WO2016048301A1 - Pharmaceutical formulation for reducing bladder spasms and method of use thereof - Google Patents
Pharmaceutical formulation for reducing bladder spasms and method of use thereof Download PDFInfo
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- WO2016048301A1 WO2016048301A1 PCT/US2014/057200 US2014057200W WO2016048301A1 WO 2016048301 A1 WO2016048301 A1 WO 2016048301A1 US 2014057200 W US2014057200 W US 2014057200W WO 2016048301 A1 WO2016048301 A1 WO 2016048301A1
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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
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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
- A61K31/16—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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- 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
- A61K31/60—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- 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
- A61P13/06—Anti-spasmodics
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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
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Definitions
- the present application generally relates to methods and compositions for reducing the occurrence and/or frequency of bladder spasms.
- 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.
- a spasm itself is the sudden, involuntary squeezing of a muscle.
- a bladder spasm or "detrusor contraction,” occurs when the bladder muscle squeezes suddenly without warning, causing an urgent need to release urine.
- the spasm can force urine from the bladder, causing leakage and may be accompanied by extreme pain.
- the bladder randomly contracts, as though the patient is about to urinate. The patient feels like he or she needs to urinate, and some leakage may occur.
- the spasms may be violent, with patients comparing them to cramps.
- Bladder spasms are particularly common in the elderly, but can also occur in young children and pregnant women as well as animals. Bladder spasms may interfere with normal activities, including the ability to sleep for sufficient uninterrupted periods of rest.
- One aspect of the present application relates to a method for reducing bladder spasms in a subject.
- the method comprises administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of acetaminophen and an effective amount of at least one non-steroidal anti-inflammatory agent (NSAED).
- NSAED non-steroidal anti-inflammatory agent
- Another aspect relates to a method for reducing bladder spasms in a subject comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of at least one prostaglandin (PG) pathway inhibitor, wherein the at least one PG pathway inhibitor is not acetaminophen or an NSAID.
- PG prostaglandin
- Another aspect relates to a pharmaceutical composition for treating bladder spasms comprising acetaminophen; one or more NSAIDs; and a pharmaceutically acceptable carrier.
- a further aspect relates to a pharmaceutical composition for treating bladder spasms comprising one or more PG pathway inhibitors; and a pharmaceutically acceptable carrier.
- Figures 1A and IB are diagrams showing that analgesics regulate expression of co-stimulatory molecules by Raw 264 macrophage cells in the absence ( Figure 1 A) or presence ( Figure IB) of LPS.
- Cells were cultured 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.
- blade spasm refers to a sudden, involuntary squeezing of a detrusor muscle.
- the term “bladder spasm” refers to a sudden, involuntary squeezing of a detrusor muscle accompanied by pain.
- the term “bladder spasm” is differentiable from the term “urinary incontinences” which generally refers to involuntary leakage of urine, or the term “overactive bladder” which generally refers to problems with bladder-storage function that cause a sudden urge to urinate.
- NSAID is an acronym for "non-steroidal antiinflammatory drug” and is a therapeutic agent with analgesic, antipyretic (lowering an elevated body temperature and relieving pain without impairing consciousness) and, in higher doses, with anti-inflammatory effects (reducing inflammation).
- non-steroidal is used to distinguish these drugs from steroids, which (among a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action.
- analgesics NSAIDs are unusual in that they are non-narcotic. NSAIDs include aspirin, ibuprofen, and naproxen.
- NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs are generally indicated for the symptomatic relief of the following conditions: rheumatoid arthritis, osteoarthritis, inflammatory arthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic). Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and
- cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes the formation of
- Prostaglandins and thromboxane from arachidonic acid act (among other things) as messenger molecules in the process of inflammation.
- COX-2 inhibitors include celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib.
- prostaglandin refers to a group of lipid compounds that are derived enzymatically from fatty acids and have a variety of physiological effects, such as regulating the contraction and relaxation of smooth muscle tissue in a subject. Every
- prostaglandin contains 20 carbon atoms, including a 5-carbon ring.
- Examples of prostaglandin include, prostaglandin Ei (PGEj), prostaglandin E 2 (PGE 2 ), Prostaglandin D 2 , prostaglandin I 2 (PGI 2 , prostacyclin), and prostaglandin F 2a (PGF 2a ).
- PG pathway inhibitor refers to agents that interact directly or indirectly with one or more components involved in the synthesis or action of PG on a target tissue, and interfere with either the levels or the ultimate actions of prostaglandin on the target tissue.
- PG pathway inhibitors include, but are not limited to, PG inhibitors, prostaglandin transporter (PGT) inhibitors and prostaglandin receptor (PGR) inhibitors.
- PTT prostaglandin transporter
- PGR prostaglandin receptor
- PG inhibitors include but are not limited to, inhibitors of PG synthesis and inhibitors of PG activity.
- inhibitors of PG synthesis refers to agents that inhibit the production of prostaglandin, such as agents that inhibit the expression or activity of phospholipase A2, the prostaglandin synthases and the tissue specific isomerases and synthase enzymes such as: thromboxane synthase, PGF synthase, cytosolic PG synthase (cPGES), prostaglandin I synthase (PGIS) and the microsomal PGES enzymes (mPGES).
- Examples of PG synthesis inhibitors include flunixin meglumine.
- the term “inhibitors of PG synthesis” or "PG synthesis inhibitors” does not include the analgesics or NSAIDs defined herein.
- inhibitors of PG activity refers to agents that antagonize the action of prostaglandin itself by any means. Agents that interfere solely with the synthesis of prostaglandins, such as by interfering with the action of prostaglandin synthases, but which do not interfere with the action of prostaglandins are not included within the definition of inhibitors of PG activity as used in this specification.
- PTT inhibitors refers to agents that inhibits the expression or the activity of PG transporters, such as ATP dependent multi-drug resistance
- MDR transporter-4 or other MDR channels, such as ABCC1, ABCC2, ABCC3, ABCC6,
- PGT inhibitors that inhibit PGT activity include, but are not limited to, compounds that inhibit MDR membrane pumps, such as triazine compounds, verapamil, and calcium channel blockers; channels include quinidines, ketoconazole, itraconazole, azithromycin, valspodar, cyclosporine, elacridar, fumitremorgin-C, gefitinib and erythromycin.
- PGT inhibitors that inhibit PGT expression include, but are not limited to, agents which control the transcription of the MDR genes by targeting the promoter region and/or transcription factors which bind to the promoter or other gene control regions.
- PGR inhibitors refers to agents that inhibits the activity or expression of PGRs.
- the PGRs comprise E prostanoid receptor (EP)1,
- EP2, EP3, and EP4 subtypes of the PGE receptor PGD receptor (DPI); PGF receptor (FP); PGI receptor (IP); and thromboxane receptor (TP).
- DPI DPI
- FP PGF receptor
- IP PGI receptor
- TP thromboxane receptor
- PGR activity inhibitors include, but are not limited to, anti-PGR antibodies and any agent that inhibits the G-protein coupled receptor signaling pathway PGR expression inhibitors include agents that inhibit PGR expression at the transcriptional level, translational level or post transcriptional level.
- PGR expression inhibitors include, but are not limited to, anti-PGR siRNA and miRNAs.
- 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 antiinflammatory agents, compounds or drugs include, but are not limited to, non-steroidal antiinflammatory 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, oxapro
- NSAIDs non-steroidal
- coxib refers to a compound or composition of compounds that is capable of inhibiting the activity or expression of COX1 and COX2 enzymes.
- 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, or protecting groups such as a benzyl group for an alcohol or thiol, or a 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.
- the term "pharmaceutically acceptable salts” refers 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 quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such
- conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like and the salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluensulfonic acid, methanesulfonic acid, ethane dislfonic acid, oxalic acid, isethionic acid, and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, n
- 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.
- 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.
- immediate-release is used with reference to a drug formulation that release the active ingredient in less than 10 min, 20 min, 30 min, 40 min 50 min, 60 min, 90 min or 120 min after administration into a patient.
- extended-release also known as sustained-release
- SR sustained-action
- S A time-release
- TR time-release
- CR controlled-release
- MR modified release
- CR continuous-release
- extended-release tablets or capsules refers to a mechanism used in medicine tablets or capsules to dissolve slowly and release the active ingredient over time.
- 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
- extended-release refers to a release profile that the active ingredient in a tablet or capsule is released over a period of 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22 or 24 hours, either continuously or in pulses after administration into a patient.
- the term "delayed-release” refers to a drug release profile that the release of the active ingredient(s) of a pharmaceutical composition is delayed or postponed for a given period of time (e.g. , 1, 2, 3, 4 or 5 hours) after administration of the pharmaceutical composition.
- the term "delayed-extended-release” refers to a drug release profile that the release of the active ingredient(s) of a pharmaceutical composition is delayed or postponed for a given period of time (e.g. , the lag period of 1, 2, 3, 4 or 5 hours, or after stomach) after administration of the pharmaceutical composition. Once the release starts, the active ingredient(s) is released slowly over time (e.g., over a period of 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22 or 24 hours), either continuously or in pulses.
- orally disintegrating formulation refers to drug formulations that rapidly disintegrate or dissolve in oral cavity. Orally disintegrating
- formulations differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole.
- the orally disintegrating formulations are designed to completely disintegrate or dissolve in oral cavity without the aid of additional water (i.e., in saliva only) in 5, 10, 20, 30, 60, 90, 120, 180, 240 or 300 seconds.
- One aspect of the present application relates to a method for reducing bladder spasms by administering to a subject in need thereof effective amounts of acetaminophen and at least one non-steroidal anti-inflammatory drug (NSAIDs).
- Other aspects of the present application relate to methods for treating urinary incontinence and/or overactive bladder by administering to a subject in need thereof effective amounts of acetaminophen and at least one non-steroidal anti-inflammatory drug (NSAIDs).
- NSAIDs can be classified based on their chemical structure or mechanism of action into the following groups: i) propionic acid derivatives, such as alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbuprofen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, ioxoprofen, ketoprofen, loxoprofen, microprofen, naproxen, oxaprozin, oxoprofen, pranoprofen, suproprofen, tiaprofen, tioxaprofen, zaltoprofen and salts thereof; ii) salicylic acid derivatives, such as aspirin, choline magnesium trisalicayate, diflunisal, olsalazine, salsalate, and sulfasalazine and
- Exemplary NSAIDS include, but are not limited to aceclofenac, acemetacin alminoprofen, aloxiprin, ampiroxicam, amtolmetin guacil, aspirin, azapropazone, benorilate, benoxaprofen, benzydamine hydrochloride, bromfenac, bromfenal, bufexamac, butibufen, carprofen, celecoxib, choline magnesium trisalicayate, clonixin, darbufelone, desoxysulindac, dexketoprofen, diclofenac, diflunisal, dipyone, droxicam, etodolac, etofenamate, etoricoxib, felbinac, fenbufen, fenoprofen, fentiazac, fepradinol, firocoxib, floctafenine, flufenamic
- the subject prior to administration, may be diagnosed as having a condition characterized by bladder spasms, wherein the subject may be prescribed a pharmaceutical composition in accordance with the present invention.
- the pharmaceutical composition includes one or more prostaglandin (PG) pathway inhibitors.
- PG pathway inhibitor is an inhibitor of PG synthetase.
- inhibitors of PG synthesis include non-steroidal antiinflammatory drugs (NSAIDs).
- the one or more PG pathway inhibitors include an inhibitor of PG activity.
- inhibitors of PG activity include, but are not limited to agents which block the binding of PG to any of its receptors: EP1, EP2, EP3, EP4. DPI, DP2, FP2, ⁇ and TP.
- examples of such inhibitors include, but are not limited to, the ⁇ receptor inhibitor developed by Roche: RO3244019, ONO-85-39 which is an EP1 receptor antagonist, the dual EP1 and EP2 receptor antagonist AH 6809, and the EP4 antagonist, RQ- 15986.
- the one or more PG pathway inhibitors include a PGT inhibitor.
- the PGT inhibitor is a PGT activity inhibitor.
- PGT activity inhibitor include, but are not limited to, anti-PGT antibodies, and any known compound which can inhibit the ATP-dependent Multi drug resistance transporter-4 or related MDR pumps that are shown to transport PGs.
- the PGT inhibitor is a PGT expression inhibitor.
- PGT expression inhibitor include, but are not limited to, anti-PGT siRNA, antisense RNAs that target PGT mRNA, and agents which control the transcription of the gene by influencing DNA methylation and or chromatin modification.
- the one or more PG pathway inhibitors include an inhibitor that targets both the COX active site and the POX active site which are contained in both COXl and COX2. In other embodiments, the one or more PG pathway inhibitors comprise an inhibitor that inhibits the PGE 2 pathway.
- the one or more PG pathway inhibitors include a PGR inhibitor.
- PGRs are G-protein-coupled receptors containing seven transmembrane domains. Examples of PGR include, EP1, EP2, EP3, EP4, DPI, DP2, FP, IP1, ⁇ 2, CRTH2 and TP receptors.
- the one or more PG pathway inhibitors comprise an inhibitor that inhibits any of the PG receptors listed above.
- the PGR inhibitor is a PGR activity inhibitor. Examples of PGR activity inhibitor include, but are not limited to, anti- PGR antibodies.
- the PGR inhibitor is an inhibitor of PGE2 receptor activity, such as EP1 activity inhibitor, EP2 activity inhibitor, EP3 activity inhibitor or EP4 activity inhibitor.
- the one or more PG pathway inhibitors include a PGR expression inhibitor.
- PGR expression inhibitor include, but are not limited to, anti- PGR siRNA, antisense RNAs that target PGR mRNA, or agents which control the transcription of the gene by influencing DNA methylation and or chromatin modification.
- the one or more PG pathway inhibitors include an inhibitor of PGE2 receptor expression, such as EP1 expression inhibitor, EP2 expression inhibitor, EP3 expression inhibitor or EP4 expression inhibitor.
- the one or more PG pathway inhibitors comprise a small molecule inhibitor.
- small molecule inhibitor refers to inhibitors having a molecular weight of 1000 daltons or less.
- the one or more PG pathway inhibitors include a short interfering RNA (siRNA).
- siRNA is a double-stranded RNA that can be engineered to induce sequence-specific post-transcriptional gene silencing of rnRNAs corresponding to a component of the PG pathway.
- siRNAs exploit the mechanism of RNA interference (RNAi) for the purpose of "silencing" gene expression of e.g., targeted PGE 2 receptor genes.
- RNAi RNA interference
- dsRNA small interfering RNAs
- siRNAs double stranded small interfering RNAs 21-23 nucleotides in length containing 2 nucleotide overhangs on their 3' ends.
- RISC RNAi induced silencing complex
- the one or more PG pathway inhibitors include a synthetic siRNA or other class of small RNA targeting a PG synthase RNA, a PGT RNA or a PGR RNA in the target cell/tissue.
- Synthetically produced siRNAs structurally mimic the types of siRNAs normally processed in cells by the enzyme Dicer.
- Synthetically produced siRNAs may incorporate any chemical modifications to the RNA structure that are known to enhance siRNA stability and functionality. For example, in some cases, the siRNAs may be synthesized as a locked nucleic acid (LNA)-modified siRNA.
- LNA locked nucleic acid
- An LNA is a nucleotide analogue that contains a methylene bridge connecting the 2'-oxygen of the ribose with the 4'-carbon.
- the bicyclic structure locks the furanose ring of the LNA molecule in a 3'-endo conformation, thereby structurally mimicking the standard RNA monomers.
- the one or more PG pathway inhibitors include an expression vector engineered to transcribe a short double-stranded hairpin-like RNA (shRNA) that is processed into a targeted siRNA inside the cell.
- shRNAs can be cloned in suitable expression vectors using kits, such as Ambion's SILENCER ® siRNA Construction Kit, Imgenex's GENESUPPRESSORTM Construction Kits and Invitrogen's BLOCK-ITTM inducible RNAi plasmid and lentivirus vectors.
- kits such as Ambion's SILENCER ® siRNA Construction Kit, Imgenex's GENESUPPRESSORTM Construction Kits and Invitrogen's BLOCK-ITTM inducible RNAi plasmid and lentivirus vectors.
- Synthetic siRNAs and shRNAs may be designed using well known algorithms and synthesized using a conventional DNA/RNA synthesizer.
- the secondary active agent comprises an antisense oligonucleotide or polynucleotide capable of inhibiting the expression of a component of the PG pathway.
- the antisense oligonucleotide or polynucleotide may comprise a DNA backbone,
- RNA backbone or chemical derivative thereof RNA backbone or chemical derivative thereof.
- oligonucleotide or polynucleotide comprises a single stranded antisense oligonucleotide or polynucleotide targeting for degradation.
- the anti-inflammatory agent comprises a single stranded antisense oligonucleotide complementary to the mRNA sequence of a component of the PG pathway.
- the single stranded antisense oligonucleotide or polynucleotide may be synthetically produced or it may be expressed from a suitable expression vector.
- the antisense nucleic acid is designed to bind via complementary binding to the mRNA sense strand so as to promote RNase H activity, which leads to degradation of the mRNA.
- the antisense oligonucleotide is chemically or structurally modified to promote nuclease stability and/or increased binding.
- the antisense oligonucleotides are modified to produce oligonucleotides with nonconventional chemical or backbone additions or substitutions, including, but not limited to, peptide nucleic acids (PNAs), locked nucleic acids (LNAs), morpholino backboned nucleic acids, methylphosphonates, duplex stabilizing stilbene or pyrenyl caps, phosphorothioates, phosphoroamidates, phosphotriesters and the like.
- PNAs peptide nucleic acids
- LNAs locked nucleic acids
- morpholino backboned nucleic acids methylphosphonates
- duplex stabilizing stilbene or pyrenyl caps phosphorothioates
- phosphoroamidates phosphotriesters and the like.
- the modified oligonucleotides may incorporate or substitute one or more of the naturally occurring nucleotides with an analog; internucleotide modifications incorporating, for example, uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) or charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.); modifications incorporating intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.) or alkylators and/or modified linkages (e.g., alpha anomeric nucleic acids, etc.).
- uncharged linkages e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.
- charged linkages e.g., phosphorothioates, phosphorod
- the single stranded oligonucleotides are internally modified to include at least one neutral charge in its backbone.
- the oligonucleotide may include a methylphosphonate backbone or peptide nucleic acid (PNA) complementary to the target-specific sequence. These modifications have been found to prevent or reduce helicase-mediated unwinding.
- PNA peptide nucleic acid
- the use of uncharged probes may further increase the rate of hybridization to polynucleotide targets in a sample by alleviating the repulsion of negatively- charges nucleic acid strands in classical hybridization.
- PNA oligonucleotides are uncharged nucleic acid analogs for which the phosphodiester backbone has been replaced by a polyamide, which makes PNAs a polymer of 2- aminoefhyl-glycine units bound together by an amide linkage.
- PNAs are synthesized using the same Boc or Fmoc chemistry as are use in standard peptide synthesis. Bases (adenine, guanine, cytosine and thymine) are linked to the backbone by a methylene carboxyl linkage. Thus, PNAs are acyclic, achiral and neutral. Other properties of PNAs are increased specificity and melting temperature as compared to nucleic acids, capacity to form triple helices, stability at acid pH, non-recognition by cellular enzymes like nucleases, polymerases, etc.
- Methylphosphonate-containing oligonucleotides are neutral DNA analogs containing a methyl group in place of one of the non-bonding phosphoryl oxygens.
- Oligonucleotides with methylphosphonate linkages were among the first reported to inhibit protein synthesis via anti-sense blockade of translation.
- the phosphate backbone in the oligonucleotides may contain phosphorothioate linkages or phosphoroamidates. Combinations of such
- oligonucleotide linkages are also within the scope of the present invention.
- the oligonucleotide may contain a backbone of modified sugars joined by phosphodiester internucleotide linkages.
- the modified sugars may include furanose analogs, including but not limited to 2-deoxyribofuranosides, a-D-arabinofuranosides, a-2'-deoxyribofuranosides and 2',3'-dideoxy-3'-aminoribofuranosides.
- furanose analogs including but not limited to 2-deoxyribofuranosides, a-D-arabinofuranosides, a-2'-deoxyribofuranosides and 2',3'-dideoxy-3'-aminoribofuranosides.
- the 2-deoxy-P-D-ribofuranose groups may be replaced with other sugars, for example, ⁇ -D-ribofuranose.
- ⁇ -D-ribofuranose may be present wherein the 2-OH of the ribose moiety is alkylated with a CI -6 alkyl group (2-(0— Cl-6 alkyl) ribose) or with a C2-6 alkenyl group (2-(0 ⁇ C2-6 alkenyl) ribose) or is replaced by a fluoro group (2-fluororibose).
- oligomer-forming sugars include those used in locked nucleic acids (LNA) as described above.
- LNA oligonucleotides include modified bicyclic monomeric units with a 2'-0-4'-C methylene bridge, such as those described in U.S. Patent No. 6,268,490.
- Chemically modified oligonucleotides may also include, singly or in any combination, 2'-position sugar modifications, 5-position pyrimidine modifications (e.g., 5-(N- benzylcarboxyamide)-2'-deoxyuridine, 5-(N-isobutylcarboxyamide)-2'-deoxyuridine, 5-(N-[2- (lH-indole-3yl)ethyl]carboxyamide)-2'-deoxyuridine, 5-(N-[l-(3-trimethylammonium) propyl]carboxyamide)-2'-deoxyuridine chloride, 5-(N-napthylcarboxyamide)-2'-deoxyuridine, 5- (N-[l-(2,3-dihydroxypropyl)]carboxyamide)-2'-deoxyuridine), 8-position purine modifications, modifications at exocyclic amines, substitution of 4-thiouridine, substitution of 5-bromo- or 5- iodo-urac
- the one or more PG pathway inhibitors include a ribozyme capable of inhibiting the expression of a component of the PG pathway.
- Ribozymes are nucleic acid molecules that are capable of catalyzing a chemical reaction, either intramolecularly or intermolecularly. Ribozymes are thus catalytic nucleic acid. It is preferred that the ribozymes catalyze intermolecular reactions.
- ribozymes that catalyze nuclease or nucleic acid polymerase type reactions which are based on ribozymes found in natural systems, such as hammerhead ribozymes, hairpin ribozymes and tetrahymena ribozymes.
- ribozymes that are not found in natural systems, but which have been engineered to catalyze specific reactions de novo.
- RNA or DNA substrates and more preferably cleave RNA substrates, such as mRNAs of components of the PG pathway.
- Ribozymes typically cleave nucleic acid substrates through recognition and binding of the target substrate with subsequent cleavage. This recognition is often based mostly on canonical or non-canonical base pair interactions. This property makes ribozymes particularly good candidates for target specific cleavage of nucleic acids because recognition of the target substrate is based on the target substrates sequence.
- the one or more PG pathway inhibitors include a triplex forming oligonucleotide capable of inhibiting the expression of a component of the PG pathway.
- Triplex forming oligonucleotides are molecules that can interact with either double- stranded and/or single-stranded nucleic acids, including both coding and non-coding regions in genomic DNA targets.
- TFOs interact with a target region, a structure called a triplex is formed, in which there are three strands of DNA forming a complex dependent on both Watson- Crick and Hoogsteen base-pairing.
- TFOs can bind target regions with high affinity and specificity.
- the triplex forming molecules bind the target molecule with a Kd less than 10-6, 10-8, 10-10 or 10-12.
- Exemplary TFOs for use in the present invention include PNAs, LNAs and LNA modified PNAs, such as Zorro-LNAs.
- the one or more PG pathway inhibitors include an external guide sequence (EGS).
- EGSs External guide sequences
- EGSs are molecules that bind a target nucleic acid molecule forming a complex. This complex is recognized by RNase P, which cleaves the target molecule.
- EGSs can be designed to specifically target an mRNA molecule of choice.
- RNAse P aids in processing transfer RNA (tRNA) within a cell.
- Bacterial RNAse P can be recruited to cleave virtually any RNA sequence by using an EGS that causes the target RNA:EGS complex to mimic the natural tRNA substrate.
- EGS RNAse P- directed cleavage of RNA can be utilized to cleave desired targets within eukaryotic cells.
- the one or more PG pathway inhibitors comprise target neutralization agents.
- target neutralization agent refers to antibodies, fragments of antibodies, or any other non-antibody peptide or synthetic binding molecule, such as an aptamer or synbody, which is capable of specifically binding directly or indirectly to a component of the PG pathway so as to interfere with the ultimate actions of prostaglandin on the target tissue.
- the target neutralization agents may be produced by any conventional method for generating high- affinity binding ligands, including SELEX, phage display and other
- An aptamer is a nucleic acid version of an antibody that comprises a class of oligonucleotides that can form specific three dimensional structures exhibiting high affinity binding to a wide variety of cell surface molecules, proteins and/or macromolecular structures.
- Aptamers are commonly identified by an in vitro method of selection sometimes referred to as Systematic Evolution of Ligands by Exponential enrichment or "SELEX". SELEX typically begins with a very large pool of randomized polynucleotides which is generally narrowed to one aptamer ligand per molecular target.
- aptamers are small nucleic acids ranging from 15-50 bases in length that fold into defined secondary and tertiary structures, such as stem-loops or G-quartets.
- An aptamer can be chemically linked or conjugated to the above described nucleic acid inhibitors to form targeted nucleic acid inhibitors, such as aptamer-siRNA chimeras.
- An aptamer-siRNA chimera contains a targeting moiety in the form of an aptamer which is linked to an siRNA.
- the aptamer can facilitate internalization into the cell where the nucleic acid inhibitor acts.
- both the aptamer and the siRNA comprises RNA.
- the aptamer and the siRNA may comprise any nucleotide modifications as further described herein.
- the aptamer comprises a targeting moiety specifically directed to binding cells expressing the chemokine-, cytokine- and or receptor target genes, such as lymphoid, epithelial cell and/or endothelial cells.
- Synbodies are synthetic antibodies produced from libraries comprised of strings of random peptides screened for binding to target proteins of interest.
- Aptamers and synbodies can be engineered to bind target molecules very tightly with Kds between 10 "10 to 10 "12 M.
- the target neutralization agent binds the target molecule with a Kd less than 10 "6 , less than 10 "8 , less than 10 "9 , less than 10 ⁇ 10 or less than 10 "12 M.
- the one or more PG pathway inhibitors comprise a polynucleotide that encodes and is adapted to express a PGT inhibitor and/or a PGR inhibitor. In other embodiments, the one or more PG pathway inhibitors comprise an expression vector that encodes and is adapted to express a PGT inhibitor and/or a PGR inhibitor.
- the PG pathway inhibitor is an engineered protein containing a TALE sequence or and engineered Zinc Finger directed at the gene encoding any component of the PG pathway.
- This TALE or zinc finger could be designed to bind directly to the gene and inhibit its expression by cleaving the gene, altering its nucleotide sequence, or tethering a repressor protein to the gene which serves to silence the gene.
- the PG pathway inhibitor is produced using the
- PG pathway gene is designed and introduced into the cell or tissue using delivery systems described above (viruses, plasmids etc).
- the action of the CRISPR/CAS system would modify the DNA sequence of the gene such that the PG pathway gene is deleted or inhibited in ability to express the RNA.
- the PG pathway inhibitor is capable of turning off the transcription of one or more PG pathway genes by targeting the chromatin associated enzymes which post translationally modify histones in chromatin.
- chromatin associated enzymes include, but not limited to histone deacetylases, histone demethylases, histone acetyltransf erases, histone methyl transferases, and helicases.
- the one or more PG pathway inhibitors target a PG pathway-sensitive gene by altering the DNA methylation status of the gene.
- Compounds which target the TET family of DNA demethylases and the DNA methyltransferases could change the expression of RNA from the any of the genes in the PG pathway.
- the expression vector of the present application may comprise a polynucleotide encoding a PG pathway inhibitor or a portion thereof.
- the expression vectors also include one or more regulatory sequences operably linked to the polynucleotide being expressed. These regulatory sequences are selected based on the type of host cells. It will be appreciated by those skilled in the art that the design of the expression vector depends on such factors as the choice of the host cells and the desired expression levels.
- the expression vector is a plasmid vector.
- the expression vector is a viral vector.
- viral vectors include, but are not limited to, retrovirus, lentivirus, adenovirus, adeno-associated virus (AAV), herpes virus, or alphavirus vectors.
- the viral vectors can also be astrovirus, coronavirus, orthomyxovirus, papovavirus, paramyxovirus, parvovirus, picornavirus, poxvirus, or togavirus vectors.
- the expression vector's control functions are often provided by viral regulatory elements.
- the expression vector contains tissue-specific regulatory elements. Delivery of the expression vector include, but are not limited to, direct infection with viral vectors, exposing target tissue to polycationic condensed DNA linked or unlinked to killed virus, ligand linked DNA, gene guns, ionizing radiation, nucleic charge neutralization, or fusion with cell membranes. Naked plasmid or viral DNA can also be employed. Uptake efficiency may be improved using biodegradable latex beads. This method can be further improved by treating the beads to increase their
- the pharmaceutical composition further comprises one or more active ingredients selected from the group consisting of analgesic agents, antimuscarinic agents, antidiuretics, spasmolytics, inhibitors of phosphodiesterase type 5 (PDE 5 inhibitors) and zolpedim.
- active ingredients selected from the group consisting of analgesic agents, antimuscarinic agents, antidiuretics, spasmolytics, inhibitors of phosphodiesterase type 5 (PDE 5 inhibitors) and zolpedim.
- antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, trospium, atropine, and tricyclic
- antidepressants examples 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. , NPRl, NPR2, and NPR3) antagonists (e.g.
- ADH antidiuretic hormone
- angiotensin II angiotensin II
- aldosterone aldosterone
- vasopressin vasopressin analogs
- vasopressin receptor agonists e.g. , desmopressin argipressin, lypressin, felypressin, ornipressin,
- 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. , somatostatin), pharmaceutically-acceptable derivatives, and analogs, salts, hydrates, and solvates thereof.
- spasmolytics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, clonidine analog, and dantrolene.
- PDE 5 inhibitors include, but are not limited to, tadalafil, sildenafil and vardenafil.
- the pharmaceutical composition may be formulated for immediate-release, extended-release, delayed-release, or combinations thereof.
- the pharmaceutical composition is formulated for immediate-release.
- the pharmaceutical composition is formulated in an orally disintegrating formulation.
- the orally disintegrating formulation is designed to completely disintegrate or dissolve in oral cavity without the aid of additional water (i.e., in saliva only) in 5, 10, 20, 30, 60, 90, 120, 180, 240 or 300 seconds.
- the orally disintegrating formulation is in the form of an orally disintegrating tablet.
- Orally disintegrating tablets may be manufactured using loose compression tabletting, a process which is not very different than the manufacturing method used for traditional tablets and lyophilization processes. In loose compression, orally disintegrating formulation is compressed at much lower forces (4 - 20 kN) than traditional tablets.
- the orally disintegrating formulation contains some form of sugar, such as mannitol, to improve mouth feel.
- the orally disintegrating tablet is produced using lyophilized orally disintegrating formulation.
- 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.
- the extended-release form is designed to release the active ingredient 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 ingredient 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 22 hours, about 20 hours, about 18 hours, about 16 hours, about 14 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 or about 2 hours following administration or following a lag period associated with delayed-release of the active ingredient.
- the constant active ingredient level may be maintained by a continuous release of the active ingredient or pulsed-release of the active ingredient.
- one or more of the active ingredient(s) in an extended- release formulation are released over a time interval of between about 2 to about 12 hours.
- the active ingredient may be released over about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10 hours, about 11 hours, or about 12 hours.
- the active ingredient in an extended-release formulation is released over a time period between about 5 to about 8 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 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.
- drug refers to the active ingredient of a pharmaceutical composition.
- the active ingredient 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 active ingredient in the core will depend on the dose that is required and typically varies from about 1 to 100 weight %, about 5 to 100 weight %, about 10 to 100 weight %, about 20 to 100 weight %, about 30 to 100 weight %, about 40 to 100 weight %, about 50 to 100 weight %, about 60 to 100 weight %, about 70 to 100 weight %, or about 80 to 100 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) is 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
- 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 agents and/or release-promoting agents.
- the active agent(s) dissolves (if soluble) and gradually diffuses 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-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). 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 to drug ratio, filler type and level, polymer to filler ratio, particle size of drug and polymer, and porosity and shape of the matrix.
- Exemplary hydrophilic and/or water-swellable, matrix forming polymers include, but are not limited to, cellulosic polymers including hydroxyalkyl celluloses and carboxyalkyl celluloses such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), carboxymethylcellulose (CMC); 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 therefrom; 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®, including CARBOPOL® 71G NF, which is available in various molecular weight grades from Noveon, Inc., Cincinnati, OH), carageenan; polyvinyl acetate (e.g., KOLLIDON® SR); and polyvinyl pyrrolidone and its derivatives such as crospovidone, polyethylene oxides, and polyvinyl alcohol.
- 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, hydroxypropylmethyl cellulose, and polyvinylpyrrolidone.
- 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 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® L100, L 30D 55, A, and FS 30D), and hypromellose acetate succinate (AQUAT HPMCAS); and xanthan gum.
- Exemplary cationic polymers include, for example, dimethylaminoethyl mefhacrylate 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.
- Exemplary 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 100), 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 100 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 a 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, and 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® L100 (Type A), EUDRAGIT® S 100 (Type B), Rohm GmbH, Germany), methacrylic acid-ethyl acrylate copolymers (e.g., EUDRAGIT® LI 00-55 (Type C) and
- EUDRAGIT® L30D-55 copolymer dispersion Rohm GmbH, Germany
- copolymers of methacrylic acid-methyl methacrylate and methyl methacrylate EUDRAGIT® FS
- HPMCP hydroxypropyl methylcellulose phthalate
- PVAP polyvinyl acetate phthalates
- COATERIC® COATERIC®, OP ADR Y® enteric white OY-P-7171
- CAS polyvinylbutyrate acetate, cellulose acetate succinates
- HPMCAS hydroxypropyl methylcellulose acetate succinate
- HPMCAS HPMCAS LF Grade, MF Grade, and HF Grade, including AQOAT® LF and AQOAT® MF, Shin-Etsu Chemical, Japan
- shellac e.g., MARCO ATTM 125 and MARCO ATTM 125N
- CAP cellulose acetate phthalates
- CAP e.g., AQUATERIC®
- Polymers may be used either alone or in combination, or together with polymers other than those mentioned above.
- Preferred enteric pH-dependent polymers are the
- methacrylic acid copolymers are anionic polymers based on methacrylic acid and methyl methacrylate and, preferably, have a mean molecular weight of about 50,000 to 200,000, preferably 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.
- 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 enhancing agents.
- the solubility enhancing agents can be ionic and non-ionic surfactants, complexing agents, hydrophilic polymers, and 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 enhancing agents can be utilized simultaneously.
- Solubility enhancing agents 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 cyclodextrins and pH modifying agents, including acidifying agents such as citric acid, fumaric acid, tartaric acid, and hydrochloric acid, and alkalizing agents such as meglumine and sodium hydroxide.
- surface active agents such as sodium docusate; sodium lauryl sulfate; sodium stearyl fumarate; Tweens® and Spans (PEO
- Solubility enhancing agents typically constitute from 1% to 80% by weight, from 1% to 60% by weight, from 1% to 50% by weight, from 1% to 40% by weight and from 1% to 30% by weight, 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, solubility enhancing agents 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 PR100, PR45, PR20, PR10, and PR7; ETHOCEL®, Dow).
- alkyl cellulose ethers such as ethyl celluloses and mixtures thereof, (e.g., ethyl cellulose grades PR100, PR45, PR20, PR10, and PR7; ETHOCEL®, Dow).
- 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 acrylate/methacrylate 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, grape seed oil, sesame oil, olive oil, and 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), glyceryl monostearate, glycerol tributyrate, polysorbate 80, polyethyleneglycol (such as PEG-4000 and PEG-400), propyleneglycol, 1,2-propyleneglycol, glycerin, sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, diethylmalonate, dibutyl succinate, fatty acids, glycerin, sorbitol, diethyl oxalate, diethyl malate, diethyl maleate, diethyl fumarate, diethyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, and mixtures
- 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. These changes include, but are not limited to, 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
- the 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. Due to 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 combination of at least two gel-forming polymers enables properties of the resultant gel, such as viscosity, to be manipulated in order to provide the desired release profile.
- the formulation comprises at least one non-ionic gel- forming polymer and at least one anionic gel-forming polymer. In another embodiment, the formulation comprises two different non-ionic gel-forming polymers. In yet another
- the formulation comprises a combination of non-ionic gel-forming polymers with the same chemistry, but 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-a- and -P-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-a- and -P-l,4-
- 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 (hydroxypropyl 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
- PVP polyvinyl pyrrolidone
- HPC hydroxypropyl cellulose
- HPMC hydroxypropyl methylcellulose
- PHEMA polyhydroxyethylmethacrylate
- water soluble nonionic polymethacrylates and their copolymers modified cellulose, modified polysaccharides, nonionic gums, non
- 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, and starch and polymethacrylates such as Eudragit NE 30D, Eudragit RL, Eudragit RS, Eudragit E, polyvinyl acetate, 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®), methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, and cellulose acetate phthalate; polyvinyl alcohol; acrylic polymers such as polyacrylates, polymethacrylates, and copolymers thereof; and other water-based or solvent-based coating materials.
- 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, and 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, and poly(a-Q)alkylenediols; and inorganic compounds such as alkali metal salts, lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, suitable calcium salts, combination thereof, and the like.
- 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, for example, 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 OP ADR Y ® 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 semipermeable 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-hydroxyethyl 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 cros
- 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 acid, glut
- 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 comprises 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 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
- enteric coatings prevent drugs having an irritant effect on the stomach, such as aspirin, from dissolving in the stomach.
- enteric 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 sometime after a gastric emptying lag period of about 3-4 hours after administration.
- 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
- 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.
- 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
- the formulation may additionally include a time delay material such as glyceryl monostearate or glyceryl distearate.
- the delayed-extended-release formulation includes an enteric coating comprising one or more polymers facilitating release of active agents in proximal or distal regions of the gastrointestinal tract.
- pH dependent enteric coatings comprise 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 have been described earlier. 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. In other embodiments, the pH-dependent polymer exhibits a pH optimum of >5.0, of >5.5, of >6.0, of >6.5, or of >7.0.
- 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 "delayed-release" or “delayed-extended-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 swells, pushing itself out of the capsule and releasing the drugs after a pre-determined lag time, which can be controlled by, for example, 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, dextran, guar gum,
- capsules or bilayered tablets may be formulated to contain a drug-containing core, covered by a swelling layer and an outer insoluble, but semi-permeable 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 oxides (having e.g., an average molecular weight between 1,000,000 and 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 25,000 to
- poly(vinyl)alcohol having a low acetal residue which is cross-linked with glyoxal, formaldehyde, or glutaraldehyde, and having a degree of polymerization 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 copolymer of maleic anhydride with styrene, ethylene, propylene, butylene, or isobutylene cross-linked with from 0.001 to 0.5 moles of saturated cross-linking agent per mole of maleic anyhydride in the copolymer;
- CARBOPOL® acidic carboxy polymers having a molecular weight of 450,000 to 4,000,000; CYANAMER® polyacrylamides; cross-linked water swellable indenemaleicanhydride polymers; GOODRITE® polyacrylic acid having a molecular weight of 80,000 to 200,000; starch graft copolymers; AQUA-KEEPS® acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan; carbomers having a viscosity of 3,000 to 60,000 mPa as a 0.5%- 1% w/v aqueous solution; cellulose ethers such as
- hydroxypropylcellulose having a viscosity of about 1000-7000 mPa s as a 1% w/w aqueous solution (25° C); hydroxypropyl methylcellulose having a viscosity of about 1000 or higher, preferably 2,500 or higher to a maximum of 25,000 mPa as a 2% w/v aqueous solution;
- polyvinylpyrrolidone havmg a viscosity of about 300-700 mPa s as a 10% w/v aqueous solution at 20° C; and combinations thereof.
- 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
- GI fluids permeate through the micropores, causing swelling of the swellable excipients, which produces an inner pressure disengaging the capsular components, including a first capsule body containing the swellable materials, a second capsule body containing the drugs, and an outer cap attached to the first capsule body.
- the delayed-release coating layer may further comprise anti-tackiness agents, such as talc and glyceryl monostearate.
- the delayed-release coating 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, ph halate 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
- 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-extended-release).
- delayed-extended-release delayed-extended-release
- delayed-extended-release 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 delayed-extended-release formulations comprise 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 1 to 100 weight %, about 5 to 100 weight %, about 10 to 100 weight %, about 20 to 100 weight %, about 30 to 100 weight , about 40 to 100 weight %, about 50 to 100 weight %, about 60 to 100 weight %bal about 70 to 100 weight %, or about 80 to 100 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. 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.
- delayed-release or delayed-extended-release compositions may be 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
- 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, 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.
- AP143/1093 resin is used as an extended-release carrier.
- DUOLITETM AP143/1093 is an insoluble, strongly basic, anion exchange resin that is suitable as a carrier for anionic (acidic) substances.
- 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, and 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.
- the pharmaceutical composition is formulated as an orally disintegrating tablet.
- 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,
- 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.
- 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. In some embodiments, the pharmaceutical composition of the present application is formulated for extended-release or delayed extended-release of 100% of the active ingredient.
- the pharmaceutical composition of the present application is formulated for a two-phase extended-release or delayed two-phase extended-release characterized by an "immediate-release” component that is released within two hours of administration and an "extended-release” component which is released over a period of 2-12 hours.
- the "immediate-release” component provides about 1-90% of the total dosage of the active agent(s) and the "extended-release” component provides 10-99% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation.
- the immediate-release component may provide about 10-90%, or about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation.
- the extended- release component provides about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% of the total dosage of the active agent(s) to be delivered by the formulation.
- the immediate-release component and the extended- release component contain the same active ingredient. In other embodiments, the immediate- release component and the extended-release component contain different active ingredients (e.g. , acetaminophen in one component and NSAID in another component). In some embodiments, the immediate-release component and the extended-release component each contains
- the immediate-release component and/or the extended-release component further comprises one or more additional active agents selected from the groups consisting of a PG pathway inhibitor, an analgesic, an antimuscarinic agent, an antidiuretic, a spasmolytic, an inhibitor of phosphodiesterase type (PDE 5 inhibitor), Zolpidem and combination thereof.
- additional active agents selected from the groups consisting of a PG pathway inhibitor, an analgesic, an antimuscarinic agent, an antidiuretic, a spasmolytic, an inhibitor of phosphodiesterase type (PDE 5 inhibitor), Zolpidem and combination thereof.
- the pharmaceutical composition comprises a plurality of active ingredients selected from the group consisting of PG pathway inhibitors, analgesics, antimuscarinic agents, antidiuretics, spasmolytics, PDE 5 inhibitors, Zolpidem and combinations thereof.
- active ingredients selected from the group consisting of PG pathway inhibitors, analgesics, antimuscarinic agents, antidiuretics, spasmolytics, PDE 5 inhibitors, Zolpidem and combinations thereof.
- antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, trospium, atropine, and tricyclic
- antidepressants examples 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.
- NPRl, NPR2, and 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., somatostatin
- pharmaceutically- acceptable derivatives e.g., somatostatin
- spasmolytics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, clonidine analog, and dantrolene.
- PDE 5 inhibitors include, but are not limited to, tadalafil, sildenafil and vardenafil.
- the pharmaceutical composition comprises a plurality of active ingredients comprising (1) acetaminophen and (2) one or more NSAIDs.
- the plurality of active ingredients are formulated for immediate-release.
- the plurality of active ingredients are formulated for extended-release.
- the plurality of active ingredients are formulated for delayed-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). In some other embodiments, the plurality of active ingredients are formulated for delayed-extended-release.
- the pharmaceutical composition comprises an immediate-release component and an extended-release component.
- the immediate-release component may comprise acetaminophen, one or more NSAIDs and/or one or more active ingredients selected from the group consisting of PG pathway inhibitors, analgesics,
- the extended-release component may comprise acetaminophen, one or more NSAIDs and/or one or more active ingredients selected from the group consisting of PG pathway inhibitors, analgesics, antimuscarinic agents, antidiuretics, spasmolytics, PDE 5 inhibitors, Zolpidem and combinations thereof.
- 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 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 an immediate- release component and a delayed-release component.
- 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.
- the components in a combined release profile formulation may contain the same active ingredient(s) or different active ingredient(s).
- the immediate-release component may provide about 1% to about 80% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation.
- the combined release profile formulation contains an immediate-release component and the immediate-release component provide about 1% to about 90%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90% or about 80% to about 90% of the total dosage of each active ingredient to be delivered by the formulation.
- the immediate-release component provides up to about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total dosage of each ingredient to be delivered by the formulation.
- the pharmaceutical 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, /. which alters the microenvironment of the drug to facilitate its release.
- the pharmaceutical composition comprises a delayed- release component 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 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 comprise a mixture of two types of release beads: a first type that exhibits immediate-release and a second type that exhibits a lag time of 1-4 hours followed with extended-release.
- the formulations are designed with a release profile such that a fraction of the active ingredient(s) (e.g., 10-80%) is released immediately or within two hours of administration, and the rest is released over an extended period of time (e.g., over a period of 2-24 hours).
- the formulations are designed with a release profile such that one active ingredient (e.g., acetaminophen or NSAID) is released immediately or within two hours of administration, and one or more other active ingredients (e.g., acetaminophen or NSAID) are released over an extended period of time (e.g., over a period of 2- 24 hours).
- the pharmaceutical composition may be administered daily or administered on an as needed basis.
- the pharmaceutical composition may be administered orally, intravenously, or intramuscularly.
- the pharmaceutical composition is administered orally.
- the pharmaceutical composition is administered by retrograde perfusion through the urinary tract.
- the pharmaceutical composition is administered by direct injection into bladder muscle.
- the pharmaceutical composition is administered daily, twice a day or three times a day. In other embodiments, the pharmaceutical composition is administered every other day, every 3 days, every 4 days, every 4 days, every 5 days, every 6 days, every week, every 2 weeks, every 3 weeks, every month, every 2 months or every 3 months.
- the pharmaceutical composition is administered at bedtime. In some embodiments, the pharmaceutical composition is administered within about two hours before bedtime, preferably within about one hour before bedtime. In another embodiment, the pharmaceutical composition is administered about 2-4 hours before bedtime. In a further embodiment, the pharmaceutical composition is administered at least 4 hours before bedtime.
- the appropriate dosage ("therapeutically effective amount") of the active ingredient(s) in the immediate-release component, the extended-release component, the delayed- release component or delayed-extended-release component will depend, for example, on the severity and course of the condition, the mode of administration, the bioavailability of the particular ingredient(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.
- acetaminophen and the one or more NS AIDs in the immediate-release component, the delayed- release component, the extended-release component and/or the delayed-extended-release component is administered in the range of about 1 ⁇ 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 1 ⁇ g/kg body weight/day to about 100 mg/kg body weight/day, 1 ⁇ g/kg body weight/day to about 30 mg/kg body weight/day, 1 ⁇ g/kg body weight/day to about 10 mg/kg body weight/day, 1 ⁇ g/kg body weight/day to about 3 mg/kg body weight/day, 1 ⁇ g kg body weight/day to about 1 mg/kg body weight/day, 1 ⁇ g/kg body weight/day to about 300 ⁇ g/kg body weight/day, 1 ⁇ g/kg body weight/day to about 100 ⁇ g kg body weight/day, 1 ⁇ g kg body weight/day to about 30 ⁇ g/kg body weight/day, 1 ⁇ g/kg body weight/day to about 10 ⁇ g kg body weight/day, 1 ⁇ g/kg body weight/day to about 3 ⁇ g kg body weight/day, 10 ⁇ g/kg body weight/day to about 100 mg/
- the therapeutically effective amount of the PG pathway inhibitor(s) and/or analgesic agent(s) in the immediate-release component, the delayed-release component, the extended-release component or the delayed-extended-release component is administered in the range of about 10 ⁇ 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 10 ⁇ g kg body weight/day to about 100 mg/kg body weight/day, 10 ⁇ g/kg body weight/day to about 30 mg/kg body weight/day, 10 ⁇ g/kg body weight/day to about 10 mg/kg body weight/day, 10 ⁇ g kg body weight/day to about 3 mg/kg body weight/day, 10 ⁇ g kg body weight/day to about 1 mg/kg body weight/day, 10 ⁇ g/kg body weight/day to about 300 ⁇ g kg body weight/day, 10 ⁇ g/kg body weight/day to about 100 ⁇ g/kg body weight/day, 10 ⁇ g kg body weight/day to about 30 ⁇ g/kg body weight/day, 30 ⁇ g/kg body weight/day to about 100 mg/kg body weight/day, 30 ⁇ g/kg body weight/day to about 30 mg/kg body weight/day, 30 ⁇ g/kg body weight/day to about 10 mg/kg body weight/day/day,
- the analgesic agent(s) described herein may be included in an immediate-release component or an extended-release component, a delayed-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, 1 mg to 1000 mg, 1 mg to 300 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 10 mg, 1 mg to 3 mg, 3 mg to 2000 mg, 3 mg to 1000 mg, 3 mg to 300 mg, 3 mg to 100 mg, 3 mg to 30 mg, 3 mg to 10 mg, 10 mg to 2000 mg, 10 mg to 1000 mg, 10 mg to 300 mg, 10 mg to 100 mg, 10 mg to 30 mg, 30 mg to 2000 mg, 30 mg to 1000 mg, 30 mg to 300 mg, 30 mg to 100 mg, 100 mg to 2000 mg, 100 mg to 1000 mg, 100 mg to 300 mg, 300 mg to 2000 mg, 300 mg to 1000 mg or 1000 mg to 2000 mg. As expected, the dosage will be dependent on the condition, size, age, and condition of the patient.
- the pharmaceutical composition comprises a pair of NSAIDs.
- paired NSAIDs include, but are not limited to, acetylsalicylic acid and ibuprofen, acetylsalicylic acid and naproxen sodium, acetylsalicylic acid and nabumetone, acetylsalicylic acid and indomethacin, ibuprofen and naproxen sodium, ibuprofen and nabumetone, ibuprofen and indomethacin, naproxen or naproxen sodium and nabumetone, naproxen or naproxen sodium and indomethacin, nabumetone and indomethacin.
- the paired NSAIDs 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. In one embodiment, the paired NSAIDs 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, atropine, and tricyclic antidepressants.
- the daily dose of antimuscarinic agent is in the range of 1 ⁇ g to 300 mg, 1 ⁇ g to 100 mg, 1 ⁇ g to 30 mg; 1 ⁇ g to 10 mg, 1 ⁇ g to 3 mg, 1 ⁇ g to 1 mg, 1 ⁇ g to 300 ⁇ g, 1 ⁇ g to 100 ⁇ g, 1 ⁇ g to 30 ⁇ g, 1 ⁇ g to 10 ⁇ g, 1 ⁇ g to 3 ⁇ g, 3 ⁇ g to 100 mg, 3 ⁇ g to 100 mg, 3 ⁇ g to 30 mg; 3 ⁇ g to 10 mg, 3 ⁇ g to 3 mg, 3 ⁇ g to 1 mg, 3 ⁇ g to 300 ⁇ g, 3 ⁇ g to 100 ⁇ g, 3 ⁇ g to 30 mg; 10 ⁇ g to 10 mg, 10 ⁇ g to 3 mg, 10 ⁇ g to 300 mg, 10 ⁇ g to 100 mg, 10 ⁇ g to 30 mg; 10 ⁇ g to 10 mg, 10 ⁇ g to 3 mg, 10 ⁇ g to 1 mg, 10
- 1 mg to 300 mg 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 3 mg, 3 mg to 300 mg, 3 mg to 100 mg, 3 mg to 30 mg, 3 mg to 10 mg, 10 mg to 300 mg, 10 mg to 100 mg, 10 mg to 30 mg, 30 mg to 300 mg, 30 mg to 100 mg or 100 mg to 300 mg.
- the pharmaceutical composition of the present application further comprises one or more antidiuretics.
- antidiuretics include, but are not limited to, antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (e.g., desmopressin argipressin, lypressin, felypressin, ornipressin, and terlipressin), vasopressin receptor agonists, atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) receptor (i.e., NPR1, NPR2, and NPR3) antagonists (e.g., HS-142-1, isatin, [Asu7,23']b-ANP-(7-28)] ( anantin, a cyclic peptide from Streptomyces coerulescens, and
- the one or more antidiuretics comprise desmopressin.
- the one or more antidiuretics is desmopressin.
- the daily dose of antidiuretic is in the range of 1 ⁇ g to 300 mg, 1 ⁇ g to 100 mg, 1 ⁇ g to 30 mg; 1 ⁇ g to 10 mg, 1 ⁇ g to 3 mg, 1 ⁇ g to 1 mg, 1 ⁇ g to 300 ⁇ g, 1 ⁇ g to 100 ⁇ g, 1 ⁇ g to 30 ⁇ g, 1 ⁇ g to 10 ⁇ g, 1 ⁇ g to 3 ⁇ g, 3 ⁇ g to 100 mg, 3 ⁇ g to 100 mg, 3 ⁇ g to 30 mg; 3 ⁇ g to 10 mg, 3 ⁇ g to 3 mg, 3 ⁇ g to 1 mg, 3 ⁇ g to 300 ⁇ g,
- 300 mg 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 3 mg, 3 mg to 300 mg, 3 mg to 100 mg, 3 mg to 30 mg, 3 mg to 10 mg, 10 mg to 300 mg, 10 mg to 100 mg, 10 mg to 30 mg, 30 mg to 300 mg, 30 mg to 100 mg or 100 mg to 300 mg.
- 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,
- the spasmolytics is used at a daily dose of 0.1 mg to 1000 mg, 0.1 mg to 300 mg, 0.1 mg to 100 mg, 0.1 mg to 30 mg, 0.1 mg to 10 mg, 0.1 mg to 3 mg, 0.1 mg to 1 mg, 0.1 mg to 0.3 mg, 0.3 mg to 1000 mg, 0.3 mg to 300 mg, 0.3 mg to 100 mg, 0.3 mg to 30 mg, 0.3 mg to 10 mg, 0.3 mg to 3 mg, 0.3 mg to 1 mg, 1 mg to 1000 mg, 1 mg to 300 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 10 mg, 1 mg to 3 mg, 3 mg to 1000 mg, 3 mg to 300 mg, 3 mg to 100 mg, 3 mg to 30 mg, 3 mg to 10 mg, 10 mg to 1000 mg, 10 mg to 300 mg, 10 mg to 100 mg, 10 mg to 30 mg, 30 mg to 1000 mg, 30 mg to 300 mg, 30 mg to 10 mg, 10 mg to 1000 mg, 10 mg to 300 mg, 10 mg to 100 mg, 10 mg to 30 mg, 30
- the pharmaceutical composition of the present application further comprises one or more PDE 5 inhibitors.
- PDE 5 inhibitors include, but are not limited to, tadalafil, sildenafil and vardenafil.
- the one or more PDE 5 inhibitors comprise tadalafil.
- the one or more PDE 5 inhibitors is tadalafil.
- the PDE 5 inhibitor is used at a daily dose of 0.1 mg to 1000 mg, 0.1 mg to 300 mg, 0.1 mg to 100 mg, 0.1 mg to 30 mg, 0.1 mg to 10 mg, 0.1 mg to 3 mg, 0.1 mg to 1 mg, 0.1 mg to 0.3 mg, 0.3 mg to 1000 mg, 0.3 mg to 300 mg, 0.3 mg to 100 mg, 0.3 mg to 30 mg, 0.3 mg to 10 mg, 0.3 mg to 3 mg, 0.3 mg to 1 mg, 1 mg to 1000 mg, 1 mg to 300 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 10 mg, 1 mg to 3 mg, 3 mg to 1000 mg, 3 mg to 300 mg, 3 mg to 100 mg, 3 mg to 30 mg, 3 mg to 10 mg, 10 mg to 1000 mg, 10 mg to 300 mg, 10 mg to 100 mg, 10 mg to 30 mg, 30 mg to 1000 mg, 30 mg to 300 mg, 30 mg to 100 mg, 100 mg to 300 mg, or 300 mg to 1000 mg.
- the pharmaceutical composition of the present application further comprises Zolpidem.
- the daily dose of Zolpidem is in the range of 100 g to 100 mg, 100 g to 30 mg, 100 g to 10 mg, 100 ⁇ g to 3 mg, 100 ⁇ g to 1 mg, 100 ⁇ g to 300 ⁇ g, 300 ⁇ g to 100 mg, 300 ⁇ g to 30 mg, 300 ⁇ g to 10 mg, 300 ⁇ g to 3 mg, 300 ⁇ g to 1 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 10 mg, 1 mg to 3 mg, 10 mg to 100 mg, 10 mg to 30 mg, or 30 mg to 100 mg.
- the PG pathway inhibitors, analgesics, antimuscarinic agents, antidiuretics, spasmolytics, PDE 5 inhibitors, Zolpidem and/or combinations thereof may be formulated, alone or together with other active ingredient(s) in the pharmaceutical composition, for immediate- release, extended-release, delayed release, delayed-extended-release or combinations thereof.
- the pharmaceutical composition is formulated for extended release and comprises (1) acetaminophen; (2) one or more NSAIDs and (3) an analgesic, an antimuscarinic agent, an antidiuretic, a spasmolytic, PDE 5 inhibitor, Zolpidem or combination thereof.
- 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 pharmaceutical composition comprises one or more NSAIDs and/or acetaminophen, individually or in combination, in an amount between 10-1000 mg, 10-800 mg, 10-600 mg, 10-500 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-100 mg 30-1000 mg, 30-800 mg, 30-600 mg, 30-500 mg, 30-400 mg, 30-300 mg, 30- 250 mg, 30-200 mg, 30-150 mg, 30-100 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-400 mg, 100-250 mg, 300-1000 mg, 300-800 mg, 300-600 mg, 300-400 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-1000 mg, 600-800 mg or 800-1000 mg, wherein the composition is formulated for extended release with a release profile in which the one or more NSAIDs and/or acetaminophen are released continuously over a period of 2-12 hours or 5-8 hours.
- the composition is formulated for extended-release with a release profile in which at least 90% of the one or more NSAIDs and/or acetaminophen are released continuously over a period of 2-12 hours or 5-8 hours.
- the composition is formulated for extended release with a release profile in which the one or more NSAIDs and/or acetaminophen are released
- composition further comprises a PG pathway inhibitor, an analgesic, an antimuscarinic agent, an antidiuretic, a spasmolytic, a PDE 5 inhibitor, Zolpidem or combination thereof.
- the composition is formulated for extended-release with a release profile in which the NSAIDs and/or acetaminophen are released at a steady rate over a period of 2-12 hours or 5-8 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 or 12 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 average release rate is 10 mg/hr during this period of time and the actual release rate at any time during this period is within the range of 3 mg/hr to 30 mg/hr (i.e., within 30% - 300% of the average release rate of
- the pharmaceutical composition further comprises a PG pathway inhibitor, an analgesic, an antimuscarinic agent, an antidiuretic, a spasmolytic, a PDE 5 inhibitor, Zolpidem or combination thereof.
- the NSAID is selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin and nabumetone.
- composition is formulated to provide a steady release of NS AIDs and/or acetaminophen 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 one or more NSAIDs and acetaminophen, each present in an amount between 10-1000 mg, 10-800 mg, 10-600 mg, 10-500 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-100 mg 30-1000 mg, 30-800 mg, 30-600 mg, 30-500 mg, 30-400 mg, 30-300 mg, 30-250 mg, 30-200 mg, 30-150 mg, 30-100 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-400 mg, 100-250 mg, 300-1000 mg, 300-800 mg, 300-600 mg, 300-400 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-1000 mg, 600-800 mg or 800-1000 mg, wherein the NSAIDs and/or acetaminophen are formulated for extended release, characterized by a two-phase release profile in which 20-60% of the analgesic agent(s) are released within 2 hours of administration and the remainder are released continuously, or at
- the NSAIDs and/or acetaminophen are 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 2-12 hours or 5-8 hours.
- the NSAIDs are selected from the group consisting of aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin and nabumetone.
- the pharmaceutical composition further comprises a PG pathway inhibitor, an analgesic, an antimuscarinic agent, an antidiuretic, a spasmolytic, PDE 5 inhibitor, Zolpidem or combination thereof.
- the PG pathway inhibitor, analgesic, antimuscarinic agent, antidiuretic, spasmolytic, PDE 5 inhibitor, Zolpidem or combination thereof is/are formulated for immediate-release.
- the pharmaceutical composition is also used for the treatment of urinary incontinence and/or overactive bladder.
- Another aspect of the present application relates to a method for reducing bladder spasms, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of the present application and an effective amount of botulinum toxin.
- the botulinum toxin is administered by injection into a bladder muscle; and orally administering to the subject the pharmaceutical composition of the present application.
- the injecting step comprises injection of 10-200 units of botulinum toxin at 5-20 sites in bladder muscle with an injection dose of 2-10 units per site.
- the injecting step comprises injection of botulinum toxin at 5 sites in bladder muscle with an injection dose of 2-10 units per site.
- the injecting step comprises injection of botulinum toxin at 10 sites in bladder muscle at an injection dose of 2-10 units per site.
- the injecting step comprises injection of botulinum toxin at 15 sites in bladder muscle at an injection dose of 2-10 units per site.
- the injecting step comprises injection of botulinum toxin at 20 sites in bladder muscle at an injection dose of 2-10 units per site.
- the injecting step is repeated every 3, 4, 6, 8, 10 or 12 months.
- the above-described method is also used for the treatment of urinary incontinence and/or overactive bladder.
- 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, stimulators 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; N-acetyl-para-aminophenol (APAP) derivative such as acetaminophen or paracetamol (Tylenol); and Celecoxib.
- salicylates such as aspir
- 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
- Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA.
- 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, ibuprofen 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, ibuprofen or naproxen
- LPS lipopolysaccharide
- carbachol or acetylcholine which are effectors of non-inflammatory stimuli
- analgesic and LPS or (5) analgesic and carba
- 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 ⁇ g / 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 ⁇ g / ml of streptomycin
- FACS buffer phosphate buffered saline (PBS) with 2% bovine serum albumin (BSA) and 0.01% NaN 3
- FACS buffer phosphate buffered saline (PBS) with 2% bovine serum albumin (BSA) and 0.01% NaN 3
- FITC-conjugated anti-CD40, PE-conjugated anti-CD80, PE-conjugated anti-CD86 antibody, anti MHC class II (I-A d ) PE (BD Bioscience). Cells were then washed by centrifugation (5 min at 1,500 rpm at 4°C) in 300 ⁇ of FACS buffer.
- Immunoplates (Nunc) coated overnight with 100 ⁇ of anti-mouse IL-6, TNF-oc mAbs (BD Biosciences) or IL- ⁇ mAb (R&D Systems) in 0.1 M sodium bicarbonate buffer (pH 9.5). After two washes with PBS (200 ⁇ per well), 200 ⁇ of PBS 3% BSA were added in each well (blocking) and the plates incubated for 2 hours at room temperature. Plates were washed again two times by addition of 200 ⁇ per well, 100 ⁇ of cytokine standards and serial dilutions of culture supernatants were added in duplicate, and the plates were incubated overnight at 4°C.
- 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, ibuprofen, 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.
- 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.
- the doses of analgesic tested in vitro in Table 2 cover the range of concentrations achievable in vivo in humans.
- 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
- the cells are then analyzed for the release of PG3 ⁇ 4; 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. Undigested fragments were further dispersed through a cell-trainer. The cell suspension was pelleted and added to a discontinue 20%, 40%. and 75% Percoll gradient for purification on mononuclear cells. Each experiment used 50-60 bladders.
- digestion buffer RPMI 1640, 2% fetal bovine serum, 0.5 mg/ml collagenase, 30 ⁇ g/ml DNase.
- Bladder slurries were enzymatically digested for
- bladder cells were resuspended RPMI 1640 supplemented with 10 % fetal bovine serum, 15 mM HEPES, 2 n M 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.
- 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.
- 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 the plates were 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 minutes, and the reaction stopped by the addition of 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
- EXAMPLE 4 EFFECT OF ANALGESIC AGENTS, BOTULINUM NEUROTOXIN AND ANTIMUSCARINIC AGENTS ON MOUSE BLADDER SMOOTH MUSCLE CELL CONTRACTION
- Example 2 The effectors, analgesic agents, and antimuscarinic agents are described in Example 2.
- Primary cultures of mouse 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
- 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. Thirty (30) minutes after last doses, the bladders are collected and stimulated ex vivo with carbachol or
- acetylcholine In selected experiments, 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, and 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 carbachol or acetylcholine.
- Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or
- the cells are then analyzed for the release of PGH 2 ; PGE; PGE 2 ; Prostacydin; Thromboxane; IL- ⁇ ; IL-6; TNFa; the COX2 activity; the production of cAMP and cGMP; the production of IL- ⁇ , IL-6, TNFa, and COX2 mRNA; and surface expression of CD80, CD86, and MHC class II molecules.
- EXAMPLE 7 EFFECT OF ANALGESIC AGENTS. BOTULINUM NEUROTOXIN AND
- antimuscarinic agent at various concentrations.
- the stimuli-induced muscle contraction is measured to evaluate the inhibitory effect of the analgesic agent and/or antimuscarinic agent.
- 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.
- Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or
- EXAMPLE 8 EFFECT OF ANALGESIC AGENTS ON NORMAL HUMAN BLADDER SMOOTH MUSCLE CELL RESPONSES TO INFLAMMATORY AND NON INFLAMMATORY SIGNALS
- Bladder smooth muscle cells trypsinized and seeded in microculture plates at a cell density of 3xl0 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 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) as an example of non- inflammatory stimuli
- LPS lipopolysaccharide
- 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.
- 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).
- 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 ⁇ .
Abstract
Description
Claims
Priority Applications (13)
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SG11201702069XA SG11201702069XA (en) | 2014-09-24 | 2014-09-24 | Pharmaceutical formulation for reducing bladder spasms and method of use thereof |
CN201480082173.0A CN107072971A (en) | 2014-09-24 | 2014-09-24 | Pharmaceutical formulations and its application method for mitigating cystospasm |
MX2017003878A MX2017003878A (en) | 2014-09-24 | 2014-09-24 | Pharmaceutical formulation for reducing bladder spasms and method of use thereof. |
CA2962004A CA2962004A1 (en) | 2014-09-24 | 2014-09-24 | Pharmaceutical formulation for reducing bladder spasms and method of use thereof |
RU2017113827A RU2017113827A (en) | 2014-09-24 | 2014-09-24 | PHARMACEUTICAL COMPOSITION FOR REDUCING SPASES OF THE BLADDER AND METHOD OF ITS APPLICATION |
JP2017512011A JP2017532301A (en) | 2014-09-24 | 2014-09-24 | Pharmaceutical formulations for reducing bladder spasms and methods of use thereof |
AU2014407186A AU2014407186A1 (en) | 2014-09-24 | 2014-09-24 | Pharmaceutical formulation for reducing bladder spasms and method of use thereof |
PCT/US2014/057200 WO2016048301A1 (en) | 2014-09-24 | 2014-09-24 | Pharmaceutical formulation for reducing bladder spasms and method of use thereof |
BR112017006141A BR112017006141A2 (en) | 2014-09-24 | 2014-09-24 | pharmaceutical compositions and their uses and methods for reducing patient bladder spasms |
EP14902616.3A EP3197441A4 (en) | 2014-09-24 | 2014-09-24 | Pharmaceutical formulation for reducing bladder spasms and method of use thereof |
KR1020177011054A KR20170049613A (en) | 2014-09-24 | 2014-09-24 | Pharmaceutical formulation for reducing bladder spasms and method of use thereof |
IL250827A IL250827A0 (en) | 2014-09-24 | 2017-02-27 | Pharmaceutical formulation for reducing bladder spasms and method of use thereof |
ZA2017/01772A ZA201701772B (en) | 2014-09-24 | 2017-03-10 | Pharmaceutical formulation for reducing bladder spasms and method of use thereof |
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EP (1) | EP3197441A4 (en) |
JP (1) | JP2017532301A (en) |
KR (1) | KR20170049613A (en) |
CN (1) | CN107072971A (en) |
AU (1) | AU2014407186A1 (en) |
BR (1) | BR112017006141A2 (en) |
CA (1) | CA2962004A1 (en) |
IL (1) | IL250827A0 (en) |
MX (1) | MX2017003878A (en) |
RU (1) | RU2017113827A (en) |
SG (1) | SG11201702069XA (en) |
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JP2018193330A (en) * | 2017-05-17 | 2018-12-06 | 小林製薬株式会社 | Muscle spasm therapeutic agent |
WO2019240755A1 (en) * | 2018-06-11 | 2019-12-19 | Wellesley Pharmaceuticals, Llc | Pharmaceutical compositions and methods for weight loss |
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MX2014008283A (en) * | 2012-01-04 | 2015-03-03 | Wellesley Pharmaceutical Llc | Extended-release formulation for reducing the frequency of urination and method of use thereof. |
-
2014
- 2014-09-24 CA CA2962004A patent/CA2962004A1/en not_active Abandoned
- 2014-09-24 BR BR112017006141A patent/BR112017006141A2/en not_active Application Discontinuation
- 2014-09-24 AU AU2014407186A patent/AU2014407186A1/en not_active Abandoned
- 2014-09-24 EP EP14902616.3A patent/EP3197441A4/en not_active Withdrawn
- 2014-09-24 WO PCT/US2014/057200 patent/WO2016048301A1/en active Application Filing
- 2014-09-24 JP JP2017512011A patent/JP2017532301A/en active Pending
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WO2019240755A1 (en) * | 2018-06-11 | 2019-12-19 | Wellesley Pharmaceuticals, Llc | Pharmaceutical compositions and methods for weight loss |
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EP3197441A4 (en) | 2018-05-23 |
RU2017113827A (en) | 2018-10-24 |
CN107072971A (en) | 2017-08-18 |
ZA201701772B (en) | 2018-08-29 |
EP3197441A1 (en) | 2017-08-02 |
AU2014407186A1 (en) | 2017-03-09 |
RU2017113827A3 (en) | 2018-10-24 |
CA2962004A1 (en) | 2016-03-31 |
BR112017006141A2 (en) | 2018-02-06 |
MX2017003878A (en) | 2017-06-28 |
SG11201702069XA (en) | 2017-04-27 |
IL250827A0 (en) | 2017-04-30 |
KR20170049613A (en) | 2017-05-10 |
JP2017532301A (en) | 2017-11-02 |
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