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Justia Patents US Patent Application for IMMEDIATE/DELAYED DRUG DELIVERY Patent Application (Application #20190125679)
IMMEDIATE/DELAYED DRUG DELIVERY
Nov 19, 2018 - UNIVERSITY OF STRATHCLYDE
In one aspect, the present invention is concerned with a treatment where it is desired that an active agent is designed to be released immediately following administration and again at a time point some time after administration of the active agent. The present invention is particularly suited to administering an agent which may be released before sleep and whilst a subject is sleeping. As well as treating certain conditions by a particular regime, the invention also provides novel formulations for an immediate, followed by a delayed release of drug.
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Time-dependent release mechanisms of drugs have been described in the literature for tablet, pellet and capsule formulation utilising a wide range of physicochemical and physicomechanical strategies. The common feature of all such formulations is that they are activated by contact with fluids following ingestion by the patient and the drug will be released at the predetermined time after administration. Only after the formulations come into contact with gastric fluids does the 'clock' start. Drug release subsequently takes place at a predicted time, although it will be appreciated that since the dosage unit will be travelling through the GI tract during the lag period, drug release will necessarily be at some unknown GI tract site. Using such formulation strategies, it will be possible to design delivery systems capable of releasing drugs according to chronotherapeutic principles and targeting release to the circadian rhythm of disease states (Stevens H N E, Chronopharmaceutical Drug Delivery. J Pharm Pharmac., 50 (s) 5 (1998))
However, many of the formulations in the art rely on complex structures which can add to the cost of the manufacture of the drug and/or can be subject to malfunction leading to incorrect/inappropriate administration of the drug.
Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which is taken to reduce inflammation and as an analgesic reducing pain in conditions such as arthritis or acute injury. It can also be used to treat menstrual pain and dysmenorrhea.
Many diclofenac formulations to be taken orally comprise an enteric coating, which minimises direct contact between the drug and the gastric mucosa. It is known that diclofenac is poorly soluble in the stomach due to the acid pH, but more soluble in the alkaline pH of the duodenum. In this manner many such formulations are generally designed to delay release until the formulation passes through the stomach.
U.S. Pat. No. 6,312,724 describes a sustained release formulation comprising diclofenac.
It is amongst the objects of the present invention to obviate and/or mitigate at least one of the aforementioned disadvantages.
It is amongst the objects of the present invention to provide a formulation which may be easily and/or cheaply manufactured and which allows for an active agent to be administered immediately and following a period of delay following administration.
SUMMARY OF INVENTION
The present inventors recognised a need to be able to administer, for example, a pharmaceutically active agent to a subject in a manner such that an immediate and a delayed release of the pharmaceutically active ingredient could be achieved. Although this may have been possible using prior device/methods known in the art, many such devices/methods were highly complex and there is distinct advantage in providing a simpler press-coated tablet formulation.
One particularly preferred embodiment relates to treating subjects with arthritis or acute pain who may suffer pain before going to bed and would also suffer pain/inflammation on waking. In a preferred embodiment therefore, the formulations of the present invention are for alleviating pain due to, for example, arthritis or acute injury. Such formulations therefore comprise a pharmaceutically active agent for alleviating pain/inflammation associated with arthritis or other conditions. Typically this may be a NSAID, such as diclofenac.
Thus, in a first aspect, the present invention provides a NSAID agent such as diclofenac, formulated as a component of a press-coated tablet for alleviating pain and/or inflammation, wherein the tablet is intended to be administered immediately prior to a subject going to sleep (i.e. when a subject goes to bed at night for a prolonged period of sleep, such as 6-10 hours and hence is distinguished over shorter sleeping periods) and wherein a portion of the NSAID is initially to be released immediately following administration and a further portion is released following a period of delay after administration.
In a further aspect there is provided a method of alleviating pain and/or inflammation such as associated with arthritis, the method comprising administering a press-coated tablet comprising an NSAID(s), such as diclofenac to a subject, immediately before the subject intends sleeping, wherein the formulation releases an NSAID immediately following administration and further releases an NSAID following a period of delay after administration of the tablet.
It is to be appreciated that said NSAIDs may be in respect of the same drug, or different drugs. Thus, for example, the first portion may release a first NSAID and the second portion may release a different or the same NSAID.
The immediate release of the active agent may be realised by way of a top-coating layer comprising an amount of the active agent together with one or more excipients therefore.
By "immediately" is understood to mean that at least 70-90%, such as 80% of the active agent in the top layer or portion of the press-coated tablet which is formulated for immediate release is released within about 5-45 mins, such as 10-30 mins following administration and the further portion is released after a period of delay which is typically from 3-8 hours following administration.
Typically delayed release of the active agent is achieved by providing a press-coated tablet comprising a delayed release layer surrounding a core comprising the active agent. The delayed release layer may comprise a wax and LH-32.
In a further aspect, the present invention provides a press-coated tablet formulation for an immediate, followed by a delayed release of an active agent, the tablet comprising
(a) a core comprising an active agent together with an excipient(s); and
(b) a delayed release layer surrounding the core and comprising a wax and LH-32 in a ratio of 40:60 to 60:40 w/w; wherein the delayed release layer substantially delays release of the active agent within the core for between 3-8 hours after administration of the tablet by a subject and thereafter a pulsed release of the active agent from the core occurs, such that substantially all (typically greater than 90%, 95%, or even 99%) of the active agent in the core is released within 5-45 mins, such as 10-30 mins; and
(c) a top-coating layer comprising a portion of an active agent together with one or more excipients wherein a substantially immediate pulsed release of the active agent occurs following administration to the subject of the tablet.
Delayed Release is More Preferably for 4-7 Hours Following Administration.
The active agents of the above aspect may be the same or different and include any active agent for which delayed followed by pulsed release is desirable. In a preferred embodiment of the invention, the active agent is a pharmaceutically acceptable active agent and includes pharmaceutical and veterinary active agents (often referred to as drugs). In other embodiments, the active agent includes agrichemical agents (such as fertilizers, herbicides, pesticides and fungicides), active agent used in the exterminating industry (such as toxins and poisons), and active agents used in industrial manufacturing (such as catalysts or catalytic quenchers).
Exemplary active agents for use in the pharmaceutical and veterinary applications of the invention include analgesics, anti-inflammatories, anaesthetics, anticonvulsants, antidiabetic agents, antihistamines, anti-infectives, antineoplastics, antiparkinsonian agents, antirheumatic agents, appetite stimulants, appetite suppressants, blood modifiers, bone metabolism modifiers, cardiovascular agents, central nervous system depressants, central nervous system stimulants, decongestants, dopamine receptor agonists, electrolytes, gastrointestinal agents, immunomodulators, muscle relaxants, narcotics, parasympathomimetics, sympathomimetics, sedatives, and hypnotics.
The press-coated tablets of the present invention may be used to treat one or more of the following conditions/disorders or diseases:
Central Nervous System disorders, e.g. Neurogenic pain, stroke, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, meningitis, spinal cord injury, cerebral vasospasm, amyotrophic lateral sclerosis
Cardiovascular disease, hypertension, atherosclerosis, angina, arterial obstruction, peripheral arterial disease, myocardial pathology, Arrhythmia, Acute Myocardial Infarction, Angina, Cardiomyopathy, Congestive heart failure, Coronary artery disease (CAD), Carotid artery disease, Endocarditis, Hypercholesterolemia, hyperlipidemia, Peripheral artery disease (PAD)
Genitourinary Disorders; erectile dysfunction, urinary organ diseases benign prostatic hypertrophy (BPH), Renal tubular acidosis, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, urinary tract infection, faecal incontinence Ocular disease glaucoma, blephartitis, ocular hypertension, retinopathy, conjunctivitis, scleritis, retinitis, keratitis, corneal ulcer, iritis, Chorioretinal inflammation, macular edema, Xerophthalmia
Pulmonary disease asthma, pulmonary hypertension, acute respiratory distress syndrome, COPD, emphysema, pneumonia, tuberculosis, bronchitis, Acute Bronchitis, Bronchiectasis, Bronchiolitis, Bronchopulmonary Dysplasia, Byssinosis, Coccidioidomycosis (Cocci), Cystic Fibrosis, Influenza, Lung Cancer, Mesothelioma
Metabolic diseases; Hypercalciuria, Hyperglycemia, Hyperinsulinemic hypoglycemia, Hyperinsulinism, Hyperlysinuria, Hypoglycemia
Exocrine and Endocrine; Addison's disease, Hypoaldosteronism, cushing's syndrome, diabetes, Goitre, Hyperthyroidism, Hypothyroidism, Thyroiditis, pancreatitis
Hepatic disorders, Hepatitis, Non-alcoholic fatty liver disease, cirrhosis, hepatic cancer, Primary sclerosing cholangitis, primary biliary cirrhosis, Budd-Chiari syndrome,
Autoimmune and Inflammatory diseases, multiple sclerosis rheumatoid arthritis, psoriasis, diabetes, sarcoidosis, Addison's Disease, Alopecia areata, Amyotrophic Lateral Sclerosis, Ankylosing Spondylitis, polyarticular Arthritis, Atopic allergy, topic Dermatitis, Autoimmune hepatitis, Celiac disease, Chagas disease, Coeliac Disease, Cogan syndrome, Crohns Disease, Cushing's Syndrome, Diabetes mellitus type 1, Endometriosis, Eosinophilic fasciitis, Fibromyalgia/Fibromyositis, Gastritis, Glomerulonephritis, Graves' disease. Guillain-Barré syndrome (GBS), Hashimoto's encephalitis, Hashimoto's thyroiditis, Haemolytic anaemia, idiopathic inflammatory Demyelinating Diseases, Idiopathic pulmonary fibrosis, interstitial cystitis, Juvenile idiopathic arthritis, Juvenile rheumatoid arthritis, Kawasaki's Disease, Lichen sclerosus, Lupus erythematosus, Ménière's disease, Myasthenia gravis, myositis, Narcolepsy, Pernicious anaemia, Perivenous encephalomyelitis, Polymyalgia rheumatica, Primary biliary cirrhosis, Psoriatic Arthritis, Reiter's syndrome, Rheumatoid fever, Sarcoidosis, Schizophrenia, Sjögren's syndrome, Spondyloarthropathy, Ulcerative Colitis
Musculoskeletal disorders: osteoarthritis, osteoporosis, Osteonecrosis, Arthritis Paget's Disease Bursitis, Costochondritis, Tendonitis
Skin disorders; Acne, alopecia, candidiasis, celluliltis, dermatitis, eczema, epidermolysis bullosa, erythrasma, herpes, erysipelas, Folliculitis, impetigo, ringworm, scabies, Tinea, Trichomycosis
ENT disorders; Otitis, sinusitis, laryngitis, pharyngitis, laryngitis, meniere's disease, labyrinthitis,
Others: acute and chronic pain, viral infection, cancer, laryngitis, mastoiditis, myringitis, otitis media, rhinitis, sinusitis, Sialadenitis, Retropharyngeal Abscess, Tonsillopharyngitis,
Irritable bowel syndrome (IBS) necrotizing entercolitis (NEC) non-ulcer dyspepsia, chronic intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstructioduodenogastric reflux, gastroesophageal reflux disease, ileus inflammation, gastroparesis, heartburn, constipation—(e.g. constipation associated with use for medications such as opioids), colorectal cancer, colonic polyps, diverticulitis, colorectal cancer, Barretts Esophagus, Bleeding in the Digestive Tract, Celiac Disease, Colon Polyps, Constipation, Crohns Disease, Cyclic Vomiting Syndrome, Delayed Gastric Emptying (Gastroparesis), Diarrhea, Diverticulosis, Duodenal Ulcers, Fecal Incontinence, Gallstones, Gas in the Digestive Tract, Gastritis, Gastroesophageal Reflux Disease (GERD), Heartburn, Hiatal Hernia, Hemochromatosis, Hemorrhoids, Hiatal Hernia, Hirschsprung's Disease, Indigestion, Inguinal Hernia, Lactose Intolerance, Peptic Ulcers, Polyps, Porphyria, Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, Proctitis, Rapid Gastric Emptying, Short Bowel Syndrome, Stomach Ulcers, Ulcerative Colitis, Ulcers, Whippies Disease
Said active agent or agents may be selected from the following:
Gastro Drugs
Antacids—aluminium hydroxide, magnesium carbonate, magnesium trisilicate, hydrotalcite, simeticonealginates,
Antispasmodics—atropine sulphate, dicycloverine hydrochloride, hyoscine butylbromine, propantheline bromide, alverine citrate, mebeverine hydrochloride,
Motility stimulants—metoclorpramide, domperidone
H2-Receptor antagonists—Cimetidine, famotidinenizatidine, ranitidine
Antimuscarinics—pirenzepine
Chelates—Tripotassium dicitratbismuthate, sucralfate,
Prostaglandin analogues—misoprostol
Aminosalicylates—balsazide sodium, mesalazine, olsalazine, sulphasalazine
Corticosteroids—beclometasone dipropionate, budenoside, hydrocortisone, pednisolone,
Affecting immune response—ciclosporin, mercaptopurine, methotrexate, adalimumab, infliximab
Stimulant Laxatives—bisacodyl, dantron, docusate, sodium picosulfate,
Drugs affecting biliary composition and flow—ursodeoxycholic acid
Bile acids sequestrants—colestyramine, Oxyphencyclimine, Camylofin
Mebeverine, Trimebutine, Rociverine, Dicycloverine, Dihexyverine, Difemerine, Piperidolate Benzilone, Mepenzolate, Pipenzolate, Glycopyrronium, Oxyphenonium, Penthienate, Methantheline, Propantheline, Otilonium bromide, Tridihexethyl, Isopropamide, Hexocyclium, Poldine, Bevonium, Diphemanil, Tiemonium iodide, Prifinium bromide, Timepidium bromide, Fenpiverinium Papaverine, Drotaverine, Moxaverine 5-HT3 antagonists (Alosetron, Cilansetron), 5-HT4 agonists (Mosapride, Prucalopride, Tegaserod) Fenpiprane, Diisopromine, Chiorbenzoxamine, Pinaverium, Fenoverine, Idanpramine, Proxazole, Alverine, Trepibutone, Isometheptene, Caroverine, Phloroglucinol, Silicones, Trimethyldiphenylpropylamine Atropine, Hyoscyamine Scopolamine (Butylscopolamine, Methylscopolamine), Methylatropine, Fentonium, Cimetropium bromide primarily dopamine antagonists (Metoclopramide/Bromopride, Clebopride, Domperidone, Alizapride), 5-HT4 agonists (Cinitapride, Cisapride),
Proton pump inhibitors Omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole sodium,
opioids and opiod receptor antagonists—e.g. codeine, morphine, loperamide, diphenoxylate, methylnaltrexone bromide
Analgesic Acetaminophen Diclofenac Diflunisal Etodolac Fenoprofen Flurbiprofen Ibuprofen Indomethacin Ketoprofen Ketorolac Meclofenamate Mefenamic Acid Meloxicam Nabumetone Naproxen Oxaprozin Phenylbutazone Piroxicam Sulindac Tolmetin Celecoxib Buprenorphine Butorphanol Codeine Hydrocodone Hydromorphone Levorphanol Meperidine Methadone Morphine Nalbuphine Oxycodone Oxymorphone Pentazocine, Propoxyphene Tramadol codeine
Sleep drugs Hypnotics—Nitrazepam, Flurazepam, Loprazolam, Lormetazepam, Temazepam, Zaleplon, Zolpidem, Zopiclone, Chloral Hydrate, Triclofos, Clomethiazole, Quazepam, triazolam Estazolam Clonazepam, Alprazolam, Eszopiclone, Rozerem, Trazodone, Amitriptyline Doxepin, Benzodiazepine drugs, melatonin, diphenhydramine and herbal remedies such as Valerian
Cardiovascular Medicines
Cardiac glycosides—Digoxin, digitoxin,
Phosphodiesterase Inhibitors—enoximone, milrinone
Thiazides and related diuretics—bendroflumethiazide, chlortalidone, cyclopenthiazide, inapamide, metolazone, xipamide
Diuretics—furosemide, bumetanide, torasemide,
Potassium sparing diuretics and aldosterone antagonists—amiloride hydrochioride, triamterene, weplerenone, spironolactone,
Osmotic diuretics—mannitol
Drugs for arrhythmias—adenosine, amiodarone hydrochloride, disopyramide, flecainide acetate, propafenone hydrochloride, lidocaine hydrochloride,
Beta adrenoreceptor blocking drugs—propanalol, atenolol, acebutolol, bisprolol fumarate, carvedilol, celiprolol, esmolol, lebatolol, metoprolol tartrate, nadolol, nebivolol, oxprenolol, pindolol, solatol, timolol,
Hypertension—ambrisentan, bosentan, diazoxide, hydralazine, iloprost, minoxidil, sildenafil, sitaxentan, sodium nitroprusside, clonidine, methyldopa, moxonidine, guanethidine monosulphate, doxazosin, indoramin, prazosin, terazosin, phenoxybenzamine, phentolamine mesilate,
Drugs affecting the renin-angiotensin system—Captropril, Cilazapril, Enalapril Maleate, Fosinopril, Imidapril, Lisinopril, Moexipril, Perindopril Erbumine, Quinapril, Ramipril, Trandolapril, Candesartan Cilexetil, Eprosartan, Irbesartan, Losartan, Olmesartan Medoxomil, Telmisartan, Valsartan, Aliskiren.
Nitrates, calcium channel Blockers and antianginal drugs—Glyceryl trinitrate, Isosorbide Dinitrate, Isosorbide Mononitrate, Amlodipine, Diltiazem, Felodipine, Isradipine, Lacidipine, Lercanidipine, Nicardipine, Nifedipine, Nimodipine, Verapamil, Ivabradine, Nicorandil, Ranolazine,
Peripheral Vasodilators and related drugs—Cilostazol, Inositol Nicotinate, Moxisylyte, Naftidrofuryl Oxalate, Pentoxifylline,
Sympathomimetics—Dopamine, Dopexamine, Ephedrine, Metaraminol, Noradrenaline Acid Tartrate, Norephidrine Bitartrate, Phenylephidrine,
Anticoagulants and Protamine—Heparin, Bemiparin, Dalteparin, Enoxaparin, Tinzaparin, Danaparoid, Bivalirudin, Lepirudin, Epoprostenol, Fondaprinux, Warfarin, Acenocoumarol, Phenindione, Dabigatran Etexilate, Rivaroxaban, Protamine Sulphate,
Antiplatelet Drugs—Abciximab, Asprin, Clopidogrel, Dipyridamole, Eptifibatide, Prasugrel, Tirofiban,
Fibrinolytic and antifibrinolytic Drugs—Alteplase, Reteplase, Streptokinase, Tenecteplase, Urokinase, Etamsylate, Tranexamic Acid,
Lipid Regulating Drugs—Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, Simvastatin, Colesevam, Colestyramine, Colestipol, Ezetimibe, Bezafibrate, Ciprofibrate, Fenofibrate, Gemfibrozyl, Acipmox, Nictotinic Acid, Omega three fatty acid compounds, Ethanolamine Oleate, Sodium Tetradecyl Suphate.
CNS Drugs—Benperidol, Chlorpromazine, Flupentixol; Haloperidol, Levomepromazine, Pericyazine, Perphenazine, Pimozide, Prochlorperazine, Promazine, Sulpiride, Trifluoperazine, Zuclopenthixol, Amisulpride, Aripiprazole, Clozapine, Olanzapine, Paliperidone, Quetiapine, Riperidone, Sertindole, Zotepine, Flupentixol, Fluphenazine, Olanzapine Embonate, Pipotiazine Palmitate, Risperidone, Zuclopenthixol Decanoate, Carbamazepine, Valproate, Valproic acid, Lithium Carbonate, Lithium Citrate, Amitriptyline, Clomipramine, Dosulepin, Imipramine, Lofepramine, Nortriptyline, Trimipramine, mianserin, Trazodone, Phenelzine, Isocarboxazid, Tranylcypromine, Moclobemide, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Agomelatine, Duloxetine, Flupentixol, Mirtazapine, Reboxetine, Trytophan, Venflaxine, Atomoxetine, Dexametamine, Methylphenidate, Modafinil, Eslicarbazepine, Ocarbazepene, Ethosuximide, Gabapentin, Pregabalin, Lacosamide, Lamotrigine, Levetiracetam, Phenobarbital, Primidone, Phenytoin, Rufinamide, Tiagabine, Topiramate, Vigabatrin, Zonisamide, ropinirole, Rotigotine, Co-Beneldopa, Levodopa, Co-Careldopa, Rasagiline, Selegiline, Entacapone, Tolcapone, Amantidine, Orphenadrine, Procyclidine, Trihexyphenidyl, Haloperidol, Piracetam, Riluzole, Tetrabenazine, Acamprosate, Disulfiram, Bupropion, Vareniciline, Buprenorphine, Lofexidine, Donepezil, Galantamine, Memantine, Rivastigimine.
Anti-Infectives—Benzylpenicillin, Phenoxymethylpenicillin, Flucloxacillin, Temocillin, Amoxicillin, Ampicillin, Co-Amoxiclav, Co-Fluampicil, Piperacillin, Ticarcillin, Pivmecillinam, Cephalosporins, Cefaclor, Cefadroxil, Cefalexin, Cefixime, Cefotaxime, Cefradine, Ceftazidime, Cefuroxime, Ertapenem, Imipenem, Meropenem, Aztreonam, Tetracycline, Demeclocycline, Doxocycline, Lymecycline, Minocycline, Oxytetracycline, Tigecycline, Gentamicin, Amikacin, Neomycin, Tobramycin, Erythromycin, Azithromycin, Clarithromycin, Telithromycin, Clindamycin, Chloramphenicol, Fusidic Acid, Vancomycin, Teicoplanin, Daptomycin, Linezolid, Quinupristin, Colistin, Co-Trimoxazole, Sulpadiazine, Trimethoprim Capreomycin, Cycloserine, Ethambutol, Isoniazid, Pyrazinamide, Rifabutin, Rifampicin, Streptomycin, Dapsone, Clofazimine, Metronidazole, Tinidazole, Ciproflaxacin, Levoflaxacin, Moxifloxacin, Nalidixic Acid, Norflaxine, Orfilaxacin, Nitrofurantoin, Methenamine Hippurate, Amphotericin, Anidulafungin, Caspofungin, Fluconazole, Flucytosine, Griseofluvin, Itraconzole, Ketoconazole, Micafungin, Nystatin, Posaconazole, Terbinafine, Voriconazole, Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir Disoproxil, Zidovudine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinair, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Efavirenz, Etravirine, Nevarapine, Enfuvirtide, Maraviroc, Raltegravir, Aciclovir, Famciclovir, Inosine Pranobex, Valaciclovir, Cidofovir, Gangciclovir, Foscarnet, Valgangciclovir, Adefovir Dipivoxil, Entecavir, Telbivudine, Amantadine, Oseltamivir, Zanamivir, Palivizumab, Ribavirin, Artemether, Chloroquine, MefloquinePrimaquine, Proguanil, Pyrimethamine, Quinine, Doxycyclin, Diloxanide Furoate, Metronidaziole, Tinidazole, MepacrineSodium Stibogluconate, Atovaquone, Pentamidine Isetionate, Mebendazole, Piperazine,
Benztropiprocyclidine biperiden, Amantadine Bromocriptine Pergolide Entacapone Tolcapone Selegeline Pramipexole, budesonide, formoterol, quetiapine fumarate, olanzapine, pioglitazone, montelukast, Zoledromic Acid, valsartan, latanoprost, Irbesartan, Clopidogrel, Atomoxetine, Dexamfetamine, Methylphenidate, Modafinil, Bleomycin, Dactinomycin, Daunorubicin, Idarubicin, Mitomycin, Mitoxantrone, Azacitidine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Fludarabine, Flourouracil, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemetrexed, Raltitrexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, Deflazacort, Dexamethosone, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Ciclosporine, Sirolimus, Tacrolimus, Interferon Alpha, Interferon Beta,
In a particularly preferred embodiment the active agent is designed to treat arthritis and/or acute pain and as such the active agent is preferably an NSAID, such as diclofenac.
The term "active agent" is understood to include solvates (including hydrates) of the free compound or salt, crystalline and non-crystalline forms, as well as various polymorphs. For example, the active agent can include all optical isomers of the compounds and all pharmaceutically acceptable salts thereof either alone or in combination threo isomers can be indicated as "threo" and the combined erythro isomers as "erythro".
In accordance with the invention, formulations are provided which are to be taken by a subject and which initially administer a portion of the active agent when the subject first takes the formulation and moreover at a later time point a further portion of the agent is administered to the subject. Preferably the immediate and/or delayed administration may be by way of a pulsed dose, where said portion of active agent is substantially delivered within about 5-45 mins, such as 10-30 mins.
The present inventors identified the need to be able to administer a pain relieving/anti-inflammatory drug to a subject before the subject went to bed, but recognised that often subjects feel pain immediately upon waking and if they were to take pain relief once awake, there would be a period of time when they suffered pain.
The present inventors therefore developed formulations which as well as delivering pain/anti-inflammatory relief prior to sleep, also deliver pain/anti-inflammatory relief shortly before waking and hence serve to improve pain management by the subject.
LH-32 is a particular type of low substituted hydroxypropyl cellulose (L-HPC) and may be obtained from Shin-Etsu Chemical Co., Ltd., Tokyo, Japan. L-HPCs are insoluble in water and comprise a glucose backbone which is substituted to a minimal extent by hydroxypropyl groups. LH-32 is micronised, with a mean particle diameter of 20 □m LH-32 has a molecular weight of around 115,000 and a hydroxypropyl cellulose content of around 8%.
The wax may be any suitable wax such as beeswax, carnuba wax, microcrystalline wax, hydrogenated castor oil. A particularly preferred wax is a glyceryl ester, such as glycerol behenate.
In a preferred formulation of the present invention as defined herein above, the wax and LH-32 are present in a ratio of 40:60 to 60:40 w/w. More preferably the ratio is 45:55 to 55:45 w/w, or 50:50 w/w. The skilled addressee will appreciate that with appropriate variation of the ratio, the delay in drug release can be tailored for a particular application. For example, a 50:50 w/w ratio of glycerol behenate as a wax, with LH-32 employed as a delayed release layer in accordance with the present invention, is observed to provide a delayed release of approximately 6 hours. However, the same ratio with LH-21 as the L-HPC provides a delay in release of only 2 hours. Thus with appropriate control of the ratio of wax to L-HPC and the type of wax/L-HPC, it is possible to control the time delay in release of the active agent, from a press-coated tablet comprising a delayed release layer surrounding a core comprising the active agent.
The delayed release layer surrounding the core may also comprise an amount of an active agent or agents, which may be the same or different to the active agent in the core and/or top layer, and which is designed to be released during dissolution/disintegration of the delayed release layer.
The top layer comprises an active ingredient for immediate release and generally comprises one or more excipients, such as a sugar and/or an L-HPC.
The subject to be treated is an animal, e.g. a mammal, especially a human.
The amount of active agent to be administered will be sufficient to be therapeutic or prophylactic. By therapeutic or prophylactic is meant one capable of achieving the desired response, and will be adjudged, typically, by a medical practitioner. The amount required will depend upon one or more of at least the active compound(s) concerned, the patient, the condition it is desired to treat or prevent and the formulation. However, it is likely to be in the order of from 1 μg to 1 g of compound per kg of body weight of the patient being treated.
Different dosing regimes may likewise be administered, again typically at the discretion of the medical practitioner. The formulation of the present invention may allow for at least daily administration although regimes where the compound(s) is (or are) administered more infrequently, e.g. every other day, weekly or fortnightly, for example, are also embraced by the present invention.
By treatment is meant herein at least an amelioration of a condition suffered by a patient; the treatment need not be curative (i.e. resulting in obviation of the condition). Analogously references herein to prevention or prophylaxis herein do not indicate or require complete prevention of a condition; its manifestation may instead be reduced or delayed via prophylaxis or prevention according to the present invention.
For use according to the present invention, the compounds or physiologically acceptable salt, solvate, ester or other physiologically acceptable functional derivative thereof described herein are presented in a press-coated tablet form comprising the compound or physiologically acceptable salt, ester or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable excipients therefore and optionally other therapeutic and/or prophylactic ingredients. Any excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The tablets of the present invention may be prepared using reagents and techniques readily available in the art and/or exemplary methods as described herein.
The tablets include those suitable for oral, rectal or vaginal administration. The tablets may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy.
Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent, together with the materials for forming the delayed release layer. The tablets also comprise a top-coat comprising a portion of the active agent for immediate release.
Tablets suitable for rectal administration are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of a tablet with the softened or melted carrier(s) followed by chilling and shaping in moulds.
The tablets of the present invention may be prepared using pharmaceutical processes namely by direct compression or by granulation processing and final tableting. The process may comprise the steps of initially forming a core comprising the active agent and subsequently surrounding core with the delayed release layer and a further top layer. The core may be formed by dispersing one or more active agents with one or more excipients, such as a sugar, microcrystalline cellulose talc, dicalcium phosphate and the like.
The delayed release layer may be formed by melting the wax component and subsequently admixing the other components including the LH-32. The mixture may then be allowed to cool and solidify before being ground and/or forced through a sieve, in order to achieve granules of the size range 500 □m-1 mm. The core may then be coated with the delayed release layer material by direct compression. Typically the core is sandwiched between top and bottom layers of the delayed release material and hence completely surrounds the core.
At the same time, the top-coating layer may be press-coated on top of the delayed release layer. The top-coating may be formed by blending together the active agents and one or more excipients, such as a sugar (e.g. lactose) and a L-HPC, such as LH-21.
The tableting for the formulation of tablets may be conducted using an apparatus ordinarily employed for the formation or granulation of tablets. Examples may include single-punch tableting machine, rotary tableting machine and tableting tester.
Tableting is conducted usually under a pressure of 50 to 300 MPa, preferably 80 to 200 MPa. At a pressure less than 50 MPa, the resulting tablet may have insufficient hardness, which disturbs easily handling, while pressures exceeding 300 MPa may serve to cause a delay in disintegration.
The core, delayed release layer and/or top-coating layer may include a filler, such as a water insoluble filler, water soluble filler, and mixtures thereof. The water insoluble filler, may be a calcium salt or talc. Exemplary water soluble fillers such as water soluble sugars and sugar alcohols, preferably lactose, glucose, fructose, mannose, galactose, the corresponding sugar alcohols and other sugar alcohols, such as mannitol, sorbitol, and xylitol.
The filler in one of the layers can be the same or different as the filler in another layer, if any. For example, the core composition can include a water-soluble filler while the top-coat composition can include a water insoluble filler.
Other excipients can also be present in the core delayed release layer and/or top-coating layer, including lubricants (such as talc and magnesium stearate), glidants (such as fumed or colloidal silica), pH modifiers (such as acids, bases and buffer systems), and pharmaceutically useful processing aids. It will be appreciated that such other excipients may be the same or different in the core and delayed release layer, if any.
In a preferred embodiment of the invention, the core components (active agent and optional excipients) are blended together and compressed into suitable cores. The blending can take place in any order of addition. Preferably, the cores are blended by starting with the smallest volume component and then successively adding the larger volume components.
The present invention will now be further described by way of example and with reference to the figures which show:
FIG. 1 shows the release profile of a tablet formulation comprising an immediate release top-coating and a delayed release layer of 50:50 w/w glycerol behenate:LH-32;
FIG. 3 shows Gamma Scintigraphy imaging of In-vivo release of controlled release Diclofenac formulation. Radiolabel was incorporated in the delayed release layer only and so only the delayed release is being visualised; and
FIG. 4 shows the analysis of blood plasma levels of Diclofenac following administration of a controlled release formulation of Diclofenac, there is a period of time between drug release and detection in blood plasma as the drug is solubilised and absorbed by the body.
This formulation is designed to relieve night-time pain (eg in arthritic patients) by releasing an immediate burst of diclofenac and then another after six hours.
Core Tablet Blend and Core Tablet Compression
(MW Diclofenac=296.2 and MW Diclofenac sodium=318.1)
(i) Diclofenac and excipients weighed into tared weigh boats and all except the magnesium stearate placed into an amber screw-top glass jar of sufficient volume (eg 125 ml) according to Table 1.
TABLE 1 API/Excipient Weight (g)
Diclofenac sodium 5.4 Ac-di-sol 1.3 Lactose 1.7 Magnesium stearate 0.6
(ii) These API/excipients blended (in the glass jar) using the Turbula mixer for 1 minute.
(iii) Magnesium stearate added and all blended for further 5 minutes 90 mg of this blend comprises each core tablet. 90 mg weighed into a tared weigh boat.
(iv) The 6.9 mm punch and die set used to compress 90 mg powder for 10 seconds at 1 ton using the IR press.
(v) Tablets stored in an amber glass screw-top jar until use.
Granules (to Surround Core Tablet)
(i) Glycerol behenate and LH-32 weighed into tared weigh boats according to Table 2:
TABLE 2 Excipient Weight (g)
GB 10 LH-32 10
(ii) GB placed in a glass beaker on a hot plate set at 100° C. Once the GB melted, LH-32 added gradually whilst stirring until a uniform mix is achieved.
(iii) The mix stirred continuously until cooled to room temperature. The granules are left for at least 30 min at room temperature before the next step.
(iv) The cooled granules forced through a 1 mm sieve (using a spatula and a brush) and collected on a 500 μm sieve so that the granules used are in the size range 500 μm-1 mm.
(v) Granules stored in amber glass screw-top jar until use.
Top Layer Blend
Diclofenac and excipients are weighed into tared weigh boats and all placed into an amber screw-top glass jar of sufficient volume (eg 125 ml) according to Table 3.
Diclofenac sodium 10.8 Lactose 8.6 LH-21 8.6
The API/excipients blended (in the glass jar) using the Turbula mixer for 15 minutes.
Formulation Compression
(i) A 13 mm die and matching flat-faced punches were used to compress the formulation. For 6 tablets, 12×250 mg granules (to surround core tablet) are weighed into tared weigh boats.
(ii) 250 mg granules placed onto the lower punch, core tablet dropped on and centralised (centralising tool) before placing the other 250 mg granules on top.
(iii) For 6 tablets, 6×140 mg top layer blend weighed into tared weigh boats.
(iv) 140 mg of the top layer blend added to the top granule layer.
(v) The formulation compressed at 5 ton for 3 minutes in a 13 mm die/punch set.
Dissolution (n=3) performed in 900 ml sodium phosphate buffer (0.01 M, pH 7) at 37° C., with UV analysis at 248 nm.
As can be seen in FIG. 1, a tablet is provided which provides an initial release of diclofenac, over about 10 minutes, followed by a delay of about 5.5. hours and a further release of diclofenac over about 30-40 mins.
This profile in FIG. 2 shows a dramatically shortened time between pulses of diclofenac e.g. with LH-21 instead, as compared to that with LH-32, thus rendering it inappropriate for the desired clinical application.
Clinical Trial Protocol
Diclofenac 50 mg immediate-release with diclofenac 50 mg delayed-release (6 hour time-delay)
Diclofenac Extraction from Plasma Calibration and Calculation of % Recovery
Preliminary Preparation:
1. Preparation of 100 ml stock solution of 3M Orthophosphoric acid (H3PO4, 98 9/mol)
(i) Using an 85% solution (VWR).
(ii) 3M=294 g/L, therefore 29.4 g in 100 ml.
(iii) Take 34.6 ml of the 85% VWR solution and make up to 100 ml with water in a volumetric flask.
2. Preparation of 1 L stock solution of Hexane:IPA, 90:10.
(i) Add 900 ml hexane and 100 ml IPA to a 1 L duran bottle. Wrap the top with parafilm for storage.
3. Ketoprofen (internal standard) stock solution (1 mg/ml)
(i) Weigh 100 mg into a weigh boat and transfer to a 100 ml volumetric flask. Add 60 ml mobile phase and dissolve. Make up to the 100 ml mark with mobile phase.
4. Diclofenac stock solutions
(i) Solution A: Weigh 100 mg diclofenac and make up to 100 ml with water in a volumetric flask (1 mg/ml).
(ii) Solution B: Take 10 ml from Solution A and make up to 100 ml with water in a volumetric flask (100 μg/ml).
(iii) Solution C: Take 10 μl of Solution A and make up to 1 ml with water (1 μg/ml).
Preparing the Standard Series of Diclofenac Solutions:
Add the required volume of either stock solution B or C to a small vial and make up to 1 ml with water as shown in the following table.
Required Conc. Vol stock Standard (μg/ml) sol. (μl) Vol H2O (μl) In 100 μl (ng)
1 0.25 250 (C) 750 25 2 0.5 500 (C) 500 50 3 1.0 10 (B) 990 100 4 2.5 25 (B) 975 250 5 5.0 50 (B) 950 500 6 10 100 (B) 900 1000 7 20 200 (B) 800 2000 8 30 300 (B) 700 3000
Extraction Procedure:
(i) Add 1 ml blank plasma to each of 8 plastic 15 ml centrifuge tubes
(ii) Add 100 μl of the diclofenac stock solutions to each
(iii)Vortex for 1 min
(iv)Add 1 ml of 3M Orthophosphoric acid to each
(v) Add 5 ml of hexane:isopropyl alcohol, 90:10
(vi) Vortex for 3 min
(vii) Centrifuge at 2000 rpm for 3 min
(viii) Extract the top (solvent) layer and transfer to a clean centrifuge tube
(ix) Evaporate the solvent to dryness under nitrogen
(x) Reconstitute residue in 100 μl mobile phase
(xi)Add 10 μl internal standard stock solution to each
(xii) Vortex
(xiii) Inject 50 μl.
The on column mass for each sample is as follows:
On column mass Sample (ng)
1 12.5 2 25 3 50 4 125 5 250 6 500 7 1000 8 1500
Clinical studies were carried out in Healthy male volunteers aged between 18-65 years inclusive with a body mass index (BMI) between 18.0 and 29.9 kg/m2. Subjects received a standard dinner comprising roast chicken with salad, low fat yoghurt and one cup of decaffeinated tea, coffee or juice 2 hours prior to dosing.
Gastrointestinal transit of the delayed-release tablets was characterised by inclusion of a radiolabel marker, technetium-99m (99mTc), complexed with diethylenetriaminepentaacetic acid (DTPA) which prevents absorption from the gastrointestinal tract. The radiolabel is incorporated into the core tablet. Each tablet was radiolabelled with 4 MBq 99mTc-DTPA and administered with 240 ml of water at bedtime.
Scintigraphic imaging was performed using a Siemens E-Cam gamma camera fitted with a low-energy high-resolution collimator. Subjects were imaged in a standing position except during periods of sleep where the subjects were imaged lying down. Anterior static acquisitions of 25-second duration each were collected immediately after dosing then every 30 minutes until 3 hours post-dose then every 15 minutes until complete release of radiolabel marker.
A 5 mL pre-dose blood sample was taken from each subject 15 minutes before dosing. Following dosing blood samples were taken. Every 15 minutes until 2 hours post-dose then every 30 minutes until burst release observed by scintigraphy then every 15 minutes for 2 hours then every 30 minutes for 1 hour then hourly until end of study day (15 hours post-dose). See FIG. 3.
Blood samples were centrifuged at 2000 g for 10 minutes and the plasma fraction removed and stored at −20° C. for subsequent analysis. See FIG. 4.
17. A press-coated tablet formulation for an immediate, followed by a delayed release of an active agent, the tablet comprising:
(b) a delayed release layer surrounding the core and comprising a wax and a low substituted hydroxypropyl cellulose in a ratio of 40:60 to 60:40 w/w; wherein the delayed release layer substantially delays release of the active agent within the core for between 3-8 hours after administration of the tablet to a subject and thereafter a pulsed release of the active agent from the core occurs, such that at least 70% of the active agent in the core is released within 5-45 minutes and wherein the low substituted hydroxypropyl cellulose is micronized with a mean particle diameter of 20 μm and has a molecular weight of 115,000 and a hydroxypropyl cellulose content of 8%; and
18. The press-coated tablet according to claim 17 further comprising an amount of an active agent, which is the same or different to the active agent in the core and/or top-coating layer, in the delayed release layer.
19. The press-coated tablet according to claim 17, comprising an active agent which is designed to treat arthritis and/or acute pain.
20. The press-coated tablet according to claim 17 wherein the wax is selected from the group consisting of beeswax, carnuba wax, microcrystalline wax, hydrogenated castor oil, and a glyceryl ester.
21. The press-coated tablet according to claim 22 wherein the glyceryl ester is glycerol behenate.
22. The press-coated tablet according to claim 17 wherein the wax and the low substituted hydroxypropyl cellulose are present in a ratio of 45:55 to 55:45 w/w.
23. The press-coated tablet according to claim 24 wherein the wax and the low substituted hydroxypropyl cellulose are present in a ratio of 50:50 w/w ratio and wherein the wax is glycerol behenate.
24. The press-coated tablet according to claim 17, further comprising one or more of the following active agents:
Antacids selected from the group consisting of aluminium hydroxide, magnesium carbonate, magnesium trisilicate, hydrotalcite, and simeticonealginates;
Antispasmodics selected from the group consisting of atropine sulphate, dicycloverine hydrochloride, hyoscine butylbromine, propantheline bromide, alverine citrate, and mebeverine hydrochloride;
Motility stimulants selected from the group consisting of metoclorpramide and domperidone;
H2-Receptor antagonists selected from the group consisting of Cimetidine, famotidinenizatidine, and ranitidine;
Antimuscarinics;
Chelates selected from the group consisting of Tripotassium dicitratbismuthate and sucralfate;
Prostaglandin analogues;
Aminosalicylates selected from the group consisting of balsazide sodium, mesalazine, olsalazine, and sulphasalazine;
Corticosteroids selected from the group consisting of beclometasone dipropionate, budenoside, hydrocortisone, and prednisolone;
Affecting immune response selected from the group consisting of ciclosporin, mercaptopurine, methotrexate, adalimumab, and infliximab;
Stimulant Laxatives selected from the group consisting of bisacodyl, dantron, docusate, and sodium picosulfate;
Drugs affecting biliary composition and flow;
Bile acids sequestrants selected from the group consisting of colestyramine, Oxyphencyclimine, Camylofin, Mebeverine, Trimebutine, Rociverine, Dicycloverine, Dihexyverine, Difemerine, Piperidolate, Benzilone, Mepenzolate, Pipenzolate, Glycopyrronium, Oxyphenonium, Penthienate, Methantheline, Propantheline, Otilonium bromide, Tridihexethyl, Isopropamide, Hexocyclium, Poldine, Bevonium, Diphemanil, Tiemonium iodide, Prifinium bromide, Timepidium bromide, Fenpiverinium, Papaverine, Drotaverine, Moxaverine, 5-HT3 antagonists, 5-HT4 agonists, Fenpiprane, Diisopromine, Chlorbenzoxamine, Pinaverium, Fenoverine, Idanpramine, Proxazole, Alverine, Trepibutone, Isometheptene, Caroverine, Phloroglucinol, Silicones, Trimethyldiphenylpropylamine, Atropine, Hyoscyamine, Scopolamine, Butylscopolamine, Methylscopolamine, Methylatropine, Fentonium, Cimetropium bromide, and primarily dopamine antagonists;
Proton pump inhibitors selected from the group consisting of Omeprazole, lansoprazole, pantoprazole, esomeprazole, and rabeprazole sodium;
Opioids and opioid receptor antagonists;
Analgesics selected from the group consisting of Acetaminophen, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Meclofenamate, Mefenamic Acid, Meloxicam, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Sulindac, Tolmetin, Celecoxib, Buprenorphine, Butorphanol, Codeine, Hydrocodone, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxymorphone, Pentazocine, Propoxyphene, and Tramadol;
Sleep drugs selected from the group consisting of Nitrazepam, Flurazepam, Loprazolam, Lormetazepam, Temazepam, Zaleplon, Zolpidem, Zopiclone, Chloral Hydrate, Triclofos, Clomethiazole, Quazepam, triazolam, Estazolam, Clonazepam, Alprazolam, Eszopiclone, Rozerem, Trazodone, Amitriptyline, Doxepin, Benzodiazepine drugs, melatonin, diphenhydramine, and herbal remedies;
Cardiac glycosides selected from the group consisting of Digoxin and digitoxin;
Phosphodiesterase inhibitors selected from the group consisting of enoximone and milrinone;
Thiazides and related diuretics selected from the group consisting of bendroflumethiazide, chlortalidone, cyclopenthiazide, inapamide, metolazone, and xipamide;
Diuretics selected from the group consisting of furosemide, bumetanide, and torasemide;
Potassium sparing diuretics and aldosterone antagonists selected from the group consisting of amiloride hydrochloride, triamterene, weplerenone, and spironolactone;
Osmotic diuretics;
Drugs for arrhythmias selected from the group consisting of adenosine, amiodarone hydrochloride, disopyramide, flecainide acetate, propafenone hydrochloride, and lidocaine hydrochloride;
Beta adrenoreceptor blocking drugs selected from the group consisting of propranolol, atenolol, acebutolol, bisoprolol fumarate, carvedilol, celiprolol, esmolol, lebatolol, metoprolol tartrate, nadolol, nebivolol, oxprenolol, pindolol, solatol, and timolol;
Hypertension drugs selected from the group consisting of ambrisentan, bosentan, diazoxide, hydralazine, iloprost, minoxidil, sildenafil, sitaxentan, sodium nitroprusside, clonidine, methyldopa, moxonidine, guanethidine monosulphate, doxazosin, indoramin, prazosin, terazosin, phenoxybenzamine, and phentolamine mesilate;
Drugs affecting the renin-angiotensin system selected from the group consisting of Captropril, Cilazapril, Enalapril Maleate, Fosinopril, Imidapril, Lisinopril, Moexipril, Perindopril Erbumine, Quinapril, Ramipril, Trandolapril, Candesartan Cilexetil, Eprosartan, Irbesartan, Losartan, Olmesartan Medoxomil, Telmisartan, Valsartan, and Aliskiren;
Nitrates, calcium channel Blockers, and antianginal drugs selected from the group consisting of Glyceryl trinitrate, Isosorbide Dinitrate, Isosorbide Mononitrate, Amlodipine, Diltiazem, Felodipine, Isradipine, Lacidipine, Lercanidipine, Nicardipine, Nifedipine, Nimodipine, Verapamil, Ivabradine, Nicorandil, and Ranolazine;
Peripheral vasodilators and related drugs selected from the group consisting of Cilostazol, Inositol Nicotinate, Moxisylyte, Naftidrofuryl Oxalate, and Pentoxifylline;
Sympathomimetics selected from the group consisting of Dopamine, Dopexamine, Ephedrine, Metaraminol, Noradrenaline Acid Tartrate, Norephidrine Bitartrate, and Phenylephidrine;
Anticoagulants and protamine selected from the group consisting of Heparin, Bemiparin, Dalteparin, Enoxaparin, Tinzaparin, Danaparoid, Bivalirudin, Lepirudin, Epoprostenol, Fondaprinux, Warfarin, Acenocoumarol, Phenindione, Dabigatran Etexilate, Rivaroxaban, and Protamine Sulphate;
Antiplatelet drugs selected from the group consisting of Abciximab, Asprin, Clopidogrel, Dipyridamole, Eptifibatide, Prasugrel, and Tirofiban;
Fibrinolytic and antifibrinolytic drugs selected from the group consisting of Alteplase, Reteplase, Streptokinase, Tenecteplase, Urokinase, Etamsylate, and Tranexamic Acid;
Lipid regulating drugs selected from the group consisting of Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, Simvastatin, Colesevam, Colestyramine, Colestipol, Ezetimibe, Bezafibrate, Ciprofibrate, Fenofibrate, Gemfibrozyl, Acipmox, Nictotinic Acid, Omega three fatty acid compounds, Ethanolamine Oleate, and Sodium Tetradecyl Suphate;
CNS Drugs selected from the group consisting of Benperidol, Chlorpromazine, Flupentixol, Haloperidol, Levomepromazine, Pericyazine, Perphenazine, Pimozide, Prochlorperazine, Promazine, Sulpiride, Trifluoperazine, Zuclopenthixol, Amisulpride, Aripiprazole, Clozapine, Olanzapine, Paliperidone, Quetiapine, Riperidone, Sertindole, Zotepine, Flupentixol, Fluphenazine, Olanzapine Embonate, Pipotiazine Palmitate, Risperidone, Zuclopenthixol Decanoate, Carbamazepine, Valproate, Valproic acid, Lithium Carbonate, Lithium Citrate, Amitriptyline, Clomipramine, Dosulepin, Imipramine, Lofepramine, Nortriptyline, Trimipramine, mianserin, Trazodone, Phenelzine, Isocarboxazid, Tranylcypromine, Moclobemide, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Agomelatine, Duloxetine, Flupentixol, Mirtazapine, Reboxetine, Trytophan, Venflaxine, Atomoxetine, Dexametamine, Methylphenidate, Modafinil, Eslicarbazepine, Ocarbazepene, Ethosuximide, Gabapentin, Pregabalin, Lacosamide, Lamotrigine, Levetiracetam, Phenobarbital, Primidone, Phenytoin, Rufinamide, Tiagabine, Topiramate, Vigabatrin, Zonisamide, ropinirole, Rotigotine, Co-Beneldopa, Levodopa, Co-Careldopa, Rasagiline, Selegiline, Entacapone, Tolcapone, Amantidine, Orphenadrine, Procyclidine, Trihexyphenidyl, Haloperidol, Piracetam, Riluzole, Tetrabenazine, Acamprosate, Disulfiram, Bupropion, Vareniciline, Buprenorphine, Lofexidine, Donepezil, Galantamine, Memantine, and Rivastigimine;
Anti-Infectives selected from the group consisting of Benzylpenicillin, Phenoxymethylpenicillin, Flucloxacillin, Temocillin, Amoxicillin, Ampicillin, Co-Amoxiclav, Co-Fluampicil, Piperacillin, Ticarcillin, Pivmecillinam, Cephalosporins, Cefaclor, Cefadroxil, Cefalexin, Cefixime, Cefotaxime, Cefradine, Ceftazidime, Cefuroxime, Ertapenem, Imipenem, Meropenem, Aztreonam, Tetracycline, Demeclocycline, Doxocycline, Lymecycline, Minocycline, Oxytetracycline, Tigecycline, Gentamicin, Amikacin, Neomycin, Tobramycin, Erythromycin, Azithromycin, Clarithromycin, Telithromycin, Clindamycin, Chloramphenicol, Fusidic Acid, Vancomycin, Teicoplanin, Daptomycin, Linezolid, Quinupristin, Colistin, Co-Trimoxazole, Sulpadiazine, Trimethoprim, Capreomycin, Cycloserine, Ethambutol, Isoniazid, Pyrazinamide, Rifabutin, Rifampicin, Streptomycin, Dapsone, Clofazimine, Metronidazole, Tinidazole, Ciproflaxacin, Levoflaxacin, Moxifloxacin, Nalidixic Acid, Norflaxine, Orflaxacin, Nitrofurantoin, Methenamine Hippurate, Amphotericin, Anidulafungin, Caspofungin, Fluconazole, Flucytosine, Griseofluvin, Itraconzole, Ketoconazole, Micafungin, Nystatin, Posaconazole, Terbinafine, Voriconazole, Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir Disoproxil, Zidovudine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinair, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Efavirenz, Etravirine, Nevarapine, Enfuvirtide, Maraviroc, Raltegravir, Aciclovir, Famciclovir, Inosine Pranobex, Valaciclovir, Cidofovir, Gangciclovir, Foscarnet, Valgangciclovir, Adefovir Dipivoxil, Entecavir, Telbivudine, Amantadine, Oseltamivir, Zanamivir, Palivizumab, Ribavirin, Artemether, Chloroquine, Mefloquine, Primaquine, Proguanil, Pyrimethamine, Quinine, Doxycyclin, Diloxanide Furoate, Metronidaziole, Tinidazole, Mepacrine, Sodium Stibogluconate, Atovaquone, Pentamidine Isetionate, Mebendazole, and Piperazine; and
other drugs selected from the group consisting of Benztropine, procyclidine, biperiden, Amantadine, Bromocriptine, Pergolide, Entacapone, Tolcapone, Selegeline, Pramipexole, budesonide, formoterol, quetiapine fumarate, olanzapine, pioglitazone, montelukast, Zoledromic Acid, valsartan, latanoprost, Irbesartan, Clopidogrel, Atomoxetine, Dexamfetamine, Methylphenidate, Modafinil, Bleomycin, Dactinomycin, Daunorubicin, Idarubicin, Mitomycin, Mitoxantrone, Azacitidine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Fludarabine, Flourouracil, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemetrexed, Raltitrexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, Deflazacort, Dexamethosone, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Ciclosporine, Sirolimus, Tacrolimus, Interferon Alpha, and Interferon Beta.
25. The press-coated tablet according to claim 24, comprising one or more of the following active agents:
pirenzepine, misoprostol, ursodeoxycholic acid, Alosetron, Cilansetron, Mosapride, Prucalopride, Tegaserod, Metoclopramide, Bromopride, Clebopride, Domperidone, Alizapride, Cinitapride, Cisapride, Codeine, Morphine, loperamide, diphenoxylate, methylnaltrexone bromide, Valerian, and mannitol.
(b) a delayed release layer surrounding the core and comprising a wax and a low substituted hydroxypropyl cellulose in a ratio of 40:60 to 60:40 w/w; wherein the delayed release layer substantially delays release of the active agent within the core for between 3-8 hours, and thereafter a pulsed release of the active agent from the core occurs, such that at least 70% of the active agent in the core is released within 5-45 minutes; wherein the low substituted hydroxypropyl cellulose is micronized with a mean particle diameter of 20 μm and has a molecular weight of 115,000 and a hydroxypropyl cellulose content of 8%; and
(c) a top-coating layer comprising a portion of an active agent together with one or more excipients wherein a substantially immediate pulsed release of the active agent occurs following administration to the subject of the tablet;
wherein said release is measured in 900 ml of 0.01M sodium phosphate buffer at pH 7, at 37° C. as determined by UV analysis at 248 nm.
28. A method of alleviating pain and/or inflammation, the method comprising administering a press-coated tablet according to claim 17.
29. The method according to claim 28 wherein delayed release of the active is achieved by providing a press-coated tablet comprising a delayed release layer surrounding a core comprising the active agent.
30. The method according to claim 29 wherein the delayed release layer comprises a wax and a low substituted hydroxypropyl cellulose, wherein the low substituted hydroxypropyl cellulose is micronized with a mean particle diameter of 20 μm and has a molecular weight of 115,000 and a hydroxypropyl cellulose content of 8%.
Filed: Nov 19, 2018
Publication Date: May 2, 2019
Applicant: UNIVERSITY OF STRATHCLYDE (Glasgow)
Inventors: Alexander MULLEN (Glasgow), Howard STEVENS (Glasgow), Sarah ECCLESTON (Glasgow)
International Classification: A61K 9/20 (20060101); A61K 31/00 (20060101); A61K 31/196 (20060101); A61K 9/24 (20060101);


Former Governor Alamieyeseigha has died. According to Channels TV, he died of cardiac arrest at the University of Port Harcourt Teaching Hospital, after slipping into coma two days ago and was placed on life support.
The Bayelsa State Commissioner for Information, Esueme Dan-Kikili, who confirmed his death said that the death of the former governor was a great loss to the Ijaw ethnic group.
There were reports during the week that the British Government was determined to resurrect an outstanding case of money laundering against the former governor and had requested for his extradition to London.
Diepreye Alamieyeseigha was born in 16 November 1952 in Amassoma, Ogboin North Local Government Area,Bayelsa State. He attended the Bishop Dimeari Grammar School, Yenagoa. He joined the Nigerian Defence Academy as a Cadet Officer in 1974, then joined the Nigerian Air Force, where he served in the department of Logistics and Supply. He held various air force positions in Enugu, Markurdi, Kaduna and Ikeja. Alamieyeseigha retired from the air force in 1992 as a Squadron Leader.
After leaving the air force he became the Sole Administrator of Pabod Supplies Port Harcourt. Later he became Head of Budget, Planning, Research and Development of the National Fertiliser Company (NAFCON).
Diepreye Alamieyeseigha was impeached on allegations of corruption on 9 December 2005.
Diepreye Alamieyeseigha was elected Governor of Bayelsa State in May 1999 as a member of the ruling People's Democratic Party (PDP). He was re-elected in 2003. Vice President Atiku Abubakar attended the March 2003 event that kicked of his campaign for re-election.
Diepreye Alamieyeseigha was detained in London on charges of money laundering in September 2005. At the time of his arrest, Metropolitan police found about £1m in cash in his London home. Later they found a total of £1.8m ($3.2m) in cash and bank accounts. He has been found to own real estate in London worth an alleged £10 million. His state's monthly federal allocation for the last six years has been in the order of £32 million. He jumped bail in December 2005 from the United Kingdom by allegedly disguising himself as a woman, though Alamieyeseigha denies this claim.
On July 26, 2007, Alamieyeseigha pled guilty before a Nigerian court to six charges and was sentenced to two years in prison on each charge; however, because the sentences were set to run concurrently and the time was counted from the point of his arrest nearly two years before the sentences, his actual sentence was relatively short. Many of his assets were ordered to be forfeited to the Bayelsa state government. According to Alamieyeseigha, he only pled guilty due to his age and would have fought the charges had he been younger. On July 27, just hours after being taken to prison, he was released due to time already served.
In April 2009, Alamieyeseigha pledged a donation of 3,000,000 Naira to the Akassa Development Foundation.
In December 2009, the federal government hired a British law firm to help dispose of four expensive properties acquired by Alamieyeseigha in London. Alamieyeseigha had bought one of these properties for £1,750,000.00 in July 2003, paying in cash. Diepreye Solomon Peter Alamieyeseigha used it as his London residence, and as the registered office of Solomon and Peters Inc.
On June 28, 2012, the United States (US) Department of Justice (DoJ) announced that it had executed an asset forfeiture order on $401,931 in a Massachusetts brokerage fund, traceable to Alamieyeseigha. US prosecutors filed court papers in April 2011 targeting the Massachusetts brokerage fund and a $600,000 Maryland home, which they alleged were the proceeds of corruption. A motion for default judgement and civil forfeiture was granted by a Massachusetts federal district judge in early June 2012. The forfeiture order was the first to be made under the DoJ's fledgling Kleptocracy Asset Recovery Initiative.
On 12 March 2013, Alamieyeseigha was pardoned by President Goodluck Jonathan, but his pardoning was criticised by many.


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text:
Rockpile
The Rockpile AVA is located on 15,400 acres in Sonoma County, California. The AVA was established in 2002 and is located northwest of the town of Healdsburg. The name originates from a local mountain top named Rockpile Peak. The mountain has a steep elevation of over 800 feet above sea level. The steep slope of the Rockpile area is an average of 18 inches deep with small rocks and gravel mixed in the soil, which allows for excellent drainage. All of the elements of the soil combine to cause the vines to struggle mightily to produce, giving vines from Rockpile low yields and intense fruit flavors. The high elevation of the region means that the vines are above the fog line that creeps in from the Pacific Ocean and makes for a very moderate climate. The area is most well known for its production of Cabernet Sauvignon, Petite Sirah, and Zinfandel.
Rockpile Ranch was founded in 1867 by Tennessee Carter Bishop who started as a sheep farm but later planted the first wine grapes in the area in 1872. He was joined in the endeavor by S.P. Hallengren whose descendants continue to produce wine grapes in the appellation.

redpajama_set_name: RedPajamaCommonCrawl


text:
if False:
    from zulip import Client

def add_subscriptions(client):
    # type: (Client) -> None

    request = [
        dict(
            name='new stream',
            description='New stream for testing',
        )
    ]
    result = client.add_subscriptions(request)
    assert result['result'] == 'success'

def create_user(client):
    # type: (Client) -> None

    request = dict(
        email='newbie@zulip.com',
        full_name='New User',
        short_name='Newbie',
        password='temp',
    )
    result = client.create_user(request)
    assert result['result'] == 'success'

def get_members(client):
    # type: (Client) -> None

    result = client.get_members()
    assert result['result'] == 'success'
    members = [m for m in result['members'] if m['email'] == 'newbie@zulip.com']
    assert len(members) == 1
    iago = members[0]

    assert not iago['is_admin']
    assert iago['full_name'] == 'New User'

def get_profile(client):
    # type: (Client) -> None

    result = client.get_profile()
    assert result['is_admin']
    assert result['email'] == 'iago@zulip.com'
    assert result['full_name'] == 'Iago'

def get_stream_id(client):
    # type: (Client) -> None

    stream_name = 'new stream'
    result = client.get_stream_id(stream_name)
    assert int(result['stream_id'])

def get_streams(client):
    # type: (Client) -> None

    result = client.get_streams()
    assert result['result'] == 'success'
    streams = [s for s in result['streams'] if s['name'] == 'new stream']
    assert streams[0]['description'] == 'New stream for testing'

def get_subscribers(client):
    # type: (Client) -> None

    result = client.get_subscribers(stream='new stream')
    assert result['subscribers'] == ['iago@zulip.com']

def get_user_agent(client):
    # type: (Client) -> None

    result = client.get_user_agent()
    assert result.startswith('ZulipPython/')

def list_subscriptions(client):
    # type: (Client) -> None

    result = client.list_subscriptions()
    assert result['result'] == 'success'
    streams = [s for s in result['subscriptions'] if s['name'] == 'new stream']
    assert streams[0]['description'] == 'New stream for testing'

def remove_subscriptions(client):
    # type: (Client) -> None

    result = client.remove_subscriptions(['new stream'])
    assert result['result'] == 'success'

    # test it was actually removed
    result = client.list_subscriptions()
    assert result['result'] == 'success'
    streams = [s for s in result['subscriptions'] if s['name'] == 'new stream']
    assert len(streams) == 0

def render_message(client):
    # type: (Client) -> None

    request = dict(content='**foo**')
    result = client.render_message(request)
    assert result['result'] == 'success'
    assert result['rendered'] == '
foo
'

def send_message(client):
    # type: (Client) -> int

    request = dict(
        type='stream',
        to='Denmark',
        subject='Copenhagen',
        content='hello',
    )
    result = client.send_message(request)
    assert result['result'] == 'success'
    message_id = result['id']

    # test it was actually sent
    url = 'messages/' + str(message_id)
    result = client.call_endpoint(
        url=url,
        method='GET'
    )
    assert result['result'] == 'success'
    assert result['raw_content'] == 'hello'

    return message_id

def update_message(client, message_id):
    # type: (Client, int) -> None

    assert int(message_id)
    request = dict(
        message_id=message_id,
        content='new content',
    )
    result = client.update_message(request)
    assert result['result'] == 'success'

    # test it was actually updated
    url = 'messages/' + str(message_id)
    result = client.call_endpoint(
        url=url,
        method='GET'
    )
    assert result['result'] == 'success'
    assert result['raw_content'] == 'new content'

# SETUP METHODS FOLLOW

def test_messages(client):
    # type: (Client) -> None

    render_message(client)
    message_id = send_message(client)
    update_message(client, message_id)

def test_users(client):
    # type: (Client) -> None

    create_user(client)
    get_members(client)
    get_profile(client)

def test_streams(client):
    # type: (Client) -> None

    add_subscriptions(client)
    list_subscriptions(client)
    get_stream_id(client)
    get_streams(client)
    get_subscribers(client)

def test_the_api(client):
    # type: (Client) -> None

    get_user_agent(client)
    test_users(client)
    test_streams(client)
    test_messages(client)

    # print(dir(client))

redpajama_set_name: RedPajamaGithub


America's Vote has been cancelled this week for Have-Nots after the latest Care Package knocked Jason out of the running to become a Have-Not this week. As a result, things have defaulted to the only other three options and the vote was called off.
Normally this season (as if anything this season is normal) we'd be voting for which three HGs get to eat Slop for a week, but with only three HGs to vote between there's no point. Of course CBS could have dropped things down to just 2 HNs this week and still held a vote, but for some reason they decided against that.
Last week we saw Justin, Kryssie, and Whitney sent off to Have-Not land but now they're back and safe from a repeat this round. Then with Jason and Shelby as the Co-HoH's this week they were off the list too. Had Justin or Whitney won the ACP Co-HoH this week then we'd still have a vote since they were both outgoing HNs, ineligible for another week, and also eligible for ACP.
This week's Have-Nots: Alex, Danielle, and Morgan.
CBS posted a brief explanation of the change of plans stating, "due to this week's Care Package winner [Jason], only three Houseguests are eligible and will be the final Have-Nots." So there you also see there are no more HNs this season after this week.
Considering this is the last week it's too bad they didn't drop us down to two HNs and still let us have the final week of Slop voting, but oh well. We'll still have plenty of America's Vote to get us through the season though so keep checking back in for the latest events and voting in our polls!
I assumed that they would have dropped the Have-nots down to 2 HGs at this point in the season as well.
I think the viewers should vote for the have nots when the main show comes back in the summer.
That would be great. I like the third nominee thing as well.
What show are these Jason, and the LNJ fans watching? Rewarding them for their deplorable behavior is ridiculous!
Deplorable? You mean like most of America.
I agree. Oh well at least Jason can't get either of the remaining care packages. And we can nominate him next week. Get disgusting loser Krissie out this week.
I really hope Alex is 3rd nom!
Or Morgan. Either one will do.
It'll never happen. She has too many fans. On BOTH sides.
Me too. It depends if she is already up, then I'll vote for Danielle. I don't want to mess up Jason's alliance, but Kryssie gets on my nerves and since Whitney is with Justin, I think he'll be fine for now.
Jason is saving Kryssie and Justin and putting Danielle (who volunteered) on the block as she'll be able to win the veto more than Kryssie or Justin will. I want Kryssie gone, but with DE coming up and how they're choosing to play the ACP, maybe Kryssie can go lickity split in DE than having her out during the first eviction of the week. Most strategically are wanting Morgan to go OTB instead to break up the sister act. I've been going back and forth with the math. Logically the one America should nom is Morgan if Alex is already up, which is who Shelby is planning to put up (more chance to win veto than if she chose to put Whitney up), then one or the other sister is sure to go home, no matter how the cards fall. The plan is whoever is the better veto winner will determine which HoH gets dibs of pulling someone off the block and replacing them with the bigger threat to him/her. Kryssie can go in the DE much easier and leave us with the more "powerful" or better likable players in the house.
Lol. Exhausting read. I wouldn't mind Danielle leaving over Kryssie. Whichever of the two will be fine by me. If one of the girls from the other side goes it will be fine as well since I want either Jason or Justin to win, but Kryssie thinks America loves her and she needs a wake up call.
Can Danielle please stop mentioning her son in the DR? As all the others calm down with the shout outs, she gets worse and worse!
Am I the only one who laughed my way through Kryssie's entire DR?
She has no idea what's coming her way. Hint – it's a seat on the block!
Nope you weren't. Surely she can't believe she will get to the final 4 with Jason, Justin and Danielle? I about spit Pepsi out my nose on that comment.


Here are some stories you might find interesting — and the links to find out more about them.
Stablecoins remain stable as everything else crashes.
The biggest news this week must surely be the dramatic drop in the price of cryptocurrencies, including Bitcoin (BTC) and Ethereum (ETH). November 14 was the worst trading day of the year. BTC reached its lowest point since October 2017, dipping below $5,600 and losing nearly 13% on the day. ETH dropped to $175, losing nearly 16% on the day.
In 24 hours, $26 billion was wiped off the crypto market.
The following graphic provided by Bitcoin News tells the sorry tale — if it's red it means it lost on the day!
BCH was worst-hit, losing 18% of its value just a day before its hard fork. Within the past seven days, BCH has dropped by over 50% against the USD and by nearly 40% against BTC. It remains to be seen how it will emerge after the fork.
Yet, in the midst of this graphic of doom and gloom, there are a few green spots. Perhaps not surprisingly, these greens are for stablecoins, apparently living up to their mission of being stable.
Some of the dollar-pegged stablecoins that fared very well on 14 November were the trueusd (TUSD), which reached $1.07 and paxos (PAX) which reached $1.05. They were up about 15% on the day. The Gemini dollar (GUSD) rose to above $1.03.
Clearly, stablecoins are not immune to the market volatility. Tether (USDT) recently slipped as low as $0.88 on suspicions that it does not actually have the fiat dollars in the bank to back it. Bitusd, which can only be traded on the Hyperledger decentralized exchange, flash-crashed to $0.83 on 14 November, before recovering to $0.97. The Dai, a decentralized cryptocurrency which uses ETH as collateral, dropped to $0.97. This relatively low drop for the Dai is perhaps thanks to the way it has been set up to deal with volatility of ETH. Those wishing to use Dai must over-collateralize, placing $500 worth of ETH as collateral for $400 worth of Dai.
While the extreme volatility in the cryptocurrency world may be the most talked-about issue this week, the behaviour of the stablecoins may be the real story to be following.
Uzbekistan has recently announced that it will set up a body of arbitrators to deal with disputes in the cryptocurrency space. This will be specifically for disagreements about investments, intellectual property and crypto-related technologies. The country's chamber of commerce has been asked to draft a law "On International Arbitration" within a month, in order to create the legal basis for this arbitration.
This move is the latest in a series of steps undertaken by the Uzbekistan government to support the digital economy and to support innovation.
In July 2018, the President of Uzbekistan issued a special decree to prepare the legal ground. The July decree pointed to the introduction and expansion of activities related to the circulation of crypto assets, mining, smart-contracts, crowdfunding and blockchain technologies that can diversify investment and entrepreneurship. It also gave assurances that there would not be taxation related to these activities.
A decree in September legalized cryptocurrency trading in Uzbekistan and introduced licensing and other requirements for crypto exchanges. Two state-owned energy companies, Uzbekenergo and Uzbekgidroenergo, have been instructed to allocate land plots for industrial-scale mining facilities. A report on mining costs around the world found that Uzbekistan has the third lowest mining cost in the world, after Venezuela and Trinidad and Tobago.
Uzbekistan's IT and telecom ministry has been tasked to develop a draft law on "Digital economy and blockchain technologies" by January 2019. The plan is that by January 2021 government will implement blockchain in government procurements, services, registries and data bases, as well as in the corporate management of the large state-controlled enterprises, in clearing operations, payment processing, financing and fundraising.
Uzbekistan is not the only CIS country that is moving towards cryptocurrencies and blockchain technology.
Kyrgyzstan has announced intentions to introduce crypto payments in public projects, while in Kazakhstan, interest in cryptocurrencies has increasedfifteen-fold over the past year. The President, Nursultan Nazarbaev, has proposed launching a cryptocurrency called G-Global, "backed by assets not just trust".
Crypto business was legalized in Belarus from March of this year with the presidential decree "On the Development of the Digital Economy". Exchange services, ICOs, mining operations and smart contracts can be undertaken, generally tax-free, to anyone registering as residents of the Belarus High Technologies Park. Even foreign nationals can be included, without the need for visas and work permits.
All of these CIS countries are clearly setting themselves up to attract business — and they are wanting to make it as easy as possible.
What do Ripple and the IMF have in common?
CEO of Ripple, Brad Garlinghouse, and the International Monetary Fund (IMF)'s Deputy General Counsel, Ross Leckow, took part in a "fireside chat" at the recent Singapore Fintech Festival. They have a surprising amount in common. Both believe in the future of blockchain and cryptocurrencies. And both believe in the power of regulation to make this future happen.
The IMF is devoting a lot of attention to Fintech and blockchain, and is looking to give advice to member countries on how to approach and benefit from the fintech trends, while also putting together regulations to minimise the risks. They have assembled a high-level advisory group of industry leaders to assist in this task. One of the members in this group is Chris Larsen, Executive Chairman of Ripple's board of directors and former CEO and co-founder of Ripple.
Garlinghouse agrees that regulatory clarity is what is required to drive adoption of digital assets and blockchain. The ASEAN market (Association of Southeast Asian Nations) is an important one for Ripple, with about half of their global customers based in the region. There is generally good regulation in this region, especially in Singapore, Thailand and the Philippines. This makes it easier for blockchain and crypto assets to be used for real-world use cases such as cross border remittances (which is Ripple's primary business).
The problem lies in banks not keeping up with the times. This would include such payment systems as PayPal and SWIFT. In fact, Garlinghouse is on recordas saying that Ripple will overtake SWIFT as the cross-border mechanism of choice. Just this week, Japan's MUFG Bank announced the signing of a Memorandum of Understanding (MoU) with Banco Bradesco S.A., a Brazil-based banking service. The MoU discussed a partnership between the two organization to create a cross-border payment corridor that would be powered by the Ripple technology.
Ripple's vision is to be part of an "Internet of Value", where money can move across the world as easily as information does. This will allow the billions of "unbanked" people around the world to become part of the global economy.
Also speaking in Singapore, the Managing Director and Chairperson of the IMF, Christine Lagarde, called on central banks around the world to consider issuing digital currencies. She has previously warned that cryptocurrencies were posing a threat to the traditional financial system because they were quicker, easier and cheaper than traditional fiat currencies and banking systems. She believes that if central banks were to issue their own cryptocurrencies, this would keep the banks relevant and provide a degree of security not always possible from current "private" cryptocurrencies.
Lagarde seems to be of the same opinion as Garlinghouse of Ripple and Ross Leckow. Regulation is necessary — but within limits, and not at the expense of innovation.
It seems that blockchain and cryptocurrencies are indeed inching into the mainstream.


text:
Standing Up for Transparent Elections by Overturning Citizens United
By Sen. Jon Tester
A century ago this year, the people of Montana stood up against some of the most influential corporations in history with a powerful message: People and their ideas -- not corporations and their money -- decide our elections.
At the turn of the century, wealthy mining magnates literally bought elections, power and influence in Washington, D.C. So in 1912, Montana voters passed an initiative limiting corporate influence on our elections.
That's because ensuring that citizens are in control of America's democracy is a Montana value. But that value has come under attack in Washington, D.C.
The U.S. Supreme Court made an unpopular decision in 2010 called Citizens United v. Federal Elections Commission. The decision means corporations can spend unlimited money on political campaigns. They can make unlimited, anonymous contributions to third-party organizations that attack political candidates -- with no transparency or accountability.
Bottom line: The Citizens United decision undermines Montana's values and America's democracy by allowing big -- even foreign -- corporations to secretly buy American political elections.
In Montana, the decision has already opened a floodgate of attack ads, funded by secretive organizations like Crossroads GPS. Nobody knows exactly where Crossroads gets its millions, but you can bet much of it comes from Wall Street and Big Oil.
Crossroads recently ran an ad attacking me that was so false, a Montana cable company pulled it off the air.
So what can we do about this attack on our democracy and the transparency all Montanans deserve? The first step begins in Congress, where efforts are underway to undo the Citizens United decision.
That's why I support passing a constitutional amendment to restore accountability and transparency to federal and state elections -- ensuring that when you see a political ad on TV, you know exactly who's responsible for it.
Americans have every right to support the candidates they believe in with the means they have. But that doesn't give free rein to big and foreign corporations to secretly buy America's elections.
We've seen that before in Montana's history, and it led to a swift rebuke that has withstood the test of time.
Earlier this month, the Montana Supreme Court upheld Montana's 1912 law. The Montana Supreme Court's decision was the nation's first rebuff of the Citizens' United decision, and it was the responsible thing to do.
Now we have a responsibility to continue our fight for the voices of real people in our democracy -- just as our ancestors did in Montana a century ago. Through legislation and grassroots efforts, we can and we must push back against the special interests who very much want to buy power and influence in Washington. Unless we do, they'll get their way.
I hope you'll join me in telling them: Not in Montana. Not in America.
Follow Sen. Jon Tester on Twitter: www.twitter.com/jontester
Sen. Jon Tester
U.S. Senator from Montana
Montana Transparency Constitutional Amendment Citizens United Senator Jon Tester


text:
by Frances Goodrich, Albert Hackett
What a is the plot summary for the play The Diary of Anne Frank by Francis Goodrich and Albert Hackett?
Walter Fischer
Top subjects are Literature, History, and Business
One of the most important and poignant examples of writing in modern history was the diary maintained by a young girl hiding in Holland with her family from the German soldiers occupying that country during World War II. Anne Frank's diary, discovered after she, her family, and another family sharing their small hiding place in the home of an employee of her father's business, were captured and sent to their deaths (Anne's father, Otto, being the sole survivor) in German concentration camps, was originally published as Diary of a Young Girl, but has since become known simply as The Diary of Anne Frank. Anne's diary is a fascinating and enormously sorrowful – especially since we know the outcome before we start reading it – account both of these two families efforts' to survive the war and the Nazi occupation and of Anne's transition from young girl to young woman (she died in the Bergen-Belsen concentration camp at the age of 15). Anne's diary was adapted into a play by Francis Goodrich and Albert Hackett, premiering on Broadway in October 1955. It has since been produced in theaters all over the world and remains a regular production.
Goodrich and Hackett's play is told in the "flashback" narrative style, with the opening scene depicting Otto Frank receiving from his old employee and protector Miep Gies the diary the latter has recovered from items left following the Frank family's capture and deportation to the death camps. Frank has initially resisted receiving any tangible reminder of this terrible period, during which he lost his wife and children, but accepts Anne's diary, triggering the memories that begin the play's dramatization of the contents of the diary. The play, then, is the diary's depiction of Anne's observations, including her resentments, ambitions, infatuations, and frustrations at her and her family's situation. Interestingly, Anne, who aspired to a literary future, did not simply write entries into the diary; rather, she wrote "letters" to a fictional friend named "Kitty." (There were fictional recipients of these "letters," but the personage of "Kitty" definitely assumed a higher status to whom Anne confided her deepest thoughts, including about her budding sexuality.)
The second family hiding with the Franks, the van Pels, include a boy, Peter, who similarly matured during their years of mutual confinement and in whom Anne confided a great deal, only to wonder during the later period of hiding whether Peter was who she hoped he could be. The play adapts entries of the diary and turns them into monologues, one of the most important of which draws from the most oft-cited entry in Anne's diary, that of Saturday, July 15,1944:
"It's difficult in times like these: ideals, dreams and cherished hopes rise within us, only to be crushed by grim reality. It's a wonder I haven't abandoned all my ideals, they seem so absurd and impractical. Yet I cling to them because I still believe, in spite of everything, that people are truly good at heart."
In the play, this passage is adapted to include a representation of Anne's thoughts concerning not just the nature of humanity, but her wishes for what Peter could have been:
"I wish you had a religion, Peter. Oh, I don't mean you have to be Orthodox, or believe in heaven and hell and purgatory and things. I just mean some religion. It doesn't matter what. Just to believe in something! When I think of all that's out there. The trees. And flowers. And seagulls. When I think of the dearness of you, Peter. And the goodness of people we know. Mr. Kraler, Miep, Dirk, the vegetable man, all risking their lives for us everyday. When I think of these good things, I'm not afraid any more. I find myself, and God, and I... We're not the only people that've had to suffer. There've always been people that've had to. Sometimes one race, sometimes another, and yet...I know it's terrible, trying to have any faith when people are doing such horrible things, but you know what I sometimes think? I think the world may be going through a phase, the way I was with Mother. It'll pass, maybe not for hundreds of years, but some day I still believe, in spite of everything, that people are really good at heart. Peter, if you'd only look at it as part of a great pattern? That we're just a little minute in the life? (She breaks off) Listen to us, going at each other like a couple of stupid grownups! Look at the sky now. Isn't it lovely?"
Goodrich and Hackett sought to retain the vital elements of Anne Frank's diary while adapting it into a different format. Vital to that effort was the use of internal monologues to substitute for some of the diary's more personal entries. The story, however, remains the same – that of a young girl forced into hiding with her family solely because of their religion only to be betrayed and sent to live under inhumane conditions until murdered by their jailers.
https://dl.previewtechs.net/multimedia/ebook-pdf/Anne-Fra...
What does Anne mean when she writes in her diary, "Paper is more patient than people?"
Compare and contrast Anne's relationship with her mother to that with her father in The Diary of Anne Frank.
In the book The Diary of Anne Frank: The Diary of a Young Girl during Anne's time in the annex, what did she give Mr. Van Daan for Hannukkah?
Why is Anne Frank's diary so important? what can we learn about it?
What is the universal theme of The Diary Of Anne Frank?
Latest answer posted June 13, 2011 at 12:49:30 PM
What are three examples of imagery in the play, The Diary of Anne Frank by Goodrich and Hackett?
Latest answer posted June 12, 2016 at 2:02:08 AM
What happens in acts 1 and 2 of "The Diary of Anne Frank" by Frances Goodrich and Albert Hackett?
Latest answer posted October 14, 2015 at 3:47:05 AM
Why might Mrs. Frank be afraid of doing something illegal in Frances Goodrich and Albert Hackett's play The Diary of Anne Frank?
In Goodrich and Hackett's drama The Diary of Anne Frank, identify one external conflict and one internal conflict in Act One.
In Goodrich and Hackett's "The Diary of Anne Frank," why is Mr. Frank a logical choice as leader of the secret annex?