EP2827852A1 - Formulation à libération prolongée pour réduire la fréquence de miction et son procédé d'utilisation - Google Patents

Formulation à libération prolongée pour réduire la fréquence de miction et son procédé d'utilisation

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Publication number
EP2827852A1
EP2827852A1 EP13763764.1A EP13763764A EP2827852A1 EP 2827852 A1 EP2827852 A1 EP 2827852A1 EP 13763764 A EP13763764 A EP 13763764A EP 2827852 A1 EP2827852 A1 EP 2827852A1
Authority
EP
European Patent Office
Prior art keywords
release
active ingredient
pharmaceutical composition
hours
formulated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13763764.1A
Other languages
German (de)
English (en)
Other versions
EP2827852A4 (fr
Inventor
David A. Dill
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wellesley Pharmaceuticals LLC
Original Assignee
Wellesley Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US13/424,000 external-priority patent/US8236857B2/en
Priority claimed from US13/487,348 external-priority patent/US20120244221A1/en
Application filed by Wellesley Pharmaceuticals LLC filed Critical Wellesley Pharmaceuticals LLC
Publication of EP2827852A1 publication Critical patent/EP2827852A1/fr
Publication of EP2827852A4 publication Critical patent/EP2827852A4/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

Definitions

  • the present application generally relates to methods and compositions for inhibiting the contraction of muscles and, in particular, to methods and compositions for inhibiting the contraction of smooth muscles of the urinary bladder.
  • the detrusor muscle is a layer of the urinary bladder wall made of smooth muscle fibers arranged in spiral, longitudinal, and circular bundles. When the bladder is stretched, this signals the parasympathetic nervous system to contract the detrusor muscle. This encourages the bladder to expel urine through the urethra.
  • the human adult urinary bladder usually holds about 300-350 ml of urine (the working volume), but a full adult bladder may hold up to about 1000 ml (the absolute volume), varying among individuals.
  • the ridges produced by folding of the wall of the bladder rugae
  • the wall of the bladder thins as it stretches, allowing the bladder to store larger amounts of urine without a significant rise in internal pressure.
  • the desire to urinate usually starts when the volume of urine in the bladder reaches around 200 ml. At this stage it is easy for the subject, if desired, to resist the urge to urinate. As the bladder continues to fill, the desire to urinate becomes stronger and harder to ignore. Eventually, the bladder will fill to the point where the urge to urinate becomes overwhelming, and the subject will no longer be able to ignore it. In some individuals, this desire to urinate starts when the bladder is less than 100% full in relation to its working volume. Such increased desire to urinate may interfere with normal activities, including the ability to sleep for sufficient uninterrupted periods of rest. In some cases, this increased desire to urinate may be associated with medical conditions such as benign prostate hyperplasia or prostate cancer in men, or pregnancy in women. However, increased desire to urinate also occurs in individuals, both male and female, who are not affected by another medical condition.
  • compositions and methods for the treatment of male and female subjects who suffer from a desire to urinate when the bladder is less than 100% full of urine in relation to its working volume are needed for the inhibition of muscle contraction in order to allow in said subjects the desire to urinate to start when the volume of urine in the bladder exceeds around 100% of its working volume.
  • One aspect of the present application relates to a method for reducing the frequency of urination.
  • the method comprises administering to a subject in need thereof a pharmaceutical composition comprising: an active ingredient comprising one or more analgesic agents in an amount of 50-400 mg per agent, wherein said one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, wherein said pharmaceutical composition is formulated for extended-release such that said active ingredient is released continuously over a period of 5-24 hours.
  • the method can be used for the treatment of nocturia or overactive bladder.
  • Another aspect of the present application relates to a method for reducing the frequency of urination.
  • the method comprises administering to a subject in need thereof a pharmaceutical composition comprising: an active ingredient comprising one or more analgesic agents in an amount of 50-400 mg per agent, wherein said one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, wherein said pharmaceutical composition is formulated for extended release, characterized by a two-phase release profile in which 20-60% of said active ingredient is released within two hours of administration and remainder of said active ingredient is released continuously over a period of 5-24 hours.
  • the method can be used for the treatment of nocturia or overactive bladder.
  • Another aspect of the present application relates to a method for reducing the frequency of urination, comprising administering to a subject in need thereof an effective amount of botulinum toxin, wherein said botulinum toxin is administered by injection into a bladder muscle; and orally administering to said subject a pharmaceutical composition comprising: an active ingredient comprising one or more analgesic agents in an amount of 50-400 mg per agent, wherein said one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen, wherein said pharmaceutical composition is formulated for extended-release.
  • the method can be used for the treatment of nocturia or overactive bladder.
  • Another aspect of the present application relates to a method for reducing the frequency of urination, comprising administering to a subject in need thereof an effective amount of one or more analgesic agents, and an effective amount of Zolpidem.
  • the method can be used for the treatment of nocturia or overactive bladder.
  • Another aspect of the present application relates to a method for reducing the frequency of urination, comprising administering to said subject a pharmaceutical composition comprising: one or more analgesic agents; and an antidiuretic, wherein said one or more analgesic agents are formulated for delayed release and wherein said antidiuretic is formulated for immediate release.
  • the method can be used for the treatment of nocturia or overactive bladder.
  • Another aspect of the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient comprising one or more analgesic agents, Zolpidem and a pharmaceutically acceptable carrier.
  • Another aspect of the present application relates to a pharmaceutical composition, comprising one or more analgesic agents and an antidiuretic, wherein said one or more analgesic agents are formulated for delayed release and wherein said antidiuretic is formulated for immediate release.
  • Figure 1 A and IB are diagrams showing that analgesics regulate expression of co-stimulatory molecules by Raw 264 macrophage cells in the absence ( Figure 1A) or presence ( Figure IB) of LPS.
  • Cells were cultures for 24 hrs in the presence of analgesic alone or together with Salmonella typhimurium LPS (0.05 ⁇ g/ml).
  • Results are mean relative % of CD40+CD80+ cells.
  • an effective amount means an amount necessary to achieve a selected result.
  • analgesic refers to agents, compounds or drugs used to relieve pain and inclusive of anti-inflammatory compounds.
  • exemplary analgesic and/or anti-inflammatory agents, compounds or drugs include, but are not limited to, the following substances: non-steroidal anti-inflammatory drugs (NSAIDs), salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, para- aminophenol derivatives, acetanilide, acetaminophen, phenacetin, fenamates, mefenamic acid, meclofenamate, sodium meclofenamate, heteroaryl acetic acid derivatives, tolmetin, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen,
  • NSAIDs non-steroidal anti
  • coxib and "COX inhibitor” refer to a composition of compounds that is capable of inhibiting the activity or expression of COX2 enzymes or is capable of inhibiting or reducing the severity, including pain and swelling, of a severe inflammatory response.
  • the term "derivative” refers to a chemically modified compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, protecting groups, such as a benzyl group for an alcohol or thiol, and tert-butoxycarbonyl group for an amine.
  • analogue refers to a compound which comprises a chemically modified form of a specific compound or class thereof, and which maintains the pharmaceutical and/or pharmacological activities characteristic of said compound or class.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quarternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonic, methanesulfonic, ethane dislfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, mal
  • the phrase "pharmaceutically acceptable” is used with reference to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • the mammal encompasses mammals.
  • the mammal is a human.
  • the mammal is a non-human primate such as chimpanzee, and other apes and monkey species.
  • the mammal is a domestic animal such as rabbit, dog, or cat.
  • the mammal is a farm animal such as cattle, horse, sheep, goat, or swine.
  • the mammal is a laboratory animal, including rodents, such as rats, mice and guinea pigs, and the like.
  • the urinary bladder has two important functions: storage of urine and emptying. Storage of urine occurs at low pressure, which implies that the detrusor muscle relaxes during the filling phase. Emptying of the bladder requires a coordinated contraction of the detrusor muscle and relaxation of the sphincter muscles of the urethra. Disturbances of the storage function may result in lower urinary tract symptoms, such as urgency, frequency, and urge incontinence, the components of the overactive bladder syndrome.
  • the overactive bladder syndrome which may be due to involuntary contractions of the smooth muscle of the bladder (detrusor) during the storage phase, is a common and underreported problem, the prevalence of which has only recently been assessed.
  • One aspect of the present application relates to a method for reducing the frequency of urination by administering to a person in need thereof a pharmaceutical composition formulated in an extended-release formulation.
  • the pharmaceutical composition comprises one or more analgesic agents and, optionally, one or more antimuscarinic agents, one or more antidiuretic agents, one or more spasmolytics and/or Zolpidem.
  • the method can be used for the treatment of nocturia and/or overactive bladder.
  • Extended-release also known as sustained-release (SR), sustained-action (SA), time-release (TR), controlled-release (CR), modified release (MR), or continuous- release (CR)
  • SR sustained-release
  • SA sustained-action
  • TR time-release
  • CR controlled-release
  • MR modified release
  • CR continuous- release
  • extended-release tablets or capsules are that they can often be taken less frequently than immediate-release formulations of the same drug, and that they keep steadier levels of the drug in the bloodstream, thus extending the duration of the drug action and lowering the peak amount of drug in the bloodstream.
  • an extended-release analgesic may allow a person to sleep through the night without getting up for the bathroom.
  • the pharmaceutical composition is formulated for extended-release by embedding the active ingredient in a matrix of insoluble substance(s) such as acrylics or chitin.
  • An extended-release form is designed to release the analgesic compound at a predetermined rate by maintaining a constant drug level for a specific period of time. This can be achieved through a variety of formulations, including, but not limited to, liposomes and drug-polymer conjugates, such as hydrogels.
  • An extended-release formulation can be designed to release the active agents at a predetermined rate so as to maintain a constant drug level for a specified, extended period of time, such as up to about 24 hours, about 20 hours, about 16 hours, about 12 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour following administration or following a lag period associated with delayed-release of the drug.
  • the active agents are released over a time interval of between about 2 to about 10 hours.
  • the active agents may be released over about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10 hours, about 12 hours, about 16 hours, about 20 hours or about 24 hours.
  • the active agents are released over a time period between about three to about eight hours following administration.
  • the extended-release formulation comprises an active core comprised of one or more inert particles, each in the form of a bead, pellet, pill, granular particle, microcapsule, microsphere, microgranule, nanocapsule, or nanosphere coated on its surfaces with drugs in the form of e.g., a drug-containing coating or film-forming composition using, for example, fluid bed techniques or other methodologies known to those of skill in the art.
  • the inert particle can be of various sizes, so long as it is large enough to remain poorly dissolved.
  • the active core may be prepared by granulating and milling and/or by extrusion and spheronization of a polymer composition containing the drug substance.
  • the active agents may be introduced to the inert carrier by techniques known to one skilled in the art, such as drug layering, powder coating, extrusion/spheronization, roller compaction or granulation.
  • the amount of drug in the core will depend on the dose that is required, and typically varies from about 5 to 90 weight %.
  • the polymeric coating on the active core will be from about 1 to 50% based on the weight of the coated particle, depending on the lag time required and/or the polymers and coating solvents chosen. Those skilled in the art will be able to select an appropriate amount of drug for coating onto or incorporating into the core to achieve the desired dosage.
  • the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. which alters the microenvironment of the drug to facilitate its release.
  • Extended-release formulations may utilize a variety of extended-release coatings or mechanisms facilitating the gradual release of active agents over time.
  • the extended-release agent comprises a polymer controlling release by dissolution controlled release.
  • the active agent(s) are incorporated in a matrix comprising an insoluble polymer and drug particles or granules coated with polymeric materials of varying thickness.
  • the polymeric material may comprise a lipid barrier comprising a waxy material, such as carnauba wax, beeswax, spermaceti wax, candellila wax, shallac wax, cocoa butter, cetostearyl alcohol, partially hydrogenated vegetable oils, ceresin, paraffin wax, ceresine, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid, along with surfactants, such as polyoxyethylene sorbitan monooleate.
  • an aqueous medium such as biological fluids
  • the polymer coating When contacted with an aqueous medium, such as biological fluids, the polymer coating emulsifies or erodes after a predetermined lag-time depending on the thickness of the polymer coating.
  • the lag time is independent of gastrointestinal motility, pH, or gastric residence.
  • the extended-release agent comprises a polymeric matrix effecting diffusion controlled release.
  • the matrix may comprise one or more hydrophilic and/or water-swellable, matrix forming polymers, pH-dependent polymers, and/or pH-independent polymers.
  • the extended-release formulation comprises a water soluble or water-swellable matrix-forming polymer, optionally containing one or more solubility-enhancing excipients and/or release-promoting agents.
  • the active agent(s) dissolve (if soluble) and gradually diffuse through the hydrated portion of the matrix.
  • the gel layer grows with time as more water permeates into the core of the matrix, increasing the thickness of the gel layer and providing a diffusion barrier to drug release.
  • the polymer chains become completely relaxed and can no longer maintain the integrity of the gel layer, leading to disentanglement and erosion of the outer hydrated polymer on the surface of the matrix. Water continues to penetrate towards the core through the gel layer, until it has been completely eroded. Whereas soluble drugs are released by this combination of diffusion and erosion mechanisms, erosion is the predominant mechanism for insoluble drugs, regardless of dose.
  • water-swellable polymers typically hydrate and swell in biological fluids forming a homogenous matrix structure that maintains its shape during drug release and serves as a carrier for the drug, solubility enhancers and/or release promoters.
  • the initial matrix polymer hydration phase results in slow-release of the drug (lag phase).
  • lag phase Once the water swellable polymer is fully hydrated and swollen, water within the matrix can similarly dissolve the drug substance and allow for its diffusion out through the matrix coating.
  • the porosity of the matrix can be increased due to the leaching out of pH-dependent release promoters so as to release the drug at a faster rate.
  • the rate of the drug release then becomes constant and is a function of drug diffusion through the hydrated polymer gel.
  • the release rate from the matrix is dependent upon various factors, including polymer type and level; drug solubility and dose; polymer: drug ratio; filler type and level; polymer to filler ratio; particle size of drug and polymer; and porosity and shape of the matrix.
  • hydrophilic and/or water-swellable, matrix forming polymers include, but are not limited to, cellulosic polymers, including hydroxyalkyl celluloses and carboxyalkyl celluloses, such as hydroxypropylmethylcellulose (HPMC),
  • HPMC hydroxypropylmethylcellulose
  • hydroxypropylcellulose HPC
  • HEC hydroxyethylcellulose
  • MC methylcellulose
  • CMC carboxymethylcellulose
  • powdered cellulose such as microcrystalline cellulose, cellulose acetate, ethylcellulose, salts thereof, and combinations thereof
  • alginates, gums including heteropolysaccharide gums and homopolysaccharide gums, such as xanthan, tragacanth, pectin, acacia, karaya, alginates, agar, guar, hydroxypropyl guar, veegum, carrageenan, locust bean gum, gellan gum, and derivatives thereofrom
  • acrylic resins including polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate and methyl methacrylate and cross-linked polyacrylic acid derivatives such as Carbomers (e.g., CARBOPOL ® , such as including CARBOPOL ® 71G NF, available in
  • polyethylene oxides polyethylene oxides; and polyvinyl alcohol.
  • Preferred hydrophilic and water-swellable polymers include the cellulosic polymers, especially HPMC.
  • the extended-release formulation may further comprise at least one binder that is capable of cross-linking the hydrophilic compound to form a hydrophilic polymer matrix (i.e., a gel matrix) in an aqueous medium, including biological fluids.
  • a hydrophilic polymer matrix i.e., a gel matrix
  • Exemplary binders include homopolysaccharides, such as galactomannan gums, guar gum, hydroxypropyl guar gum, hydroxypropylcellulose (HPC; e.g., Klucel EXF) and locust bean gum.
  • the binder is an alginic acid derivative, HPC or microcrystallized cellulose (MCC).
  • Other binders include, but are not limited to, starches, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
  • the introduction method is drug layering by spraying a suspension of active agent(s) and a binder onto the inert carrier.
  • the binder may be present in the bead formulation in an amount of from about 0.1% to about 15% by weight, and preferably of from about 0.2% to about 10% by weight.
  • the hydrophilic polymer matrix may further include an ionic polymer, a non-ionic polymer, or water-insoluble hydrophobic polymer to provide a stronger gel layer and/or reduce pore quantity and dimensions in the matrix so as to slow diffusion and erosion rates and concomitant release of the active agent(s). This may additionally suppress the initial burst effect and produce a more steady, "zero order release" of active agent(s).
  • Exemplary ionic polymers for slowing dissolution rate include both anionic and cationic polymers.
  • Exemplary anionic polymers include, for example, sodium carboxymethylcellulose (Na CMC), sodium alginate, polymers of acrylic acid or carbomers (e.g., CARBOPOL ® 934, 940, 974P NF); enteric polymers, such as polyvinyl acetate phthalate (PVAP), methacrylic acid copolymers (e.g., EUDRAGIT LI 00, L 30D 55, A, and FS 30D), hypromellose acetate succinate (AQUAT HPMCAS); and xanthan gum.
  • PVAP polyvinyl acetate phthalate
  • EUDRAGIT LI 00, L 30D 55, A, and FS 30D hypromellose acetate succinate
  • xanthan gum xanthan gum.
  • Exemplary cationic polymers include, for example, dimethylaminoethyl methacrylate copolymer (e.g., EUDRAGIT ® E 100). Incorporation of anionic polymers, particularly enteric polymers, is useful for developing a pH- independent release profile for weakly basic drugs as compared to hydrophilic polymer alone.
  • non-ionic polymers for slowing dissolution rate include, for example, hydroxypropylcellulose (HPC) and polyethylene oxide (PEO) (e.g., POLYOXTM)
  • HPC hydroxypropylcellulose
  • PEO polyethylene oxide
  • POLYOXTM polyethylene oxide
  • Exemplary hydrophobic polymers include ethylcellulose (e.g., ETHOCELTM, SURELEASE ® ), cellulose acetate, methacrylic acid copolymers (e.g., EUDRAGIT ® NE 30D), ammonio-methacrylate copolymers (e.g., EUDRAGIT ® RL 100 or PO RS I 00), polyvinyl acetate, glyceryl monostearate, fatty acids, such as acetyl tributyl citrate, and combinations and derivatives thereof.
  • ETHOCELTM SURELEASE ®
  • EUDRAGIT ® NE 30D methacrylic acid copolymers
  • EUDRAGIT ® RL 100 or PO RS I 00 ammonio-methacrylate copolymers
  • polyvinyl acetate glyceryl monostearate
  • fatty acids such as acetyl tributyl citrate
  • the swellable polymer can be incorporated in the formulation in proportion from 1% to 50% by weight, preferably from 5% to 40% by weight, most preferably from 5% to 20% by weight.
  • the swellable polymers and binders may be incorporated in the formulation either prior to or after granulation.
  • the polymers can also be dispersed in organic solvents or hydro-alcohols and sprayed during granulation.
  • Exemplary release-promoting agents include pH-dependent enteric polymers that remain intact at pH value lower than about 4.0 and dissolve at pH values higher than 4.0, preferably higher than 5.0, most preferably about 6.0, are considered useful as release- promoting agents for this invention.
  • Exemplary pH-dependent polymers include, but are not limited to, methacarylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (e.g., EUDRAGIT ® LI 00 (Type A), EUDRAGIT ® SI 00 (Type B), Rohm GmbH, Germany; methacrylic acid-ethyl acrylate copolymers (e.g., EUDRAGIT ® L100-55 (Type C) and EUDRAGIT ® L30D-55 copolymer dispersion, Rohm GmbH, Germany); copolymers of methacrylic acid-methyl methacrylate and methyl methacrylate (EUDRAGIT ® FS);
  • cellulose acetate phthalates CAP
  • HPMCP hydroxypropyl methylcellulose phthalate
  • PVAP polyvinyl acetate phthalates
  • COATERIC ® COATERIC ®
  • OPADRY ® enteric white OY-P-7171
  • polyvinylbutyrate acetate cellulose acetate succinates
  • CAS hydroxypropyl methylcellulose acetate succinate
  • MARCOATTM 125 & MARCOATTM 125N vinyl acetate-maleic anhydride copolymer; styrene-maleic monoester copolymer; carboxymethyl ethylcellulose (CMEC, Freund Corporation, Japan); cellulose acetate phthalates (CAP) (e.g., AQUATERIC ® ); cellulose acetate trimellitates (CAT); and mixtures of two or more thereof at weight ratios between about 2: 1 to about 5: 1, such as, for instance, a mixture of EUDRAGIT ® L 100-55 and EUDRAGIT ® S 100 at a weight ratio of about 3: 1 to about 2: 1, or a mixture of EUDRAGIT ® L 30 D-55 and EUDRAGIT ® FS at a weight ratio of about 3: 1 to about 5: 1.
  • CAP cellulose acetate phthalates
  • CAT cellulose acetate trimellitates
  • enteric pH-dependent polymers are the pharmaceutically acceptable methacrylic acid copolymers. These copolymers are anionic polymers based on methacrylic acid and methyl methacrylate and, preferably, have a mean molecular weight of about 135,000. A ratio of free carboxyl groups to methyl-esterified carboxyl groups in these copolymers may range, for example, from 1 : 1 to 1 :3, e.g. around 1 : 1 or 1 :2.
  • Such polymers are sold under the trade name Eudragit ® such as the Eudragit L series e.g., Eudragit L 12.5 ® , Eudragit L 12.5P ® , Eudragit L100 ® , Eudragit L 100-55 ® , Eudragit L- 30D ® , Eudragit L-30 D-55 ® , the Eudragit S ® series e.g., Eudragit S 12.5 ® , Eudragit S 12.5P ® , Eudragit S I 00 ® .
  • the release promoters are not limited to pH dependent polymers. Other hydrophilic molecules that dissolve rapidly and leach out of the dosage form quickly leaving a porous structure can be also be used for the same purpose.
  • the matrix may include a combination of release promoters and solubility enhancers.
  • the solubility enhancers can be ionic and non-ionic surfactants, complexing agents, hydrophilic polymers, pH modifiers, such as acidifying agents and alkalinizing agents, as well as molecules that increase the solubility of poorly soluble drug through molecular entrapment. Several solubility enhancers can be utilized simultaneously.
  • Solubility enhancers may include surface active agents, such as sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate, Tweens ® and Spans (PEO modified sorbitan monoesters and fatty acid sorbitan esters), poly(ethylene oxide)-polypropylene oxide-poly (ethylene oxide) block copolymers (aka PLURONICSTM); complexing agents such as low molecular weight polyvinyl pyrrolidone and low molecular weight hydroxypropyl methyl cellulose; molecules that aid solubility by molecular entrapment such as
  • Solubility enhancing agents typically constitute from 1% to 80% by weight, preferably from 1% to 60%, more preferably from 1% to 50%, of the dosage form and can be incorporated in a variety of ways. They can be incorporated in the formulation prior to granulation in dry or wet form. They can also be added to the formulation after the rest of the materials are granulated or otherwise processed. During granulation, solubilizers can be sprayed as solutions with or without a binder.
  • the extended-release formulation comprises a water- insoluble water-permeable polymeric coating or matrix comprising one or more water- insoluble water-permeable film-forming over the active core.
  • the coating may additionally include one or more water soluble polymers and/or one or more plasticizers.
  • the water- insoluble polymer coating comprises a barrier coating for release of active agents in the core, wherein lower molecular weight (viscosity) grades exhibit faster release rates as compared to higher viscosity grades.
  • the water-insoluble film-forming polymers include one or more alkyl cellulose ethers, such as ethyl celluloses and mixtures thereof, (e.g., ethyl cellulose grades P 100, PR45, PR20, PR10 and PR7; ETHOCEL ® , Dow).
  • alkyl cellulose ethers such as ethyl celluloses and mixtures thereof, (e.g., ethyl cellulose grades P 100, PR45, PR20, PR10 and PR7; ETHOCEL ® , Dow).
  • An exemplary water-soluble polymer such as polyvinylpyrrolidone
  • the water-insoluble polymer provides suitable properties (e.g., extended-release characteristics, mechanical properties, and coating properties) without the need for a plasticizer.
  • suitable properties e.g., extended-release characteristics, mechanical properties, and coating properties
  • coatings comprising polyvinyl acetate (PVA), neutral copolymers of aery late/methacry late esters such as commercially available Eudragit NE30D from Evonik Industries, ethyl cellulose in combination with hydroxypropylcellulose, waxes, etc. can be applied without plasticizers.
  • the water-insoluble polymer matrix may further include a plasticizer.
  • the amount of plasticizer required depends upon the plasticizer, the properties of the water-insoluble polymer, and the ultimate desired properties of the coating. Suitable levels of plasticizer range from about 1% to about 20%, from about 3% to about 20%, about 3% to about 5%, about 7% to about 10%, about 12% to about 15%, about 17% to about 20%, or about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20% by weight relative to the total weight of the coating, inclusive of all ranges and sub-ranges therebetween.
  • Exemplary plasticizers include, but are not limited to, triacetin, acetylated monoglyceride, oils (castor oil, hydrogenated castor oil, rape seed oil, sesame oil, olive oil, etc.); citrate esters, triethyl citrate, acetyltriethyl citrate acetyltributyl citrate, tributyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl phthalate, dioctyl phthalate, methyl paraben, propyl paraben, propyl paraben, butyl paraben, diethyl sebacate, dibutyl sebacate, glyceroltributyrate, substituted triglycerides and glycerides, monoacetylated and diacetylated glycerides (e.g., MYVACET® 9-45), glyceroltribut
  • Plasticizers can be high boiling point organic solvents used to impart flexibility to otherwise hard or brittle polymeric materials and can affect the release profile for the active agent(s). Plasticizers generally cause a reduction in the cohesive intermolecular forces along the polymer chains resulting in various changes in polymer properties including a reduction in tensile strength, and increase in elongation and a reduction in the glass transition or softening temperature of the polymer. The amount and choice of the plasticizer can affect the hardness of a tablet, for example, and can even affect its dissolution or disintegration characteristics, as well as its physical and chemical stability. Certain plasticizers can increase the elasticity and/or pliability of a coat, thereby decreasing the coat's brittleness.
  • the extended-release formulation comprises a combination of at least two gel-forming polymers, including at least one non-ionic gel- forming polymer and/or at least one anionic gel-forming polymer.
  • the gel formed by the combination of gel-forming polymers provides controlled release, such that when the formulation is ingested and comes into contact with the gastrointestinal fluids, the polymers nearest the surface hydrate to form a viscous gel layer. Because of the high viscosity, the viscous layer dissolves away only gradually, exposing the material below to the same process. The mass thus dissolves away slowly, thereby slowly releasing the active ingredient into the gastrointestinal fluids.
  • the formulation comprises at least one non-ionic gel-forming polymer and at least one anionic gel-forming polymer.
  • the formulation comprises two different non-ionic gel-forming polymers.
  • the formulation comprises a combination of non-ionic gel-forming polymers of the same chemistry, but having different solubilities, viscosities, and/or molecular weights (for example a combination of hydroxyproplyl methylcellulose of different viscosity grades, such as HPMC K100 and HPMC K15M or HPMC K100M).
  • Exemplary anionic gel forming polymers include, but are not limited to, sodium carboxymethylcellulose (Na CMC), carboxymethyl cellulose (CMC), anionic polysaccharides such as sodium alginate, alginic acid, pectin, polyglucuronic acid (poly- - and " -l,4-glucuronic acid), polygalacturonic acid (pectic acid), chondroitin sulfate, carrageenan, furcellaran, anionic gums such as xanthan gum, polymers of acrylic acid or carbomers (Carbopol ® 934, 940, 974P NF), Carbopol ® copolymers, a Pemulen ® polymer, polycarbophil, and others.
  • Na CMC sodium carboxymethylcellulose
  • CMC carboxymethyl cellulose
  • anionic polysaccharides such as sodium alginate, alginic acid, pectin, polyglucuronic acid (poly- - and " -l,4-glucur
  • non-ionic gel-forming polymers include, but are not limited to, Povidone (PVP: polyvinyl pyrrolidone), polyvinyl alcohol, copolymer of PVP and polyvinyl acetate, HPC (hydroxypropyl cellulose), HPMC (hydroxy propyl methylcellulose), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate (PHEMA), water soluble nonionic polymethacrylates and their copolymers, modified cellulose, modified polysaccharides, nonionic gums, nonionic polysaccharides and/or mixtures thereof.
  • PVP polyvinyl pyrrolidone
  • HPC hydroxypropyl cellulose
  • HPMC hydroxy propyl methylcellulose
  • PHEMA polyhydroxyethylmethacrylate
  • water soluble nonionic polymethacrylates and their copolymers modified cellulose, modified poly
  • the formulation may optionally comprise an enteric polymer as described above, and/or at least one excipient, such as a filler, a binder (as described above), a disintegrant, and/or a flow aid or glidant.
  • excipient such as a filler, a binder (as described above), a disintegrant, and/or a flow aid or glidant.
  • Exemplary fillers include but are not limited to, lactose, glucose, fructose, sucrose, dicalcium phosphate, sugar alcohols also known as "sugar polyol” such as sorbitol, manitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates (a blend of several sugar alcohols), corn starch, potato starch, sodium carboxymethycellulose, ethylcellulose and cellulose acetate, enteric polymers, or a mixture thereof.
  • sugar alcohols also known as "sugar polyol” such as sorbitol, manitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates (a blend of several sugar alcohols)
  • corn starch potato starch
  • sodium carboxymethycellulose ethylcellulose and cellulose acetate
  • enteric polymers or
  • Exemplary binders include but are not limited to, water-soluble hydrophilic polymers, such as Povidone (PVP: polyvinyl pyrrolidone), copovidone (a copolymer of polyvinyl pyrrolidone and polyvinyl acetate), low molecular weight HPC (hydroxypropyl cellulose) low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxy methyl cellulose, ethylcellulose, gelatin, polyethylene oxide, acacia, dextrin, magnesium aluminum silicate, starch, and polymethacrylates such as Eudragit NE 30D, Eudragit RL, Eudragit RS, Eudragit E, polyvinyl acetate, and enteric polymers, or mixtures thereof.
  • PVP polyvinyl pyrrolidone
  • copovidone a copolymer of polyvinyl pyrrolidone and polyvinyl acetate
  • HPC hydroxypropyl cellulose
  • Exemplary disintegrants include but are not limited to low-substituted carboxymethyl cellulose sodium, crospovidone (cross-linked polyvinyl pyrrolidone), sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose (Croscarmellose), pregelatinized starch (starch 1500), microcrystalline cellulose, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, and magnesium or aluminum silicate.
  • Exemplary glidants include but are not limited to, magnesium, silicon dioxide, talc, starch, titanium dioxide, and the like.
  • the extended-release formulation is formed by coating a water soluble/dispersible drug-containing particle, such as a bead or bead population therein (as described above), with a coating material, and, optionally, a pore former and other excipients.
  • the coating material is preferably selected from a group comprising cellulosic polymers, such as ethylcellulose (e.g., SURELEASE ® ),
  • the release-controlling coating for a given bead population may be controlled by at least one parameter of the release controlling coating, such as the nature of the coating, coating level, type and concentration of a pore former, process parameters and combinations thereof.
  • a parameter such as a pore former concentration, or the conditions of the curing, allows for changes in the release of active agent(s) from any given bead population, thereby allowing for selective adjustment of the formulation to a pre-determined release profile.
  • Pore formers suitable for use in the release controlling coating herein can be organic or inorganic agents, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
  • Exemplary pore forming agents include, but are not limited to, organic compounds such as mono-, oligo-, and polysaccharides including sucrose, glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran;
  • polymers soluble in the environment of use such as water-soluble hydrophilic polymers, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, Carbopol, and the like, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols, or block polymers thereof, polyglycols, poly(a-Q)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, combination thereof, and the like.
  • the release controlling coating can further comprise other additives known in the art, such as plasticizers, anti-adherents, glidants (or flow aids), and antifoams.
  • the coated particles or beads may additionally include an "overcoat," to provide, e.g., moisture protection, static charge reduction, taste-masking, flavoring, coloring, and/or polish or other cosmetic appeal to the beads.
  • an overcoat to provide, e.g., moisture protection, static charge reduction, taste-masking, flavoring, coloring, and/or polish or other cosmetic appeal to the beads.
  • Suitable coating materials for such an overcoat are known in the art, and include, but are not limited to, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose and microcrystalline cellulose, or combinations thereof (for example, various OPADRY ® coating materials).
  • the coated particles or beads may additionally contain enhancers that may be exemplified by, but not limited to, solubility enhancers, dissolution enhancers, absorption enhancers, permeability enhancers, stabilizers, complexing agents, enzyme inhibitors, p- glycoprotein inhibitors, and multidrug resistance protein inhibitors.
  • the formulation can also contain enhancers that are separated from the coated particles, for example in a separate population of beads or as a powder.
  • the enhancer(s) may be contained in a separate layer on coated particles either under or above the release controlling coating.
  • the extended-release formulation is formulated to release the active agent(s) by an osmotic mechanism.
  • a capsule may be formulated with a single osmotic unit or it may incorporate 2, 3, 4, 5, or 6 push-pull units encapsulated within a hard gelatin capsule, whereby each bilayer push pull unit contains an osmotic push layer and a drug layer, both surrounded by a semi-permeable membrane. One or more orifices are drilled through the membrane next to the drug layer. This membrane may be additionally covered with a pH-dependent enteric coating to prevent release until after gastric emptying. The gelatin capsule dissolves immediately after ingestion.
  • the enteric coating breaks down, which then allows fluid to flow through the semi-permeable membrane, swelling the osmotic push compartment to force to force drugs out through the orifice(s) at a rate precisely controlled by the rate of water transport through the semi-permeable membrane. Release of drugs can occur over a constant rate for up to 24 hours or more.
  • the osmotic push layer comprises one or more osmotic agents creating the driving force for transport of water through the semi-permeable membrane into the core of the delivery vehicle.
  • osmotic agents include water-swellable hydrophilic polymers, also referred to as “osmopolymers” and “hydrogels,” including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2- hydroxy ethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium
  • osmogens which are capable of imbibing water to effect an osmotic pressure gradient across the semi-permeable membrane.
  • exemplary osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • the extended-release formulation may comprise a polysaccharide coating that is resistant to erosion in both the stomach and intestine.
  • a polysaccharide coating that is resistant to erosion in both the stomach and intestine.
  • Such polymers can be only degraded in the colon, which contains a large microflora containing biodegradable enzymes breaking down, for example, the polysaccharide coatings to release the drug contents in a controlled, time-dependent manner.
  • Exemplary polysaccharide coatings may include, for example, amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin, xylan, and combinations or derivatives therefrom.
  • the pharmaceutical composition is formulated for delayed extended-release.
  • delayed-release refers to a medication that does not immediately disintegrate and release the active ingredient(s) into the body.
  • the term “delayed extended-release” is used with reference to a drug formulation having a release profile in which there is a predetermined delay in the release of the drug following administration.
  • the delayed extended-release formulation includes an extended-release formulation coated with an enteric coating, which is a barrier applied to oral medication that prevents release of medication before it reaches the small intestine.
  • Delayed-release formulations such as enteric coatings, prevent drugs having an irritant effect on the stomach, such as aspirin, from dissolving in the stomach.
  • Such coatings are also used to protect acid-unstable drugs from the stomach's acidic exposure, delivering them instead to a basic pH environment (intestine's pH 5.5 and above) where they do not degrade, and give their desired action.
  • pulsatile release is a type of delayed-release, which is used herein with reference to a drug formulation that provides rapid and transient release of the drug within a short time period immediately after a predetermined lag period, thereby producing a "pulsed" plasma profile of the drug after drug administration.
  • Formulations may be designed to provide a single pulsatile release or multiple pulsatile releases at predetermined time intervals following administration, or a pulsatile release (e.g., 20-60% of the active ingredient) followed with extended release over a period of time (e.g., a continuous release of the remainder of the active ingredient).
  • a delayed-release or pulsatile release formulation generally comprises one or more elements covered with a barrier coating, which dissolves, erodes or ruptures following a specified lag phase.
  • the pharmaceutical composition of the present application is formulated for extended-release or delayed extended-release and comprises 100% of the total dosage of a given active agent administered in a single unit dose.
  • the pharmaceutical composition comprises an extended/delayed-release component and an immediate-release component.
  • the immediate- release component and the extended/delayed-release component contain the same active ingredient.
  • extended/delayed-release component contain different active ingredients (e.g. , an analgesic in one component and an antimuscarinic agent in another component).
  • the first and second components each contains an analgesic selected from the group consisting of aspirin, ibuprofen, naproxen sodium, indomethacin, nabumetone, and acetaminophen.
  • the extended/delayed-release component is coated with an enteric coating.
  • the immediate-release component and/or the extended/delayed-release component further comprises an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.
  • the analgesic agent in each component is administered orally at a daily dose of 5 mg - 2000 mg, 20 mg - 1000 mg, 50 mg - 500 mg or 250-1000 mg.
  • the immediate-release component and/or the extended/delayed-release component further comprises an antidiuretic agent, an antimuscarinic agent or both.
  • the treatment method includes administering to a subject a diuretic at least 8 or 7 hours prior to a target time, such as bedtime, and administering to the subject the pharmaceutical composition comprising the immediate-release component and/or the extended/delayed-release component within 2 hours prior to the target time.
  • the "immediate-release” component provide about 5- 50% of the total dosage of the active agent(s) and the “extended-release” component provides 50-95% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation.
  • the immediate-release component may provide about 20-60%, or about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation.
  • the extended-release component provides about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% of the total dosage of the active agent(s) to be delivered by the formulation.
  • the extended- release component further comprises a barrier coating to delay the release of the active agent.
  • a barrier coating for delayed-release may consist of a variety of different materials, depending on the objective.
  • a formulation may comprise a plurality of barrier coatings to facilitate release in a temporal manner.
  • the coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or a coating based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose.
  • the formulation may additionally include a time delay material such as, for example, glyceryl monostearate or glyceryl distearate.
  • the delayed, extended-release formulation includes an enteric coating comprised one or more polymers facilitating release of active agents in proximal or distal regions of the gastrointestinal tract.
  • enteric polymer coating is a coating comprising of one or more polymers having a pH dependent or pH-independent release profile.
  • An enteric coated pill will not dissolve in the acidic juices of the stomach (pH ⁇ 3), but they will in the alkaline (pH 7-9) environment present in the small intestine or colon.
  • An enteric polymer coating typically resists releases of the active agents until some time after a gastric emptying lag period of about 3-4 hours after administration.
  • pH dependent enteric coatings comprises one or more pH-dependent or pH-sensitive polymers that maintain their structural integrity at low pH, as in the stomach, but dissolve in higher pH environments in more distal regions of the gastrointestinal tract, such as the small intestine, where the drug contents are released.
  • pH dependent is defined as having characteristics (e.g., dissolution) which vary according to environmental pH.
  • Exemplary pH-dependent polymers include, but are not limited to, methacarylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (e.g., EUDRAGIT ® LI 00 (Type A), EUDRAGIT ® S I 00 (Type B), Rohm GmbH, Germany; methacrylic acid-ethyl acrylate copolymers (e.g., EUDRAGIT ® L100-55 (Type C) and EUDRAGIT ® L30D-55 copolymer dispersion, Rohm GmbH, Germany); copolymers of methacrylic acid-methyl methacrylate and methyl methacrylate (EUDRAGIT ® FS);
  • cellulose acetate phthalates CAP
  • HPMCP hydroxypropyl methylcellulose phthalate
  • PVAP polyvinyl acetate phthalates
  • COATERIC ® COATERIC ® , OPADRY ® enteric white OY-P-7171
  • CAS hydroxypropyl methylcellulose acetate succinate
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • shellac e.g., MarcoatTM 125 & MarcoatTM 125N
  • carboxymethyl ethylcellulose CMEC, Freund Corporation, Japan
  • pH-dependent polymers typically exhibit a characteristic pH optimum for dissolution.
  • the pH-dependent polymer exhibits a pH optimum between about 5.0 and 5.5, between about 5.5 and 6.0, between about 6.0 and 6.5, or between about 6.5 and 7.0.
  • the pH-dependent polymer exhibits a pH optimum of >5.0, of >5.5, of >6.0, of >6.5, or of >7.0.
  • enteric pH-dependent polymers are the pharmaceutically acceptable methacrylic acid copolymers. These copolymers are anionic polymers based on methacrylic acid and methyl methacrylate and, preferably, have a mean molecular weight of about 135,000. A ratio of free carboxyl groups to methyl-esterified carboxyl groups in these copolymers may range, for example, from 1 : 1 to 1 :3, e.g. around 1 : 1 or 1 :2.
  • Such polymers are sold under the trade name Eudragit ® 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 ® , the Eudragit S ® series e.g., Eudragit S 12.5 ® , Eudragit S 12.5P ® , Eudragit S 100 ® .
  • the release promoters are not limited to pH dependent polymers. Other hydrophilic molecules that dissolve rapidly and leach out of the dosage form quickly leaving a porous structure can be also be used for the same purpose.
  • the coating methodology employs the blending of one or more pH-dependent and one or more pH-independent polymers.
  • the blending of pH- dependent and pH-independent polymers can reduce the release rate of active ingredients once the soluble polymer has reached its optimum pH of solubilization.
  • a "time-controlled" or “time-dependent” release profile can be obtained using a water insoluble capsule body containing one or more active agents, wherein the capsule body closed at one end with an insoluble, but permeable and swellable hydrogel plug.
  • the plug Upon contact with gastrointestinal fluid or dissolution medium, the plug swells, pushing itself out of the capsule and releasing the drugs after a pre-determined lag time, which can be controlled by e.g., the position and dimensions of the plug.
  • the capsule body may be further coated with an outer pH-dependent enteric coating keeping the capsule intact until it reaches the small intestine.
  • Suitable plug materials include, for example, polymethacrylates, erodible compressed polymers (e.g., HPMC, polyvinyl alcohol), congealed melted polymer (e.g., glyceryl mono oleate) and enzymatically controlled erodible polymers (e.g., polysaccharides, such as amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin and xylan).
  • erodible compressed polymers e.g., HPMC, polyvinyl alcohol
  • congealed melted polymer e.g., glyceryl mono oleate
  • enzymatically controlled erodible polymers e.g., polysaccharides, such as amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin
  • capsules or bilayered tablets may be formulated to contain a drug-containing core, covered by a swelling layer, and an outer insoluble, but semipermeable polymer coating or membrane.
  • the lag time prior to rupture can be controlled by the permeation and mechanical properties of the polymer coating and the swelling behavior of the swelling layer.
  • the swelling layer comprises one or more swelling agents, such as swellable hydrophilic polymers that swell and retain water in their structures.
  • Exemplary water swellable materials to be used in the delayed-release coating include, but are not limited to, polyethylene oxide (having e.g., an average molecular weight between 1,000,000 to 7,000,000, such as POLYOX ® ), methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; polyalkylene oxides having a weight average molecular weight of 100,000 to 6,000,000, including but not limited to poly(methylene oxide), poly(butylene oxide); poly(hydroxy alkyl methacrylate) having a molecular weight of from 25,000 to 5,000,000; poly(vinyl)alcohol, having a low acetal residue, which is cross- linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; mixtures of methyl cellulose, cross-linked agar and carboxymethyl cellulose; hydrogel forming copolymers produced by forming a dispersion of a finely divided
  • the release time of the drugs can be controlled by a
  • disintegration lag time depending on the balance between the tolerability and thickness of a water insoluble polymer membrane (such as ethyl cellulose, EC) containing predefined micropores at the bottom of the body and the amount of a swellable excipient, such as low substituted hydroxypropyl cellulose (L-HPC) and sodium glycolate.
  • a water insoluble polymer membrane such as ethyl cellulose, EC
  • L-HPC low substituted hydroxypropyl cellulose
  • the enteric layer may further comprise anti-tackiness agents, such as talc or glyceryl monostearate and/or plasticizers.
  • the enteric layer may further comprise one or more plasticizers including, but not limited to, triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate, polyethylene glycol acetylated monoglycerides, glycerin, triacetin, propylene glycol, phthalate esters ⁇ e.g., diethyl phthalate, dibutyl phthalate), titanium dioxide, ferric oxides, castor oil, sorbitol and dibutyl sebacate.
  • plasticizers including, but not limited to, triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate, polyethylene glycol acetylated monoglycerides, glycerin, triacetin, propylene glycol, phthalate esters ⁇ e.g., diethyl phthalate, dibutyl phthalate), titanium dioxide, ferric oxides,
  • the delayed release formulation employs a water- permeable but insoluble film coating to enclose the active ingredient and an osmotic agent. As water from the gut slowly diffuses through the film into the core, the core swells until the film bursts, thereby releasing the active ingredients.
  • the film coating may be adjusted to permit various rates of water permeation or release time.
  • the delayed release formulation employs a water- impermeable tablet coating whereby water enters through a controlled aperture in the coating until the core bursts. When the tablet bursts, the drug contents are released immediately or over a longer period of time.
  • the active agents are delivered in a formulation to provide both delayed-release and extended-release (delayed-sustained).
  • delayed- extended-re lease is used herein with reference to a drug formulation providing pulsatile release of active agents at a pre-determined time or lag period following administration, which is then followed by extended-release of the active agents thereafter.
  • immediate-release, extended-release, delayed-release, or delay ed-extended-release formulations comprises an active core comprised of one or more inert particles, each in the form of a bead, pellet, pill, granular particle, microcapsule, microsphere, microgranule, nanocapsule, or nanosphere coated on its surfaces with drugs in the form of e.g., a drug-containing film-forming composition using, for example, fluid bed techniques or other methodologies known to those of skill in the art.
  • the inert particle can be of various sizes, so long as it is large enough to remain poorly dissolved.
  • the active core may be prepared by granulating and milling and/or by extrusion and
  • the amount of drug in the core will depend on the dose that is required, and typically varies from about 5 to 90 weight %.
  • the polymeric coating on the active core will be from about 1 to 50% based on the weight of the coated particle, depending on the lag time and type of release profile required and/or the polymers and coating solvents chosen.
  • the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. which alters the microenvironment of the drug to facilitate its release.
  • delayed-re lease or delayed-extended- release compositions may 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 polymer and the enteric polymer may be present at a weight ratio of from 4: 1 to 1 : 1, and the total weight of the coatings is 10 to 60 weight % based on the total weight of the coated beads.
  • the drug layered beads may optionally include an inner dissolution rate controlling membrane of ethylcellulose.
  • the composition of the outer layer, as well as the individual weights of the inner and outer layers of the polymeric membrane are optimized for achieving desired circadian rhythm release profiles for a given active, which are predicted based on in vitro/in vivo correlations.
  • the formulations may comprise a mixture of immediate- release drug-containing particles without a dissolution rate controlling polymer membrane and delayed-extended-release beads exhibiting, for example, a lag time of 2-4 hours following oral administration, thus providing a two-pulse release profile.
  • the active core is coated with one or more layers of dissolution rate-controlling polymers to obtain desired release profiles with or without a lag time.
  • An inner layer membrane can largely control the rate of drug release following imbibition of water or body fluids into the core, while the outer layer membrane can provide for a desired lag time (the period of no or little drug release following imbibition of water or body fluids into the core).
  • the inner layer membrane may comprise a water insoluble polymer, or a mixture of water insoluble and water soluble polymers.
  • the polymers suitable for the outer membrane which largely controls the lag time of up to 6 hours may comprise an enteric polymer, as described above, and a water insoluble polymer at 10 to 50 weight %.
  • the ratio of water insoluble polymer to enteric polymer may vary from 4: 1 to 1 :2, preferably the polymers are present at a ratio of about 1 : 1.
  • the water insoluble polymer typically used is ethylcellulose.
  • Exemplary water insoluble polymers include ethylcellulose, polyvinyl acetate (Kollicoat SR#0D from BASF), neutral copolymers based on ethyl acrylate and
  • methylmethacrylate copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as EUDRAGIT* NE, RS and RS30D, RL or RL30D and the like.
  • exemplary water soluble polymers include low molecular weight HPMC, HPC,
  • methylcellulose methylcellulose, polyethylene glycol (PEG of molecular weight>3000) at a thickness ranging from 1 weight % up to 10 weight % depending on the solubility of the active in water and the solvent or latex suspension based coating formulation used.
  • the water insoluble polymer to water soluble polymer may typically vary from 95:5 to 60:40, preferably from 80:20 to 65:35.
  • AMBERLITETM IRP69 resin is used as an extended- release carrier.
  • AMBERLITETM IRP69 is an insoluble, strongly acidic, sodium form cation exchange resin that is suitable as carrier for cationic (basic) substances.
  • DUOLITETM AP143/1093 resin is used as an extended-release carrier.
  • DUOLITETM AP 143/1093 is an insoluble, strongly basic, anion exchange resin that is suitable as a carrier for anionic (acidic) substances.
  • AMBERLITE IRP69 or/and DUOLITETM When used as a drug carrier, AMBERLITE IRP69 or/and DUOLITETM
  • AP143/1093 resin provides a means for binding medicinal agents onto an insoluble polymeric matrix. Extended-release is achieved through the formation of resin-drug complexes (drug resinates). The drug is released from the resin in vivo as the drug reaches equilibrium with the high electrolyte concentrations, which are typical of the gastrointestinal tract. More hydrophobic drugs will usually elute from the resin at a lower rate, owing to hydrophobic interactions with the aromatic structure of the cation exchange system.
  • the pharmaceutical composition is formulated for oral administration.
  • Oral dosage forms include, for example, tablets, capsules, caplets, and may also comprise a plurality of granules, beads, powders or pellets that may or may not be encapsulated. Tablets and capsules represent the most convenient oral dosage forms, in which case solid pharmaceutical carriers are employed.
  • one or more barrier coatings may be applied to pellets, tablets, or capsules to facilitate slow dissolution and concomitant release of drugs into the intestine.
  • the barrier coating contains one or more polymers encasing, surrounding, or forming a layer, or membrane around the therapeutic composition or active core.
  • the active agents are delivered in a formulation to provide delayed-release at a pre-determined time following 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.
  • Various coating techniques may be applied to granules, beads, powders or pellets, tablets, capsules or combinations thereof containing active agents to produce different and distinct release profiles.
  • the pharmaceutical composition is in a tablet or capsule form containing a single coating layer. In other embodiments, the pharmaceutical composition is in a tablet or capsule form containing multiple coating layers.
  • the pharmaceutical composition comprises a plurality of active ingredients selected from the group consisting of analgesics, antimuscarinic agents, antidiuretics, spasmolytics and Zolpidem.
  • active ingredients selected from the group consisting of analgesics, antimuscarinic agents, antidiuretics, spasmolytics and Zolpidem.
  • antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin and atropine.
  • antidiuretics include, but are not limited to, antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (e.g., desmopressin argipressin, lypressin, felypressin, ornipressin, terlipressin; vasopressin receptor agonists, atrial natriuretic peptide (ANP) and C- type natriuretic peptide (CNP) receptor (i.e., NPR1, NPR2, NPR3) antagonists (e.g., HS-142- 1 , isatin, [Asu7,23']b-ANP-(7-28)], anantin, a cyclic peptide from Streptomyces coerulescens, and 3G12 monoclonal antibody); somatostatin type 2 receptor antagonists (e.g., ADH), angiotensin II, aldosterone,
  • the pharmaceutical composition comprises one or more analgesics.
  • the pharmaceutical composition comprises (1) one or more analgesics, and (2) one or more other active ingredients selected from the group consisting of antimuscarinic agents, antidiuretics and spasmolytics.
  • the pharmaceutical composition comprises (1) one or more analgesics and (2) one or more antimuscarinic agents. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics and (2) one or more antidiuretics. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics and (2) one or more spasmolytics. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics and (2) Zolpidem. In another embodiment, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or two
  • the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more spasmolytics agents, and (3) one or more antidiuretics. In yet another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more antidiuretics, and (3) Zolpidem. [0111] In one embodiment, the plurality of active ingredients are formulated for immediate-release. In other embodiment, the plurality of active ingredients are formulated for extended-release.
  • the plurality of active ingredients are formulated for both immediate-release and extended-release (e.g., a first portion of each active ingredient is formulated for immediate-release and a second portion of each active ingredient is formulated for extended-release).
  • some of the plurality of active ingredients are formulated for immediate-release and some of the plurality of active ingredients are formulated for extended-release (e.g., active ingredients A, B, C are formulated for immediate-release and active ingredients C and D are formulated for extended-release).
  • the immediate-release component and/or the extended-release component is further coated with a delayed-release coating, such as an enteric coating.
  • the pharmaceutical composition comprises an immediate-release component and an extended-release component.
  • the immediate-release component may comprise one or more active ingredients selected from the group consisting of analgesics, antimuscarinic agents, antidiuretics and spasmolytics.
  • the extended-release component may comprise one or more active ingredients selected from the group consisting of analgesics, antimuscarinic agents, antidiuretics and spasmolytics.
  • the immediate-release component and the extended-release component have exactly the same active ingredients.
  • the immediate-release component and the extended-release component have different active ingredients.
  • the immediate-release component and the extended-release component have one or more common active ingredients.
  • the immediate-release component and/or the extended-release component is further coated with a delayed-release coating, such as an enteric coating.
  • the pharmaceutical composition comprises two or more active ingredients (e.g., two or more analgesic agents, or a mixture of one or more analgesic agent and one or more antimuscarinic agents or antidiuretics or spasmolytics or zolidem), formulated for immediate-release at about the same time.
  • the pharmaceutical composition comprises two ore more active ingredients, formulated for extended-release at about the same time.
  • the pharmaceutical composition comprises two or more active ingredients formulated as two extended-release components, each providing a different extended-release profile. For example, a first extended-release component releases a first active ingredient at a first release rate and a second extended-release component releases a second active ingredient at a second release rate.
  • the pharmaceutical composition comprises two or more active ingredients, both formulated for delayed release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated for delayed release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated as two delayed-release components, each providing a different delayed-release profile. For example, a first delayed-release component releases a first active ingredient at a first time point and a second delayed-release component releases a second active ingredient at a second time point. In another embodiment, the pharmaceutical composition comprises two or more active ingredients, one or more of which are formulated for immediate-release and the others are formulated for extended-release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients, a fraction of which is formulated for immediate-release and the remainder is formulated for extended-release.
  • the pharmaceutical composition comprises two active ingredients (e.g., two analgesic agents, or a mixture of one analgesic agent and one antimuscarinic agent or antidiuretic or spasmolytic or Zolpidem) formulated for immediate- release, and (2) two active ingredients (e.g., two analgesic agents, or a mixture of one analgesic agent and one antimuscarinic agent or antidiuretic or spasmolytic or Zolpidem) formulated for extended-release.
  • the pharmaceutical composition comprises three active ingredients formulated for immediate-release, and (2) three active ingredients formulated for extended-release.
  • the pharmaceutical composition comprises four active ingredients formulated for immediate-release, and (2) four active ingredients formulated for extended-release.
  • the active ingredient(s) in the immediate-release component can be the same as, or different from, the active ingredient(s) in the extended-release component.
  • the immediate-release component and/or the extended-release component is further coated with a delayed-release coating, such as an enteric coating.
  • the pharmaceutical composition comprises one or more analgesic agents; and an antidiuretic, wherein the one or more analgesic agents are formulated for delayed release and wherein the antidiuretic is formulated for immediate release.
  • the pharmaceutical composition further comprises an additional agent selected from the group consisting of an antimuscarinic agent, an antidiuretic agent, a spasmolytic and Zolpidem, wherein the additional agent is formulated for delayed release.
  • the delayed release formulation delays the release of the active ingredient (e.g., the analgesic agent, antimuscarinic agent, antidiuretic agent, spasmolytic and/or Zolpidem) for a period of 1, 2, 3, 4 or 5 hours.
  • the active ingredient e.g., the analgesic agent, antimuscarinic agent, antidiuretic agent, spasmolytic and/or Zolpidem
  • immediate-release is used herein with reference to a drug formulation that does not contain a dissolution rate controlling material. There is substantially no delay in the release of the active agents following administration of an immediate-release formulation.
  • An immediate-release coating may include suitable materials immediately dissolving following administration so as to release the drug contents therein.
  • Exemplary immediate-release coating materials include gelatin, polyvinyl alcohol polyethylene glycol (PVA-PEG) copolymers (e.g., KOLLICOAT ® ) and various others materials known to those skilled in the art.
  • An immediate-release composition may comprise 100% of the total dosage of a given active agent administered in a single unit dose.
  • an immediate-release component may be included as a component in a combined release profile formulation that may provide about 1% to about 60% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation.
  • the immediate-release component may provide about 5%-60%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 30%, about 30% to about 60%, about 30% to about 50%, about 40% to about 60%, about 40% to about 50%, about 45% to about 60% or about 45%) to about 50% of the total dosage of the active agent(s) to be delivered by the formulation.
  • the immediate-release component provides about 2, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55or 60% of the total dosage of the active agent(s) to be delivered by the formulation.
  • the immediate-release or delayed-release formulation comprises an active core comprised of one or more inert particles, each in the form of a bead, pellet, pill, granular particle, microcapsule, microsphere, microgranule, nanocapsule, or nanosphere coated on its surfaces with drugs in the form of e.g., a drug-containing film- forming composition using, for example, fluid bed techniques or other methodologies known to those of skill in the art.
  • the inert particle can be of various sizes, so long as it is large enough to remain poorly dissolved.
  • the active core may be prepared by granulating and milling and/or by extrusion and spheronization of a polymer composition containing the drug substance.
  • the amount of drug in the core will depend on the dose that is required, and typically varies from about 5 to 90 weight %.
  • the polymeric coating on the active core will be from about 1 to 50% based on the weight of the coated particle, depending on the lag time and type of release profile required and/or the polymers and coating solvents chosen.
  • the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. which alters the microenvironment of the drug to facilitate its release.
  • the 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 polymer and the enteric polymer may be present at a weight ratio of from 4: 1 to 1 : 1, and the total weight of the coatings is 10 to 60 weight % based on the total weight of the coated beads.
  • the drug layered beads may optionally include an inner dissolution rate controlling membrane of ethylcellulose.
  • the composition of the outer layer, as well as the individual weights of the inner and outer layers of the polymeric membrane are optimized for achieving desired circadian rhythm release profiles for a given active, which are predicted based on in vitro/in vivo correlations.
  • the formulations comprise a mixture of immediate- release drug-containing particles without a dissolution rate controlling polymer membrane and delayed-release beads exhibiting, for example, a lag time of 2-4 hours following oral administration, thus providing a two-pulse release profile.
  • the formulations comprise a mixture of two types of delayed-release beads: a first type that exhibits a lag time of 1-3 hours and a second type that exhibits a lag time of 4-6 hours.
  • the formulations are designed with release profiles to limit interference with restful sleep, wherein the formulation releases the medicine when the individual would normally be awakened by an urge to urinate. For example, consider an individual who begins sleeping at 1 1 PM and is normally awakened at 12:30 AM, 3:00 AM, and 6:00 AM to urinate. A delayed, extended-release vehicle could be taken at 10 PM and start delivering the medicine at 12 AM and gradually release the medicine over a period of 5- 8 hours,thereby delaying or eliminate the need to urinate.
  • the formulations are designed with a release profile such that a fraction of the medicine (e.g., 20-60%) is released immediately or within 2 hours of administration and the rest is released over an extended period of time.
  • the pharmaceutical composition may be administered daily or administered on an as needed basis.
  • the pharmaceutical composition is administered to the subject prior to bedtime.
  • the pharmaceutical composition is administered immediately before bedtime.
  • the pharmaceutical composition is administered within about two hours before bedtime, preferably within about one hour before bedtime.
  • the pharmaceutical composition is administered about two hours before bedtime.
  • the pharmaceutical composition is administered at least two hours before bedtime.
  • the pharmaceutical composition is administered about one hour before bedtime.
  • the pharmaceutical composition is administered at least one hour before bedtime. In a still further embodiment, the pharmaceutical composition is administered less than one hour before bedtime. In still another embodiment, the pharmaceutical composition is administered immediately before bedtime. Preferably, the pharmaceutical composition is administered orally.
  • the appropriate dosage ("therapeutically effective amount") of the active agent(s) in the immediate-release component or the extended-release component will depend, for example, on the severity and course of the condition, the mode of administration, the bioavailability of the particular agent(s), the age and weight of the patient, the patient's clinical history and response to the active agent(s), discretion of the physician, etc.
  • the therapeutically effective amount of the active agent(s) in the immediate-release component, the extended-release component or the delayed-extended-re lease component is administered in the range of about 100 ⁇ g/kg body weight/day to about 100 mg/kg body weight/day whether by one or more administrations.
  • the range of each active agent administered daily in a single dose or in multiple does is from about 100 ⁇ g/kg body weight/day to about 50 mg/kg body weight/day, 100 ⁇ g/kg body weight/day to about 10 mg/kg body weight/day, 100 ⁇ g/kg body weight/day to about 1 mg/kg body weight/day, 100 ⁇ g/kg body weight/day to about 10 mg/kg body weight/day, 500 ⁇ g/kg body weight/day to about 100 mg/kg body weight/day, 500 ⁇ g/kg body weight/day to about 50 mg/kg body weight/day, 500 ⁇ g/kg body weight/ day to about 5 mg/kg body weight/ day, 1 mg/kg body weight/day to about 100 mg/kg body weight/day, 1 mg/kg body weight/day to about 50 mg/kg body weight/ day, 1 mg/kg body weight/day to about 10 mg/kg body weight/day, 5 mg/kg body weight/dose to about 100 mg/kg body weight/day, 5 mg/kg body weight/dose to about 100
  • the active agent(s) described herein may be included in an immediate-release component or an extended-release component, a delayed-extended-release component or combinations thereof for daily oral administration at a single dose or combined dose range of 1 mg to 2000 mg, 5 mg to 2000 mg, 10 mg to 2000 mg, 50 mg to 2000 mg, 100 mg to 2000 mg, 200 mg to 2000 mg, 500 mg to 2000 mg, 5 mg to 1800 mg, 10 mg to 1600 mg, 50 mg to 1600 mg, 100 mg to 1500 mg, 150 mg to 1200 mg, 200 mg to 1000 mg, 300 mg to 800 mg, 325 mg to 500 mg, 1 mg to 1000 mg, 1 mg to 500 mg, 1 mg to 200 mg, 5 mg to 1000 mg, 5 mg to 500 mg, 5 mg to 200 mg, 10 mg to 1000 mg, 10 mg to 500 mg, 10 mg to 200 mg, 50 mg to 1000 mg, 50 mg to 500 mg, 50 mg to 200 mg, 250 mg to 1000 mg, 250 mg to 500 mg, 500 mg to 1000 mg, 500 mg to 2000 mg. As expected, the dosage will be dependent on the condition,
  • the pharmaceutical composition comprises a single analgesic agent.
  • the single analgesic agent is aspirin.
  • the single analgesic agent is ibuprofen.
  • the single analgesic agent is naproxen or naproxen sodium.
  • the single analgesic agent is indomethacin.
  • the single analgesic agent is nabumetone.
  • the single analgesic agent is acetaminophen.
  • the single analgesic agent is given at a daily dose of 1 mg to 2000 mg, 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg or 500 mg to 1000 mg.
  • the pharmaceutical composition comprises acetylsalicylic acid, ibuprofen, naproxen, naproxen sodium, indomethancin, nabumetone or acetaminophen as a single analgesic agent and the analgesic agent is administered orally at a daily dose in the range of 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg or 500 mg to 1000 mg.
  • a second analgesic agent is given at a daily dose of 1 mg to 2000 mg, 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg or 500 mg to 1000 mg.
  • the pharmaceutical composition comprises a pair of analgesic agents.
  • paired analgesic agents include, but are not limited to, acetylsalicylic acid and ibuprofen, acetylsalicylic acid and naproxen sodium, acetylsalicylic acid and nabumetone, acetylsalicylic acid and acetaminophen, acetylsalicylic acid and indomethancin, ibuprofen and naproxen sodium, ibuprofen and nabumetone, ibuprofen and acetaminophen, ibuprofen and indomethancin, naproxen, naproxen sodium and nabumetone, naproxen sodium and acetaminophen, naproxen sodium and indomethancin, nabumetone and acetaminophen, naproxen sodium and indomethancin, nabumetone and aceta
  • the paired analgesic agents are mixed at a weight ratio in the range of 0.1 : 1 to 10: 1, 0.2: 1 to 5: 1 or 0.3: 1 to 3: 1, with a combined dose in the range of 5 mg to 2000 mg, 20 mg to 2000 mg, 100 mg to 2000 mg, 200 mg to 2000 mg, 500 mg to 2000 mg, 5 mg to 1 00 mg, 20 mg to 1500 mg, 100 mg to 1500 mg, 200 mg to 1500 mg, 500 mg to 1500 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 100 mg to 1000 mg, 250 mg to 500 mg, 250 mg to 1000 mg, 250 mg to 1500 mg, 500 mg to 1000 mg, 500 mg to 1500 mg, 1000 mg to 1500 mg, and 1000 mg to 2000 mg.
  • the paired analgesic agents are mixed at a weight ratio of 1 : 1.
  • the pharmaceutical composition of the present application further comprises one or more antimuscarinic agents.
  • antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, trospium and atropine.
  • the daily dose of antimuscarinic agent is in the range of 0.01 mg to 100 mg, 0.1 mg to 100 mg, 1 mg to 100 mg, 10 mg to 100 mg, 0.01 mg to 25 mg, 0.1 mg to 25 mg, 1 mg to 25 mg, 10 mg to 25 mg, 0.01 mg to 10 mg, 0.1 mg to 10 mg, 1 mg to 10 mg, 10 mg to 100 mg and 10 mg to 25 mg.
  • the pharmaceutical composition comprises an analgesic agent selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen, naproxen sodium, nabumetone, acetaminophen and indomethancin, and an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.
  • an analgesic agent selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen, naproxen sodium, nabumetone, acetaminophen and indomethancin
  • an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.
  • Another aspect of the present application relates to a method for reducing the frequency of urination by administering to a person in need thereof a pharmaceutical composition formulated in an immediate-release formulation.
  • the pharmaceutical composition comprises a plurality of analgesic agents and/or antimuscarinic agents.
  • the pharmaceutical composition comprises two or more analgesic agents. In other embodiments, the pharmaceutical composition comprises one or more analgesic agents and one or more antimuscarinic agents.
  • the pharmaceutical composition may be formulated into a tablet, capsule, dragee, powder, granulate, liquid, gel or emulsion form. Said liquid, gel or emulsion may be ingested by the subject in naked form or contained within a capsule.
  • the analgesic agent is selected from the group consisting of salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, para-aminophenol derivatives, acetanilide, acetaminophen, phenacetin, fenamates, mefenamic acid, meclofenamate, sodium meclofenamate, heteroaryl acetic acid derivatives, tolmetin, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin; enolic acids, oxicam derivatives, piroxicam, meloxicam, tenoxicam, ampiroxicam, droxicam, pivoxicam, pyrazolon
  • the pharmaceutical composition comprises a single analgesic agent and a single antimuscarinic agent.
  • the single analgesic agent is aspirin.
  • the single analgesic agent is ibuprofen.
  • the single analgesic agent is naproxen or naproxen sodium.
  • the single analgesic agent is indomethacin.
  • the single analgesic agent is nabumetone.
  • the single analgesic agent is acetaminophen.
  • the analgesic agent and anti-muscarinic agent may be given at doses in the ranges described above.
  • the pharmaceutical composition comprises one or more analgesic agents, individually or in combination, in an amount between 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-400 mg, 100-250 mg, 250-2000 mg, 250-1500 mg, 250-1200 mg, 250-1000 mg, 250-800 mg, 250-600 mg, 250-400 mg, 400-2000 mg, 400- 1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1500 mg, 1000 mg, 1000
  • the composition is formulated for extended release with a release profile in which at least 90% of the one or more analgesic agents are released continuously over a period of 5-24 hours, 5-8, 8-16 hours or 16-24 hours.
  • the composition is formulated for extended release with a release profile in which the one or more analgesic agents are released continuously over a period of 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
  • the pharmaceutical composition further comprises an antimuscarinic agent, an antidiuretic agent or a spasmolytic.
  • the composition is formulated for extended release with a release profile in which the analgesic agent is released at a steady rate over a period of 5-24 hours, 5-8, 8-16 hours or 16-24 hours.
  • the composition is formulated for extended release with a release profile in which the analgesic agent is released at a steady rate over a period of 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
  • a steady rate over a period of time is defined as a release profile in which the release rate at any point during a given period of time is within 30% - 300% of the average release rate over that given period of time.
  • the pharmaceutical composition further comprises an antimuscarinic agent, an antidiuretic agent or a spasmolytic.
  • the analgesic agent is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, nabumetone and acetaminophen.
  • the pharmaceutical composition is formulated to provide a steady release of small amount of the analgesic agent to maintain an effective drug concentration in the blood such that the overall amount of the drug in a single dosage is reduced compared to the immediate release formulation.
  • the pharmaceutical composition comprises 50-250 mg, 250-400 mg or 400-600 mg of an analgesic agent formulated for extended release with a release profile in which at least 90% of the analgesic agent is released continuously, or at a steady rate, over a period of 5-24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 50- 250 mg of acetaminophen formulated for extended release with a release profile in which at least 90% of acetaminophen is released continuously, or at a steady rate, over a period of 5- 24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 250-400 mg of acetaminophen formulated for extended release with a release profile in which 90%) of acetaminophen is released continuously, or at a steady rate over a period of 5-24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 400-600 mg of acetaminophen formulated for extended release with a release profile in which 90% of acetaminophen is released continuously, or at a steady rate over a period of 5-24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 600-800 mg of acetaminophen formulated for extended release with a release profile in which 90% of acetaminophen is released continuously, or at a steady rate over a period of 5-24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 800- 1000 mg of acetaminophen formulated for extended release with a release profile in which at least 90% of acetaminophen is released continuously, or at a steady rate over a period of 5- 24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises one or more analgesic agent(s), individually or in combination, in an amount between 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50- 300 mg, 50-250 mg, 50-200 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 200-600 mg, 200-400 mg, 400- 2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500
  • the analgesic agent(s) is formulated for extended release with a two-phase release profile in which 20, 30, 40, 50 or 60% of the analgesic agent(s) are released within 2 hours of administration and the remainder are released continuously, or at a steady rate, over a period of 5-8, 8-16 or 16-24 hours.
  • the analgesic agent(s) are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, nabumetone and acetaminophen.
  • the analgesic agent is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, nabumetone and acetaminophen.
  • the analgesic agent is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, nabumetone and acetaminophen
  • the pharmaceutical composition further comprises an antimuscarinic agent, an antidiuretic agent, a spasmolytic, or Zolpidem.
  • the pharmaceutical composition comprises 50-400 mg of acetaminophen formulated for extended release with a two-phase release profile in which 20%, 30%, 40%, 50% or 60% of the acetaminophen is released within 2 hours of administration and the remainder is released continuously, or at a steady rate, over a period of 5-24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 100-300 mg of acetaminophen formulated for extended release with a two-phase release profile in which 20%, 30%, 40% 50% or 60% of the acetaminophen is released within 2 hours of administration and the remainder is released at a steady rate over a period of 5-24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 400-600 mg of acetaminophen formulated for extended release with a two-phase release profile in which 20%, 30%, 40% 50% or 60%> of the acetaminophen is released within 2 hours of administration and the remainder is released continuously, or at a steady rate, in a period of 5- 24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 600-800 mg of acetaminophen formulated for extended release with a two-phase release profile in which 20%>, 30%, 40%) 50% or 60% of the acetaminophen is released within 2 hours of administration and the remainder is released continuously, or at a steady rate, in a period of 5- 24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 800-1000 mg of acetaminophen formulated for extended release with a two-phase release profile in which 20%, 30%, 40% 50% or 60%> of the acetaminophen is released within 2 hours of administration and the remainder is released continuously, or at a steady rate, in a period of 5- 24, 5-8, 8-16 or 16-24 hours.
  • the pharmaceutical composition comprises 1000-1200 mg of acetaminophen formulated for extended release with a two-phase release profile in which 20%), 30%), 40% 50%> or 60%> of the acetaminophen is released within 2 hours of administration and the remainder is released continuously, or at a steady rate, in a period of 5- 24, 5-8, 8-16 or 16-24 hours.
  • Another aspect of the present application relates to a method for treating nocturia by administering to a person in need thereof a first pharmaceutical composition comprising a diuretic, followed with a second pharmaceutical composition comprising one or more analgesic agents.
  • the first pharmaceutical composition is dosed and formulated to have a diuretic effect within 6 hours of administration and is administered at least 8 or 7 hours 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.
  • diuretics include, but are not limited to, acidifying salts, such as CaCl 2 and NH 4 CI; arginine vasopressin receptor 2 antagonists, such as amphotericin B and lithium citrate; aquaretics, such as Goldenrod and Junipe; Na-H exchanger antagonists, such as dopamine; carbonic anhydrase inhibitors, such as acetazolamide and dorzolamide; loop diuretics, such as bumetanide, ethacrynic acid, furosemide and torsemide; osmotic diuretics, such as glucose and mannitol; potassium-sparing diuretics, such as amiloride, spironolactone, triamterene, potassium canrenoate; thiazides, such as bendroflumethiazide and
  • hydrochlorothiazide such as caffeine, theophylline and theobromine.
  • the second pharmaceutical composition further comprises one or more antimuscarinic agents. In some other embodiments, the second pharmaceutical composition further comprises one or more antidiuretic agents. In some other embodiments, the second pharmaceutical composition further comprises one or more spasmolytics. In some other embodiments, the second pharmaceutical composition further comprises Zolpidem.
  • the second pharmaceutical composition may be formulated in immediate-release formulation or delayed-release formulation.
  • Another aspect of the present application relates to a method for reducing the frequency of urination by administering to a subject in need thereof, two or more analgesic agents alternatively to prevent the development of drug resistance.
  • the method comprises administering a first analgesic agent for a first period of time and then administering a second analgesic agent for a second period of time.
  • the method further comprises administering a third analgesic agent for a third period of time.
  • the first, second and third analgesic agents are different from each other and at least one of which is formulated for extended-release or delayed, extended-release.
  • the first analgesic agent is acetaminophen
  • the second analgesic agent is ibuprofen
  • the third analgesic agent is naproxen sodium.
  • the length of each period may vary depending on the subject's response to each analgesic agent. In some embodiments, each period lasts from 3 days to three weeks. In another embodiment, the first, second and third analgesic are all formulated for extended-release or delayed, extended-release.
  • 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.
  • the plurality of active ingredients comprises one or more analgesics, and one or more antidiuretic agents.
  • the plurality of active ingredients comprises one or more analgesics and one or more antimuscarinic agents.
  • the plurality of active ingredients comprises one or more analgesics and zolpedim.
  • the plurality of active ingredients comprises one or more analgesics, one or more antidiuretic agents and one or more antimuscarinic agent.
  • the plurality of active ingredients comprises one or more analgesics, zopedim and one or more antidiuretic agents or one or more antimuscarinic agents.
  • the antimuscarinic agent may be selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.
  • the pharmaceutical composition comprises two different analgesics selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen sodium, naproxen, nabumetone, acetaminophen and indomethancin.
  • the pharmaceutical composition comprises one analgesic selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen sodium, nabumetone, acetaminophen and indomethancin; and an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.
  • analgesic selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen sodium, nabumetone, acetaminophen and indomethancin
  • an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.
  • the pharmaceutical composition of the present application further comprises one or more spasmolytics.
  • spasmolytics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, clonidine analog, and dantrolene.
  • the spasmolytics is used at a daily dose of 1 mg to 1000 mg, 1 mg to 100 mg, 10 mg to 1000 mg, 10 mg to 100 mg, 20 mg to 1000 mg, 20 mg to 800 mg, 20 mg to 500 mg, 20 mg to 200 mg, 50 mg to 1000 mg, 50 mg to 800 mg, 50 mg to 200 mg, 100 mg to 800 mg, 100 mg to 500 mg, 200 mg to 800 mg, and 200 mg to 500 mg.
  • the spasmolytics may be formulated, alone or together with other active ingredient(s) in the pharmaceutical composition, for immediate- release, extended-release, delayed-extended-release or combinations thereof.
  • the pharmaceutical composition comprises one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone and acetaminophen in an amount of 50-400 mg per agent, and one or more antimuscarinic agents selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine in a total amount of 1-25 mg, wherein the pharmaceutical composition is formulated for extended release with a two-phase release profile in which 20-60% of the active ingredients are released within 2 hours of administration, and the remainder of the active ingredients are released continuously, or at a steady rate, in a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.
  • analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone and acetaminophen in an amount of 50
  • the pharmaceutical composition comprises one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone and acetaminophen in an amount of 50-400 mg per agent, and one or more antidiuretic agents selected from the group consisting of antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (e.g., desmopressin argipressin, lypressin, felypressin, ornipressin, terlipressin); vasopressin receptor agonists, atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) receptor (i.e., NPR1, NPR2, NPR3) antagonists (e.g., HS-142-1, isatin, [Asu7,23, aminophen in an
  • compositions are formulated for extended release with a two-phase release profile in which 20-60% of the active ingredients are released within 2 hours of administration, and the remainder are released continuously, or at a steady rate, in a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.
  • the pharmaceutical composition comprises one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen , naproxen sodium, indomethacin, nabumetone and acetaminophen in an amount of 50-400 mg per agent, and one or more spasmolytics selected from the group consisting of carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, clonidine analog, and dantrolene in a total amount of 50-500 mg, wherein the pharmaceutical composition is formulated for extended release with a two-phase release profile in which 20- 60%) of the active ingredients are released within 2 hours of administration, and the remainder are released continuously, or at a steady rate, in a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.
  • analgesic agents selected from the group consisting of aspirin, ibuprofen, nap
  • EXAMPLE 2 EFFECT OF ANALGESIC AGENTS, BOTULINUM NEUROTOXIN AND ANTIMUSCARINIC AGENTS ON MACROPHAGE RESPONSES TO INFLAMMATORY AND NON-INFLAMMATORY STIMULI
  • This study is designed to determine the dose and in vitro efficacy of analgesics and antimuscarinic agents in controlling macrophage response to inflammatory and noninflammatory stimuli mediated by COX2 and prostaglandins (PGE, PGH, etc.). It establishes baseline (dose and kinetic) responses to inflammatory and non-inflammatory effectors in bladder cells. Briefly, cultured cells are exposed to analgesic agents and/or antimuscarinic agents in the absence or presence of various effectors.
  • the effectors include: lipopolysaccharide (LPS), an inflammatory agent and Cox2 inducer, as inflammatory stimuli; carbachol or acetylcholine, a stimulator of smooth muscle contraction, as non-inflammatory stimuli; botulinum neurotoxin A, a known inhibitor of acetylcholine release, as positive control; and arachidonic acid (AA), gamma linolenic acid (DGLA) or eicosapentaenoic acid (EPA) as precursors of prostaglandins, which are produced following the sequential oxidation of AA, DGLA or EPA inside the cell by cyclooxygenases (COX1 and COX2) and terminal prostaglandin synthases.
  • LPS lipopolysaccharide
  • COX1 and COX2 cyclooxygenases
  • the analgesic agents include: Salicylates such as aspirin, iso-butyl-propanoic- phenolic acid derivative (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 derivative such as
  • indomethacin Indocin
  • l-naphthaleneacetic acid derivative such as nabumetone or relafen
  • APAP N-acetyl-para-aminophenol
  • Tetaminophen or paracetamol Teylenol
  • Celecoxib N-acetyl-para-aminophenol
  • the antimuscarinic agents include: oxybutynin, solifenacin, darifenacin and atropine.
  • Macrophages are subjected to short term (1-2 hrs) or long term (24-48 hrs) stimulation with:
  • Each analgesic agent at various doses in the presence of AA, DGLA, or EPA.
  • Botulinum neurotoxin A at various doses in the presence of carbachol or acetylcholine.
  • Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA.
  • the cells are then analyzed for the release of PGH 2 , PGE, PGE 2 , Prostacydin, Thromboxane, IL- ⁇ ⁇ , IL-6, TNF-a, the COX2 activity, the production of cAMP and cGMP, the production of IL- ⁇ ⁇ , IL-6, TNF-a and COX2 mRNA, and surface expression of CD80, CD86 and MHC class II molecules.
  • Murine RAW264.7 or J774 macrophage cells were used in this study. Cells were maintained in a culture medium containing RPMI 1640 supplemented with 10 % fetal bovine serum (FBS), 15 mM HEPES, 2 mM L-glutamine, 100 U/ml penicillin, and 100 ⁇ g / ml of streptomycin. Cells were cultured at 37° C in a 5 % C0 2 atmosphere and split (passages) once a week.
  • FBS fetal bovine serum
  • HEPES 15 fetal bovine serum
  • 2 mM L-glutamine 100 U/ml penicillin
  • streptomycin 100 ⁇ g / ml of streptomycin
  • RAW264.7 macrophage cells were seeded in 96-well plates at a cell density of 1.5xl0 5 cells per well in 100 ⁇ of the culture medium.
  • the cells were treated with (1) various concentrations of analgesic (acetaminophen, aspirin, ibuprophen or naproxen), (2) various concentrations of lipopolysaccharide (LPS), which is an effector of inflammatory stimuli to macrophage cells, (3) various concentrations of carbachol or acetylcholine, which are effectors of non-inflammatory stimuli, (4) analgesic and LPS or (5) analgesic and carbachol or acetylcholine.
  • analgesic acetaminophen, aspirin, ibuprophen or naproxen
  • LPS lipopolysaccharide
  • carbachol or acetylcholine which are effectors of non-inflammatory stimuli
  • analgesic and LPS or (5) analgesic and carbachol or
  • the analgesics were dissolved in FBS-free culture medium (i.e., RPMI 1640 supplemented with 15 mM HEPES, 2 mM L-glutamine, 100 U / ml penicillin, and 100 ⁇ / ml of streptomycin), and diluted to desired concentrations by serial dilution with the same medium.
  • FBS-free culture medium i.e., RPMI 1640 supplemented with 15 mM HEPES, 2 mM L-glutamine, 100 U / ml penicillin, and 100 ⁇ / ml of streptomycin
  • macrophages were diluted in 100 ⁇ of FACS buffer (phosphate buffered saline (PBS) with 2% bovine serum albumin (BSA) and 0.01% NaN 3 ) and stained 30 min at 4°C by addition of FITC-conjugated anti-CD40, PE-conjugated anti-CD80, PE-conjugated anti-CD86 antibody, anti MHC class II (I-A d ) PE (BD
  • the colorimetric reaction was developed by the addition of 2,2'-azino-bis (3)- ethylbenzylthiazoline-6-sulfonic acid (ABTS) substrate and H2Q2 (Sigma) and the absorbance measured at 415 nm with a Victor ® V multilabel plate reader (PerkinElmer).
  • ABTS 2,2'-azino-bis (3)- ethylbenzylthiazoline-6-sulfonic acid
  • H2Q2 Sigma
  • COX2 activity in the cultured macrophages is determined by sequential competitive ELISA (R&D Systems).
  • the production of cAMP and cGMP is determined by the cAMP assay and cGMP assay. These assays are performed routinely in the art.
  • Table 1 summarizes the experiments performed with Raw 264 macrophage cell line and main findings in terms of the effects of analgesics on cell surface expression of costimulatory molecules CD40 and CD80. Expression of these molecules is stimulated by COX2 and inflammatory signals and thus, was evaluated to determine functional consequences of inhibition of COX2.
  • acetaminophen, aspirin, ibuprophen and naproxen inhibit basal expression of co-stimulatory molecules CD40 and CD80 by macrophages at all the tested doses ⁇ i.e., 5x 10 5 nM, 5x 10 4 nM, 5x 10 3 nM, 5x 10 2 nM, 50 nM and 5 nM), except for the highest dose ⁇ i.e., 5x 10 6 nM), which appears to enhance, rather than inhibit, expression of the co-stimulatory molecules.
  • CD40, CD80, CD86 and MHC class II CD40, CD80, CD86 and MHC class II
  • Table 3 summarizes the results of several studies that measured serum levels of analgesic after oral therapeutic doses in adult humans. As shown in Table 3, the maximum serum levels of analgesic after an oral therapeutic dose are in the range of 10 4 to 10 5 nM. Therefore, the doses of analgesic tested in vitro in Table 2 cover the range of concentrations achievable in vivo in humans.
  • EXAMPLE 3 EFFECT OF ANALGESIC AGENTS. BOTULINUM NEUROTOXIN AND ANTIMUSCARINIC AGENTS ON MOUSE BLADDER SMOOTH MUSCLE CELL RESPONSES TO INFLAMMATORY AND NON-INFLAMMATORY STIMULI
  • Example 2 This study is designed to characterize how the optimal doses of analgesics determined in Example 2 affect bladder smooth muscle cells in cell culture or tissue cultures, and to address whether different classes of analgesics can synergize to more efficiently inhibit COX2 and PGE2 responses.
  • Each analgesic agent at various doses in the presence of AA, DGLA, or EPA.
  • Botulinum neurotoxin A at various doses in the presence of carbachol or acetylcholine.
  • Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA.
  • the cells are then analyzed for the release of PGH 2 , PGE, PGE 2 , Prostacydin, Thromboxane, IL- ⁇ ⁇ , IL-6, TNF-a, the COX2 activity, the production of cAMP and cGMP, the production of IL- ⁇ ⁇ , IL-6, TNF-a and COX2 mRNA, and surface expression of CD80, CD86 and MHC class II molecules.
  • Bladder cells were removed from euthanized animals C57BL/6 mice (8-12 weeks old) and cells were isolated by enzymatic digestion followed by purification on a Percoll gradient. Briefly, bladders from 10 mice were minced with scissors to fine slurry in 10 ml of digestion buffer (RPMI 1640, 2% fetal bovine serum, 0.5 mg/ml collagenase, 30 ⁇ g/ml DNase). Bladder slurries were enzymatically digested for 30 minutes at 37°C.
  • digestion buffer RPMI 1640, 2% fetal bovine serum, 0.5 mg/ml collagenase, 30 ⁇ g/ml DNase.
  • bladder cells were resuspended RPMI 1640 supplemented with 10 % fetal bovine serum, 15 mM HEPES, 2 mM L-glutamine, 100 U/ml penicillin, and 100 ⁇ g / ml of streptomycin and seeded in clear-bottom black 96-well cell culture microculture plates at a cell density of 3xl0 4 cells per well in 100 ⁇ . Cells were cultured at 37° C in a 5 % C0 2 atmosphere. In vitro treatment of cells with analgesics
  • Bladder cells were treated with analgesic solutions (50 ⁇ / well) either alone or together with carbachol (10-Molar, 50 ⁇ / well), as an example of non-inflammatory stimuli, or lipopolysaccharide (LPS) of Salmonella typhimurium (1 ⁇ g/ml, 50 ⁇ / well), as an example of non-inflammatory stimuli.
  • analgesic solutions 50 ⁇ / well
  • carbachol 10-Molar, 50 ⁇ / well
  • LPS lipopolysaccharide
  • Salmonella typhimurium 1 ⁇ g/ml, 50 ⁇ / well
  • COX2 responses were analyzed by a Cell-Based ELISA using Human/mouse total COX2 immunoassay (R&D Systems), following the instructions of the manufacturer. Briefly, after cells fixation and permeabilization, a mouse anti-total COX2 and a rabbit anti- total GAPDH were added to the wells of the clear-bottom black 96-well cell culture microculture plates. After incubation and washes, an HRP-conjugated anti-mouse IgG and an AP-conjugated anti-rabbit IgG were added to the wells. Following another incubation and set of washes, the HRP- and AP-fluorogenic substrates were added.
  • R&D Systems Human/mouse total COX2 immunoassay
  • Prostaglandin E2 responses were analyzed by a sequential competitive ELISA (R&D Systems). More specifically, culture supernatants or PGE2 standards were added to the wells of a 96-well polystyrene microplate coated with a goat anti-mouse polyclonal antibody. After one hour incubation on a microplate shaker, an HRP-conjugated PGE2 was added and plates incubated for an additional two hours at room temperature. The plates were then washed and HRP substrate solution added to each well. The color was allowed to develop for 30 min and the reaction stopped by addition sulfuric acid before reading the plate at 450 nm with wavelength correction at 570 nm. Results are expressed as mean pg/ml of PGE2. Other assays
  • Analgesics inhibit COX2 responses of mouse bladder cells to an inflammatory stimulus
  • Analgesics inhibit PGE2 responses of mouse bladder cells to an inflammatory stimulus
  • mice bladder smooth muscle cells are subjected to short term (1-2 hrs) or long term (24-48 hrs) stimulation with:
  • Each analgesic agent at various doses in the presence of AA, DGLA, or EPA.
  • Botulinum neurotoxin A at various doses in the presence of carbachol or acetylcholine.
  • Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA.
  • EXAMPLE 5 EFFECT OF ORAL ANALGESIC AGENTS AND ANTIMUSCARINIC AGENTS ON COX2 AND PGE2 RESPONSES OF MOUSE BLADDER SMOOTH MUSCLE CELLS.
  • mice and mice with over active bladder syndrome are given oral doses of aspirin, naproxen sodium, ibuprofen, Indocin, nabumetone, Tylenol, Celecoxib, oxybutynin, solifenacin, darifenacin, atropine and combinations thereof.
  • Control groups include untreated normal mice and untreated OAB mice with over active bladder syndrome.
  • the bladders are collected and stimulated ex vivo with carbachol or acetylcholine.
  • the bladders are treated with botulinum neurotoxin A before stimulation with carbachol. Animals are maintained in metabolic cages and frequency (and volume) of urination are evaluated.
  • Bladder outputs are determined by monitoring water intake and cage litter weight. Serum PGH 2 , PGE, PGE 2 , Prostacydin, Thromboxane, IL- ⁇ ⁇ , IL-6, TNF-a, cAMP, and cGMP levels are determined by ELISA. CD80, CD86, MHC class II expression in whole blood cells are determined by flow cytometry.
  • EXAMPLE 6 EFFECT OF ANALGESIC AGENTS, BOTULINUM NEUROTOXIN AND ANTIMUSCARINIC AGENTS ON HUMAN BLADDER SMOOTH MUSCLE CELL RESPONSES TO INFLAMMATORY AND NON-INFLAMMATORY STIMULI
  • Human bladder smooth muscle cells are subjected to short term (1-2 hrs) or long term (24-48 hrs) stimulation with:
  • Each analgesic agent at various doses in the presence of AA, DGLA, or EPA.
  • Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA.
  • the cells are then analyzed for the release of PGH 2 , PGE, PGE 2 , Prostacydin, Thromboxane, IL- ⁇ , IL-6, TNF-a, the COX2 activity, the production of cAMP and cGMP, the production of IL- ⁇ ⁇ , IL-6, TNF-a and COX2 mRNA, and surface expression of CD80, CD86 and MHC class II molecules.
  • EXAMPLE 7 EFFECT OF ANALGESIC AGENTS, BOTULINUM NEUROTOXIN AND ANTIMUSCARINIC AGENTS ON HUMAN BLADDER SMOOTH MUSCLE CELL CONTRACTION.
  • Human bladder smooth muscle cells are subjected to short term (1-2 hrs) or long term (24-48 hrs) stimulation with:
  • Each analgesic agent at various doses in the presence of AA, DGLA, or EPA.
  • Botulinum neurotoxin A at various doses in the presence of carbachol or acetylcholine.
  • EXAMPLE 8 EFFECT OF ANALGESIC AGENTS ON NORMAL HUMAN BLADDER SMOOTH MUSCLE CELL RESPONSES TO INFLAMMATORY AND NON INFLAMMATORY SIGNALS EXPERIMENTAL DESIGN
  • Bladder smooth muscle cells trypsinized and seeded in microculture plates at a cell density of 3x10 4 cells per well in 100 ⁇ were treated with analgesic solutions (50 ⁇ / well) either alone or together carbachol (10-Molar, 50 ⁇ / well), as an example of noninflammatory stimuli, or lipopolysaccharide (LPS) of Salmonella typhimurium (1 ⁇ g/ml, 50 ⁇ / well), as an example of non-inflammatory stimuli.
  • analgesic solutions 50 ⁇ / well
  • carbachol (10-Molar, 50 ⁇ / well) as an example of noninflammatory stimuli
  • lipopolysaccharide (LPS) of Salmonella typhimurium (1 ⁇ g/ml, 50 ⁇ / well
  • Analgesics inhibit COX2 responses of normal human bladder smooth muscle cells to inflammatory and non- inflammatory stimuli - Analysis of cells and culture supernatants after 24 hours of cultures showed that none of the analgesics tested alone induced COX2 responses in normal human bladder smooth muscle cells. However, as summarized in Table 6, carbachol induced low, but significant COX2 responses in normal human bladder smooth muscle cells. On the other hand, LPS treatment resulted in higher levels of COX2 responses in normal human bladder smooth muscle cells. Acetaminophen, aspirin, ibuprofen and naproxen could all suppress the effect of carbachol and LPS on COX2 levels. The suppressive effect of the analgesics was seen on LPS-induced responses when these drugs were tested at either 5 ⁇ or 50 ⁇ .
  • Analgesics inhibit PGE2 responses of normal human bladder smooth muscle cells to inflammatory and non- inflammatory stimuli - Consistent with the induction of COX2 responses described above, both carbachol and LPS induced production of PGE2 by normal human bladder smooth muscle cells. Acetaminophen, aspirin, ibuprofen and naproxen were also found to suppress the LPS-induced PGE2 responses at either 5 ⁇ or 50 ⁇ (Table 7). Table 7. PGE2 secretion by normal human bladder smooth muscle cells after in vitro stimulation with inflammatory and non- inflammatory stimuli and treatment with analgesic
  • Analgesics inhibit cytokine responses of normal human bladder cells to inflammatory stimuli - Analysis of cells and culture supernatants after 24 hours of culture showed that none of the analgesics tested alone induced IL-6 or TNFa secretion in normal human bladder smooth muscle cells. As shown in Tables 8 and 9, the doses of carbachol tested induced low, but significant TNFa and IL-6 responses in normal human bladder smooth muscle cells. On the other hand, LPS treatment resulted in massive induction of these proinflammatory cytokines. Acetaminophen, aspirin, ibuprofen and naproxen suppress the effect of carbachol and LPS on TNFa and IL-6 responses. The suppressive effect of the analgesics on LPS-induced responses was seen when these drugs were tested at either 5 ⁇ or 50 ⁇ .

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Abstract

L'invention concerne des procédés et des compositions pour réduire la fréquence de miction. Un procédé consiste à administrer à un sujet en ayant besoin une quantité efficace d'une composition pharmaceutique comprenant un agent analgésique formulé dans une formulation à libération prolongée. Un autre procédé consiste à administrer à un sujet en ayant besoin une quantité efficace d'une composition pharmaceutique comprenant de multiples principes actifs formulés pour une libération prolongée.
EP13763764.1A 2012-03-19 2013-03-13 Formulation à libération prolongée pour réduire la fréquence de miction et son procédé d'utilisation Withdrawn EP2827852A4 (fr)

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Application Number Priority Date Filing Date Title
US13/424,000 US8236857B2 (en) 2010-07-08 2012-03-19 Extended-release formulation for reducing the frequency of urination and method of use thereof
US13/487,348 US20120244221A1 (en) 2010-07-08 2012-06-04 Extended-release formulation for reducing the frequency of urination and method of use thereof
PCT/US2013/030901 WO2013142197A1 (fr) 2012-03-19 2013-03-13 Formulation à libération prolongée pour réduire la fréquence de miction et son procédé d'utilisation

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AU (4) AU2013235518B2 (fr)
BR (2) BR112014020271A8 (fr)
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HK (3) HK1251469A1 (fr)
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NZ (6) NZ714288A (fr)
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KR101809908B1 (ko) * 2014-07-21 2018-01-25 주식회사 종근당 5-알파환원효소억제제를 포함하는 조성물
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EP3355864A4 (fr) * 2015-09-30 2019-05-22 Wellesley Pharmaceuticals, LLC Composition pour réduire la fréquence de la miction, procédé de fabrication et d'utilisation de celle-ci
WO2017058436A1 (fr) * 2015-09-30 2017-04-06 Wellesley Pharmaceuticals, Llc Composition pour réduire la fréquence de la miction, procédé de fabrication et d'utilisation de celle-ci
CN105238124B (zh) * 2015-11-16 2018-02-09 太仓东能环保设备有限公司 一种抗菌腻子粉
JP6294924B2 (ja) 2016-09-05 2018-03-14 株式会社Ｓｕｂａｒｕ 車両の走行制御装置

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RU2016133305A3 (fr) 2018-12-10
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MX2014011129A (es) 2015-08-10
AU2013235507A1 (en) 2014-08-21
AU2017203246B2 (en) 2018-10-18
MY174090A (en) 2020-03-09
AU2013235518A2 (en) 2014-10-09
CN104302284A (zh) 2015-01-21
JP2015510928A (ja) 2015-04-13
RU2014142066A (ru) 2016-05-10
WO2013142274A1 (fr) 2013-09-26
MX2019008817A (es) 2019-09-26
CN107157991A (zh) 2017-09-15
EP2827852A4 (fr) 2016-03-02
NZ630471A (en) 2016-04-29
KR20140134284A (ko) 2014-11-21
BR112014020113A2 (fr) 2017-06-20
RU2599017C2 (ru) 2016-10-10
CN107789626A (zh) 2018-03-13
HK1243921A1 (zh) 2018-07-27
NZ714288A (en) 2016-12-23
CA2866853A1 (fr) 2013-07-26
JP2018024693A (ja) 2018-02-15
NZ714662A (en) 2016-08-26
AU2017203139B2 (en) 2018-07-19
ZA201406146B (en) 2016-08-31
MY175764A (en) 2020-07-08
SG11201500409SA (en) 2015-03-30
RU2016133305A (ru) 2018-12-10
MX2014011128A (es) 2015-08-10
JP2016172752A (ja) 2016-09-29
AU2017203139A1 (en) 2017-06-01
BR112014020113A8 (pt) 2017-07-11
EP2827851A4 (fr) 2015-10-14
KR20170015537A (ko) 2017-02-08
NZ628079A (en) 2016-05-27
AU2017203246A1 (en) 2017-06-08
WO2013142197A1 (fr) 2013-09-26
BR112014020271A2 (fr) 2017-06-20
NZ718163A (en) 2017-09-29
HK1251469A1 (zh) 2019-02-01
HK1204553A1 (en) 2015-11-27
KR20140134333A (ko) 2014-11-21
JP2018138602A (ja) 2018-09-06
RU2669565C2 (ru) 2018-10-12
CA2866755A1 (fr) 2013-09-26
KR20190003840A (ko) 2019-01-09
NZ712594A (en) 2016-09-30
AU2013235518B2 (en) 2017-03-02
EP2827851A1 (fr) 2015-01-28
RU2014142025A (ru) 2016-05-10
AU2013235507B2 (en) 2017-03-23
BR112014020271A8 (pt) 2017-07-11
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CN104321056A (zh) 2015-01-28
ZA201405862B (en) 2016-08-31

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