released within 2 hours of administration and the remainder is released continuously or at a steady rate over a period of 5-8, 8-16, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 100-300mg of extended release acetaminophen formulated to have a two-phase release profile in which 20, 30, 40, or 50% of the acetaminophen is released within 2 hours of administration and the remainder is released continuously or at a steady rate over a period of 5-8, 8-16, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 400-600mg of extended release acetaminophen formulated to have a two-step release profile in which 20, 30, 40, or 50% of the acetaminophen is released within 2 hours of administration and the remainder is released continuously or at a steady rate over a period of 5-8, 8-16, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 600-800mg of extended release acetaminophen formulated to have a two-step release profile in which 20, 30, 40, or 50% of the acetaminophen is released within 2 hours of administration and the remainder is released continuously or at a steady rate over a period of 5-8, 8-16, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 800-1000mg of extended release acetaminophen formulated to have a two-step release profile in which 20, 30, 40, or 50% of the acetaminophen is released within 2 hours of administration and the remainder is released continuously or at a steady rate over a period of 5-8, 8-16, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 1000-1200mg of extended release acetaminophen formulated to have a two-step release profile in which 20, 30, 40, or 50% of the acetaminophen is released within 2 hours of administration and the remainder is released continuously or at a steady rate over a period of 5-8, 8-16, or 16-24 hours. The other active ingredients may be released immediately after administration or with the analgesic.

Another aspect of the present application relates to a method of treating nocturia by administering to a subject in need thereof (1) one or more analgesics, (2) an alpha-blocker or a 5 alpha-reductase inhibitor or a combination of both, and (3) one or more antidiuretic agents. In certain embodiments, the antidiuretic agent is for: (1) increase vasopressin secretion; (2) increasing vasopressin receptor activation; (3) reducing secretion of Atrial Natriuretic Peptide (ANP) or C-type natriuretic peptide (CNP); or (4) reduce ANP and/or CNP receptor activation.

Examples of antidiuretic agents include, but are not limited to, antidiuretic hormone (ADH), angiotensin ii, aldosterone, vasopressin analogs (e.g., desmopressin, lypressin, phenlyspressin, ornipressin, terlipressin); vasopressin receptor agonists, Atrial Natriuretic Peptide (ANP), and C-type natriuretic peptide (CNP) receptor (i.e., NPR1, NPR2, NPR3) antagonists (e.g., HS-142-1, isatin, [ Asu7, 23' ] b-ANP- (7-28) ], ansamitene, cyclic peptides from Streptomyces coerulescens, and the 3G12 monoclonal antibody); somatostatin type 2 receptor antagonists (e.g., somatostatin), and pharmaceutically acceptable derivatives, analogs, salts, hydrates, and solvates thereof.

In one embodiment, the one or more analgesic agents, alpha-blocker agents and/or 5 alpha-reductase inhibitors are formulated for extended release and the one or more antidiuretic agents are formulated for immediate release. In other embodiments, the one or more analgesic agents, alpha-blocker agents, and/or 5 alpha-reductase inhibitors are formulated for delayed release and the antidiuretic agent is formulated for immediate release. In some embodiments, the delayed release formulation delays release of the active ingredient (e.g., the analgesic, antimuscarinic, antidiuretic, and spasmolytic) for 1,2, 3, 4, or 5 hours.

Another aspect of the present application relates to a method of reducing urinary frequency by administering to a human in need thereof a first pharmaceutical composition comprising a diuretic, followed by a second pharmaceutical composition comprising (1) one or more analgesics and (2) one or more alpha-blockers, one or more 5 alpha-reductase inhibitors, or a combination of both. The first pharmaceutical composition is dosed and formulated to have a diuretic effect within 6 hours of administration and is administered at least 8 or 7 hours before bedtime. The second pharmaceutical composition is administered within 2 hours before bedtime. The first pharmaceutical composition is formulated for immediate release and the second pharmaceutical composition is formulated for extended release, or delayed extended release.

Examples of diuretics include, but are not limited to, acidifying salts, such as CaCl2 and NH4 Cl; arginine vasopressin receptor 2 antagonists such as amphotericin B and lithium citrate; water-excretion promoting agents, such as daylily (golden) and juniper (Junipe); Na-H exchanger antagonists, such as dopamine; carbonic anhydrase inhibitors such as acetazolamide and dorzolamide; loop diuretics such as bumetanide, ethacrynic acid, furosemide and torsemide; osmotic diuretics, such as glucose and mannitol; potassium sparing diuretics such as amiloride, spironolactone, triamterene, potassium clonorcipropion; thiazines such as benflumethiazide and hydrochlorothiazide; and xanthines, such as caffeine, theophylline, and theobromine.

In some embodiments, the second pharmaceutical composition further comprises one or more antimuscarinic agents. Examples of the antimuscarinic agent include, but are not limited to oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, trospium chloride, and atropine. The second pharmaceutical composition may be formulated as an immediate release formulation or a delayed release formulation or an extended release formulation. In other embodiments, the second pharmaceutical composition further comprises one or more antidiuretic agents. In some other embodiments, the second pharmaceutical composition further comprises one or more spasmolytics. Another aspect of the present application relates to a method of preventing the development of resistance to reduce urinary frequency by selectively administering two or more analgesics to a subject in need thereof. In one embodiment, the method comprises administering a first analgesic for a first period of time, followed by administration of a second analgesic for a second period of time. In another embodiment, the method further comprises administering a third analgesic for a third period of time. The first, second and third analgesic agents are different from one another and at least one of them is formulated for extended release or delayed extended release. In one embodiment, the first analgesic agent is acetaminophen, the second analgesic agent is ibuprofen and the third analgesic agent is naproxen sodium. The length of each period may vary depending on the subject's response to each analgesic. In some embodiments, each period lasts from three days to three weeks. In another embodiment, the first, second and third analgesic agents are all formulated for extended release or delayed extended release.

Another aspect of the present application relates to a pharmaceutical composition comprising a plurality of active ingredients and a pharmaceutically acceptable carrier, wherein at least one of the plurality of active ingredients is formulated for extended release or delayed extended release. In some embodiments, the plurality of active ingredients comprises one or more analgesics and one or more antidiuretic agents. In other embodiments, the plurality of active ingredients comprises one or more analgesics, one or more alpha-blockers, one or more 5 alpha-reductase inhibitors, and one or more antimuscarinic agents. In other embodiments, the plurality of active ingredients comprises one or more analgesics, one or more alpha-blockers, one or more antidiuretic agents, and one or more antimuscarinic agents. In other embodiments, the pharmaceutical composition comprises two different analgesic agents selected from the group consisting of acetylsalicylic acid, ibuprofen, naproxen sodium, naproxen, nabumetone, acetaminophen, and indomethacin. In other embodiments, the pharmaceutical composition comprises an analgesic agent selected from the group consisting of acetylsalicylic acid, ibuprofen, naproxen sodium, nabumetone, acetaminophen, and indomethacin; one or more alpha-blockers and an antimuscarinic agent selected from oxybutynin, solifenacin, darifenacin, and atropine.

In some further embodiments, the pharmaceutical compositions described herein further comprise one or more spasmolytic and/or one or more antidiuretic agents. Examples of antispasmodics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine analogs, and dantrolene. In some embodiments, the spasmolytic is used at a dose of 1mg to 1000mg,1mg to 100mg,10mg to 1000mg,10mg to 100mg,20mg to 1000mg,20mg to 800mg,20mg to 500mg,20mg to 200mg,50mg to 1000mg,50mg to 800mg,50mg to 200mg,100mg to 800mg,100mg to 500mg,200mg to 800mg, and 200mg to 500mg daily. The spasmolytic may be formulated for immediate release, extended release, delayed-extended release, or a combination thereof, alone or with other active ingredients in the pharmaceutical composition.

In some embodiments, the pharmaceutical composition comprises one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen in a total amount of 50-400mg per dose, one or more alpha-blockers, and one or more antimuscarinic agents selected from the group consisting of oxybutynin, solifenacin, darifenacin, and atropine in a total amount of 1-25mg, wherein the pharmaceutical composition is formulated to have an extended release with a two-phase release profile in which 20-60% of the active ingredient is released within 2 hours of administration and the remainder of the active ingredient is released continuously or at a sustained rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

In some embodiments, the pharmaceutical composition comprises one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen in a total amount of 50-400mg per dose, one or more alpha-blockers, and one or more antidiuretic agents selected from the group consisting of antidiuretic hormone (ADH), angiotensin ii, aldosterone, vasopressin analogs (e.g., desmopressin argirelin, lyspressin, phenipressin, ornipressin, terlipressin); vasopressin receptor agonists, Atrial Natriuretic Peptide (ANP), and C-type natriuretic peptide (CNP) receptor (i.e., NPR1, NPR2, NPR3) antagonists (e.g., HS-142-1, isatin, [ Asu7, 23' ] b-ANP- (7-28) ], ansamitene (antanin), cyclic peptides from Streptomyces coerulescens, and the 3G12 monoclonal antibody); a somatostatin type-2 receptor antagonist (e.g., somatostatin), and pharmaceutically acceptable derivatives, analogs, salts, hydrates and solvates thereof, wherein the pharmaceutical composition is formulated to have an extended release with a biphasic release profile in which 20-60% of the active ingredient is released within 2 hours of administration and the remainder is released continuously or at a sustained rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

In some embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen in an amount of 50-400mg per dose, (2) one or more alpha-blockers, or one or more 5 alpha-reductase inhibitors, or both, and (3) one or more spasmolytic agents selected from the group consisting of carisoprodol, benz (and) diazepines, baclofen, cyclobenzaprine beads, metaxalone, methocarbamol, clonidine analogs, and dantrolene in a total amount of 50-500mg, wherein the pharmaceutical composition is formulated to have an extended release with a two-phase release profile in which 20-60% of the active ingredient is released within 2 hours of administration and the remainder is released within 5-24 hours, Is released continuously or at a steady rate over a period of 5-8 hours, 8-16 hours, or 16-24 hours.

As used herein, "pharmaceutically acceptable carrier" includes all and any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweeteners, and the like. The pharmaceutically acceptable carriers can be prepared from a wide range of materials including, but not limited to, flavoring agents, sweetening agents, and miscellaneous materials such as buffers and absorbents required to prepare a particular therapeutic composition. The use of such media and agents with pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.

The invention will be further illustrated by the following non-limiting examples. The contents of all references, patents and published patent applications cited in this application are incorporated by reference into this application.

Example 1: suppression of voiding impulsion

20 volunteer subjects enrolled in both men and women, each experienced a premature urge to urinate or a need to urinate, interfering with their ability to sleep for a period of time sufficient to feel full rest. Each subject ingested 400 to 800mg ibuprofen in a single dose prior to bedtime. At least 14 subjects reported that they were able to rest better because they were not awakened by frequent urge to urinate.

Several subjects reported that the benefits of infrequent voiding strokes were no longer realized after several weeks of overnight ibuprofen use. However, all of these subjects further reported that such benefits were achieved after giving up taking the medicament for several days.

Example 2: analgesic, botulinum neurotoxin and antimuscarinic agents against inflammation by macrophages And effects of non-inflammatory stimuli

Design of experiments

The present study is directed to determining the dose and in vitro efficacy of analgesic and antimuscarinic agents in controlling macrophage responses to inflammatory and non-inflammatory stimuli mediated by COX2 and prostaglandins (PGE, PGH, etc.). It establishes a baseline (dose and kinetics) response to inflammatory and non-inflammatory effectors in bladder cells. Briefly, cultured cells are exposed to an analgesic and/or an antimuscarinic agent in the absence or presence of various effectors.

The effectors include: lipopolysaccharide (LPS), an inflammatory agent, and an inducer of Cox2, as inflammatory stimulators; carbachol or acetylcholine, smooth muscle contraction stimulator, as a non-inflammatory stimulant; botulinum neurotoxin a, a known inhibitor of acetylcholine release, as a positive control; arachidonic Acid (AA), gamma linolenic acid (DGLA) or eicosapentaenoic acid (EPA) as precursors of prostaglandins, which are produced after sequentially oxidizing AA, DGLA or EPA in cells by cyclooxygenase (COX1 and COX-2) and a terminal prostaglandin synthase.

The analgesic agent comprises: salicylates such as aspirin, isobutylpropionic acid phenolic acid derivatives (ibuprofen) such as javain (Advil), ibuprofen preparation (Motrin), sulfamethoxazole (Nuprin) and Medipren; naproxen sodium, such as naproxen sodium (Aleve), naproxen formulation (Anaprox), Antalgin, femimax Ultra, naproxen (flanaax), inda, Midol Extended Relief, Nalgesin, naproxen sustained release tablet (naperlan), naproxen (Naprosyn) suspension, EC-naproxen (EC-Naprosyn), Narocin, naproxen (Proxen), Synflex, and Xenobid; acetic acid derivatives, such as indomethacin (Indocin); 1-naphthylacetic acid derivatives such as nabumetone or rilifen; n-acetyl-p-aminophenol (APAP) derivatives, such as acetaminophen or paracetamol (tylenol) and celecoxib.

The antimuscarinic agents include: oxybutynin, solifenacin, darifenacin, and atropine.

Subjecting macrophages to short-term (1-2 hours) or long-term (24-48 hours) stimulation with:

(1) different doses of each individual analgesic.

(2) Different doses of each analgesic in the presence of LPS.

(3) Different doses of each analgesic in the presence of carbachol or acetylcholine.

(4) Different doses of each analgesic in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin a alone.

(6) Different doses of botulinum neurotoxin a in the presence of LPS.

(7) Different doses of botulinum neurotoxin a in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin a at different doses in the presence of AA, DGLA or EPA.

(9) A different dose of each antimuscarinic agent alone.

(10) Different doses of each antimuscarinic agent in the presence of LPS.

(11) Different doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.

(12) Different doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

Cells were then analyzed for PGH₂、PGE、PGE₂The release of prostacyclin, thromboxane, IL-1 β, IL-6, TNF- α, COX2 activity, the production of cAMP and cGMP, the production of IL-1 β, IL-6, TNF- α and COX2mRNA, and the surface expression of CD80, CD86 and MHC class II molecules.

Materials and methods

Macrophage cell

Murine RAW264.7 or J774 macrophages (obtained from ATCC) were used in this study. Cells were maintained in medium containing RPMI1640 and supplemented with 10% Fetal Bovine Serum (FBS), 15mM HEPES, 2mM L-glutamine, 100U/ml penicillin and 100. mu.g/ml streptomycin. Cells were incubated at 37 ℃ with 5% CO₂Incubate under atmosphere and segregate (passage) once per week.

In vitro treatment of macrophages with analgesics

RAW264.7 macrophages were dosed at 1.5x10⁵Cell density of individual cells/well (in 100. mu.l medium) were seeded in 96-well plates. The cells were treated with: (1) different concentrations of analgesic (acetaminophen, aspirin, ibuprofen or naproxen), (2) different concentrations of Lipopolysaccharide (LPS), which is an effector of inflammatory stimulation of macrophages, (3) different concentrations of carbachol or acetylcholine, which are non-inflammatory effectors of stimulation, (4) analgesic and LPS or (5) analgesic and carbachol or acetylcholine. Briefly, analgesics were dissolved in FBS-free medium (i.e., RPMI1640 supplemented with 15mM HEPES, 2mM levoglutamide, 100U/ml penicillin and 100 μ g/ml streptomycin) and diluted to the desired concentration by serial dilution with the same medium. For cells treated with the analgesic in the absence of LPS, 50 μ l of the analgesic solution and 50 μ l of FBS-free medium were added to each well. For cells treated with analgesic in the presence of LPS, 50 μ l of analgesic solution and 50 μ l of LPS (from Salmonella typhimurium) in FBS-free medium were added to each well. All conditions were tested in duplicate.

After 24 or 48 hours of incubation, 150 μ l of culture supernatant was collected, spun at 4 ℃,8,000 rpm for 2 minutes to remove cells and debris, and stored at-70 ℃ for analysis of cytokine response by ELISA. Cells were collected and washed by centrifugation (5 minutes at 4 ℃,1,500 rpm) in 500. mu.l of Phosphate Buffered Saline (PBS). Half of the cells were then snap frozen in liquid nitrogen and stored at-70 ℃. The remaining cells were stained with fluorescent monoclonal antibodies and analyzed by flow cytometry.

Flow cytometric analysis of costimulatory molecule expression

For flow cytometry analysis, macrophages were diluted in 100 μ l of FACS buffer (phosphate buffered saline (PBS) with 2% Bovine Serum Albumin (BSA) and 0.01% NaN 3) and purified by addition of FITC-bound anti-CD 40, PE-bound anti-CD 80, PE-bound anti-CD 86 antibody, anti-MHC class II (I-a)^d) PE (BD biosciences) at 4 ℃ for 30 minutes. The cells were then washed by centrifugation (5 min at 4 ℃,1,500 rpm) in 300. mu.l of FACS buffer. After the second wash, the cells were resuspended in 200 μ l FACS buffer and the percentage of cells expressing a given marker (single positive) or a combination of markers (double positive) was analyzed by means of AccuriC6 flow cytometry (BD bioscience).

Analysis of cytokine response by ELISA

The culture supernatants were subjected to cytokine-specific ELISA to determine IL-1 β, IL-6 and TNF- α responses in cultures of macrophages treated with analgesics, LPS alone or a combination of LPS and analgesics. These assays were performed in 100. mu.l of anti-mouse IL-6, TNF-. alpha.mAbs (BD biosciences) or IL-1. beta. mAb (R) in 0.1M sodium bicarbonate buffer (pH9.5)&System D) was coated overnight on Nunc MaxiSorp immunolates (Nunc). After washing twice with PBS (200 μ Ι per well), 200 μ Ι of PBS 3% BSA was added to each well (zone) and the plates were incubated for 2 hours at room temperature. The plate was washed twice again by adding 200. mu.l per well, 100. mu.l of cytokine standard and serial dilutions of culture supernatant were added repeatedly, andthe plates were incubated overnight at 4 ℃. Finally, the plate was washed twice and 100. mu.l biotinylated anti-murine IL-6, TNF α mAbs (BD bioscience) or IL-1 β (R)&System D), followed by incubation with peroxidase-labeled goat anti-biotin mAb (Vector laboratories). By adding 2, 2' -azino-bis (3-ethylbenzylthiazoline-6-sulfonic Acid) (ABTS) substrate andH ₂ O ₂ (Sigma) to develop the colorimetric reaction and absorbance was usedV Multi-labeled microplate detector (Perkinelmer) at 415 nm.

Determination of COX2 Activity and production of cAMP and cGMP

The activity of COX2 in cultured macrophages was determined by sequential competition ELISA (R & D system). The production of cAMP and cGMP was determined by cAMP and cGMP assays. These assays are commonly performed in the art.

Results

Table 1 summarizes the experiments performed by the Raw264 macrophage strain and the main findings in terms of the effect of analgesics on the cell surface expression of the co-stimulatory molecules CD40 and CD 80. Expression of these molecules was stimulated by COX2 and inflammatory signals, and expression of these molecules was therefore assessed to determine the functional consequences of inhibition of COX 2.

As shown in table 2, except for the highest dose (i.e., 5x 10)⁶nM) (which showed enhanced, rather than inhibited, expression of costimulatory molecules), acetaminophen, aspirin, ibuprofen, and naproxen at all doses tested (i.e., 5x 10)⁵nM、5x10⁴nM、5x10³nM、5x10²nM, 50nM and 5nM) inhibits basal expression of the co-stimulatory molecules CD40 and CD80 of macrophages. As shown in fig. 1A and 1B, such inhibitory effects on CD40 and CD50 expression were observed at analgesic doses as low as 0.05nM (i.e., 0.00005 μ M). This finding supports the idea that: controlled release ratio of small dose analgesic agentAcute delivery of the amount is more preferred. Experiments also showed that acetaminophen, aspirin, ibuprofen, and naproxen had similar inhibitory effects on LPS-induced expression of CD40 and CD 80.

TABLE 1 summary of the experiments

TABLE 2 summary of the main findings

^*ND: not performed (toxicity)

Table 3 summarizes the results of several studies that measured the serum levels of analgesics in adults following oral therapeutic doses. As shown in Table 3, the maximum serum level of the analgesic after oral therapeutic dose was 10⁴To 10⁵In the nM range. Thus, the analgesic doses tested in vitro in table 2 cover the range of concentrations achievable in humans.

TABLE 3 serum levels of analgesic in human blood following oral therapeutic dose

Example 3: analgesic, botulinum neurotoxin and antimuscarinic agents against mouse bladder smooth muscle Effect of cell response to inflammatory and non-inflammatory stimuli

Design of experiments

This study was intended to demonstrate how the optimal dose of analgesic as determined in example 2 affects bladder smooth muscle cells in cell or tissue culture and to investigate whether different classes of analgesics can act synergistically to more effectively inhibit COX2 and PGE2 responses.

Effectors, analgesics, and antimuscarinic agents are described in example 2.

Primary cultures of mouse bladder smooth muscle cells were subjected to short-term (1-2 hours) or long-term (24-48 hours) stimulation with:

(1) different doses of each individual analgesic.

(2) Different doses of each analgesic in the presence of LPS.

(3) Different doses of each analgesic in the presence of carbachol or acetylcholine.

(4) Different doses of each analgesic in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin a alone.

(6) Different doses of botulinum neurotoxin a in the presence of LPS.

(7) Different doses of botulinum neurotoxin a in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin a at different doses in the presence of AA, DGLA or EPA.

(9) A different dose of each antimuscarinic agent alone.

(10) Different doses of each antimuscarinic agent in the presence of LPS.

(11) Different doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.

(12) Different doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

Cells were then analyzed for PGH₂、PGE、PGE₂The release of prostacyclin, thromboxane, IL-1 β, IL-6, TNF- α, COX2 activity, the production of cAMP and cGMP, the production of IL-1 β, IL-6, TNF- α and COX2mRNA, and the surface expression of CD80, CD86 and MHC class II molecules.

Materials and methods

Isolation and purification of mouse bladder cells

Bladder cells were removed from euthanized animals, C57BL/6 mice (8-12 weeks old), and cells were isolated by enzymatic digestion followed by purification with a Percoll gradient. Briefly, the bladders obtained from 10 mice were minced with scissors into a purified slurry in 10ml of digestion buffer (RPMI 1640, 2% fetal bovine serum, 0.5mg/ml collagenase, 30. mu.g/ml DNase). The bladder slurry was enzymatically digested at 37 ℃ for 30 minutes. Undigested debris was further dispersed by cell-trainer (cell-trainer). The cell suspension was pelleted and added to discrete 20%, 40% and 75% Percoll gradients to purify monocytes. 50-60 bladders were used for each experiment.

After washing with RPMI1640, bladder cells were resuspended in RPMI1640 supplemented with 10% fetal bovine serum, 15mM HEPES, 2mM L-glutamine, 100U/ml penicillin and 100. mu.g/ml streptomycin at 3X10⁴Cell density of individual cells/well (100 μ Ι) were seeded into clear-bottom black 96-well cell culture micro-culture plates. Cells were incubated at 37 ℃ with 5% CO₂Culturing under an atmosphere.

In vitro treatment of cells with analgesics

Bladder cells were treated with an analgesic solution (50. mu.l/well) alone or in combination with carbachol (10 moles, 50. mu.l/well) as an example of a non-inflammatory stimulant or with Lipopolysaccharide (LPS) of Salmonella typhimurium (1. mu.g/ml, 50. mu.l/well) as an example of a non-inflammatory stimulant. When no other effectors were added to the cells, 50 μ l of RPMI1640 without fetal bovine serum was added to the wells to adjust the final volume to 200 μ l.

After 24 hours of incubation, 150. mu.l of culture supernatant was collected, spun at 4 ℃,8,000 rpm for 2 minutes to remove cells and debris, and stored at-70 ℃ for analysis of prostaglandin E2 (PGE) by ELISA₂) The reaction of (1). Cells were fixed, permeabilized and blocked to detect cyclooxygenase-2 (COX-2) using a fluorogenic substrate. In selected experiments, cells were stimulated in vitro for 12 hours for analysis of the COX2 response.

Analysis of COX2 reaction

COX2 response was determined by using a human/mouse total COX2 immunoassay (R)&D system) was performed according to the manufacturer's instructions. Briefly, after cell fixation and permeabilization, mouse anti-total COX2 and rabbit anti-total GAPDH were added to wells of clear-bottom, black 96-well cell culture micro-culture plates. After incubation and washing, HRP-conjugated anti-mouse IgG and AP-conjugated anti-rabbit IgG were added to the wells. After another incubation and washing, HRP-fluorogenic substrate and AP-fluorogenic substrate are added. Finally, useThe fluorescence emitted at 600nm (COX2 fluorescence) and 450nm (GAPDH fluorescence) was read by a V multi-label microplate detector (PerkinElmer). Results are expressed as relative levels of total COX2, determined by Relative Fluorescence Units (RFUs) and normalized to housekeeping protein GAPDH.

PGE2 reaction analysis

The response of prostaglandin E2 was analyzed by sequential competition ELISA (R & D system). Specifically, culture supernatant or PGE2 standard was added to wells of 96-well polystyrene microwell plates coated with goat anti-mouse polyclonal antibody. After one hour incubation on a microplate shaker, HRP-conjugated PGE2 was added and the plate was incubated for an additional two hours at room temperature. The plate was then washed and HRP substrate solution was added to each well. Color development was allowed for 30 minutes and the reaction was stopped by adding sulfuric acid before reading the plate at 450nm (wavelength corrected at 570 nm). The results are expressed as mean pg/ml of PGE 2.

Other experiments

PGH2, PGE, prostacyclin (prostacyclin), thromboxane, IL-1 β, IL-6 and TNF- α release, cAMP and cGMP production, IL-1 β, IL-6, TNF- α and COX2mRNA production, and surface expression of CD80, CD86 and MHC class II molecules were determined using the methods described in example 2.

Analgesics inhibit COX2 responses in mouse bladder cells to inflammatory stimuli

Several analgesics (acetaminophen, aspirin, ibuprofen, and naproxen) were tested at concentrations of 5 μ M or 50 μ M against mouse bladder cells to determine whether the analgesics could induce a COX2 response. Analysis of the 24 hour culture showed that none of the tested analgesics induced a COX2 response in mouse bladder cells in vitro.

The effect of these analgesics on in vitro mouse bladder cell responses to carbachol or LPS stimulated COX2 was also tested. As shown in table 1, the dose of carbachol tested had no significant effect on COX-2 levels in mouse bladder cells. LPS on the other hand significantly increased total COX2 levels. Notably, acetaminophen, aspirin, ibuprofen, and naproxen all inhibited the effect of LPS on COX2 levels. The inhibitory effect of the analgesic can be seen when these drugs are tested at 5 μ M or 50 μ M (Table 4).

TABLE 4 COX2 expression in mouse bladder cells following in vitro stimulation and analgesic treatment

Analgesic Agents inhibit PGE2 response of mouse bladder cells to inflammatory stimuli

The secretion of PGE2 in the mouse bladder cell culture supernatant was measured to determine the biological significance of the changes in mouse bladder cell COX2 levels due to analgesics. As shown in table 5, no PGE2 was detected in the culture supernatants of unstimulated bladder cells or bladder cells cultured in the presence of carbachol. Stimulation of mouse bladder cells with LPS induced high levels of secretion of PGE2, consistent with the COX2 response described above. Addition of the analgesics acetaminophen, aspirin, ibuprofen and naproxen inhibited the effect of LPS on PGE2 secretion and no difference was observed between cell responses treated with 5 or 50 μ M doses of the analgesic.

TABLE 5 PGE2 secretion from mouse bladder cells following in vitro stimulation and analgesic treatment

Taken together, these data indicate that the use of analgesics alone at 5 μ M or 50 μ M did not induce COX2 and PGE2 responses in mouse bladder cells. However, at 5 μ M or 50 μ M, the analgesic significantly inhibited COX2 and PGE2 responses in mouse bladder cells stimulated in vitro by LPS (1 μ g/ml). No significant effect of the analgesic on COX2 and PGE2 responses in mouse bladder cells stimulated by carbachol (1mM) was observed.

Example 4: analgesic, botulinum neurotoxin and antimuscarinic agents against mouse bladder smooth muscle Effect of cell contraction

Design of experiments

The cultured mouse or rat bladder smooth muscle cells and mouse or rat bladder smooth muscle tissue are exposed to an inflammatory stimulus and a non-inflammatory stimulus in the presence of different concentrations of an analgesic agent and/or an antimuscarinic agent. The stimulation-induced muscle contraction is measured to assess the inhibitory effect of the analgesic and/or antimuscarinic agent.

Effectors, analgesics, and antimuscarinic agents are described in example 2.

Primary cultures of mouse bladder smooth muscle cells were subjected to short-term (1-2 hours) or long-term (24-48 hours) stimulation with:

(1) different doses of each individual analgesic.

(2) Different doses of each analgesic in the presence of LPS.

(3) Different doses of each analgesic in the presence of carbachol or acetylcholine.

(4) Different doses of each analgesic in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin a alone.

(6) Different doses of botulinum neurotoxin a in the presence of LPS.

(7) Different doses of botulinum neurotoxin a in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin a at different doses in the presence of AA, DGLA or EPA.

(9) A different dose of each antimuscarinic agent alone.

(10) Different doses of each antimuscarinic agent in the presence of LPS.

(11) Different doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.

(12) Different doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

Materials and methods

Primary mouse bladder cells were isolated as described in example 3. In selected experiments, cultures of bladder tissue were used. Bladder smooth muscle cell contractions were recorded using a Grass multichannel recorder (Quincy Mass, usa).

Example 5: COX2 and antimuscarinic agents on mouse bladder smooth muscle cells by oral analgesic and antimuscarinic agents Effect of PGE2 reaction.

Design of experiments

Administering to normal mice and mice with overactive bladder syndrome an oral dose of aspirin, naproxen sodium, ibuprofen, indomethacin, nabumetone, tenolin, celecoxib, oxybutynin, solifenacin, darifenacin, atropine, and combinations thereof. The control group included untreated normal mice and untreated OAB mice with overactive bladder syndrome. After 30 minutes of the final dose, the bladder was collected and stimulated ex vivo with carbachol or acetylcholine. In selected experiments, the bladder was treated with botulinum neurotoxin a prior to stimulation with carbachol. Animals were kept in metabolic cages and the frequency (and volume) of urination was assessed. Bladder output was determined by monitoring water intake and cage weight. Determination of serum PGH by ELISA₂、PGE、PGE₂Prostacyclin, thromboxane, IL-1 β, IL-6, TNF- α, cAMP and cGMP levels. Expression of CD80, CD86, MHC class II in whole blood cells was detected by flow cytometry.

At the end of the experiment, animals were euthanized and isolated bladder contractions were recorded using a Grass multichannel recorder. Bladder sections were fixed in formalin and COX2 responses were analyzed by immunohistochemistry.

Example 6: analgesic, botulinum neurotoxin and antimuscarinic agents on human bladder smooth muscle cells Effect of cell response to inflammatory and non-inflammatory stimuli

Design of experiments

This study was designed to characterize how the optimal dose of analgesic as determined in examples 1 to 5 affects human bladder smooth muscle cells in cell culture or tissue culture, and to investigate whether different classes of analgesics could cooperate to more effectively inhibit COX2 and PGE2 responses.

Effectors, analgesics, and antimuscarinic agents are described in example 2.

Human bladder smooth muscle cells were subjected to short-term (1-2 hours) or long-term (24-48 hours) stimulation with:

(1) different doses of each individual analgesic.

(2) Different doses of each analgesic in the presence of LPS.

(3) Different doses of each analgesic in the presence of carbachol or acetylcholine.

(4) Different doses of each analgesic in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin a alone.

(6) Different doses of botulinum neurotoxin a in the presence of LPS.

(7) Different doses of botulinum neurotoxin a in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin a at different doses in the presence of AA, DGLA or EPA.

(9) A different dose of each antimuscarinic agent alone.

(10) Different doses of each antimuscarinic agent in the presence of LPS.

(11) Different doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.

(12) Different doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

Cells were then analyzed for PGH₂、PGE、PGE₂The release of prostacyclin, thromboxane, IL-1 β, IL-6, TNF- α, COX2 activity, the production of cAMP and cGMP, the production of IL-1 β, IL-6, TNF- α and COX2mRNA, and the surface expression of CD80, CD86 and MHC class II molecules.

Example 7: analgesic, botulinum neurotoxin and antimuscarinic agents on human bladder smooth muscle cells Effect of cell contraction

Design of experiments

Exposing cultured human bladder smooth muscle cells to an inflammatory stimulus and a non-inflammatory stimulus in the presence of varying concentrations of an analgesic agent and/or an antimuscarinic agent. The stimulation-induced muscle contraction is measured to assess the inhibitory effect of the analgesic and/or antimuscarinic agent.

Effectors, analgesics, and antimuscarinic agents are described in example 2.

Human bladder smooth muscle cells were subjected to short-term (1-2 hours) or long-term (24-48 hours) stimulation with:

(1) different doses of each individual analgesic.

(2) Different doses of each analgesic in the presence of LPS.

(3) Different doses of each analgesic in the presence of carbachol or acetylcholine.

(4) Different doses of each analgesic in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin a alone.

(6) Different doses of botulinum neurotoxin a in the presence of LPS.

(7) Different doses of botulinum neurotoxin a in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin a at different doses in the presence of AA, DGLA or EPA.

(9) A different dose of each antimuscarinic agent alone.

(10) Different doses of each antimuscarinic agent in the presence of LPS.

(11) Different doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.

(12) Different doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

Bladder smooth muscle cell contractions were recorded using a Grass multichannel recorder (Quincy Mass, usa).

Example 8: reversal of inflammatory and non-inflammatory signs by analgesics on normal human bladder smooth muscle cells Influence of stress

Experiment design:

culture of Normal human bladder smooth muscle cells

Normal human bladder smooth muscle cells were isolated from the macroscopic normal portion of the human bladder by enzymatic digestion. Cells were passed in vitro through 5% CO at 37 deg.C₂Was grown in RPMI1640 supplemented with 10% fetal bovine serum, 15mM HEPES, 2mM L-glutamine, 100U/ml penicillin and 100mg/ml streptomycin and passaged once a week by treatment with trypsin to isolate cells followed by re-inoculation in a new culture flask. The first week of culture, the medium was supplemented with 0.5ng/ml epidermal growth factor, 2ng/ml fibroblast growth factor and 5. mu.g/ml insulin.

In vitro analgesic treatment of normal human bladder smooth muscle cells

Will be trypsinized and digested at 3X10⁴Individual cell/well(100. mu.l) cell density bladder smooth muscle cells seeded in micro culture plates were treated with analgesic solution (50. mu.l/well) alone or in combination with carbachol (10 mol, 50. mu.l/well) as an example of a non-inflammatory stimulant or with Lipopolysaccharide (LPS) of Salmonella typhimurium (1. mu.g/ml, 50. mu.l/well) as an example of a non-inflammatory stimulant. When no other effectors were added to the cells, 50 μ l of RPMI1640 without fetal bovine serum was added to the wells to adjust the final volume to 200 μ l.

After 24 hours of incubation, 150. mu.l of culture supernatant was collected, spun at 4 ℃,8,000 rpm for 2 minutes to remove cells and debris, and stored at-70 ℃ for analysis of prostaglandin E2 (PGE) by ELISA₂) The reaction of (1). Cells were fixed, permeabilized and blocked for detection of COX2 using a fluorogenic substrate. In selected experiments, cells were stimulated in vitro for 12 hours for analysis of COX2, PGE2, and cytokine responses.

COX2, PGE2 and cytokine response assays

COX2 and PGE2 reactions were analyzed as described in example 3. Cytokine responses were analyzed as described in example 2.

Results

Analgesics inhibited the COX2 response of normal human bladder smooth muscle cells to inflammatory and non-inflammatory stimuli-analysis of cells and culture supernatants after 24 hours of culture indicated that no analgesic tested alone induced a COX2 response in normal human bladder smooth muscle cells. However, as summarized in table 6, carbachol induced a low but significant COX2 response in normal human bladder smooth muscle cells. LPS treatment, on the other hand, resulted in higher levels of COX2 responses in normal human bladder smooth muscle cells. Acetaminophen, aspirin, ibuprofen, and naproxen all inhibited the effects of carbachol and LPS on COX2 levels. The inhibitory effect of the analgesic on LPS-induced responses was seen when these drugs were tested at 5. mu.M or 50. mu.M.

TABLE 6 COX2 expression in normal human bladder smooth muscle cells after in vitro stimulation with inflammatory and non-inflammatory stimuli and treatment with analgesics

^#Data are expressed as the mean of duplicate replicates

Analgesics inhibited the PGE2 response of normal human bladder smooth muscle cells to inflammatory and non-inflammatory stimuli-consistent with the induction of the COX2 response described above, both carbachol and LPS induced PGE2 production of normal human bladder smooth muscle cells. Acetaminophen, aspirin, ibuprofen, and naproxen were also found to inhibit LPS-induced PGE2 responses at 5 μ M or 50 μ M (table 7).

TABLE 7 PGE2 secretion from normal human bladder smooth muscle cells after in vitro stimulation with inflammatory and non-inflammatory stimuli and treatment with analgesics

^#Data are expressed as the mean of duplicate replicates

Analgesics inhibited the cytokine response of normal human bladder cells to inflammatory stimuli-analysis of cells and culture supernatants after 24 hours of culture showed that no analgesic tested alone induced secretion of IL-6 or TNF α in normal human bladder smooth muscle cells. As shown in tables 8 and 9, the dose of carbachol tested induced low but significant TNF α and IL-6 responses in normal human bladder smooth muscle cells. LPS treatment, on the other hand, results in massive induction of these pro-inflammatory cytokines. Acetaminophen, aspirin, ibuprofen, and naproxen all inhibited the effects of carbachol and LPS on TNF α and IL-6 responses. The inhibitory effect of the analgesic on LPS-induced responses was seen when these drugs were tested at 5. mu.M or 50. mu.M.

TABLE 8 TNF α secretion from normal human bladder smooth muscle cells following in vitro stimulation with inflammatory and non-inflammatory stimuli and treatment with analgesics

^#Data are expressed as the mean of duplicate replicates

TABLE 9 IL-6 secretion from normal human bladder smooth muscle cells following in vitro stimulation with inflammatory and non-inflammatory stimuli and treatment with analgesics

^#Data are expressed as the mean of duplicate replicates

Primary normal human bladder smooth muscle cells were isolated, cultured and evaluated for their response to analgesics in the presence of non-inflammatory (carbachol) and inflammatory (LPS) stimuli. The purpose of this study was to determine whether normal human bladder smooth muscle cells could reproduce the aforementioned phenomenon obtained with murine bladder cells.

The above experiments were repeated with analgesic and/or antimuscarinic agents in a delayed release or extended release formulation or in a delayed and extended release formulation.

The above description is for the purpose of teaching the person of ordinary skill in the art how to practice the present invention and it is not intended to detail those obvious modifications and variations of it which will become apparent to the skilled worker upon reading the description. It is intended, however, that all such obvious modifications and variations be included within the scope of the present invention, which is defined by the following claims. Unless the context clearly dictates otherwise, the claims are intended to cover the claimed components and steps in any sequence that is effective to achieve their intended purpose.

Claims (36)

1. A method of reducing urinary frequency, comprising:

administering to a subject in need thereof a pharmaceutical composition comprising:

one or more analgesic agents; and

one or more additional active ingredients selected from the group consisting of alpha-blockers and 5 alpha-reductase inhibitors.

2. The method of claim 1, wherein said one or more analgesic agents and said one or more additional active ingredients are formulated for immediate release.

3. The method of claim 1, wherein said one or more analgesic agents and said one or more additional active ingredients are formulated for delayed release.

4. The method of claim 1, wherein the one or more analgesic agents and the one or more additional active ingredients are formulated for extended release.

5. The method of claim 4, wherein the one or more analgesic agents are administered in an amount of 50-400mg per agent, wherein the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein the pharmaceutical composition is formulated for extended release such that the one or more analgesic agents and the one or more additional active ingredients are released continuously over a period of 5-24 hours.

6. The method of claim 5, wherein said one or more additional active ingredients comprise tamsulosin.

7. The method of claim 5, wherein the one or more additional active ingredients comprise finasteride.

8. The method of claim 5, wherein said one or more additional active ingredients comprise tamsulosin and finasteride.

9. The method of claim 4, wherein the one or more analgesic agents are administered in an amount of 50-400mg per agent, wherein the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein the pharmaceutical composition is formulated for extended release characterized by a two-phase release profile in which 20-60% of the one or more analgesic agents are released within 2 hours of administration and the remainder of the one or more analgesic agents are released continuously over a period of 5-24 hours.

10. The method of claim 9, wherein said one or more additional active ingredients comprise tamsulosin.

11. The method of claim 9, wherein the one or more additional active ingredients comprise finasteride.

12. The method of claim 9, wherein said one or more additional active ingredients comprise tamsulosin and finasteride.

13. The method of claim 1, wherein the one or more analgesic agents are formulated for extended release and the one or more additional active ingredients are formulated for immediate release.

14. The method of claim 13, wherein the one or more analgesic agents are administered in an amount of 50-400mg per agent, wherein the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein the one or more analgesic agents are formulated for extended release such that the one or more analgesic agents are released continuously over a period of 5-24 hours.

15. The method of claim 14, wherein said one or more additional active ingredients comprise tamsulosin.

16. The method of claim 14, wherein the one or more additional active ingredients comprise finasteride.

17. The method of claim 14, wherein said one or more additional active ingredients comprise tamsulosin and finasteride.

18. The method of claim 13, wherein the one or more analgesic agents are administered in an amount of 50-400mg per agent, wherein the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein the one or more analgesic agents are formulated for extended release characterized by a two-phase release profile in which 20-60% of the one or more analgesic agents are released within 2 hours of administration and the remainder of the one or more analgesic agents are released continuously over a period of 5-24 hours.

19. The method of claim 18, wherein said one or more additional active ingredients comprise tamsulosin.

20. The method of claim 18, wherein the one or more additional active ingredients comprise finasteride.

21. The method of claim 18, wherein said one or more additional active ingredients comprise tamsulosin and finasteride.

22. The method of claim 1, wherein the pharmaceutical composition further comprises an antimuscarinic agent.

23. The method of claim 1, wherein the pharmaceutical composition further comprises an antidiuretic.

24. The method of claim 1, wherein said pharmaceutical composition further comprises a spasmolytic.

25. The method of claim 1, further comprising the step of administering an effective amount of a diuretic prior to administering the pharmaceutical composition, wherein the diuretic is administered 7 or 8 hours prior to bedtime.

26. The method of claim 1, wherein the subject is a mammal.

27. A pharmaceutical composition for reducing urinary frequency, comprising:

one or more analgesic agents;

one or more alpha-blockers; and

a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier,

wherein the one or more analgesic agents are formulated for extended release, and wherein the one or more alpha-blockers are formulated for immediate release.

28. The pharmaceutical composition of claim 27, comprising one or more analgesic agents in an amount of 50-400mg per agent, wherein the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein the one or more analgesic agents are formulated for extended release such that the one or more analgesic agents are released continuously over a period of 5-24 hours.

29. The pharmaceutical composition of claim 28, wherein said one or more analgesic agents comprise acetaminophen, and wherein said one or more a-blockers comprise tamsulosin.

30. The pharmaceutical composition of claim 27, comprising one or more analgesic agents in an amount of 50-400mg per agent, wherein the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein the pharmaceutical composition is formulated for extended release characterized by a two-phase release profile in which 20-60% of the one or more analgesic agents are released within 2 hours of administration and the remainder of the one or more analgesic agents are released continuously over a period of 5-24 hours.

31. The pharmaceutical composition of claim 30, wherein said one or more analgesic agents comprise acetaminophen, and wherein said one or more a-blockers comprise tamsulosin.

32. A pharmaceutical composition for reducing urinary frequency, comprising:

one or more analgesic agents;

one or more 5 α -reductase inhibitors; and

a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier,

wherein the one or more analgesic agents are formulated for extended release, and wherein the one or more 5 α -reductase inhibitors are formulated for immediate release.

33. The pharmaceutical composition of claim 32, comprising one or more analgesic agents in an amount of 50-400mg per agent, wherein the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein the one or more analgesic agents are formulated for extended release such that the one or more analgesic agents are released continuously over a period of 5-24 hours.

34. The pharmaceutical composition of claim 33, wherein the one or more analgesic agents comprise acetaminophen, and wherein the one or more 5 a-reductase inhibitors comprise finasteride.

35. The pharmaceutical composition of claim 32, comprising one or more analgesic agents in an amount of 50-400mg per agent, wherein the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and the pharmaceutical composition is formulated for extended release characterized by a two-phase release profile in which 20-60% of the one or more analgesic agents are released within 2 hours of administration and the remainder of the one or more analgesic agents are released continuously over a period of 5-24 hours.

36. The pharmaceutical composition of claim 35, wherein the one or more analgesic agents comprise acetaminophen, and wherein the one or more 5 a-reductase inhibitors comprise finasteride.