JP2018138602A - Extended release formulation for reducing urination frequency and method of use thereof - Google Patents

Abstract

A method for reducing the frequency of urination is provided. The use of a pharmaceutical composition in the manufacture of a pharmaceutical formulation for reducing the frequency of urination in a subject with nocturia, comprising: (1) acetaminophen, 2) comprising three active ingredients consisting of ibuprofen and (3) α-blocker, each of acetaminophen and ibuprofen formulated for extended release, delayed release or delayed extended release, The above uses, which are formulated for release, and wherein only the above active ingredient is the active ingredient contained in the pharmaceutical composition. As the α-blocker, tamsulosin is preferred. [Selection diagram] Fig. 1

Description

  This application claims priority from US Patent Application No. 13 / 487,348, filed June 4, 2012, and US Patent Application No. 13 / 424,000, filed March 19, 2012. To do.

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

  The detrusor is a layer of the bladder wall that consists of smooth muscle fibers arranged in a spiral, longitudinal and annular bundle. As the bladder extends, it sends a signal to the parasympathetic nervous system to contract the detrusor muscle. This prompts the bladder to drain through the urethra.

  In order for urine to leave the bladder, the autonomously controlled internal sphincter and the optionally controlled external sphincter must open. These muscle problems can lead to incontinence. If the amount of urine reaches 100% of the absolute volume of the bladder, the voluntary sphincter becomes involuntary and urine will be excreted immediately.

  Although the human adult bladder usually holds about 300-350 mL of urine (working volume), a full adult bladder can hold up to about 1000 mL (absolute volume), depending on the individual. As the urine accumulates, the bulges produced by the wrinkles of the bladder wall flatten and become thinner as the bladder wall stretches, so the bladder accumulates more urine without a significant increase in internal pressure can do.

  In most people, urination usually begins when the volume of urine in the bladder reaches around 200 mL. At this stage, it is easy for the subject to resist the urination impulse, if desired. As the bladder continues to fill, urinary will become stronger and more difficult to ignore. Eventually, the bladder will be filled to the point where the urination impulse becomes overwhelming, and the subject will no longer be able to ignore it. In some individuals, this urgency begins when the bladder is less than 100% full of capacity. Such increased urinary potential can interfere with normal activities, including the ability to sleep for a sufficient continuous rest period. In some instances, this increased urinary urgency may be associated with a medical condition such as male benign prostatic hypertrophy or prostate cancer, or female pregnancy. However, increased urination occurs in both men and women in individuals who do not suffer from other medical conditions.

  Accordingly, there is a need for compositions and methods for the treatment of male and female subjects suffering from urinary urgency when the urine fullness of the bladder is less than 100% of its working volume. The compositions and methods are needed for the inhibition of muscle contraction aimed at allowing urinary intent to begin when the volume of urine in the bladder exceeds about 100% of its working capacity in the subject. Is done.

  One aspect of the present application relates to a method for reducing the frequency of urination in a subject. The method comprises, for a subject in need thereof, an effective amount of one or more analgesics and one or more additional selected from the group consisting of an α-blocker and a 5α-reductase inhibitor. Administration of an effective amount of the active ingredient. The method can be used for the treatment of nocturia or overactive bladder.

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

FIG. 3 shows that analgesics modulate costimulatory molecule expression by Raw 264 macrophage cells in the absence (FIG. 1A) or presence (FIG. 1B) of LPS. Cells were cultured for 24 hours in the presence of analgesics alone or with Salmonella typhimurium LPS (0.05 μg / mL). The result is the average relative percentage of CD40 + CD80 + cells.

  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 in order to provide a thorough understanding of the present invention. However, it will be apparent to those skilled in the art that these specific details are not required in order to practice the present invention. A specific application description is provided only as an exemplary embodiment. The present invention is not limited to the embodiments presented, but is intended to be understood in the broadest possible scope consistent with the principles and properties disclosed herein.

  The term “effective amount” as used herein means the amount necessary to achieve a selected result.

  As used herein, the term “analgesic” means a substance, compound or agent used to alleviate pain and includes anti-inflammatory compounds. Typical analgesics and / or anti-inflammatory substances, compounds or agents include, but are not limited to: non-steroidal anti-inflammatory drugs (NSAIDs), salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, Salsalate, olsalazine, sulfasalazine, paraaminophenol derivatives, acetanilide, acetaminophen, phenacetin, phenamates, mefenamic acid, meclofenamate, sodium meclofenamic acid, heteroaryl acetic acid derivative, tolmethine, ketorolac, diclofenac, propionic acid derivative, ibuprofen , Naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin; enolic acid, oxicam derivative, piroxicam, Roxicam, Tenoxicam, Ampiroxicam, Droxicam, Pivoxicam, Pyrazolone derivatives, Phenylbutazone, Oxyphenbutazone, Antipyrine, Aminopyrine, Dipyrone, Coxibs, Celecoxib, Rofecoxib, Nabumetone, Apazone, Indomethacin, Sulindac, Etodolac, Isobutylphenylpropionic acid , Lumiracoxib, etoricoxib, parecoxib, valdecoxib, thylakoxib, etodolac, dalbuferon, dexketoprofen, aceclofenac, lycoferon, bromfenac, loxoprofen, pranoprofen, piroxicam, nimesulide, sizoliline-7-formylamino-7-formylamino-7 -4H-1-benzopyran-4-one, meloxicam, Lunoxicam, d-indobufen, mofezolac, amtomethine, pranoprofen, tolfenamic acid, flurbiprofen, suprofen, oxaprozin, zaltoprofen, aluminoprofen, thiaprofenic acid, pharmacological salt thereof, hydrate, and solvate thereof .

  The terms “coxib” and “COX inhibitor” as used herein can inhibit the activity or expression of the COX2 enzyme or inhibit or severity of a severe inflammatory response, including pain and swelling. Means a composition of a compound capable of lowering

  The term “derivative” as used herein is a chemically modified compound, such as an ester or amide of an acid, a benzyl group for an alcohol or thiol, and a protecting group such as a tert-butoxycarbonyl group for an amine. Means a compound characterized in that it is considered routine by a chemist with ordinary skill.

  As used herein, the term “analog” includes a chemically modified form of a particular compound or class thereof and maintains the pharmacological and / or pharmacological activity characteristic of said compound or class. Means a compound.

  As used herein, the term “subject” or “patient” includes mammals. In one aspect, the mammal is a human. In other embodiments, the mammal is a chimpanzee and other non-human primates, such as apes and monkeys. In one embodiment, the mammal is a domestic animal such as a rabbit, dog, or cat. In other embodiments, the mammal is a livestock animal such as a cow, horse, sheep, goat or pig. In other embodiments, the mammal is a laboratory animal including rodents such as rats, mice, and guinea pigs.

  As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound, wherein the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic 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 usual non-toxic or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such normal non-toxic salts are derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; and acetic acid, propionic acid, succinic acid, glycolic acid, stearin Acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid Salts prepared from organic acids such as methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like.

  The phrase “pharmaceutically acceptable” as used herein is within the scope of normal medical judgment, without reasonable toxicity / irritation, allergic reactions, or other problems or complications. Used with respect to compounds, materials, compositions, and / or dosage forms suitable for use in contact with human and animal tissues commensurate with the risk ratio.

  The bladder has two important functions: accumulation of urine and excretion of contents. Urine accumulation occurs at low pressure, which means that the detrusor relaxes in the filling phase. Excretion of the bladder contents requires coordination of detrusor contraction and urethral sphincter relaxation. Accumulation impairment can result in lower urinary tract symptoms such as urgency, frequency, and urge incontinence that are components of overactive bladder syndrome. Overactive bladder syndrome can be caused by involuntary contraction of bladder smooth muscle (detrusor) during the accumulation phase and is a common and underreported problem whose prevalence has only recently been evaluated. ing.

  One aspect of the present application relates to a method for reducing the frequency of urination. The method includes administering to a subject in need thereof an effective amount of one or more analgesics and an effective amount of an α-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, one or more analgesics and alpha-blockers are both formulated for immediate release after administration. In other embodiments, one or more analgesics and alpha-blockers are both formulated for delayed release after administration. In other embodiments, one or more analgesics and alpha-blockers are both formulated for extended release after administration. In other embodiments, one or more analgesics and alpha-blockers are both formulated for delayed-extended release after administration. In other embodiments, one or more analgesics are formulated for delayed release, extended release, or delayed extended release, and alpha-blockers are formulated for immediate release. In still other embodiments, one or more analgesics 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 for the treatment of nocturia or overactive bladder. Another aspect of the present application relates to a pharmaceutical composition comprising an active ingredient comprising one or more analgesics, an alpha-blocker, and a pharmaceutically acceptable carrier.

  Alpha blockers, also called α-adrenergic antagonists or α-blockers, accept α-adrenergic receptors that are further classified into α1-adrenergic receptors and α2-adrenergic receptors. It is a pharmacological substance that acts as a body antagonist. Alpha blockers are classified as selective blockers that act selectively at α1-adrenoceptor or α2-adrenoceptor and non-selective alpha blockers that act on both types of α-adrenergic receptors. The

  Examples of selective α1-adrenergic blockers include, but are not limited to, alfuzosin, prazosin, doxazosin, tamsulosin, terazosin, carvedilol, labetalol, and silodosin. Examples of selective α2-adrenergic blockers include, but are not limited to, atipamezole, idazoxan and yohimbine. Examples of non-selective α-adrenergic blockers include: phenoxybenzamine, phentolamine, tolazoline, trazodone, typical and atypical antipsychotics.

  In some embodiments, the one or more analgesics are 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50 -300 mg, 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 200-600 mg, 200-400 mg, 400-2000 mg, 400-1 00 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg administered orally in individual or combined daily doses; and one or more alpha-blockers Is 0.01-100 mg, 0.01-30 mg, 0.01-10 mg, 0.01-3 mg, 0.01-1 mg, 0.01-0.3 mg, 0.01-0.1 mg, 0.01 ~ 0 0.03 mg, 0.03 to 100 mg, 0.03 to 30 mg, 0.03 to 10 mg, 0.03 to 3 mg, 0.03 to 1 mg, 0.03 to 0.3 mg, 0.03 to 0.1 mg, 0 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1-3 mg, 0.1-1 mg, 0.1-0.3 mg, 0.3-100 mg, 0.3-30 mg, 0 . Orally administered in individual or combined daily doses between 3-10 mg, 0.3-3 mg, 0.3-1 mg and 0.2-1 mg.

  In some embodiments, the α-blocker is a non-selective α-blocker. In other embodiments, the α-blocker is a selective α1-adrenergic blocker. In other embodiments, the α-blocker is a selective α2-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 the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen.

  In some embodiments, the pharmaceutical composition is 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg individually or in combination with one or more analgesics. 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100 -500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 200-600 mg, 200-400 g, 400-2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, In an amount between 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg; and one or more α- 0.01-100 mg, 0.01-30 mg, 0.01-10 mg, 0.01-3 mg, 0.01-1 mg, 0.01-0.3 mg, 0.01-0.1 mg, 0.01-0.03 mg, 0.03-100 mg, 0.03-30 mg, 0.03-10 mg, 0.03-3 mg, 0.03-1 mg, 0.03-0.3 mg, 0.03- 0.1 mg, 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1-3 mg, 0.1-1 mg, 0.1-0.3 mg, 0.3-100 mg,. Contains in amounts between 3-30 mg, 0.3-10 mg, 0.3-3 mg, 0.3-1 mg and 0.2-1 mg.

  In some embodiments, the α-blocker is a non-selective α-blocker. In other embodiments, the α-blocker is a selective α1-adrenergic blocker. In other embodiments, the α-blocker is a selective α2-adrenergic blocker. In other embodiments, the alpha blocker is tamsulosin.

  In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount between 100-200 mg, 200-400 mg, 400-600 mg, 600-800 mg, 800-1000 mg, or 1000-1200 mg, and tamsulosin of 0.1. In an amount between 1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg, 0.9-1.2 mg or 1.2-1.5 mg.

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

  In other embodiments, one or more analgesics are formulated for extended release and one or more alpha-blockers are formulated for immediate release. In some embodiments, the one or more analgesics are released continuously over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours, or at a constant rate. . In some embodiments, at least 90% of the one or more analgesics are continuously or at a constant rate for 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours. Released at.

  In some embodiments, the one or more analgesics are released within 2 hours of administration, and the remainder between 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours Over time or at a constant rate.

  In other embodiments, one or more analgesics and 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 one or more analgesics and one or more alpha-blockers. Is formulated for extended release such that is released continuously for 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours, or at a constant rate. In some embodiments, both the one or more analgesics and the one or more alpha-blockers are one or more analgesics and one or more alpha-blockers. 20-60% is released within 2 hours of administration, and the rest is released continuously or at a constant rate over a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours Formulated for extended release with a two-phase release profile.

  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 in an amount of 0.1-1 Acetaminophen and tamsulosin in combination with tamsulosin in an amount between 0.2 mg, 0.1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg or 0.9-1.2 mg Of acetaminophen and tamsulosin having a drug release profile wherein at least 90% of the drug is released continuously over 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours, or at a constant rate The composition is blended for the purpose of extended release of both.

  In other embodiments, the pharmaceutical composition is 500-1000 mg, 50-200 mg, 50-400 mg, 100-400 mg, 100-300 mg, 200-400 mg, 400-600 mg, 600-800 mg, 800-1000 mg, or 1000-1000. Acetaminophen in an amount between 1200 mg and 0.1-1.2 mg, 0.1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg or 0.9-1.2 mg Between 20 and 60% of acetaminophen and tamsulosin are released within 2 hours of administration, and the rest are 5-24 hours, 5-8 hours, 8-16 hours or 16-24 Composition for extended release with a biphasic release profile released continuously over time or at a constant rate Characterized in that it is formulated.

  “Extended release”, also known as sustained release (SR), sustained action (SA), timed release (TR), controlled release (CR), modified release (MR) or continuous release (CR), slowly dissolves And a mechanism used in pharmaceutical tablets or capsules that release the active ingredient over time. The advantage of extended release tablets or capsules is that they can often be taken less often than immediate release formulations of the same drug, and extend the duration of drug action by keeping the level of drug in the bloodstream more constant And reducing the peak amount of the drug in the bloodstream. For example, an extended release analgesic may allow a person to sleep overnight without getting up in the bathroom.

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

  The extended release formulation is about 24 hours, about 20 hours, about 16 hours, about 12 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours after administration or after a delay time associated with delayed release of the drug. To maintain a constant drug level for a specified, extended period of time, such as up to about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or up to about 1 hour, etc. It can be designed to release the active substance at a predetermined rate.

  In certain preferred embodiments, the active substance is released over a time interval of about 2 to about 10 hours. Alternatively, the active substance is about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9, about 10 hours, about 12 hours, about 16 hours, about 20 hours or It can be released over about 24 hours. In yet other embodiments, the active substance is released over a period of about 3 to about 8 hours after administration.

  In some embodiments, the extended release formulation is surfaced by a drug, eg, in the form of a drug-containing coating or film-forming composition, such as using fluid bed technology or other methodologies known to those skilled in the art. Active composed of one or more inert particles each in the form of coated beads, pellets, pills, granular particles, microcapsules, microspheres, microgranules, nanocapsules, or nanospheres Including the nucleus. The inert particles can be of various sizes as long as they are large enough to remain low soluble. Alternatively, the active core may be prepared by granulation and grinding and / or extrusion and spheronization of a polymer composition containing a drug substrate.

  The active ingredient may be introduced into the inert carrier by techniques known to those skilled in the art such as drug layer formation, powder coating, extrusion / spheronization, roller compaction or granulation. The amount of drug in the nucleus will depend on the dose required and typically varies from about 5 to 90% by weight. In general, the polymer coating on the active core will be about 1 to 50% of the weight of the coated particles, depending on the delay time required and / or the polymer and coating solvent selected. One skilled in the art will be able to select the appropriate amount of agent to coat or incorporate into the nucleus to achieve the desired dose. In one embodiment, the inert nucleus is a sphere of sugar that alters its microenvironment to promote drug release, or crystals of buffering agents such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, or It can be an encapsulated buffer crystal.

  Another aspect of the present application relates to a method for reducing the frequency of urination. The method includes 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 5α-reductase inhibitors include, but are not limited to finasteride, bexosterolide, epristeride, izonsteride, lapisteride and turosteride. In one embodiment, 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, one or more analgesics and a 5α-reductase inhibitor are both formulated for immediate release after 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, one or more analgesics and a 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, one or more analgesics are formulated for delayed release, extended release, or delayed extended release, and 5α-reductase inhibitors are formulated for immediate release. In yet other embodiments, the one or more analgesics 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 for the treatment of nocturia or overactive bladder. Another aspect of the present application relates to a pharmaceutical composition comprising an active ingredient comprising one or more analgesics, a 5α-reductase inhibitor, and a pharmaceutically acceptable carrier.

  In some embodiments, the one or more analgesics are 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50 -300 mg, 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 200-600 mg, 200-400 mg, 400-2000 mg, 400-1 00 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg administered orally in individual or combined daily doses; and one or more 5α-reductase inhibition The agent is 0.1-250 mg, 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1-3 mg, 0.1-1 mg, 0.3-250 mg, 0.3-10 0 mg, 0.3-30 mg, 0.3-10 mg, 0.3-3 mg, 0.3-1 mg, 1-100 mg, 1-30 mg, 1-10 mg, 1-3 mg, 3-7 mg and 4-6 mg Orally administered in separate or combined daily doses.

  In one embodiment, 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 the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen.

  In some embodiments, the pharmaceutical composition is 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg individually or in combination with one or more analgesics. 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100 -500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 200-600 mg, 200-400 g, 400-2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, In an amount between 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg; and one or more 5α- 0.1 to 250 mg, 0.1 to 100 mg, 0.1 to 30 mg, 0.1 to 10 mg, 0.1 to 3 mg, 0.1 to 1 mg, 0.3 to 250 mg of a reductase inhibitor, 0.3-100 mg, 0.3-30 mg, 0.3-10 mg, 0.3-3 mg, 0.3-1 mg, 1-100 mg, 1-30 mg, 1-10 mg, 1-3 mg, 3-7 mg and Contains in amounts between 4-6 mg.

  In some embodiments, the α-blocker is a non-selective α-blocker. In other embodiments, the α-blocker is a selective α1-adrenergic blocker. In other embodiments, the α-blocker is a selective α2-adrenergic blocker. In other embodiments, the alpha blocker is tamsulosin.

  In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount between 100-200 mg, 200-400 mg, 400-600 mg, 600-800 mg, 800-1000 mg, or 1000-1200 mg, and finasteride of 0.1. In an amount between 1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg, 0.9-1.2 mg or 1.2-1.5 mg.

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

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

  In some embodiments, the one or more analgesics are released within 2 hours of administration, and the remainder between 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours Over time or at a constant rate.

  In other embodiments, one or more analgesics and one or more 5α-reductase inhibitors are both formulated for extended release. In some embodiments, both the one or more analgesics and the one or more 5α-reductase inhibitors are one or more analgesics and one or more 5α-reductases. Formulated for extended release such that the inhibitor is released continuously over a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours, or at a constant rate. In some other embodiments, both the one or more analgesics and the one or more 5α-reductase inhibitors are one or more analgesics and one or more 5α. -20-60% of the reductase inhibitor is released within 2 hours of administration and the remainder is continuously or constant over a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours Formulated for extended release with a two-phase release profile released at a rate.

  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 in an amount of 1-20 mg, 1 -3 mg, 3-7 mg, 7-10 mg, 10-15 mg or 15-20 mg in combination with finasteride in an amount of at least 90% of acetaminophen and finasteride for 5-24 hours, 5-8 hours, 8 Characterized in that the composition is formulated for the extended release of both acetaminophen and finasteride having a drug release profile that is released continuously or at a constant rate for between -16 hours or 16-24 hours And

  In other embodiments, the pharmaceutical composition comprises acetaminophen 50-1000 mg, 50-100 mg, 50-200 mg, 50-300 mg, 50-400 mg, 50-600 mg, 50-800 mg, 100-200 mg, 100- 300 mg, 100-400 mg, 100-600 mg, 100-800 mg, 100-1000 mg, 200-400 mg, 200-600 mg, 200-800 mg, 200-1000 mg, 400-600 mg, 400-800 mg, 400-1000 mg, 600-800 mg, In amounts between 600-1000 mg, 800-1000 mg, or 1000-1200 mg, and finasteride 1-20 mg, 1-3 mg, 1-7 mg, 1-10 mg, 1-15 mg, 3-7 mg, 3-10 m 3-15 mg, 3-20 mg, 7-10 mg, 7-15 mg, 7-20 mg, 10-15 mg, 10-20 mg or 15-20 mg, wherein 20-60% of acetaminophen and finasteride A biphasic release profile that is released within 2 hours of administration and the remainder is released continuously or at a constant rate for 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours. The composition is formulated for the purpose of extended release.

  “Extended release”, also known as sustained release (SR), sustained action (SA), timed release (TR), controlled release (CR), modified release (MR) or continuous release (CR), slowly dissolves And a mechanism used in pharmaceutical tablets or capsules that release the active ingredient over time. The advantage of extended release tablets or capsules is that they can often be taken less often than immediate release formulations of the same drug, and extend the duration of drug action by keeping the level of drug in the bloodstream more constant And reducing the peak amount of the drug in the bloodstream. For example, an extended release analgesic may allow a person to sleep overnight without getting up in the bathroom.

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

  The extended release formulation is about 24 hours, about 20 hours, about 16 hours, about 12 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours after administration or after a delay time associated with delayed release of the drug. To maintain a constant drug level for a specified, extended period of time, such as up to about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or up to about 1 hour, etc. It can be designed to release the active substance at a predetermined rate.

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

  In some embodiments, the extended release formulation is surfaced by a drug, eg, in the form of a drug-containing coating or film-forming composition, such as using fluid bed technology or other methodologies known to those skilled in the art. Active composed of one or more inert particles each in the form of coated beads, pellets, pills, granular particles, microcapsules, microspheres, microgranules, nanocapsules, or nanospheres Including the nucleus. The inert particles can be of various sizes as long as they are large enough to remain low soluble. Alternatively, the active core may be prepared by granulation and grinding and / or extrusion and spheronization of a polymer composition containing a drug substrate.

  The active ingredient may be introduced into the inert carrier by techniques known to those skilled in the art such as drug layer formation, powder coating, extrusion / spheronization, roller compaction or granulation. The amount of drug in the nucleus will depend on the dose required and typically varies from about 5 to 90% by weight. Overall, the polymer coating on the active nuclei will be about 1 to 50% of the weight of the coated particles, depending on the delay time required and / or the polymer and coating solvent selected. One skilled in the art will be able to select the appropriate amount of agent to coat or incorporate into the nucleus to achieve the desired dose. In one embodiment, the inert nucleus is a sphere of sugar that alters its microenvironment to promote drug release, or crystals of buffering agents such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, or It can be an encapsulated buffer crystal.

  Extended release formulations may utilize a variety of extended release coatings or mechanisms that facilitate timed release of the active agent over time. In some embodiments, the extended release agent comprises polymer controlled release by dissolution controlled release. In a specific embodiment, the active substance is incorporated into a matrix comprising drug particles or granules coated with insoluble polymers and polymeric materials of different thicknesses. Polymer materials include carnauba wax, beeswax, whale wax, candelilla wax, shellac wax, cocoa butter, cetostearyl alcohol, partially hardened vegetable oil, ceresin, paraffin wax, ceresin, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid. Can be included with a surfactant such as polyoxyethylene sorbitan monooleate. Upon contact with an aqueous medium such as a biological fluid, the polymer coating is emulsified or eroded after a predetermined delay time depending on the thickness of the polymer coating. The lag time is independent of gastrointestinal motility, pH or gastric residence.

  In other embodiments, the extended release agent comprises a polymer matrix acting diffusion controlled release. The matrix can include 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 that optionally contains one or more dissolution enhancing additives and / or release enhancing agents. Upon dissolution of the water-soluble polymer, the active substance dissolves (if soluble) and gradually diffuses through the hydrated portion of the matrix. The gel layer grows over time as more water penetrates into the matrix nuclei, increasing the thickness of the gel layer and providing a diffusion barrier to drug release. As the outer layer is fully hydrated, the polymer chains are completely loosened and the integrity of the gel layer can no longer be maintained, leading to the detachment and erosion of the outer hydrated polymer on the matrix surface. Water continues to penetrate through the gel layer to the nucleus until the gel layer is completely eroded. While soluble drugs are released by this combination of diffusion and erosion mechanisms, erosion is a major mechanism for insoluble drugs regardless of dose.

  Similarly, water-swellable polymers typically hydrate and swell in biological fluids, maintain their shape during drug release and the role of the carrier, dissolution enhancer and / or release enhancer for the drug To form a uniform matrix structure. The initial matrix polymer hydrated phase results in a sustained release of the drug (delayed phase). Once the water-swellable polymer is fully hydrated and swollen, the water in the matrix can similarly dissolve the drug substance and prepare for its outward diffusion through the matrix coating.

  Furthermore, since the drug is released at a faster rate, the porosity of the matrix can be increased by reaching the exterior of the pH dependent release enhancer. The drug release rate is then constant and is a function of drug diffusion through the hydrated polymer gel. The rate of release from the matrix is: polymer type and level; drug solubility and dose; polymer: drug ratio; filler type and level; polymer to filler ratio; drug and polymer particle size; and matrix porosity. And depends on a variety of factors including shape.

  Typical hydratable and / or water swellable matrix-forming polymers are hydroxyalkyl such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), carboxymethylcellulose (CMC). Cellulose-based polymers including powdered cellulose such as cellulose and carboxyalkyl cellulose, microcrystalline cellulose, cellulose acetate, ethyl cellulose, salts thereof and combinations thereof; alginate, xanthan, tragacanth, pectin, gum arabic, karaya gum, alginate, agar, Guar, hydroxypropyl guar, veegum, carrageenan, locust bean gum, gellan gum, and their derivatives Gums including heteropolysaccharide gums and homopolysaccharide gums; polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, and methyl methacrylate, and carbomers (eg, Noveon, Cincinnati, Ohio), available in various molecular weight grades Acrylic resins containing crosslinked polyacrylic acid derivatives such as CARBOPOL® 71G NF, including possible CARBOPOL® 71G NF; carrageenan; polyvinyl acetate (eg, KOLLIDON® SR); polyvinylpyrrolidone and crospovidone Derivatives thereof; polyethylene oxide; and polyvinyl alcohol, but is not limited thereto. Preferred hydrophilic and water swellable polymers include cellulosic polymers, particularly HPMC.

  The extended release formulation may further comprise at least one binder that can crosslink the hydrophilic compound in an aqueous medium containing a biological fluid to form a hydrophilic polymer matrix (ie, a gel matrix).

  Typical binders include homopolysaccharides such as galactomannan gum, guar gum, hydroxypropyl guar gum, hydroxypropyl cellulose (HPC; eg, Klucel EXF) and locust bean gum. In other embodiments, the binder is an alginate derivative, HPC or microcrystalline cellulose (MCC). Other binders include but are not limited to starch, microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.

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

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

  In some embodiments, the hydrophilic polymer matrix provides a stronger gel layer and / or the amount of voids in the matrix to slow diffusion and erosion rates and concomitant active substance release. It may further comprise an ionic polymer that reduces the size, a nonionic polymer, or a water-insoluble hydrophobic polymer. This can additionally suppress the initial burst effect and result in a more stable “zero order release” of the active substance.

  Typical ionic polymers for slowing the dissolution rate include both anionic and cationic polymers. Typical anionic polymers are, for example, sodium carboxymethylcellulose (Na CMC), sodium alginate, acrylic acid polymers or carbomers (eg CARBOPOL® 934, 940, 974P NF); polyvinyl acetate phthalate (PVAP) , Methacrylic acid copolymers (eg EUDRAGIT® L100, L 30D 55, A, and FS 30D), enteric polymers such as hypromellose acetate succinate (AQUAT HPMCAS); and xanthan gum and the like. Typical cationic polymers include, for example, dimethylaminoethyl methacrylate copolymer (eg, EUDRAGIT® E100). Incorporation of anionic polymers, specifically enteric polymers, is useful for developing a pH independent release profile for weakly basic drugs compared to hydrophilic polymers alone.

  Typical nonionic polymers for slowing the dissolution rate include, for example, hydroxypropylcellulose (HPC) and polyethylene oxide (PEO) (eg, POLYOX®).

  Typical hydrophobic polymers are ethyl cellulose (eg, ETHOCEL®, SURELEASE®), cellulose acetate, methacrylic acid copolymer (eg, EUDRAGIT® NE30D), ammonio-methacrylic acid copolymer (eg: EUDRAGIT® RL100 or PO RS100), fatty acids such as polyvinyl acetate, glyceryl monostearate, acetyltributyl citrate, and combinations and derivatives thereof.

  The swellable polymer can be incorporated into the formulation in a proportion of 1% to 50% by weight, preferably 5% to 40% by weight, most preferably 5% to 20% by weight. The swellable polymer and binder can be incorporated into the formulation before or after granulation. The polymer can also be dispersed in an organic solvent or hydroalcohol and sprayed during granulation.

  Typical release enhancers remain unchanged at pH values below about 4.0 and dissolve at pH values above 4.0, preferably above 5.0, and most preferably above 6.0 PH-dependent enteric polymers that are considered useful as release enhancers for the present invention. Typical pH-dependent polymers are methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (eg EUDRAGIT® L100 (type A), EUDRAGIT® S100 (type B), Rohm GmbH, Germany; Methacrylic acid-ethyl acrylate copolymer (eg EUDRAGIT® L100-55 (C type) and EUDRAGIT® L30D-55 copolymer dispersant, Rohm GmbH, Germany); methacrylic acid-methyl methacrylate and methacrylic acid Copolymer of methyl (EUDRAGIT® FS); terpolymer of methacrylic acid, methacrylic acid ester and ethyl acrylate; cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP) (Example: HP-55, HP-50, HP-55S, Shin-Etsu Chemical, Japan); Polyvinyl acetate phthalate (PVAP) (Example: COATERIC (registered trademark), OPADRY (registered trademark) enteric white OY-P-7171); polyvinyl butyrate acetate; cellulose acetate succinate (CAS); hydroxypropylmethylcellulose succinate acetate (HPMCAS), eg AQOAT® LF and AQOAT® MF (Shin-Etsu Chemical), Japan) HPMCAS LF grade, MF grade, HF grade; Shin-Etsu Chemical, Japan); shellac (eg, MARCOAT® 125 and MARCOAT® 125N); vinyl acetate-maleic anhydride copolymer; styrene- Maleic acid monoester co Carboxymethyl ethyl cellulose (CMEC, Freund Sangyo, Japan); cellulose acetate phthalate (CAP) (eg; AQUATERIC®); cellulose acetate trimellitic acid (CAT); and, for example, from a weight ratio of about 3: 1 A mixture of about 2: 1 EUDRAGIT® L100-55 and EUDRAGIT® S100, or about 3: 1 to about 5: 1 weight ratio EUDRAGIT® L30 D-55 and EUDRAGIT® ) Including, but not limited to, a mixture of the two or more weight ratios between about 2: 1 and about 5: 1, such as a mixture of FS.

  These polymers can be used alone or in combination with polymers other than those described above, or simultaneously. A preferred enteric pH dependent polymer is a pharmaceutically acceptable methacrylic acid copolymer. These copolymers are anionic polymers with methacrylic acid and methyl methacrylate, and preferably have an average molecular weight of about 135,000. The ratio of free carboxyl groups to methyl esterified carboxyl groups in these copolymers can vary, for example, from 1: 1 to 1: 3, such as 1: 1 or around 1: 2. Such polymers include Eudragit L 12.5®, Eudragit L 12.5P®, Eudragit L100®, Eudragit L 100-55®, Eudragit L-30D®. ), Eudragit L series such as Eudragit L-30 D-55 (registered trademark), and Eudragit S such as Eudragit S 12.5 (registered trademark), Eudragit S 12.5P (registered trademark), Eudragit S100 (registered trademark) It is sold under the trade name Eudragit (registered trademark) such as the (registered trademark) series. Release enhancers are not limited to pH dependent polymers. Other hydrophilic molecules that dissolve quickly and quickly reach the outside of the dosage form leaving a void structure can also be used for the same purpose.

  Release enhancers can be incorporated in amounts of 10% to 90%, preferably 20% to 80%, most preferably 30% to 70% by weight of the dosage unit. Release enhancers can be incorporated into the formulation before or after granulation. Release enhancers can be added to the formulation as a dry material, or dispersed or dissolved in a suitable solvent and dispersed during granulation.

  In some embodiments, the matrix can include a combination of a release enhancer and a dissolution enhancer. Solubility promoters are molecules that enhance the solubility of ionic and non-ionic surfactants, complexing agents, hydrophilic polymers, acidifying and alkaline agents, and other poorly soluble drugs by molecular trapping. It can be. Several types of dissolution promoters can be used simultaneously.

  Solubilizers include doxate sodium, sodium lauryl sulfate, sodium stearyl fumarate, Tweens® and Spans (PEO modified sorbitan monoester and fatty acid sorbitan ester), poly (ethylene oxide) -polypropylene oxide-poly (ethylene oxide) block Surfactants such as copolymers (also known as PLURONICS®); complexing agents such as low molecular weight polyvinylpyrrolidone and low molecular weight hydroxymethylcellulose; molecules that aid dissolution by molecular trapping such as cyclodextrins, and citric acid, fumaric acid, tartaric acid, And acid modifiers such as hydrochloric acid; and pH modifiers including alkaline agents such as meglumine and sodium hydroxide.

  Solubilizers typically constitute 1% to 80%, preferably 1% to 60%, more preferably 1% to 50% by weight of the dosage form and can be incorporated in a variety of ways. Prior to granulation, it can be incorporated into the formulation in dry or wet form. It can also be added to the formulation after the remaining material has been granulated or otherwise processed. During granulation, the solubilizer can be sprayed as a solution with or without a binder.

  In some embodiments, the extended release formulation comprises a polymer matrix that can provide drug release after a period of time independent of pH. For the purposes of the present invention, “pH independence” is defined as having a property that is hardly affected by pH (eg, dissolution). A pH independent polymer is often referred to in the context of a “time controlled” or “time dependent” release profile.

  A pH independent polymer can be used to coat the active substance and / or to provide the polymer to a hydrophilic matrix in an extended release coating thereon. The pH independent polymer can be water insoluble or water soluble. Typical water-insoluble pH-independent polymers are neutral methacrylic acid esters (eg, EUDRAGIT® RS and EUDRAGIT® RL; a small amount of trimethylammonioethyl methacrylate moieties); Neutral ester dispersants without any (eg EUDRAGIT® NE30D and EUDRAGIT® NE30); cellulosic polymers such as ethyl cellulose, hydroxyethyl cellulose, cellulose acetate or mixtures and other pH-independent coating products Typical water-soluble pH-independent polymers include, but are not limited to, hydroxyalkylcelluloses such as hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC). Ether; polyvinylpyrrolidone (PVP), methyl cellulose, OPADRY (TM) amb, guar gum, xanthan gum, gum arabic, hydroxyethyl cellulose, and ethyl acrylate and methyl methacrylate copolymer dispersion or a combination 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 film formations covering the active core. The coating may additionally contain one or more water-soluble polymers and / or one or more plasticizers. Water-insoluble polymer coatings include barrier coatings aimed at the release of active substances in the nucleus, characterized in that low molecular weight (viscous) grades exhibit a fast release rate compared to high viscosity grades.

  In preferred embodiments, the water-insoluble film-forming polymer is one or more alkyl cellulose ethers such as ethyl cellulose or mixtures thereof (eg, ethyl cellulose grades PR100, PR45, PR20, PR10 and PR7; ETHOCEL®). , Dow).

  Typical water soluble polymers such as polyvinylpyrrolidone (POVIDONE®, hydroxypropylmethylcellulose, hydroxypropylcellulose and mixtures thereof.

  In some embodiments, the water insoluble polymer provides suitable properties (eg, extended release, mechanical properties, and coating properties) without the need for plasticizers. For example, a coating comprising a neutral copolymer of acrylic acid / methacrylic acid ester such as polyvinyl acetate (PVA), Eudragit NE30D commercially available from Evonik Industries, ethyl cellulose combined with hydroxypropyl cellulose, wax, etc., is used with a plasticizer. Can be applied without.

  In still other embodiments, the water insoluble polymer matrix can further comprise a plasticizer. The amount of plasticizer required depends on the plasticizer, the properties of the water-insoluble polymer, and the final desired coating properties. Suitable levels of plasticizer are from about 1% to about 20%, from about 3% to about 20%, from about 3% to about 5%, based on the total weight of the coating, including all ranges and subranges therebetween. About 7% to about 10%, about 12% to about 15%, about 17% to about 20%, or about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, It is in the range of about 7%, about 8%, about 9%, about 10%, about 15% or about 20%.

  Typical plasticizers are triacetin, acetylated monoglycerides, oils (castor oil, hydrogenated castor oil, rapeseed oil, sesame oil, olive oil, etc.); citrate esters, triethyl citrate, acetyl triethyl citrate acetyl citrate Tributyl, tributyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl phthalate, dioctyl phthalate, methyl paraben, propyl paraben, propyl paraben, butyl paraben, diethyl sebacate, dibutyl sebacate, glycero tributyrate , Substituted triglycerides and glycerides, monoacetylated and diacetylated glycerides (eg MYVACET® 9-45), glyceryl monostearate, glyceryl tributyrate, polysorbate 80, polyethylene Recall (PEG-4000, PEG-400, etc.), propylene glycol, 1,2-propylene glycol, glycerin, sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, diethyl malonate, dibutyl succinate, fatty acid, glycerin, Including, but not limited to, sorbitol, diethyl oxalate, diethyl malate, diethyl maleate, diethyl fumarate, diethyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, and mixtures thereof. The plasticizer can have surface active properties such that it can act as a release modifier. For example, nonionic surfactants such as in Brij58 (polyoxyethylene (20) cetyl ether) and others can be used.

  The plasticizer can be a high boiling organic solvent used to impart flexibility to otherwise hard or brittle polymer materials and can affect the release profile of the active substance. Plasticizers generally cause a reduction in cohesive intermolecular forces along the polymer chain, resulting in a decrease in the tensile strength of the polymer and various changes in polymer properties including increased elongation and decreased glass transition or softening temperature Bring. The amount and choice of plasticizer can affect the hardness of the tablet, for example, and can affect its dissolution or disintegration properties, as well as its physical and chemical stability. Certain plasticizers can increase the elasticity and / or flexibility of the coating and thereby reduce the brittleness of the coating.

  In other embodiments, the extended release formulation comprises a combination of at least two gel-forming polymers, including at least one non-ionic gel-forming polymer and / or at least one anionic gel-forming polymer. Gels formed by a combination of gel-forming polymers provide controlled release such that the polymer closest to the surface hydrates to form a viscous gel layer when the formulation is ingested and in contact with gastrointestinal fluid To do. Due to the high viscosity, the viscous layer only dissolves gradually, exposing the underlying material to the same process. The agglomerates are therefore slowly dissolved, thereby slowly releasing the active ingredient into the gastrointestinal fluid. A combination of at least two gel-forming polymers can manipulate properties such as the viscosity of the resulting gel to provide the desired release profile.

  In a specific embodiment, the formulation comprises at least one nonionic gel-forming polymer and at least one anionic gel-forming polymer. In other embodiments, the formulation comprises two different nonionic gel-forming polymers. In yet other embodiments, the formulation is a combination of non-ionic gel-forming polymers that have the same chemical properties but different solubility, viscosity, and / or molecular weight (eg, HPMC K100 and HPMC K15M or HPMC K100M, etc. A combination of hydroxypropyl methylcelluloses of different viscosity grades).

  Typical anionic gel-forming polymers are sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose (CMC), sodium alginate, alginic acid, pectin, polyglucuronic acid (poly-α- and β-1,4-glucuronic acid) ), Polygalacturonic acid (pectinic acid), anionic polysaccharides such as chondroitin sulfate, carrageenan, furseleran, anionic gums such as xanthan gum, acrylic acid polymers or carbomers (Carbopol® 934, 940, 974P NF) , Carbopol® copolymer, Pemulen® polymer, polycarbophil and others.

  Typical nonionic gel-forming polymers are povidone (PVP: polyvinylpyrrolidone), polyvinyl alcohol, copolymers of PVP and polyvinyl acetate, HPC (hydroxypropylcellulose), HPMC (hydroxypropylmethylcellulose), hydroxyethylcellulose, hydroxymethylcellulose. , Gelatin, polyethylene oxide, gum arabic, dextrin, starch, polyhydroxyethyl methacrylate (PHEMA), water-soluble nonionic polymethacrylate and copolymers thereof, modified cellulose, modified polysaccharide, nonionic gum, nonionic poly Including but not limited to sugars and / or mixtures thereof.

  The formulation may optionally include at least one additive such as the enteric polymers described above and / or fillers, binders (as described above), disintegrants, and / or glidants and lubricants.

  Typical fillers include sugar alcohols, also known as “sugar polyols” such as lactose, glucose, fructose, sucrose, dicalcium phosphate, sorbitol, mannitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates. Including, but not limited to, degradation products (a mixture of several sugar alcohols), corn starch, potato starch, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, enteric polymers or mixtures thereof.

  Typical binders are povidone (PVP: polyvinylpyrrolidone), copovidone (copolymer of polyvinylpyrrolidone and polyvinyl acetate), low molecular weight HPC (hydroxypropylcellulose), low molecular weight HPMC (hydroxypropylmethylcellulose), low molecular weight carboxymethylcellulose, ethylcellulose Water soluble hydrophilics such as gelatin, polyethylene oxide, gum arabic, dextrin, magnesium aluminum silicate, starch, and polymethacrylates such as Eudragit NE 30D, Eudragit RL, Eudragit RS, Eudragit E, polyvinyl acetate, and enteric polymers Including but not limited to polymers or mixtures thereof.

  Typical disintegrants are low substituted sodium carboxymethylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), sodium carboxymethyl starch (starch glycolate), crosslinked sodium carboxymethylcellulose (Croscarmellose), pregelatinized starch (starch 1500), microcrystals , Non-water soluble starch, water insoluble starch, carboxymethylcellulose calcium, low substituted hydroxypropylcellulose, and magnesium or aluminum silicate.

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

  In yet other embodiments, the extended release formulation is coated with water soluble / dispersible drug-containing particles such as beads (as described above) or a population of beads therein, and optionally void formers and other additives. It is formed by coating with. The coating material is preferably a cellulosic polymer such as ethylcellulose (eg SURELEASE®), methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate, and cellulose acetate phthalate; polyvinyl alcohol; polyacrylate, poly Selected from the group comprising acrylic polymers such as methacrylic esters and copolymers thereof, and other water-based or solvent-based coating materials. The controlled release coating for a given bead population can be controlled by at least one parameter of the controlled release coating, such as the nature of the coating, the coating level, the type and concentration of voiding agent, process parameters and combinations thereof. Therefore, by changing parameters such as void former concentration or curing conditions, it can be used to selectively change the active substance release from any given bead population, thereby making the formulation a selective release profile. I have it.

  Void forming agents suitable for use in controlled release coatings in this application can be organic or inorganic materials, and include materials that can be eluted, extracted or leached from the coating in the environment of use. Typical voiding agents are sucrose, glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, monosaccharides including dextran, oligosaccharides and polysaccharides; water soluble hydrophilic polymers, hydroxyalkylcelluloses, carboxyalkyl Cellulose, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinyl pyrrolidone, crosslinked polyvinyl pyrrolidone, polyethylene oxide, carbowax, carbopol, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene For use environments such as glycols, polypropylene glycols, or block polymers thereof, polyglycols, poly (α-Ω) alkylenediols Organic compounds such as soluble polymers; inorganic compounds such as alkali metal salts, lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, suitable calcium salts, combinations thereof, etc. Including, but not limited to.

  The controlled release coating can further include other additives known in the art such as plasticizers, anti-adhesives, lubricants (or glidants), and antifoaming agents.

  In some embodiments, the coated particles or beads are “overcoats” that provide, for example, moisture protection, anti-static, taste-masking, flavoring, coloring, and / or gloss or other aesthetic appeal to the beads. Can be additionally included. Suitable coating materials for such overcoats are known in the art, and cellulosic systems such as hydroxypropylmethylcellulose, hydroxypropylcellulose and microcrystalline cellulose, or combinations thereof (eg, various OPADRY® coating materials) Including but not limited to polymers.

  Coated particles or beads can be dissolution enhancers, elution enhancers, absorption enhancers, penetration enhancers, stabilizers, complexing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistant protein inhibitors, etc. May further contain an accelerator, but not limited thereto. Alternatively, the formulation can also contain an accelerator separated from the coating particles, for example as another bead population or powder. In still other embodiments, the accelerator may be contained on the coating particle in another layer, either below or above the controlled release coating.

  In other embodiments, the extended release formulation is formulated to release the active agent by an osmotic mechanism. By way of example, a capsule may be formulated with a single osmotic unit or may incorporate 2, 3, 4, 5, or 6 push-pull units encapsulated within a hard gelatin capsule, thereby Each bilayer push-pull unit includes an osmotic push layer and a drug layer, both surrounded by a semi-permeable membrane. One or more openings are drilled through the membrane adjacent to the drug layer. The membrane can be further coated with a pH dependent enteric coating that prevents release until after gastric emptying. Gelatin capsules dissolve immediately after ingestion. As the push-pull unit enters the small intestine, the enteric coating disintegrates, which in turn allows liquid to flow through the semipermeable membrane, the osmotic push compartment swells, and the water transport rate through the semipermeable membrane Forces the drug through the opening at a precisely controlled rate. Drug release can occur at a constant rate for up to 24 hours or longer.

  The osmotic push layer includes one or more osmotic agents that create a driving force for transport of water through the semipermeable membrane to the delivery carrier core. One class of osmotic agents is hydrophilic vinyl and acrylic acid polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate). PVA / with hydrophobic monomers such as poly (acrylic) acid, poly (methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymer, methyl methacrylate and vinyl acetate PVP copolymer, hydrophilic polyurethane containing large molecular PEO block, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), also called “osmopolymers” and “hydrogels” including, but not limited to, sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate Contains a water-swellable hydrophilic polymer.

  Another class of osmotic agents includes osmogens that can absorb water and produce an osmotic gradient across the semi-permeable membrane. Typical osmogens are inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfate, lithium sulfate, potassium chloride, and sodium sulfate; dextrose, Sugars such as fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; 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, and other organic acids; urea; and mixtures thereof.

  Materials useful in forming semi-permeable membranes are water permeable and water insoluble at physiologically relevant pH, or change to water insoluble by chemical modification such as crosslinking. Includes various grades of sensitive acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives.

  In some embodiments, the extended release formulation can include a polysaccharide coating that is resistant to erosion in both the stomach and intestine. Such polymers can only degrade in the colon housing large microflora containing biodegradable enzymes that degrade, for example, polysaccharide coatings and release drug content in a controlled time-dependent manner. . Typical polysaccharide coatings can include, for example, amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin, xylan, and combinations or derivatives thereof.

  In some embodiments, the pharmaceutical compositions of the present application are formulated for delayed extended release. As used herein, the term “delayed release” refers to a pharmaceutical agent that does not immediately disintegrate in the body to release the active ingredient. In some embodiments, the term “delayed extended release” is used in reference to a pharmaceutical formulation having a release profile with a predetermined delay in the release of the drug after administration. In some embodiments, the delayed extended release formulation comprises an extended release formulation coated with an enteric coating that is a barrier applied to oral pharmaceuticals that prevents the drug from releasing before reaching the small intestine. Delayed release formulations such as enteric coatings prevent drugs that have an irritating action on the stomach, such as aspirin, from dissolving in the stomach. Such coatings protect acid labile drugs from gastric acid exposure and instead deliver them to a basic pH environment that is not degraded (intestinal pH 5.5 and above) and deliver their desired effects. Also used to obtain.

  The term “pulsed release” is a type of delayed release, and in this application provides a rapid and transient release of a drug within a short period of time immediately after a predetermined delay time, whereby the drug after administration of the drug. Used for pharmaceutical formulations that produce a “pulsed” plasma profile. The formulation may be a single pulse release after administration or a multi-pulse release at predetermined time intervals, or an extended release over a period of time after a pulsed release (eg 20-60% of the active ingredient) (eg remaining active ingredient) Can be designed to provide continuous release).

  Delayed release or pulsed release formulations generally comprise one or more elements coated with a barrier coating that dissolves, erodes or ruptures after a defined delayed phase. In some embodiments, the pharmaceutical composition of the present application is formulated for extended or delayed extended release and comprises 100% of the total dose of a given active substance administered in a single unit dose. In other embodiments, the pharmaceutical composition comprises an extended / delayed release component and an immediate release component. In some embodiments, the immediate release component and the extended / delayed release component contain the same active ingredient. In other embodiments, the immediate release component and the extended / delayed release component contain different active ingredients (eg, an analgesic in one component and an alpha-blocker in the other component). In some embodiments, the first and second components contain an α-blocker and an analgesic selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, respectively. In other embodiments, the first and second components are finasteride, bexosterolide, epristeride, izonsteride, lapisteride and turosteride, a 5α-reductase inhibitor, and aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone. And an analgesic selected from the group consisting of acetaminophen. In other embodiments, the extended / delayed release component is coated with an enteric coating. In other embodiments, the immediate release component and / or extended / delayed release component further comprises an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin, and atropine. In other embodiments, the immediate release component and / or the extended / delayed release component further comprises an antidiuretic, an antimuscarinic agent, or both. In other embodiments, the method of treatment comprises administering a diuretic to the subject at least 8 or 7 hours prior to a target time, such as bedtime, and an immediate release component and / or extension within 2 hours prior to the target time. / Administering to a subject a pharmaceutical composition comprising a delayed release component.

  In other embodiments, the “immediate release” component provides 5-50% of the total dose of active substance to be delivered by the pharmaceutical composition, and the “extended release” component is 50% of the total dose of active substance. Provides ~ 95%. For example, the immediate release component is about 20-60%, or about 20%, 25%, 30%, 35%, 40%, 45%, 50%, of the total dose of active substance to be delivered by the pharmaceutical formulation, 55%, 60% can be provided. The extended release component provides about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% of the total dose of active substance to be delivered by the formulation. In some embodiments, the extended release component further comprises a barrier coating that retards the release of the active agent.

  Barrier coatings intended for delayed release can be composed of a variety of different materials depending on the purpose. In addition, the formulation can include multiple barrier coatings to temporarily facilitate release. The coating can be sugar-coated, film coating (eg based on hydroxypropylmethylcellulose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymer, polyethylene glycol and / or polyvinylpyrrolidone) or methacrylic It can be a coating with an acid copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate acetate, polyvinyl acetate phthalate, shellac and / or ethylcellulose. In addition, the formulation may additionally include a time delay material such as glyceryl monostearate or glyceryl distearate.

  In some embodiments, the delayed extended release formulation includes an enteric coating that includes one or more polymers that facilitate the release of the active agent in the proximal or distal region of the gastrointestinal tract. As used herein, the term “enteric polymer coating” is a coating composed of one or more polymers having a pH dependent or pH independent release profile. Typically, the coating resists dissolution in the acidic medium of the stomach, but dissolves or erodes in more distal regions of the digestive tract, such as the small intestine or colon. The enteric polymer coating typically resists release of active substance for some time after a delay due to gastric emptying about 3-4 hours after administration.

  A pH-dependent enteric coating maintains its structural integrity at low pH, such as in the stomach, but dissolves in a higher pH environment in more distal regions of the digestive tract, such as the small intestine, where the drug Contains one or more pH dependent or pH sensitive polymers from which the contents are released. For the purposes of the present invention, “pH dependence” is defined as having properties (eg, dissolution) that vary with environmental pH. Typical pH-dependent polymers are methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (eg EUDRAGIT® L100 (type A), EUDRAGIT® S100 (type B), Rohm GmbH, Germany; Methacrylic acid-ethyl acrylate copolymers (eg, EUDRAGIT® L100-55 (C type) and EUDRAGIT® L30D-55 copolymer dispersant, Rohm GmbH, Germany); methacrylic acid-methyl methacrylate and methacrylic acid Methyl copolymer (EUDRAGIT® FS); terpolymers of methacrylic acid, methacrylic acid esters and ethyl acrylate; cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate ( HPMCP) (eg: HP-55, HP-50, HP-55S, Shin-Etsu Chemical, Japan); polyvinyl acetate phthalate (PVAP) (eg: COATERIC (registered trademark), OPADRY (registered trademark) enteric white OY -P-7171); cellulose acetate succinate (CAS); hydroxypropyl methylcellulose acetate succinate (HPMCAS), eg: HPMCAS LF including AQOAT® LF and AQOAT® MF (Shin-Etsu Chemical, Japan) Grade, MF grade, HF grade; Shin-Etsu Chemical, Japan); shellac (eg, Marcoat® 125 and Marcoat® 125N); carboxymethyl ethyl cellulose (CMEC, Freund Industries, Japan), cellulose acetate phthalate (CAP) (eg; QUATERIC®); cellulose trimellitic acid cellulose (CAT); and a mixture of EUDRAGIT® L100-55 and EUDRAGIT® S100, for example in a weight ratio of about 3: 1 to about 2: 1, or weight The two in a weight ratio of about 2: 1 to about 5: 1, such as a mixture of EUDRAGIT® L30 D-55 and EUDRAGIT® FS in a ratio of about 3: 1 to about 5: 1 Including, but not limited to, further mixtures.

  The pH dependent polymer typically exhibits a characteristic pH optimum for dissolution. In some embodiments, the pH dependent polymer is between about 5.0 and 5.5, between about 5.5 and 6.0, between about 6.0 and 6.5, or about 6. An optimum pH between 5 and about 7.0 is exhibited. In other embodiments, the pH dependent polymer exhibits an optimum pH of ≧ 5.0, ≧ 5.5, ≧ 6.0, ≧ 6.5, or ≧ 7.0.

  In certain embodiments, the coating methodology employs blending one or more pH dependent polymers and one or more pH independent polymers. By blending the pH-dependent and pH-independent polymers, it is possible to reduce the release rate of the active ingredient once the soluble polymer reaches its optimum solubilization pH.

  In some embodiments, a water-insoluble capsule body containing one or more active substances, wherein one end of the capsule body is an insoluble but permeable and swellable hydrogel plug. A water-insoluble capsule body characterized by being closed can be used to obtain a “time-controlled” or “time-dependent” release profile. Upon contact with gastrointestinal fluid or solvent, the plug swells and pushes itself out of the capsule, releasing the drug after a predetermined delay time, which can be adjusted, for example, by the position or size of the plug. The capsule body may be further coated with an outer layer pH-dependent enteric coating to keep the capsule intact until the capsule reaches the small intestine. Suitable plug materials include, for example, polymethacrylates, erodible compression polymers (eg, HPMC, polyvinyl alcohol), condensation melt polymers (eg, glyceryl monooleate), and enzyme-controlled erodible polymers (eg, amylose, Polysaccharides such as 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 polymer coating or membrane that is insoluble but semi-permeable. The delay time before rupture can be adjusted by the penetration and mechanical properties of the polymer coating and the swelling behavior of the swelling layer. Typically, the swelling layer includes one or more swelling agents such as a swellable hydrophilic polymer that swells and retains water within its structure.

  Typical water swellable materials used for delayed release coatings are polyethylene oxide (for example having an average molecular weight between 1,000,000 and 7,000,000 like POLYOX®), methylcellulose, hydroxy Polyalkylene oxide having a weight average molecular weight of 100,000 to 6,000,000 including, but not limited to, propyl cellulose, hydroxypropyl methylcellulose; poly (methylene oxide), poly (butylene oxide); 25,000 to 5, Poly (hydroxyalkyl methacrylate) having a molecular weight of 1,000,000; poly (vinyl) acrylate having low acetal residues that crosslink with glyoxal, formaldehyde, or glutaraldehyde and having a degree of polymerization of 200 to 30,000 A mixture of methylcellulose, cross-linked agar and carboxymethylcellulose; maleic anhydride and styrene, ethylene, propylene, butylene or cross-linked with 0.001 to 0.5 mole of saturated crosslinker per mole of maleic anhydride in the copolymer Hydrogel-forming copolymer produced by forming a dispersion of finely divided copolymer of isobutylene; CARBOPOL® acidic carboxy copolymer having a molecular weight of 450,000 to 4,000,000; CYAMANER® ) Polyacrylamide; cross-linked water-swellable indene maleic anhydride polymer; GOODRITE® polyacrylic acid having a molecular weight of 80,000 to 200,000; starch graft copolymer; AQUA-KEEPS® acrylic polymer polysaccharide composed of condensed glucose units such as liglycans; carbomer having a viscosity of 3,000 to 60,000 mPa as 0.5-1% w / v aqueous solution; 1% w / w Cellulose ethers such as hydroxypropylcellulose having a viscosity of about 1000 to 7000 mPa as an aqueous solution (25 ° C.); Viscosity of about 1000 or more, preferably 2,500 or more to a maximum of 25,000 mPa as a 2% w / v aqueous solution Including, but not limited to, hydroxypropyl methylcellulose having a viscosity of about 300-700 mPa as a 10% w / v aqueous solution at 20 ° C; and combinations thereof.

  Alternatively, the drug release time is determined by the resistance and thickness of a water-insoluble polymer membrane (such as ethylcellulose (EC)) at the bottom of the body and containing certain pores, and low substituted hydroxypropylcellulose (L-HPC) And can be controlled by a disintegration delay depending on the balance between the amount of swellable excipients such as sodium glycolate. After oral administration, the GI solution penetrates through the pores, causing swelling of the swellable excipient, which contains the first capsule body containing the swellable material, the second capsule body containing the drug, and the first This provides an internal pressure that separates the capsule components including the outer cap that contacts the capsule body.

  The enteric layer may further comprise an anti-adhesive agent such as talc or glyceryl monostearate and / or a plasticizer. Enteric layer consists of triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, polyethylene glycol acetylated monoglyceride, glycerin, triacetin, propylene glycol, phthalate ester (eg diethyl phthalate, dibutyl phthalate), titanium dioxide, One or more plasticizers may further be included, including but not limited to ferric oxide, castor oil, sorbitol and dibutyl sebacate.

  In other embodiments, the delayed release formulation employs a water permeable but water insoluble film coating that encapsulates the active ingredient and osmotic agent. As water from the intestine slowly diffuses through the film and into the nucleus, the nucleus expands until the film ruptures, thereby releasing the active ingredient. The film coating can be adjusted to allow for various water penetration rates or release times.

  In other embodiments, the delayed release formulation employs a non-water permeable tablet coating that allows water to enter the coating through a controlled opening until the nucleus ruptures. When the tablet ruptures, the drug content is released immediately or over a longer period of time. These and other techniques can be modified to take into account a predetermined delay time before the drug release is initiated.

  In other embodiments, the active agent is delivered in a formulation to provide both delayed and extended release after administration (delay-sustained). The term “delayed-extended release” is used herein for a pharmaceutical formulation that provides a pulsed release of an active substance at a predetermined time or a post-administration lag time, after which the active substance is then extended released.

  In some embodiments, immediate release, extended release, delayed release, or delayed-extended release formulations can be prepared using, for example, fluid-bed technology or other methodologies known to those skilled in the art, such as drug-containing film-forming One or more of each in the form of beads, pellets, pills, granular particles, microcapsules, microspheres, microgranules, nanocapsules, or nanospheres whose surfaces are coated with an agent that takes the form of a composition Active nuclei composed of inert particles. The inert particles can be of various sizes as long as they are large enough to remain low soluble. Alternatively, the active core may be prepared by granulation and grinding and / or extrusion and spheronization of a polymer composition containing a drug substrate.

  The amount of drug in the nucleus will depend on the dose required and typically varies from about 5 to 90% by weight. In general, the polymer coating on the active nuclei is about 1 to 50% of the weight of the particles to be coated, depending on the delay time and type of release profile required and / or the polymer and coating solvent selected. It will be. One skilled in the art will be able to select the appropriate amount of agent to coat or incorporate into the nucleus to achieve the desired dose. In one embodiment, the inert nucleus is a sphere of sugar that alters its microenvironment to promote drug release, or crystals of buffering agents such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, or It can be an encapsulated buffer crystal.

  In some embodiments, for example, a delayed release or delayed-extended release composition comprises a water soluble / dispersible drug-containing particle such as a bead and a water insoluble polymer and enteric polymer from 4: 1 to 1: 1. And the total weight of the coating may be from 10 to the total weight of the coated beads, and may be formed by coating with a mixture of a water-insoluble polymer and an enteric polymer, characterized in that 60% by weight. The drug-laminated beads can optionally include an internal elution rate control membrane for ethylcellulose. The composition of the outer layer of the polymer membrane, as well as the individual weights of the inner and outer layers, is optimized to achieve the desired circadian release profile for a given activity, predicted based on in vitro / in vivo correlations. The

  In other embodiments, the formulation comprises a mixture of immediate release drug-containing particles without a dissolution rate controlling polymer membrane and delayed-extended release beads exhibiting a lag time of, for example, 2-4 hours after oral administration. Can provide a two-pulse release profile.

  In some embodiments, active nuclei are coated with one or more elution rate controlling polymers to obtain a desired release profile with or without a lag time. The inner membrane can primarily control the rate of drug release after absorption of water or fluid into the nucleus, while the outer membrane provides the desired lag time (time when there is little drug release after absorption of water or fluid into the nucleus). be able to. The inner layer membrane may comprise a water insoluble polymer or a mixture of a water insoluble polymer and a water soluble polymer.

  Polymers suitable for outer membranes that primarily control delay times of up to 6 hours may include 10 to 50 wt% of the enteric and water-insoluble polymers described above. The ratio of water insoluble polymer to enteric polymer can vary from 4: 1 to 1: 2, preferably the polymer is present in a ratio of about 1: 1. A typically used water-insoluble polymer is ethyl cellulose.

  Typical water-insoluble polymers are neutral copolymers based on ethyl cellulose, polyvinyl acetate (Kollicoat SR # 0D from BASF), ethyl acrylate and methyl methacrylate, EUDRAGIT® NE, RS and RS30D, RL or RL30D And copolymers of acrylic acid and methacrylic acid esters having a quaternary ammonium group. A typical water soluble polymer is a low molecular weight HPMC with a concentration ranging from about 1% to 10% by weight, depending on the solubility of activity in the water or solvent or latex suspension base coating formulation used, Contains HPC, methylcellulose, polyethylene glycol (PEG with molecular weight> 3000). The water-insoluble polymer relative to the water-soluble polymer can typically vary between 95: 5 and 60:40, preferably between 80:20 and 65:35.

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

  When used as a pharmaceutical carrier, AMBERLITE IRP69 or / and DUOLITE® AP143 / 1093 resin provide a means to bind the drug onto an insoluble polymer matrix. Extended release is achieved through the formation of a resin-drug complex (resin acid salt). As the drug reaches equilibrium with the high electrolyte concentration typical of the gastrointestinal tract, the drug is released from the resin in vivo. More hydrophobic drugs will usually elute from the resin at a lower rate due to hydrophobic interactions with the aromatic structure of the cation exchange system.

  Most enteric coatings work by presenting a surface that is stable at the high acid pH found in the stomach but rapidly disintegrates at less acidic (relatively basic) pH. Thus, enteric coated pills will not dissolve in acidic gastric fluid (about pH 3) but will dissolve in the alkaline (pH 7-9) environment present in the small intestine. Examples of enteric coating materials are methyl acrylate-methacrylic acid copolymer, cellulose succinate acetate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose 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, caplets and the like, and may also include multiple granules, beads, powders or pellets that may or may not be encapsulated. Tablets and capsules represent the simplest oral dosage form when a solid pharmaceutical carrier is employed.

  In delayed release formulations, one or more barrier coatings may be applied to pellets, tablets, or capsules to facilitate slow dissolution and concomitant release of the drug into the intestine. Typically, the barrier coating contains one or more polymers that enclose, surround, or form a layer or film around the therapeutic composition or active core.

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

  A variety of coating techniques may be applied to granules, beads, powders or pellets, tablets, capsules, or combinations thereof containing active substances to provide different and characteristic release profiles. In some embodiments, the pharmaceutical composition is in tablet or capsule form comprising a single coating layer. In other embodiments, the pharmaceutical composition is in the form of a tablet or capsule comprising a plurality of coating layers.

  In some embodiments, the pharmaceutical composition is selected from the group consisting of one or more analgesic agents, one or more alpha-blockers, and antimuscarinic, antidiuretic and antispasmodic agents. One or more other active ingredients. In other embodiments, the pharmaceutical composition comprises one or more analgesics, one or more 5α-reductase inhibitors, and antimuscarinic agents, antidiuretics, α-blockers and antispasmodic agents. One or more other active ingredients selected from: Examples of antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin and atropine. Examples of antidiuretics are antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogues (eg desmopressin argypressin, repressin, ferripressin, ornipressin, terlipressin; vasopressin receptor agonist, atrial natriuretic Peptide (ANP) and C-type natriuretic peptide (CNP) receptor (ie, NPR1, NPR2, NPR3) antagonists (eg, HS-142-1, Isatin, [Asu7,23 ′] b-ANP- (7-28 )], Ananthin, Streptomyces coerulescens-derived cyclic peptide, and 3G12 monoclonal antibody), somatostatin type 2 receptor antagonist (eg, somatostatin), and pharmaceutically acceptable derivatives, analogs thereof, Examples of antispasmodic agents include carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, metocarbamol, clonidine, clonidine analogues, and dantrolene, including but not limited to hydrates and solvates. Including, but not limited to.

  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 antimuscarinic agents. including. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more alpha-blockers, and (3) one or more antidiuretics. including. 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 more analgesics, (2) one or more alpha-blockers, (3) one or more antimuscarinic agents, And (4) one or more 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) Contains one or more antidiuretics.

  In some embodiments, the pharmaceutical composition comprises one or more analgesics and one or more 5α-reductase inhibitors. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents, (2) one or more 5α-reductase inhibitors, and (3) one or more antimuscarinic agents. Contains 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 antidiuretics. Contains 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 antispasmodics. Including. In other embodiments, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or more 5α-reductase inhibitors, (3) one or two antimuscarinic agents, and (4) Contains one or two antidiuretic agents. In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, (3) one or more antispasmodics, and (4) includes 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- Contains a blocking agent. 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 antidiuretic agents. 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 antispasmodic agents. In other embodiments, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or more 5α-reductase inhibitors, (3) one or two antimuscarinic agents, ( 4) includes 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 antispasmodics, ( 4) one or more antidiuretics and (5) one or more alpha-blockers.

  In one embodiment, the plurality of active ingredients are formulated for immediate release. In other embodiments, the plurality of active ingredients are formulated for extended release. In other embodiments, the plurality of active ingredients are formulated for both immediate release and extended release (eg, the first portion of each active ingredient is formulated for immediate release and the first of each active ingredient is formulated). 2 parts are formulated for extended release). In still other embodiments, some of the plurality of active ingredients are formulated for immediate release, and some of the plurality of active ingredients are formulated for extended release (eg, active ingredients A, B, C is 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 extended release component is further coated with a delayed release coating, such as an enteric coating.

  In some embodiments, the pharmaceutical composition includes 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, α-blockers, 5α-reductase inhibitors, antimuscarinic agents, antidiuretics and antispasmodic agents. The extended release component can comprise one or more active ingredients selected from the group consisting of analgesics, alpha-blockers, antimuscarinic agents, antidiuretics and antispasmodic agents. 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 yet other embodiments, the immediate release component and the extended release component have one and more common active ingredients. In some other embodiments, the immediate release component and / or extended release component is further coated with a delayed release coating, such as an enteric coating.

  In one embodiment, the pharmaceutical composition comprises two or more active ingredients (eg, one or more analgesics and one or more) formulated for near simultaneous immediate release. An α-blocker, one or more 5α-reductase inhibitors, a mixture of one or more antimuscarinic or antidiuretic or antispasmodic agents). In other embodiments, the pharmaceutical composition comprises two or more active ingredients formulated for near simultaneous extended release. In other embodiments, the pharmaceutical composition comprises two or more active ingredients formulated as two extended release components, each 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 other embodiments, any pharmaceutical composition comprises two or more active ingredients formulated for delayed release. In other embodiments, the pharmaceutical composition comprises two or more active ingredients formulated for delayed release. In other embodiments, the pharmaceutical composition comprises two or more active ingredients formulated as two delayed release components, each providing a different delayed release profile. For example, a first delayed release component releases a first active ingredient at a first time point and a second delayed release component releases a second active ingredient at a second time point. In other embodiments, the pharmaceutical composition comprises two or more active ingredients, one or more of which is formulated for immediate release and the other is formulated for extended release. In other embodiments, the pharmaceutical composition comprises two or more active ingredients, some of which are formulated for immediate release and the remainder are formulated for extended release.

  In some embodiments, the pharmaceutical composition is characterized in that one or more analgesics and one or more alpha-blockers are formulated for delayed release, and an antidiuretic One or more analgesics, and one or more α-blockers, 5α-reductase inhibitors, antidiuretics, characterized in that is formulated for immediate release. In other embodiments, the pharmaceutical composition comprises an analgesic, alpha-blocker, 5 alpha-reductase inhibitor, antimuscarinic, antidiuretic, characterized in that the additional drug is formulated for delayed release. And further comprising an additional agent selected from the group consisting of an agent and an antispasmodic agent. 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” is used herein for pharmaceutical formulations that do not contain dissolution rate controlling materials. There is almost no delay in the release of the active substance after administration of the immediate release formulation. The immediate release coating may include a suitable material that dissolves immediately after administration to release the drug content therein. Typical immediate release coating materials include gelatin, polyvinyl alcohol polyethylene glycol (PVA-PEG) copolymers (e.g., KOLLICOAT®) and a variety of other materials known to those skilled in the art.

  An immediate release composition may comprise 100% of the total dose of a given active substance administered in a single unit dose. Alternatively, the immediate release component can be included as a component in a complex release profile formulation that can provide from about 1% to about 60% of the total dose of active substance to be delivered by the pharmaceutical formulation. For example, the immediate release component is about 5% to 60%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40% of the total dose of active substance 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% may be provided. In another embodiment, the immediate release component is about 2, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, of the total dose of active substance to be delivered by the formulation. Provide 55 or 60%.

  In some embodiments, the immediate release or delayed release formulation is administered by an agent, for example, in the form of a drug-containing film-forming composition, such as using fluid bed technology or other methodologies known to those skilled in the art. Activity composed of one or more inert particles each in the form of surface-coated beads, pellets, pills, granular particles, microcapsules, microspheres, microgranules, nanocapsules, or nanospheres Including the core. The inert particles can be of various sizes as long as they are large enough to remain low soluble. Alternatively, the active core may be prepared by granulation and grinding and / or extrusion and spheronization of a polymer composition containing a drug substrate.

  The amount of drug in the nucleus will depend on the dose required and typically varies from about 5 to 90% by weight. In general, the polymer coating on the active nuclei is about 1 to 50% of the weight of the particles to be coated, depending on the delay time and type of release profile required and / or the polymer and coating solvent selected. It will be. One skilled in the art will be able to select an appropriate amount of agent to coat or incorporate into the nucleus to achieve the desired dose. In one embodiment, the inert nucleus is a sphere of sugar that alters its microenvironment to promote drug release, or crystals of buffering agents such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, or It can be an encapsulated buffer crystal.

  In some embodiments, the delayed release formulation can include water-soluble / dispersible drug-containing particles such as beads, water-insoluble polymer and enteric polymer in a weight ratio of 4: 1 to 1: 1. And the total weight of the coating is from 10 to 60% by weight of the total weight of the coated beads. The drug-laminated beads can optionally include an internal elution rate control membrane for ethylcellulose. The composition of the outer layer of the polymer membrane, as well as the individual weights of the inner and outer layers, is optimized to achieve the desired circadian release profile for a given activity, predicted based on in vitro / in vivo correlations. The

  In other embodiments, the formulation comprises a mixture of immediate release drug-containing particles without an elution rate controlling polymer membrane and delayed release beads exhibiting a lag time of, for example, 2-4 hours after oral administration. Provides a pulsed release profile. In yet another embodiment, the formulation comprises: a mixture of two types of delayed release beads, a first type exhibiting a lag time of 1-3 hours and a second type exhibiting a lag time of 4-6 hours.

  Preferably, the formulation is designed with a release profile to limit peaceful sleep interruptions, characterized in that the formulation releases the drug when an individual will normally wake up due to the urination impulse. For example, consider a person who begins to sleep at 11:00 pm and usually wakes up to urinate at 12:30 am, 3:00 am and 6:00 am. Delayed extended release carrier can be ingested at 10:00 pm, start delivery of the drug at 12:00 am, and gradually release the drug over a period of 5-8 hours to delay or eliminate the need for urination It is. In other embodiments, the formulation is designed with a release profile in which a portion of the drug (eg, 20-60%) is released immediately or within 2 hours of administration, and the remainder is released over an extended period of time. . The pharmaceutical composition may be administered daily or as needed. In certain embodiments, the pharmaceutical composition is administered to the subject prior to going to bed. In some embodiments, the pharmaceutical composition is administered just before bedtime. In some embodiments, the pharmaceutical composition is administered within about 2 hours before bedtime, preferably within about 1 hour before bedtime. In other embodiments, the pharmaceutical composition is administered about 2 hours before bedtime. In a further embodiment, the pharmaceutical composition is administered at least 2 hours before bedtime. In other embodiments, the pharmaceutical composition is administered about 1 hour before bedtime. In a further embodiment, the pharmaceutical composition is administered at least 1 hour before bedtime. In yet further embodiments, the pharmaceutical composition is administered less than 1 hour before bedtime. In still other embodiments, the pharmaceutical composition is administered immediately before going to bed. Preferably, the pharmaceutical composition is administered orally. Compositions suitable for oral administration include, but are not limited to: tablets, coated tablets, dragees, capsules, powders, granules and soluble tablets, and liquid forms such as, for example, suspensions, dispersions or solutions. .

  The appropriate dose of active substance in an immediate release component or extended release component ("therapeutically effective amount") is, for example, the severity and course of the condition, mode of administration, bioavailability of the individual substance, patient age and weight , Will depend on the patient's clinical history and response to the active substance, physician discretion, etc.

  As a general proposition, the therapeutically effective amount of the active substance in the immediate release component, extended release component or delayed-extended release component is about 100 μg, whether by one dose or more. / Kg body weight / day to about 100 mg / kg body weight / day. In some embodiments, the range of each active agent administered daily in single or multiple doses is from about 100 μg / kg body weight / day to about 50 mg / kg body weight / day, from 100 μg / kg body weight / day to about 10 mg / kg body weight / day, 100 μg / kg body weight / day to about 1 mg / kg body weight / day, 100 μg / kg body weight / day to about 10 mg / kg body weight / day, 500 μg / kg body weight / day to about 100 mg / kg body weight / day Day, 500 μg / 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 / dose to about 100 mg / kg body weight / day, 5 g / kg body weight / dose to about 50 mg / kg of body weight / day, 10 mg / kg body weight / day to about 100 mg / kg of body weight / day, and 10 mg / kg body weight / day to about 50 mg / kg of body weight / day.

  The active substances described in this application are 1 mg to 2000 mg, 5 mg to 2000 mg, 10 mg to 2000 mg, 50 mg to 2000 mg, 100 mg to 2000 mg, 200 mg to 2000 mg, 500 mg to 2000 mg, 5 mg to 1800 mg, 10 mg to 1600 mg, 50 mg to 1600 mg, 100 mg to 100 mg 1500 mg, 150 mg to 1200 mg, 200 mg to 1000 mg, 300 mg to 800 mg, 325 mg to 500 mg, 1 mg to 1000 mg, 1 mg to 500 mg, 1 mg to 200 mg, 5 mg to 1000 mg, 5 mg to 500 mg, 5 mg to 200 mg, 10 mg to 1000 mg, 10 mg to 500 mg, 10 mg to 200 mg, 50 mg to 1000 mg, 50 mg 500 mg, 50 mg to 200 mg, 250 mg to 1000 mg, 250 mg to 500 mg, 500 mg to 1000 mg, 500 mg to 2000 mg, single release or combined dose range for immediate daily or extended release components, delayed-extended release components for daily oral administration Or it may be included in the combination. As expected, the dose will depend on the condition, size, age and patient condition.

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

  In some embodiments, a single analgesic is 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 It is administered at a daily dose of 500 mg to 1000 mg. In certain embodiments, the pharmaceutical composition comprises acetylsalicylic acid, ibuprofen, naproxen, sodium naproxen, indomethacin, nabumetone or acetaminophen as a single analgesic and the analgesic is from 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 orally administered daily. In some embodiments, the second analgesic is 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 It is administered at a daily dose of 500 mg to 1000 mg.

  In other embodiments, the pharmaceutical composition comprises a pair of analgesics and one or more alpha-blockers. Examples of such a pair of analgesics are acetylsalicylic acid and ibuprofen, acetylsalicylic acid and naproxen sodium, acetylsalicylic acid and nabumetone, acetylsalicylic acid and acetaminophen, acetylsalicylic acid and indomethacin, ibuprofen and naproxen sodium, ibuprofen and nabumetone, ibuprofen and acetoacetate. Aminophen, ibuprofen and indomethacin, naproxen, naproxen sodium and nabumetone, naproxen sodium and acetaminophen, naproxen sodium and indomethacin, nabumetone and acetaminophen, nabumetone and indomethacin, and acetaminophen and indomethacin . Analgesic pairs are 5 mg to 2000 mg, 20 mg to 2000 mg, 100 mg to 2000 mg, 200 mg to 2000 mg, 500 mg to 2000 mg, 5 mg to 1500 mg, 20 mg to 1500 mg, 100 mg to 1500 mg, 200 mg to 1500 mg, 500 mg to 1500 mg, 5 mg to 1000 mg, 0.1: 1 to 10: multiple doses ranging from 20 mg to 1000 mg, 100 mg to 1000 mg, 250 mg to 500 mg, 250 mg to 1000 mg, 250 mg to 1500 mg, 500 mg to 1000 mg, 500 mg to 1500 mg, 1000 mg to 1500 mg and 1000 mg to 2000 mg. 1, in weight ratios ranging from 0.2: 1 to 5: 1 or 0.3: 1 to 3: 1 It is engaged. In one embodiment, the analgesic pair is mixed in a 1: 1 weight ratio.

  In some other embodiments, the pharmaceutical composition of the present application further comprises one or more antimuscarinic agents. Examples of antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, tropium, and atropine. The daily dose of antimuscarinic agent is 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, 0.1 mg to 10 mg, 1 mg to 10 mg, 10 mg to 100 mg and 10 mg to 25 mg.

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

  Another aspect of the present application relates to a method for reducing urination frequency by administering a pharmaceutical composition formulated in an immediate release formulation to a person in need thereof. The pharmaceutical composition comprises one or more analgesics and one or more additional selected from the group consisting of 5α-reductase inhibitors, α-blockers, antimuscarinic agents, antidiuretics, and antispasmodic agents. Contains active ingredients. The pharmaceutical composition can be formulated in the form of tablets, capsules, dragees, powders, granules, solutions, gels, or emulsions. The liquid, gel or emulsion can be ingested by the subject in a naked form or contained in a capsule.

  In certain embodiments, the analgesic is a salicylate, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, paraaminophenol derivative, acetanilide, acetaminophen, phenacetin, phenamates, mefenamic acid, meclofena Mate, sodium meclofenamic acid, heteroaryl acetic acid derivative, tolmethine, ketorolac, diclofenac, propionic acid derivative, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin; enolic acid, oxicam derivative, piroxicam, meloxicam , Tenoxicam, ampiroxicam, droxicam, pivoxicam, pyrazolone derivatives, phenyl Zon, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, coxibs such as celecoxib, rofecoxib, nabumetone, apazone, nimesulide, indomethacin, sulindac, etodolac, is selected from the group consisting of diflunisal and isobutyl phenylpropionic acid. The antimuscarinic agent is selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.

  In some embodiments, the pharmaceutical composition comprises a single analgesic, a single alpha-blocker and a single antimuscarinic agent. 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 other embodiments, the single analgesic is ibuprofen. In other embodiments, the single analgesic is naproxen or naproxen sodium. In other embodiments, the single analgesic is indomethacin. In other embodiments, the single analgesic is nabumetone. In other embodiments, the single analgesic is acetaminophen. In other embodiments, the single α-blocker is tamsulosin. Analgesics, α-blockers, 5α-reductase inhibitors and antimuscarinic agents may be administered at doses in the ranges described above. In some embodiments, the pharmaceutical composition further comprises an antidiuretic or antispasmodic agent.

  In some embodiments, the pharmaceutical composition is 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg individually or in combination with one or more analgesics. 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100 -600 mg, 100-400 mg, 100-250 mg, 250-2000 mg, 250-1500 mg, 250-1200 mg, 250-1000 mg, 250-800 mg, 250-600 mg, 250-400 mg, 400-2000 g, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg, and one or more analgesics are included in 5-24 The composition is formulated for extended release with a release profile that is continuously released over a period of time, 5-8, 8-16 hours or 16-24 hours.

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

  In some embodiments, the composition has a release profile in which the active ingredient is released continuously over 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours. Is formulated for the purpose of extended release.

  In other embodiments, the composition is intended for extended release with the active ingredient and a release profile that is released at a constant rate over a period of 5-24 hours, 5-8, 8-16 hours, or 16-24 hours. Is formulated as In other embodiments, the composition has a release profile in which the active ingredient is released at a constant rate over 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours. Formulated for the purpose of having extended release. As used herein, “constant rate over” is defined as a release profile in which the release rate at any point during a given time is within 30-300% of the average release rate over that given time. The For example, if 80 mg of aspirin is released at a constant rate over 8 hours, the average release rate for this time is 10 mg / hour, and the actual release rate at any point during this time is 3 mg / hour to 30 mg. / Hour (ie within 30% to 300% of the average release rate of 10 mg / hour during 8 hours).

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

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

  In one specific embodiment, the pharmaceutical composition has a release profile in which at least 90% of the acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16, or 16-24 hours. 50-250 mg acetaminophen formulated for extended release with Other active ingredients may be released immediately after administration or with an analgesic.

  In other specific embodiments, the pharmaceutical composition has a release profile in which 90% of acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16, or 16-24 hours. Contains 250-400 mg of acetaminophen formulated for extended release. Other active ingredients may be released immediately after administration or with an analgesic.

  In other specific embodiments, the pharmaceutical composition has a release profile in which 90% of acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16, or 16-24 hours. Contains 400-600 mg of acetaminophen formulated for extended release. Other active ingredients may be released immediately after administration or with an analgesic.

  In other specific embodiments, the pharmaceutical composition has a release profile in which 90% of acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16, or 16-24 hours. Contains 600-800 mg of acetaminophen formulated for extended release. Other active ingredients may be released immediately after administration or with an analgesic.

  In still other embodiments, the pharmaceutical composition has a release profile in which at least 90% of the acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16, or 16-24 hours. Contains 800-1000 mg of acetaminophen formulated for extended release. Other active ingredients may be released immediately after administration or with an analgesic.

  In some other embodiments, the pharmaceutical composition is 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50, individually or in combination with one or more analgesics. -600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-500 mg 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 200-600 mg, 200-400 mg, 400- 000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg, with 20-50% of the analgesic being 2 hours of administration Analgesics are formulated for extended release, characterized by a two-phase release profile that is released within and the remainder is released continuously for 5-24 hours or at a constant rate It is characterized in. Other active ingredients may be released immediately after administration or with an analgesic.

  In still other embodiments, the analgesic is released within 2, 2 hours of administration of the analgesic over the course of 5-8, 8-16 or 16-24 hours. Formulated for extended release with a two-phase release profile released continuously or at a constant rate. In one embodiment, the analgesic is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, nabumetone, and acetaminophen. In other embodiments, the analgesic is acetaminophen. In some embodiments, the pharmaceutical composition further comprises an antimuscarinic, antidiuretic or antispasmodic agent. Other active ingredients may be released immediately after administration or with an analgesic.

  In other embodiments, the pharmaceutical composition is wherein 20, 30, 40 or 50% of the acetaminophen is released within 2 hours of administration and the remainder between 5-8, 8-16 or 16-24 hours 50-400 mg acetaminophen formulated for extended release with a biphasic release profile released continuously or at a constant rate. Other active ingredients may be released immediately after administration or with an analgesic.

  In other embodiments, the pharmaceutical composition is wherein 20, 30, 40 or 50% of the acetaminophen is released within 2 hours of administration and the remainder between 5-8, 8-16 or 16-24 hours Contains 100-300 mg acetaminophen formulated for extended release with a biphasic release profile released at a constant rate over time. Other active ingredients may be released immediately after administration or with an analgesic.

  In other embodiments, the pharmaceutical composition is wherein 20, 30, 40 or 50% of the acetaminophen is released within 2 hours of administration and the remainder between 5-8, 8-16 or 16-24 hours 400-600 mg of acetaminophen formulated for extended release with a biphasic release profile released continuously or at a constant rate. Other active ingredients may be released immediately after administration or with an analgesic.

  In other embodiments, the pharmaceutical composition is wherein 20, 30, 40 or 50% of the acetaminophen is released within 2 hours of administration and the remainder between 5-8, 8-16 or 16-24 hours Containing 600-800 mg of acetaminophen formulated for extended release with a biphasic release profile released continuously or at a constant rate. Other active ingredients may be released immediately after administration or with an analgesic.

  In other embodiments, the pharmaceutical composition is wherein 20, 30, 40 or 50% of the acetaminophen is released within 2 hours of administration and the remainder between 5-8, 8-16 or 16-24 hours Containing 800-1000 mg of acetaminophen formulated for extended release with a biphasic release profile released continuously or at a constant rate. Other active ingredients may be released immediately after administration or with an analgesic.

  In other embodiments, the pharmaceutical composition is wherein 20, 30, 40 or 50% of the acetaminophen is released within 2 hours of administration and the remainder between 5-8, 8-16 or 16-24 hours Containing 1000 to 1200 mg of acetaminophen formulated for extended release with a biphasic release profile released continuously or at a constant rate. Other active ingredients may be released immediately after administration or with an analgesic.

  Other aspects of the present application provide for a subject in need thereof: (1) one or more analgesics, (2) an α-blocker or a 5α-reductase inhibitor or both, and (3) 1 It relates to a method for treating nocturia by administering one or more antidiuretics. In certain embodiments, the antidiuretic agent: (1) increases vasopressin secretion; (2) enhances vasopressin receptor activation; (3) atrial natriuretic peptide (ANP) or C-type natriuretic peptide Acts to reduce secretion of (CNP); or (4) reduce ANP and / or CNP receptor activation.

  Typical antidiuretics are antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogues (eg desmopressin argypressin, repressin, ferripressin, ornipressin, telluripressin); vasopressin receptor agonist, atrial Natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) receptor (ie, NPR1, NPR2, NPR3) antagonists (eg, HS-142-1, Isatin, [Asu7,23 ′] b-ANP- (7 -28)], ananthin, Streptomyces coerulescens-derived cyclic peptide, and 3G12 monoclonal antibody), somatostatin type 2 receptor antagonist (eg, somatostatin), and pharmaceutically acceptable derivatives thereof, etc. Body, salt, including hydrates and solvates, are not limited thereto.

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

  Another aspect of the present application is to administer a first pharmaceutical composition comprising a diuretic to a person in need thereof, then (1) one or more analgesics and (1) one or more The present invention relates to a method for reducing the frequency of urination by administering a second pharmaceutical composition comprising the above α-blocking agent, one or more 5α-reductase inhibitors, or both. The first pharmaceutical composition is administered and formulated to exhibit a diuretic effect within 6 hours of administration and is administered at least 8 or 7 hours before bedtime. The second pharmaceutical composition is administered within 2 hours before bedtime. The first pharmaceutical composition is formulated for immediate release and the second pharmaceutical composition is formulated for extended or delayed extended release.

Examples of diuretics are acidified salts such as CaCl ₂ and NH ₄ Cl; arginine vasopressin receptor 2 antagonists such as amphotericin B and lithium citrate; aquatic diuretics such as red ginseng and Junipe; Na-H exchange such as dopamine Antagonists; carbonic anhydrase inhibitors such as acetazolamide and dorzolamide; loop diuretics such as bumetanide, ethacrynic acid, furosemide and torsemide; osmotic diuretics such as glucose and mannitol; amiloride, spironolactone, triamterene, potassium canrenoate, etc. Including but not limited to potassium-sparing diuretics; thiazides such as bendroflumethiazide 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 antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, tropium, and atropine. The second pharmaceutical composition can be formulated into an immediate release formulation or a delayed release formulation or an extended release formulation. In some embodiments, the second pharmaceutical composition further comprises one or more antidiuretic agents. In some other embodiments, the second pharmaceutical composition further comprises one or more antispasmodic agents. Another aspect of the present application is a method for reducing urination frequency by alternately administering two or more analgesics to a subject in need thereof to prevent the development of drug resistance. About. In one embodiment, the method includes administering a first analgesic during a first period and then administering a second analgesic during a second period. In other embodiments, the method further comprises administering a third analgesic during the third period. The first, second and third analgesics are different 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 3 days to 3 weeks. In other embodiments, the first, second and third analgesics are all formulated for extended or delayed extended release.

  Another aspect of the present application is 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 the purpose of extended release or delayed extended release. To a pharmaceutical composition. In some embodiments, the plurality of active ingredients includes one or more analgesics and one or more antidiuretics. In other embodiments, the plurality of active ingredients is one or more analgesics, one or more α-blockers, one or more 5α-reductase inhibitors and one or more. Contains antimuscarinic agents. In other embodiments, the plurality of active ingredients is one or more analgesics, one or more alpha-blockers, one or more antidiuretics and one or more antimuscarins. Contains agents. In other embodiments, the pharmaceutical composition comprises two different analgesics selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen sodium, naproxen, nabumetone, acetaminophen, and indomethacin. In yet other embodiments, the pharmaceutical composition is one analgesic selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen sodium, nabumetone, acetaminophen, and indomethacin; one or more alpha-blockers and One antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.

  In other embodiments, the pharmaceutical composition of the present application further comprises one or more antispasmodics and / or one or more antidiuretics. Examples of antispasmodic agents include, but are not limited to carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, metcarbamol, clonidine, clonidine analogs, and dantrolene. In some embodiments, the antispasmodic agent is 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 800 mg, Used in daily doses of 50 mg to 200 mg, 100 mg to 800 mg, 100 mg to 500 mg, 200 mg to 800 mg, and 200 mg to 500 mg. Antispasmodic agents can be formulated into pharmaceutical compositions alone or with other active ingredients for immediate release, extended release, delayed-extended release or combinations thereof.

  In some embodiments, the pharmaceutical composition has a total amount of one or more analgesics selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen per agent. -400 mg comprising one or more alpha-blockers and one or more antimuscarinic agents selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine in a total amount of 1 to 25 mg, 20-60% of the active ingredient is released within 2 hours of administration and the remainder of the active ingredient is continuously between 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours, Or formulated for extended release with a two-phase release profile released at a constant rate Characterized in that it is.

  In some embodiments, the pharmaceutical composition comprises 50 or more analgesics selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen per agent. One or more alpha-blockers and an antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (eg desmopressin argipresin, repressin, ferripressin, ornipressin, telliprecin) in an amount of ~ 400 mg ); Vasopressin receptor agonist, atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) receptor (ie, NPR1, NPR2, NPR3) antagonists (eg, HS-142-1, Isachi) , [Asu7,23 ′] b-ANP- (7-28)], ananthin, Streptomyces coerulescens-derived cyclic peptide, and 3G12 monoclonal antibody); somatostatin type 2 receptor antagonist (eg, somatostatin), and pharmaceutically acceptable Comprising one or more antidiuretics selected from its derivatives, analogs, salts, hydrates and solvates, wherein the pharmaceutical composition comprises 20-60% of the active ingredient within 2 hours of administration For extended release with a biphasic release profile that is released and the remainder is released continuously or at a constant rate for 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours It is characterized by being blended.

  In some embodiments, the pharmaceutical composition is (1) 1 in an amount of 50-400 mg per drug selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone and acetaminophen. One or more analgesics, (2) one or more α-blockers, or one or more 5α-reductase inhibitors, or both, and (3) carisoprodol, a benzodiazepine, A pharmaceutical composition comprising one or more antispasmodic agents in a total amount of 50 to 500 mg selected from the group consisting of baclofen, cyclobenzaprine, metaxalone, metcarbamol, clonidine, clonidine analogues, and dantrolene, 20-60% are released within 2 hours of administration, The remainder is formulated for extended release with a biphasic release profile that is released continuously or at a constant rate during 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours. It is characterized by that.

  As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweeteners and the like. Pharmaceutically acceptable carriers include a wide range of materials including, but not limited to, a variety of materials such as flavoring agents, sweeteners, and buffering agents and absorbents that may be required to prepare a particular therapeutic composition. Can be prepared. The use of such media and materials with pharmaceutically active substances is well known in the art. Except insofar as any conventional medium or substance is incompatible with the active ingredient, its use in a therapeutic composition is contemplated.

  The invention is further illustrated by the following examples that should not be construed as limiting. The contents of all references, patents and published patent specifications cited throughout the specification are hereby incorporated by reference in their entirety.

(Inhibition of urination impulse)
Twenty male and female volunteers, each of whom experienced premature urge to urinate or urine, who were impeded in their ability to sleep for a sufficient amount of time to feel moderate rest, were included. Each subject took ibuprofen 400-800 mg as a single dose before going to bed. At least 14 subjects reported better rest due to less frequent wake-up due to urination impulses.

  Several subjects reported that after using ibuprofen for several weeks at night, the benefits of reducing the frequency of urination urges were no longer recognized. However, both of these subjects further reported that profits recovered after a few days of taking the dose.

(Effects of analgesics, botulinum neurotoxins and antimuscarinic agents on the response of macrophages to inflammatory and non-inflammatory stimuli)
(Experimental design)
This study determines the dose and in vitro efficacy of analgesics and antimuscarinic agents in controlling macrophage response to inflammatory and non-inflammatory stimuli via COX2 and prostaglandins (PGE, PGH, etc.) It is designed as follows. Establish a baseline (dose and kinetic) response to inflammatory and non-inflammatory effectors in bladder cells. Briefly, cultured cells are exposed to analgesics and / or antimuscarinic agents in the presence and absence of various effectors.

  The effectors are: lipopolysaccharide (LPS), which is an inflammatory substance and Cox2 inducer as an inflammatory stimulus; carbachol or acetylcholine, which is a smooth muscle contraction stimulant as a non-inflammatory stimulus; an acetylcholine release inhibitor known as a positive control Botulinum neurotoxin A; and produced after sequential oxidation of arachidonic acid (AA), γ-linolenic acid (DGLA) or eicosapentaenoic acid (EPA) by cyclooxygenases (COX1 and COX2) and terminal prostaglandin synthase in cells As a prostaglandin precursor, AA, DGLA or EPA is included.

  Analgesics: salicylates such as aspirin, isobutylpropanephenolic acid derivatives (ibuprofen) such as advil, motrin, nuprin and mediprene, areve, anaprox, antaldin, feminax ultra, flanax, in the, midol long analgesia, nargesine, Naposin, naprelan, naprogesic, naprosin, naprosin suspension, naproxen sodium such as EC-naprosin, narosin, proxen, symflex and xenovid, acetic acid derivatives such as indomethacin (indocin), 1-naphthalene acetic acid derivatives such as nabumetone or lerafen, N-acetyl-para-aminophenol (APAP) derivatives such as acetaminophen or paracetamol (tylenol), and celecoxie Including the drive.

  Antimuscarinic drugs include: oxybutynin, solifenacin, darifenacin and atropine.

Macrophages are subjected to short (1-2 hours) or long (24-48 hours) stimulation by:
1) Various doses of each analgesic alone.
(2) Various doses of each analgesic in the presence of LPS.
(3) Various analgesics at various doses in the presence of carbachol or acetylcholine.
(4) Various analgesics at various doses in the presence of AA, DGLA or EPA.
(5) Various doses of botulinum neurotoxin A alone.
(6) Various doses of botulinum neurotoxin A in the presence of LPS.
(7) Various doses of botulinum neurotoxin A in the presence of carbachol or acetylcholine.
(8) Various doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.
(9) Various doses of each antimuscarinic agent alone.
(10) Various doses of each antimuscarinic agent in the presence of LPS.
(11) Various doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.
(12) Various doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

_Then, PGH 2, PGE, PGE _2, prostacyclin Jin, thromboxanes, IL-1β, IL-6 , TNF-α release, COX2 activity, production of cAMP and cGMP, IL-1β, IL- 6, TNF Analyze cells for production of α and COX2 mRNA and surface expression of CD80, CD86 and MHC class II molecules.

(Materials and methods)
(Macrophage cells)
In this test, mouse RAW264.7 or J774 macrophage cells (obtained from ATCC) were used. Cells were maintained in media 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. The cells were cultured at 37 ° C. in a 5% CO ₂ atmosphere and divided (passaged) once a week.

(In vitro analgesic treatment of macrophage cells)
RAW 264.7 macrophage cells were seeded in 96-well plates at a cell density of 1.5 × 10 ⁵ cells / well in 100 μL of cell culture medium. The cells are (1) various concentrations of analgesics (acetaminophen, aspirin, ibuprofen or naproxen), (2) various concentrations of lipopolysaccharide (LPS) that are inflammatory stimulating effectors for macrophage cells, (3) Treated with various concentrations of carbachol or acetylcholine, (4) analgesic and LPS or (5) analgesic and carbachol or acetylcholine, effectors of non-inflammatory stimuli. Briefly, the analgesic is dissolved in FBS-free medium (ie RPMI 1640 supplemented with 15 mM HEPES, 2 mM L-glutamine, 100 U / mL penicillin, and 100 μg / mL streptomycin) and serially diluted in the same medium to obtain the desired Dilute to concentration. For cells treated with analgesic in the absence of LPS, 50 μL of analgesic solution and 50 μL of FBS-free medium were added to each well. For cells treated with analgesic in the presence of LPS, 50 μL of analgesic solution and 50 μL of LPS (derived from Salmonella typhimurium) in FBS-free medium were added to each well. All conditions were tested twice.

  After culturing for 24 or 48 hours, 150 μL of the culture supernatant was collected, centrifuged at 8,000 rpm at 4 ° C. for 2 minutes to remove cells and debris, and stored at −70 ° C. for analysis of cytokine response by ELISA. Cells were washed in 500 μL of phosphate buffered saline (PBS) and centrifuged (1,500 rpm, 4 ° C. for 5 minutes). Thereafter, half of the cells were snap frozen in liquid nitrogen and stored at -70 ° C. The remaining cells were stained with a fluorescent monoclonal antibody and analyzed by flow cytometry.

(Flow cytometric analysis of costimulatory molecule expression)
For flow cytometric analysis, macrophages were diluted with 100 μL FACS buffer (2% bovine serum albumin (BSA) and phosphate buffered saline (PBS) with 0.01% NaN ₃ ) and FITC-conjugated. gate anti CD40, stained PE- conjugated anti-CD80, PE-conjugated anti-CD86 antibody, in addition to 4 ° C. the anti-MHC class ^{II (I-a d) PE} (BD Biosciences) for 30 minutes. The cells were then washed by centrifugation (1,500 rpm, 4 ° C. for 5 minutes) in 300 μL of FACS buffer. After the second wash, the cells were resuspended in 200 μL of FACS buffer and further expressed a given marker (single positive) or a combination of markers (double positive) on an Accuri C6 flow cytometer (BD Bioscience) The percentage of cells was analyzed.

(Analysis of cytokine response by ELISA)
Culture supernatants were subjected to cytokine specific ELISA to determine IL-1β, IL-6 and TNF-α responses in macrophage cultures treated with analgesics, LPS alone or a combination of LPS and analgesics. Analysis was performed overnight with Nunc MaxiSorp coated with 100 μL of anti-mouse IL-6, TNA-α mAbs (BD Biosciences) or IL-1β mAb (R & D Systems) in 0.1 M sodium bicarbonate buffer (pH 9.5). Performed on Immunoplates (Nunc). After washing twice with PBS (200 μL / well), 200 μL of PBS 3% BSA was added to each well (blocking), and the plate was further incubated at room temperature for 2 hours. The plate was washed twice again by adding 200 μL / well, 100 μL of serial dilutions of cytokine standard and culture supernatant were added to each 2 well, and the plate was further incubated at 4 ° C. overnight. Finally, the plate was washed twice and further 100 μL of secondary biotinylated anti-mouse IL-6, TNA-α mAbs (BD Biosciences) or IL-1β (R & D Systems) followed by peroxidase-labeled goat anti-biotin mAb (Vector Laboratories) ). A color reaction is generated by the addition of 2,2′-azino-bis (3) -ethylbenzylthiazoline-6-sulfonic acid (ABTS) substrate and H ₂ O ₂ (Sigma), and the Victor® V multi Absorbance at 415 nm was measured with a label plate reader (Perkin Elmer).

(Measurement of COX2 activity and production of cAMP and cGMP)
COX2 activity in cultured macrophages is measured by continuous competition ELISA (R & D Systems). Production of cAMP and cGMP is measured by cAMP assay and cGMP assay. These assays are routinely performed in the art.

(result)
Table 1 summarizes the experiments performed using the Raw 264 macrophage cell line and the main findings about the effect of analgesics on cell surface expression of the costimulatory molecules CD40 and CD80. Since the expression of these molecules is stimulated by COX2 and inflammatory signals, it was evaluated to determine the functional consequences of COX2 inhibition.

As shown in Table 2, acetaminophen, aspirin, ibuprofen and naproxen all tested except for the highest dose that appears to promote rather than inhibit the expression of costimulatory molecules (ie 5 × 10 ⁶ nM). The basal expression of the costimulatory molecules CD40 and CD80 by macrophages is inhibited at doses (ie 5 × 10 ⁵ nM, 5 × 10 ⁴ nM, 5 × 10 ³ nM, 5 × 10 ² nM, 50 nM and 5 nM). As shown in FIGS. 1A and 1B, such inhibitory effects on CD40 and CD50 expression were observed at analgesic doses as low as 0.05 nM (ie 0.00005 μM). This finding supports the notion that controlled release of small doses of analgesics can be preferable to rapid delivery of large doses. Experiments also revealed that acetaminophen, aspirin, ibuprofen and naproxen have similar inhibitory effects on LPS-induced CD40 and CD80 expression.

(Table 1. Summary of experiment)

(Table 2. Summary of key findings)

Table 3 summarizes the results of several studies that measured serum levels of analgesics after oral therapeutic dose administration in human adults. As shown in Table 3, the maximum serum level of analgesic after oral therapeutic dose administration is in the range of 10 ⁴ to 10 ⁵ nM. Thus, the doses of analgesics tested in vitro in Table 2 encompass the range of concentrations that can be achieved in vivo in humans.

(Table 3. Serum levels of analgesics in human blood after oral therapeutic dose administration)

(Effects of analgesics, botulinum neurotoxins and antimuscarinic agents on mouse bladder smooth muscle cell responses to inflammatory and non-inflammatory stimuli)
(Experimental design)
This study characterizes how the optimal dose of analgesic determined in Example 2 affects bladder smooth muscle cells in cell culture or tissue culture, and different classes of analgesics cooperate to produce COX2. And designed to investigate whether the PGE2 reaction can be more efficiently inhibited.

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

Primary cultures of mouse bladder smooth muscle cells are subjected to short (1-2 hours) or long (24-48 hours) stimulation by:
(1) Various doses of each analgesic alone.
(2) Various doses of each analgesic in the presence of LPS.
(3) Various analgesics at various doses in the presence of carbachol or acetylcholine.
(4) Various analgesics at various doses in the presence of AA, DGLA or EPA.
(5) Various doses of botulinum neurotoxin A alone.
(6) Various doses of botulinum neurotoxin A in the presence of LPS.
(7) Various doses of botulinum neurotoxin A in the presence of carbachol or acetylcholine.
(8) Various doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.
(9) Various doses of each antimuscarinic agent alone.
(10) Various doses of each antimuscarinic agent in the presence of LPS.
(11) Various doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.
(12) Various doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

_Then, PGH 2, PGE, PGE _2, prostacyclin Jin, thromboxanes, IL-1β, IL-6 , TNF-α release, COX2 activity, production of cAMP and cGMP, IL-1β, IL- 6, TNF Analyze cells for production of α and COX2 mRNA and surface expression of CD80, CD86 and MHC class II molecules.

(Materials and methods)
(Separation and purification of mouse bladder cells)
Bladder cells were excised from euthanized C57BL / 6 mice (8-12 weeks old), further separated by enzymatic digestion and purified on a Percoll gradient. Briefly, urinary bladder from 10 mice was finely divided into a fine slurry with scissors in 10 mL of digestion buffer (RPMI 1640, 2% fetal calf serum, 0.5 mg / mL collagenase, 30 μg / mL DNase). I refused. The bladder slurry was enzymatically digested at 37 ° C. for 30 minutes. Undigested fragments were further dispersed with a cell strainer. The cell suspension was pelleted and added to discontinuous 20%, 40%, and 75% Percoll gradients for mononuclear cell purification. Each experiment used 50-60 bladders.

After multiple washes 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 100 μL was clear bottom black A 96-well cell culture microplate was seeded at a cell density of 3 × 10 ⁴ / well. The cells were cultured at 37 ° C. in a 5% CO ₂ atmosphere.

(In vitro analgesic treatment of cells)
Bladder cells can be treated with an analgesic solution (50 μL / well) alone, or carbachol (10 mol, 50 μL / well) as an example of a non-inflammatory stimulus, or Salmonella typhimurium lipopolysaccharide (LPS) as an example of a non-inflammatory stimulus (1 μg / mL, 50 μL / well). When no other effector was added to the cells, RPMI 1640 containing no fetal calf serum was added to the wells to adjust the final volume to 200 μL.

  After culturing for 24 hours, 150 μL of culture supernatant was collected, centrifuged at 8,000 rpm, 4 ° C. for 2 minutes to remove cells and debris, and -70 for analysis of prostaglandin E2 (PGE2) reaction by ELISA Stored at ° C. Cells were fixed, permeabilized and blocked, and cyclooxygenase-2 (COX2) was detected using a fluorescent substrate. Some experimental cells were stimulated in vitro for 12 hours for analysis of COX2 responses.

(Analysis of COX2 reaction)
The COX2 response was analyzed by cell-based ELISA using a human / mouse total COX 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 clear bottom black 96 well cell culture microplate. After incubation and washing, HRP-conjugated anti-mouse IgG and AP-conjugated anti-rabbit IgG were added to the wells. After further incubation and one wash, HRP- and AP-fluorogenic substrates were added. Finally, the fluorescence emitted at 600 nm (COX2 fluorescence) and 450 nm (GAPDH fluorescence) was read using a Victor® V multilabel plate reader (Perkin Elmer). Results are measured as relative fluorescence units (RFU) and expressed as relative levels of total COX2 normalized to the housekeeping protein GAPDH.

(Analysis of PGE2 reaction)
Prostaglandin E2 reaction was analyzed by continuous competition ELISA (R & D Systems). More specifically, the culture supernatant or PGE2 standard solution was added to the wells of a 96-well polystyrene microplate coated with goat anti-mouse polyclonal antibody. After 1 hour incubation on a microplate shaker, HRP conjugated PGE2 was added and the plate was incubated for an additional 2 hours at room temperature. The plate was then washed and HRP substrate solution was added to each well. After coloring for 30 minutes and further stopping the reaction by adding sulfuric acid, the plate was read at 450 nm while correcting the wavelength at 570 nm. Results are expressed as the average pg / mL of PGE2.

(Other analysis)
PGH _2, PGE, prostacyclin Jin, thromboxanes, IL-1β, IL-6 , and the release of TNF-alpha, production of cAMP and cGMP, IL-l [beta], the production of IL-6, TNF-α and COX2 mRNA, And surface expression of CD80, CD86 and MHC class II molecules is determined as described in Example 2.

(Analgesic inhibits mouse bladder cell COX2 response to inflammatory stimuli)
Several analgesics (acetaminophen, aspirin, ibuprofen and naproxen) were tested on mouse bladder cells at a concentration of 5 μM or 50 μM to determine if the analgesic was able to induce a COX2 response. Analysis of the 24-hour culture showed that none of the analgesics tested induced the COX2 response of mouse bladder cells in vitro.

  The effects of these analgesics on the COX2 response of mouse bladder cells to carbachol or LPX stimulation were also tested in vitro. As shown in Table 1, the doses of carbachol tested have no significant effect on mouse bladder cell COX2 levels. On the other hand, LPS significantly increased total COX2 levels. Interestingly, acetaminophen, aspirin, ibuprofen and naproxen all were able to suppress the action of LPS on COX2 levels. The inhibitory effect of analgesics was seen when these drugs were tested at either 5 μM or 50 μM (Table 4).

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

(Analgesic inhibits mouse bladder cell PGE2 response 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 mouse bladder cell COX2 levels by 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 suppressed the effect of LPS on PGE2 secretion, and there was no difference between the responses of cells treated with 5 or 50 μM doses of analgesic.

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

  Taken together, these data indicate that 5 μM or 50 μM analgesic alone does not induce COX2 and PGE2 responses in mouse bladder cells. However, 5 μM or 50 μM analgesic significantly inhibits COX2 and PGE2 responses in mouse bladder cells stimulated in vitro with LPS (1 μg / ml). There was no significant effect of analgesics on COX2 and PGE2 responses in mouse bladder cells stimulated with carbachol (1 mM).

(Effects of analgesics, botulinum neurotoxins and antimuscarinic agents on mouse bladder smooth muscle cell contraction)
(Experimental design)
Cultured mouse or rat bladder smooth muscle cells and mouse or rat bladder smooth muscle tissue are exposed to inflammatory and non-inflammatory stimuli in the presence of various concentrations of analgesics and / or antimuscarinic agents. Stimulator-induced muscle contraction is measured to assess the inhibitory effect of analgesics and / or antimuscarinic agents.

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

Primary cultures of mouse bladder smooth muscle cells are subjected to short (1-2 hours) or long (24-48 hours) stimulation by:
(1) Various doses of each analgesic alone.
(2) Various doses of each analgesic in the presence of LPS.
(3) Various analgesics at various doses in the presence of carbachol or acetylcholine.
(4) Various analgesics at various doses in the presence of AA, DGLA or EPA.
(5) Various doses of botulinum neurotoxin A alone.
(6) Various doses of botulinum neurotoxin A in the presence of LPS.
(7) Various doses of botulinum neurotoxin A in the presence of carbachol or acetylcholine.
(8) Various doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.
(9) Various doses of each antimuscarinic agent alone.
(10) Various doses of each antimuscarinic agent in the presence of LPS.
(11) Various doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.
(12) Various doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

(Materials and methods)
Primary mouse bladder cells are isolated as described in Example 3. In some experiments, bladder tissue culture is used. Bladder smooth muscle cell contraction is recorded on a Grass polygraph (Quincy Mass, USA).

(Effects of oral analgesics and antimuscarinic agents on COX2 and PGE2 responses in mouse bladder smooth muscle cells)
(Experimental design)
Normal mice and mice with overactive bladder syndrome are administered oral doses of aspirin, naproxen sodium, ibuprofen, indosin, nabumetone, tylenol, celecoxib, oxybutynin, solifenacin, darifenacin, atropine and combinations thereof. The control group includes untreated normal mice and untreated OAB mice with overactive bladder syndrome. Thirty minutes after the final administration, the bladder is collected and stimulated in vitro with carbachol or acetylcholine. In some experiments, the bladder is treated with botulinum neurotoxin A prior to stimulation with carbachol. Animals are maintained in metabolic cages and urination frequency (and volume) is assessed. Bladder excretion is calculated by monitoring water intake and cage lay weight. Serum _PGH 2, PGE, PGE ₂ by ELISA, prostacyclin Jin, thromboxanes, IL-1β, IL-6 , TNF-α, measuring cAMP and cGMP levels. Flow cytometry measures CD80, CD86, MHC class II expression in whole blood cells.

  At the end of the experiment, animals are euthanized and ex vivo bladder contractions are recorded on a Grass polygraph. A portion of the bladder is fixed with formalin and the COX2 response is analyzed by immunohistochemistry.

(Effects of analgesics, botulinum neurotoxins and antimuscarinic agents on the response of human bladder smooth muscle cells to inflammatory and non-inflammatory stimuli)
(Experimental design)
This study characterizes how the optimal dose of analgesic determined in Examples 1-5 acts on human bladder smooth muscle cells in cell culture or tissue culture, and different types of analgesics cooperate Is designed to investigate whether COX2 and PGE2 reactions can be more efficiently inhibited.

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

Human bladder smooth muscle cells are subjected to short (1-2 hours) or long (24-48 hours) stimulation by:
(1) Various doses of each analgesic alone.
(2) Various doses of each analgesic in the presence of LPS.
(3) Various analgesics at various doses in the presence of carbachol or acetylcholine.
(4) Various analgesics at various doses in the presence of AA, DGLA or EPA.
(5) Various doses of botulinum neurotoxin A alone.
(6) Various doses of botulinum neurotoxin A in the presence of LPS.
(7) Various doses of botulinum neurotoxin A in the presence of carbachol or acetylcholine.
(8) Various doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.
(9) Various doses of each antimuscarinic agent alone.
(10) Various doses of each antimuscarinic agent in the presence of LPS.
(11) Various doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.
(12) Various doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

_Then, PGH 2, PGE, PGE _2, prostacyclin Jin, thromboxanes, IL-1β, IL-6 , TNF-α release, COX2 activity, production of cAMP and cGMP, IL-1β, IL- 6, TNF Analyze cells for production of α and COX2 mRNA and surface expression of CD80, CD86 and MHC class II molecules.

(Effects of analgesics, botulinum neurotoxins and antimuscarinic agents on human bladder smooth muscle cell contraction)
(Experimental design)
Cultured human bladder smooth muscle cells are exposed to inflammatory and non-inflammatory stimuli in the presence of various concentrations of analgesics and / or antimuscarinic agents. Stimulator-induced muscle contraction is measured to assess the inhibitory effect of analgesics and / or antimuscarinic agents.

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

Human bladder smooth muscle cells are subjected to short (1-2 hours) or long (24-48 hours) stimulation by:
(1) Various doses of each analgesic alone.
(2) Various doses of each analgesic in the presence of LPS.
(3) Various analgesics at various doses in the presence of carbachol or acetylcholine.
(4) Various analgesics at various doses in the presence of AA, DGLA or EPA.
(5) Various doses of botulinum neurotoxin A alone.
(6) Various doses of botulinum neurotoxin A in the presence of LPS.
(7) Various doses of botulinum neurotoxin A in the presence of carbachol or acetylcholine.
(8) Various doses of botulinum neurotoxin A in the presence of AA, DGLA or EPA.
(9) Various doses of each antimuscarinic agent alone.
(10) Various doses of each antimuscarinic agent in the presence of LPS.
(11) Various doses of each antimuscarinic agent in the presence of carbachol or acetylcholine.
(12) Various doses of each antimuscarinic agent in the presence of AA, DGLA or EPA.

  Bladder smooth muscle cell contraction is recorded on a Grass polygraph (Quincy Mass, USA).

Effect of analgesics on the response of normal human bladder smooth muscle cells to inflammatory and non-inflammatory signals
(Experimental design)
(Culture of normal human bladder smooth muscle cells)
Normal human bladder smooth muscle cells were isolated from macroscopically normal human bladder pieces by enzymatic digestion. The cells were suspended in vitro by culturing at 37 ° C. in 5% CO ₂ atmosphere in RPMI 1640 supplemented with 10% fetal calf serum, 15 mM HEPES, 2 mM L-glutamine, 100 U / mL penicillin and 100 mg / mL streptomycin, The cells were subcultured once a week by replating in a new culture flask after trypsinization to detach the cells. In the first week of culture, 0.5 ng / mL epidermal growth factor, 2 ng / mL fibroblast growth factor, and 5 μg / mL insulin were added to the medium.

(In vitro analgesic treatment of normal human bladder smooth muscle cells)
Bladder smooth muscle cells that were trypsinized and seeded at 100 × L in a microculture plate at a cell density of 3 × 10 ⁴ cells / well were treated with analgesic solution (50 μL / well) alone, or carbachol (as an example of a non-inflammatory stimulus). 10 mol, 50 μL / well), or Salmonella typhimurium lipopolysaccharide (LPS) (1 μg / mL, 50 μL / well) as an example of a non-inflammatory stimulus. When no other effector was added to the cells, RPMI 1640 containing no fetal calf serum was added to the wells to adjust the final volume to 200 μL.

After culturing for 24 hours, 150 μL of the culture supernatant was collected, centrifuged at 8,000 rpm at 4 ° C. for 2 minutes to remove cells and residues, and for analysis of prostaglandin E2 (PGE ₂ ) reaction by ELISA— Stored at 70 ° C. Cells were fixed, permeabilized and blocked, and COX2 was detected using a fluorescent substrate. Some experimental cells were stimulated in vitro for 12 hours to analyze COX2, PGE2 and cytokine responses.

(Analysis of COX2, PGE2 and cytokine responses)
The COX2 and PGE2 reactions were analyzed by the method described in Example 3. Cytokine responses were analyzed by the method described in Example 2.

(result)
Analgesics inhibit the COX2 response of normal human bladder smooth muscle cells to inflammatory and non-inflammatory stimuli--analysis of cells and culture supernatants after 24 hours of culture, and all analgesics tested alone are normal humans It was shown not to induce a COX2 response 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 higher levels of COX2 response in normal human bladder smooth muscle cells. Acetaminophen, aspirin, ibuprofen and naproxen all were able to suppress the effects of carbachol and LPS on COX2 levels. When these drugs were tested at either 5 μM or 50 μM, analgesic inhibitory effects on LPS-induced responses were seen.

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

  Analgesics inhibit PGE2 responses of normal human bladder smooth muscle cells to inflammatory and non-inflammatory stimulants-- consistent with the induction of the COX2 response described above, both carbachol and LPS are PGE2 by normal human bladder smooth muscle cells. Induced production. Acetaminophen, aspirin, ibuprofen and naproxen were also confirmed to inhibit LPS-induced PGE2 response at 5 μM or 50 μM (Table 7).

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

  Analgesics inhibit the cytokine response of normal human bladder smooth muscle cells to inflammatory stimuli-analysis of cells and culture supernatants after 24 hours of culture, and all analgesics tested alone were normal human bladder smooth muscle cells It was shown not to induce IL-6 or TNFα secretion. As shown in Tables 8 and 9, the carbachol test dose induced a low but significant TNFα and IL-6 response in normal human bladder smooth muscle cells. On the other hand, LPS treatment resulted in strong induction of these pro-inflammatory cytokines. Acetaminophen, aspirin, ibuprofen and naproxen inhibit the effects of carbachol and LPS on TFNα and IL-6 reactions. When these drugs were tested at either 5 μM or 50 μM, analgesic inhibitory effects on LPS-induced responses were seen.

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

Table 9. IL-6 secretion by normal human bladder smooth muscle cells after in vitro stimulation with analgesic and non-inflammatory stimulants and analgesic treatment

  Primary normal human bladder smooth muscle cells were isolated, cultured, and evaluated for their response to analgesics in the presence of non-inflammatory (carbacol) and inflammatory (LPS) stimulants. The goal of this study was to determine whether normal human bladder smooth muscle cells reproduce the findings previously seen in mouse bladder cells.

  The above experiments will be repeated with delayed release, or extended release formulations, or analgesics and / or antimuscarinic agents in delayed and extended release formulations.

  The above is intended to teach those skilled in the art how to practice the present invention, and details any obvious modifications or variations thereof that will become apparent to those skilled in the art after reading this description. Not intended to explain. However, all such obvious modifications and variations are intended to be included within the scope of the present invention as defined in the following claims. The claims are intended to cover the claimed elements and steps in any order effective to fulfill their intended purpose, unless the context clearly indicates otherwise.

Claims (12)

Use of a pharmaceutical composition in the manufacture of a pharmaceutical formulation for reducing the frequency of urination in subjects with nocturia,
The pharmaceutical composition comprises three active ingredients consisting of (1) acetaminophen, (2) ibuprofen and (3) an α-blocker,
Each of acetaminophen and ibuprofen is formulated for extended release, delayed release, or delayed extended release,
an α-blocker is formulated for immediate release;
The use, wherein only the active ingredient is an active ingredient contained in the pharmaceutical composition.   Use according to claim 1, characterized in that each of acetaminophen and ibuprofen is formulated for extended release.   Use according to claim 1, characterized in that each of acetaminophen and ibuprofen is formulated for delayed release.   Use according to claim 1, characterized in that each of acetaminophen and ibuprofen is formulated for delayed extended release.   The use according to claim 1, wherein acetaminophen and ibuprofen are administered in an amount of 50 to 400 mg per drug.   Use according to claim 5, characterized in that the α-blocker is tamsulosin. Each of acetaminophen and ibuprofen is administered in an amount of 50-400 mg;
Use according to claims 1, 5 and 6, characterized in that it is formulated for extended release such that each of acetaminophen and ibuprofen is continuously released over a period of 5 to 24 hours.   Each of acetaminophen and ibuprofen is released in 20-60% of the acetaminophen and ibuprofen within 2 hours of administration and the rest of the acetaminophen and ibuprofen are continuously released over 5-24 hours Use according to claim 1, 5 and 6, characterized in that it is formulated for extended release characterized by a two-phase release profile. A pharmaceutical composition for reducing urination frequency in subjects with nocturia:
(1) an active ingredient comprising acetaminophen, ibuprofen and an α-blocker; and (2) comprising a pharmaceutically acceptable carrier, each of acetaminophen and ibuprofen being formulated for extended release and an α-blocker Said pharmaceutical composition formulated for immediate release.   The active ingredient comprises acetaminophen and ibuprofen in an amount of 50-400 mg per drug, each formulated so that each of acetaminophen and ibuprofen is released continuously over a period of 5-24 hours. Item 10. A pharmaceutical composition according to Item 9.   Extended release of acetaminophen and ibuprofen is released within 20 hours of each of the acetaminophen and ibuprofen within 2 hours of administration and the remainder of the acetaminophen and ibuprofen is continuous over a period of 5-24 hours 11. A pharmaceutical composition according to claim 9 or 10, characterized by a two-phase release profile released into the body.   The pharmaceutical composition according to claim 9, 10 or 11, characterized in that the α-blocker is tamsulosin.