TWI587879B - Extended-release formulation for reducing the frequency of urination and method of use thereof - Google Patents

Description

Extended release preparation for reducing urination frequency and method of use thereof

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

The detrusor is a layer of the bladder wall that is formed by smooth muscle fibers arranged in a spiral bundle, a longitudinal bundle, and a circular bundle. When the bladder is stretched, this signals the parasympathetic nervous system to contract the detrusor. Thereby causing the bladder to discharge urine through the urethra.

In order for the urine to drain out of the bladder, the autonomically controlled internal sphincter and the voluntary external sphincter must be open. These muscle problems can cause incontinence. If the urine volume reaches 100% of the absolute volume of the bladder, the sphincter of the consciousness becomes unconscious and the urine will be expelled immediately.

Adult bladders typically hold about 300-350 milliliters of urine (working capacity), but depending on the individual, a complete adult bladder can hold up to about 1000 milliliters (absolute amount). As the urine accumulates, the ridge-like ridges due to the folding (wrinkles) of the bladder wall flatten and the bladder wall becomes thinner as it stretches, allowing the bladder to be stored without a significant increase in internal pressure. A lot of urine.

For most individuals, urine is usually produced when the volume of urine in the bladder reaches 200 ml. At this stage, if the individual needs it, he can easily resist the urge to urinate. As the bladder continues to fill, the urinary tract becomes stronger and more difficult to ignore. Eventually, the bladder is filled to such an extent that the urinary impulse cannot be resisted and the individual will no longer be able to ignore it. For some individuals, urinary tract is initiated when the bladder is filled with less than 100% of its working capacity. This increased urinary tract may affect normal activities, including providing adequate restless sleep. ability. In some cases, this increased urinary tract may be related to medical conditions, such as benign prostatic hyperplasia or prostate cancer in men, or pregnancy in women. However, increased urinary tract also occurs in individuals who are not affected by other medical conditions, both male and female.

Thus, there is a need for compositions and methods for treating their bladders in both male and female individuals who suffer from urinary infestation when filled with less than 100% of their working capacity. The compositions and methods are needed to inhibit muscle contraction, thereby allowing the individual to begin to have urinary tract when the volume of urine in the bladder exceeds about 100% of their working capacity.

One aspect of the present application relates to a method of reducing the frequency of urination. The method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a first analgesic selected from the group consisting of acetaminophen and aspirin. Ibuprofen, naproxen sodium, indomethacin, and nabumetone, wherein the pharmaceutical composition is formulated as an extended release preparation. In one embodiment, the first analgesic is administered orally at a dose of from 0.1 micrograms to 5 milligrams per day. The method can be used for the treatment of nocturia.

Another aspect of the present application relates to a method of reducing the frequency of urination. The method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: a first component formulated for immediate release; and a second component formulated for extended release, wherein the first component and The second component each comprises an analgesic selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and p-acetamidophenol. In one embodiment, the first component and the second component are each administered orally at a dose of from 0.1 micrograms to 5 milligrams per day. This method can be used for the treatment of nocturia.

Another aspect of the present application relates to a method of treating nocturia. The method comprises administering to a human in need thereof a pharmaceutical composition comprising one or more analgesic agents and one or more antidiuretics, wherein the pharmaceutical composition is formulated for extended release.

Another aspect of the present application relates to a pharmaceutical composition comprising two or more analgesic agents selected from the group consisting of acetaminophen, aspirin, ibuprofen, naproxen sodium, strontium Mesin and nabumetone and a pharmaceutically acceptable carrier, wherein the two or more analgesic agents are formulated for extended release.

Another aspect of the present application relates to a pharmaceutical composition comprising: one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone And p-acetamido phenol; one or more antidiuretics and optionally one or more anti-drug agents; and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated for extended release.

In other embodiments, the first analgesic is selected from the group consisting of: aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and p-acetamidophenol, It is administered at a dose of 0.1 to 10 mg per day.

In other embodiments, the pharmaceutical composition is administered from 1 to 3 hours prior to bedtime.

In other embodiments, the pharmaceutical composition further comprises a second analgesic selected from the group consisting of: aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and For acetaminophen, wherein the second analgesic is different from the first analgesic.

In other embodiments, the pharmaceutical composition further comprises a first anti-drug agent selected from the group consisting of oxybutynin, solfnacnin, darifenacin And atropine (atropine).

Another aspect of the present application relates to a pharmaceutical composition for reducing the frequency of urination comprising a first component formulated for immediate release; and a second component formulated for extended release, wherein the first component and the The second component each comprises an analgesic selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and p-acetamidophenol.

In other embodiments, the second component is coated with an enteric coating.

In other embodiments, the first component further comprises an anti-drug agent selected from the group consisting of oxybutynin, solifena, dafenazone, and atropine.

In other embodiments, the second component further comprises an anti-drug agent selected from the group consisting of oxybutynin, solifena, dafenacin, and atropine.

In other embodiments, the first component and the second component each further comprise an anti-drug agent selected from the group consisting of oxybutynin, solifena, dafenazone, and atropine. In other embodiments, the analgesic dose in the first component is from 0.1 to 100 micrograms and the analgesic dose in the second component is from 0.1 to 100 micrograms.

In other embodiments, the first and second components each comprise two analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin , nabumetone and p-acetamidophenol. In a related embodiment, the combined dose of the two analgesics in the first component is from 0.1 to 100 micrograms and the combined dose of the two analgesics in the second component is from 0.1 to 100 micrograms.

Another aspect of the invention relates to a composition for reducing the frequency of urination comprising a first pharmaceutical composition comprising a diuretic, and a second pharmaceutical composition comprising one or more analgesics, wherein the first pharmaceutical combination The composition is formulated and formulated to have a diuretic effect within 6 hours of administration, and is administered at least 8 hours prior to bedtime, and wherein the second pharmaceutical composition is formulated for extended release and administered within 2 hours prior to bedtime.

In other embodiments, the second pharmaceutical composition further comprises one or more anti-drug agents.

Another aspect of the invention relates to a pharmaceutical composition comprising two or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, Nabumetone and p-acetamido phenol, and a pharmaceutically acceptable carrier, wherein the two or more analgesic agents are formulated for extended release.

Another aspect of the invention relates to a pharmaceutical composition for treating nocturia comprising one or more analgesics and one or more antidiuretics, wherein the pharmaceutical composition is formulated for extended release.

One aspect of the present application relates to a method of reducing the frequency of urination. The method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a first analgesic selected from the group consisting of aspirin, ibuprofen, naproxen sodium, comparable Xin, nabumetone, and p-acetamidophenol, wherein the pharmaceutical composition is formulated as an extended release preparation.

Another aspect of the present application relates to a method of reducing the frequency of urination. The method comprises administering to a human in need thereof a first pharmaceutical composition comprising a diuretic; and administering thereto a second pharmaceutical composition comprising one or more analgesic agents, wherein the first pharmaceutical composition is modulated and formulated to be The diuretic effect is administered within 6 hours of administration and is administered at least 8 hours prior to bedtime, and wherein the second pharmaceutical composition is formulated for extended release and administered within 2 hours prior to bedtime.

Another aspect of the present application relates to a method of treating nocturia. The method comprises administering to a human in need thereof a pharmaceutical composition comprising one or more analgesic agents and one or more antidiuretics, wherein the pharmaceutical composition is formulated for extended release.

Another aspect of the present application relates to a pharmaceutical composition comprising two or more selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and p-acetaminophen An analgesic; and a pharmaceutically acceptable carrier, wherein the two or more analgesic agents are formulated for extended release.

Another aspect of the present application is directed to a pharmaceutical composition comprising: a first component formulated for immediate release, a second component formulated for extended release, and a pharmaceutically acceptable carrier, wherein the first component and The second component each comprises one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and p-acetamidophenol.

In other embodiments, the first component, the second component, or both components further comprise one or more anti-drug agents.

In other embodiments, the anti-drug agent is selected from the group consisting of oxybutynin, solifena, dafenacin, and atropine.

The following detailed description is presented to enable a person skilled in the art to make and use the invention. For the purposes of explanation, specific terms are set forth below to fully understand the invention. However, it is apparent to those skilled in the art that these specific details are not required to be implemented in the present invention. The description of the specific application is provided only as a representative example. The present invention is not intended to be limited to the embodiments shown, but is intended to include the broadest possible scope of the principles and features disclosed herein.

The term "effective amount" as used herein refers to an amount sufficient to achieve a selected result.

The term "analgesic" as used herein refers to an agent, compound or drug for relieving pain and including anti-inflammatory compounds. Analgesic and/or anti-inflammatory agents, compounds or drug kits Including but not limited to the following: salicylate, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, Sulfasalazine, a derivative of p-aminophenol, acetophenone, p-acetamido phenol, phenacetin, fenamates, mefenamic acid ), meclofenamates, sodium meclofenamate, heteroaryl acetate derivatives, tolmetin, ketorolac, diclofenac, c Acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin , enolic acid, oxicam derivatives, piroxicam, meloxicam, tenoxicam, ampiroxicam ), droxicam, pivotoxicam, pyrazolone derivative, phenylbutazone, hydroxy Oxyphenbutazone, antipyrine, aminopyrine, dipyrone, coxib, celecoxib, rofecoxib ), nabumetone, apazone, indomethacin, sulindac, etodolac, isobutyl phenylpropionate, luminacoxib ), etoricoxib, parecoxib, valdecoxib, tiracoxib, darbufelone, dexketoprofen, aceclofen Acid (aceclofenac), licofelone, bromfenac, loxoprofen, pranoprofen, nimesulide, cizolirine, 3-a Mercaptoamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzo Pyran-4-one, lornoxicam, d-indobufen, mofezolac, amtolmetin, pranoprofen ), tolfenamic acid, suprofen, zaltoprofen, alminoprofen, tiaprofenic acid, and pharmaceutically acceptable salts thereof, Hydrates and solvates.

The terms "coxib" and "COX inhibitor" as used herein mean the ability to inhibit the activity or performance of a COX-2 enzyme, or to inhibit or reduce the severity of a severe inflammatory response including pain and swelling. A composition of the compound.

The bladder has two important functions: storing urine and emptying it. Storage of urine occurs at low pressure, which means that the detrusor relaxes during the filling phase. Evacuation of the bladder requires coordinated contraction of the detrusor and relaxation of the urethral sphincter. Disorders in storage function can lead to lower urinary tract symptoms such as urgency, frequent urination, and urge incontinence, a component of overactive bladder syndrome. Overactive bladder syndrome may be due to unintentional contraction of the bladder smooth muscle (detrusor) during storage, a common and underestimated problem that has only recently been evaluated.

One aspect of the present application relates to a method of reducing the frequency of urination by administering to a human in need thereof a pharmaceutical composition formulated as an extended release formulation. The pharmaceutical composition includes one or more analgesics, and optionally one or more anti-drugs, or one or more antidiuretics. This method can be used for the treatment of nocturia.

"Extended release", also known as sustained-release (SR), sustained-action (SA), time-release (TR), controlled-release (CR), modified release ( Modified release, MR) or even Continuous-release (CR) is a mechanism used in pharmaceutical tablets or capsules to allow the active ingredient to slowly dissolve and release over a prolonged period of time. The advantage of extended release tablets or capsules is that they are generally capable of being administered less frequently than immediate release formulations of the same drug, and that they maintain a more stable drug concentration in the bloodstream, thereby extending the duration of drug action. For example, extended release analgesics can make people sleep all night without getting up in the bathroom.

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

The extended release formulation can be designed to release the active agent at a predetermined rate to maintain a constant drug concentration for a specified extended period of time, such as up to one, after administration, or after a delay time associated with delayed release of the drug. About 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour.

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

In some embodiments, the extended release formulation comprises an active core comprising one or more inert particles, each in the form of a bead, a pellet, a pill, a particle, a microcapsule, a microsphere, a microparticle, The form of the nanocapsule or nanosphere is coated on its surface by a drug in the form of, for example, a drug-containing coating or film-forming composition using, for example, a fluidized bed technique or other methods known to those skilled in the art. The inert particles can be of different sizes as long as they are sufficient to maintain a size that is not readily soluble. Alternatively, the active core can be prepared by granulation and milling and/or extrusion and spheronization of the polymer composition containing the drug substance.

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

Prolonged release formulations may employ a variety of extended release coatings or mechanisms that aid in the gradual release of the active agent over time. In some embodiments, the extended release formulation comprises a polymer that is controlled to release release by controlling dissolution release. In a particular embodiment, the active agent is incorporated into a matrix comprising insoluble polymer and drug particles or particles coated with a polymeric material of varying thickness. The polymeric material may include lipid barriers containing waxy materials such as carnauba wax, beeswax, cetyl wax, candelilla wax, shellac wax, Cocoa butter, cetostearyl alcohol, partially hydrogenated vegetable oil, ceresin, paraffin, ceresine, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid Acids, as well as surfactants, such as polyoxyethylene sorbitan monooleate. When it comes into contact with an aqueous medium, such as a biological fluid, the polymer coating is emulsified or eroded after a predetermined delay time, depending on the thickness of the polymer coating. This delay time is independent of gastrointestinal motility, pH, or a gastric residence in the stomach.

In other embodiments, the extended release agent comprises a polymer matrix that achieves controlled diffusion 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, optionally containing one or more excipients and/or a promoting release agent that enhance solubility. As the water-soluble polymer is solubilized, the active agent dissolves (if soluble) and the hydrated portion that passes through the matrix gradually diffuses. As more water penetrates into the matrix core, the gel layer grows over time, increasing the thickness of the gel layer and providing diffusion separation of drug release. As the outer layer becomes fully hydrated, the polymer chain is fully stretched and the integrity of the gel layer is no longer maintained, resulting in untangling and erosion of the outer hydrated polymer on the surface of the substrate. Water continues to penetrate the core through the gel layer until it is completely eroded. Soluble drugs are released through this combination of diffusion and erosion mechanisms, and for insoluble drugs, erosion is the primary mechanism regardless of dosage.

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

In addition, due to the filtration of the pH dependent release promoting agent, the porosity of the matrix increases, thereby releasing the drug at a faster rate. Subsequently, the drug release rate becomes constant and it becomes a function of drug diffusion across the hydrated polymer gel. The release rate from the matrix depends on different parameters, including polymer type and grade; drug solubility and dosage; polymer to drug ratio; filler type and grade; polymer to filler ratio; drug and polymer particle size ; and the porosity and shape of the matrix.

Exemplary hydrophilic and/or water swellable, matrix-forming polymers include, but are not limited to, cellulosic polymers, including hydroxyalkyl celluloses and carboxyalkyl celluloses, such as hydroxypropyl methylcellulose ( HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), carboxymethyl cellulose (CMC), powdered cellulose (eg microcrystalline cellulose, acetic acid) Cellulose, ethyl cellulose, salts thereof, and combinations thereof; alginate, gum, including allopolysaccharide gum and homoglycan gum, such as xanthan, tragacanth , pectin, acacia, karaya, agar, guar, hydroxypropyl guar, veegum, carrageenan, locust bean Locust bean gum, gellan gum and its derivatives; acrylic resins, including polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate and methyl methacrylate, and crosslinked polyacrylic acid derivatives, such as carbomers (carbomers) (e.g., CARBOPOL ^®, e.g., including CARBOPOL ^® 71G NF, having different points Weight grades from Noveon Company, Cincinnati, OH); polyvinyl acetate (e.g., KolliDON ^® SR); polyvinylpyrrolidone and derivatives thereof, such as cross-povidone (crospovidone); polyethylene oxide; And polyvinyl alcohol. Preferred hydrophilic and water swellable polymers include cellulosic polymers, particularly HPMC.

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

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

In one embodiment, the method of introducing is to form a drug layer by spraying a suspension of the active agent and the binder onto an inert carrier.

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

In some embodiments, the hydrophilic polymer matrix can further comprise an ionic polymer, a nonionic polymer, or a water insoluble hydrophobic polymer to provide a more powerful gel layer and/or reduce the number of pores in the matrix. And size, thereby slowing the rate of diffusion and erosion and the accompanying release of the active agent. This can additionally inhibit the initial burst effect and produce a more stable "zero-order release" of the active agent.

Exemplary ionic polymers for slowing the dissolution rate include anionic polymers and cationic polymers. Exemplary anionic polymers include, for example, sodium carboxymethyl cellulose (Na CMC), sodium alginate, acrylic or carbomer polymers (eg, CARBOPOL ^® 934, 940, 974P NF); enteric polymers, Such as polyvinyl acetate phthalate (PVAP), methacrylic acid copolymers (such as EUDRAGIT ^® L100, L 30D 55, A and FS 30D), hydroxypropyl methylcellulose acetate succinate (AQUAT HPMCAS) ; and Sanxianjiao. Exemplary cationic polymers include, for example, dimethylaminoethyl methacrylate copolymers (e.g., EUDRAGIT ^® E 100). The incorporation of anionic polymers, especially enteric polymers, is useful for developing a pH-independent release profile of a weakly basic drug compared to a hydrophilic polymer alone.

For Exemplary nonionic polymers include slowing the dissolution rate, for example, hydroxypropylcellulose (HPC) and polyethylene oxide (the PEO) (e.g., POLYOX ^TM).

Exemplary embodiments of the hydrophobic polymer include ethyl cellulose (e.g., ETHOCEL ^TM, SURELEASE ^®), cellulose acetate, methacrylic acid copolymers (e.g., EUDRAGIT ^® NE 30D), an ammonium group - methacrylate copolymers ( For example, EUDRAGIT ^® RL 100 or PO RS100), polyvinyl acetate, glyceryl monostearate, fatty acids such as tributyl citrate, and combinations and derivatives thereof.

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

Exemplary promote release agents include pH dependent enteric polymers that remain intact at pH to below about 4.0 and are above pH 4.0, preferably above 5.0, at pH values. It is preferably dissolved at about 6.0 and is considered to be useful as a release-promoting agent in the present invention. Exemplary pH dependent polymers include, but are not limited to, methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (eg EUDRAGIT ^® L100 (type A), EUDRAGIT ^® S100 (B) from Rohm, Germany Type)); methacrylic acid-ethyl acrylate copolymer (such as EUDRAGIT ^® L100-55 (type C) and EUDRAGIT ^® L30D-55 copolymer dispersion from Rohm, Germany); methacrylic acid-methyl methacrylate and Copolymer of methyl methacrylate (EUDRAGIT ^® FS); terpolymer of methacrylic acid, methacrylate and ethyl acrylate; cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose Phthalates (HPMCP) (for example, HP-55, HP-50, HP-55S from Shin-Etsu Chemical Co., Ltd.); Polyvinyl acetate phthalate (PVAP) (for example, COATERIC ^® , OPADRY ^® Enteric white OY-P-7171); polyvinyl acetate butyrate; cellulose acetate succinate (CAS); hydroxypropyl methylcellulose acetate succinate (HPMCAS), for example, HPMCAS LF Grade, MF grade, HF grade, including AQOAT ^® LF and AQOAT ^® MF (Japan Shin-Etsu Chemical); Shin-Etsu Chemical of Japan): Shellac (example Such as, MARCOAT ^TM 125 and MARCOAT ^TM 125N); vinyl acetate - maleic anhydride copolymer; a styrene - maleic monoester copolymer (styrene-maleic monoester copolymer); carboxymethyl ethylcellulose (CMEC, Freund Corporation , Japan); cellulose acetate phthalate (CAP) (for example, AQUATERIC ^® ); cellulose acetate-1,2,4-benzenetricarboxylate (CAT); and weight ratio of about 2:1 to about 5: A mixture of two or more thereof, for example, a mixture of EUDRAGIT ^® L 100-55 and EUDRAGIT ^® S 100 in a weight ratio of from about 3:1 to about 2:1, or a weight ratio of from about 3:1 to about 5 :1 mixture of EUDRAGIT ^® L 30 D-55 and EUDRAGIT ^® FS.

These polymers may be used singly or in combination or together with a polymer other than the above. Preferred pH dependent enteric polymers are pharmaceutically acceptable methacrylic acid copolymers. These copolymers are anionic polymers based on methacrylic acid and methyl methacrylate, and preferably have an average molecular weight of about 135,000. In these copolymers, the ratio of the free carboxyl group to the methyl esterified carboxyl group ranges, for example, from 1:1 to 1:3, such as from 1:1 or 1:2. This polymer is sold under the trade name Eudragit ^® commercially, such as the Eudragit L series, ^{e.g., Eudragit L 12.5 ®, Eudragit L} 12.5P ®, Eudragit L 100 ®, Eudragit L 100-55 ®, Eudragit L-30D ®, Eudragit L-30 D-55 ^® , Eudragit S ^® series, for example, Eudragit S 12.5 ^® , Eudragit S 12.5P ^® , Eudragit S100 ^® . Promoting release agents are not limited to pH dependent polymers. Other hydrophilic molecules that rapidly dissolve and rapidly filter out the dosage form leaving a porous structure can also be used for the same purpose.

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

In some embodiments, the matrix can include a combination of a promoting release agent and a solubilizing agent. The solubilizing agent may be an ionic or nonionic surfactant, a complexing agent, a hydrophilic polymer, a pH adjusting agent such as an acidifying agent and an alkalizing agent, and a molecule which increases the solubility of the poorly soluble drug by molecular entrapment. Several solubilizers can be used simultaneously.

The solubilizing agent may include a surface active agent such as sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate, Tweens ^® and Sprinkles (Spans) (PEO modified sorbitol monoester and fatty acid sorbitol ester), poly(ethylene oxide)-polypropylene oxide-poly(ethylene oxide) block copolymer (aka PLURONICS ^TM ); a complexing agent such as a low molecular weight polyvinylpyrrolidone and a low molecular weight hydroxypropyl methylcellulose; a molecule that is solubilized by molecular entrapment, such as a cyclodextrin; and a pH adjusting agent, including an acidifying agent such as a lemon a regulator of acid, fumaric acid, tartaric acid and hydrochloric acid; and an alkalizing agent such as meglumine and sodium hydroxide.

The solubilizer typically constitutes from 1% to 80% by weight of the dosage form, preferably from 1% to 60% by weight, more preferably from 1% to 50% by weight, and which may be incorporated in different ways. They can be incorporated into the formulation in a dry or moist form prior to granulation. They can also be added to the formulation after granulation or other processing of other materials. The solubilizer may be added as a solution or may be sprayed without the addition of a binder during granulation.

In some embodiments, the extended release formulation comprises a polymeric matrix that is capable of releasing the drug independent of pH after a certain period of time. For the purposes of the present invention, "non-pH dependent" is defined as having properties (eg, dissolution) that are substantially unaffected by pH. Non-pH dependent polymers are generally referred to as "time controlled" or "time dependent" release profiles.

The pH-independent polymer can be used to coat the active agent and/or to provide a polymer for the hydrophilic matrix in the extended release coating thereon. Non-pH dependent polymers can be water insoluble or water soluble. Exemplary water insoluble, pH-independent polymers include, but are not limited to, neutral methacrylates having a small portion of trimethylammonioethyl methacrylate chloride (eg, EUDRAGIT) ^® RS and EUDRAGIT ^® RL; neutral ester dispersions without any functional groups (eg EUDRAGIT ^® NE30D and EUDRAGIT ^® NE30); cellulosic polymers such as ethyl cellulose, hydroxyethyl cellulose, cellulose acetate Or mixtures; and other non-pH dependent coating products. Exemplary water soluble pH independent polymers include hydroxyalkyl cellulose ethers such as hydroxypropyl methylcellulose (HPMC), and hydroxypropyl Cellulose (HPC); polyvinylpyrrolidone (PVP), methylcellulose, OPADRY ^® amb, guar gum, tri-gum arabic, gum arabic, hydroxyethyl cellulose, and ethyl acrylate and methacrylic acid A methyl ester copolymer dispersion, or a combination thereof.

In one embodiment, the extended release formulation comprises a water insoluble, permeable polymeric coating or matrix comprising one or more water insoluble, water permeable film forming layers on the active core. The coating may additionally comprise one or more water soluble polymers and / or one or more plasticizers. The water insoluble polymeric coating includes a barrier coating for releasing the active agent in the core, wherein the low molecular weight (viscosity) rating shows a faster release rate than the higher viscosity grade.

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

Exemplary water soluble polymers such as polyvinylpyrrolidone (POVIDONE®), hydroxypropyl methylcellulose, hydroxypropylcellulose, and mixtures thereof.

In some embodiments, the water insoluble polymer provides suitable properties (eg, extended release properties, mechanical properties, and coating properties) without the need for a plasticizer. For example, a coating comprising the following materials may be used without a plasticizer: polyvinyl acetate (PVA), a neutral copolymer of acrylate/methacrylate (eg, Eudragit NE30D available from Evonik Industries), B. The base cellulose is combined with hydroxypropyl cellulose, wax, and the like.

In another embodiment, the water insoluble polymer matrix can further comprise a plasticizer. The amount of plasticizer required depends on the nature of the plasticizer, the water insoluble polymer, and the final desired coating properties. A suitable concentration of plasticizer is from about 1% to about 20% by weight, from about 3% to about 20% by weight, from about 3% to about 5% by weight, and about 7% by weight, relative to the total weight of the coating. Up to about 10% by weight, about 12% to about 15% by weight, about 17% to about 20% by weight, or about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5 parts by weight %, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 15% by weight or about 20% by weight, inclusive of all ranges and subranges therein.

Exemplary plasticizers include, but are not limited to, triacetin, acetylated monoglyceride, oil (castor oil, hydrogenated castor oil, rapeseed oil, sesame oil, olive oil, etc.) Citric acid ester, triethyl citrate, triethyl ethyl citrate, tributyl citrate, tributyl citrate, tri-n-butyl citrate, phthalic acid Ethyl ester, dibutyl phthalate, dioctyl phthalate, methyl paraben, propyl paraben, butyl paraben, diethyl sebacate, sebacic acid Dibutyl ester, glyceryl tributyrate, substituted triglycerides and glycerides, monoethylated and diacetylated glycerides (eg MYVACET ^® 9-45), glyceryl monostearate, tributyl Acid glyceride, polysorbate 80, polyethylene glycol (such as PEG-4000, PEG-400), propylene glycol, 1,2-propanediol, glycerin, sorbitol, diethyl oxalate, diethyl malate, rich Diethyl methacrylate, diethyl malonate, dibutyl succinate, fatty acid, diethyl maleate, diethyl succinate, dioctyl phthalate And mixtures thereof. The plasticizer can have the property of a surfactant so that it can act as a release modifier. For example, a nonionic detergent such as Brij 58 (polyoxyethylene (20) cetyl ether) or the like can be used.

Plasticizers are high boiling organic solvents used to impart flexibility to other hard or brittle polymeric materials, and which can affect the release profile of the active agent. Plasticizers typically result in a decrease in the intermolecular forces of bonding along the polymer chain, resulting in a variety of polymer properties, including reduced tensile strength, increased elongation, and glass transition and softening temperatures of the polymer. Decline. For example, the amount and choice of plasticizer can affect the hardness of the tablet, and can even affect its dissolution or decomposition characteristics, as well as its physical and chemical stability. Some plasticizers increase the elasticity and/or flexibility of the coating, thereby reducing the brittleness of the coating.

In another embodiment, the extended release formulation comprises a combination of at least two gel forming polymers comprising at least one nonionic gel forming polymer and/or at least one anionic gel forming polymer. Things. The gel formed by the combination of gel-forming polymers provides controlled release such that when the formulation is ingested and exposed to the gastrointestinal fluid, the polymer closest to the surface hydrates to form a viscous gel layer. Due to the high viscosity, the viscous layer only dissolves gradually, exposing the underlying material in the same process. Therefore, the substance dissolves slowly, thereby slowly releasing the active ingredient to the gastrointestinal fluid. The combination of at least two gel-forming polymers allows the properties of the resulting gel, such as viscosity, to be manipulated to provide the desired release profile.

In a particular embodiment, the formulation comprises at least one nonionic gel forming polymer and at least one anionic gel forming polymer. In another embodiment, the formulation comprises two different non-ionic gel-forming polymers. In another embodiment, the formulation comprises a combination of nonionic gel-forming polymers of the same chemical nature but having different solubilities, viscosities and/or molecular weights (eg, hydroxypropyl methyl fibers of different viscosity grades) Combination of factors such as HPMC K100 and HPMC K15M or HPMC K100M).

Exemplary anionic gel-forming polymers include, but are not limited to, sodium carboxymethyl cellulose (Na CMC); carboxymethyl cellulose (CMC); anionic polysaccharides such as sodium alginate, alginic acid, pectin , polyglucuronic acid (poly alpha- and -β-1,4-glucuronic acid), polygalacturonic acid (pectate), chondroitin sulfate, carrageenan, furcellaran; Glue, such as Sanxianjiao; acrylic or carbomer polymers (such as Carbopol ^® 934, 940, 974P NF); Carbopol ^® copolymer; Pemulen ^® polymer; polycarbophil.

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

The formulation may optionally include the enteric polymers described above, and/or at least one excipient such as a filler, a binder (as described above), a disintegrant, and/or a glidant or a glidant.

Exemplary fillers include, but are not limited to, lactose, glucose, fructose, sucrose, dibasic calcium phosphate, sugar alcohols, also known as "sugar polyols" such as sorbitol, manitol, lactitol, xylitol, and isoforms. Isomalt, erythritol and hydrogenated starch hydrolysate (blend of various sugar alcohols), corn starch, potato starch, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, enteric polymer, Or a mixture thereof.

Exemplary binders include, but are not limited to, water soluble hydrophilic polymers such as povidone (PVP, polyvinylpyrrolidone), copovidone (polyvinylpyrrolidone and polyvinyl acetate copolymer), low Molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose, ethyl cellulose, gelatin, polyethylene oxide, gum arabic, Dextrin, magnesium and aluminum citrate, starch and polymethacrylates such as Eudragit NE 30D, Eudragit RL, Eudragit RS, Eudragit E, polyvinyl acetate and enteric polymers, or mixtures thereof.

Exemplary disintegrants include, but are not limited to, low substituted sodium carboxymethylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), sodium carboxymethyl starch (sodium starch glycolate) )), croscarmellose sodium (croscarmellose), pregelatinized starch (starch 1500), microcrystalline cellulose, water insoluble starch, calcium carboxymethylcellulose, low substituted hydroxypropyl Cellulose, as well as magnesium or aluminum citrate.

Exemplary slip agents include, but are not limited to, magnesium, cerium oxide, talc, starch, titanium dioxide, and the like.

In another embodiment, the extended release formulation is passed through a particle that will contain a water soluble/dispersible drug, such as a bead or bead population (as described above), from the coating material and optionally pore formers and other The agent is formed by coating. The coating material is preferably selected from the following group: cellulose polymers such as ethyl cellulose (e.g., SURELEASE ^®), methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate Cellulose and cellulose acetate phthalate; polyvinyl alcohol; acrylic polymers such as polyacrylates, polymethacrylates and copolymers thereof; and other water or solvent based coating materials. The controlled release coating for a population of given beads can be controlled by controlling at least one parameter of the release coating, such as the nature of the coating, the coating level, the type and concentration of the pore former, the processing parameters, and Its combination. Thus, by varying the parameters (e.g., pore former concentration) or curing conditions, the active agent is allowed to be released from the population of a given bead, thereby allowing the formulation to be selectively adjusted to a predetermined release profile.

Here, the porogen suitable for use in the controlled release coat can be an organic or inorganic agent and include materials that can be dissolved, extracted or filtered from the coating in the environment of use. Exemplary pore formers include, but are not limited to, organic compounds such as monosaccharides, oligosaccharides, and polysaccharides, including sucrose, glucose, fructose, mannitol, mannose, galactose, sorbitol, amylopectin, and glucosamine. Dextran; a polymer soluble in the environment of use, such as water-soluble hydrophilic polymers, hydroxyalkyl cellulose, carboxyalkyl cellulose, hydroxypropyl methyl cellulose, cellulose ether, acrylic resin, poly Vinyl pyrrolidone, crosslinked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, Carbopol, etc., glycols, polyols, polyhydric alcohols, Polyalkylene glycols, polyethylene glycol, polypropylene glycol, or block polymers thereof, polyglycols, poly(α-Ω)alkylene glycols (poly(α-Ω)alkylenediols) Inorganic compounds such as alkali metal salts, lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, suitable calcium salts, combinations thereof, and the like.

The controlled release coat may further comprise other additives known in the art, such as plasticizers, anti-adherents, slip agents (or glidants), and antifoaming agents.

In some embodiments, the coated particles or beads may additionally include an "overcoat" to provide, for example, moisture, antistatic, taste masking, flavoring, coloring, and/or buffing or other decorative effects on the beads. Suitable coating materials for such overcoats are well known in the art and include, but are not limited to, cellulosic polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and microcrystalline cellulose or combinations thereof ( For example, different Opadry ^® coating materials).

The coated particles or beads may additionally comprise an enhancer, for example, which may be illustrative but not limited to dissolution enhancers, dissolution enhancers, absorption enhancers, penetration enhancers, stabilizers, complexing agents, enzyme inhibitors, P-sugars Protein inhibitors and multidrug resistant protein inhibitors. Alternatively, the formulation may also comprise an enhancer separate from the coated particles, for example in a population of isolated beads or as a powder. In another embodiment, the enhancer may be included in a separate layer on the coated particles, either below or above the controlled release coating.

In other embodiments, the extended release formulation is formulated to release the active agent through an osmotic mechanism. For example, the capsule may be made as a single osmotic unit, or it may contain 2, 3, 4, 5 or 6 push-pull units enclosed in hard gelatin capsules, whereby each double-layer push-pull unit comprises an osmotic push layer and a drug Layers, and both are surrounded by a semi-permeable membrane. One or more holes are drilled through the membrane adjacent to the drug layer. This film may additionally be covered by a pH dependent enteric coating to prevent release until the stomach is emptied. Gelatin capsules dissolve immediately after ingestion. As the push-pull unit enters the small intestine, the enteric coating decomposes, and then the fluid flows through the semi-permeable membrane, causing the permeate push chamber to expand, thereby forcing the drug to pass through the orifice at a rate that is transported by the water through the semi-permeable membrane. Rate and precise control. The release of the drug can be carried out at a constant rate for up to 24 hours.

The osmotic push layer includes one or more penetrants that generate a driving force for transporting water through the semipermeable membrane into the core of the delivery vehicle. One type of penetrant comprises a water-swellable hydrophilic polymer, also referred to as "osmopolymers" and "hydrogels" including, but not limited to, hydrophilic vinyl and acrylic polymers such as alginic acid. Calcium polysaccharides, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid) , polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone, polyvinyl alcohol (PVA), PVA/PVP copolymerization , PVA/PVP copolymer with hydrophobic monomer such as methyl methacrylate and vinyl acetate, hydrophilic polyurethane containing large PEO block, croscarmellose sodium, carrageenan, Hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate , polycarbophil, gelatin, sanxian gum and sodium starch glycolate.

Another type of penetrant includes a zymogen that is capable of absorbing water to achieve an osmotic pressure gradient across the semipermeable membrane. Exemplary zymogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and Sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids such as ascorbic acid, benzene Formic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, ethylenediaminetetraacetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof .

Materials useful for forming semipermeable membranes include different grades of acrylic, vinyl, etheric, polyamide, polyester, and cellulosic derivatives which are permeable to water at physiologically relevant pH values. Water is insoluble, or these materials are susceptible to chemical incorporation, such as cross-linking to exhibit water insolubility.

In some embodiments, the extended release formulation can include a polysaccharide coating that is resistant to attack in the stomach and intestines. Such polymers can only be degraded in the colon containing a large number of microorganisms containing biodegradable enzymes such as polysaccharide coatings to release the drug contents in a controlled time-dependent manner. Exemplary polysaccharide coatings can include, for example, amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin, wood poly Sugar and combinations or derivatives thereof.

In some embodiments, the pharmaceutical composition is formulated as a delayed extended release. The term "delayed release" as used herein refers to a drug treatment that does not immediately disintegrate and release the active ingredient in the body. In some embodiments, the term "delayed extended release" is used with reference to a pharmaceutical formulation having a release profile in which there is a predetermined delay in the release of the drug after administration. In some embodiments, the delayed extended release formulation comprises an extended release formulation coated with an enteric coating which is applied to the isolation of the oral drug to prevent release prior to delivery of the drug to the small intestine. An enteric coated delayed release formulation prevents the gastric stimulating drug, such as aspirin, from dissolving in the stomach. The coating is also used to protect the acid-labile drug from exposure to the acidic environment of the stomach and to deliver it to an alkaline pH environment (the pH of the intestinal tract is above 5.5) in the alkaline environment. It does not degrade and gives them the desired effect.

The term "pulse release" is a type of delayed release, which is used herein with reference to a pharmaceutical formulation that provides rapid and transient drug release immediately after a predetermined delay period, thereby producing a drug after administration of the drug. "Pulse" plasma distribution. The formulation can be designed to provide a single pulse release or multiple pulsed release at predetermined time intervals after administration.

Delayed release or pulsed release formulations typically include one or more elements covered by a barrier coating that dissolve, erode or rupture after a particular period of delay. In some embodiments, the pharmaceutical compositions of the present application are formulated for extended release or delayed extended release, and comprise 100% of the total dose of a given active agent administered in a single unit dose. In other embodiments, the pharmaceutical compositions include an extended/delayed release component and an immediate release component. In some embodiments, the immediate release component and the extended/delayed release component comprise the same active ingredient. In other embodiments, the immediate release component and The extended/delayed release component contains different active ingredients (e.g., an analgesic in one component and an anti-drug agent in the other component). In some embodiments, the first and second components each comprise an analgesic selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and For acetaminophen. In other embodiments, the extended/delayed release component is coated with an enteric coating. In other embodiments, the immediate release component and/or the extended/delayed release component further comprises an anti-drug agent selected from the group consisting of oxybutynin, solifena, dafenacin, and atropine . In other embodiments, the analgesic in each component is administered orally at a dose of from 1 microgram to 1 milligram or 1 microgram to 100 microgram per day. In other embodiments, the immediate release component and/or the extended/delayed release component further comprises an antidiuretic, an antidote, or both. In other embodiments, the method of treatment comprises administering a diuretic to the individual at least 8 hours prior to bedtime, and administering to the individual a pharmaceutical composition comprising an immediate release component and/or an extended/delayed release component within 2 hours prior to bedtime. .

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

Depending on the purpose, the release coating for delayed release can be composed of a variety of different materials. In addition, the formulation may include multiple barrier coatings to aid in release in a timely manner. The coating can Is a sugar coating, film coating (for example, hydroxypropyl methylcellulose, methyl cellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymer, poly Glycol and/or polyvinylpyrrolidone as matrix), or methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose A coating of acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethyl cellulose. In addition, the formulation may additionally comprise a time delay material, for example, glyceryl monostearate or glyceryl distearate.

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

pH-dependent enteric coatings include one or more pH-dependent or pH-sensitive polymers that retain their structural integrity at lower pH conditions (eg, in the stomach) while in the gastrointestinal tract The more distal area, such as the lower pH of the small intestine, dissolves, thereby releasing the drug content there. For the purposes of the present invention, "pH dependent" is defined as having properties (eg, dissolution) that vary according to environmental pH. Exemplary pH dependent polymers include, but are not limited to, methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (eg EUDRAGIT ^® L100 (type A), EUDRAGIT ^® S100 (B) from Rohm, Germany Type)); methacrylic acid-ethyl acrylate copolymer (such as EUDRAGIT ^® L100-55 (type C) and EUDRAGIT ^® L30D-55 copolymer dispersion from Rohm, Germany); methacrylic acid-methyl methacrylate and Copolymer of methyl methacrylate (EUDRAGIT ^® FS); terpolymer of methacrylic acid, methacrylate and ethyl acrylate; cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose Phthalates (HPMCP) (for example, HP-55, HP-50, HP-55S from Shin-Etsu Chemical Co., Ltd.); Polyvinyl acetate phthalate (PVAP) (for example, COATERIC ^® , OPADRY ^® Enteric white OY-P-7171); cellulose acetate succinate (CAS); hydroxypropyl methylcellulose acetate succinate (HPMCAS), for example, HPMCAS LF grade, MF grade, HF grade , including AQOAT ^® LF and AQOAT ^® MF (Japan Shin-Etsu Chemical; Japan Shin-Etsu Chemical); shellac (for example, Marcoat ^TM 125 and Marc Oat ^TM 125N); carboxymethyl ethyl cellulose (CMEC, Freund, Japan), cellulose acetate phthalate (CAP) (eg AQUATERIC ^® ); acetate-1,2,4-benzenetricarboxylic acid fiber And (CAT); and mixtures of two or more thereof in a weight ratio of from about 2:1 to about 5:1, for example, EUDRAGIT ^® L 100-55 and EUDRAGIT in a weight ratio of from about 3:1 to about 2:1. A mixture of ^® S 100, or a mixture of EUDRAGIT ^® L 30 D-55 and EUDRAGIT ^® FS in a weight ratio of from about 3:1 to about 5:1.

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

In some embodiments, the coating process employs the incorporation of one or more pH dependent and one or more pH independent polymers. Once the soluble polymer reaches the optimum pH for dissolution, the blending of pH dependent and pH independent polymers can reduce the release rate of the active ingredient.

In some embodiments, a "time-controlled" or "time-dependent" release profile can be obtained using a water-insoluble capsule comprising one or more active agents, wherein the capsule is insoluble at one end, but The infiltrated and expandable hydrogel plug is closed. When in contact with the digestive tract liquid or dissolution medium, the plug expands, ejects itself into the capsule, and releases the drug after a predetermined delay time (which is permeable, for example, the position and size control of the plug). The capsule body can be further coated with an external pH dependent enteric coating to keep the capsule intact until it reaches the small intestine. Suitable plug materials include, for example, polymethacrylates, erosive compression polymers (eg, HPMC, polyvinyl alcohol), coagulated molten polymers (eg, glycerol monooleate), and enzymatically controlled aggressive polymers. (for example, polysaccharides such as amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin and xylan).

In other embodiments, the capsule or bilayer tablet can be formulated to include a drug-containing core that is covered by an intumescent layer and an outer insoluble but semi-permeable polymer coating or film. The delay time prior to rupture can be controlled by the permeation and mechanical properties of the polymer coating, as well as the expansion behavior of the intumescent layer. Typically, the intumescent layer comprises one or more bulking agents, such as an expandable hydrophilic polymer that swells and retains moisture in its structure.

Exemplary materials that are water swellable for use in the delayed release coating include, but are not limited to, polyethylene oxide (having an average molecular weight of, for example, 1,000,000 to 7,000,000, such as POLYOX®), methylcellulose, hydroxypropyl. Cellulose, hydroxypropyl methylcellulose; polyalkylene oxide having a weight average molecular weight of 100,000 to 6,000,000, including but not limited to polymethylene oxide, polybutylene oxide; molecular weight of 25,000 to 5,000,000 Poly(hydroxyalkyl methacrylate); polyvinyl alcohol crosslinked with glyoxal, formaldehyde or glutaraldehyde, having a degree of polymerization of from 200 to 30,000, and having a lower acetal residue; methyl cellulose, a mixture of crosslinked agar and carboxymethylcellulose; a hydrogel-forming copolymer prepared by copolymerizing maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene and in the copolymer mole of maleic anhydride unsaturated crosslinking agent from 0.001 to 0.5 mole of the copolymer to form a dispersion of fine; molecular weight of CARBOPOL ^® acidic carboxy polymers of 450,000 to 4,000,000; CYANAMER ^® polyacrylamide; crosslinkable Water-swellable indene maleic anhydride polymers; molecular weight of 80,000 to 200,000 GOODRITE ^® polyacrylic acid; starch graft copolymers; manufactured by condensation of glucose units (e.g. diesters dextran crosslinked poly (polyglucan)) composed AQUA- KEEPS ^® acrylate polymer polysaccharide; carbomer with a viscosity of 3,000 to 60,000 mPa in 0.5% to 1% w/v aqueous solution; cellulose ether, such as 25 ° C, 1% w/v aqueous solution with a viscosity of about 1,000 to 7,000 Hydroxypropylcellulose of millipascal; hydroxypropylmethylcellulose having a viscosity of about 1000 or more, preferably 2,500 or more, up to 25,000 mpa in a 2% w/v aqueous solution; 10% by weight at 20 ° C a polyvinylpyrrolidone having a viscosity of about 300 to 700 mPa in an aqueous solution of a volume; and a combination thereof.

Alternatively, the release time of the drug can be controlled by a disintegration delay time which depends on the balance between the tolerance and thickness of the water-insoluble polymer film (e.g., ethyl cellulose, EC), which is insoluble in polymerization. The membrane contains predetermined micropores at the bottom of the body, as well as a quantity of expandable excipients such as low substituted hydroxypropylcellulose (L-HPC) and sodium glycolate. After oral administration, the gastrointestinal fluid penetrates through the micropores, causing swelling of the expandable excipients. Thereby an internal pressure is generated which disintegrates the capsule portion, the capsule portion comprising a first capsule body comprising an expandable material, a second capsule body containing the drug and an outer cover attached to the first capsule body.

The enteric layer may further comprise an anti-adhesive such as talc or glyceryl monostearate and/or a plasticizer. The enteric layer may further comprise one or more plasticizers including, but not limited to, triethyl citrate, triethyl citrate, tributyl citrate, polyethylene Alcohol acetylated monoglyceride, glycerin, triacetin, propylene glycol, phthalate (such as diethyl phthalate, dibutyl phthalate), titanium dioxide, iron oxide, castor oil, Sorbitol and dibutyl sebacate.

In another embodiment, the delayed release formulation employs a water permeable but insoluble film coating to coat the active ingredient and the penetrant. As water slowly diffuses from the intestinal tract through the membrane into the core, the core swells until the membrane ruptures, releasing the active ingredient. The film coating can be adjusted to allow for different water permeation rates or release times.

In another embodiment, the delayed release formulation employs a water impermeable tablet coating whereby water passes through the controlled pores into the coating until the core ruptures. When the tablet breaks, the contents of the drug are immediately released or released over a longer period of time. These and other techniques can be modified to allow for the formation of a predetermined delay period before the drug begins to release.

In another embodiment, the active agent is delivered in a formulation to provide delayed release and extended release (delay-sustained). The term "delay-extension-release" is used herein with reference to the following: during a predetermined time or delay after administration, the pharmaceutical formulation provides a pulsed release of the active agent followed by an extended release of the active agent.

In some embodiments, the immediate release, extended release, delayed release or delayed-extended release formulation comprises an active core comprising one or more inert particles, each In the form of beads, pills, pills, granules, microcapsules, microspheres, microparticles, nanocapsules or nanospheres, the surface of which is used in the form of a drug-like film-forming composition such as a fluidized bed. The technique is coated with other methods known to those skilled in the art. The inert particles can be of different sizes as long as they are sufficient to maintain a size that is not readily soluble. Alternatively, the active core can be prepared by granulation and milling of the polymer composition containing the drug substance and/or by extrusion and spheronization.

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

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

In other embodiments, the formulation may include immediate release drug particles comprising a polymeric film that does not control the rate of dissolution, and delayed-extended release beads, which are shown, For example, a delay time of 2 to 4 hours after oral administration provides a double pulse release profile.

In some embodiments, the active core is coated with one or more polymer layers that control the rate of dissolution to achieve the desired release profile (with or without delay time). The inner membrane can greatly control the rate of drug release after absorbing water or body fluids into the core, while the outer membrane can provide the desired delay time (without or little drug release after absorbing water or body fluids into the core) ). The inner film may comprise a water insoluble polymer, or a mixture of water insoluble and water soluble polymers.

As noted above, polymers suitable for the outer film that have a large controlled delay time of up to 6 hours include enteric polymers, and from 10 to 50% by weight of water insoluble polymers. 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 commonly used water insoluble polymer is ethyl cellulose.

Exemplary water insoluble polymers include ethyl cellulose, polyvinyl acetate (Kollicoat SR #0D from BASF), neutral copolymers based on ethyl acrylate and methyl methacrylate, and quaternary ammonium groups. Copolymer of acrylic acid and methacrylate (such as EUDRAGIT ^® NE, RS and RS30D, RL or RL30D, etc.). Exemplary water soluble polymers include low molecular weight HPMC, HPC, methyl cellulose, polyethylene glycol (PEG with a molecular weight > 3000), depending on the active solubility in water and solvent, or emulsion suspension used The liquid-based coating formulation has a consistency ranging from 1% by weight up to 10% by weight. The water insoluble polymer typically varies from 95:5 to 60:40, preferably from 80:20 to 65:35, for the water soluble polymer.

In some aspects of the embodiments, using as a carrier a resin AMBERLITE ^TM IRP69 extended release. AMBERLITE ^TM IRP69 is an insoluble sodium form strong acid cation exchange resins, it is suitable as cationic (basic) carrier substance. In other embodiments aspects, a DUOLITE ^TM AP143 / 1093 resin as a carrier extended release. DUOLITE ^TM AP143 / 1093 is an insoluble strongly basic anion exchange resin, an anion which is suitable as a carrier (acidic) species.

When used as a drug carrier, AMBERLITE IRP69 or / and DUOLITE ^TM AP143 / 1093 resin provides a method of bonding agent to the insoluble polymer matrix. Prolonged release is achieved by the formation of a resin-drug complex (a resin treated drug). As the drug reaches equilibrium with the high electrolyte concentration in the typical gastrointestinal tract, the drug is released from the resin in the body. Due to the hydrophobic interaction with the aromatic structure of the cation exchange system, typically more hydrophobic drugs will elute from the resin at a lower rate.

Preferably, the formulation is designed to have a release profile that is capable of limiting its interference with restless sleep, wherein the formulation releases the drug when the individual is typically awakened by urgency. For example, consider an individual who usually starts to sleep at 11 pm and is usually awakened by urgency at 12:30 am, 3:00 am, and 6:00 am. The delayed release carrier is capable of delivering the drug at 12:15 am, thereby delaying the urination requirement by about 2 to 3 hours. By further including an additional extended release profile or additional pulse release, the need to wake up due to urgency can be reduced or eliminated.

The pharmaceutical composition can be administered daily or as needed. In some embodiments, the pharmaceutical composition is administered to an individual prior to bedtime. In some embodiments, the pharmaceutical composition is administered just prior to bedtime. In some embodiments, the pharmaceutical composition is administered within about two hours prior to bedtime, preferably within about one hour prior to bedtime. In another embodiment, the pharmaceutical composition is administered about two hours prior to bedtime. In another embodiment, the pharmaceutical combination The substance is applied at least two hours before bedtime. In another embodiment, the pharmaceutical composition is administered about one hour prior to bedtime. In another embodiment, the pharmaceutical composition is administered at least one hour prior to bedtime. In another embodiment, the pharmaceutical composition is administered less than one hour prior to bedtime. In another embodiment, the pharmaceutical composition is administered just prior to bedtime. Preferably, the pharmaceutical composition is administered orally. Compositions suitable for oral administration include, but are not limited to, lozenges, coated lozenges, dragees, capsules, powders, granules, and soluble lozenges, as well as liquid forms such as suspensions, dispersions or solutions.

Most enteric coatings work by setting them under conditions of higher acidic pH (i.e., conditions in the stomach), but at lower acidic pH conditions (relatively more alkaline) to decompose the surface. Therefore, enteric coated pills are insoluble in acidic gastric juice (pH ~ 3), but they are soluble in the alkaline environment (pH 7 to 9) present in the small intestine. Examples of enteric coating materials include, but are not limited to, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose. Acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, sodium alginate and stearic acid .

In some embodiments, the pharmaceutical composition is administered orally by a different pharmaceutical formulation designed to provide delayed release. Delayed release oral dosage forms include, for example, troches, capsules, caplets, and may also include a plurality of granules, beads, powders or pills that may or may not be encapsulated. Tablets and capsules represent the most convenient oral dosage form, in which case a solid pharmaceutical carrier is used.

In a delayed release formulation, one or more barrier coatings may be applied to the pill, lozenge or capsule to help slow the dissolution of the drug in the intestinal tract and consequent release. Usually The barrier coating comprises one or more polymers surrounding, surrounding or forming a layer or film around the therapeutic composition or active core.

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

In other embodiments, delayed release may result from an infiltration mechanism. For example, the capsule may be formulated as a single osmotic unit, or it may contain 2, 3, 4, 5 or 6 push-pull units enclosed in hard gelatin capsules, whereby each double-layer push-pull unit comprises an osmotic push layer and The drug layer, and both are surrounded by a semi-permeable membrane. One or more holes are drilled through the membrane adjacent to the drug layer. This film may additionally be covered by a pH dependent enteric coating to prevent release until the stomach is emptied. Gelatin capsules dissolve immediately after ingestion. As the push-pull unit enters the small intestine, the enteric coating decomposes, and then the fluid flows through the semipermeable membrane, causing the permeate push chamber to expand, thereby forcing the drug to pass through the orifice at a rate that is transported by the water through the semi-permeable membrane. Rate and precise control. The release of the drug can be carried out at a constant rate for up to 24 hours.

The osmotic push layer includes one or more penetrants that generate a driving force for passing water through the semipermeable membrane into the core of the delivery vehicle. One class of penetrants includes water-swellable hydrophilic polymers, also known as "osmopolymers" and "hydrogels" including, but not limited to, hydrophilic vinyl and acrylic polymers such as alginic acid. Calcium polysaccharide, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid) , polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymer, with a PVA/PVP copolymer of hydrophobic monomer of methyl acrylate and vinyl acetate, hydrophilic polyurethane containing large PEO block, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil , gelatin, Sanxian gum and sodium starch glycolate.

Another type of penetrant includes a zymogen that is capable of absorbing water to achieve an osmotic pressure gradient across the semipermeable membrane. Exemplary zymogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and Sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids such as ascorbic acid, benzoic acid, rich Horse acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, ethylenediaminetetraacetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

Materials useful for forming semipermeable membranes include different grades of acrylic, vinyl, ether, polyamide, polyester, and cellulosic derivatives that are permeable to water and water at physiologically relevant pH values. Insoluble, or, these materials are susceptible to chemical incorporation, such as cross-linking, to exhibit water insolubility.

In another embodiment, the delayed release formulation employs a water impermeable tablet coating whereby water passes through the controlled pores into the coating until the core ruptures. When the tablet breaks, the contents of the drug are immediately released or released over a longer period of time. These and other techniques can be modified to allow for the formation of a predetermined delay period before the drug begins to release.

Different coating techniques can be applied to granules, beads, powders or pills containing active agents, troches, capsules or combinations thereof to produce different and distinct release profiles. In some implementations In the present case, 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 lozenge or capsule comprising a multi-coat layer.

In some embodiments, a pharmaceutical composition includes a plurality of active ingredients. In another embodiment, the pharmaceutical composition comprises two formulations that are formulated to delay release of the active ingredient (eg, two analgesics, or an analgesic and an anti-drug agent). In another embodiment, the pharmaceutical composition comprises two active ingredients, one formulated as an immediate release component and the other as a delayed release component. In another embodiment, the pharmaceutical composition comprises two active ingredients formulated as two delayed release components, each providing a different delayed release profile. For example, the first delayed release component releases the first active ingredient at the first time point and the second delayed release component releases the second active ingredient at the second time point.

The term "immediate release" as used herein refers to a pharmaceutical preparation that does not contain a dissolution rate controlling material. The release of the active agent is substantially without delay after administration of the immediate release formulation. The immediate release coating can include a suitable material that dissolves immediately after application to release the drug content therein. Exemplary immediate release coating materials include gelatin, polyvinyl alcohol polyethylene glycol (PVA-PEG) copolymers (such as Kollicoat®), and various other materials well known to those skilled in the art.

The immediate release composition can include 100% of the total dose of a given active agent administered in a unit dose. Alternatively, the immediate release component can be included as a component in a combined release profile formulation which can provide from about 1% to about 50% of the total dose of active agent to be delivered through the pharmaceutical formulation. . For example, the immediate release component can provide at least about 5%, or from about 10% to about 30%, or from about 45% to about 50% of the total dose of the active agent to be delivered through the formulation. In another embodiment, The immediate release component provides about 2, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50% of the total dose of active agent to be delivered through the formulation.

In some embodiments, the immediate release or delayed release formulation comprises an active core comprising one or more inert particles, each in the form of beads, pills, pills, granules, microcapsules, microspheres, microparticles, nanocapsules Or in the form of a nanosphere, coated on its surface by a drug in the form of, for example, a film-forming composition comprising a drug, for example using fluidized bed technology or other methods known to those skilled in the art. The inert particles may be of different sizes as long as they are sufficient to maintain a size that is not readily soluble. Alternatively, the active core can be prepared by granulation and milling of the polymer composition containing the drug substance and/or by extrusion and spheronization.

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

In some embodiments, the delayed release formulation is formed by coating a water-soluble/dispersible drug-containing particle (such as a bead) with a mixture of a water-insoluble polymer and an enteric polymer, wherein the water-insoluble polymerization The enteric polymer and the enteric polymer may be present in a weight ratio of from 4:1 to 1:1, and the total weight of the coating is from 10 to 60% by weight based on the total weight of the coated beads. The drug layered beads may optionally include an ethylcellulose membrane that controls the rate of dissolution in the interior. Optimizing the composition of the outer layer, as well as the individual weights of the inner and outer layers of the polymer film, for The given activity achieves the ideal circadian rhythm release profile, which is expected based on in vitro/in vivo correlation.

In other embodiments, the formulation comprises a mixture of particles comprising immediate release drug and delayed release beads to provide a dual pulse release profile, wherein the immediate release drug-containing particles do not have a polymeric film that controls the dissolution rate, Delayed release beads show, for example, a delay time of 2 to 4 hours after oral administration. In other embodiments, the formulation comprises a mixture of two types of delayed release beads: a first type that exhibits a 1 to 3 hour delay time and a second type that exhibits a 4 to 6 hour delay time.

In some embodiments, the active core is coated with one or more polymer layers that control the rate of dissolution to achieve the desired release profile (with or without delay time). The inner membrane can control the rate of drug release to a large extent after absorbing water or body fluids into the core, while the outer membrane can provide the desired delay time (during the period of absorption of water or body fluid into the core with little or no drug release). The inner film may comprise a water insoluble polymer, or a mixture of water insoluble and water soluble polymers.

As noted above, polymers suitable for the outer film that have a controlled degree of delay for up to 6 hours include enteric polymers, and water insoluble polymers having a consistency of 10 to 50% by weight. 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 commonly used water insoluble polymer is ethyl cellulose.

Exemplary water insoluble polymers include ethyl cellulose, polyvinyl acetate (Kollicoat SR #0D from BASF), neutral copolymers based on ethyl acrylate and methyl methacrylate, and quaternary ammonium groups. Copolymer of acrylic acid and methacrylate (such as Eudragit® NE, RS and RS30D, RL or RL30D, etc.). Exemplary water soluble Polymers include low molecular weight HPMC, HPC, methyl cellulose, polyethylene glycol (PEG with a molecular weight > 3000), depending on the active solubility in water and solvent, or the emulsion suspension-based package used. A coating formulation ranging from 1% by weight up to 10% by weight. The water insoluble polymer typically varies from 95:5 to 60:40, preferably from 80:20 to 65:35, for the water soluble polymer.

Preferably, the formulation is designed to have a release profile that is capable of limiting its interference with restless sleep, wherein the formulation releases the drug when the individual is typically awakened by urgency. For example, consider an individual who usually starts to sleep at 11 pm and is usually awakened by urgency at 12:30 am, 3:00 am, and 6:00 am. The delayed extended release carrier is capable of delivering the drug at 12:15 am, thereby delaying the urine for about 2 to 3 hours.

The pharmaceutical composition can be administered daily or as needed. In some embodiments, the pharmaceutical composition is administered to an individual prior to bedtime. In some embodiments, the pharmaceutical composition is administered just prior to bedtime. In some embodiments, the pharmaceutical composition is administered within about two hours prior to bedtime, preferably within about one hour prior to bedtime. In another embodiment, the pharmaceutical composition is administered about two hours prior to bedtime. In another embodiment, the pharmaceutical composition is administered at least two hours prior to bedtime. In another embodiment, the pharmaceutical composition is administered about one hour prior to bedtime. In another embodiment, the pharmaceutical composition is administered at least one hour prior to bedtime. In another embodiment, the pharmaceutical composition is administered less than one hour prior to bedtime. In another embodiment, the pharmaceutical composition is administered just prior to bedtime. Preferably, the pharmaceutical composition is administered orally.

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

It is generally recommended that the therapeutically effective amount, immediate release component or extended release component of the active agent be administered by one or more administrations at a dose of from about 1 ng/kg body weight per dose to about 100 mg/kg body weight per dose. In a particular embodiment, each active agent is used in a range from about 1 ng/kg body weight/dose to about 1 microgram/kg body weight/dose, 1 ng/kg body weight/dose to about 100 ng/kg body weight. / dose, 1 ng / kg body weight / dose to about 10 ng / kg body weight / dose, 10 ng / kg body weight / dose to about 1 μg / kg body weight / dose, 10 ng / kg body weight / dose to about 100 Ng / kg body weight / dose, 100 Ng / kg body weight / dose to about 1 μg / kg body weight / dose, 100 Ng / kg body weight / dose to about 10 μg / kg body weight / dose, 1 μg / kg body weight / dose to about 10 μg / kg body weight / dose, 1 μg / kg body weight / dose to about 100 μg / kg body weight / dose, 10 μg / kg body weight / dose to about 100 μg / kg body weight / dose, 10 μg / kg Weight/dose to about 1 mg/kg body weight/dose, 10 μg/kg body weight/dose to about 10 mg/kg body weight/dose, 100 μg/kg body weight/dose to about 10 mg/kg body weight/dose, 100 μg/ Kg body weight / dose to about 1 mg / kg body weight / dose, about 500 μg / kg body weight / dose Amount to about 50 mg / kg body weight / dose, about 500 μg / kg body weight / dose to about 5 mg / kg body weight / dose, 1 mg / kg body weight / dose to about 100 mg / kg body weight / dose, 1 mg / kg Weight/dose to about 50 mg/kg body weight/dose, 1 mg/kg body weight/dose to about 10 mg/kg body weight/dose, 5 mg/kg body weight/dose to about 50 mg/kg body weight/dose, and 10 mg / kg body weight / dose to about 100 mg / kg body weight / dose.

The active agents described herein can be included in an immediate release component or extended release component for oral administration in a single active dose or a combined active dose daily, in a dosage range of from 1 ng to 100 ng. , 1 ng to 10 ng, 10 ng to 100 ng, 0.1 μg to 5 mg, 0.1 μg to 1 mg, 0.1 μg to 100 μg, 0.1 μg to 10 μg, 0.1 μg to 1 μg, 1 μg to 5 mg, 1 μg to 1 mg, 1 μg to 100 μg, 1 μg to 10 μg, 10 μg to 25 mg, 10 μg to 5 mg, 10 μg to 1 mg, 10 μg to 100 μg, 50 μg to 5 mg 50 μg to 1 mg, 0.1 mg to 5 mg, 0.1 mg to 1 mg, 1 mg to 10 mg, 1 mg to 5 mg, 5 mg to 100 mg, 10 mg to 100 mg, 50 mg to 1000 mg, 500 Mg to 5000 mg, 200 mg to 2000 mg, or 400 mg to 1000 mg, or 500 mg to 5000 mg. In other embodiments, each agent is at about 0.0006 mg/dose, 0.001 mg/dose, 0.003 mg/dose, 0.006 mg/dose, 0.01 mg/dose, 0.03 mg/dose, 0.06 mg/dose, 0.1 mg/dose. Dosage, 0.3 mg / dose, 0.6 mg / dose, 1 mg / dose, 3 mg / dose, 6 mg / dose, 10 mg / dose, 30 mg / dose, 60 mg / dose, 100 mg / dose, 300 mg / Dosage, 600 mg/dose, 1000 mg/dose, 2000 mg/dose, 5000 mg/dose, or 10,000 mg/dose. As expected, the dosage will depend on the condition, size, age and condition of the patient.

In some embodiments, the pharmaceutical composition comprises a single analgesic. In one embodiment, the single analgesic is aspirin. In another embodiment, the single analgesic is ibuprofen. In another embodiment, the single analgesic is naproxen sodium. In another embodiment, the single analgesic is indomethacin. In another embodiment, The single analgesic is nabumetone. In another embodiment, the single analgesic is p-aminophenol.

In some embodiments, the single analgesic is administered in a single daily dose of from 1 ng to 1000 mg. In certain embodiments, the pharmaceutical composition comprises aspirin (acetylsalicylic acid), ibuprofen, naproxen sodium, indomethacin, nabumetone or p-acetaminophen as a single analgesic, and The analgesic is administered at a daily oral dose of 0.1 μg to 50 mg, 0.1 μg to 10 mg, 0.1 μg to 5 mg, 1 μg to 10 mg, 1 μg to 1 mg, 1 Ng to 100 Ng, 0.1 μg to 10 μg. , 0.1 μg to 100 μg, 1 μg to 100 μg, 0.05 mg to 5 mg, 0.1 mg to 10 mg, 0.5 mg to 50 mg, 0.1 mg to 10 mg, 0.1 mg to 0.5 mg, 0.5 mg to 5 mg, 2.5 Dosage is administered in the range of milligrams to 10 milligrams, 10 milligrams to 50 milligrams, 50 milligrams to 250 milligrams, or 250 milligrams to 1000 milligrams.

In other embodiments, the pharmaceutical composition comprises a pair of analgesics. Examples of such paired analgesics include, but are not limited to, aspirin and ibuprofen, aspirin and naproxen sodium, aspirin and nabumetone, aspirin and p-acetamide Phenol, aspirin and indomethacin, ibuprofen and naproxen sodium, ibuprofen and nabumetone, ibuprofen and p-acetaminophen, ibuprofen and indomethacin , naproxen sodium and nabumetone, naproxen sodium and p-acetaminophen, naproxen sodium and indomethacin, nabumetone and p-acetaminophen, nabumetone and Indomethacin, as well as p-acetaminophen and indomethacin. The paired analgesic is mixed in a weight ratio of 0.3:1 to 3:1, and the combined dose is 1 to 100 Ng, 0.1 to 10 μg, 0.1 to 100 μg, 0.1 to 10 mg, 0.1 to 0.5 mg, 0.5 to 2.5 mg, 2.5 to 10 mg, 10 to 50 mg, 50 to 250 mg. In one embodiment, the paired analgesic is mixed in a weight ratio of 1:1.

In other embodiments, the pharmaceutical composition of the present application further comprises one or more anti-drug agents. Examples of such anti-drug agents include, but are not limited to, oxybutynin, solifena, dafenazone, fesoterodine, tolterodine, trospium, and atropine. . In certain embodiments, the pharmaceutical composition comprises an analgesic selected from the group consisting of acetaminophen, ibuprofen, naproxen sodium, nabumetone, p-amylaminophenol, and indomethacin, And an anti-drug agent selected from the group consisting of oxybutynin, sofina, dafinacin and atropine. The daily oral dose of the analgesic is from 0.1 μg to 5 mg, 1 μg to 1 mg, 1 μg to 100 μg, 1 to 100 Ng, 0.1 to 10 μg, 0.1 to 100 μg, 0.05 to 5 mg, 0.1 to 10 Mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.5 to 2.5 mg, 1 to 10 mg, 2.5 to 10 mg, 10 to 100 mg, 10 to 50 mg, 50 to 250 mg, 100 to 1000 mg or 250 to 1000 Within the range of milligrams. The dose of the anti-drug agent is 0.01 to 0.05 mg, 0.05 to 0.25 mg, 0.25 to 1 mg, 1 to 5 mg, 5 to 25 mg, 0.01 to 0.1 mg, 0.1 to 1 mg, 1 to 10 mg, and 10 to 25 Within the range of milligrams.

Another aspect of the present application relates to a method of reducing the frequency of urination by administering to a human in need a pharmaceutical composition formulated as an immediate release formulation. The pharmaceutical composition includes a variety of analgesics and/or anti-drugs.

In some embodiments, the pharmaceutical composition includes two or more analgesics. In other embodiments, the pharmaceutical composition includes one or more analgesics, and one or more anti-drug agents. The pharmaceutical compositions can be formulated in the form of lozenges, capsules, dragees, powders, granules, liquids, gels or emulsions. The liquid, gel or emulsion can be ingested by the individual in a direct form or in a form contained in a capsule.

In some embodiments, the analgesic is selected from the group consisting of salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, and willow Sulfapyridine, a derivative of p-aminophenol, indoxyaniline, p-acetamidophenol, phenacetin, fenalate, mefenamic acid, meclofenamic acid, meclofenamic acid Sodium, heteroaryl acetic acid derivatives, tolmetine, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen , oxaprozine, enolic acid, oxicam (benzothiazine) derivatives, piroxicam, meloxicam, tenoxicam, ampoxicam, dexamethasone, puffa Kang, pyrazolone derivatives, phenylbutazone, hydroxybutazone, antipyrine, aminopyrinoline, dipyridamole, oxicam, celecoxib, rofecoxib, nabumetone , azaprozin, nimesulide, indomethacin, sulindac, etodolac, and isobutylphenylpropionic acid. The anti-drug agent is selected from the group consisting of oxybutynin, solifena, dafenacin and atropine.

In some embodiments, the pharmaceutical composition comprises a single analgesic and a monoclonal anti-drug agent. In one embodiment, the single analgesic is aspirin. In another embodiment, the single analgesic is ibuprofen. In another embodiment, the single analgesic is naproxen sodium. In another embodiment, the single analgesic is indomethacin. In another embodiment, the single analgesic is nabumetone. In another embodiment, the single analgesic is p-aminophenol. The analgesic and anti-drug agent can be administered in a dose within the above range.

Another aspect of the present application relates to a method of treating nocturia by administering (1) one or more analgesics and (2) one or more antidiuretics to an individual in need thereof. In certain embodiments, the antidiuretic is used to: (1) increase secretion of vasopressin (antidiuretic hormone); (2) increase vasopressin receptor activation; (3) reduce atrial natriuretic sodium Peptide Secretion of natriuretic peptide, ANP) or C-type natriuretic peptide (CNP); or (4) reduction of receptor activation by ANP and/or CNP.

Exemplary antidiuretics include, but are not limited to, antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (eg, desmopressin) , argipressin, lypressin, felypressin, ornipressin, terlipressin; vasopressor Receptor antagonists, atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) receptor (ie, NPR1, NPR2, NPR3) antagonists (eg, HS-142-1, isatin, [Asu7,23']b-ANP-(7-28)], anantin, a cyclic peptide from Streptomyces coerulescens, and a 3G12 monoclonal antibody; auxin suppressor type 2 Body antagonists (e.g., auxin), and pharmaceutically acceptable derivatives, analogs, salts, hydrates and solvates thereof.

In some embodiments, the one or more analgesic agents and one or more antidiuretic agents are formulated as an extended release form.

Another aspect of the present application relates to a method of reducing the frequency of urination by administering to a human in need a first pharmaceutical composition comprising a diuretic followed by a second pharmaceutical composition comprising one or more analgesics. The dosage and formulation of the first pharmaceutical composition is set to have a diuretic effect within 6 hours of administration and at least 8 hours prior to bedtime. The second pharmaceutical composition is administered within 2 hours prior to bedtime. The first pharmaceutical composition is formulated for immediate release and the second pharmaceutical composition is formulated for extended release, or delayed extended release.

Examples of diuretics include, but are not limited to, acid salts such as calcium chloride and ammonium chloride; vasopressin vasopressin receptor 2 antagonists such as amphotericin B and lithium citrate; (aquaretics), such as Goldenrod and Junipe; Na-H exchange antagonists such as dopamine; carbonic anhydrase inhibitors such as acetazolamide and dozolamide; high performance Loop diuretics, such as bumetanide, ethacrynic acid, furosemide, and torsemide; osmotic diuretics such as glucose and mannitol Potassium-sparing diuretics, such as amiloride, spironolactone, triamterene, potassium canrenoate; thiazides, such as Benzofluothiazide and hydrochlorothiazide; and xanthine such as caffeine, theophylline and theobromine.

In some embodiments, the second pharmaceutical composition further comprises one or more anti-drug agents. Examples of such anti-drugs include, but are not limited to, oxybutynin, sofinal, dafenazone, fesoterodine, tolterodine, trosyl ammonium, and atropine.

Another aspect of the present application relates to a method of treating nocturia by administering a first pharmaceutical composition comprising a diuretic to a human in need thereof, and then administering a second pharmaceutical composition comprising one or more analgesics. The dosage and formulation of the first pharmaceutical composition is set to have a diuretic effect within 6 hours of administration and at least 8 hours prior to bedtime. The second pharmaceutical composition is formulated for extended release or delayed extended release and is administered within 2 hours prior to bedtime.

Examples of diuretics include, but are not limited to, acid salts such as calcium chloride and ammonium chloride; vasopressin vasopressin receptor 2 antagonists such as amphotericin B and lithium citrate; and urinary tract such as yellow flowers And juniper; Na-H exchange antagonists such as dopamine; carbonic anhydrase inhibitors such as oxazolamide and dorzolamide; high-performance diuretics such as bumetanide, etalic acid, furosemide and Tosemide; osmotic diuretics, such as glucose and mannitol; potassium-sparing diuretics, such as amiloride, Spiral lactone sterol, triamine, potassium testosterone; thiazides such as benzfluorothiazide and hydrochlorothiazide; and xanthine such as caffeine, theophylline and theobromine.

In some embodiments, the second pharmaceutical composition further comprises one or more anti-drug agents. Examples of such anti-drugs include, but are not limited to, oxybutynin, sofinal, dafenazone, fesoterodine, tolterodine, trosyl ammonium, and atropine. The second pharmaceutical composition can be formulated as an immediate release formulation or as a delayed release formulation. In other embodiments, the second pharmaceutical composition further comprises one or more antidiuretics.

Another aspect of the present application relates to a method of preventing the occurrence of drug resistance to reduce the frequency of urination by alternately administering two or more analgesics to an individual in need thereof. In one embodiment, the method comprises administering a first analgesic for a first period of time and then administering a second analgesic for a second period of time. In another embodiment, the method further comprises administering a third analgesic for a third period of time. The first, second, and third analgesic agents are different from each other, and at least one of them is formulated to be extended release or delayed extended release. In one embodiment, the first analgesic is p-aminophenol, the second analgesic is ibuprofen and the third analgesic is naproxen sodium. The length of each time period may vary depending on the individual's response to each analgesic. In some embodiments, each time period lasts from three days to three weeks. In another embodiment, the first, second, and third analgesic agents are all formulated for extended release or delayed extended release.

Another aspect of the present application is directed to a pharmaceutical composition comprising a plurality of active ingredients and a pharmaceutically acceptable carrier, wherein at least one of the plurality of active ingredients is formulated for extended release or delayed extended release. In some embodiments, the plurality of active ingredients comprise one or more analgesics and one or more antidiuretics. In other embodiments, the plurality of active ingredients comprise one or more analgesics and one or more antidiuretics. In other implementations In one aspect, the plurality of active ingredients comprise one or more analgesics and one or more antidiuretics and an anti-drug agent. The anti-drug agent can be selected from the group consisting of oxybutynin, solifena, dafenacin and atropine. In other embodiments, the pharmaceutical composition comprises two different analgesic agents selected from the group consisting of acetaminophen, ibuprofen, naproxen sodium, nabumetone, p-acetamide Phenol and indomethacin. In other embodiments, the pharmaceutical composition comprises an analgesic selected from the group consisting of acetaminophen, ibuprofen, naproxen sodium, nabumetone, p-acetaminophen and Indomethacin, and anti-drugs selected from the group consisting of oxybutynin, solifena, dafenacin, and atropine.

"Pharmaceutically acceptable carrier" as used herein includes all, any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweetening agents and the like. The pharmaceutically acceptable carrier can be prepared from a wide variety of materials including, but not limited to, flavoring agents, sweeteners, and miscellaneous materials, such as buffers and absorbents which may be employed in the preparation of particular therapeutic compositions. The use of such media and agents having pharmaceutically active substances is well known in the art. In addition to conventional media or agents that are incompatible with the active ingredients, the use of other materials in the therapeutic compositions is contemplated.

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

Example 1: Inhibition of urination impulse

Twenty volunteers enrolled in both men and women, who each experienced premature urgency or urination, interfered with their ability to sleep long enough to feel adequate rest. Each subject received 400 to 800 mg of ibuprofen in a single dose before bedtime. At least Fourteen subjects reported that they were better able to rest because they were not awakened by frequent urgency.

Several subjects reported that after a few weeks of ibuprofen use at night, the benefits of reducing urgency could no longer be achieved. However, all of these subjects further reported that they had gained such benefits a few days after stopping taking the drug.

Example 2: Effects of analgesics, botulinum neurotoxins and anti-drugs on inflamed and non-inflammatory stimulating macrophage responses experimental design

This study aimed to determine the dose and in vitro efficacy of analgesics and anti-drugs in controlling macrophage responses to inflammatory and non-inflammatory stimuli regulated by COX2 and prostaglandins (PGE, PGH, etc.). It establishes a response to the baseline (dose and kinetics) of inflammatory and non-inflammatory effectors in bladder cells. Briefly, cultured cells are exposed to an analgesic and/or anti-drug agent drug in the absence or presence of various effectors.

The effector comprises: lipopolysaccharide (LPS), inflammatory agent and COX2 inducer as an inflammatory stimulator; carbachol or acetylcholine, smooth muscle contraction stimulator, as a non-inflammatory stimulator; botulinum neuropathy Toxin A, a known release inhibitor of acetylcholine, as a positive control; arachidonic acid (AA), gamma-linolenic acid (DGLA) or eicosapentaenoic acid (EPA), as prostate Precursors, which are prepared by sequentially oxidizing AA, DGLA or EPA in cells by cyclooxygenase (COX1 and COX-2) and terminal prostaglandin synthetase.

The analgesics include: salicylates such as aspirin, isobutyl propofuronic acid derivatives (ibuprofen) such as Advil, Motrin, Nuprin and Medipren; naproxen sodium such as Aleve, Anaprox, Antalgin , Feminax, Ultra, Flanax, Inza, Midol Extended Relief, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Naprosyn suspension, EC-Naprosyn, Narocin, Proxen, Synflex and Xenobid; acetic acid derivatives such as indomethacin (Indocin); 1-naphthaleneacetic acid derivatives such as naphthalene Butanone or relafen; N-acetyl-p-aminophenol (APAP) derivatives such as p-acetaminophen or paracetamol (Tylenol) and celecoxib.

The anti-drug agents include: oxybutynin, solifena, dafenacin and atropine.

Macrophage cell lines are stimulated by short-term (1 to 2 hours) or long-term (24 to 48 hours) of:

(1) Different doses of various individual analgesics.

(2) Different doses of various analgesics in the presence of LPS.

(3) Different doses of various analgesics in the presence of carbachol or acetylcholine.

(4) Different doses of various analgesics in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin A alone.

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

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

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

(9) Different doses of various anti-drug agents.

(10) Different doses of various anti-drugs in the presence of LPS.

(11) Different doses of various anti-drug agents in the presence of carbachol or acetylcholine.

(12) Different doses of various anti-drug agents in the presence of AA, DGLA or EPA.

The cells were then analyzed to characterize the release of PGH ₂ , PGE, PGE ₂ , prostacyclin, thromboxane, IL-1β, IL-6, TNF-α, COX2 activity, cAMP and cGMP production, IL-1β, Production of IL-6, TNF-α and COX2 mRNA, and surface manifestations of CD80, CD86 and MHC class II molecules.

Materials and Method

Macrophages

Mouse RAW264.7 or J774 macrophages (obtained by ATCC) were used in this study. The cells were maintained in medium containing RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 15 mM HEPES, 2 mM L-glutamic acid, 100 units/ml penicillin and 100 μg/ml streptomycin. The cells were cultured at 37 ° C, 5% CO ₂ atmosphere, and dialed once a week (subculture).

Macrophage treatment with NSAIDs (non-steroidal anti-inflammatory drugs) or in vitro treatment with acetaminophen

RAW264.7 macrophages were seeded in 96-well plates at a cell density of ^1.5 x 105 cells/well (100 microliters of medium). The cells are treated with: (1) different concentrations of analgesics (for acetaminophen, aspirin, ibuprofen or naproxen), (2) different concentrations of lipopolysaccharide (LPS), which Is an effector of inflammatory stimuli on macrophages, (3) different concentrations of carbachol or acetylcholine, which are non-inflammatory stimuli, (4) NSAID or p-acetaminophen and LPS or (5) NSAID or p-acetaminophen and carbachol or acetylcholine. Briefly, NSAIDs or p-acetaminophen were dissolved in FBS-free medium (ie, RPMI 1640 supplemented with 15 mM HEPES, 2 mM L-glutamic acid, 100 units/ml penicillin, and 100 μg/ml of Streptomyces) And) serially diluted to the desired concentration by using the same medium. For cells treated with NSAID or acetaminophen in the absence of LPS, 50 microliters of NSAID solution and 50 microliters of FBS-free medium were added to each well. For cells treated with NSAID or acetaminophen in the presence of LPS, add 50 μl of NSAID or p-acetaminophen solution and 50 μl of medium in FBS-free medium to each well. LPS (from Salmonella typhimurium). Repeat the test twice for all conditions.

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

Flow cytometry analysis of the expression of co-stimulatory molecules

Flow cytometry analysis, macrophage was diluted in 100 μl of FACS buffer (2% bovine serum albumin (BSA) and 0.01% NaN ₃ in phosphate buffered saline (PBS)) and added FITC-conjugated anti-CD40, PE-conjugated anti-CD80, PE-conjugated anti-CD86 antibody, anti-MHC class II (IA ^d )PE (BD Biosciences) were stained for 30 minutes at 4 °C. The cells were then washed by centrifugation (at 4 ° C, 1,500 rpm for 5 minutes) in 300 μl of FACS buffer. After the second wash, the cells were resuspended in 200 μl of FACS buffer and analyzed by the Accuri C6 flow cytometer (BD Biosciences) for the given marker (single positive) or combination of markers (double Percentage of cells that are positive.

Analysis of cytokine responses by ELISA

The culture supernatant was treated with a cytokine-specific ELISA to determine the medium in macrophages treated with NSAID or with acetaminophen, LPS alone or with LPS and NSAID or for acetaminophen combination. IL-1β, IL-6 and TNF-α react. These assays were coated overnight with 100 μl of anti-mouse IL-6, TNF-α mAbs (BD Biosciences) or IL-1β mAb (R&D Systems) in 0.1 M sodium bicarbonate buffer (pH 9.5). Performed on a Nunc MaxiSorp Immunoassay Plate (Nunc). After washing twice with PBS (200 microliters per well), 200 microliters of PBS 3% BSA was added to each well (block), and the plate was incubated for 2 hours at room temperature. 200 microliters was added per well, the plate was washed twice more, and serial dilutions of 100 microliters of cytokine and serial dilutions of the culture supernatant were repeated, and the plate was incubated overnight at 4 °C. Finally, the plate was washed twice and with 100 microliters of secondary biotinylated anti-mouse IL-6, TNFα mAbs (BD Biosciences) or IL-1β (R&D Systems) followed by peroxidase labeling Sheep avidin mAb (Vector Laboratories). The colorimetric reaction was carried out by adding 2,2'-azo-bis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) matrix and H ₂ O ₂ (Sigma), and the absorbance was measured using Victor. ^{The ®} V multilabel microplate reader (PerkinElmer) was measured at 415 nm.

Activity determination of COX2 and production of cAMP and cGMP

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

result

Table 1 summarizes the experiments performed by the Raw 264 macrophage cell line and mainly found the effect of NSAIDs or on the cell surface performance of the co-stimulatory molecules CD40 and CD80. The performance of these molecules is stimulated by COX2 and inflammatory signals, and thus the performance of these molecules is assessed to determine the functional consequences of inhibition of COX2.

As shown in Table 2, acetaminophen, aspirin, ibuprofen, and naproxen were tested at all doses (ie, 5 x ^{10 5} nM, 5 x ^{10 4} nM, 5 x 10 ³ nM, 5 x 10 ² nM, 50 nM). suppress costimulatory molecules CD40 and CD80 basic performance (basal expression) of 5 nM and through macrophages) lower, except the highest dose (i.e., 5x10 ⁶ nM) than that exhibit enhanced, rather than inhibit expression of costimulatory molecules. As shown in Figures 1A and 1B, such inhibitory effects on CD40 and CD50 performance were observed with NSAID or p-acetaminophen doses as low as 0.05 nM (i.e., 0.00005 μM). This finding supports the notion that a small dose of NSAID or controlled release of acetaminophen is better than a large dose of acute delivery. Experiments have also shown that acetaminophen, aspirin, ibuprofen and naproxen have similar inhibitory effects on LPS-induced CD40 and CD80 expression.

Table 3 summarizes the results of studies that measured the NSAID or serum concentration of acetaminophen in adults after oral administration. As shown in Table 3, the maximum serum concentration of NSAID or acetaminophen after oral administration was in the range of 10 ⁴ to 10 ⁵ nM. Thus, the in vitro tested NSAID or acetaminophen doses in Table 2 cover the range of concentrations achievable in humans.

Example 3: Effects of analgesics, botulinum neurotoxins and anti-drugs on bladder smooth muscle cells in inflammatory and non-inflammatory stimuli

experimental design

This study was designed to demonstrate how the optimal dose of NSAID or acetaminophen determined in Example 2 affects bladder smooth muscle cells in cell culture or tissue culture, and discusses different classes of NSAIDs or acetaminophen Whether it can synergistically inhibit COX2 and PGE2 reactions more effectively.

Effectors, analgesics and anti-drugs are described in Example 2.

Primary culture of mouse bladder smooth muscle cells is stimulated by short-term (1 to 2 hours) or long-term (24 to 48 hours) of:

(1) Different doses of various individual analgesics.

(2) Different doses of various analgesics in the presence of LPS.

(3) Different doses of various analgesics in the presence of carbachol or acetylcholine.

(4) Different doses of various analgesics in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin A alone.

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

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

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

(9) Different doses of various anti-drug agents.

(10) Different doses of various anti-drugs in the presence of LPS.

(11) Different doses of various anti-drug agents in the presence of carbachol or acetylcholine.

(12) Different doses of various anti-drug agents in the presence of AA, DGLA or EPA.

The cells were then analyzed to characterize the release of PGH ₂ , PGE, PGE ₂ , prostacyclin, thromboxane, IL-1β, IL-6, TNF-α, COX2 activity, cAMP and cGMP production, IL-1β, IL-6 , TNF-α and COX2 mRNA production, and surface manifestations of CD80, CD86 and MHC class II molecules.

Materials and Method

Isolation and purification of mouse bladder cells

Bladder cells were removed from euthanized animal C57BL/6 mice (8 to 12 weeks old), and the cells were separated by enzymatic digestion, followed by purification with a Percoll gradient. Briefly, the bladder from 10 mice was chopped into 10 ml of digestion buffer (RPMI 1640, 2% fetal bovine serum, 0.5 mg/ml collagenase, 30 μg/ml DNase). Fine slurry in (DNase)). The bladder slurry was enzymatically digested at 37 ° C for 30 minutes. The undigested fragments were further dispersed through a cell-trainer. The cell suspension was pelleted and added to discrete 20%, 40% and 75% Percoll gradients to purify monocytes. 50 to 60 bladders were used per experiment.

After washing with RPMI 1640, the bladder cells were resuspended in RPMI 1640 supplemented with 10% fetal bovine serum, 15 mM HEPES, 2 mM L-glutamic acid, 100 units/ml penicillin and 100 μg/ml streptomycin. The cells were seeded at a cell density of 3 x 10 ⁴ cells/well (100 microliters) into a clear bottom black 96-well cell culture microplate. The cells were cultured at 37 ° C in a 5% CO ₂ atmosphere.

In vitro treatment of cells with NSAIDs or acetaminophen

Bladder cells are treated with an NSAID or a solution of acetaminophen (50 μL/well) alone or with carbachol (10 mol, 50 μl/well) as an example of a non-inflammatory irritant, or An example of a non-inflammatory stimulator was treated with lipopolysaccharide (LPS) of Salmonella typhimurium (1 microgram/ml, 50 microliters/well). When no other effector was added to the cells, 50 microliters of RPMI 1640 without fetal bovine serum was added to the wells to adjust the final volume to 200 microliters.

After 24 hours of culture, 150 μl of the culture supernatant was collected, and rotated at 4 ° C, 8,000 rpm for 2 minutes to remove cells and debris, and stored at -70 ° C for analysis of prostaglandin E2 (PGE _{2 by} ELISA). )Reaction. Cells were fixed, permeabilized and blocked to detect cyclooxygenase-2 (COX-2) using a fluorescent matrix. In the selected experiments, cells were stimulated in vitro for 12 hours for analysis of the COX2 response.

COX2 reaction analysis

The COX2 reaction was analyzed by a cell-based ELISA using a human/mouse full COX2 immunoassay (R&D system), which was performed according to the manufacturer's instructions. Briefly, after cell fixation and permeabilization, mouse anti-total COX2 and rabbit anti-total GAPDH were added to 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 another incubation and washing, HRP- and AP-fluorescent matrices were added. Finally, the fluorescence emitted at 600 nm (COX2 fluorescence) and 450 nm (GAPDH fluorescence) was read using a Victor ^® V multi-label microplate reader (PerkinElmer). Results are expressed as relative concentrations of total COX2, determined by relative fluorescence units (RFUs), and normalized to the housekeeping protein GAPDH.

PGE2 reaction analysis

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

Other tests

Release of PGH ₂ , PGE, prostacyclin, thromboxane, IL-1β, IL-6 and TNF-α, production of cAMP and cGMP, production of IL-1β, IL-6, TNF-α and COX2 mRNA, and The surface behavior of CD80, CD86 and MHC class II molecules was determined using the method described in Example 2.

NSAIDs and acetaminophen inhibit COX2 response to inflammatory stimuli in mouse bladder cells

Mouse bladder cells were tested at several concentrations of 5 μM or 50 μM for several analgesics (for acetaminophen, aspirin, ibuprofen and naproxen) to determine NSAIDs or acetaminophen Whether phenol can induce COX2 reaction. Analysis of the 24 hour culture indicated that NSAIDs not tested or acetaminophen showed an induction of COX2 response in mouse bladder cells in vitro.

These NSAIDs were also tested for CX2 or LPS-stimulated COX2 responses in mouse bladder cells in vitro. As shown in Table 1, the dose of carbachol tested had no significant effect on the COX-2 concentration in mouse bladder cells. On the other hand, LPS significantly increased the total COX2 concentration. It is worth noting that the effects of LPS on COX-2 concentration were inhibited by acetaminophen, aspirin, ibuprofen and naproxen. When these drugs were tested at 5 μM or 50 μM (Table 4), the inhibitory effect of NSAID or acetaminophen was observed.

NSAIDs and acetaminophen inhibit PGE2 response to inflammatory stimuli in mouse bladder cells

The amount of PGE2 secreted in mouse bladder cell culture supernatants was measured to determine the biological significance of changes in COX2 concentration in mouse bladder cells due to NSAIDs or acetaminophen. As shown in Table 5, PGE2 was not detected in the culture supernatant of unstimulated bladder cells or bladder cells cultured in the presence of carbachol. Consistent with the COX2 reaction described above, stimulation of mouse bladder cells by LPS induced a high concentration of PGE2 secretion. The addition of NSAIDs or acetaminophen to acetaminophen, aspirin, ibuprofen and naproxen inhibited the effect of LPS on PGE2 secretion, and at 5 or 50 μM doses of NSAID or acetamidine No difference was observed between the aminophenol treated cell reactions.

Taken together, these data indicate that COX2 and PGE2 responses in mouse bladder cells are not induced with either NSAIDs or acetaminophen at 5 μM or 50 μM. However, at 5 μM or 50 μM, NSAIDs or p-acetaminophen significantly inhibited COX2 and PGE2 responses in mouse bladder cells stimulated by LPS (1 μg/ml) in vitro. No significant effect of NSAIDs or response to acetaminophen on COX2 and PGE2 responses in mouse bladder cells stimulated by carbachol (1 mM) was observed.

Example 4: Effects of analgesics, botulinum neurotoxins and anti-drugs on contraction of mouse bladder smooth muscle cells

experimental design

Cultured mouse or rat bladder smooth muscle cells and mouse or rat bladder smooth muscle tissue are exposed to inflammatory stimuli and non-inflammatory stimuli in the presence of various concentrations of analgesics and/or anti-drugs. Stimulation-induced muscle contraction was measured to assess the inhibitory effect of an analgesic and/or anti-drug.

Effectors, analgesics and anti-drugs are described in Example 2.

Primary culture of mouse bladder smooth muscle cells is stimulated by short-term (1 to 2 hours) or long-term (24 to 48 hours) of:

(1) Different doses of various individual analgesics.

(2) Different doses of various analgesics in the presence of LPS.

(3) Different doses of various analgesics in the presence of carbachol or acetylcholine.

(4) Different doses of various analgesics in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin A alone.

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

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

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

(9) Different doses of various anti-drug agents.

(10) Different doses of various anti-drugs in the presence of LPS.

(11) Different doses of various anti-drug agents in the presence of carbachol or acetylcholine.

(12) Different doses of various anti-drug agents in the presence of AA, DGLA or EPA.

Materials and Method

Primary mouse bladder cells were isolated as described in Example 3. Bladder tissue culture was used in the selected experiments. Bladder smooth muscle cell contraction was recorded using a Grass multichannel recorder (Quincy Mass, USA).

Example 5: Effect of oral analgesics and anti-drugs on the response of mouse bladder smooth muscle cells to COX2 and PGE2.

experimental design:

Oral doses of aspirin, naproxen sodium, ibuprofen, indomethacin, nabumetone, Tylenol, celecoxib, and oxime to normal mice and mice with overactive bladder Bunin, sofina, dafinaxin, atropine and combinations thereof. The control group included untreated normal mice and untreated OAB mice without overactive bladder. After a final dose of 30 minutes, the bladder was collected and stimulated ex vivo with either cholestyramine or acetylcholine. In the selected experiment, the bladder was treated with botulinum neurotoxin A prior to stimulation with carbachol. Keep the animals in a metabolic cage, And evaluate the frequency (and volume) of urination. Bladder excretion was determined by monitoring water uptake and cage litter weight. Serum PGH2, PGE, PGE2, prostacyclin, thromboxane, IL-1β, IL-6, TNF-α, cAMP and cGMP concentrations were determined by ELISA. The expression of CD80, CD86, MHC class II in whole blood cells was detected by flow cytometry.

At the end of the experiment, the animals were euthanized and the excised bladder contractions were recorded using a Grass multichannel recorder. The bladder portion was fixed in formalin and analyzed for COX2 by immunohistochemistry.

Example 6: Effects of analgesics, botulinum neurotoxins and anti-drugs on the response of human bladder smooth muscle cells to inflammatory and non-inflammatory stimuli

experimental design

This study was designed to characterize how the optimal dose of NSAID or acetaminophen determined in Examples 1 to 5 affects human bladder smooth muscle cells in cell culture or tissue culture, and discusses different classes of NSAIDs or pairs of acetamidines. Whether the aminophenols can synergistically inhibit the COX2 and PGE2 reactions more effectively.

Effectors, analgesics and anti-drugs are described in Example 2.

Human bladder smooth muscle cells are stimulated by short-term (1 to 2 hours) or long-term (24 to 48 hours) of:

(1) Different doses of various individual analgesics.

(2) Different doses of various analgesics in the presence of LPS.

(3) Different doses of various analgesics in the presence of carbachol or acetylcholine.

(4) Different doses of various analgesics in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin A alone.

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

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

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

(9) Different doses of various anti-drug agents.

(10) Different doses of various anti-drugs in the presence of LPS.

(11) Different doses of various anti-drug agents in the presence of carbachol or acetylcholine.

(12) Different doses of various anti-drug agents in the presence of AA, DGLA or EPA.

The cells were then analyzed to characterize the release of PGH2, PGE, PGE2, prostacyclin, thromboxane, IL-1β, IL-6, TNF-α, COX2 activity, cAMP and cGMP production, IL-1β, IL-6, TNF - Production of alpha and COX2 mRNA, as well as surface manifestations of CD80, CD86 and MHC class II molecules.

Example 7: Effects of analgesics, botulinum neurotoxins and anti-drugs on contraction of human bladder smooth muscle cells

experimental design

Cultured human bladder smooth muscle cells are exposed to inflammatory stimuli and non-inflammatory stimuli in the presence of various concentrations of analgesics and/or anti-drugs. Stimulation-induced muscle contraction was measured to assess the inhibitory effect of an analgesic and/or anti-drug.

Effectors, analgesics and anti-drugs are described in Example 2.

Human bladder smooth muscle cells are stimulated by short-term (1 to 2 hours) or long-term (24 to 48 hours) of:

(1) Different doses of various individual analgesics.

(2) Different doses of various analgesics in the presence of LPS.

(3) Different doses of various analgesics in the presence of carbachol or acetylcholine.

(4) Different doses of various analgesics in the presence of AA, DGLA or EPA.

(5) Different doses of botulinum neurotoxin A alone.

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

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

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

(9) Different doses of various anti-drug agents.

(10) Different doses of various anti-drugs in the presence of LPS.

(11) Different doses of various anti-drug agents in the presence of carbachol or acetylcholine.

(12) Different doses of various anti-drug agents in the presence of AA, DGLA or EPA.

Bladder smooth muscle cell contraction was recorded using a Grass multichannel recorder (Quincy Mass, USA).

Example 8: Effect of analgesic 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 are separated from the macroscopic normal portion of the human bladder by enzymatic digestion. The cells were perfused in vitro supplemented with 10% fetal bovine serum, 15 mM HEPES, 2 mM L-glutamic acid, 100 units/ml penicillin, and 100 mg/ml streptomycin at 37 ° C in a 5% CO ₂ atmosphere. The RPMI 1640 was cultured and depleted, and was treated by trypsinization to separate the cells once a week, followed by re-inoculation in a new culture flask. For the first week of culture, the medium was supplemented with 0.5 ng/ml epidermal growth factor, 2 ng/ml fibroblast growth factor and 5 μg/ml insulin.

NSAIDs or acetaminophen treatment of normal human bladder smooth muscle cells in vitro

Bladder smooth muscle cells inoculated with trypsin and seeded at a cell density of 3×10 ⁴ cells/well (100 μl) in a microplate using NSAID or p-acetaminophen solution (50 μL/well) Treated alone or in combination with cholesteric (10 mol, 50 μl/well) as an example of a non-inflammatory stimulator, or with lipopolysaccharide (LPS) of Salmonella typhimurium (1 μg/ml, 50 μm) Liter/hole) treatment as an example of a non-inflammatory stimulator. When no other effector was added to the cells, 50 microliters of RPMI 1640 without fetal bovine serum was added to the wells to adjust the final volume to 200 microliters.

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

Analysis of COX2, PGE2 and cytokine responses

The COX2 and PGE2 reactions were analyzed as described in Example 3. The cytokine response was analyzed as described in Example 2.

result

NSAIDs and acetaminophen inhibit normal COX2 responses to inflammatory and non-inflammatory stimuli in human bladder smooth muscle cells - analysis of cells and culture supernatants after 24 hours of culture showed normal human bladder smooth muscle In the cells, there was no NSAIDs tested or the COX2 response was induced by acetaminophen alone. However, as summarized in Table 6, carbachol induced a lower, but significant, COX-2 response in normal human bladder smooth muscle cells. On the other hand, LPS treatment results in a higher concentration of COX2 response in normal human bladder smooth muscle cells. The effects of carbachol and LPS on COX-2 concentration were inhibited by acetaminophen, aspirin, ibuprofen and naproxen. When these drugs were tested at 5 μM or 50 μM, the inhibitory effect of the analgesic on the LPS-induced response was observed.

NSAIDs and PGE2 responses to inflammatory and non-inflammatory stimuli in human bladder smooth muscle cells inhibited by acetaminophen - consistent with the above induction of COX2 response, carbachol and LPS pass through normal human bladder Smooth muscle cells induce the production of PGE2. It was also found that acetaminophen, aspirin, ibuprofen and naproxen also inhibited LPS-induced PGE2 responses at 5 μM or 50 μM- (Table 7).

NSAIDs and cytokines in response to acetaminophen inhibiting normal human bladder cells against inflammatory stimuli - analysis of cells and culture supernatants after 24 hours of culture showed that in normal human bladder smooth muscle cells, Untested NSAIDs or acetaminophen alone induced IL-6 or TNFα secretion. As shown in Tables 8 and 9, the dose of carbachol tested induced lower, but significant, TNF[alpha] and IL-6 responses in normal human bladder smooth muscle cells. On the other hand, LPS treatment results in a large amount of induction of these pro-inflammatory cytokines. The effects of carbachol and LPS on the response of TNFα and IL-6 were inhibited by acetaminophen, aspirin, ibuprofen and naproxen. When these drugs were tested at 5 μM or 50 μM, the inhibitory effect of NSAIDs or acetaminophen on LPS-induced responses can be seen.

Primary human normal bladder smooth muscle cells were isolated and cultured and evaluated for their response to NSAIDs or to acetaminophen in the presence of non-inflammatory (carboncholine) and inflammatory (LPS) stimuli. The purpose of this study was to determine whether normal human bladder smooth muscle cells could reproduce the aforementioned phenomenon obtained from mouse bladder cells.

The above experiment was repeated with a delayed or extended release formulation, or with an analgesic and/or anti-drug agent that delays and prolongs the release formulation.

The above description is intended to teach a person of ordinary skill in the art how to practice the present invention. It is not intended to describe the obvious modifications and changes which are obvious to those of ordinary skill in the art. However, it is intended to include all obvious modifications and variations within the scope of the present invention. definition. Unless the context clearly dictates otherwise, the scope of such patent application is intended to cover the required components and steps in any order that can effectively achieve the desired purpose.

Figures 1A and 1B show the performance of NSAIDs or acetaminophen in the regulation of co-stimulatory molecules via Raw 264 macrophages in the absence of LPS (Fig. 1A) or LPS lipopolysaccharide (Fig. 1B). Figure. The cells were cultured for 24 hours in the presence of NSAID or in the presence of acetaminophen alone or in combination with Salmonella typhimurium lipopolysaccharide (LPS) (0.05 μg/ml). The result is the average relative percentage of CD40+CD80+ cells.

Claims (15)

A use of acetaminophen for the preparation of a pharmaceutical composition for reducing the frequency of urination, wherein the pharmaceutical composition comprises acetaminophen as a single active ingredient, or comprises a combination of acetaminophen and phenol Free analgesics of the following group as the only active ingredients: aspirin, ibuprofen, naproxen, naproxen sodium, strontium Indomethacin and nabumetone, wherein the pharmaceutical composition comprises an extended release formulation of acetaminophen at a daily dose of 5 mg to 2000 mg to reduce the frequency and demand of urination of the administered individual . The use according to claim 1, wherein the pair of acetaminophen is administered at a dose of from 100 mg to 500 mg per day. The use according to claim 1, wherein the pair of acetaminophen is administered at a dose of from 500 mg to 2000 mg per day. The use according to claim 1, wherein the pair of acetaminophen is administered at a dose of 50 mg to 1000 mg per day. The use according to claim 1, wherein the pharmaceutical composition comprises p-acetaminophen and ibuprofen as the only active ingredients. The use according to claim 1, wherein the pair of acetaminophen is embedded in a matrix of an insoluble matter. The use of claim 1, wherein the pharmaceutical composition comprises a polymer that is controlled to release by controlling dissolution release. The use according to claim 1, wherein the pharmaceutical composition comprises a water-soluble or water-swellable matrix-forming polymer. The use according to claim 1, wherein the pharmaceutical composition further comprises an enteric coating. The use according to claim 1, wherein the pharmaceutical composition is administered orally. The use according to claim 1, wherein the extended release preparation of the acetaminophen comprises an extended release component to acetaminophen and an immediate release component to acetaminophen. The use according to claim 11, wherein the pharmaceutical composition is administered orally. The use according to claim 11, wherein the extended release component of the acetaminophen is coated with a delayed release coating. The use according to claim 13 wherein the delayed release coating is an enteric coating. The use according to claim 13, wherein the pharmaceutical composition is administered orally.