CN104321056A - Extended-release formulation for reducing the frequency of urination and method of use thereof - Google Patents

Abstract

The application discloses a method for alleviating frequent urination. The method includes administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising one or more analgesics and one or more alpha-blockers. In one embodiment, the one or more analgesic agents are formulated for extended release.

Description

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

This application claims priority to US Patent Application Serial No. 13/487,348, filed June 4, 2012, and US Patent Application Serial No. 13/424,000, filed March 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 technique

The detrusor muscle is a layer of the bladder wall that is formed by smooth muscle fibers arranged in helical, longitudinal, and annular bundles. When the bladder is stretched, this signals the parasympathetic nervous system to contract the detrusor muscle. This encourages the bladder to pass urine through the urethra.

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

An adult bladder typically holds about 300-350ml of urine (working volume), but depending on the individual, a full adult bladder may hold up to about 1000ml (absolute volume). 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 without a significant rise in internal pressure Urine.

For most individuals, the need to void usually begins when the volume of urine in the bladder reaches approximately 200 ml. At this stage, the individual can easily suppress the urge to urinate if desired. As the bladder continues to fill, the need to urinate becomes stronger and harder to ignore. Eventually, the bladder will fill to such an extent that the urge to urinate becomes overwhelming and the individual will no longer be able to ignore it. In some individuals, this need to void occurs when the bladder is less than 100% full compared to its working volume. This increased need to urinate may interfere with normal activities, including the ability to provide adequate uninterrupted sleep during rest. In some cases, this increased need to urinate may be related to a medical condition, such as benign prostatic hyperplasia or prostate cancer in men, or pregnancy in women. However, increased need to void also occurs in individuals (male and female) not affected by other medical conditions.

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

Contents of the invention

One aspect of the present application relates to a method of alleviating urinary frequency in a subject. The method comprises administering to a subject in need thereof an effective amount of one or more analgesics and an effective amount of one or more additional active ingredients selected from alpha-blockers and 5a-reductase inhibitors. The method can be used to treat nocturia or an overactive bladder.

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

Another aspect of the present application relates to a pharmaceutical composition comprising: an active ingredient including one or more analgesics, a 5α-reductase inhibitor, and a pharmaceutically acceptable carrier.

Description of drawings

Figures 1A and 1B are graphs showing that analgesics modulate the expression of co-stimulatory molecules in Raw 264 macrophages in the absence of LPS (Figure 1A) or the presence of LPS (Figure 1B). Cells were incubated for 24 hours in the presence of analgesics alone or in the presence of Salmonella typhimurium LPS (0.05 μg/ml). Results are mean relative percentages of CD40+CD80+ cells.

Detailed ways

The following detailed description is presented to enable any person skilled in the art to make and use the invention. For purposes of explanation, specific terms are set forth below in order to fully understand 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 as typical examples only. The present invention is not intended to be limited to the embodiments shown, but is intended to include the widest possible scope consistent with the principles and features disclosed herein.

As used herein, the term "effective amount" refers to an amount required 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, meclofenac Esters, meclofenamic acid sodium, heteroaryl acetic acid derivatives, tolmetin, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketones Kibuprofen, flurbiprofen, oxaprozin; enolic acid, oxicam derivatives, piroxicam, meloxicam, tenoxicam, ampiraxicam, droxicam, pivoxicam Kang, pyrazolone derivatives, phenylbutazone, hydroxybutazone, antipyrine, aminopyrine, metamizole, coxibs, celecoxib, rofecoxib, nabudine Metone, azapropazone, indomethacin, sulindac, etodolac, isobutylphenylpropionic acid, lumiracoxib, etoricoxib, parecoxib, valdecoxib, tiracoxib, etodolac, dalbufenone, dexketoprofen, aceclofenac, licofelone, bromfenac, chlorxoprofen, pyranoprofen, piroxicam, nicotinic acid Mesulide, Cizoletine, 3-Formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one, Meloxicam, Lornoxi Kang, dextroindobufen, mobendazole acid, amtolmetin (amtolmetin), pranoprofen, tolfenamic acid, flurbiprofen, suprofen, oxaprozin, zaltoprofen, Aminoprofen, tiaprofen acid, their pharmaceutically acceptable salts, their hydrates and their solvates.

The terms "coxib" and "COX inhibitor" as used herein refer to compounds containing the ability to inhibit the activity or expression of the COX2 enzyme or to inhibit or alleviate the severity of severe inflammatory reactions, including pain and swelling Compositions.

The term "derivative" as used herein refers to a chemically modified compound which is recognized by the ordinary skilled chemist as a routine route, such as an ester or amide of an acid, a protecting group, such as for an alcohol or a thiol benzyl for amines and tert-butoxycarbonyl for amines.

As used herein, the term "analogue" refers to a compound comprising a chemically modified form of a particular compound or class thereof that retains the pharmacological and/or pharmacologically active characteristics of said particular compound or class thereof.

"Subject" or "patient" as used herein includes mammals. In one aspect, the mammal is a human. Mammals, on the other hand, are non-human primates such as orangutans 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, a mammal is a farm animal such as a cow, horse, sheep, goat or pig. On the other hand, mammals are experimental animals including rodents such as rats, mice, guinea pigs and the like.

As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds whose parent compounds 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 such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic or quaternary ammonium salts of the parent compound (eg, formed 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 those prepared from organic acids, Such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxyl Maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic , Methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, etc.

As used herein, the phrase "pharmaceutically acceptable" is used in connection with compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in Contact with human or animal tissue without undue toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

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

One aspect of the present application relates to a method of alleviating urinary frequency. The method includes administering to a subject in need thereof an effective amount of one or more analgesics and an effective amount of an alpha-blocker. In some embodiments, the one or more analgesics and the alpha-blocker are administered separately in different dosage forms. In other embodiments, the one or more analgesics and the alpha-blocker are administered simultaneously in a single dosage form (eg, in a single pill or tablet). In some embodiments, the one or more analgesics and the alpha-blocker are both formulated for immediate release upon administration. In other embodiments, the one or more analgesics and the alpha-blocker are both formulated for delayed release after administration. In other embodiments, the one or more analgesics and the alpha-blocker are both formulated for extended release following administration. In other embodiments, the one or more analgesics and the alpha-blocker 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 after administration, while the alpha-blocker is formulated for immediate release. In yet 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: an active ingredient including one or more analgesics, an alpha-blocker and a pharmaceutically acceptable carrier.

Alpha blockers, also known as alpha-adrenergic antagonists or alpha-blockers, are drugs that act on alpha-adrenergic receptors (which are further divided into alpha1-adrenergic receptors and alpha2-adrenergic receptors. Pharmaceutical formulations of receptor antagonists of adrenergic receptors). Alpha blockers can be divided into selective blockers that act selectively on α1-adrenergic receptors or α2-adrenergic receptors, and non-selective blockers that act on both types of α-adrenergic receptors Sex alpha blockers.

Examples of selective alpha1-adrenergic blockers include, but are not limited to: alfuzosin, prazosin, doxazosin, tamsulosin, terazosin, carvedilol, salivazolin Ding and Silodosin. Examples of selective alpha2-adrenergic blockers include, but are not limited to: atipamezole, mizoxan, and yohimbine. Examples of nonselective alpha-adrenergic blockers include: phenoxybenzamine, phentolamide, benzazolidine, trazodone, typical and atypical antipsychotics.

In some embodiments, the one or more analgesics are used in a single or combined dose of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-500 mg per day ,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, 400-1200mg ,400-1000mg,400-800mg,400-600mg,600-2000mg,600-1500mg,600-1200mg,600-1000mg,600-800mg,800-2000mg,800-1500mg,800-1200mg,800-1000mg,1000 - 2000mg, 1000-1500mg, 1000-1200mg, 1200-2000mg, 1200-1500mg or 1500-2000mg orally administered; the one or more α-blockers are administered in 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, 0.3-1 mg and 0.2-1 mg are administered orally.

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 alpha2-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 analgesics; one or more alpha-blockers; and a pharmaceutically acceptable carrier. In some embodiments, the one or more analgesics are selected from aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen.

In some embodiments, the pharmaceutical composition comprises 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-500 mg, 50-400 mg alone or in combination ,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, 400-1200mg, 400-1000mg ,400-800mg,400-600mg,600-2000mg,600-1500mg,600-1200mg,600-1000mg,600-800mg,800-2000mg,800-1500mg,800-1200mg,800-1000mg,1000-2000mg,1000 - 1500mg, 1000-1200mg, 1200-2000mg, 1200-1500mg or 1500-2000mg of one or more analgesics; and dosages 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, One or more of 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 0.2-1mg Alpha-blockers.

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 alpha2-adrenergic blocker. In other embodiments, the alpha-blocker is tamsulosin.

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

In other embodiments, the one or more analgesics and the one or more alpha-blockers are both formulated for immediate release. In other embodiments, the one or more analgesics are formulated for immediate release and the one or more alpha-blockers are formulated for extended release.

In other embodiments, the one or more analgesics 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 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 analgesics are continuously or stabilized over a period of time or 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours released at a rapid rate.

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

In other embodiments, the one or more analgesics and the one or more alpha-blockers are both formulated for extended release. In some embodiments, both the one or more analgesics and the one or more alpha-blockers are formulated for extended release such that the one or more analgesics and the The one or more alpha-blockers 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 other embodiments, both the one or more analgesics and the one or more alpha-blockers are formulated for extended release with a biphasic release profile in which the 20-60% of the one or more analgesics and the one or more alpha-blockers are released within 2 hours of administration, while the remainder are released within 5-24 hours, 5-8 hours, 8 hours - Released continuously or at a steady rate over a period of 16 hours or 16-24 hours.

In some embodiments, the pharmaceutical composition comprises 50-1000 mg, 50-250 mg, 250-400 mg, 400-600 mg, 600-800 mg or 800-1000 mg of acetaminophen used in combination and 0.1- 1.2mg, 0.1-0.3mg, 0.3-0.6mg, 0.6-0.9mg or 0.9-1.2mg of tamsulosin, wherein the composition is formulated to prolong the release of acetaminophen and tamsulosin, which has a A drug release profile in which at least 90% of the acetaminophen and tamsulosin are continuously or release at a steady rate.

In other embodiments, the pharmaceutical composition comprises 500-1000mg, 50-200mg, 50-400mg, 100-400mg, 100-300mg, 200-400mg, 400-600mg, 600-800mg, 800-1000mg Or 1000-1200mg of acetaminophen 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 to prolong release, which has a two-stage release profile in which 20-60% of the acetaminophen and tamsulosin are released within 2 hours of application, while the remainder is released within 5-24 hours, 5-8 hours, Released continuously or at a steady rate over a period of 8-16 hours or 16-24 hours.

"Extended release", also known as sustained release (sustained-release, SR), sustained action (sustained-action, SA), time-release (time-release, TR), controlled release (controlled-release, CR), modified release ( Modified release (MR), or continuous-release (CR), is a mechanism used in pharmaceutical tablets or capsules to slowly dissolve and release active ingredients over time. The advantages of extended-release tablets or capsules are that they can generally be administered less frequently than immediate-release formulations of the same drug, and they maintain more stable drug levels in the bloodstream, prolonging the duration of drug action and reducing The peak amount of a drug in the bloodstream. For example, extended-release pain relievers enable a person to sleep through the night without waking up.

In one embodiment, the pharmaceutical composition is formulated for extended release by entrapping the active ingredient in a matrix of insoluble substances such as acrylates or chitin. Extended release forms are 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 through different formulations including, but not limited to, liposomes and drug-polymer conjugates such as hydrogels.

Extended release formulations can be designed to release the active agent at a predetermined rate to maintain a constant drug level over a specified extended period of time, for example, 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.

In certain preferred embodiments, the active agent is released over a time interval of about 2 hours to about 10 hours. In addition, the active agent can also be at 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 release in approximately 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 consisting of one or more inert particles each coated with a drug on its surface (e.g., with a drug-containing coating Beads, pills, pills, granules, microcapsules, microspheres, microparticles, nanocapsules or nanospheres in the form of film-forming compositions (using, for example, fluidized bed techniques or other methods known to those skilled in the art) form. The inert particles can be of various sizes as long as they are large enough to remain insoluble. Alternatively, the active core can be prepared by granulation and milling of a polymer composition containing a pharmaceutical ingredient and/or by extrusion and spheronization.

The active agent can be introduced into the inert carrier by techniques well known to those skilled in the art, eg, drug layering, powder coating, extrusion/spheronization, rolling or granulation. The amount of drug in the core will depend on the dose required 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. Those skilled in the art will be able to select the appropriate amount of drug to coat or incorporate on the core to achieve the desired dosage. In one embodiment, the inactive core can be sugar spheres or buffer crystals or encapsulated buffer crystals, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alter the microenvironment of the drug to facilitate its release.

Another aspect of the present application relates to a method of alleviating urinary frequency. The method comprises administering to a subject in need thereof an effective amount of one or more analgesics, and an effective amount of a 5α-reductase inhibitor. Examples of 5[alpha]-reductase inhibitors include, but are not limited to: finasteride, bechloride, apretide, ezonide, lapisteride, and torosteride. In some embodiments, the 5α-reductase inhibitor is finasteride.

In some embodiments, the one or more analgesics and the 5α-reductase inhibitor are administered separately in different dosage forms. In other embodiments, the one or more analgesics and the alpha-blocker are administered simultaneously in a single dosage form (eg, in a single pill or tablet). In some embodiments, the one or more analgesics and the 5α-reductase inhibitor are both formulated for immediate release upon administration. In other embodiments, the one or more analgesics and the 5α-reductase inhibitor are both formulated for delayed release after administration. In other embodiments, the one or more analgesics and the 5α-reductase inhibitor are both formulated for extended release after administration. In other embodiments, the one or more analgesics and the 5α-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 5α-reductase inhibitor is formulated for immediate release. In yet other embodiments, the one or more analgesic agents are formulated for immediate release and the 5α-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: active ingredients including one or more analgesics, a 5α-reductase inhibitor and a pharmaceutically acceptable carrier.

In some embodiments, the one or more analgesics are used in a single or combined dose of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-500 mg per day ,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, 400-1200mg ,400-1000mg,400-800mg,400-600mg,600-2000mg,600-1500mg,600-1200mg,600-1000mg,600-800mg,800-2000mg,800-1500mg,800-1200mg,800-1000mg,1000 -2000mg, 1000-1500mg, 1000-1200mg, 1200-2000mg, 1200-1500mg or 1500-2000mg for oral administration; while 5α-reductase inhibitors are administered in single or combined daily doses 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 - 3 mg, 3-7 mg and 4-6 mg orally administered.

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

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

In some embodiments, the pharmaceutical composition comprises a single or combined dosage 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, 400-1500mg, 400-1200mg, 400-1000mg, - 1500mg, 1000-1200mg, 1200-2000mg, 1200-1500mg or 1500-2000mg of one or more analgesics; and dosages 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 of one or more 5α-reductase inhibitors.

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 alpha2-adrenergic blocker. In other embodiments, the alpha-blocker is tamsulosin.

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

In other embodiments, the one or more analgesics and the one or more 5α-reductase inhibitors are both formulated for immediate release. In other embodiments, the one or more analgesics are formulated for immediate release and the one or more alpha-blockers are formulated for extended release.

In other embodiments, the one or more analgesics are formulated for extended release and the one or more 5α-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 analgesics are administered 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 rate release.

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

In other embodiments, the one or more analgesics and the one or more 5α-reductase inhibitors are both formulated for extended release. In some embodiments, the one or more analgesics and the one or more 5α-reductase inhibitors are both formulated for extended release such that the one or more analgesics and the The one or more 5α-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 other embodiments, the one or more analgesics and the one or more 5α-reductase inhibitors are both formulated for extended release with a biphasic release profile in which In the curve, 20-60% of the one or more analgesics and the one or more 5α-reductase inhibitors are released within 2 hours of administration, while the remaining part is released within 5-24 hours, 5- Released continuously or at a steady rate over a period of 8 hours, 8-16 hours, or 16-24 hours.

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

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,100-600mg,100-800mg,100-1000mg,200-400mg,200-600mg,200-800mg,200-1000mg,400-600mg,400-800mg,400-1000mg,600-800mg,600 -1000mg, 800-1000mg or 1000-1200mg of acetaminophen and dosages of 1-20mg, 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 of finasteride, wherein the composition is formulated for extended release with a two-stage release profile, In this two-stage release profile, 20-60% of acetaminophen and finasteride are released within 2 hours of administration, while the remainder is released within 5-24 hours, 5-8 hours, 8-16 hours or 16- Released continuously or at a steady rate over a 24 hour period.

"Extended release", also known as sustained release (sustained-release, SR), sustained action (sustained-action, SA), time-release (time-release, TR), controlled release (controlled-release, CR), modified release ( Modified release (MR), or continuous-release (CR), is a mechanism used in pharmaceutical tablets or capsules to slowly dissolve and release active ingredients over time. The advantages of extended-release tablets or capsules are that they can often be administered less frequently than immediate-release formulations of the same drug, and they maintain more stable drug levels in the bloodstream, thereby prolonging the duration of drug action and reducing The peak amount of a drug in the bloodstream. For example, extended-release pain relievers enable a person to sleep through the night without waking up.

In one embodiment, the pharmaceutical composition is formulated for extended release by entrapping the active ingredient in a matrix of insoluble substances such as acrylates or chitin. Extended release forms are 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 through different formulations including, but not limited to, liposomes and drug-polymer conjugates such as hydrogels.

Prolonged release formulations can be designed to release the active ingredient at a predetermined rate to maintain a constant drug level for a specified extended period of time, for example, up to about 24 hours, after administration, or after a lag period associated with delayed drug release. 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 Hour.

In certain preferred embodiments, the active agent is released during a time interval between about 2 hours and about 10 hours. Alternatively, the active agent is activated 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 Release within 24 hours. In other embodiments, the active agent is released within a period of between about three hours and about eight hours after administration.

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

The active agent can be introduced into the inert carrier by techniques well known to those skilled in the art, eg, drug layering, powder coating, extrusion/spheronization, rolling or granulation. The amount of drug in the core will depend on the dose required 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. Those skilled in the art will be able to select the appropriate amount of drug to coat or incorporate on the core to achieve the desired dosage. In one embodiment, the inactive core can be sugar spheres or buffer crystals or encapsulated buffer crystals, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alter the microenvironment of the drug to facilitate its release.

Such extended release formulations may employ various extended release coatings or mechanisms that facilitate gradual release of the active agent over time. In some embodiments, extended release formulations comprise polymers that control release by controlled dissolution. In a particular embodiment, the active agent is incorporated into a matrix comprising an insoluble polymer and drug particles or granules coated with polymeric material of varying thickness. Polymeric materials may include lipid barriers containing waxy materials such as carnauba wax, beeswax, spermaceti wax, candelilla wax, shellac wax, cocoa butter, cetostearyl alcohol , partially hydrogenated vegetable oils, ozokerite, paraffin, ozokerite, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid, together with surfactants such as polyoxyethylenesorbitan monooleate. Upon contact with an aqueous medium, such as a biological fluid, 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 gastric residence.

In other embodiments, extended release formulations comprise a polymer matrix for controlled diffuse 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 with one or more solubilizing excipients and/or release-promoting agents. Upon solubilization by 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 for drug release. As the outer layer becomes fully hydrated, the polymer chains fully stretch and can no longer maintain the integrity of the gel layer, causing unentanglement and erosion of the outer layer of hydrated polymer on the surface of the substrate. Water continues to penetrate the core through the gel layer until it is completely eroded. Soluble drugs are released by this combination of diffusion and erosion, whereas for insoluble drugs erosion is the dominant 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 serves as a carrier, solubilizer and/or release enhancer. The initial matrix polymer hydration phase results in slow drug release (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 the leaching of pH-dependent release enhancers, thereby releasing the drug at a faster rate. Subsequently, the rate of drug release becomes constant and becomes a function of drug diffusion through the hydrated polymer gel. The release rate from the matrix depends on various parameters including polymer type and grade; drug solubility and dosage; polymer to drug ratio; filler type and grade; polymer to filler ratio; drug and polymer particle size ; and 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 hydroxyalkylcelluloses and carboxyalkylcelluloses, such as hydroxypropylmethylcellulose ( HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), carboxymethyl cellulose (CMC), powdered cellulose such as microcrystalline cellulose, acetic acid Cellulose, ethyl cellulose, their salts, and combinations thereof; alginates, gums, including heteropolysaccharide gums and homopolysaccharide gums, such as xanthan gum, tragacanth gum, pectin, acacia gum, karaya gum, alginic acid Salt, agar, guar gum, hydroxypropyl guar gum, magnesium aluminum silicate, carrageenan, carob gum, gellan gum, and their derivatives; acrylic resins, including acrylic acid, methacrylic acid, Polymers and copolymers of methyl acrylate and methyl methacrylate, and cross-linked polyacrylic acid derivatives such as carbomers (e.g., such as including 71G NF, with different molecular weight grades, from Noveon Company, Cincinnati, Ohio); carrageenan; 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, especially 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) in aqueous media, including biological fluids. matrix).

Exemplary binders include homopolysaccharides such as galactomannan gum, guar gum, hydroxypropyl guar gum, hydroxypropyl cellulose (HPC; eg Klucel EXF), and carob 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 methyl cellulose, and polyvinylpyrrolidone.

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

The binder may be present in the bead formulation at a level of from about 0.1 wt% to about 15 wt%, and preferably from about 0.2 wt% to about 10 wt%.

In some embodiments, the hydrophilic polymer matrix may further comprise ionic polymers, non-ionic polymers, or water-insoluble hydrophobic polymers to provide a stronger gel layer and/or reduce porosity in the matrix The number and size of the ions, thereby slowing down the rate of diffusion and erosion and the concomitant release of the active agent. This additionally suppresses the initial burst effect and produces a more stable "zero order release" of the active agent.

Exemplary ionic polymers for slowing dissolution rates include anionic polymers and cationic polymers. Exemplary anionic polymers include, for example, polymers of sodium carboxymethylcellulose (Na CMC), sodium alginate, acrylic acid, or carbomer (such as 934, 940, 974P NF); enteric polymers such as polyvinyl acetate phthalate (PVAP), methacrylic acid copolymers (such as L100, L 30D 55, A and FS 30D), hydroxypropylmethylcellulose acetate succinate (AQUAT HPMCAS); and xanthan gum. Exemplary cationic polymers include, for example, dimethylaminoethyl methacrylate copolymers (e.g., E100). The incorporation of anionic polymers, especially enteric polymers, is useful for creating a pH-independent release profile for weakly basic drugs compared to hydrophilic polymers alone.

Exemplary nonionic polymers for slowing dissolution rates include, for example, hydroxypropylcellulose (HPC) and polyethylene oxide (PEO) (eg, POLYOX ^™ ).

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

The swelling polymer may be incorporated into the formulation in a proportion of 1 wt% to 50 wt%, preferably 5 wt% to 40 wt%, most preferably 5 wt% to 20 wt%. The swelling polymer and binder can be incorporated into the formulation before or after granulation. The polymers can also be dispersed in organic solvents or aqueous alcohols and sprayed during granulation.

Exemplary release-enhancing agents include pH-dependent enteric polymers that remain intact at pH values below about 4.0 and remain intact at pH values above 4.0, preferably above 5.0, most preferably above 6.0, and is considered useful as an enhanced release agent in the present invention. Exemplary pH-dependent polymers include, but are not limited to, methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (such as those from Rohm AG, Germany). L100 (Type A), S100 (B type)); Methacrylic acid-ethyl acrylate copolymer (such as Rohm Co., Ltd. of Germany L100-55 (Type C) and L30D-55 copolymer dispersion); methacrylic acid-copolymer of methyl methacrylate and methyl methacrylate ( FS); terpolymers of methacrylic acid, methacrylate and ethyl acrylate; cellulose acetate phthalate (CAP); hydroxypropylmethylcellulose phthalate (HPMCP) (e.g. , HP-55, HP-50, HP-55S of Shin-Etsu Chemical); polyvinyl acetate phthalate (PVAP) (for example, Enteric white (OY-P-7171); polyvinyl acetate butyrate; cellulose acetate succinate (CAS); hydroxypropylmethylcellulose acetate succinate (HPMCAS), for example, HPMCAS LF class, MF class, HF class, including LF and MF (Shin-Etsu Chemical); Shellac (for example, MARCOAT ^™ 125 and MARCOAT™ 125N); Vinyl acetate-maleic anhydride copolymer; Styrene-maleic monoestercopolymer ; carboxymethyl ethyl cellulose (CMEC, Freund Company, Japan); cellulose acetate phthalate (CAP) (for example, ); and mixtures of two or more thereof in a weight ratio of from about 2:1 to about 5:1, for example, as in a weight ratio of about 3 :1 to about 2:1 L 100-55 and A mixture of S 100, or a weight ratio of about 3:1 to about 5:1 L 30D-55 and Mixture of FS.

These polymers may be used alone or in combination, or may be used together with polymers other than those described above. A 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 preferably have an average molecular weight of about 135,000. In these copolymers, the ratio of free carboxyl groups to methylated carboxyl groups ranges, for example, from 1:1 to 1:3, eg, about 1:1 or 1:2. This polymer is commercially available as Available under trade names such as the Eudragit L series, e.g., Eudragit L Eudragit L Eudragit L Eudragit L Eudragit Eudragit L-30 series, e.g. Eudragit S Eudragit S Eudragit Release enhancers are not limited to pH-dependent polymers. Other hydrophilic molecules that dissolve quickly and leach the dosage form quickly leaving a porous structure can also be used for the same purpose.

Release-enhancing agents may be incorporated in amounts of 10% to 90%, preferably 20% to 80%, and most preferably 30% to 70% by weight of the dosage form unit. The agent can be incorporated into the formulation before or after granulation. The enhanced release agent can be added to the formulation as a dry material, or it can be dispersed or dissolved in a suitable solvent and dispersed during granulation.

In some embodiments, the matrix can include a combination of release enhancers and solubilizers. The solubilizing agent can be ionic or nonionic surfactant, complexing agent, hydrophilic polymer, pH regulator (such as acidifying agent and alkalizing agent), and increase the concentration of insoluble drugs by molecular embedding. Solubility molecules. Several solubilizers can be used simultaneously.

Solubilizers may include surfactants such as docusate sodium, sodium lauryl sulfate, sodium stearyl fumarate, Tweens and Spans (PEO-modified sorbitan monoesters and fatty acid sorbitan esters), poly(ethylene oxide)-polypropylene oxide-poly(ethylene oxide) block copolymers (also known as PLURONICS ^TM ); complexing agents, such as low molecular weight polyvinylpyrrolidone and low molecular weight hydroxypropylmethylcellulose; molecules that aid solubility by molecular entrapment, such as cyclodextrins; and pH regulators, including acidifying agents such as citric acid, fumaric acid, tartaric acid, and hydrochloric acid; and alkalizing agents such as meglumine and sodium hydroxide.

Solubilizers generally constitute 1 to 80 wt%, preferably 1 to 60 wt%, more preferably 1 to 50 wt% of the dosage form, and they can be incorporated in different ways. They can be incorporated into the formulation dry or wet before granulation. They may also be added to the formulation after granulation of other materials or other processes. During granulation, the solubilizer can be added as a 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 over time independent of pH. For the purposes of the present invention, "pH independent" is defined as having properties (eg, dissolution) that are essentially independent of pH. pH-independent polymers are often referred to as the case for "time-controlled" or "time-dependent" release profiles.

A pH-independent polymer may be used to coat the active agent and/or provide a hydrophilic matrix for use in an extended release coat thereon. A pH independent polymer may be water insoluble or water soluble. Examples of water-insoluble, pH-independent polymers include, but are not limited to, neutral methacrylates with a small fraction of trimethylammonium chloride ethyl methacrylate (e.g., RS and RL; neutral ester dispersion without any functional groups, (for example, NE30D and NE30); cellulosic polymers such as ethylcellulose, hydroxyethylcellulose, cellulose acetate or blends; and other pH-independent coated products. Exemplary water-soluble, pH-independent polymers include hydroxyalkylcellulose ethers such as hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC); polyvinylpyrrolidone (PVP), methylcellulose base cellulose, amb, guar gum, xanthan gum, acacia gum, 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 the active core. The coating may additionally comprise one or more water-soluble polymers and/or one or more plasticizers. Water-insoluble polymer coatings include barrier coatings for releasing the active agent in the core, where lower molecular weight (viscosity) grades exhibit a faster release rate 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., grades PR100, PR45, PR20, PR10, and PR7 ethyl cellulose; Dow Corporation).

Exemplary water soluble polymers such as polyvinylpyrrolidone Hydroxypropylmethylcellulose, hydroxypropylcellulose and mixtures thereof.

In some embodiments, the water-insoluble polymer provides suitable properties (eg, extended release properties, mechanical properties, and coating properties) without the need for plasticizers. For example, coatings containing polyvinyl acetate (PVA), neutral copolymers of acrylates/methacrylates (e.g., commercially available Eudragit NE30D from Evonik Industries) can be used without plasticizers, Co-application of base cellulose and hydroxypropyl cellulose, wax, etc.

In yet another embodiment, the water-insoluble polymer matrix may further comprise a plasticizer. The desired level of plasticizer depends on the properties of the plasticizer, the water-insoluble polymer, and the final desired properties of the coating. Suitable levels of plasticizer are about 1 wt% to about 20 wt%, about 3 wt% to about 20 wt%, about 3 wt% to about 5 wt%, about 7 wt% to about 10 wt%, about 12 wt%, relative to the total weight of the coating % 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.

Exemplary plasticizers include, but are not limited to, triacetin, ethyl acetyl monoglyceride, oils (castor oil, hydrogenated castor oil, rapeseed oil, sesame oil, olive oil, etc.); citric acid esters, citric acid Triethyl ester, Acetyl triethyl citrate, Acetyl tributyl citrate, Tributyl citrate, Acetyl tri-n-butyl citrate, Diethyl phthalate, Dibutyl phthalate , Dioctyl phthalate, Methylparaben, Propylparaben, Propylparaben, Butylparaben, Diethyl Sebacate, Dibutyl Sebacate , tributyrin, substituted triglycerides and glycerolipids, monoacetylated and diacetylated glycerolipids (such as 9-45), glyceryl monostearate, tributyrin, polysorbate 80, polyethylene glycol (such as PEG-4000, PEG-400), propylene glycol, 1,2-propylene glycol, glycerin, sorbitol Alcohol, diethyl oxalate, diethyl malate, diethyl fumarate, diethylmalonate, dibutyl succinate, fatty acid, glycerin, sorbitol, diethyl oxalate, diethyl oxalate Malate, diethyl maleate, diethyl fumarate, diethyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, and mixtures thereof. The plasticizer may have surfactant properties such that it may act as a release modifier. For example, nonionic detergents such as Brij 58 (polyoxyethylene (20) cetyl ether) and the like can be used.

Plasticizers can be high boiling organic solvents used to impart elasticity to otherwise hard or brittle polymeric materials and which can affect the release profile of the active agent. Plasticizers generally cause a reduction in the cohesive intermolecular forces along the polymer chain, resulting in changes in a variety of polymer properties, including a decrease in the polymer's tensile strength, increase in elongation, and glass transition temperature or a drop in softening temperature. For example, the content and selection of plasticizers can affect the hardness of a tablet, and can even affect its dissolution or disintegration properties, as well as its physical and chemical stability. Some plasticizers can 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 comprising at least one nonionic gel-forming polymer and/or at least one anionic gel-forming polymer. Glue polymers. Gels formed from combinations of gel-forming polymers provide controlled release such that when the formulation is ingested and exposed to gastrointestinal fluids, the polymers closest to the surface hydrate to form a viscous gel layer. Due to the high viscosity, the sticky 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 of the resulting gel, such as viscosity, to be manipulated to provide a desired release profile.

In a particular embodiment, said formulation comprises at least one nonionic gel-forming polymer and at least one anionic gel-forming polymer. In another embodiment, the formulation comprises two different nonionic gel-forming polymers. In yet another embodiment, the formulation comprises a combination of non-ionic gel-forming polymers of the same chemical nature but with different solubility, viscosity and/or molecular weight (e.g. hydroxypropyl methylcellulose of different viscosity grades combination of factors 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); carboxymethylcellulose (CMC); anionic polysaccharides such as sodium alginate, alginic acid, fruit Gum, polyglucuronic acid (poly-alpha- and -beta-1,4-glucuronic acid), polygalacturonic acid (pectinic acid), chondroitin sulfate, carrageenan, furfuralan (furcellaran); anionic gums such as xanthan gum; polymers of acrylic or carbomer (such as 934, 940, 974PNF); copolymer; Polymer; polycarbophil etc.

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

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

Exemplary fillers include, but are not limited to, lactose, glucose, fructose, sucrose, dicalcium phosphate, sugar alcohols, also known as "sugar polyols" such as sorbitol, manitol, lactitol, xylitol, Isomalt, Erythritol and Hydrogenated Starch Hydrolyzate (Mixture of Multiple Sugar Alcohols), Corn Starch, Potato Starch, Sodium Carboxymethyl Cellulose, Ethyl Cellulose, Cellulose Acetate, Enteric Coated polymers, or mixtures thereof.

Exemplary binders include, but are not limited to, water-soluble hydrophilic polymers such as povidone (PVP, polyvinylpyrrolidone), copovidone (copolymer of polyvinylpyrrolidone and polyvinyl acetate), low molecular weight HPC (Hydroxypropyl Cellulose), Low Molecular Weight HPMC (Hydroxypropyl Methyl Cellulose), Low Molecular Carboxymethyl Cellulose, Ethyl Cellulose, Gelatin, Polyethylene Oxide, Gum Arabic, Paste Fine, magnesium aluminum silicate, starch and polymethacrylates such as Eudragit NE 30D, 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 carboxymethylcellulose, crospovidone (cross-linked polyvinylpyrrolidone), sodium carboxymethyl starch (sodium starch glycolate), croscarmellose Cellulose sodium (croscarmellose), pregelatinized starch (Starch 1500), microcrystalline cellulose, water-insoluble starch, carmellose calcium, low-substituted hydroxypropyl cellulose, and silicic acid 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 water-soluble/dispersible drug-containing particles, such as beads, with a coating material and optionally pore formers and other excipients. or bead populations (as described above). The covering material is preferably selected from cellulosic polymers such as ethyl cellulose (e.g., ), methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate, and cellulose acetate phthalate; polyvinyl alcohol; acrylic polymers such as polyacrylates, polymethyl Acrylates and their copolymers; and other water-based or solvent-based coating materials. The controlled release coating for a given population of beads can be controlled by controlling at least one parameter of the release coating, such as properties of the coating, coating level, pore former type and concentration, process parameters, and combinations thereof. Thus, by changing parameters such as pore former concentration or curing conditions, the release of active agent from any given population of beads is allowed to be varied, thereby allowing the formulation to be selectively tuned to a predetermined release profile.

Here, pore formers suitable for use in controlled release coatings can be organic or inorganic agents, and include materials that are capable of being dissolved, extracted or leached from the coating in the 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, pullulan, dextran ;Soluble polymers in the use environment, such as water-soluble hydrophilic polymers, hydroxyalkylcellulose, carboxyalkylcellulose, hydroxypropylmethylcellulose, cellulose ether, acrylic resin, polyvinylpyrrolidone, Cross-linked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, carbopol, etc., diols, polyols, polyols, polyalkylene glycols, polyethylene glycol, polypropylene glycol, or their embedded Segment polymers, 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, appropriate calcium salts, combinations thereof, and the like.

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

In some embodiments, coated particles or beads may additionally include an "overcoat" to provide, for example, moisture protection, static reduction, taste masking, flavoring, coloring, and/or polishing 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 hydroxypropylmethylcellulose, hydroxypropylcellulose and microcrystalline cellulose or their combinations (for example, various coating material).

The coated particles or beads may additionally comprise enhancers such as, for example, which may be illustrative but not limited to enhanced dissolution agents, enhanced dissolution agents, absorption enhancers, penetration enhancers, stabilizers, complexing agents, enzyme inhibitors, P-glycoprotein inhibitors and multidrug resistance protein inhibitors. Alternatively, the formulation may also contain the enhancer separately from the coated particles, for example in a separate population of beads or as a powder. In yet another embodiment, the enhancer may be included in a separate layer on the coated particle, either below or above the controlled release coat.

In other embodiments, the extended release formulation is formulated to release the active agent by an osmotic mechanism. For example, the capsule can be made as a single osmotic unit, or it can comprise 2, 3, 4, 5 or 6 push-pull units enclosed in a hard gelatin capsule, whereby each bilayer push-pull unit comprises an osmotic push layer and a drug layer , and both are surrounded by a semipermeable membrane. One or more holes are drilled through the membrane adjacent to the drug layer. This membrane can 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 breaks down and then allows fluid to flow through the semipermeable membrane, causing the osmotic push to partially swell, thereby forcing the drug through the pores at a rate determined by the rate at which water passes through the semipermeable membrane And precise control. Drug release can occur at a constant rate for over 24 hours.

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

Another class of osmotic agents includes zymogens, which are capable of absorbing water to achieve an osmotic pressure gradient across a semipermeable membrane. Examples of zymogens 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, fructose, 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 their mixture.

Materials that contribute to the formation of semipermeable membranes include different grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water permeable and insoluble at physiologically relevant pH values, Alternatively, these materials are susceptible to water insolubility through chemical alteration, such as crosslinking.

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

In some embodiments, the pharmaceutical compositions of the present application are formulated for delayed extended release. The term "delayed release" as used herein refers to a drug therapy 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 in which there is a predetermined delay in the release of the drug after administration. In some embodiments, delayed extended release formulations include extended release formulations coated with an enteric coating, which is a barrier applied to orally administered drugs to prevent release before the drug reaches the small intestine. Delayed release formulations such as enteric coatings prevent gastric irritating drugs such as aspirin from dissolving in the stomach. This coating is also used to protect acid-labile drugs from exposure to the acidic environment of the stomach and instead deliver them to an alkaline pH environment (intestinal pH above 5.5), where described Alkaline environments do not degrade them and give them their desired effect.

The term "pulsatile release" is a type of delayed release, which is used herein with reference to pharmaceutical formulations that provide rapid and transient release of drug over a short period of time immediately after a predetermined lag period, resulting in the release of the drug after administration of the drug. "pulse" plasma distribution. Formulations may be designed to provide single or multiple pulses of release at predetermined intervals after administration, or to provide pulsatile release (e.g., 20-60% of the active ingredient).

Delayed or pulsatile release formulations generally comprise one or more elements covered by a barrier coating, which dissolve, erode or rupture after a specified lag period. In some embodiments, the pharmaceutical compositions of the present application are formulated for extended release or delayed extended release and comprise 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 as well as 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 ). In some embodiments, the first and second components each comprise an alpha-blocker and an analgesic selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, Nabumetone and acetaminophen. In some other embodiments, each of the first and second components comprises a 5α-reductase inhibitor and an analgesic, and the 5α-reductase inhibitor is selected from the group consisting of finasteride, becloteride, ethanol Listeride, Ezondil, Lapisteride, and Torosteramide, and the analgesic 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 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, darfinacin and atropine. In other embodiments, the immediate release component and/or the extended/delayed release component further comprises an antidiuretic, an antimuscarinic, or a combination of both. In other embodiments, the method of treatment comprises administering a diuretic to the subject at least 7 to 8 hours before a target time point (such as bedtime), and administering a diuretic to the subject within 2 hours before the target time point. The subject is administered a pharmaceutical composition comprising an immediate release component and/or an extended/delayed release component.

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

The barrier coating for delayed release can consist of various materials depending on the purpose. Additionally, formulations may include multiple barrier coats to facilitate time-wise release. The coating may be a sugar coating, a film coating (for example, based on hydroxypropylmethylcellulose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylic acid ester copolymers, polyethylene glycol and/or polyvinylpyrrolidone), or based on methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethyl Coatings of cellulose acetate succinate, polyvinyl acetate phthalate, shellac and/or ethyl cellulose. In addition, the formulations 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 compounds that facilitate release of the active agent in the proximal or distal regions of the gastrointestinal tract. polymer. As used herein, the term "enteric polymer coating" refers to a coating comprising one or more polymers with a release profile that is pH dependent or pH independent. Typically, the coating resists dissolution in the acidic medium of the stomach, but dissolves or erodes in more distal regions of the gastrointestinal tract, such as the small intestine or colon. Enteric polymer coatings generally resist release of the active agent until sometime after the lag period of gastric emptying of about 3-4 hours after administration.

pH-dependent enteric coatings comprise one or more pH-dependent or pH-sensitive polymers that maintain their structural integrity at lower pH conditions (e.g., in the stomach) The higher pH of the more distal regions of the gastrointestinal tract (such as the small intestine) dissolves, thereby releasing the drug contents. For the purposes of the present invention, "pH dependent" is defined as having a property (eg, dissolution) that changes 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 (such as those from Rohm AG, Germany). L100 (Type A), S100 (B type)); Methacrylic acid-ethyl acrylate copolymer (such as Rohm Co., Ltd. of Germany L100-55 (Type C) and L30D-55 copolymer dispersion); methacrylic acid-copolymer of methyl methacrylate and methyl methacrylate ( FS); methacrylic acid, terpolymers of methacrylate and ethyl acrylate; cellulose acetate phthalate (CAP); hydroxypropylmethylcellulose phthalate (HPMCP) (e.g. , HP-55, HP-50, HP-55S of Shin-Etsu Chemical); polyvinyl acetate phthalate (PVAP) (for example, Enteric white (OY-P-7171); cellulose acetate succinate (CAS); hydroxypropylmethylcellulose acetate succinate (HPMCAS), e.g., HPMCAS grades LF, MF, HF level, including LF and MF (Shin-Etsu Chemical); Shellac (eg, Marcoat ^TM 125 and Marcoat ^TM 125N); carboxymethyl ethyl cellulose (CMEC, Freund Company, Japan), cellulose acetate phthalate ( CAP) (for example, ); cellulose acetate-1,2,4-trimesate (CAT); and mixtures of two or more thereof in a weight ratio of about 2:1 to about 5:1, for example, a weight ratio of about 3 :1 to about 2:1 L100-55 and A mixture of S100, or a weight ratio of about 3:1 to about 5:1 L30D-55 and Mixture of FS.

A pH-dependent polymer usually exhibits 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, > 5.5, > 6.0, > 6.5, or > 7.0.

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

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

In other embodiments, capsules or bilayer tablets may be formulated to include a drug-containing core covered by a swelling layer and an outer insoluble but semipermeable polymeric coating or membrane. The lag time before rupture can be controlled by the osmotic and mechanical properties of the polymer coating and the swelling behavior of the swollen layer. Typically, the swelling layer contains one or more swelling agents, such as swellable hydrophilic polymers that swell and retain water within their structure.

Exemplary water-swellable materials for use in delayed-release coatings 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., ), methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose; polyalkylene oxides with a weight-average molecular weight of 100,000 to 6,000,000, including but not limited to polyoxymethylene (poly(methylene oxide)), polycyclic Oxybutane; poly(hydroxyalkylmethacrylates) having a molecular weight of 25,000 to 5,000,000; polyethylene crosslinked with glyoxal, formaldehyde or glutaraldehyde, having lower acetal residues and having a degree of polymerization of 200 to 30,000 alcohol; a mixture of methylcellulose, cross-linked agar, and carboxymethylcellulose; a hydrogel-forming copolymer prepared by forming very finely divided maleic anhydride with styrene, ethylene, propylene, butyl Dispersions of copolymers of ethylene or isobutylene crosslinked in the copolymer with 0.001 to 0.5 moles of a saturated crosslinking agent per mole of maleic anhydride; Acid carboxyl polymer; Polyacrylamide; cross-linked water-swellable indene maleic anhydride polymer; molecular weight 80,000 to 200,000 Polyacrylic acid; starch graft copolymer; composed of condensed glucose units (e.g., diester-crosslinked polydextran) Acrylate polymer polysaccharides; carbomers with a viscosity of 3,000 to 60,000 mPa in 0.5% to 1% w/v aqueous solution; Hydroxypropyl cellulose; hydroxypropyl methylcellulose with a viscosity of about 1000 or more, preferably more than 2,500, up to 25,000 mPa at 2% w/v aqueous solution; a viscosity of about 10% w/v aqueous solution at 20°C Polyvinylpyrrolidone from 300 to 700 mPa; and mixtures thereof.

Alternatively, the release time of the drug can be controlled by the disintegration lag time, which depends on the balance between the tolerance and thickness of the water-insoluble polymer film (such as ethyl cellulose, EC), The water-insoluble polymer film contains predetermined micropores at the bottom of the main body, and a certain amount of swellable auxiliary materials, such as lower-substituted hydroxypropyl cellulose (L-HPC) and sodium glycolate. After oral administration, gastrointestinal fluids permeate through the micropores, causing swelling of the swellable excipient, which creates an internal pressure that disintegrates the capsule portion comprising the first capsule body containing the swellable material, the drug-containing The second capsule body and the outer cover attached to the first capsule body.

The enteric layer may further comprise anti-adhesive agents such as talc or glyceryl monostearate and/or plasticizers. The enteric layer may further comprise one or more plasticizers, including, but not limited to, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, polyethylene glycol Glycol Acetylated Monoglyceride, Glycerin, Glyceryl Triacetate, Propylene Glycol, Phthalates (such as 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 intestinal tract through the membrane into the core, the core swells until the membrane ruptures, releasing the active ingredient. Film coatings can be tailored to achieve different rates of water penetration or release times.

In another embodiment, the delayed release formulation employs a water-impermeable tablet coating whereby water enters through controlled pores in the coating until the core bursts. When the tablet bursts, the drug contents are released immediately, or over an extended period of time. These and other techniques can be modified to allow for a predetermined lag period before drug release begins.

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

In some embodiments, the immediate-release, extended-release, delayed-release, or delayed-extended-release formulation includes an active core consisting of one or more inert particles each coated on its surface with Beads, pellets, pellets, granules, microcapsules, microspheres, In the form of microparticles, nanocapsules or nanospheres. The inert particles can be of various sizes as long as they are large enough to remain insoluble. Alternatively, the active core can be prepared by granulation and milling of a polymer composition containing a pharmaceutical ingredient and/or by extrusion and spheronization.

The amount of drug in the core will depend on the dose required and will generally 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. Those skilled in the art will be able to select the appropriate amount of drug to coat or incorporate into the core to achieve the desired dosage. In one embodiment, the inactive core can be sugar spheres or buffer crystals or encapsulated buffer crystals, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alter 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 (such as beads) with a mixture of water-insoluble polymers and enteric polymers. , wherein the water-insoluble polymer and the enteric polymer may exist in a weight ratio of 4:1 to 1:1, and based on the total weight of the coated beads, the total weight of the coating is 10 to 60 wt%. Drug layered beads may optionally include an ethylcellulose membrane to control the rate of internal dissolution. The composition of the outer layer, as well as the individual weights of the inner and outer layers of the polymeric film, is optimized to achieve the desired circadian release profile for a given activity, as predicted based on in vitro/in vivo correlations.

In other embodiments, the formulation may comprise granules containing immediate release drug (without a polymeric membrane to control the dissolution rate) and delayed-extended release beads (which exhibit, for example, 2 to 4 hours after oral administration). hours of lag time) to provide a double-pulse release profile.

In some embodiments, the active core is coated with a layer of one or more polymers that control the dissolution rate so that a desired release profile (with or without lag time) is obtained. The inner membrane can largely control the drug release rate after uptake of water or body fluid into the core, while the outer membrane can provide the desired lag time (period of no or little drug release after uptake of 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 noted above, suitable polymers for the outer membrane that largely control the lag time up to 6 hours include enteric polymers, and 10 to 50% by weight 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, acrylates with quaternary ammonium groups and methacrylate copolymers (such as NE, RS and RS30D, RL or RL30D, etc.). Examples of water-soluble polymers include low molecular weight HPMC; HPC; methylcellulose; polyethylene glycol (PEG with a molecular weight >3000), depending on the solubility of the activity in water and solvents, or on the coating formulation used The emulsion suspension ranges from 1 wt% up to 10 wt%. The ratio of water-insoluble polymer to water-soluble polymer may generally vary from 95:5 to 60:40, preferably from 80:20 to 65:35.

In some embodiments, AMBERLITE™ IRP69 resin is used as the extended release carrier. AMBERLITE ^™ IRP69 is an insoluble, strongly acidic sodium type cation exchange resin, which is suitable as a carrier for cationic (basic) substances. In other embodiments, DUOLITE ^™ AP143/1093 resin is used as the extended release carrier. DUOLITE ^™ AP143/1093 is an insoluble, strongly basic anion exchange resin suitable as a carrier for anionic (acidic) substances.

When used as a drug carrier, AMBERLITE IRP69 or/and DUOLITE ^(TM) AP143/1093 resins provide a means of binding pharmaceutical agents to insoluble polymer matrices. Extended release is achieved through the formation of resin-drug complexes (drug resinates). The drug is released from the resin in vivo as the drug equilibrates with the high electrolyte concentration, which is typical for drug release from the gastrointestinal tract. Typically, more hydrophobic drugs will elute from the resin at a slower rate due to hydrophobic interactions with the aromatic structures of the cation exchange system.

Most enteric coatings work by presenting a surface that is stable at higher acidic pH conditions (ie conditions in the stomach), but breaks down at lower acidic pH conditions (relatively more alkaline). Thus, enteric-coated pills are insoluble in the acidic gastric juices (pH ~3), but they will dissolve 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, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose Vegan 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 pellets, which 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 pills, tablets or capsules to help slow the dissolution and concomitant release of the drug in the intestinal tract. Typically, the barrier coat comprises one or more polymers that surround, surround or form a layer or film around the pharmaceutical composition or active core.

In some embodiments, the active agent is delivered in a formulation that provides 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 longer.

Different coating techniques can be applied to granules, beads, powders or pellets, tablets, capsules or combinations thereof containing the active agent to produce different and differentiated 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 agents selected from antimuscarinic agents, antidiuretics, and antispasmodics other active ingredients of the drug. In some embodiments, the pharmaceutical composition comprises one or more analgesics, one or more 5α-reductase inhibitors and one or more selected from antimuscarinic agents, antidiuretics, Alpha-blockers and other active ingredients of antispasmodics. Examples of antimuscarinic agents include, but are not limited to: oxybutynin, solifenacin, darfenacin, and atropine. Examples of antidiuretics include, but are not limited to, antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (e.g., desmopressin, arginopressin, lysinopressin, phenylespressin, 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)], anantin, from Cerulean cyclic peptide of Streptomyces coerulescens, and 3G12 monoclonal antibody); somatostatin type 2 receptor antagonists (e.g., somatostatin), and pharmaceutically acceptable derivatives thereof, similar compounds, salts, hydrates and solvates. Examples of antispasmodics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, clonidine-like and dantrolene.

In some embodiments, the pharmaceutical composition comprises one or more analgesics and one or more alpha-blockers. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more alpha-blockers, and (3) one or more antitoxic Muscarinic agents. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more alpha-blockers and (3) one or more antidiuretics . In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more alpha-blockers and (3) one or more antispasmodics . In other embodiments, the pharmaceutical composition comprises 1) one or two analgesics, (2) one or more alpha-blockers, (3) one or two antimuscarinic agent and (4) one or two antidiuretics. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more alpha-blockers, (3) one or more antispasmodics and (4) one or more antidiuretics.

In some embodiments, the pharmaceutical composition comprises one or more analgesics and one or more 5α-reductase inhibitors. In some other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, (3) one or more antitoxic Muscarinic agents. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors and (3) one or more antidiuretic agent. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors and (3) one or more antispasmodic agent. In other embodiments, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or more 5α-reductase inhibitors, (3) one or two antitoxic agents Muscarinic agents and (4) one or both antidiuretics. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, (3) one or more antispasmodic agent and (4) one or more antidiuretics.

In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-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 5α-reductase inhibitors, (3) one or more α- blockers and (4) one or more antidiuretics. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, (3) one or more α- blockers and (4) one or more antispasmodics. In other embodiments, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or more 5α-reductase inhibitors, (3) one or two antitoxic agents Muscarinic agents, (4) one or two antidiuretics and (5) one or more alpha-blockers. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, (3) one or more antispasmodic agent, (4) one or more antidiuretics and (5) one or more alpha-blockers.

In one embodiment, the majority of the active ingredients are formulated to be immediate release. In other embodiments, the majority of the active ingredients are formulated for extended release. In other embodiments, the plurality of active ingredients are formulated for immediate release and extended release (eg, 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 the active ingredients are formulated for immediate release, while some of the majority of the 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 some other embodiments, the immediate release component and/or the prolonged release component are further coated with a delayed release coating (such as 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, 5a-reductase inhibitors, antimuscarinic agents, antidiuretics and antispasmodics. The extended release component may comprise one or more active ingredients selected from the group consisting of analgesics, alpha-blockers, antimuscarinic agents, antidiuretics and antispasmodics. 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 are further coated with a delayed release coating (such as an enteric coating).

In one embodiment, the pharmaceutical composition comprises two or more active ingredients formulated for immediate release at about the same time (e.g., one or more analgesics and one or more alpha- blockers, one or more 5α-reductase inhibitors, one or more antimuscarinic or antidiuretic or antispasmodic mixtures). In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated for extended release at about the same time. 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 and 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 each 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 into two delayed release components, each delayed release component providing a different delayed release profile. For example, a first delayed release component releases a first active ingredient at a first time point and a second delayed release component releases a second active ingredient at a second time point. In another embodiment, the pharmaceutical composition comprises two or more active ingredients, one or more of which are formulated for immediate release and the remainder are formulated for extended release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients, a portion of which are formulated for immediate release and the remainder are formulated for extended release.

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

The term "immediate release" as used herein refers to pharmaceutical formulations that do not contain dissolution rate controlling materials. Following administration of an immediate release formulation, there is substantially no delay in the release of the active agent. Immediate release coatings may comprise 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 (such as ) and various other materials known to those skilled in the art.

Immediate release compositions 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 provides from about 1% to about 60% of the total dose of active agent to be delivered by the pharmaceutical formulation. %. For example, the immediate release component can provide from about 5% to 60%, from about 10% to about 60%, from about 10% to about 50%, from about 10% to about 40%, of the total dose of active agent to be delivered by the formulation. 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%. In other embodiments, the immediate release component provides about 2, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60%.

In some embodiments, immediate release or delayed release formulations include an active core consisting of one or more inert particles each coated with a drug on its surface (e.g., in a drug-containing Beads, pellets, pills, granules, microcapsules, microspheres, microparticles, nanocapsules or nanospheres in the form of film-forming compositions (using, for example, fluidized bed techniques or other methods known to those skilled in the art) form. The inert particles can be of various sizes as long as they are large enough to remain insoluble. Alternatively, the active core can be prepared by granulation and milling of a polymer composition containing a pharmaceutical ingredient and/or by extrusion and spheronization.

The amount of drug in the core will depend on the dose required and will generally 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. Those skilled in the art will be able to select the appropriate amount of drug coated on or incorporated into the core to achieve the desired dosage. In one embodiment, the inactive core can be sugar spheres or buffer crystals or encapsulated buffer crystals, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alter the microenvironment of the drug to facilitate its release.

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

In other embodiments, the formulation comprises immediate release drug containing granules (without a polymeric membrane to control the dissolution rate) and delayed release beads (which exhibit, for example, a lag time of 2 to 4 hours after oral administration). ) to provide a double pulse 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 limits its disturbance of restful sleep, wherein the formulation releases the drug when the individual is normally aroused by the urge to urinate. For example, consider an individual who usually goes to sleep at 11 pm and is usually awakened to urinate at 12:30 am, 3:00 am, and 6:00 am. Delayed extended release vehicles can be taken at 10 pm and start delivering drug at 12 am and gradually release drug over a 5-8 hour period, thereby delaying or eliminating the need to urinate. In other embodiments, the formulation is designed to have a release profile in which a fraction (eg, 20-60%) of the drug is released immediately or within 2 hours of administration and the remainder is released over an extended period of time. The pharmaceutical composition can be administered daily or as needed. In certain embodiments, the pharmaceutical composition is administered to the subject at bedtime. In some embodiments, the pharmaceutical composition is administered immediately at 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, said 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, said pharmaceutical composition is administered at least one hour before bedtime. In a still further embodiment, said pharmaceutical composition is administered less than one hour before bedtime. In another further embodiment, said pharmaceutical composition is administered immediately before bedtime. Preferably, the pharmaceutical composition is administered orally. Suitable compositions for oral administration include, but are not limited to, tablets, coated tablets, lozenges, capsules, powders, granules, and soluble tablets, as well as liquid forms (eg, 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 patient's Age and weight, patient's clinical history and response to active agents, physician orders, etc.

It is generally recommended that the therapeutically effective amount of the active agent in the immediate-release component, extended-release component or delayed-extended-release component range from about 100 μg/kg body weight/day to about 100 mg/kg body weight/day, regardless of single or multiple administrations. Apply within a daily range. In some embodiments, each active agent is administered daily in single or multiple doses in the range of about 100 μg/kg body weight/day to about 50 mg/kg body weight/day, 100 μg/kg body weight/day to about 10 mg/kg body weight /day, 100μg/kg body weight/day to about 1mg/kg body weight/day, 100μg/kg body weight/day to about 10mg/kg body weight/day, 500μg/kg body weight/day to about 100mg/kg body weight/day, 500μg/kg body weight/day kg body weight/day to about 50 mg/kg body weight/day, 500 μg/kg body weight/day to about 5 mg/kg body weight/day, 1 mg/kg body weight/day to about 100 mg/kg body weight/day, 1 mg/kg body weight/day to About 50 mg/kg body weight/day, 1 mg/kg body weight/day to about 10 mg/kg body weight/day, 5 mg/kg body weight/day to about 100 mg/kg body weight/day, 5 mg/kg body weight/day to about 50 mg/kg body weight/day /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 an immediate-release component or an extended-release component, a delayed-extended release component, or a combination thereof for daily oral administration in single or multiple doses ranging from 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 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, 500mg to 1000mg, 500mg to 2000mg. 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, and one or more α-blockers or one or more 5α-reductase inhibitors. In one embodiment, the single analgesic is aspirin. In another embodiment, the single analgesic is ibuprofen. In another embodiment, the single analgesic is naproxen or naproxen sodium. In another embodiment, the single analgesic is indomethacin. In another embodiment, the single analgesic is nabumetone. In another embodiment, the single analgesic is acetaminophen. In another embodiment, said single analgesic is acetaminophen and said one or more alpha-blockers comprises tamsulosin. In another embodiment, said single analgesic agent is acetaminophen and said one or more 5α-reductase inhibitors comprise finasteride.

In some embodiments, the single analgesic is administered at 1 mg to 2000 mg, 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg per day Or doses from 500mg to 1000mg are given. In certain embodiments, the pharmaceutical composition comprises acetylsalicylic acid, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, or acetaminophen as the sole analgesic agent. phenol, and the analgesic is taken orally in a daily dosage range of 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg, or 500 mg to 1000 mg apply. In some embodiments, at a daily dose of 1 mg to 2000 mg, 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg, or 500 mg to 1000 mg Administer a second analgesic.

In other embodiments, the pharmaceutical composition includes 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 paraacetyl Aminophenol, Acetylsalicylic Acid and Indomethacin, Ibuprofen and Naproxen Sodium, Ibuprofen and Nabumetone, Ibuprofen and Acetaminophen, Ibuprofen and Indomethacin, Naphthalene Proxen, Naproxen Sodium and Nabumetone, Naproxen Sodium and Acetaminophen, Naproxen Sodium and Indomethacin, Nabumetone and Acetaminophen, Nabumetone and Indole Methacin, as well as 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, and the combined dose ranges from 5 mg to 2000 mg, 20 mg to 2000 mg, 100 mg 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 2000mg. In one embodiment, the paired analgesics are mixed in a 1:1 weight ratio.

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

In certain embodiments, the pharmaceutical composition comprises one or more alpha-blockers selected from acetylsalicylic acid, ibuprofen, naproxen, naproxen sodium, nabumetone, para Analgesics of acetaminophen and indomethacin, and antimuscarinic agents selected from the group consisting of oxybutynin, solifenacin, darfenacine and atropine.

Another aspect of the present application relates to a method of alleviating urinary frequency by administering to a human in need thereof a pharmaceutical composition formulated in an immediate release formulation. The pharmaceutical composition comprises one or more analgesics and one or more additional active agents selected from the group consisting of 5α-reductase inhibitors, α-blockers, antimuscarinic agents, antidiuretics and antispasmodics Element. 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 directly or contained in a capsule.

In some embodiments, the analgesic is selected from the group consisting of salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine Pyridine, derivatives of p-aminophenol, acetanilide, acetaminophen, phenacetin, fenamate, mefenamic acid, meclofenamate, meclofenamic acid sodium, heteroaryl acetic acid derivatives, trol Mebutin, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin; enolic acid, Oxicam (benzothiazine) derivatives, piroxicam, meloxicam, tenoxicam, ampiraxicam, droxicam, pivoxicam, pyrazolone derivatives, phenylbutazone, Hydroxybuzone, Antipyrine, Aminopyrine, Analgin, Coxib, Celecoxib, Rofecoxib, Nabumetone, Azaprozone, Nimesulide, Indomel Acrylic, sulindac, etodolac, diflunisal, and isobutylphenylpropionic acid. The antimuscarinic agent is selected from oxybutynin, solifenacin, darfinacine and atropine.

In some embodiments, the pharmaceutical composition comprises a single analgesic, a single alpha-blocker, and a single antimuscarinic. In some embodiments, the pharmaceutical composition comprises a single analgesic, a single 5α-reductase inhibitor, and a single antimuscarinic agent. In one embodiment, the single analgesic is aspirin. In another embodiment, the single analgesic is ibuprofen. In another embodiment, the single analgesic is naproxen or naproxen sodium. In another embodiment, the single analgesic is indomethacin. In another embodiment, the single analgesic is nabumetone. In another embodiment, the single analgesic is acetaminophen. In another embodiment, the single alpha-blocker is tamsulosin. The analgesics, α-blockers, 5α-reductase inhibitors and antimuscarinic agents can be administered at doses within the above ranges. In some embodiments, the pharmaceutical composition further comprises an antidiuretic or antispasmodic agent.

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 alone or in combination ,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, 400-1000mg ,400-800mg,400-600mg,600-2000mg,600-1500mg,600-1200mg,600-1000mg,600-800mg,800-2000mg,800-1500mg,800-1200mg,800-1000mg,1000-2000mg,1000 - 1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg of an analgesic, wherein said composition is formulated for extended release with a release profile in which said one The one or more analgesic agents are released continuously over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

In some embodiments, the composition is formulated for extended release with a release profile in which at least 90% of the active ingredient is present within 5-24 hours, 5-8 hours, 8-16 hours, or 16 hours. - Continuous release over a 24-hour period.

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

In other embodiments, the composition is formulated for extended release with a release profile in which the active ingredient is released within 5-24 hours, 5-8, 8-16 hours, or 16-24 hours. released at a steady rate over a period of time. In other embodiments, the composition is formulated for extended release with a release profile in which the active ingredient is present at 5, 6, 7, 8, 10, 12, 14, 16, 18, Release at a steady rate over a period of 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 in a given period of time is between 30% and 300% of the average release rate for the given period of time %Inside. For example, if 80 mg of aspirin is released at a steady rate over an 8-hour period with an average rate of 10 mg/hr over that period, the actual rate of release at any time during the period is in the range of 3 mg/hr to 30 mg/hr ( That is, within 30%-300% of the average release rate of 10 mg/hr over an 8 hour period).

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

In some embodiments, the pharmaceutical composition comprises 50-400 mg, 50-250 mg, 250-400 mg, or 400-600 mg of the 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 ingredient may be released immediately after administration or with the analgesic.

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

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

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

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

In another specific embodiment, said pharmaceutical composition comprises 800-1000 mg of extended-release acetaminophen formulated to have a release profile in which at least 90% of the acetaminophen The release is continuous or at a steady rate over a period of 5-8, 8-16 hours or 16-24 hours. The other active ingredient 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,200-2000mg,200-1500mg,200-1200mg,200-1000mg,200-800mg,200-600mg,200-400mg,400-2000mg,400-1500mg,400-1200mg,400 -1000mg, 400-800mg, 400-600mg, 600-2000mg, 600-1500mg, 600-1200mg, 600-1000mg, 600-800mg, 800-2000mg, 800-1500mg, 800-1200mg, 800-1000mg, 1000-2000mg , 1000-1500mg, 1000-1200mg, 1200-2000mg, 1200-1500mg or 1500-2000mg of an analgesic, wherein the analgesic is formulated as a prolonged release characterized by a two-stage release profile, in which In the release profile, 20-50% of the analgesic is released within 2 hours of administration, while the remainder is released continuously or at a steady rate over a period of 5-24 hours. The other active ingredient may be released immediately after administration or with the analgesic.

In another embodiment, the analgesic is formulated as an extended release with a two-stage release profile in which 20, 30, 40 or 50% of the analgesic is within 2 hours of administration released while 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 is selected from aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, nabumetone, and acetaminophen. In another embodiment, the analgesic is acetaminophen. In some embodiments, the pharmaceutical composition further comprises an antimuscarinic, antidiuretic, or antispasmodic agent. The other active ingredient may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 50-400 mg of extended release acetaminophen formulated to have a two-stage release profile in which 20, 30, 40 or 50% are released within 2 hours of application, while 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 ingredient may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 100-300 mg of extended release acetaminophen formulated to have a two-stage release profile in which 20, 30, 40 or 50% are released within 2 hours of application, while 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 ingredient may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 400-600 mg of extended release acetaminophen formulated to have a two-stage release profile in which 20, 30, 40 or 50% are released within 2 hours of application, while 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 ingredient may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 600-800 mg of extended release acetaminophen formulated to have a two-stage release profile in which 20, 30, 40 or 50% are released within 2 hours of application, while 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 ingredient may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 800-1000 mg of extended release acetaminophen formulated to have a two-stage release profile in which 20, 30, 40 or 50% are released within 2 hours of application, while 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 ingredient may be released immediately after administration or with the analgesic.

In another embodiment, the pharmaceutical composition comprises 1000-1200 mg of extended release acetaminophen formulated to have a two-stage release profile in which 20, 30, 40 or 50% are released within 2 hours of application, while 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 ingredient may be released immediately after administration or with the analgesic.

Another aspect of the present application relates to a method by administering to a subject in need thereof (1) one or more analgesics, (2) an α-blocker or a 5α-reductase inhibitor or a combination of both , and (3) a method of treating nocturia with one or more antidiuretics. In certain embodiments, the antidiuretic is used to: (1) increase vasopressin secretion; (2) increase vasopressin receptor activation; (3) decrease atrial natriuretic peptide (ANP) or C secretion of natriuretic peptide (CNP); or (4) reduction of ANP and/or CNP receptor activation.

Examples of antidiuretics include, but are not limited to, antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (e.g., desmopressin, arginopressin, lysinopressin, phenylespressin, 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)], Annantine, from Streptomyces coelicolor ( cyclic peptides of Streptomyces coerulescens), and 3G12 monoclonal antibody); somatostatin type 2 receptor antagonists (e.g., somatostatin), and pharmaceutically acceptable derivatives, analogs, salts, Hydrates and Solvates.

In a certain embodiment, said one or more analgesics, α-blockers and/or 5α-reductase inhibitors are formulated for extended release, and said one or more antidiuretics are Formulated for immediate release. In other embodiments, the one or more analgesics, α-blockers and/or 5α-reductase inhibitors are formulated for delayed release and the antidiuretics are formulated for immediate release. In some embodiments, the delayed release formulation delays the release of the active ingredient (eg, the analgesic, antimuscarinic, antidiuretic, and antispasmodic) for 1, 2, 3, 4, or 5 hours.

Another aspect of the present application relates to a method by administering to a person in need thereof a first pharmaceutical composition comprising a diuretic, followed by administration comprising (1) one or more analgesics and (2) one or more alpha - A method for alleviating urinary frequency with a second pharmaceutical composition of a blocker, one or more 5α-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 it is administered at least 8 or 7 hours before bedtime. The second pharmaceutical composition is administered within 2 hours before going to bed. 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 NH4Cl; arginine vasopressin receptor 2 antagonists, such as amphotericin B and lithium citrate; hydroqueretics, such as Goldenrod and Junipe; Na-H exchanger antagonists such as dopamine; carbonic anhydrase inhibitors such as acetazolamide and dorzolamide; loop diuretics such as bumetanide, ethacrynic acid, furfural Semide and torsemide; osmotic diuretics, such as dextrose and mannitol; potassium-sparing diuretics, such as amiloride, spironolactone sterol, triamterene, potassium renzopropionate; thiazides , such as bendrofluthiazide 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 such antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darfinex, 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 some other embodiments, the second pharmaceutical composition further comprises one or more antidiuretics. In some other embodiments, the second pharmaceutical composition further comprises one or more antispasmodics. Another aspect of the present application relates to a method for alleviating urinary frequency by selectively administering two or more analgesics to a subject in need thereof to prevent development of drug resistance. In one embodiment, the method comprises administering a first analgesic for a first period of time and then administering a second analgesic for a second period of time. In another embodiment, the method further comprises administering a third analgesic for the third period of time. The first, second and third analgesics are distinct from each other and at least one of them is formulated for extended release or delayed extended release. In one embodiment, the first analgesic is acetaminophen, the second analgesic is ibuprofen and the third analgesic is naproxen sodium. The length of each period can 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 antidiuretics. In other embodiments, the plurality of active ingredients comprises one or more analgesics, one or more α-blockers, one or more 5α-reductase inhibitors and one or more An antimuscarinic agent. In other embodiments, the plurality of active ingredients comprises one or more analgesics, one or more alpha-blockers, one or more antidiuretics, and one or more antidote Muscarinic agents. In other embodiments, the pharmaceutical composition comprises two different drugs selected from the group consisting of acetylsalicylic acid, ibuprofen, naproxen sodium, naproxen, nabumetone, acetaminophen and indomethene Sim's analgesic. In other embodiments, the pharmaceutical composition comprises an analgesic selected from acetylsalicylic acid, ibuprofen, naproxen sodium, nabumetone, acetaminophen, and indomethacin; One or more alpha-blockers and an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darfinacine and atropine.

In other embodiments, the pharmaceutical composition described herein further comprises one or more antispasmodics and/or one or more antidiuretics. Examples of antispasmodics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, clonidine-like and dantrolene. In some embodiments, the antispasmodic agent is administered daily at 1 mg to 1000 mg, 1 mg to 100 mg, 10 mg to 1000 mg, 10 mg to 100 mg, 20 mg to 1000 mg, 20 mg to 800 mg, 20 mg to 500 mg, 20 mg to 200 mg, 50 mg to 1000 mg, 50 mg to Doses of 800mg, 50mg to 200mg, 100mg to 800mg, 100mg to 500mg, 200mg to 800mg and 200mg to 500mg are used. The antispasmodic agent 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 total agents selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen. Analgesics in an amount of 50-400 mg per dose, one or more alpha-blockers and one or more selected from oxybutynin, solifenacin, darfenacin and atropine in a total amount of 1-25 mg of an antimuscarinic agent, wherein said pharmaceutical composition is formulated for extended release with a two-stage release profile in which 20-60% of the active ingredient is absorbed within 2 hours of administration Release while the remainder of the active ingredient 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 some embodiments, the pharmaceutical composition comprises one or more total agents selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen. Analgesics in amounts of 50-400 mg per dose, one or more alpha-blockers and one or more antidiuretics selected from the group consisting of antidiuretic hormone (ADH), angiotensin II , aldosterone, vasopressin, vasopressin analogs (eg, desmopressin, arginopressin, lysmopressin, phenylespressin, 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, indigo red, [Asu7,23']b-ANP-(7-28)], anantin, cyclic peptide from Streptomyces coerulescens, and 3G12 monoclonal antibody); somatostatin Type 2 receptor antagonists (e.g., somatostatin), and pharmaceutically acceptable derivatives, analogs, salts, hydrates and solvates thereof, wherein the pharmaceutical composition is formulated to have a Extended release of a two-stage release profile in which 20-60% of the active ingredient is released within 2 hours of application and the remainder at 5-24 hours, 5-8 hours, 8-16 hours or 16 hours - Released continuously or at a steady rate over a period of 24 hours.

In some embodiments, the pharmaceutical composition comprises (1) one or more selected from aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen Analgesics in an amount of 50-400 mg per dose of phenol, (2) one or more α-blockers, or one or more 5α-reductase inhibitors or both, and (3) a One or more selected from carisoprodol, benzodiazepines, baclofen, cyclobenzalkon beads, metaxalone, methocarbamol, clonidine, clonidine analogues and dantrolol The total amount of forest is 50-500 mg of antispasmodic agent, wherein said pharmaceutical composition is formulated to have a prolonged release with a two-stage release profile in which 20-60% of the active ingredient is present after administration 2 is released within hours, 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.

As used herein, "pharmaceutically acceptable carrier" includes all and any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweetening agents and the like. The pharmaceutically acceptable carrier can be prepared from a wide range of materials including, but not limited to, flavoring, sweetening, and miscellaneous materials, such as buffering agents and absorbing agents necessary to prepare a particular therapeutic composition. agent. The use of such media and agents for use with pharmaceutically active substances is well known in the art. In addition to conventional media or agents incompatible with the active ingredient, other included materials are contemplated for use in therapeutic compositions.

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 hereby incorporated by reference.

Example 1: Inhibition of the Urinary Urge

Twenty volunteer subjects of both sexes were enrolled, each of whom experienced a premature urge to urinate or need to urinate, which interfered with their ability to sleep for a period sufficient to feel fully rested. Each subject ingested 400 to 800 mg of ibuprofen in a single dose before bedtime. At least 14 of the subjects reported being able to rest better because they were not aroused by the frequent urge to urinate.

Several subjects reported that after several weeks of nocturnal use of ibuprofen, the benefits of infrequent urge to urinate were no longer realized. However, all of these subjects further reported resuming the benefit a few days after abstaining from the drug.

Example 2: Analgesics, Botulinum Neurotoxin and Antimuscarinic Agents on Macrophages on Inflammation and responses to non-inflammatory stimuli

experimental design

This study aimed to determine 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 baseline (dose and kinetic) responses to inflammatory and non-inflammatory effectors in bladder cells. Briefly, cultured cells are exposed to analgesic and/or antimuscarinic agents in the absence or presence of various effectors.

The effectors include: lipopolysaccharide (LPS), inflammatory agents and Cox2 inducers, as inflammatory stimuli; carbachol or acetylcholine, smooth muscle contraction stimulants, as non-inflammatory stimuli; 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, they are Produced after the sequential intracellular oxidation of AA, DGLA or EPA by cyclooxygenases (COX1 and COX-2) and terminal prostaglandin synthases.

The analgesics include: salicylate, such as aspirin, isobutylpropionate phenolic acid derivatives (ibuprofen), such as Advil (Advil), ibuprofen preparations (Motrin), sulfamethoxazole ( Nuprin) and Medipren; naproxen sodium, such as naproxen sodium (Aleve), naproxen formulation (Anaprox), Antalgin, Feminax Ultra, naproxen (Flanax), Inza, Midol Extended Relief, Nalgesin, Naposin, naphthalene Proxen Extended Release Tablets (Naprelan), Naprogesic, Naprosyn, Naprosyn Suspension, EC-Naprosyn, Narocin, Naproxen, Synflex and Xenobid; acetic acid derivatives, such as indomethacin (Indocin); 1-naphthylacetic acid derivatives, such as nabumetone or relifene; N-acetyl p-aminophenol (APAP) derivatives, such as acetaminophen phenol or paracetamol (Tylenol) and celecoxib.

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

Short-term (1-2 hours) or long-term (24-48 hours) stimulation of macrophages by:

(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) Different doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.

(9) Different doses 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.

Then the release of PGH ₂ , PGE, PGE ₂ , prostacyclin, thromboxane, IL-1β, IL-6, TNF-α, COX2 activity, production of cAMP and cGMP, IL-1β, IL-6, Production of TNF-α and COX2 mRNA, and surface expression of CD80, CD86, and MHC class II molecules.

Materials and methods

Macrophages

Murine RAW264.7 or J774 macrophages (obtained from ATCC) were used in this study. Cells were maintained in medium containing RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 15 mM HEPES, 2 mM L-glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin. Cells were cultured at 37°C in a 5% CO ₂ atmosphere and isolated (passaged) once a week.

In vitro treatment of macrophages with analgesics

RAW264.7 macrophages were seeded in 96-well plates at a cell density of ^1.5x105 cells/well (in 100 μl medium). Cells were treated with (1) varying concentrations of analgesics (acetaminophen, aspirin, ibuprofen, or naproxen), (2) varying concentrations of lipopolysaccharide (LPS), which is Effectors of inflammatory stimuli of cells, (3) different concentrations of carbachol or acetylcholine, which are effectors of non-inflammatory stimuli, (4) analgesic and LPS or (5) analgesic and carbachol or Acetylcholine. Briefly, analgesics were dissolved in FBS-free medium (i.e., RPMI 1640 supplemented with 15 mM HEPES, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin) and Serial dilutions of medium are diluted to the desired concentration. For cells treated with analgesic in the absence of LPS, add 50 μl of analgesic solution and 50 μl of medium without FBS to each well. For cells treated with analgesic in the presence of LPS, 50 μl of analgesic solution and 50 μl of LPS (from Salmonella typhimurium) in FBS-free medium were added to each well . All conditions were tested in duplicate.

After 24 or 48 h of culture, 150 μl of culture supernatant was collected, spun at 4 °C, 8,000 rpm for 2 min to remove cells and debris, and stored at −70 °C for analysis of cytokine responses by ELISA. Cells were harvested and washed by centrifugation (5 minutes at 1,500 rpm at 4°C) in 500 μl of phosphate buffered saline (PBS). Half of the cells were then snap-frozen in liquid nitrogen and stored at -70°C. The remaining cells were stained with fluorescent monoclonal antibodies and analyzed by flow cytometry.

Flow cytometric analysis of co-stimulatory molecule expression

For flow cytometry analysis, macrophages were diluted in 100 μl of FACS buffer (phosphate buffered saline (PBS) with 2% bovine serum albumin (BSA) and 0.01% NaN3) and incubated by adding FITC- Conjugated anti-CD40, PE-conjugated anti-CD80, PE-conjugated anti-CD86 antibody, anti-MHC class II (IA ^d ) PE (BD Biosciences) were stained at 4°C for 30 minutes. Cells were then washed by centrifugation in 300 μl of FACS buffer (5 min at 4° C., 1,500 rpm). After the second wash, cells were resuspended in 200 μl of FACS buffer, and cells expressing a given marker (single positive) or a combination of markers (double positive) were analyzed by means of an AccuriC6 flow cytometer (BD Biosciences). percentage.

Analysis of cytokine responses by ELISA

Cytokine-specific ELISA was performed on culture supernatants to determine IL-1β, IL-6, and TNF- alpha response. These assays were coated overnight with 100 μl of anti-mouse IL-6, TNF-α mAbs (BD Biosciences) or IL-1β mAb (R&D Systems) in 0.1 M sodium bicarbonate buffer (pH 9.5). Performed on Nunc MaxiSorp Immunoplates (Nunc). After washing twice with PBS (200 μl per well), 200 μl of PBS 3% BSA was added to each well (section), and the plate was incubated at room temperature for 2 hours. Wash the plate twice again by adding 200 μl per well, repeat the addition of 100 μl of cytokine standards and serially diluted culture supernatants, and incubate the plate overnight at 4°C. Finally, the plate was washed twice and treated with 100 μl of biotinylated secondary antibodies against mouse IL-6, TNFα mAbs (BD Biosciences) or IL-1β (R&D Systems), followed by peroxidase-labeled goat antibody. Primer mAb (Vector Laboratories) was incubated. The colorimetric reaction was developed by adding 2,2′-azino-bis( ₃ -ethylbenzylthiazoline-6-sulfonic acid) (ABTS) substrate and H2O2 ( _Sigma ), and the absorbance was measured using V Multilabel Microplate Reader (PerkinElmer) measured at 415nm.

COX2 activity assay and cAMP and cGMP production

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

result

Table 1 summarizes the experiments performed with the Raw 264 macrophage cell line and the main findings regarding the effect of analgesics on the cell surface expression of co-stimulatory molecules CD40 and CD80. The expression of these molecules is stimulated by COX2 and inflammatory signaling, and therefore was assessed to determine the functional consequences of inhibition of COX2.

As shown in Table 2, acetaminophen, aspirin, ibuprofen, and naproxen were effective at all but the highest dose (ie, 5x10 ⁶ nM), which appeared to enhance, rather than inhibit, expression of co-stimulatory molecules. Basal expression of the co-stimulatory molecules CD40 and CD80 in macrophages was inhibited at the doses tested (ie, 5x10 ⁵ nM, 5x10 ⁴ nM, 5x10 ³ nM, 5x10 ² nM, 50 nM and 5 nM). Such an inhibitory effect on CD40 and CD50 expression was observed at analgesic doses as low as 0.05 nM (ie, 0.00005 μM) as shown in Figures 1A and 1B. This finding supports the idea that controlled release of small doses of analgesics is preferable to acute delivery of large doses. The experiments also showed that acetaminophen, aspirin, ibuprofen, and naproxen had similar inhibitory effects on LPS-induced expression of CD40 and CD80.

Table 1. Experiment summary

Table 2. Summary of key findings

^* ND: Not performed (toxicity)

Table 3 summarizes the results of several studies that measured serum levels of analgesics in adults following oral therapeutic doses. As shown in Table 3, the maximum serum levels of analgesics ranged from 10 ⁴ to 10 ⁵ nM following oral therapeutic doses. Thus, the analgesic doses tested in vitro in Table 2 cover the concentration range achievable in humans.

Table 3. Serum levels of analgesics in human blood following oral administration of therapeutic doses

Example 3: Effects of Analgesics, Botulinum Neurotoxin, and Antimuscarinic Agents on Mouse Bladder Smooth Muscle Influence of cellular responses to inflammatory and non-inflammatory stimuli

experimental design

This study aims to illustrate how the optimal dose of analgesic identified in Example 2 affects bladder smooth muscle cells in cell culture or tissue culture, and to discuss whether different classes of analgesics can synergistically inhibit COX2 more effectively And PGE2 reaction.

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) Different doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.

(9) Different doses 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.

Then the release of PGH ₂ , PGE, PGE ₂ , prostacyclin, thromboxane, IL-1β, IL-6, TNF-α, COX2 activity, production of cAMP and cGMP, IL-1β, IL-6, Production of TNF-α and COX2 mRNA, and 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 the cells were isolated by enzymatic digestion followed by purification with a Percoll gradient. Briefly, bladders from 10 mice were minced with scissors into 10 ml of digestion buffer (RPMI 1640, 2% fetal bovine serum, 0.5 mg/ml collagenase, 30 μg/ml DNase). Refined slurry. Bladder slurries were enzymatically digested at 37°C for 30 min. The undigested debris was further dispersed through a cell-trainer. The cell suspension was pelleted and added to a stepwise 20%, 40% and 75% Percoll gradient to purify monocytes. 50-60 bladders were used per experiment.

After washing with RPMI 1640, the bladder cells were resuspended in RPMI 1640 supplemented with 10% fetal bovine serum, 15 mM HEPES, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin, and diluted with ^3x104 Cells/well (100 μl) were seeded into black 96-well cell culture microplates with clear bottoms. Cells were cultured at 37 °C in a 5% _CO2 atmosphere.

In vitro treatment of cells with analgesics

Bladder cells were treated with analgesic solution (50 μl/well) alone or with carbachol (10 molar, 50 μl/well) (as an example of a non-inflammatory stimulus), or with lipopolysaccharide (LPS) of Salmonella typhimurium ) (1 μg/ml, 50 μl/well) (as an example of non-inflammatory stimuli) co-treatment. When no other effectors were added to the cells, 50 μl of RPMI1640 without fetal bovine serum was added to the wells to adjust the final volume to 200 μl.

After 24 hours of culture, 150 μl of culture supernatant was collected, spun at 4°C, 8,000 rpm for 2 minutes to remove cells and debris, and stored at -70°C for analysis of prostaglandin E2 (PGE ₂ ) by ELISA reaction. Cells were fixed, permeabilized and blocked for detection of cyclooxygenase-2 (COX-2) using a fluorogenic substrate. In selected experiments, cells were stimulated for 12 hours in vitro for analysis of COX2 responses.

COX2 Response Analysis

COX2 responses were analyzed by cell-based ELISA using the human/mouse total COX2 immunoassay (R&D Systems) according to the manufacturer's instructions. Briefly, after cell fixation and permeabilization, mouse anti-total COX2 and rabbit anti-total GAPDH were added to the wells of a black 96-well cell culture microplate with a clear bottom. After incubation and washing, HRP-conjugated anti-mouse IgG and AP-conjugated anti-rabbit IgG were added to the wells. After another incubation and wash, HRP-fluorosubstrate and AP-fluorosubstrate were added. Finally, use Fluorescence was read at 600 nm (COX2 fluorescence) and 450 nm (GAPDH fluorescence) on a V Multilabel Microplate Reader (PerkinElmer). Results are expressed as relative levels of total COX2, determined by relative fluorescence units (RFUs), and normalized to the housekeeping protein GAPDH.

PGE2 Reaction Analysis

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

other experiments

Release of PGH2, PGE, Prostacydin, Thromboxane, IL-1β, IL-6 and TNF-α, production of cAMP and cGMP, production of IL-1β, IL-6, TNF-α and COX2 mRNA, And the surface expression of CD80, CD86 and MHC class II molecules was determined using methods as described in Example 2.

Analgesics inhibit the COX2 response of mouse bladder cells to inflammatory stimuli

Several analgesics (acetaminophen, aspirin, ibuprofen, and naproxen) were tested on mouse bladder cells at concentrations of 5 μM or 50 μM to determine whether the analgesics induced COX2 responses. Analysis of 24-hour cultures showed that none of the analgesics tested induced a COX2 response in mouse bladder cells in vitro.

The effect of these analgesics on the COX2 response of mouse bladder cells to carbachol or LPS stimulation in vitro was also tested. As shown in Table 1, the doses of carbachol tested had no significant effect on COX-2 levels in mouse bladder cells. On the other hand, LPS 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 was seen when these drugs were tested at 5 μM or 50 μM (Table 4).

Table 4. COX2 expression in mouse bladder cells after stimulation and analgesic treatment in vitro

Analgesics inhibit the PGE2 response of mouse bladder cells to inflammatory stimuli

The secretion of PGE2 in the culture supernatant of mouse bladder cells was measured to determine the biological significance of changes in COX2 levels in mouse bladder cells due to analgesics. As shown in Table 5, PGE2 was not detected in the culture supernatant of unstimulated bladder cells or bladder cells cultured in the presence of carbachol. Consistent with the COX2 response described above, stimulation of mouse bladder cells with LPS induced high levels of PGE2 secretion. Addition of the analgesics acetaminophen, aspirin, ibuprofen and naproxen inhibited the effect of LPS on PGE2 secretion and no difference was observed between the responses of cells treated with analgesics at doses of 5 or 50 μM .

Table 5. PGE2 secretion of mouse bladder cells after stimulation and analgesic treatment in vitro

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

Example 4: Effects of Analgesics, Botulinum Neurotoxin, and Antimuscarinic Agents on Mouse Bladder Smooth Muscle The effect of cell shrinkage

experimental design

Expose cultured mouse or rat bladder smooth muscle cells and mouse or rat bladder smooth muscle tissue to inflammatory and non-inflammatory stimuli in the presence of varying concentrations of analgesic and/or antimuscarinic agents thing. Stimulation-induced muscle contraction is measured to assess the inhibitory effect of analgesic and/or antimuscarinic agents.

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) Different doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.

(9) Different doses 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 contraction was recorded using a Grass multi-channel recorder (Quincy Mass, USA).

Embodiment 5: Oral analgesic and antimuscarinic agent to the COX2 of mouse bladder smooth muscle cell and Effect of PGE2 Response.

experimental design

Oral doses of aspirin, naproxen sodium, ibuprofen, indomethacin, nabumetone, tylenol, celecoxib, oxime Coxybutynin, solifenacin, darfinacine, atropine, and combinations thereof. Control groups included untreated normal mice and untreated OAB mice with overactive bladder syndrome. Thirty minutes after the last dose, bladders were harvested and stimulated ex vivo with carbachol or acetylcholine. In selected experiments, bladders were treated with botulinum neurotoxin A prior to stimulation with carbachol. Animals were kept in metabolic cages and voiding frequency (and volume) was assessed. Bladder output was determined by monitoring water intake and cage litter weight. Serum levels of PGH ₂ , PGE, PGE ₂ , prostacyclin, thromboxane, IL-1β, IL-6, TNF-α, cAMP and cGMP were measured by ELISA. The expression of CD80, CD86, and MHC class II in whole blood cells was detected by flow cytometry.

At the end of the experiment, animals were euthanized and bladder contractions were recorded ex vivo with a Grass multichannel recorder. Bladder sections were fixed in formalin and analyzed for COX2 response by immunohistochemistry.

Example 6: Effects of analgesics, botulinum neurotoxins and antimuscarinic agents on human bladder smooth muscle cells Influence of cellular responses to inflammatory and non-inflammatory stimuli

experimental design

This study was designed to characterize how the optimal doses of analgesics identified in Examples 1 to 5 affect human bladder smooth muscle cells in cell culture or tissue culture, and to discuss whether different classes of analgesics can synergize to be more effective Inhibit COX2 and PGE2 responses.

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

Short-term (1-2 hours) or long-term (24-48 hours) stimulation of human bladder smooth muscle cells by:

(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) Different doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.

(9) Different doses 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.

Then the release of PGH ₂ , PGE, PGE ₂ , prostacyclin, thromboxane, IL-1β, IL-6, TNF-α, COX2 activity, production of cAMP and cGMP, IL-1β, IL-6, Production of TNF-α and COX2 mRNA, and surface expression of CD80, CD86, and MHC class II molecules.

Example 7: Effects of analgesics, botulinum neurotoxins and antimuscarinic agents on human bladder smooth muscle cells The effect of cell contraction

experimental design

Cultured human bladder smooth muscle cells are exposed to inflammatory and non-inflammatory stimuli in the presence of varying concentrations of analgesic and/or antimuscarinic agents. Stimulation-induced muscle contraction is measured to assess the inhibitory effect of analgesic and/or antimuscarinic agents.

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

Short-term (1-2 hours) or long-term (24-48 hours) stimulation of human bladder smooth muscle cells by:

(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) Different doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.

(9) Different doses 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 contraction was recorded using a Grass multi-channel recorder (Quincy Mass, USA).

Example 8: Response of analgesics to normal human bladder smooth muscle cells to inflammatory and non-inflammatory signals should affect

experimental design:

Culture of Normal Human Bladder Smooth Muscle Cells

Normal human bladder smooth muscle cells were isolated from macroscopically normal sections of human bladder by enzymatic digestion. Cells were incubated in vitro at 37 °C in an atmosphere of 5% _CO in RPMI 1640 supplemented with 10% fetal bovine serum, 15 mM HEPES, 2 mM L-glutamine, 100 U/ml penicillin and 100 mg/ml streptomycin Cultures were expanded and passaged weekly by trypsinization to detach cells followed by reseeding in new flasks. During the first week of culture, the medium was supplemented with 0.5 ng/ml epidermal growth factor, 2 ng/ml fibroblast growth factor and 5 μg/ml insulin.

Normal Human Bladder Smooth Muscle Cells Treated with Analgesics in Vitro

Analgesic solution (50 μl/well) alone or with carbachol ⁽ 10 M , 50 μl/well) (as an example of a non-inflammatory stimulus) or with lipopolysaccharide (LPS) of Salmonella typhimurium (1 μg/ml, 50 μl/well) (as an example of a non-inflammatory stimulus) . When no other effectors were added to the cells, 50 μl of RPMI 1640 without fetal bovine serum was added to the wells to adjust the final volume to 200 μl.

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

COX2, PGE2 and cytokine response analysis

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

result

Analgesics Inhibit COX2 Responses of Normal Human Bladder Smooth Muscle Cells to Inflammatory and Non-Inflammatory Stimuli—Analysis of Cells and Culture Supernatants After 24 Hours of Culture Shows No Analgesics Tested Alone Induces Normal Human Bladder Stimuli COX2 responses in 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. On the other hand, LPS treatment resulted in a higher level of COX2 response 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 analgesics on LPS-induced responses was seen when these drugs were tested at 5 μM or 50 μM.

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

^#The data is expressed as the mean of two repetitions

Analgesics inhibit PGE2 responses in normal human bladder smooth muscle cells to inflammatory and non-inflammatory stimuli - Consistent with induction of COX2 responses described above, both carbachol and LPS induce PGE2 responses in normal human bladder smooth muscle cells produce. Acetaminophen, aspirin, ibuprofen and naproxen were also found to inhibit LPS-induced PGE2 responses at 5 μM or 50 μM (Table 7).

Table 7. PGE2 secretion of normal human bladder smooth muscle cells after stimulation with inflammatory and non-inflammatory stimuli and analgesic treatment in vitro

^#The data is expressed as the mean of two repetitions

Analgesics Suppress Cytokine Responses in Normal Human Bladder Cells to Inflammatory Stimuli—Analysis of cells and culture supernatants after 24 hours in culture showed that none of the analgesics tested alone induced induction in normal human bladder smooth muscle cells. Secretion of IL-6 or TNFα. As shown in Tables 8 and 9, the doses of carbachol tested induced low but significant TNF[alpha] and IL-6 responses in normal human bladder smooth muscle cells. On the other hand, LPS treatment resulted in a massive induction of these pro-inflammatory cytokines. Acetaminophen, aspirin, ibuprofen, and naproxen all inhibited the effects of carbachol and LPS on TNFα and IL-6 responses. The inhibitory effect of analgesics on LPS-induced responses was seen when these drugs were tested at 5 μM or 50 μM.

Table 8. TNFα secretion of normal human bladder smooth muscle cells after stimulation with inflammatory and non-inflammatory stimuli and analgesic treatment in vitro

^#The data is expressed as the mean of two repetitions

Table 9. IL-6 secretion of normal human bladder smooth muscle cells after stimulation with inflammatory and non-inflammatory stimuli in vitro and treatment with analgesics

^#The data is expressed as the mean of two repetitions

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 previously described phenomenon with murine bladder cells.

The above experiment was repeated with the analgesic and/or antimuscarinic agent in delayed release or extended release formulations or delayed and extended release formulations.

The description above is used to teach those skilled in the art how to practice the present invention, and it is not intended to describe in detail those obvious modifications and changes that would be obvious to those skilled in the art after reading the description. However, all obvious modifications and changes are intended to be included within the scope of the present invention as defined by the following claims. Unless the context clearly indicates to the contrary, the claims are intended to cover the claimed components and steps in any order effective to achieve their desired purpose.

Claims (36)

1. A method for alleviating frequent urination, comprising: administering to a subject in need thereof a pharmaceutical composition comprising: one or more pain relievers; and One or more additional active ingredients selected from alpha-blockers and 5-alpha-reductase inhibitors. 2. The method of claim 1, wherein the one or more analgesic agents and the one or more additional active ingredients are formulated for immediate release. 3. The method of claim 1, wherein the one or more analgesic agents and the 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 according to claim 4, wherein the one or more analgesics are administered in an amount of 50-400 mg per dose, wherein the one or more analgesics are selected from aspirin, cloth iprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein said pharmaceutical composition is formulated for extended release such that said one or more sedatives The pain agent 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 the 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 the one or more additional active ingredients comprise tamsulosin and finasteride. 9. The method according to claim 4, wherein the one or more analgesics are administered in an amount of 50-400 mg per dose, wherein the one or more analgesics are selected from aspirin, cloth iprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein the pharmaceutical composition is formulated for extended release characterized by a two-stage release profile, in In this release profile, 20-60% of the one or more analgesics are released within 2 hours of administration, while the remainder of the one or more analgesics are released within a period of 5-24 hours. continuous release. 10. The method of claim 9, wherein the 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 the 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 according to claim 13, wherein the one or more analgesics are administered in an amount of 50-400 mg per dose, wherein the one or more analgesics are selected from aspirin, cloth iprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein said one or more analgesics are formulated for extended release such that said one The one or more analgesic agents are released continuously over a period of 5-24 hours. 15. The method of claim 14, wherein the 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 the one or more additional active ingredients comprise tamsulosin and finasteride. 18. The method of claim 13, wherein the one or more analgesics are administered in an amount of 50-400 mg per dose, wherein the one or more analgesics are selected from aspirin, cloth Iprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein said one or more analgesics are formulated to be characterized by a two-stage release profile In this release profile, 20-60% of the one or more analgesics are released within 2 hours of administration, while the remainder of the one or more analgesics are released within 5-24 are released continuously over a period of hours. 19. The method of claim 18, wherein the 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 the 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 the pharmaceutical composition further comprises an antispasmodic agent. 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 before bedtime. 26. The method of claim 1, wherein the subject is a mammal. 27. A pharmaceutical composition for alleviating frequent urination, comprising: one or more pain relievers; One or more alpha-blockers; and pharmaceutically acceptable carrier, wherein the one or more analgesics are formulated for extended release, and wherein the one or more alpha-blockers are formulated for immediate release. 28. The pharmaceutical composition according to claim 27, which comprises one or more analgesics in an amount of 50-400 mg per dose, wherein the one or more analgesics are selected from aspirin, ibuprofen, Fen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein said one or more analgesics are formulated for extended release such that said one The analgesic(s) are released continuously over a period of 5-24 hours. 29. The pharmaceutical composition of claim 28, wherein the one or more analgesics comprise acetaminophen, and wherein the one or more alpha-blockers comprise tamsulosin . 30. The pharmaceutical composition according to claim 27, comprising one or more analgesics in an amount of 50-400 mg per dose, wherein the one or more analgesics are selected from aspirin, ibuprofen, Fen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein the pharmaceutical composition is formulated for extended release characterized by a two-stage release profile, in which A release profile in which 20-60% of the one or more analgesics are released within 2 hours of administration and the remainder of the one or more analgesics is continuously released over a period of 5-24 hours freed. 31. The pharmaceutical composition of claim 30, wherein the one or more analgesics comprise acetaminophen, and wherein the one or more alpha-blockers comprise tamsulosin . 32. A pharmaceutical composition for alleviating frequent urination, comprising: one or more pain relievers; one or more 5α-reductase inhibitors; and pharmaceutically acceptable carrier, wherein the one or more analgesic agents are formulated for extended release, and wherein the one or more 5α-reductase inhibitors are formulated for immediate release. 33. The pharmaceutical composition according to claim 32, comprising one or more analgesics in an amount of 50-400 mg per dose, wherein the one or more analgesics are selected from aspirin, ibuprofen, Fen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and wherein said one or more analgesics are formulated for extended release such that said one The analgesic(s) are released continuously over a period of 5-24 hours. 34. The pharmaceutical composition of claim 33, wherein the one or more analgesics comprise acetaminophen, and wherein the one or more 5α-reductase inhibitors comprise phena androstamine. 35. The pharmaceutical composition according to claim 32, comprising one or more analgesics in an amount of 50-400 mg per dose, wherein the one or more analgesics are selected from aspirin, ibuprofen, Fen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, and the pharmaceutical composition are formulated for extended release characterized by a two-stage release profile in which wherein 20-60% of the one or more analgesics are released within 2 hours of administration, while the remainder of the one or more analgesics are released continuously over a period of 5-24 hours. 36. The pharmaceutical composition of claim 35, wherein the one or more analgesics comprise acetaminophen, and wherein the one or more 5α-reductase inhibitors comprise phena androstamine.