JP2017532301A - Pharmaceutical formulations for reducing bladder spasms and methods of use thereof - Google Patents

Abstract

Methods and compositions for reducing bladder spasm are disclosed. The method includes administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of acetaminophen and an effective amount of at least one nonsteroidal anti-inflammatory agent (NSAID). In another embodiment, a method for reducing bladder spasm, wherein a pharmaceutical composition comprising an effective amount of at least one prostaglandin (PG) pathway inhibitor is administered to a subject in need thereof. Wherein the at least one PG pathway inhibitor is not acetaminophen or NSAID. [Selection] Figure 1

Description

  The present application relates generally to methods and compositions for reducing the incidence and / or frequency of bladder spasms.

  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.

  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 bulge produced by the wrinkles of the bladder wall flattens and thins as the bladder wall stretches, so the bladder accumulates more urine without a significant increase in internal pressure can do.

  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.

  Usually, as the bladder slowly fills with urine, it will gradually recognize the need to urinate. This sensation is a signal to start looking for the toilet. However, in people with bladder spasms, the sensations occur suddenly and often severely. The convulsions themselves are sudden and involuntary muscle compressions. Bladder spasm, or “detrusor muscle contraction”, occurs when the bladder muscles suddenly compress without warning, causing the need for urgent urination. Convulsions can push urine out of the bladder, causing leakage and can be extremely painful. When bladder spasm occurs, the bladder randomly contracts as if the patient was just before urinating. The patient feels that urination is necessary, and some leakage may occur. The convulsions are intense and the patient may like to pull it.

  Bladder spasms are particularly common in older adults, but can occur in children and pregnant women, and even in animals. Bladder spasm can interfere with normal activity, including the ability to sleep at successive and sufficient rest periods.

  A person who has experienced such a convulsion describes it as convulsive pain and sometimes a feeling of heat. Some women with severe bladder spasm compare muscle contraction to severe menstrual cramps, or even labor pains experienced during childbirth. In some instances, increased urinary urgency may be associated with medical conditions such as male benign prostatic hypertrophy or prostate cancer, or female pregnancy.

  Accordingly, there is a need for compositions and methods aimed at treating male and female subjects with bladder spasm.

  One aspect of the present application relates to a method for reducing bladder spasm in a subject. The method includes administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of acetaminophen and an effective amount of at least one nonsteroidal anti-inflammatory agent (NSAID).

  Another aspect is a method for reducing bladder spasm in a subject, wherein a pharmaceutical composition comprising an effective amount of at least one prostaglandin (PG) pathway inhibitor is administered to the subject in need thereof. And wherein the at least one PG pathway inhibitor is not acetaminophen or NSAID.

  Another aspect relates to a pharmaceutical composition for treating bladder spasm, comprising acetaminophen; one or more NSAIDs; and a pharmaceutically acceptable carrier.

  A further aspect relates to a pharmaceutical composition for treating bladder spasm, comprising one or more PG pathway inhibitors; and a pharmaceutically acceptable carrier.

FIG. 2 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 one skilled in the art that these specific details are not required in order to practice the present invention. Specific application descriptions are provided as exemplary embodiments only. The present invention is not intended to be limited to the embodiments presented, but is to be accorded the widest possible scope consistent with the principles and features disclosed herein.

  As used herein, the term “bladder spasm” refers to sudden and involuntary compression of the detrusor muscle. In some embodiments, the term “bladder spasm” refers to sudden and involuntary compression of the detrusor with pain. The term “bladder spasm” generally refers to the term “urinary incontinence”, which generally means involuntary urinary leakage, or the term “overactive bladder,” which generally refers to the problem of bladder storage function that causes sudden urination urges. ".

The term “NSAID” used in the present application is an acronym for “non-stereoidal anti-inflammatory drug”, which is an analgesic and antipyretic effect (lowering elevated body temperature without impairing consciousness and reducing pain) The term "non-steroidal" has a similar eicosanoid-suppressing anti-inflammatory effect (among other broad effects), at higher doses and with an anti-inflammatory effect (reduction of inflammation). These drugs are used to distinguish them from steroids. As an analgesic, NSAIDs are unique in that they are non-narcotic. NSAIDs include aspirin, ibuprofen, and naproxen. NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs are generally indicated for the reduction of symptoms in the following conditions: rheumatoid arthritis, osteoarthritis, inflammatory arthritis (eg ankylosing spondylitis, psoriatic arthritis, Reiter syndrome, acute gout, dysmenorrhea Disease, metastatic bone pain, headache and migraine, postoperative pain, mild to moderate pain due to inflammation and tissue damage, fever, ileus, and renal colic). Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase and inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isotopes. Cyclooxygenase arachidonic acid (itself phospholipase A ₂ by being derived from cellular phospholipids bilayers) catalyzes the prostaglandins and thromboxane formation from. Prostaglandins act (among other things) as messenger molecules in the inflammatory process. COX-2 inhibitors include celecoxib, etolicoxib, luminacoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib.

The term “prostaglandin (PG)” refers to a group of lipid compounds that are enzymatically derived from fatty acids and have a variety of physiological effects, such as regulating the contraction and relaxation of smooth muscle tissue in a subject. Each prostaglandin contains 20 carbon atoms including a five-carbon ring. Examples of prostaglandins are prostaglandin E ₁ (PGE ₁ ), prostaglandin E ₂ (PGE ₂ ), prostaglandin D ₂ , prostaglandin I ₂ (PGI ₂ , prostacyclin), and prostaglandin. F _2α (PGF _2α ) is included.

  The term “prostaglandin (PG) pathway inhibitor” as used herein refers to interacting directly or indirectly with one or more components involved in the synthesis or action of PG on the target tissue, and the target tissue Means an agent that interferes with prostaglandin levels or final action above. PG pathway inhibitors include, but are not limited to, PG inhibitors, prostaglandin transporter (PGT) inhibitors, and prostaglandin receptor (PGR) inhibitors. However, the term “PG pathway inhibitor” does not include an analgesic or NSAID as defined herein.

  The term “PG inhibitor” as used herein includes, but is not limited to, inhibitors of PG synthesis and inhibitors of PG activity. As used herein, the term “inhibitor of PG synthesis” includes phospholipase A2, prostaglandin synthase and tissue specific isomerase, and thromboxane synthase, PGF synthase, cytosolic PG synthase (cPGES), prostaglandin I synthase (PGIS). And agents that inhibit the production of prostaglandins, such as agents that inhibit the expression or activity of a synthase enzyme such as the microsomal PEGS enzyme (mPGES). Examples of PG synthesis inhibitors include flunixin meglumine. The term “inhibitor of PG synthesis” or “PG synthesis inhibitor” as used herein does not include analgesics or NSAIDs as defined herein.

  The term “inhibitor of PG activity” as used herein refers to an agent that antagonizes the action of prostaglandin itself by any means. Agents that interfere only with prostaglandin synthesis, such as by interfering with the action of prostaglandin synthase but not with the action of prostaglandin, are within the definition of an inhibitor of PG activity as used herein. Not included.

  As used herein, the term “PTG inhibitor” refers to the expression of PG transporters such as ATP-dependent multidrug resistance (MDR) transporter 4 or other MDR channels such as ABCC1, ABCC2, ABCC3, ABCC6, ABCG2 and ABCB11. Or an agent that inhibits activity. Examples of PGT inhibitors that inhibit PGT activity include, but are not limited to, compounds that inhibit MDR membrane pumps such as triazine compounds, verapamil, and calcium channel blockers; channels are quinidine, ketoconazole, itraconazole, azithromycin , Valspodar, cyclosporine, elacridar, fumitremolgin-C, gefitinib, and erythromycin. Examples of PGT inhibitors that inhibit PGT expression include promoter regions and / or transcription factors that bind to the promoter, or agents that control transcription of the MDR gene by targeting other gene regulatory regions. It is not limited. The term “PGR inhibitor” as used herein refers to an agent that inhibits the activity or expression of PGR. In some embodiments, the PGR is an E prostanoid receptor (EP) 1, EP2, EP3, and EP4 subtype of the PGE receptor; PGD receptor (DP1); PGF receptor (FP); PGI receptor Body (IP); and thromboxane receptor (TP). Alternative splicing generates two additional isoforms of human TP (TPα and TPβ) that differ only in their C-terminal tail, and FP (FPA and FPB) and eight EP3 variants. In some embodiments, the PGR further comprises a G protein-coupled receptor designated as a chemo-attractant receptor-homogeneous molecule (CRHME). In other embodiments, the PGR comprises all receptors that activate rhodopsin-like 7-transmembrane G protein coupled receptors.

  Examples of PGR activity inhibitors include, but are not limited to, anti-PGR antibodies and any agent that inhibits the G protein-coupled receptor signaling pathway. PGR expression inhibitors may be at the transcriptional level, translational level, or post-transcriptional level. An agent that inhibits PGR expression. Examples of PGR expression inhibitors include but are not limited to anti-PGR siRNA and miRNA.

  As used herein, the term “effective amount” means an amount necessary to achieve a selected result.

  As used herein, the term “analgesic” means a substance, compound or drug used to alleviate pain and includes anti-inflammatory compounds. Typical analgesics and / or anti-inflammatory agents, compounds or drugs are 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, meclofenamic acid sodium, 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, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, coxibs, celecoxib, rofecoxib, nabumetone, apazone, indomethacin, sulindac, etodolac, isobutylphenylpropionic acid, lumiracoxib, etoroxib, patricoxib Valdecoxib, thylakoxib, etodolac, dalbuferon, dexketoprofen, aceclofenac, lycoferon, bromfenac, loxoprofen, pranoprofen, piroxicam, nimesulide, sizoliline, 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran- 4-one, meloxicam, lornoxicam, d-indobufen, mofezo , Amtormethine, pranoprofen, tolfenamic acid, flurbiprofen, suprofen, oxaprozin, zaltoprofen, aluminoprofen, thiaprofenic acid, its pharmaceutical salts, its hydrates, and its solvates. It is not limited.

  As used herein, the term “coxib” means a compound or composition of compounds capable of inhibiting the activity or expression of a COX1 or COX2 enzyme.

  As used herein, the term “derivative” is a chemically modified compound, such as an ester or amide of an acid, or its modification, such as a protecting group such as a benzyl group for an alcohol or thiol or a tert-butoxycarbonyl group for an amine, A compound that is considered routine by a chemist with ordinary skill.

  As used herein, the term “analog” refers to a compound that retains a pharmacological and / or pharmacological activity that includes a particular compound or chemically modified form of that class and is characteristic of said compound or class. means.

  The term “pharmaceutically acceptable salt” as used herein means a derivative of the disclosed compound wherein the parent compound is modified by making its acid or base salts. 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, for example, conventional non-toxic salts, 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 those 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, Stearic 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, toluenesulfone Including salts prepared from organic acids such as acids, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like.

  The phrase “pharmaceutically acceptable” as used herein refers to reasonable benefits / risks within normal medical judgment and without excessive toxicity, irritation, allergic reactions, or other problems or complications. Used with respect to compounds, materials, compositions and / or formulations suitable for use in contact with human and animal tissues that are commensurate with the ratio.

  The term “immediate release” is used herein for pharmaceutical formulations that do not contain dissolution rate controlling materials. There is little 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. In some embodiments, the term “immediate release” refers to a drug that releases the active ingredient in less than 10, 20, 30, 40, 50, 60, 90, or 120 minutes after administration to a patient. Used for formulation.

  The term “extended release” as used herein is also known as sustained release (SR), sustained action (SA), time release (TR), controlled release (CR), modified release (MR) or continuous release (CR). Means the mechanism used in pharmaceutical tablets or capsules which dissolve slowly and 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 the duration of drug action by keeping the level of drug in the bloodstream more constant Is to reduce the peak amount of drug in the bloodstream. In some embodiments, the term “extended release” means that the active ingredient in a tablet or capsule is 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 after administration to a patient. Means a release profile that is released continuously or in pulses over a period of 16, 16, 18, 20, 22 or 24 hours.

  As used herein, the term “delayed release” refers to delaying or delaying the release of an active ingredient of a pharmaceutical composition for a given time (eg, 1, 2, 3, 4 or 5 hours) after administration of the pharmaceutical composition. Refers to drug release profile.

  The term “delayed extended release” as used herein refers to the release of an active ingredient of a pharmaceutical composition for a given time after administration of the pharmaceutical composition (eg, a delay time of 1, 2, 3, 4 or 5 hours, or Refers to a drug release profile that is delayed or postponed after passage through the stomach. Once the release begins, the active ingredient is slowly released over time (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22 or 24 hours) Over)) in a continuous or pulsed manner.

  The term “orally disintegrating preparation” used in the present application means a preparation that rapidly disintegrates or dissolves in the oral cavity. Orally disintegrating formulations differ from conventional tablets in that they are designed to dissolve on the tongue rather than swallowing the whole. In some embodiments, the orally disintegrating formulation can be used in the oral cavity in 5, 10, 20, 30, 60, 90, 120, 180, 240 or 300 seconds without additional water (ie, saliva alone). Designed to completely disintegrate or dissolve in

(Methods for reducing bladder spasms)
One aspect of the present application relates to a method for reducing bladder spasm by administering to a subject in need thereof an effective amount of acetaminophen and at least one non-steroidal anti-inflammatory drug (NSAID). . Another aspect of the present application provides urinary incontinence and / or overactive bladder by administering an effective amount of acetaminophen and at least one non-steroidal anti-inflammatory drug (NSAID) to a subject in need thereof. It relates to a method for treatment.

  NSAIDs are divided into the following groups based on their chemical structure and mechanism of action: i) aluminoprofen, benoxaprofen, carprofen, dexbuprofen, dexketoprofen, fenbuprofen, fenoprofen, Fluprofen, flurbiprofen, ibuprofen, ioxoprofen, ketoprofen, loxoprofen, microprofen, naproxen, oxaprozin, oxoprofen, pranoprofen, suprofen, thiaprofen, thixaprofen, zaltoprofen, and Propionic acid derivatives such as salts thereof; ii) salicylic acid derivatives such as aspirin, choline magnesium trisalicylic acid, diflunisal, olsalazine, salsalate, and sulfasalazine and salts thereof; ii ) Acetic acid derivatives such as aceclofenac, acemetacin, amfenac, diclofenac, etodolac, fenbufen, indomethacin, ketorolac, luminacoxib, nabumetone, progouracacine maleate, sulindac, tetradecylthioacetic acid, tolmetine and its salts; iv) meclofenamic acid, mefenamic acid Fenamic acid derivatives such as flufenamic acid, tolfenamic acid and salts thereof; v) enolic acid (oxicam) derivatives such as droxicam, isoxicam, lornoxicam, meloxicam, piroxicam and tenoxicam; Nimesulide, parecoxib, parecoxib sodium, rofecoxib, sulfonanilides, valdecoxib, o- ( Cetoxyphenyl) hept-2-ynyl-2-sulfide (APHS), DuP-697, JTE-522, L-745337, L-748780, L-761066, N- [2- (cyclohexyloxy) -4-nitro Phenyl] -methanesulfonamide (NS-398), RS-57067, S-2474, SC-57666. COX-2 inhibitors such as SC-58125 and its salts.

  Typical NSAIDS are aceclofenac, acemetacin aluminoprofen, aloxiprine, ampiroxicam, amtormetic acyl, aspirin, azapropazone, benolylate, benoxaprofen, benzydamine hydrochloride, bromfenal, bromfenal, bufexamac, butibufen, carprofen, carprofen, carprofen Celecoxib, choline magnesium trisalicylic acid, clonixin, dalbferon, desoxysulindac, dexketoprofen, diclofenac, diflunisal, dipion, droxicam, etodolac, etofenamate, ettricoxib, felbinac, fenbufen, fenoprofen, fentifenac, feprazin, feprazinoc Flufenamic acid, flurbipro Nen, ibuprofen, indomethacin, indoprofen, isoxicam, ketoprofen, ketolalac, ketorolac, lycoferon, romoxicam, lornoxicam, loxoprofen, luminacoxib, meclofenamate, meclofenamic acid, mefenamic acid, meloxicam, morniflumate, nabumetone, naproton Naproxen sodium, nebumetone, nepafenac, niflumic acid, nimesulide, oxaprozene, oxaprozin, oxyphenbutazone, parecoxib, phenylbutazone, piketoprofen, piroxicam, pirprofen, pranoprofen, preazolac, propifenazone, procazone, rofecoxib, salate ), Salicylamide, salicylates (eg, choline salicylic acid, Magnesium salicylate, choline magnesium salicylic acid, sodium salicylate, choline magnesium trisalicylic acid, etc.), salicylic acid, salicylic acids (eg aspirin / acetylsalicylic acid, etc.), salsalate, sodium meclofenamic acid, sodium thiosalicylate, sulindac, suprofen, tenidap, tenoxycam, Including, but not limited to, thiaprofenic acid, thylakoxib, tolfenamic acid, tolmetin, tramadol, tolamine salicylate, valdecoxib, zaltoprofen, zomepirac, salts thereof and combinations thereof.

  In certain embodiments, prior to administration, the subject may be diagnosed with a condition characterized by bladder spasm, and a pharmaceutical composition according to the present invention may be prescribed to the subject.

  In other embodiments, the pharmaceutical composition comprises one or more prostaglandin (PG) pathway inhibitors. In one embodiment, the PG pathway inhibitor is an inhibitor of PG synthetase. Examples of inhibitors of PG synthesis include non-steroidal anti-inflammatory drugs (NSAIDs).

  In other embodiments, the one or more PG pathway inhibitors comprises an inhibitor of PGR activity. Examples of inhibitors of PG activity include, but are not limited to, agents that block the binding of PG to any of its receptors: EP1, EP2, EP3, EP4, DP1, DP2, FP2, IP and TP. Examples of such inhibitors are the IP receptor inhibitors developed by Roche: RO3244019, the EP1 receptor antagonist ONO-85-39, the EP1 and EP2 receptor dual antagonist AH6809, and the EP4 antagonist RQ -15986, but is not limited to this.

  In some embodiments, the one or more PG pathway inhibitors comprises a PGT inhibitor. In certain embodiments, the PGT inhibitor is a PGT activity inhibitor. Examples of PGT activity inhibitors include anti-PGT antibodies and any known compounds capable of inhibiting ATP-dependent multidrug resistance transporter 4 or related MDR pumps that have been shown to transport PG. However, it is not limited to this. In other embodiments, the PGT inhibitor is a PGT expression inhibitor. Examples of PGT expression inhibitors include, but are not limited to, anti-PGT siRNA, antisense RNA targeting PGT mRNA, and agents that suppress gene transcription by affecting DNA methylation and / or chromatin modification.

In some embodiments, the one or more PG pathway inhibitors include inhibitors that target both the COX and POX active sites contained in both COX1 and COX2. In other embodiments, one or more of the PG pathway inhibitors including inhibitors that inhibit PGE ₂ pathway.

  In certain embodiments, the one or more PG pathway inhibitors comprises a PGR inhibitor. PGR is a G protein-coupled receptor that contains seven transmembrane domains. Examples of PGR include EP1, EP2, EP3, EP4, DP1, DP2, FP, IP1, IP2, CRTH2 and TP receptors. In some embodiments, the one or more PG pathway inhibitors comprise inhibitors that inhibit any of the PG receptors listed above. In some embodiments, the PGR inhibitor is a PGR activity inhibitor. Examples of PGR activity inhibitors include but are not limited to anti-PGR antibodies. In some embodiments, the PGR inhibitor is an inhibitor of PGE2 receptor activity, such as an EP1 activity inhibitor, an EP2 activity inhibitor, an EP3 activity inhibitor, or an EP4 activity inhibitor.

  In other embodiments, the one or more PG pathway inhibitors comprises a PGR expression inhibitor. Examples of PGR expression inhibitors include, but are not limited to, anti-PGR siRNA, antisense RNA targeting PGR mRNA, or agents that suppress gene transcription by affecting DNA methylation and / or chromatin modification.

  In some embodiments, the one or more PGR pathway inhibitors comprise an inhibitor of PGE2 receptor expression, such as an EP1 expression inhibitor, an EP2 expression inhibitor, an EP3 expression inhibitor or an EP4 expression inhibitor. . In some embodiments, the one or more PG pathway inhibitors comprises a small molecule inhibitor. As used herein, the term “small molecule inhibitor” means an inhibitor having a molecular weight of 1000 Daltons or less.

In some embodiments, the one or more PG pathway inhibitors comprise short interfering RNA (siRNA). siRNAs are double-stranded RNAs that can be engineered to induce sequence-specific post-transcriptional gene silencing of mRNAs corresponding to components of the PG pathway. siRNA, for example the expression of a gene, such as PGE ₂ receptor gene targeting purposes "silencing", utilizes the mechanism of RNA interference (RNAi). This “silencing” was initially observed in the context of transfecting cells with double-stranded RNA (dsRNA). After entering the dsRNA, it is cleaved by the RNase III-like enzyme Dicer into a double-stranded short interfering RNA (siRNA) 21-23 nucleotides in length containing a 2 nucleotide overhang at its 3 ′ end. Was confirmed. In an ATP-dependent step, siRNA is incorporated into a multi-subunit RNAi-induced silencing complex (RISC), which presents a signal for AGO2-mediated cleavage of the complementary mRNA sequence, which is subsequently followed by its cellular endonuclease. Bring about decomposition.

  In certain embodiments, the one or more PG pathway inhibitors comprise a synthetic siRNA or other class of small RNA that targets PG synthase RNA, PGT RNA or PGR RNA in the target cell / tissue. . The synthetically generated siRNA structurally mimics the type of siRNA that is normally processed by the enzyme Dicer in the cell. Synthetically generated siRNA may incorporate any chemical modification to the RNA structure known to promote siRNA stability and functionality. For example, in some examples, siRNA may be synthesized as locked nucleic acid (LNA) modified siRNA. LNA is a nucleic acid analog containing a methylene bridge that connects the 2 'oxygen of ribose to the 4' carbon. The bicyclic structure structurally mimics standard RNA monomers by immobilizing the furanose ring of the LNA molecule in the 3'-end conformation.

  In some embodiments, the one or more PG pathway inhibitors are engineered to transcribe short double-stranded hairpin-like RNA (shRNA) that is processed inside the cell to become the target siRNA. Includes vectors. shRNA can be generated using appropriate kits and lentiviral vectors such as Ambion's SILENCER® siRNA construction kit, Imgenex's GENESUPPRESSOR® construction kit, and Invitrogen's BLOCK-IT®-derived RNAi plasmid. It can be cloned into an expression vector. Synthetic siRNA and shRHA can be designed using well-known algorithms and synthesized using a conventional DNA / RNA synthesizer.

  In some embodiments, the secondary active agent comprises an antisense oligonucleotide or polynucleotide capable of inhibiting the expression of a component of the PG pathway. An antisense oligonucleotide or polynucleotide can comprise a DNA backbone, an RNA backbone, or a chemical derivative thereof. In one embodiment, the antisense oligonucleotide or polynucleotide comprises a single stranded antisense oligonucleotide or polynucleotide targeted for degradation. In certain embodiments, the anti-inflammatory agent comprises a single stranded antisense oligonucleotide complementary to the mRNA sequence of a component of the PG pathway. Single-stranded antisense oligonucleotides or polynucleotides can be produced synthetically or expressed from a suitable expression vector. Antisense nucleic acids are designed to bind via complementary binding to the mRNA sense strand to promote RNase H activity that results in degradation of the mRNA. Preferably, the antisense oligonucleotide is chemically or structurally modified to promote increased nuclease stability and / or binding.

  In some embodiments, the antisense oligonucleotide is a peptide nucleic acid (PNA), locked nucleic acid (LNA), morpholino backbone nucleic acid, methylphosphonic acid, double stabilized stilbene or pyrenyl cap, phosphorothioate, phosphoramidate, Modified to produce oligonucleotides with unconventional chemical or backbone additions or substitutions, including but not limited to phosphate triesters and the like. By way of example, a modified oligonucleotide can incorporate one or more naturally occurring nucleotides or be replaced with an analog; internucleotide modifications can be performed, for example, by uncharged bonds (eg, methylphosphonic acid, phosphate Incorporates triesters, phosphoramidates, carbamates, etc.) or charged bonds (eg, phosphorothioates, phosphorodithioates, etc.); modifications are interfering substances (eg, acridine, psoralen, etc.), chelating agents (eg, metals, radioactive) Metal, boron, metal oxide, etc.), or alkylating agents and / or modified linkages (eg, alpha anomeric nucleic acids, etc.).

  In some embodiments, the single stranded oligonucleotide is internally modified and includes at least one neutral charge in its backbone. For example, the oligonucleotide may comprise a methylphosphonic acid backbone or peptide nucleic acid (PNA) that is complementary to the target specific sequence. These modifications have been confirmed to prevent or reduce unwinding through helicases. The use of uncharged probes can further increase the rate of hybridization to the polynucleotide target in the sample by mitigating the repulsion of negatively charged nucleic acid strands in classical hybridization.

  PNA oligonucleotides are uncharged nucleic acid analogs in which the phosphodiester backbone is replaced by polyamide, so that PNA becomes a polymer in which two aminoethylglycine units are linked together by amide bonds. PNA is synthesized using Boc or Fmoc chemistry similar to its use in standard peptide synthesis. Bases (adenine, guanine, cytosine and thymine) are attached to the backbone by methylene carbonyl bonds. Therefore, PNA is acyclic, achiral, and neutral. Other properties of PNA are high specificity and melting point compared to nucleic acids, ability to form triple helices, stability at acidic pH, not recognized by cellular enzymes such as nucleases and polymerases.

  Oligonucleotides containing methylphosphonic acid are neutral DNA analogs that contain a methyl group in place of one of the unbound phosphoryl oxygens. Oligonucleotides with methylphosphonic acid linkages are among those first reported to inhibit protein synthesis through antisense blocking of translation.

  In some embodiments, the phosphate backbone of the oligonucleotide may include phosphorothioate linkages or phosphoramidates. Such combinations of oligonucleotide bonds are also within the scope of the present invention.

  In other embodiments, the oligonucleotide may comprise a modified sugar backbone connected by phosphodiester internucleotide linkages. Modified sugars include, but are not limited to, 2-deoxyribofuranoside, α-D-arabinofuranoside, α-2′-deoxyribofuranoside, and 2 ′, 3′-dideoxy-3′-aminoribofuranoside. May include furanose analogs. In an alternative embodiment, the 2-deoxy-β-D-ribofuranose group can be replaced with other sugars such as, for example, β-D-ribofuranose. Further, the 2-OH of the ribose moiety is alkyl with a C1-6 alkyl group (2- (O—C1-6 alkyl) ribose) or a C2-6 alkenyl group (2- (O—C2-6 alkenyl) ribose). There may be β-D-ribofuranose that is converted to or substituted by a fluoro group (2-fluororibose).

  Related oligomer-forming sugars include those used for the above-mentioned locked nucleic acids (LNA). A typical LNA oligonucleotide comprises a modified bicyclic monomer unit having a 2′-O-4′-C methylene bridge, such as those described in US Pat. No. 6,268,490. .

  In addition, chemically modified oligonucleotides may be used alone or in any combination as a 2′-position sugar modification, a 5-position pyrimidine modification (eg, 5- (N-benzylcarboxamido) -2′-deoxyuridine, 5- (N-isobutylcarboxamido) -2′-deoxyuridine, 5- (N- [2- (1H-indol-3-yl) ethyl] carboxamido) -2′-deoxyuridine, 5- (N- [1 -(3-trimethylammonium) propyl] carboxamido) -2'-deoxyuridine, 5- (N-naphthylcarboxamido) -2'-deoxyuridine, 5- (N- [1- (2,3-dihydroxypropyl) )] Carboxamide) -2'-deoxyuridine), 8-position purine modification, exocyclic amine modification, 4-thiouridine substitution, 5-bromine Or 5-iodo uracil substituted, methylation may also include combinations of special base pairs, such as iso bases isocytidine and isoguanine.

  In some embodiments, the one or more PG pathway inhibitors comprise a ribozyme capable of inhibiting the expression of a component of the PG pathway. Ribozymes are nucleic acid molecules that can catalyze either chemical reactions within or between molecules. Ribozymes are thus catalytic nucleic acids. It is desirable that ribozymes catalyze intermolecular reactions. There are many different types of ribozymes that catalyze nuclease or nucleic acid polymerase type reactions based on naturally occurring ribozymes such as hammerhead ribozymes, hairpin ribozymes, and tetrahymena ribozymes. There are many ribozymes that are not found in natural systems but have been newly engineered to catalyze specific reactions. Preferred ribozymes cleave RNA or DNA substrates, and more preferably cleave RNA substrates such as mRNA, a component of the PG pathway. Typically, a ribozyme cleaves a nucleic acid substrate by recognition and binding of a target substrate and subsequent cleavage. This recognition is often based largely on standard or non-standard base pair interactions. This property makes ribozymes particularly good candidates for target-specific cleavage of nucleic acids because target substrate recognition is based on the target substrate sequence.

  In some embodiments, the one or more PG pathway inhibitors comprise a triplex-forming oligonucleotide capable of inhibiting expression of a component of the PG pathway. Triplex forming oligonucleotides (TFOs) are molecules that can interact with either double-stranded and / or single-stranded nucleic acids, including both coding and non-coding regions within a genomic DNA target. When TFO interacts with the target region, a structure called a triplex is formed, in which there are DNA triplexes that form complexes that depend on both Watson-Crick and Hoogsteen base pairs. TFO can bind to the target region with high affinity and specificity. In preferred embodiments, the triplex-forming molecule binds to the target molecule with a Kd of less than 10-6, 10-8, 10-10 or 10-12. Typical TFOs intended for use in the present invention include LNA modified PNAs such as PNA, LNA and Zorro-LNA.

  In some embodiments, the one or more PG pathway inhibitors comprise an external guide sequence (EGS). An external guide sequence (EGS) is a molecule that binds to a target nucleic acid to form a complex. This complex is recognized by RNase P which cleaves the target molecule. EGS can be designed to specifically target selected mRNA molecules. RNAase P facilitates processing of transfer RNA (tRNA) in the cell. By using EGS that mimics the natural tRNA substrate in the target RNA: EGS complex, bacterial RNAase P can be recruited to cleave almost any RNA sequence. Similarly, RNA cleavage by induction of eukaryotic cell EGS / RNAase P can be used to cleave a desired target in a eukaryotic cell.

  In other embodiments, the one or more PG pathway inhibitors comprise a target neutralizing agent. As used herein, the term “target neutralizing agent” refers to an antibody that is capable of specifically directly or indirectly binding a component of the PG pathway to interfere with the final action of prostaglandins on the target tissue. By fragment, or any other non-antibody peptide or synthetic binding molecule, such as an aptamer or synbody.

  Target neutralizing agents are generated by any conventional method for making high affinity binding ligands, including SELEX, phage display, and other methodologies, including combinatorial chemistry and / or high throughput methods. sell.

  Aptamers are nucleic acid versions of antibodies that contain a class of oligonucleotides that can form specific three-dimensional structures that exhibit high affinity binding to a variety of cell surface molecules, proteins and / or macromolecular structures. Aptamers are often identified by an in vitro selection method, sometimes referred to as systematic evolution of ligands by experimental enrichment, or “SELEX”. Typically, SELEX begins with a very large pool of randomized polynucleotides, usually narrowed down to one aptamer ligand per molecular target. Aptamers are typically small nucleic acids that range in length from 15 to 50 bases and fold into a defined secondary or tertiary structure such as a stem loop or G quartet.

  Aptamers can be chemically coupled or conjugated with the nucleic acid inhibitors described above to form targeted nucleic acid inhibitors such as aptamer-siRNA chimeras. Aptamer-siRNA chimeras contain a targeting moiety in the form of an aptamer associated with siRNA. When using an aptamer-siRNA chimera, it is preferable to use a cell internalized aptamer. Aptamers can promote internalization into cells where nucleic acid inhibitors act after binding to specific cell surface molecules. In one embodiment, both the aptamer and siRNA comprise RNA. Aptamers and siRNAs can include any nucleotide modification described further herein. Preferably, the aptamer comprises a targeting moiety specifically directed to the binding of cells expressing chemokine-, cytokine-, and / or receptor target genes, such as lymphoid cells, epithelial cells and / or endothelial cells. .

  Synbodies are synthetic antibodies generated from a library composed of random peptide strings that have been screened for binding to a target protein of interest.

Aptamers and synbodies can be engineered to bind very tightly to the target molecule with a Kd between 10 ⁻¹⁰ and 10 ⁻¹² M. In some embodiments, the target neutralizing agent less than ^{10 -6,} less than ^{10 -8,} less than ^{10 -9,} bind the target molecule with ^{10 -10} or less than ^{10 -12} less than Kd.

  In certain embodiments, the one or more PG pathway inhibitors comprise a polynucleotide that encodes and is modified to express a PGT inhibitor and / or a PGR inhibitor. In other embodiments, the one or more PG pathway inhibitors comprise an expression vector that encodes and is modified to express a PGT inhibitor and / or a PGR inhibitor.

  In some embodiments, the PG pathway inhibitor is an engineered protein comprising a TALE sequence or engineered zinc finger directed to a gene encoding any component of the PG pathway. This TALE or zinc finger is directly expressed by binding the repressor protein to a gene that directly binds to the gene and further cleaves the gene to modify the nucleotide sequence or plays a role in silencing the gene. It is also possible to design to inhibit

  In some embodiments, the PG pathway inhibitor is produced using a CRISPR / CAS system. In this strategy, a guide molecule specific to the gene sequence of each PG pathway gene is designed and introduced into a cell or tissue using the delivery system (virus, plasmid, etc.) described above. The action of the CRISPR / CAS system will modify the DNA sequence of the gene so that the PG pathway gene is deleted or the ability to express RNA is inhibited.

  In some embodiments, a PG pathway inhibitor can stop transcription of one or more PG pathway genes by targeting a chromatin-related enzyme that modifies histones in chromatin after translation. It is. Examples of such enzymes include, but are not limited to, histone deacetylase, histone demethylase, histone acetyltransferase, histone methyltransferase, and helicase.

  In some embodiments, one or more PG pathway inhibitors target a PG pathway sensitive gene by altering the DNA methylation status of the gene. Compounds targeting the TET family of DNA demethylases and DNA methyltransferases (DNMT1, DNMTa, and DNMTb) can also alter the expression of RNA from any of the genes in the PG pathway.

  The expression vector of the present application may contain a polynucleotide encoding a PG pathway inhibitor or a part thereof. The expression vector also includes one or more regulatory sequences that are operably linked to the polynucleotide being expressed. These regulatory sequences are selected based on the type of host cell. It will be appreciated by those skilled in the art that the design of an expression vector depends on factors such as the choice of host cell and the desired level of expression.

  In some embodiments, the expression vector is a plasmid vector. In other embodiments, the expression vector is a viral vector. Examples of viral vectors include, but are not limited to, retrovirus, lentivirus, adenovirus, adeno-associated virus (AAV), herpes virus or alphavirus vector. The viral vector can also be an astrovirus, coronavirus, orthomyxovirus, papovavirus, paramyxovirus, parvovirus, picornavirus, poxvirus, or togavirus vector. When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus and simian virus 40. In some embodiments, the expression vector comprises a tissue specific regulator. Expression vector delivery includes direct infection of viral vectors, exposure of target tissues to polycation-enriched DNA bound or not bound to killed viruses, ligand-bound DNA, gene guns, ionizing radiation, in nuclear charge Including but not limited to sum or fusion with cell membranes. Naked plasmid or viral DNA can also be used. Uptake efficiency can be improved using biodegradable latex beads. This method can be further improved by treating the beads to increase their hydrophobicity. Liposome methods can also be used to introduce plasmids or viral vectors into the target tissue.

  In some embodiments, the pharmaceutical composition is selected from the group consisting of analgesics, antimuscarinic agents, antidiuretics, antispasmodic agents, inhibitors of type 5 phosphodiesterase (PDE5 inhibitors), and zolpedim (zolpidem). It further comprises one or more active ingredients.

  Examples of antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, tropium, atropine, and tricyclic antidepressants. Examples of antidiuretics include antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogues (eg desmopressin argipresin, repressin, ferripressin, ornipressin, telluripressin), vasopressin receptor agonists, atrial natriuretic peptide ( ANP) and C-type natriuretic peptide (CNP) receptor (ie, NPR1, NPR2, and 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), pharmaceutically acceptable derivatives thereof, and Including but not limited to analogs, salts, hydrates and solvates. Examples of antispasmodic agents include, but are not limited to carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, metcarbamol, clonidine, clonidine analogs, and dantrolene. Examples of PDE5 inhibitors include but are not limited to tadalafil, sildenafil and vardenafil.

  The pharmaceutical composition may be formulated for immediate release, extended release, delayed release, or a combination thereof.

  In some embodiments, the pharmaceutical composition is formulated for immediate release.

  In some embodiments, the pharmaceutical composition is formulated in an orally disintegrating formulation. In certain embodiments, the orally disintegrating formulation is completely in the oral cavity at 5, 10, 20, 30, 60, 90, 120, 180, 240 or 300 seconds and without additional water (ie, saliva alone). Designed to disintegrate or dissolve.

  In some embodiments, the orally disintegrating formulation is in the form of an orally disintegrating tablet. Orally disintegrating tablets can be manufactured using low compression tablets, which is a process that is not significantly different from the manufacturing methods used for conventional tablets and lyophilization processes. At low compression, the orally disintegrating formulation is compressed with a lower force (4-20 kN) than conventional tablets. In some embodiments, the orally disintegrating formulation comprises a form of sugar that improves mouthfeel, such as mannitol. In some embodiments, the orally disintegrating tablet is manufactured using a lyophilized orally disintegrating formulation.

  In other embodiments, 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 active ingredient at a predetermined rate by maintaining a constant drug level for a specific time. This can be achieved by a variety of formulations including, but not limited to, liposomes and drug-polymer conjugates such as hydrogels.

  The extended release formulation is about 24 hours, about 22 hours, about 20 hours, about 18 hours, about 16 hours, about 14 hours, about 12 hours, about 12 hours after administration or after the delay time associated with delayed release of the active ingredient. Certain medications for specified and extended times such as up to 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, or up to about 2 hours, etc. In order to maintain the level, the active ingredient can be designed to be released at a predetermined rate. A constant active ingredient level can be maintained by continuous release of the active ingredient or pulsed release of the active ingredient.

  In certain embodiments, the one or more active ingredients in the extended release formulation are released over a time interval between about 2 and about 12 hours. Alternatively, the active ingredient can be released over about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 or about 12 hours. In yet other embodiments, the active ingredient in the extended release formulation is released over a period of about 5 to about 8 hours after administration.

  In some embodiments, the extended release formulation is surfaced by an agent 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. Effectively composed of one or more inert particles each taking the form of coated beads, pellets, pills, granular particles, microcapsules, microspheres, microgranules, nanocapsules, or nanospheres Includes core. The inert particles can be of various sizes as long as they are large enough to remain low soluble. Alternatively, an effective core may be prepared by granulation and grinding and / or extrusion and spheronization of a polymer composition containing the drug substance. As used herein, the term “drug” means an active ingredient of a pharmaceutical composition.

  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 active ingredient in the core depends on the dose required and is typically about 1 to 100%, about 5 to 100%, about 10 to 100%, about 20 to 100%, It varies from about 30 to 100%, about 40 to 100%, about 50 to 100%, about 60 to 100%, about 70 to 100%, or about 80 to 100% by weight.

  Generally, the polymer coating on the effective core will be about 1 to 50% of the weight of the particles to be coated, depending on the delay time required and / or the polymer and coating solvent selected. One skilled in the art can select the appropriate amount of agent to coat or incorporate into the core to achieve the desired dose. In one embodiment, the inert core is a sugar sphere that alters its microenvironment to facilitate drug release, or crystals of buffering agents such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, or It can be encapsulated buffer crystals.

  Extended release formulations may utilize a variety of extended release coatings or mechanisms that facilitate gradual 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 insoluble polymers and drug particles or granules coated with different thickness polymeric materials. Polymer materials include waxy waxes such as 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. The material can include a lipid barrier that includes a surfactant such as polyoxyethylene sorbitan monooleate. When contacted 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 retention.

  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 enhancers and / or release enhancers. 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 core, 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 detachment and erosion of the outer hydrated polymer on the matrix surface. Water continues to penetrate through the gel layer and into the core 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, a water-swellable polymer typically hydrates and swells in biological fluids, maintains its shape during drug release, and is a carrier for drug, dissolution enhancer and / or release enhancer. A uniform matrix structure that plays a role is formed. 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 allow it to diffuse out through the matrix coating.

  Further, the release of the drug at a faster rate can increase the porosity of the matrix by reaching the exterior of the pH-dependent release enhancer. Thereafter, the drug release rate is constant and is a function of drug diffusion through the hydrated polymer gel. The rate of release from the matrix is the polymer type and level, drug solubility and dose, polymer to drug ratio, filler type and level, polymer to filler ratio, drug and polymer particle size, and matrix voids. Depends on a variety of factors including rate and shape.

  Typical hydrophilic and / or water-swellable matrix-forming polymers are hydroxy, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), carboxymethylcellulose (CMC) and the like. Alkyl cellulose and carboxyalkyl cellulose; cellulosic polymers including powdered cellulose such as 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 derivatives thereof Gums including bi- and homopolysaccharide gums; acrylic resins including polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, and methyl methacrylate; and carbomers (eg CARBOPOL® 71G NF, Cross-linked polyacrylic acid derivatives such as CARBOPOL® available in various molecular weight grades from Noveon (Cincinnati, Ohio), carrageenan; polyvinyl acetate (eg, KOLLIDON® SR); and polyvinylpyrrolidone and Including, but not limited to, its derivatives such as crospovidone, polyethylene oxide, and polyvinyl alcohol. Preferred hydrophilic and water swellable polymers include cellulosic polymers, particularly HPMC.

  The extended release formulation may further comprise at least one binder capable of crosslinking the hydrophilic compound 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 the diffusion and erosion rates and concomitant release of active substances. And an ionic polymer that reduces the size, a nonionic polymer, or a water-insoluble hydrophobic polymer. This may 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) ), Enteric polymers such as methacrylic acid copolymers (eg, EUDRAGIT® L100, L30D55, A, and FS 30D), and hypromellose acetate succinate (AQUAT HPMCAS); and xanthan gum and the like. Typical cationic polymers include, for example, dimethylaminoethyl methacrylate copolymer (eg, EUDRAGIT® E100) and the like. The 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 include ethyl cellulose (eg, ETHOCEL®, SURELEASE®), cellulose acetate, methacrylic acid copolymer (eg, EUDRAGIT® NE 30D), ammonio-methacrylic acid copolymer (eg, : EUDRAGIT® RL 100 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 at pH values above 4.0, preferably above 5.0, and most preferably above 6.0. It contains a pH-dependent enteric polymer that dissolves and is considered useful as a release enhancer 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 copolymers (eg EUDRAGIT® L100-55 (type C) and EUDRAGIT® L30D-55 copolymer dispersant, Rohm GmbH, Germany); methacrylic acid-methyl methacrylate and methacrylic Copolymer of methyl acrylate (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); hydroxypropyl methylcellulose acetate succinate (HPMCAS) (eg AQOAT® LF and AQOAT® MF (Shin-Etsu Chemical) HPMCAS LF grade, MF grade, and HF grade), shellac (eg MARCOAT® 125 and MARCOAT® 125N); vinyl acetate-maleic anhydride copolymer, styrene-maleic acid monoester Copolymer Boxymethylethylcellulose (CMEC, Freund Sangyo, Japan); cellulose acetate phthalate (CAP) (eg; AQUATERIC®), cellulose acetate trimellitic acid (CAT), and a weight ratio of about 3: 1 to about 2: 1 EUDRAGIT®, a mixture of L 100-55 and EUDRAGIT® S 100, or a EUDRAGIT® L 30 D-55 and EUDRAGIT® registered in a weight ratio of about 3: 1 to about 5: 1 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.

  The polymers can be used alone or in combination or with other polymers than those described above. A preferred enteric pH dependent polymer is a pharmaceutically acceptable methacrylic acid copolymer. These copolymers are anionic polymers based on methacrylic acid and methyl methacrylate, and preferably have an average molecular weight of about 50,000 to 200,000, preferably about 135,000. The ratio of free carboxyl groups to methyl esterified carboxyl groups in these copolymers can vary, for example, in the range from 1: 1 to 1: 3, such as 1: 1 or 1: 2. 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.

  In some embodiments, the matrix can include a combination of a release enhancer and a dissolution enhancer. Solubilizers enhance the solubility of ionic and non-ionic surfactants, complexing agents, hydrophilic polymers, pH modifiers such as acidifying and alkaline agents, and poorly soluble drugs by molecular trapping. It can be a molecule. Several types of dissolution promoters can be used simultaneously.

  Solubilizers are: doxate sodium; sodium lauryl sulfate; sodium stearyl fumarate; Tween® and Span (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 promote dissolution by molecular trapping such as cyclodextrins, and citric acid, fumaric acid, PH modifiers may be included including acidifying agents such as tartaric acid and hydrochloric acid, and alkaline agents such as meglumine and sodium hydroxide.

  Dissolution promoters are typically 1% to 80% by weight of the dosage form, 1% to 60% by weight, 1% to 50% by weight, 1% to 40% by weight and 1% to 30% by weight. % And can be incorporated in a variety of ways. They can be incorporated into the formulation prior to dry or wet granulation. They can also be added to the formulation after the remaining material has been granulated or otherwise processed. During granulation, the dissolution enhancer can be sprayed as a solution with or without a binder.

  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 over 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 intended for the release of active substances in the core, where the low molecular weight (viscous) grade exhibits a fast release rate compared to the high viscosity grade.

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

  In some embodiments, the water insoluble polymer provides suitable properties (eg, extended release, mechanical properties, and coating properties) without the need for a plasticizer. For example, coatings containing polyvinyl acetate (PVA), neutral copolymers of acrylic acid / methacrylic acid esters such as Eudragit NE30D commercially available from Evonik Industries, ethyl cellulose in combination with hydroxypropyl cellulose, waxes, etc., with plasticizers 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 properties of the plasticizer, the water-insoluble polymer and the final desired coating properties. Suitable levels of plasticizer include about 1% to about 20%, about 3% to about 20%, about 3% to about 5% by weight relative to 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% , 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, grape seed oil, sesame oil, olive oil, etc.); citrate esters, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate , 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, glycerol tributyrate, polysorbate 80, polyethylene Glycols (such as PEG-4000 and PEG-400), 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, a nonionic surfactant such as Brij58 (polyoxyethylene (20) cetyl ether) can be used.

  Plasticizers can be high boiling organic solvents that are otherwise used to impart flexibility to hard or brittle polymer materials and can affect the release profile of the active substance. . Plasticizers generally cause a decrease in intermolecular cohesion along the polymer chain, resulting in a variety of changes in polymer properties. These changes include, but are not limited to, a decrease in the tensile strength of the polymer and an increase in stretching, a decrease in glass transition or softening temperature. 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, thereby reducing 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. The combination of at least two gel-forming polymers can manipulate the properties of the resulting gel, such as viscosity, 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 still 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 Including but not limited to polysaccharides 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 are “such as lactose, glucose, fructose, sucrose, dicalcium phosphate, sorbitol, mannitol, lactitol, xylitol, isomalt, erythritol and hydrogenated starch hydrolysates (mixtures of several sugar alcohols). Sugar alcohols, also known as “sugar polyols”, include but are not limited to sugar alcohols, corn starch, potato starch, sodium carboxymethyl cellulose, ethyl cellulose, 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, Ethyl cellulose, gelatin, polyethylene oxide, gum arabic, dextrin, magnesium aluminum silicate, and starch, and polymethacrylates such as Eudragit NE 30D, Eudragit RL, Eudragit RS, Eudragit E, polyvinyl acetate, enteric polymer or the like Including but not limited to water-soluble hydrophilic polymers such as mixtures.

  Typical disintegrants are low-substituted sodium carboxymethylcellulose, crospovidone (cross-linked polyvinyl pyrrolidone), sodium carboxymethyl starch (starch sodium glycolate), cross-linked sodium carboxymethyl cellulose (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 comprises a water-soluble / water-dispersible drug-containing particle, such as one bead or bead population therein (as described above), a coating material, and optionally void formation. Formed by coating with agents and other additives. The coating material is preferably a cellulosic polymer such as ethylcellulose (eg SURELEASE®), methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate, and cellulose acetate phthalate; polyvinyl alcohol; polyacrylic ester, poly Acrylic polymers such as methacrylic esters and copolymers thereof; and other water-based or solvent-based coating materials are selected from the group comprising. The controlled release coating for a given bead population may 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. Thus, changing parameters such as void former concentration or curing conditions allows changes in active agent release from any given bead population, thereby selectively adjusting the formulation to a predetermined release profile. Make it possible.

  Void forming agents suitable for use in the controlled release coatings herein include materials that can be organic or inorganic materials and that can be eluted, extracted or leached from the coating in the environment of use. Typical voiding agents are organic compounds such as monosaccharides, oligosaccharides and polysaccharides including sucrose, glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, and dextran; water soluble hydrophilic polymers, hydroxyalkyl Cellulose, carboxyalkyl cellulose, hydroxypropyl methylcellulose, cellulose ether, acrylic resin, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyethylene oxide, carbowax, carbopol, diol, polyol, polyhydric alcohol, polyalkylene glycol, polyethylene glycol, polypropylene glycol , Or its block polymers, polyglycols, and poly (α-Ω) alkylenediols Soluble polymers; and 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 may further comprise 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, static reduction, flavoring, 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 in the form of another bead population or as a powder. In still other embodiments, the accelerator may be contained in a separate layer on the coating particle, 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, capsules can be formulated with a single osmotic unit, or each bilayer by incorporating 2, 3, 4, 5, or 6 push-pull units encapsulated within a gelatin hard capsule. The push-pull unit can include 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 speed. 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 the transport of water through the semipermeable membrane to the delivery carrier core. One class of osmotic agents includes hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate). ), Poly (acrylic) acid, poly (methacrylic acid), polyvinyl pyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymer, PVA having hydrophobic monomers such as methyl methacrylate and vinyl acetate / PVP copolymer, hydrophilic polyurethane with large PEO block, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cell “Osmopolymer” and “Hydrogel” including, but not limited to, ose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate Water swellable hydrophilic polymer, also referred to as

  Another class of osmotic agents includes osmogens that can absorb water and provide 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 sulfite, 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 a variety of materials that are water permeable and water insoluble at physiologically reasonable pH, or can be made water insoluble by chemical modification such as crosslinking. Grade acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives.

  In some embodiments, the extended release formulation comprises a polysaccharide coating that is resistant to erosion in both the stomach and intestine. Such polymers can only be degraded in the colon containing large microflora, including biodegradable enzymes that degrade, for example, polysaccharide coatings, and the drug content can be released 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, at least one or more active agents in the pharmaceutical composition are formulated for delayed release or delayed extended release. 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. As used herein, the term “enteric coating” is a coating composed of one or more polymers having a pH dependent or pH independent release profile. Enteric coated pills do not dissolve in acidic gastric fluid (pH about 3), but dissolve in an alkaline (pH 7-9) environment present in the small or large intestine. Enteric polymer coatings typically resist release of the active substance for some time after a lag time due to gastric emptying about 3-4 hours after administration.

  Such coatings protect acid labile drugs from gastric acid exposure and instead deliver them to a basic pH environment that does not degrade (intestinal pH 5.5 and above) and obtain its desired effect. Also used for. The term “pulsed release” is a type of delayed release, and in this application provides a rapid and transient release of the drug within a short time immediately after a predetermined delay time, thereby allowing Used for pharmaceutical formulations that produce a “pulsed” plasma profile of a drug. Formulations can be single-pulse release or multi-pulse release at predetermined time intervals after administration, or extended release over a period of time (eg, 20-60% of active ingredient) (eg, of 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.

  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 is a sugar coating, a film coating (eg, based on hydroxypropylmethylcellulose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymer, polyethylene glycol, and / or polyvinylpyrrolidone), or It may be a coating with a methacrylic 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 comprises an enteric coating comprising one or more polymers that facilitate the release of the active agent in the proximal or distal region of the gastrointestinal tract. A pH-dependent enteric coating maintains its structural integrity at low pH, as in the stomach, but dissolves in a higher pH environment in more distal regions of the gastrointestinal 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 a property (eg, dissolution) that varies with environmental pH. Typical pH dependent polymers have been described previously. 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 uses a blend of one or more pH dependent polymers and one or more pH independent polymers. By blending the pH-dependent and pH-independent polymers, the release rate of the active ingredient can be reduced once the soluble polymer has reached 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 With a water-insoluble capsule body closed with a “delayed release” or “delayed extended release” profile can be obtained. Upon contact with gastrointestinal fluid or solvent, the plug swells and after a predetermined delay time pushes itself out of the capsule to release the drug, which can be controlled, 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 that keeps 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, arabi). Polysaccharides such as nogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin and xylan).

  In other embodiments, capsules or bilayer tablets may be formulated to include a swelling layer and a drug-containing core covered by an insoluble but semi-permeable outer layer polymer coating or membrane. The lag time before rupture can be controlled by the penetration and mechanical properties of the polymer coating and the swelling behavior of the swelling layer. Typically, the swelling layer comprises 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 Hydroxyalkyl methylcellulose; polyalkylene oxide having a weight average molecular weight of 100,000 to 6,000,000 including but not limited to poly (methylene oxide), poly (butylene oxide), 25,000 to 5, Poly (vinyl) having a molecular weight of 1,000,000, 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 cross-linked with 0.001 to 0.5 mole of saturated cross-linking agent per mole of maleic anhydride in the copolymer Or a hydrogel-forming copolymer produced by forming a dispersion of a finely divided copolymer of isobutylene; a CARBOPOL® acidic carboxy copolymer having a molecular weight of 450,000 to 4,000,000; 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 ter-crosslinked polyglycans; carbomers having a viscosity of 3,000 to 60,000 mPa as 0.5-1% w / v aqueous solution; 1% Cellulose ethers such as hydroxypropylcellulose having a viscosity of about 1000-7000 mPa as w / w aqueous solution (25 ° C.); about 1000 or more, preferably 2,500 or more up to 25, as 2% w / v aqueous solution Including, but not limited to, hydroxypropyl methylcellulose having a viscosity of 000 mPa; polyvinylpyrrolidone having a viscosity of about 300-700 mPa as a 10% w / v aqueous solution at 20 ° C .; and combinations thereof.

  Alternatively, the release time of the drug can be determined by the resistance and thickness of a water-insoluble polymer membrane (such as ethyl cellulose (EC)) at the bottom of the body and containing predetermined pores, and low substituted hydroxypropyl cellulose (L- It can be controlled by a disintegration delay depending on the balance with the amount of swellable additives such as HPC) and sodium glycolate. After oral administration, the GI fluid penetrates through the pores, causing swelling of the swellable additive, which contains the first capsule body containing the swellable material, the second capsule body containing the drug, and the first An internal pressure is provided that separates the capsule components including an outer cap that contacts the capsule body.

  The delayed release coating layer may further comprise anti-adhesive agents such as talc and glyceryl monostearate. Delayed release coating layer is triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, polyethylene glycol acetylated monoglyceride, glycerin, triacetin, propylene glycol, phthalate (eg diethyl phthalate, dibutyl phthalate), titanium dioxide One or more plasticizers can be further included, including but not limited to, ferric oxide, castor oil, sorbitol, and dibutyl sebacate.

  In other embodiments, the delayed release formulation uses 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 core, the core 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 uses a non-water permeable tablet coating that allows water to flow through the controlled opening in the coating until the core 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 allow a predetermined delay time before the drug release is initiated.

  In other embodiments, the active agent is delivered in the form of a formulation that provides both delayed and extended release (delayed extended release). As used herein, the term “delayed extended release” is used in reference to a pharmaceutical formulation that provides a pulsed release of an active substance at a predetermined time or delay time after administration, followed by an extended release of the active substance.

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

  The amount of drug in the core depends on the dose required and is typically about 1 to 100%, about 5 to 100%, about 10 to 100%, about 20 to 100%, It varies from 30 to 100 wt%, from about 40 to 100 wt%, from about 50 to 100 wt%, from about 60 to 100 wt%, from about 70 to 100 wt%, or from about 80 to 100 wt%. In general, the polymer coating on the effective core is about 1 to 50% of the weight of the particles to be coated, depending on the type of lag time and release profile required and / or the polymer and coating solvent selected. Become. One skilled in the art can select the appropriate amount of agent to coat or incorporate into the core to achieve the desired dose. In one embodiment, the inert core is a sugar sphere that alters its microenvironment to facilitate drug release, or crystals of buffering agents such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, or It can be encapsulated buffer crystals.

  In some embodiments, for example, a delayed release or delayed extended release composition comprises a water-soluble / water-dispersible drug-containing particle such as a bead and a water-insoluble polymer and enteric polymer from 4: 1 to 1: 1. Can be formed by coating with a mixture of a water-insoluble polymer and an enteric polymer, the total weight of the coating being 10 to 60% by weight of the total weight of the beads to be coated It is. The drug-laminated beads may optionally include an internal dissolution rate control membrane of 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 extended release beads exhibiting a lag time of, for example, 2-4 hours after oral administration, whereby 2 A pulsed release profile may be provided.

  In some embodiments, the effective core is coated with one or more elution rate controlling polymers to obtain the desired release profile with or without a lag time. The inner membrane can primarily control the drug release rate after absorption of water or fluid into the core, while the outer membrane provides the desired lag time (the time when there is little drug release after absorption of water or fluid into the core). Can be provided. 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 ethylcellulose.

  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 copolymers of acrylic and methacrylic acid esters having quaternary ammonium groups, such as RL30D. Typical water soluble polymers are low molecular weight HPMCs with concentrations ranging from about 1% to 10% by weight, depending on the solubility of activity in the water and solvent or latex suspension base coating formulation used. , HPC, methylcellulose, polyethylene glycol (PEG with molecular weight> 3000). The water-insoluble polymer relative to the water-soluble polymer can typically vary from 95: 5 to 60:40, preferably from 80:20 to 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 the 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 in vivo, the drug is released from the resin. 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.

  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 some embodiments, the pharmaceutical composition is formulated as an orally disintegrating tablet.

  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 contain, surround, or form a layer or film around the therapeutic composition or effective core. In some embodiments, the active agent is delivered in the form of a formulation that provides 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 can 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 the form of a tablet or capsule comprising a single coating layer. In other embodiments, the pharmaceutical composition is in the form of a tablet or capsule comprising a plurality of coating layers. In some embodiments, the pharmaceutical compositions of the present application are formulated for 100% extended or delayed extended release of the active ingredient.

  In other embodiments, the pharmaceutical compositions of the present application are characterized by an “immediate release” component that is released within 2 hours of administration and an “extended release” component that is released over a period of 2 to 12 hours. Formulated for two-phase extended release or delayed two-phase extended release. In some embodiments, the “immediate release” component provides about 1-90% of the total dose of active substance delivered by the pharmaceutical formulation, and the “extended release” component is 10% of the total dose of active substance. Provides ~ 99%. For example, the immediate release component is about 10-90% of the total dose of active substance delivered by the pharmaceutical formulation, or about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50% , 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%. The extended release component is about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% of the total dose of active substance delivered by the formulation, Provides 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99%.

  In some embodiments, the immediate release component and the extended release component contain the same active ingredient. In other embodiments, the immediate release component and the extended release component contain different active ingredients (eg, acetaminophen in one component and NSAID in the other component). In some embodiments, the immediate release component and the extended release component contain acetaminophen and one NSAID, respectively. In other embodiments, the immediate release component and / or extended release component is a PG pathway inhibitor, analgesic, antimuscarinic, antidiuretic, antispasmodic, type phosphodiesterase inhibitor (PDE5 inhibitor), zolpidem, and the like It further comprises one or more additional active substances selected from the group consisting of combinations.

  In some embodiments, the pharmaceutical composition comprises a plurality of active ingredients selected from the group consisting of a PG pathway inhibitor, analgesic, antimuscarinic, antidiuretic, antispasmodic, PDE5 inhibitor, zolpidem and combinations thereof. Including. Examples of antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, tropium, atropine, and tricyclic antidepressants. Examples of antidiuretics are antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (eg desmopressin argipresin, repressin, ferripressin, ornipressin, telluripressin); vasopressin receptor agonist, atrial natriuretic peptide ( ANP) and C-type natriuretic peptide (CNP) receptor (ie, NPR1, NPR2, and 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), pharmaceutically acceptable derivatives thereof, and Including but not limited to analogs, salts, hydrates and solvates. Examples of antispasmodic agents include, but are not limited to carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, metcarbamol, clonidine, clonidine analogs, and dantrolene. Examples of PDE5 inhibitors include but are not limited to tadalafil, sildenafil and vardenafil.

  In some embodiments, the pharmaceutical composition comprises a plurality of active ingredients comprising (1) acetaminophen and (2) one or more NSAIDs. In some embodiments, multiple active ingredients are formulated for immediate release. In other embodiments, the plurality of active ingredients are formulated for extended release. In other embodiments, multiple active ingredients are formulated for delayed release. In other embodiments, a plurality of active ingredients are formulated for both immediate release and extended release (eg, a first portion of each active ingredient is formulated for immediate release, and each active ingredient's The second part is 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 embodiments, multiple active ingredients are formulated for delayed extended release.

  In certain embodiments, the pharmaceutical composition includes an immediate release component and an extended release component. The immediate release component is from the group consisting of acetaminophen, one or more NSAIDs, and / or a PG pathway inhibitor, analgesic, antimuscarinic, antidiuretic, antispasmodic, PDE5 inhibitor, zolpidem and combinations thereof It may contain one or more active ingredients selected. Similarly, the extended release component is from acetaminophen, one or more NSAIDs, and / or PG pathway inhibitors, analgesics, antimuscarinic agents, antidiuretics, antispasmodic agents, PDE5 inhibitors, zolpidem and combinations thereof. It may contain one or more active ingredients selected from the group consisting of: 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 or 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 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 certain embodiments, the pharmaceutical composition includes an immediate release component and a delayed release component. 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.

  Components in a composite release profile formulation (eg, combination of immediate release and extended release components, combination of immediate release and delayed release components, combination of immediate release, delayed release and extended release components, two or more A combination of delayed release components or a combination of two or more extended release components) may contain the same active ingredient or different active ingredients. In some embodiments, the immediate release component may provide from about 1% to about 80% of the total dose of active substance delivered by the pharmaceutical formulation. In some embodiments, the composite release profile formulation contains an immediate release component, and the immediate release component is from about 1% to about 90%, from about 10% of the total dose of each active ingredient delivered by the formulation. About 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90% %, Or about 80% to about 90%. In other embodiments, the immediate release component is up to about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% of the total dose of each active ingredient delivered by the formulation, or Offer up to 90%.

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

  The amount of drug in the core depends on the dose required and typically varies from about 5 to 90% by weight. In general, the polymer coating on the effective core is about 1 to 50% of the weight of the particles to be coated, depending on the type of lag time and release profile required and / or the polymer and coating solvent selected. Become. One skilled in the art can select the appropriate amount of agent to coat or incorporate into the core to achieve the desired dose. In one embodiment, the inert core is a sphere of sugar that alters its microenvironment to promote drug release, or calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid. Such as buffer crystals or encapsulated buffer crystals.

  In some embodiments, the pharmaceutical composition can include water-soluble / water-dispersible drug-containing particles, such as beads, in a water-insoluble polymer and enteric polymer in a weight ratio of 4: 1 to 1: 1. A delayed release component formed by coating with a mixture of a water insoluble polymer and an enteric polymer, and the total weight of the coating is 10 to 60% by weight of the total weight of the beads to be coated. The drug-laminated beads may optionally include an internal dissolution rate control membrane of 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, whereby two pulses Provides a release profile. In yet another embodiment, the formulation comprises two types of delayed release beads: a first type exhibiting a delay time of 1-3 hours and a second type of mixture exhibiting a delay time of 4-6 hours. In yet another embodiment, the formulation comprises two types of release beads: a first type that exhibits immediate release and a second type of mixture that exhibits an extended release after exhibiting a delay time of 1 to 4 hours.

  In some embodiments, the formulation comprises a portion of the active ingredient (eg, 10-80%) released immediately or within 2 hours of administration, and the remainder over an extended period of time (eg, 2-24 hours). Designed with a release profile such that it is released. In other embodiments, the formulation has one active ingredient (eg, acetaminophen or NSAID) released immediately or within 2 hours of administration, and one or more other active ingredients (eg, acetoacetate). Aminophen or NSAID) is designed with a release profile such that it is released over an extended period of time (eg, over 2-24 hours).

  The pharmaceutical composition can be administered daily or as needed. The pharmaceutical composition can be administered orally, intravenously, or intramuscularly. In preferred embodiments, the pharmaceutical composition is administered orally. In other embodiments, the pharmaceutical composition is administered by reverse perfusion from the urinary tract. In other embodiments, the pharmaceutical composition is administered by direct injection into the bladder muscle.

  In some embodiments, the pharmaceutical composition is administered once a day, twice a day, or three times a day. In other embodiments, the pharmaceutical composition is every other day, every 3 days, every 4 days, every 4 days, every 5 days, every 6 days, every week, every 2 weeks, every 3 weeks, every month, every 2 months, or every 3 months. To be administered.

  In some embodiments, the pharmaceutical composition is administered at 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 2-4 hours prior to bedtime. In a further embodiment, the pharmaceutical composition is administered at least 4 hours before bedtime.

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

  As a general proposal, a therapeutically effective amount of acetaminophen and one or more NSAIDs in an immediate release component, delayed release component, extended release component and / or delayed extended release component is It is administered in a range of about 1 μg / kg body weight / day to about 100 mg / kg body weight / day, whether by administration or more. In some embodiments, the range of each active agent administered daily in a single dose or in combination is from about 1 μg / kg body weight / day to about 100 mg / kg body weight / day, 1 μg / kg body weight / day to about 30 mg. / Kg body weight / day, 1 μg / kg body weight / day to about 10 mg / kg body weight / day, 1 μg / kg body weight / day to about 3 mg / kg body weight / day, 1 μg / kg body weight / day to about 1 mg / kg body weight / day 1 μg / kg body weight / day to about 300 μg / kg body weight / day, 1 μg / kg body weight / day to about 100 μg / kg body weight / day, 1 μg / kg body weight / day to about 30 μg / kg body weight / day, 1 μg / kg body weight / Day to about 10 μg / kg body weight / day, 1 μg / kg body weight / day to about 3 μg / kg body weight / day, 10 μg / kg body weight / day to about 100 mg / kg body weight / day, 10 μg / kg body weight / day to about 30 mg / K g body weight / day, 10 μg / kg body weight / day to about 10 mg / kg body weight / day, 10 μg / kg body weight / day to about 3 mg / kg body weight / day, 10 μg / kg body weight / day to about 1 mg / kg body weight / day, 10 μg / kg body weight / day to about 300 μg / kg body weight / day, 10 μg / kg body weight / day to about 100 μg / kg body weight / day, 10 μg / kg body weight / day to about 30 μg / kg body weight / day, 30 μg / kg body weight / day About 100 mg / kg body weight / day from day, 30 μg / kg body weight / day to about 30 mg / kg body weight / day, 30 μg / kg body weight / day to about 10 mg / kg body weight / day, 30 μg / kg body weight / day to about 3 mg / day kg body weight / day, 30 μg / kg body weight / day to about 1 mg / kg body weight / day, 30 μg / kg body weight / day to about 300 μg / kg body weight / day, 30 μg / kg body weight / day to about 100 μg / k Body weight / day, 100 μg / kg body weight / day to about 100 mg / kg body weight / day, 100 μg / kg body weight / day to about 30 mg / kg body weight / day, 100 μg / kg body weight / day to about 10 mg / kg body weight / day, 100 μg / Kg body weight / day to about 3 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 300 μg / kg body weight / day, 300 μg / kg body weight / day To about 100 mg / kg body weight / day, 300 μg / kg body weight / day to about 30 mg / kg body weight / day, 300 μg / kg body weight / day to about 10 mg / kg body weight / day, 300 μg / kg body weight / day to about 3 mg / kg Body weight / day, 300 μg / kg body weight / day to about 1 mg / kg body weight / day, 1 mg / kg / kg body weight / day to about 100 mg / kg body weight / day, 1 mg / kg Weight / day to about 30 mg / kg body weight / day, 1 mg / kg body weight / day to about 10 mg / kg body weight / day, 1 mg / kg body weight / day to about 3 mg / kg body weight / day, about 3 mg / kg body weight / day to about 100 mg / kg body weight / day, 3 mg / kg body weight / day to about 30 mg / kg body weight / day, 3 mg / kg body weight / day to about 10 mg / kg body weight / day, 10 mg / kg body weight / day to about 100 mg / kg body weight / day Day, 10 mg / kg body weight / day to about 30 mg / kg body weight / day or 30 mg / kg body weight / day to about 100 mg / kg body weight day.

  As a general suggestion, a therapeutically effective amount of a PG pathway inhibitor and / or analgesic in an immediate release component, a delayed release component, an extended release component or a delayed extended release component may be due to a single administration. Or, more or less, it is administered in the range of about 10 μg / kg body weight / day to about 100 mg / kg body weight / day. In some embodiments, the range of each active agent administered daily in a single dose or combined doses is from about 10 μg / kg body weight / day to about 100 mg / kg body weight / day, 10 μg / kg body weight / day to about 30 mg. / Kg body weight / day, 10 μg / kg body weight / day to about 10 mg / kg body weight / day, 10 μg / kg body weight / day to about 3 mg / kg body weight / day, 10 μg / kg body weight / day to about 1 mg / kg body weight / day 10 μg / kg body weight / day to about 300 μg / kg body weight / day, 10 μg / kg body weight / day to about 100 μg / kg body weight / day, 10 μg / kg body weight / day to about 30 μg / kg body weight / day, 30 μg / kg body weight / Day to about 100 mg / kg body weight / day, 30 μg / kg body weight / day to about 30 mg / kg body weight / day, 30 μg / kg body weight / day to about 10 mg / kg body weight / day, 30 μg / k Body weight / day to about 3 mg / kg body weight / day, 30 μg / kg body weight / day to about 1 mg / kg body weight / day, 30 μg / kg body weight / day to about 300 μg / kg body weight / day, 30 μg / kg body weight / day to about 100 μg / kg body weight / day, 100 μg / kg body weight / day to about 100 mg / kg body weight / day, 100 μg / kg body weight / day to about 30 mg / kg body weight / day, 100 μg / kg body weight / day to about 10 mg / kg body weight / day Day, 100 μg / kg body weight / day to about 3 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 300 μg / kg body weight / day, 300 μg / kg Body weight / day to about 100 mg / kg body weight / day, 300 μg / kg body weight / day to about 30 mg / kg body weight / day, 300 μg / kg body weight / day to about 10 mg / kg body / Day, 300 μg / kg body weight / day to about 3 mg / kg body weight / day, 300 μg / kg body weight / day to about 1 mg / kg body weight / day, 1 mg / kg body weight / day to about 100 mg / kg body weight / day, 1 mg / day From kg body weight / day to about 30 mg / kg body weight / day, from 1 mg / kg body weight / day to about 10 mg / kg body weight / day, from 1 mg / kg body weight / day to about 3 mg / kg body weight / day, from 3 mg / kg body weight / day About 100 mg / kg body weight / day, 3 mg / kg body weight / day to about 30 mg / kg body weight / day, 3 mg / kg body weight / day to about 10 mg / kg body weight / day, 10 mg / kg body weight / day to about 100 mg / kg body weight / Day, 10 mg / kg body weight / day to about 30 mg / kg body weight / day or 30 mg / kg body weight / day to about 100 mg / kg body weight / day.

  The analgesics described in this application are 1 mg to 2000 mg, 1 mg to 1000 mg, 1 mg to 300 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 10 mg, 1 mg to 3 mg, 3 mg to 2000 mg, 3 mg to 1000 mg, 3 mg to 300 mg, 3 mg to 3 mg. 100 mg, 3 mg to 30 mg, 3 mg to 10 mg, 10 mg to 2000 mg, 10 mg to 1000 mg, 10 mg to 300 mg, 10 mg to 100 mg, 10 mg to 30 mg, 30 mg to 2000 mg, 30 mg to 1000 mg, 30 mg to 300 mg, 30 mg to 100 mg, 100 mg to 2000 mg, 100 mg to 1000 mg, 100 mg to 300 mg, 300 mg to 2000 mg, 300 mg to 1000 mg For the 1000mg of daily oral administration of a single dose or a composite dosage range of 2000 mg, the immediate release component or extended release components, delayed release component may include a delay extended release component or combination thereof. As expected, the dose will depend on the condition, size, age, and patient condition.

  In other embodiments, the pharmaceutical composition comprises a pair of NSAIDs. Examples of such a pair of analgesics are acetylsalicylic acid and ibuprofen, acetylsalicylic acid and naproxen sodium, acetylsalicylic acid and nabumetone, acetylsalicylic acid and indomethacin, ibuprofen and naproxen sodium, ibuprofen and nabumetone, ibuprofen and indomethacin, naproxen or naproxen sodium and naproxen sodium. , Naproxen or naproxen sodium and indomethacin, nabumetone and indomethacin, but are not limited thereto. NSAID pairs are mixed in a weight ratio ranging from 0.1: 1 to 10: 1, 0.2: 1 to 5: 1, or 0.3: 1 to 3: 1. In one embodiment, NSAID pairs are mixed in a weight ratio of 1: 1.

  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, atropine, and tricyclic antidepressants. The daily dose of antimuscarinic agent is 1 μg to 300 mg, 1 μg to 100 mg, 1 μg to 30 mg; 1 μg to 10 mg, 1 μg to 3 mg, 1 μg to 1 mg, 1 μg to 300 μg, 1 μg to 100 μg, 1 μg to 30 μg, 1 μg to 10 μg, 1 μg to 3 μg, 3 μg to 100 mg, 3 μg to 100 mg, 3 μg to 30 mg; 3 μg to 10 mg, 3 μg to 3 mg, 3 μg to 1 mg, 3 μg to 300 μg, 3 μg to 100 μg, 3 μg to 30 μg, 3 μg to 30 μg, 3 μg to 300 μg, 10 μg to 300 mg, 10 μg to 100 mg, 10 μg to 30 mg; 10 μg to 10 mg, 10 μg to 3 mg, 10 μg to 1 mg, 10 μg to 300 μg, 10 μg to 100 μg, 10 μg to 30 μg, 30 μg to 300 mg, 30 μg to 100 mg mg, 30 μg to 30 mg; 30 μg to 10 mg, 30 μg to 3 mg, 30 μg to 1 mg, 30 μg to 300 μg, 30 μg to 100 μg, 100 μg to 300 mg, 100 μg to 100 mg, 100 μg to 30 mg; 100 μg to 10 mg, 100 μg to 3 mg, 100 μg to 1 mg, 100 μg to 300 μg, 300 μg to 300 mg, 300 μg to 100 mg, 300 μg to 30 mg; 300 μg to 10 mg, 300 μg to 3 mg, 300 μg to 1 mg, 1 mg to 300 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 3 mg, 3 mg to 300 mg, 3 mg to 100 mg, 3 mg to 30 mg, 3 mg to 10 mg, 10 mg to 300 mg, 10 mg to 100 mg, 10 mg to 3 mg, in the range 300mg, from 100mg or 100mg of 30mg 300mg of from 30mg.

  In some other embodiments, the pharmaceutical composition of the present application further comprises one or more antidiuretic agents. Examples of antidiuretics are antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (eg desmopressin argypressin, repressin, ferripressin, ornipressin, and terripressin), vasopressin receptor agonists, atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) receptor (ie, NPR1, NPR2, and 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), pharmaceutically acceptable derivatives, and Analogs, salts, hydrates and solvates of, but not limited to. In some embodiments, the one or more antidiuretic agent comprises desmopressin. In other embodiments, the one or more antidiuretic agent is desmopressin. Daily dose of antidiuretic is 1 μg to 300 mg, 1 μg to 100 mg, 1 μg to 30 mg; 1 μg to 10 mg, 1 μg to 3 mg, 1 μg to 1 mg, 1 μg to 300 μg, 1 μg to 100 μg, 1 μg to 30 μg, 1 μg to 10 μg, 1 μg to 3 μg, 3 μg to 100 mg, 3 μg to 100 mg, 3 μg to 30 mg; 3 μg to 10 mg, 3 μg to 3 mg, 3 μg to 1 mg, 3 μg to 300 μg, 3 μg to 100 μg, 3 μg to 30 μg, 3 μg to 30 μg, 3 μg to 300 μg, 10 μg to 300 mg, 10 μg to 100 mg, 10 μg to 30 mg; 10 μg to 10 mg, 10 μg to 3 mg, 10 μg to 1 mg, 10 μg to 300 μg, 10 μg to 100 μg, 10 μg to 30 μg, 30 μg to 300 mg, 30 μg to 100 mg, 30 μg to 30 mg; 30 μg to 10 mg, 30 μg to 3 mg, 30 μg to 1 mg, 30 μg to 300 μg, 30 μg to 100 μg, 100 μg to 300 mg, 100 μg to 100 mg, 100 μg to 30 mg; 100 μg to 10 mg, 100 μg to 3 mg, 100 μg to 1 mg, 100 μg to 300 μg, 300 μg to 300 mg, 300 μg to 100 mg, 300 μg to 30 mg; 300 μg to 10 mg, 300 μg to 3 mg, 300 μg to 1 mg, 1 mg to 300 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 3 mg, 3 mg to 300 mg, 3 mg to 100 mg, 3 to 30 mg, 3 to 10 mg, 10 to 300 mg, 10 to 100 mg, 10 to 30 mg 300mg of 30mg, in the range of 100mg or 100mg 300mg of from 30 mg.

  In other embodiments, the pharmaceutical composition of the present application further comprises one or more antispasmodic agents. 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 from 0.1 mg to 1000 mg, 0.1 mg to 300 mg, 0.1 mg to 100 mg, 0.1 mg to 30 mg, 0.1 mg to 10 mg, 0.1 mg to 3 mg, 0.1 mg to 0.1 mg. 1 mg, 0.1 mg to 0.3 mg, 0.3 mg to 1000 mg, 0.3 mg to 300 mg, 0.3 mg to 100 mg, 0.3 mg to 30 mg, 0.3 mg to 10 mg, 0.3 mg to 3 mg, 0.3 mg 1 mg, 1 mg to 1000 mg, 1 mg to 300 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 10 mg, 1 mg to 3 mg, 3 mg to 1000 mg, 3 mg to 300 mg, 3 mg to 100 mg, 3 mg to 30 mg, 3 mg to 10 mg, 10 mg to 1000 mg, 1 300mg From mg, 100 mg from 10 mg, 1000mg 30mg, from 30mg from 10 mg, 300mg from 30mg, 100 mg from 30mg, 1000mg from 100mg, used at a daily dose of 1000mg from 300mg or 300mg, from 100 mg.

  In other embodiments, the pharmaceutical composition of the present application further comprises one or more PDE5 inhibitors. Examples of PDE5 inhibitors include but are not limited to tadalafil, sildenafil and vardenafil. In some embodiments, the one or more PDE5 inhibitors comprises tadalafil. In other embodiments, the one or more PDE5 inhibitors is tadalafil. In some embodiments, the PDE5 inhibitor is 0.1 mg to 1000 mg, 0.1 mg to 300 mg, 0.1 mg to 100 mg, 0.1 mg to 30 mg, 0.1 mg to 10 mg, 0.1 mg to 3 mg,. 1 mg to 1 mg, 0.1 mg to 0.3 mg, 0.3 mg to 1000 mg, 0.3 mg to 300 mg, 0.3 mg to 100 mg, 0.3 mg to 30 mg, 0.3 mg to 10 mg, 0.3 mg to 3 mg,. 3 mg to 1 mg, 1 mg to 1000 mg, 1 mg to 300 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 10 mg, 1 mg to 3 mg, 3 mg to 1000 mg, 3 mg to 300 mg, 3 mg to 100 mg, 3 mg to 30 mg, 3 mg to 10 mg, 10 mg to 1000 g, 300mg from 10mg, 1000mg 100mg, 30mg, from 30mg of 10mg of 10mg, 300mg from 30mg, 1000mg 100mg, from 100mg of 30mg, used at a daily dose of 1000mg from 300mg or 300mg, from 100mg.

  In some other embodiments, the pharmaceutical composition of the present application further comprises zolpidem. The daily dose of zolpidem is 100 μg to 100 mg, 100 μg to 30 mg, 100 μg to 10 mg, 100 μg to 3 mg, 100 μg to 1 mg, 100 μg to 300 μg, 300 μg to 100 mg, 300 μg to 30 mg, 300 μg to 10 mg, 300 μg to 3 mg, 300 μg to 1 mg, Within the range of 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 10 mg, 1 mg to 3 mg, 10 mg to 100 mg, 10 mg to 30 mg, or 30 mg to 100 mg.

  PG pathway inhibitor, analgesic, antimuscarinic, antidiuretic, antispasmodic, PDE5 inhibitor, zolpidem, and / or combinations thereof are intended for immediate release, extended release, delayed release, delayed extended release or combinations thereof, It can be incorporated into a pharmaceutical composition alone or together with other active ingredients.

  In certain embodiments, the pharmaceutical composition is formulated for extended release and (1) acetaminophen; (2) one or more NSAIDs and (3) an analgesic, antimuscarinic, antidiuretic Agent, antispasmodic agent, PDE5 inhibitor, zolpidem, or a combination thereof.

  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 some embodiments, the pharmaceutical composition comprises 10-1000 mg, 10-800 mg, 10-600 mg, 10-500 mg, 10-500 mg, individually or in combination with one or more NSAIDs and / or acetaminophen. -400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-100 mg 30-1000 mg, 30-800 mg, 30-600 mg, 30-500 mg, 30-400 mg, 30-300 mg, 30-250 mg, 30-200 mg, 30-150 mg, 30-100 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-400 mg, 100-250 mg, 300-1000 mg, 300-800 mg, 300-600 mg, 300- Comprising in an amount between 00 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-1000 mg, 600-800 mg or 800-1000 mg, the composition comprising one or more NSAIDs and / or acetaminophen Are formulated for extended release with a release profile that is continuously released over a period of 2 to 12 hours, or 5 to 8 hours.

  In some embodiments, the composition continuously releases at least 90% of one or more NSAIDs and / or acetaminophen over a period of 2-12 hours, or 5-8 hours. Formulated for extended release with a release profile.

  In some embodiments, the composition has a release profile in which one or more NSAIDs and / or acetaminophen is continuously released over 5, 6, 7, 8, 10 or 12 hours. It is formulated for the purpose of extended release. In some embodiments, the pharmaceutical composition further comprises a PG pathway inhibitor, analgesic, antimuscarinic, antidiuretic, antispasmodic, PDE5 inhibitor, zolpidem or a combination thereof.

  In other embodiments, the composition is formulated for extended release with a release profile where the NSAID and / or acetaminophen is released at a constant rate over a period of 2-12 hours, or 5-8 hours. The In other embodiments, the composition is formulated for extended release with a release profile in which the analgesic is released at a constant rate over 5, 6, 7, 8, 10 or 12 hours. As used herein, “constant rate across” 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. For example, if 80 mg of aspirin is released at a constant rate over a period of 8 hours, the average release rate during this time is 10 mg / hour, and the actual release rate at any point in time is from 3 mg / hour. Within the range of 30 mg / hour (ie within 30% to 300% of the average release rate of 10 mg / hour during 8 hours). In some embodiments, the pharmaceutical composition further comprises a PG pathway inhibitor, analgesic, antimuscarinic, antidiuretic, antispasmodic, PDE5 inhibitor, zolpidem or a combination thereof.

  In some embodiments, the NSAID is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, and nabumetone. The pharmaceutical composition provides a constant release of NSAID and / or acetaminophen 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 To be formulated.

  In some other embodiments, the pharmaceutical compositions are each 10-1000 mg, 10-800 mg, 10-600 mg, 10-500 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10 -150 mg, 10-100 mg 30-1000 mg, 30-800 mg, 30-600 mg, 30-500 mg, 30-400 mg, 30-300 mg, 30-250 mg, 30-200 mg, 30-150 mg, 30-100 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-400 mg, 100-250 mg, 300-1000 mg, 300-800 mg, 300-600 mg, 300-400 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600 One or more NSAIDs and acetaminophen present in an amount between 1000 mg, 600-800 mg or 800-1000 mg, where NSAID and / or acetaminophen is 2-60 hours of administration of the analgesic Formulated for extended release, characterized by a two-phase release profile that is released within and the remainder is released continuously or at a constant rate over a period of 2-12 hours or 5-8 hours.

  In still other embodiments, the NSAID and / or acetaminophen are released within 2, 2 hours of administration of 20, 30, 40, 50 or 60% of the analgesic and the remainder 2-12 or 5-8. Formulated for extended release with a two-phase release profile that is released continuously over time or at a constant rate. In one embodiment, the NSAID is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, and nabumetone.

  In some embodiments, the pharmaceutical composition further comprises a PG pathway inhibitor, analgesic, antimuscarinic, antidiuretic, antispasmodic, PDE5 inhibitor, zolpidem or a combination thereof. In some embodiments, the PG pathway inhibitor, analgesic, antimuscarinic, antidiuretic, antispasmodic, PDE5 inhibitor, zolpidem or a combination thereof is formulated for immediate release.

  In some embodiments, the pharmaceutical composition is also used for the treatment of urinary incontinence and / or overactive bladder.

  Another aspect of the present application relates to a method for reducing bladder spasm, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of the present application and an effective amount of a botulinum toxin.

  In some embodiments, the botulinum toxin is administered by intravesical injection; and the pharmaceutical composition of the present application is administered orally to the subject. In some embodiments, the injecting step comprises injection of 10-200 units of botulinum toxin into 5-20 sites in the bladder muscle at an injection dose of 2-10 units at each site. In one embodiment, the injecting step comprises injection of botulinum toxin into 5 sites in the bladder muscle at an injection dose of 2-10 units at each site. In other embodiments, the injecting step comprises injection of botulinum toxin into 10 intravesical muscle sites at an injection dose of 2-10 units at each site. In other embodiments, the injecting step comprises injection of botulinum toxin into 15 sites in the bladder muscle at an injection dose of 2-10 units at each site. In yet another embodiment, the step of injecting comprises injection of botulinum toxin into 20 intravesical muscle sites at an injection dose of 2-10 units at each site. In some embodiments, the step of injecting is repeated every 3, 4, 6, 8, 10 or 12 months.

  In some embodiments, the above methods are also used for the treatment of urinary incontinence and / or overactive bladder.

  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 entire text of this application are incorporated herein by reference in their entirety.

(Inhibition of urination impulse by ibuprofen)
Twenty male and female volunteers were recruited, each experiencing premature urge to urinate or urinating, impeding their ability to sleep enough time to feel reasonably rested. Each subject took ibuprofen 400-800 mg as a single dose before bedtime. At least 14 subjects reported that they were able to take a better rest because they were not frequently awakened by the urge to urinate.

  Several subjects reported that after using ibuprofen for several weeks at night, the benefits from reducing the frequency of urination were no longer recognized. However, both of these subjects further reported that profits recovered after a few days of taking the dose. More recent studies have confirmed that similar results can be achieved at lower doses without any subsequent reduction in benefits.

(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), an inflammatory substance and Cox2 inducer as an inflammatory stimulus; carbachol or acetylcholine, a smooth muscle contraction stimulator, 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), gamma-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 are: salicylates such as aspirin; isobutylpropanephenolic acid derivatives (ibuprofen) such as advil, motrine, nuprin and medprene; areve, anaprox, antaldin, feminax ultra, flanax, in the, midor long analgesia, nargesine, Naproxen sodium such as naposin, naprelan, naprogesic, naprosin, naprosin suspension, EC-naprosin, narosin, proxen, symflex and xenovid; acetic acid derivatives such as indomethacin (indocin); 1-naphthalene acetic acid derivatives such as nabumetone or laraphene; N-acetyl paraaminophenol (APAP) derivatives such as acetaminophen or paracetamol (tylenol); and celecoxib Including.

  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. Next, PGH ₂ ; PGE; PGE ₂ ; Prostacyclin; Thromboxane; IL-1β; IL-6; Release of TNF-α; COX2 activity; Production of cAMP and cGMP; IL-1β, IL-6, TNF- Cells are analyzed 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)
RAW264.7 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 per well. Cells are (1) various concentrations of analgesics (acetaminophen, aspirin, ibuprofen or naproxen), (2) various concentrations of lipopolysaccharide (LPS), which is an effector of inflammatory stimuli on macrophage cells, (3 ) Treated with various concentrations of carbachol or acetylcholine, (4) analgesic and LPS or (5) analgesic and carbachol or acetylcholine, which are 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 collected and washed by centrifugation (1,500 rpm, 4 ° C. for 5 minutes) in 500 μL phosphate buffer (PBS). 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 (phosphate buffered saline (PBS) containing 2% bovine serum albumin (BSA) and 0.01% NaN ₃ ) and FITC-conjugated. gate anti CD40, PE- conjugated anti-CD80, PE-conjugated anti-CD86 antibody, with the addition of anti-MHC class ^{II (I-a d) PE} (BD Biosciences) and stained for 30 min at 4 ° C.. 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, cells are resuspended in 200 μL of FACS buffer and further used with Accuri C6 flow cytometer (BD Biosciences) for a given marker (single positive) or a combination of markers (double positive) The percentage of cells that expressed was analyzed.

(Analysis of cytokine response by ELISA)
Culture supernatants were subjected to a cytokine-specific ELISA to determine IL-1β, IL-6 and TNF-α responses in cultures of macrophages 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, TNF-α mAb (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 incubated overnight at 4 ° C. Finally, the plate is washed twice and incubated with 100 μL of secondary biotinylated anti-mouse IL-6, TNFα mAb (BD Biosciences) or IL-1β (R & D Systems) followed by peroxidase-labeled goat anti-biotin mAb (Vector Laboratories) did. 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 multilabel Absorbance at 415 nm was measured with a 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 determined by cAMP and cGMP assays. These assays are routinely performed in the art.

  Table 1 summarizes the experiments performed using the Raw 264 macrophage cell line and the main findings about the effect of analgesics on the cell surface expression of the costimulatory molecules CD40 and CD80. Since the expression of these molecules is stimulated by COX2 and inflammatory signals, this 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 dose (ie 5 × 10 ⁵ nM, 5 × 10 ⁴ nM, 5 × 10 ³ nM, 5 × 10 ² nM, 50 nM and 5 nM) inhibits basal expression of the costimulatory molecules CD40 and CD80 by macrophages. 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 3 summarizes the results of several trials that measured serum levels of analgesics after administration of oral therapeutic doses in human adults. As shown in Table 3, the highest serum level after administration of the oral therapeutic dose 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.

(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 synergistic effects of different classes of analgesics. Are designed to investigate whether COX2 and PGE2 reactions 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.

Next, PGH ₂ ; PGE; PGE ₂ ; Prostacidin; Thromboxane; IL-1β; IL-6; Release of TNF-α; 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, a bladder collected from 10 mice was slurried with scissors in 10 mL of digestion buffer (RPMI 1640, 2% fetal calf serum, 0.5 mg / mL collagenase, 30 μg / mL DNase). Shredded into a shape. The bladder slurry was enzymatically digested at 37 ° C. for 30 minutes. Undigested fragments were further dispersed with a cell trainer. The cell suspension was pelleted and added to purification discontinuous 20%, 40%, and 75% Percoll gradients on mononuclear cells. 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 a clear bottom black 96-well cell A culture microplate was seeded with 100 μL 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 were treated with 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 without fetal calf serum was added to the wells at 50 μL 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, blocked, and cyclooxygenase-2 (COX2) was detected using a fluorogenic 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 expressed as relative levels of total COX2, measured as relative fluorescence units (RFU) and 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 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, prostacidin; thromboxane; IL-1β; IL-6; and TNF-α release; cAMP and cGMP production; IL-1β, IL-6, TNF-α and COX2 mRNA production; And surface expression of CD80, CD86 and MHC class II molecules is determined as described in Example 2.

(result)
(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 effect of these analgesics on the COX2 response of mouse bladder cells to carbachol or LPS stimulation was 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 effects of analgesics were seen when these drugs were tested at either 5 μM or 50 μM (Table 4).

(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 bladder cells cultured in the presence of unstimulated bladder cells or carbachol. Consistent with the COX2 response described above, stimulation of mouse bladder cells with LPS induced high levels of PGE2 secretion. The 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 analgesic doses of 5 or 50 μM It was.

  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 the COX2 and PGE2 responses of 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. Stimulation-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 last dose, 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 urine volume) is assessed. Bladder excretion is calculated by monitoring water intake and cage bed 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, and MHC class II expression in whole blood cells.

  Animals are euthanized at the end of the experiment 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 amount of analgesic determined in Examples 1-5 affects human bladder smooth muscle cells in cell culture or tissue culture, and different classes of analgesics It is designed to investigate whether it can synergize to inhibit COX2 and PGE2 reactions more efficiently.

  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.

Next, PGH ₂ ; PGE; PGE ₂ ; Prostacidin; Thromboxane; IL-1β; IL-6; Release of TNFα; COX2 activity; Production of cAMP and cGMP; IL-1β, IL-6, TNFα and COX2 Cells are analyzed for mRNA production; 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. Stimulation-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. Cells are consumed 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, Once a week, after trypsinization to detach the cells, the cells were passaged by reseeding into a new culture flask. 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 in microculture plates at a cell density of 3 × 10 ⁴ cells / well 100 μL were treated with analgesic solution (50 μL / well) alone or carbachol (10 Mole, 50 μL / well), or Salmonella typhimurium lipopolysaccharide (LPS) (1 μg / mL, 50 μL / well) as an example of a non-inflammatory stimulus. If no other effector was added to the cells, 50 μL of RPMI 1640 without 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, blocked, and COX2 was detected using a fluorogenic substrate. In some experiments, cells were stimulated in vitro for 12 hours for the purpose of analyzing 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--all analgesics tested alone are normal by analysis of cells and culture supernatant after 24 hours of culture It was shown not to induce a COX2 response in human bladder smooth muscle cells. However, as summarized in Table 6, carbachol induced a low but significant COX2 response in normal human bladder smooth muscle cells. On the other hand, LPS treatment resulted in a higher level of COX2 response in normal human bladder smooth muscle cells. Acetaminophen, aspirin, ibuprofen and naproxen all 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.

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

  Analgesics inhibit the cytokine response of normal human bladder cells to inflammatory stimuli--analysis of cells and culture supernatants after 24 hours of culture showed that all analgesics tested alone were IL in normal human bladder smooth muscle cells It has been shown not to induce -6 or TNFα secretion. As shown in Tables 8 and 9, carbachol test doses induced significant but low TNFα and IL-6 responses 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.

  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 would repeat the findings previously found in mouse bladder cells.

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

  The above is intended to teach those skilled in the art how to practice the invention, and details all of the obvious modifications or variations that will become apparent to those skilled in the art after reading this description. Not intended. 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 include the elements in any order effective to fulfill the claimed element and its intended purpose, unless the context clearly indicates otherwise.

Claims (33)

A method for reducing bladder spasm in a subject comprising:
Said method comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of acetaminophen and an effective amount of at least one non-steroidal anti-inflammatory agent (NSAID).   2. The method of claim 1, wherein the NSAID is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, nabumetone, salts thereof, and combinations thereof.   2. The method of claim 1, wherein the pharmaceutical composition is formulated for immediate release, delayed release, or extended release.   2. The method of claim 1, wherein the pharmaceutical composition is administered orally. A pharmaceutical composition for treating bladder spasm, comprising:
Acetaminophen;
One or more NSAIDs; and a pharmaceutically acceptable carrier.   6. The pharmaceutical composition of claim 5, further comprising a PG pathway inhibitor, analgesic, antimuscarinic, antidiuretic, antispasmodic, zolpidem or a combination thereof.   6. The pharmaceutical composition according to claim 5, wherein at least one active substance in the pharmaceutical composition is formulated for immediate release.   6. The pharmaceutical composition according to claim 5, wherein at least one active substance in the pharmaceutical composition is formulated for the purpose of delayed release.   6. The pharmaceutical composition according to claim 5, wherein at least one active substance in the pharmaceutical composition is formulated for the purpose of extended release.   6. The pharmaceutical composition according to claim 5, wherein at least one active substance in the pharmaceutical composition is coated with an enteric coating.   6. The pharmaceutical composition according to claim 5, wherein at least one active substance in the pharmaceutical composition is formulated for oral administration.   6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is blended in an orally disintegrating preparation. A method for reducing bladder spasm in a subject comprising:
A method comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of at least one prostaglandin (PG) pathway inhibitor, said at least one PG pathway inhibitor comprising acetamino Said method which is not phen or NSAID.   14. The method of claim 13, wherein the at least PG pathway inhibitor is an inhibitor of prostaglandin activity.   14. The method of claim 13, wherein the at least PG pathway inhibitor is an inhibitor of prostaglandin transporter activity.   14. The method of claim 13, wherein the at least PG pathway inhibitor is an inhibitor of prostaglandin transporter expression.   14. The method of claim 13, wherein the at least PG pathway inhibitor is an inhibitor of prostaglandin receptor activity.   14. The method of claim 13, wherein the at least PG pathway inhibitor is an inhibitor of prostaglandin receptor expression.   14. The method of claim 13, wherein the pharmaceutical composition is formulated for immediate release, delayed release, or extended release.   14. The method of claim 13, wherein the pharmaceutical composition is administered orally. A pharmaceutical composition for treating bladder spasm, comprising:
Said pharmaceutical composition comprising one or more PG pathway inhibitors; and a pharmaceutically acceptable carrier comprising:
The pharmaceutical composition wherein the one or more PG pathway inhibitors do not comprise acetaminophen or NSAID.   24. The pharmaceutical composition of claim 21, wherein the one or more PG pathway inhibitors comprises an inhibitor of prostaglandin activity.   24. The pharmaceutical composition of claim 21, wherein the one or more PG pathway inhibitors comprises an inhibitor of prostaglandin transporter activity.   24. The pharmaceutical composition of claim 21, wherein the one or more PG pathway inhibitors comprises an inhibitor of prostaglandin transporter expression.   24. The pharmaceutical composition of claim 21, wherein the one or more PG pathway inhibitors comprises an inhibitor of prostaglandin receptor activity.   24. The pharmaceutical composition of claim 21, wherein the one or more PG pathway inhibitors comprises an inhibitor of prostaglandin receptor expression.   22. The pharmaceutical composition of claim 21, further comprising an NSAID, an analgesic, an antimuscarinic, an antidiuretic, an antispasmodic, a PDE5 inhibitor, zolpidem or a combination thereof.   22. The pharmaceutical composition according to claim 21, wherein at least one active substance in the pharmaceutical composition is formulated for immediate release.   22. The pharmaceutical composition according to claim 21, wherein at least one active substance in the pharmaceutical composition is formulated for the purpose of delayed release.   22. The pharmaceutical composition according to claim 21, wherein at least one active substance in the pharmaceutical composition is formulated for extended release.   31. The pharmaceutical composition according to claim 30, wherein at least one active substance in the pharmaceutical composition is coated with an enteric coating.   22. The pharmaceutical composition according to claim 21, wherein at least one active substance in the pharmaceutical composition is formulated for oral administration.   22. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition is blended in an orally disintegrating preparation.

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