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US009283192B2

(12) United States Patent (10) Patent No.: US 9,283,192 B2 Mullen et al. (45) Date of Patent: Mar. 15, 2016

(54) DELAYED PROLONGED DRUG DELIVERY 2009. O1553.58 A1 6/2009 Diaz et al. 2009,02976O1 A1 12/2009 Vergnault et al. 2010.0040557 A1 2/2010 Keet al. (75) Inventors: Alexander Mullen, Glasgow (GB); 2013, OO17262 A1 1/2013 Mullen et al. Howard Stevens, Glasgow (GB); Sarah 2013/0022676 A1 1/2013 Mullen et al. Eccleston, Scotstoun (GB) FOREIGN PATENT DOCUMENTS (73) Assignee: UNIVERSITY OF STRATHCLYDE, Glasgow (GB) EP O 546593 A1 6, 1993 EP 1064937 1, 2001 EP 1607 O92 A1 12/2005 (*) Notice: Subject to any disclaimer, the term of this EP 2098 250 A1 9, 2009 patent is extended or adjusted under 35 JP HO5-194188 A 8, 1993 U.S.C. 154(b) by 0 days. JP 2001-515854. A 9, 2001 JP 2001-322927 A 11, 2001 JP 2003-503340 A 1, 2003 (21) Appl. No.: 131582,926 JP 2004-300148 A 10, 2004 JP 2005-508326 A 3, 2005 (22) PCT Filed: Mar. 4, 2011 JP 2005-508327 A 3, 2005 JP 2005-508328 A 3, 2005 (86). PCT No.: PCT/GB2O11AOOO3O7 JP 2005-510477 A 4/2005 JP 2008-517970 A 5, 2008 JP 2009-514989 4/2009 S371 (c)(1), WO WO99,12524 A1 3, 1999 (2), (4) Date: Oct. 2, 2012 WO WOO1 OO181 A2 1, 2001 WO WOO3,O266.15 A2 4/2003 (87) PCT Pub. No.: WO2011/107750 WO WOO3,O26625 A1 4/2003 WO WO 03/026626 A2 4/2003 PCT Pub. Date: Sep. 9, 2011 WO WOO3/030920 A1 4/2003 WO WO 2006/045618 A1 5, 2006 (65) Prior Publication Data WO WO 2008/07.9102 A1 T 2008 WO WO 2008/081891 A1 T 2008 US 2013/OO22677 A1 Jan. 24, 2013 (Continued) (30) Foreign Application Priority Data OTHER PUBLICATIONS Mar. 5, 2010 (GB) ...... 10O3734.9 Ghimire et al., “In-vitro/In-vivo Correlation of Pulsatile Drug Release from Press-Coated Tablet Formulations: A (51) Int. Cl. Pharmacoscintigraphic Study in the Beagle Dog”. European Journal A6 IK9/20 (2006.01) of Pharmaceutics and Biopharmaceutics, 2007, vol. 67, pp. 515 A6 IK 9/22 (2006.01) 523.: A6 IK9/24 (2006.01) Ghimire, M. et al. "In-vitro/In-vivo Correlation of Pulsatile Drug (52) U.S. Cl. Release from Press-Coated Tablet Formulations: A CPC ...... A61K9/209 (2013.01); A61 K9/2013 Pharmacoscintigraphic Study in the Beagle Dog. European Journal (2013.01); A61 K9/2054 (2013.01) of Pharmaceutics and Biopharmaceutics, 2007, vol. 67, No. 2, 515 (58) Field of Classification Search 523. None Written Opinion of the International Searching Authority (Form See application file for complete search history. PCT/ISA/237) mailed Mar. 12, 2012, for International Application No. PCT/GB2011/000307, 14 pages. (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner — Michael B Pallay 4,832,958 A 5, 1989 Baudier et al. 4,871,549 A 10, 1989 Ueda et al. (74) Attorney, Agent, or Firm — Hoxie & Associates LLC 5,145,644 A 9, 1992 Park et al. 5,508,044 A 4, 1996 Buxton et al. (57) ABSTRACT 5,558,879 A 9, 1996 Chen et al. 5,614,220 A 3, 1997 Hirakawa et al. In one aspect, the present invention is concerned with a treat 5,788,987 A 8, 1998 Busetti et al. 6,312,724 B1 1 1/2001 Odidi et al. ment where it is desired that an active agent is designed to be 6,610,323 B1 8/2003 Lundberg et al. released in a prolonged manner at a time point sometime after 6,632,451 B2 10/2003 Penhasi et al. administration of the active agent. The present invention is 6,740,339 B1 5, 2004 Ohkouchi et al. particularly Suited to administering an agent which may be 8, 168,218 B2 5/2012 Vergnault et al. released whilst a Subject is sleeping, shortly before waking 2004.0062804 A1* 4/2004 Lee et al...... 424/471 2004/0241100 A1 12/2004 Kramer et al. and continues to administer the drug during the early waking 2005/O152974 A1 7/2005 Boehm et al. hours. As well as treating certain conditions by a particular 2005/022O877 A1 10/2005 Patel et al. regime, the invention also provides novel formulations for a 2006/0177506 A1* 8/2006 Yanai et al...... 424/468 delayed, followed by a prolonged release of drug. 2006, O2574.82 A1 11/2006 Kumar et al. 2007/OO98788 A1 5, 2007 Gore et al. 2009.0053308 A1 2/2009 Ishida et al. 24 Claims, 5 Drawing Sheets US 9,283,192 B2 Page 2

(56) References Cited Alvarez-Lorenzo, C. et al., “Evaluation of Low-substituted Hydroxypropylceulluloses (LHPCs) as Filler-Binders for Direct Compression.” International Journal of Pharmaceutics, 2000, 197, FOREIGN PATENT DOCUMENTS 107-116. English-language abstract of JP 2001-322927. Date of publication of WO WO 2008, 129517 A2 10/2008 application Nov. 20, 2001, 1 page. WO WO 2009,154810 A2 12/2009 English-language machine translation of JP 2001-322927, retrieved from the Japanese Patent Office website on May 2, 2015, 15 pages. Fukui, E. et al., “Studies on Applicability of Press-coated Tablets OTHER PUBLICATIONS Using Hydroxypropylcellulose (HPC) in the Outer Shell for Timed Stevens, H.N.E., "Chronopharmaceutical Drug Delivery,” Journal of release Preparations,” Journal of Controlled Release, 2000, 68,215 Pharmacy and Pharmacology, 1998, 50 (Supplement 9), 5. 223. Written Opinion of the International Searching Authority (Form Kleinebudde, P. "Application of Low Substituted Hydroxypropycel PCT/ISA/237) mailed Mar. 12, 2012, for International Application lulose (L-HPC) in the Production of Pellets. Using Extrusion / No. PCT/GB2011/000306, 15 pages. Spheronization” International Journal of Pharmaceutics, 96, pp. 119 128, (1993). Written Opinion of the International Searching Authority (Form Shin-Etsu Guide on Low Substituted Hydroxypropyl Cellulose NF, PCT/ISA/237) mailed Mar. 12, 2012, for International Application cited in U.S. Appl. No. 13/582.913 in which Examiner listed publi No. PCT/GB2011/000314, 14 pages. cation date as 2008. Rowe, R. et al., Eds. Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, London, 2009, pp. 317-324. * cited by examiner U.S. Patent Mar. 15, 2016 Sheet 1 of 5 US 9,283,192 B2

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F.G. 5 US 9,283,192 B2 1. 2 DELAYED PROLONGED DRUG DELVERY It is amongst the objects of the present invention to provide a formulation which may be easily and/or cheaply manufac CROSS REFERENCE TO RELATED tured and which allows for an active agent to be administered APPLICATIONS in a prolonged manner, following a period of delay following administration. This application is a U.S. application under 35 U.S.C. 371 claiming benefit of PCT application No. PCT/GB2012/ SUMMARY OF INVENTION 000307, filed on Mar. 4, 2011, which claims the benefit of GB application No. 1003734.9, filed on Mar. 5, 2010, the contents The present inventors recognised a need to be able to of each of which are incorporated herein by reference. 10 administer, for example, a pharmaceutically active agent to a Subject in a manner Such that a delayed release of the phar FIELD OF INVENTION maceutically active ingredient could be achieved, followed by a prolonged delivery of the agent. Although this may have In one aspect, the present invention is concerned with a been possible using prior device/methods known in the art, treatment where it is desired that an active agent is designed 15 many such devices/methods do not result in a desired physi to be released in a prolonged manner at a time point some time cochemical and/or physicomechanical profile and many are after administration of the active agent. The present invention highly complex. As such there is therefore a distinct advan is particularly Suited to administering an agent which may be tage in providing a simpler press-coated tablet formulation released whilst a Subject is sleeping, shortly before waking and method of treatment. and continues to administer the drug during the early waking One particularly preferred embodiment relates to treating hours. As well as treating certain conditions by a particular Subjects who suffer from cardiovascular conditions. In a pre regime, the invention also provides novel formulations for a ferred embodiment therefore, the formulations of the present delayed, followed by a prolonged release of drug. invention are for treating cardiovascular conditions such as , pectoris, cardiac failure, pulmonary BACKGROUND TO THE INVENTION 25 hypertension, the primary or secondary prevention of cardio vascular disease, peripheral vascular disease, stroke, oedema, Time-dependent release mechanisms of drugs have been arrhythmias. Such formulations therefore comprise a phar described in the literature for tablet, pellet and capsule for maceutically active agent for treating Such cardiovascular mulation utilising a wide range of physicochemical and conditions. For example this may be a physicomechanical Strategies. The common feature of all 30 blocker, such as . such formulations is that they are activated by contact with Thus, in a first aspect, the present invention provides a fluids following ingestion by the patient and the drug will be cardiovascular agent such as Verapamil, formulated as a com released at the predetermined time after administration. Only ponent of a press-coated tablet for treating a cardiovascular after the formulations come into contact with gastric fluids condition, wherein the formulation is intended to be admin does the clock start. Drug release Subsequently takes place 35 istered immediately prior to a subject going to sleep (i.e. when at a predicted time, although it will be appreciated that since a subject goes to bed at night for a prolonged period of sleep, the dosage unit will be travelling through the GI tract during such as 6-10 hours and hence is distinguished over shorter the lag period, drug release will necessarily be at Some sleeping periods) and wherein the cardiovascular agent is unknown GI tract site. Using Such formulation strategies, it substantially (such as less than 10%, 5% or even 1%) not will be possible to design delivery systems capable of releas 40 released from the formulation for a period between 2-8 hours, ing drugs according to chronotherapeutic principles and tar such as 3-6 hours after administration of the formulation to geting release to the circadian rhythm of disease states the subject and thereafter the agent is released from the for (Stevens HN E. Chronopharmaceutical Drug Delivery. J mulation in a prolonged manner Such that the agent within the Pharm Pharmac., 50 (s) 5 (1998)). formulation is released continuously over a period of up to However, many of the formulations in the art rely on com 45 2-8 hours, such as 3-6 hours. plex structures which can add to the cost of the manufacture In a further aspect there is provided a method of treating a of the drug and/or can be subject to malfunction leading to cardiovascular condition, the method comprising administer incorrect/inappropriate administration of the drug. ing a press-coated tablet comprising a cardiovascular agent, Delayed prolonged release formulations of Verapamil, Such as a Verapamil to a Subject, immediately before the Such as COVERA-HS(R) are known in the art. COVERA-HS(R) 50 Subject intends sleeping, wherein the formulation Substan is a formulation designed to initiate release of Verapamil 4-5 tially delays release of the drug for 2-8 hours, such as 3-6 hours after ingestion. The delay in release is due to a layer hours following administration of the formulation and there between the active drug core and an outer semi-permeable after the drug is released continuously over a period of up to membrane. However, the formulation is complex in its con 2-8 hours, such as 3-6 hours. struction, requiring precision drilled holes in the outer mem 55 Typically delayed release of the active agent is achieved by brane being formed. providing a press-coated tablet comprising a delayed release Other tablet formulations have been described for pulsed layer Surrounding a core comprising the active agent. The release of Verapamil, where a delay in release is effected by delayed release layer may comprise a wax and a low-substi way of an outer hydroxypropylmethyl cellulose coating. tuted hydroxypropyl cellulose (L-HPC), such as LH-32. The There is the proposal to use such formulations in a chrono 60 prolonged release of the active agent may be achieved by therapeutic manner. providing a core in which the active agent is admixed with a Further Verapamil formulations are described in U.S. Pat. wax such as beeswax, carnuba wax, microcrystalline wax, No. 4,832,958, for example, although there is no teaching of hydrogenated castor oil. A particularly preferred wax is a formulations which show a delay in Verapamil release. glyceryl ester, Such as glycerol behenate. It is amongst the objects of the present invention to obviate 65 In a further aspect, the present invention provides a press and/or mitigate at least one of the aforementioned disadvan coated tablet formulation for a delayed, followed by a pro tages. longed release of an active agent, the tablet comprising US 9,283,192 B2 3 4 (a) a core comprising the active agent together with a wax and Exocrine and Endocrine; Addison's disease, Hypoaldoster optionally one or more fillers; and onism, cushing's syndrome, diabetes, Goitre, Hyperthy (b) a delayed release layer Surrounding the core and compris roidism, Hypothyroidism, Thyroiditis, pancreatitis ing a wax and LH-32 in a ratio of 20:80 to 50:50 w/w: Hepatic disorders, , Non-alcoholic fatty liver dis wherein the delayed release layer substantially delays 5 ease, cirrhosis, hepatic cancer, Primary Sclerosing cholan release of the active agent within the core for between 2-8 gitis, primary biliary cirrhosis, Budd-Chiari syndrome, hours, such as 3-6 hours after administration of the tablet Autoimmune and Inflammatory diseases, multiple Sclerosis by a subject and thereafter a prolonged release of the active rheumatoid arthritis, psoriasis, diabetes, sarcoidosis, Addi agent from the core occurs, such that the active agent in the son's Disease. Alopecia greata, Amyotrophic Lateral Scle 10 rosis, Ankylosing Spondylitis, polyarticular Arthritis, core is continuously released over a period of up to 2-8 Atopic , topic Dermatitis, Autoimmune hepatitis, hours, such as 3-6 hours. Celiac disease, Chagas disease, Coeliac Disease, Cogan The press coated tablets of the present invention, may syndrome, Crohns Disease, Cushing's Syndrome, Diabe further comprise: tes mellitus type 1, Endometriosis, Eosinophilic fasciitis, (c) a top-coating layer comprising an active agent together 15 Fibromyalgia/Fibromyositis, Gastritis, Glomerulonephri with one or more excipients wherein a Substantially imme tis, Graves disease. Guillain-Barré syndrome (GBS), diate pulsed release of the active agent occurs following Hashimoto's encephalitis, Hashimoto's thyroiditis, administration to the subject of the tablet. Haemolytic anaemia, Idiopathic Inflammatory Demyeli By “immediately' is understood to mean that at least nating Diseases, Idiopathic pulmonary fibrosis, interstitial 70-90%, such as 80% of the active agent in the top layer or cystitis, Juvenile idiopathic arthritis, Juvenile rheumatoid portion of the prerss-coated tablet, which is formulated for arthritis, Kawasaki's Disease, Lichen Sclerosus, Lupus immediate release, is released within about 5-45 mins, such erythematosus, Méniere's disease, Myasthenia gravis, as 10-30 mins following administration. myositis, Narcolepsy, Pernicious anaemia, Perivenous The active agents of the above aspect include any active encephalomyelitis, Polymyalgia rheumatica, Primary bil agent for which delayed followed by prolonged release is 25 iary cirrhosis, Psoriatic Arthritis, Reiter's syndrome, desirable. In a preferred embodiment of the invention, the Rheumatoid fever, Sarcoidosis, Schizophrenia, Sjögren's active agent is a pharmaceutically acceptable active agent and syndrome, Spondyloarthropathy, Ulcerative Colitis includes pharmaceutical and Veterinary active agents (often Musculoskeletal disorders: osteoarthritis, osteoporosis, referred to as drugs). In other embodiments, the active agent Osteonecrosis, Arthritis, Paget’s Disease Bursitis, Costo includes agrichemical agents (such as fertilizers, herbicides, 30 chondritis, Tendonitis pesticides and fungicides), active agent used in the extermi Skin disorders; Acne, alopecia, candidiasis, celluliltis, der nating industry (such as toxins and poisons), and active agents matitis, eczema, epidermolysis bullosa, erythrasma, her used in industrial manufacturing (Such as catalysts or cata pes, erysipelas, Folliculitis, impetigo, ringworm, Scabies, lytic quenchers). Tinea, Trichomycosis 35 ENT disorders; Otitis, sinusitis, laryngitis, pharyngitis, lar The press-coated tablets of the present invention may be yngitis, meniere's disease, labyrinthitis, used to treat one or more of the following conditions/disor Others: acute and chronic pain, viral infection, cancer, laryn ders or diseases: gitis, mastoiditis, myringitis, otitis media, rhinitis, sinusi Central Nervous System disorders, e.g. Neurogenic pain, tis, Sialadenitis, Retropharyngeal Abscess, Tonsillophar stroke, dementia, Alzheimer's disease, Parkinson's disease, 40 yngitis, neuronal degeneration, meningitis, spinal cord injury, cere Gastro-intestinal Disorders bral vasospasm, amyotrophic lateral Sclerosis (IBS) necrotizing entercolitis Cardiovascular disease, hypertension, atherosclerosis, (NEC) non-ulcer dyspepsia, chronic intestinal pseudo-ob angina, arterial obstruction, peripheral arterial disease, struction, functional dyspepsia, colonic pseudo-obstruc myocardial pathology, Arrhythmia, Acute Myocardial Inf 45 tioduodenogastric reflux, gastroesophageal reflux disease, arction, Angina, Cardiomyopathy, Congestive heart fail illeus inflammation, gastroparesis, heartburn, — ure, Coronary artery disease (CAD), Carotid artery dis (e.g. constipation associated with use for such as ease, Endocarditis, Hypercholesterolemia, ), colorectal cancer, colonic polyps, diverticulitis, col hyperlipidemia, Peripheral artery disease (PAD) orectal cancer, Barretts Esophagus, Bleeding in the Digestive Genitourinary Disorders; erectile dysfunction, urinary organ 50 Tract, Celiac Disease, Colon Polyps, Constipation, Crohns diseases benign prostatic hypertrophy (BPH), Renal tubu Disease, Cyclic Syndrome, Delayed Gastric Emp lar acidosis, diabetic nephropathy, glomerulonephritis, tying (Gastroparesis), , Diverticulosis, Duodenal glomerulosclerosis, urinary tract infection, faecal inconti Ulcers, Fecal Incontinence, Gallstones, Gas in the Digestive CC Tract, Gastritis, Gastroesophageal Reflux Disease (GERD), Ocular disease glaucoma, blephartitis, ocular hypertension, 55 Heartburn, Hiatal Hernia, Hemochromatosis, Hemorrhoids, retinopathy, conjunctivitis, Scleritis, retinitis, keratitis, cor Hiatal Hernia, Hirschsprung's Disease, Indigestion, Inguinal neal ulcer, iritis, Chorioretinal inflammation, macular Hernia, Lactose Intolerance, Peptic Ulcers, Polyps, Porphy edema, Xerophthalmia ria, Primary Biliary Cirrhosis, Primary Sclerosing Cholangi Pulmonary disease asthma, , acute tis, Proctitis, Rapid Gastric Emptying, Short Bowel Syn respiratory distress syndrome, COPD, emphysema, pneu 60 drome, Stomach Ulcers, Ulcerative Colitis, Ulcers, Whipples monia, tuberculosis, bronchitis, Acute Bronchitis, Bron Disease. chiectasis, Bronchiolitis, Bronchopulmonary Dysplasia, Exemplary active agents for use in the pharmaceutical and Byssinosis, Coccidioidomycosis (Cocci), Cystic Fibrosis, Veterinary applications of the invention include analgesics, Influenza, Lung Cancer, Mesothelioma anaesthetics, , antidiabetic agents, antihista Metabolic diseases; Hypercalciuria, , Hyper 65 mines, anti-infectives, antineoplastics, antiparkinsonian insulinemic hypoglycemia, Hyperinsulinism, Hyperlysi agents, antirheumatic agents, appetite , appetite nuria, Hypoglycemia Suppressants, blood modifiers, bone metabolism modifiers, US 9,283,192 B2 5 6 cardiovascular agents, central nervous system , Sleep Drugs central nervous system stimulants, decongestants, —, , , receptoragonists, electrolytes, gastrointestinal agents, immu Lorimetazepam, , , , Zopi nomodulators, muscle relaxants, narcotics, parasympathomi clone, Hydrate, , , metics, sympathomimetics, , and hypnotics. , , Alpra Said active agent or agents may be selected from the follow Zolam, , RoZerem, , ing: , drugs, , diphenhy Gastro Drugs dramine and herbal remedies such as Antacids—aluminium hydroxide, carbonate, Cardiovascular Medicines magnesium trisilicate, hydrotalcite, simeticonealginates, 10 Cardiac glycosides—Digoxin, digitoxin, — Sulphate, hydro Phosphodiesterase Inhibitors—, chloride, hyoscine butylbromine, propantheline , and related diuretics—bendroflumethiazide, chlo citrate, hydrochloride, rtalidone, cyclopenthiazide, inapamide, metolaZone, Xipa Motility stimulants—metoclorpramide, 15 mide H2- antagonists—Cimetidine, famotidinenizati Diuretics—, , torasemide, dine, ranitidine Potassium sparing diuretics and aldosterone antagonists— Antimuscarinics— hydrochloride, , weplerenone, Chelates—Tripotassium dicitratbismuthate. Sucralfate, spironolactone, Prostaglandin analogues—misoprostol Osmotic diuretics—mannitol Aminosalicylates—balsazide Sodium, mesalazine, olsala Drugs for arrhythmias—adenosine, hydrochlo Zine, SulphaSalazine ride, , acetate, hydro Corticosteroids—beclometasone dipropionate, budenoside, chloride, hydrochloride, hydrocortisone, prednisolone, Beta adrenoreceptor blocking drugs propanalol, . Affecting immune response—ciclosporin, mercaptopurine, 25 , bisprolol fumarate, , , methotrexate, adalimumab, infliximab esmolol, lebatolol, tartrate, , , Laxatives—bisacodyl, dantron, docusate, sodium , , solatol, . picosulfate, Hypertension-, , , hydrala Drugs affecting biliary composition and flow—ursodeoxy Zine, iloprost, , . , Sodium 30 nitroprusside, , , , cholic acid monoSuiphate, , , pra acids sequestrants colestyramine, Zosin, , , mesi , , Mebeverine, , late, , Dicycloverine, Dilhexyverine. , Drugs affecting the renin-angiotensin system—Captropril, , , Pipenzolate, Glyco 35 Cilazapril, Enalapril Maleate, Fosinopril, Imidapril, Lisi pyrronium, Oxyphenonium, , , nopril, Moexipril, Perindopril Erbumine, Quinapril, Rami Propantheline, , , Isopro pril, Trandolapril, Candesartan Cilexetil, Eprosartan, Irbe pamide, , , , Diphemanil, Sartan, Losartan, Olmesartan Medoxomil, Telmisartan, , , Timepidium bro Valsartan, Aliskiren. mide, , , Moxaver 40 Nitrates, calcium channel Blockers and drugs— ine 5-HT3 antagonists (, ), 5-HT4 Glyceryl trinitrate, Isosorbide Dinitrate, Isosorbide Mono agonists (, Prucalopride, Tegaserod) Fen nitrate, , , , , piprane, , , Pinaverium, , , , , , , , Alverine, Trepibu , Verapamil, Ivabradine, , Ranola tone, , , , Sili 45 Z1ne, cones, Trimethyldiphenylpropylamine Atropine, Hyos Peripheral Vasodilators and related drugs—Cilostazol, Inosi cyamine (Butylscopolamine, tol Nicotinate, , Oxalate, Pen Methylscopolamine), , Fentonium, toxifylline, primarily dopamine antagonists Sympathomimetics—Dopamine, , , (/, , Domperi 50 , Noradrenaline Acid Tartrate, Norephidrine done, ), 5-HT4 agonists (, Bitartrate, Phenylephidrine, ), Anticoagulants and Protamine-Heparin, Bemiparin, Dalte Proton pump inhibitors Omeprazole, lansoprazole, pantopra parin, Enoxaparin, Tinzaparin, Danaparoid, Bivalirudin, Zole, esomeprazole, rabeprazole Sodium, Lepirudin, Epoprostenol, Fondaprinux, Warfarin, Aceno opioids and opiod receptor antagonists—e.g. , mor 55 coumarol, Phenindione, Dabigatran Etexilate, Rivaroxa phine, , diphenoxylate, methylmaltrexone bro ban, Protamine Sulphate, mide Antiplatelet Drugs—Abciximab, Asprin, Clopidogrel, Dipy Analgesic ridamole, Eptifibatide, Prasugrel, Tirofiban, Acetaminophen Diclofenac Diflunisal Etodolac Fenoprofen Fibrinolytic and antifibrinolytic Drugs—Alteplase, Flurbiprofen Indomethacin Ketoprofen Ketoro 60 Reteplase, Streptokinase, Tenecteplase, Urokinase, Etam lac Meclofenamate Meloxicam Nabume Sylate, Tranexamic Acid, tone Naproxen Oxaprozin Phenylbutazone Piroxicam Lipid Regulating Drugs—Atorvastatin, Fluvastatin, Pravas Sulindac Tolimetin Celecoxib Butorphanol tatin, Rosuvastatin, Simvastatin, Colesevam, Col Codeine Hydrocodone Hydromorphone estyramine, Colestipol, Ezetimibe, Bezafibrate, Ciprofi Meperidine Nalbuphine Oxycodone 65 brate, Fenofibrate, Gemfibrozyl, Acipmox, Nictotinic Oxymorphone Pentazocine, Propoxyphene Acid, Omega three fatty acid compounds, Ethanolamine codeine Oleate, Sodium Tetradecyl Suphate. US 9,283,192 B2 7 8 CNS Drugs , , , rate, , pioglitaZone, montelukast, Zoledromic , , Pericyazine, Perphena Acid, Valsartan, latanoprost, Irbesartan, Clopidogrel, Ato zine, , , , , moxetine, Dexamfetamine, , , , , , Aripipra Bleomycin, Dactinomycin, Daunorubicin, Idarubicin, Zole, , Olanzapine, , , Mitomycin, Mitoxantrone, AZacitidine, Capecitabine, Riperidone, , , Flupentixol, Fluphena Cladribine, Clofarabine, Cytarabine, Fludarabine, Flour zine, Olanzapine Embonate, Palmitate, Ris ouracil, Gemcitabine, mercaptopurine, methotrexate, peridone, Zuclopenthixol Decanoate, , Nelarabine, Pemetrexed, Raltitrexed. Thioguanine, Apo , Valproic acid, Lithium Carbonate, Lithium Cit morphine, Betamethasone, Cortisone, Deflazacort, Dex rate, Amitriptyline, , , Imi 10 amethosone, Hydrocortisone, Methylprednisolone, Pred pramine, , , , nisolone, Triamcinolone, Ciclosporine, Sirolimus, , Trazodone, Phenelzine, Isocarboxazid, Tranyl Tacrolimus, Interferon Alpha, Interferon. cypromine, Moclobemide, , , Flu In a particularly preferred embodiment the active agent is oxetine, , , , Ago designed to treat cardiovascular conditions, such as hyperten melatine, , Flupentixol, , 15 Sion, angina pectoris and cardiac arrhythmia and as Such the , Trytophan, Venflaxine, , Dexam active agent is a cardiovascular agent, Such as Verapamil. etamine, Methylphenidate, Modafinil, Eslicarbazepine, The term “active agent' is understood to include solvates Ocarbazepene, , , , (including hydrates) of the free compound or salt, crystalline , , , , and non-crystalline forms, as well as various polymorphs. For , , , Tiagabine, Topira example, the active agent can include all optical isomers of mate, Vigabatrin, , , , Co the compounds and all pharmaceutically acceptable salts Beneldopa, Levodopa, Co-Careldopa, Rasagiline, Sel thereof either alone or in combination threo isomers can be egiline, Entacapone, Tolcapone, Amantidine, indicated as “threo” and the combined erythro isomers as , , , Haloperi “erythro’. dol, Piracetam, , , Acamprosate, 25 In accordance with the invention, formulations are pro Disulfiram, , Vareniciline, Buprenorphine, vided which are to be taken by a subject and which do not , Donepezil, Galantamine, , Rivas initially administer the active agent when the subject first tigimine. takes the formulation. However, at a later time point the agent Anti-Infectives—, Phenoxymethylpenicil is administered to the Subject in a prolonged manner over a lin, Flucloxacillin, Temocillin, , Ampicillin, 30 period of time. Co-Amoxiclav, Co-Fluampicil, Piperacillin, Ticarcillin, In relation to the treatment of cardiovascular conditions, it Pivmecillinam, Cephalosporins, Cefaclor, Cefadroxil, is known that many complications often occur early in the Cefalexin, Cefixime, Cefotaxime, Cefradine, Ceftazidime, morning, Soon after a patient wakes up. Thus, it is desirable to Cefuroxime, Ertapenem, , Meropenem, AZtre be able to provide a cardiovascular agent before a patient onam, Tetracycline, Demeclocycline, Doxocycline, Lyme 35 wakes up and during the hours following awakening. It is with cycline, Minocycline, Oxytetracycline, Tigecycline, Gen this in mind, that the present inventors sought to develop tamicin, Amikacin, Neomycin, Tobramycin, formulations which are designed to release a cardiovascular , Azithromycin, , Telithro agent prior to a patient waking up and for a period thereafter. mycin, Clindamycin, Chloramphenicol, Fusidic Acid, Such formulations would be designed to be taken prior to the Vancomycin, Teicoplanin, Daptomycin, Linezolid, Quinu 40 Subject going to bed the night before and would have to pristin, Colistin, Co-Trimoxazole, Sulpadiazine, Trime display a significant delay in release of the cardiovascular thoprim Capreomycin, Cycloserine, Ethambutol, Iso agent. This has been achieved with the press-coated tablet niazid, Pyrazinamide, Rifabutin, Rifampicin, formulations of the present invention. Streptomycin, Dapsone, Clofazimine, Metronidazole, LH-32 is a particular type of low substituted hydroxypro Tinidazole, Ciproflaxacin, Levoflaxacin, Moxifloxacin, 45 pyl cellulose (L-HPC) and may be obtained from Shin-Etsu Nalidixic Acid, Norflaxine, Orflaxacin, Nitrofurantoin, Chemical Co., Ltd., Tokyo, Japan. L-HPCs are insoluble in Methenamine Hippurate, Amphotericin, Anidulafungin, water and comprise a glucose backbone which is Substituted Caspofungin, Fluconazole, Flucytosine, Griseofluvin, Itra to a minimal extent by hydroxypropyl groups. LH-32 is conzole, , Micafungin, NyStatin, Posacona micronised, with a mean particle diameter of 20 Lum LH-32 Zole, Terbinafine, Voriconazole, Abacavir, Didanosine, 50 has a molecular weight of 115,000 and a hydroxypropyl cel Emtricitabine, Lamivudine, Stavudine, Tenofovir Diso lulose content of 8%. proxil, Zidovudine, Atazanavir, Darunavir, Fosam The wax for use in the core and the delayed release layer prenavir, Indinavir, Lopinair, Nelfinavir, Ritonavir, may be any Suitable wax Such as beeswax, carnuba wax, Saquinavir, Tipranavir, , Etravirine, Nevarapine, microcrystalline wax, hydrogenated castor oil. A particularly Enfluvirtide, Maraviroc, Raltegravir, Aciclovir, Famciclo 55 preferred wax is a glyceryl ester, Such as glycerol behenate. vir, Inosine Pranobex, Valaciclovir, Cidofovir, Gangciclo The wax in the core and the delayed release layer may be the vir, Foscarnet, Valgangciclovir, Adefovir Dipivoxil, Ente same or different. cavir, Telbivudine, , Oseltamivir, Zanamivir, In a preferred formulation of the present invention as Palivizumab, Ribavirin, Artemether, Chloroquine, Meflo defined herein above, the wax and LH-32 are present in a ratio quinePrimaquine, Proguanil, Pyrimethamine, Quinine, 60 of 25:75 to 40:60 w/w. More preferably the ratio is 25:75 to Doxycyclin, Diloxanide Furoate, Metronidaziole, Tinida 35:65 w/w, or 30:70 w/w. The skilled addressee will appre Zole, MepacrineSodium Stibogluconate, Atovaquone, ciate that with appropriate variation of the ratio, the delay in Pentamidine Isetionate, Mebendazole, , drug release can be tailored for a particular application. For Other: example, a 30:70 w/w ratio of glycerol behenate as a wax, Benztropine, procyclidine, , Amantadine, Bro 65 with LH-21 as the L-HPC employed as a delayed release layer mocriptine, , Entacapone, Tolcapone, Selegeline, in accordance with the present invention, is observed to pro , budesonide, , quetiapine fuma vided a delayed release of approximately 1 hour. However,

US 9,283,192 B2 11 12 Preferably, the cores are blended by starting with the smallest (V) Granules Stored in amberglass Screw-top jar until use. Volume component and then successively adding the larger (vi) For 6 core tablets, 6x234.5 mg core tablet granules Volume components. weighed into tared weigh boats and compressed in 10 The tablet can be further coated with optional additional mm die/punch set for 1 minute at 2 tons. coatings. The additional coatings can be pH-dependent on 5 Granules (to Surround Core Tablet) pH-independent, aesthetic or functional; where the coating is (i) Glycerol behenate and LH-32 weighed into tared weigh a gastro-resistant coating (intented to prevent release in the boats according to Table 2: stomach), the clock or time for delayed release, as defined herein, will not start until gastric emptying occurs and disso TABLE 2 lution of the gastro-resistant coating takes place (as can be 10 determined, for example, by employing Scintigraphy studies). Excipient Weight (g) The time taken for dissolution of the gastro-resistant coating GB 6 together with the delay from the time-delay layer will ensure LH-32 14 drug release in the lower reaches of the intestine, particularly the distal ileum and/or colon. Such additional coatings pref 15 erably include film forming materials. (ii) GB placed in a glass beaker on a hot plate set at 100°C. Once the GB melted, LH-32 added gradually whilst DETAILED DESCRIPTION stirring until a uniform mix is achieved. (iii) The mix stirred continuously until cooled to room The present invention will now be further described by way temperature. The granules are left for at least 30 min at of example and with reference to the figures which show: room temperature before the next step. FIG. 1 shows the release profile of a drug from a tablet (iv) The cooled granules forced through a 1 mm sieve comprising glycerol behenate and LH-32 in a 30:70 w/w ratio (using a spatula and a brush) and collected on a 500 um in a delayed release layer, and sieve so that the granules used are in the size range 500 FIG. 2 shows the release profile of a drug from a tablet 25 Lum-1 mm. comprising glycerol behenate and LH-21 in a 30:70 w/w ratio (V) Granules Stored in amberglass Screw-top jar until use. in a delayed release layer, Formulation Compression FIG. 3 shows Gamma Scintigraphy imaging of In-vivo (i) A 13 mm die and matching flat-faced punches used to release of controlled release Verapamil formulation; and compress the formulation. For 6 tablets, 12x250 mg FIGS.4 and 5 show Pharmacokinetic analysis of Verapamil 30 granules (to Surroundcore tablet) are weighed into tared and levels in plasma, in 6 Subjects. Verapamil is weighboats. quickly metabolized to its active metabolite nor-Verapamilso (ii) 250 mg granules placed onto the lower punch, core both variants were measured in blood plasma. tablet dropped on and centralised before placing the other 250 mg granules on top. CLINICAL NEED 35 (iii) The formulation compressed at 5 ton for 2 minutes in a 13 mm die/punch set. This formulation is designed to be taken at night, with slow Dissolution release of the Verapamil after a 3-4 hour delay. Complete Dissolution performed in 900 ml sodium phosphate buffer release is achieved after approximately 7 hours which ensures (0.01 M, pH 7) at 37° C., with UV analysis at 279 mm. the drug is available continuously during both the pre-wake 40 Results (30:70, GB:LH-32) up and wake up period when there is the greatest cardiovas As can be seen in FIG. 1, there is a delay in release of cular clinical need. Verapamil of about 3.5 hours, with substantially (i.e. >90%) Methods all the Verapamil being released by about 7 hours. Core Tablet Blend and Core Tablet Compression Supporting Data (194.5 mg Verapamil HCl=180 mg Verapamil) 45 LH-21 instead of LH-32 (30:70, GB:LH-21) (i) Verapamil and excipients weighed into tared weigh As can be seen in FIG. 2, substituting LH-21 for LH-32, boats according to Table 1. shortens the period of delay, to approximately 1 hour, with substantially (i.e. >90%) all the Verapamil being released TABLE 1. within 6 hours. 50 This profile shows a dramatically shortened delay time API/Excipient Weight (g) before drug release commences which renders this inappro Verapamil HCl 5.835 priate for our chosen application where the four hour delay Glycerol behenate (GB) 0.7 before drug release is essential. Lactose 0.7 Extraction Method/Analysis of Plasma levels of Verapamil 55 Materials (ii) GB placed in a glass beaker on a hot plate set at 100° C. Human plasma, lithium heparin, origin USA: Sera labora Once the GB melted, the lactose and Verapamil HCl are tories international Ltd, BX H911239 Verapamil HCl added gradually whilst stirring until a sticky granular Norverapamil HCl, Sigma Aldrich, lot 019K46152 mass is achieved. DEE: Fisher laboratory reagent grade BX 1097413 (iii) The mix taken off the hotplate and stirred continuously 60 Methods until cooled to room temperature. The granules are left Calibration: for at least 30 min at room temperature before the next Vortex blank plasma step. add 400 ul blank plasma to glass screw cap tubes using gilson (iv) The cooled granules forced through a 1 mm sieve pipette (using a spatula and a brush) and collected on a 500 um 65 blank preparation—to be prepped before standards sieve so that the granules used are in the size range 500 add 100 ul mobile phase to 400 ul blank plasma um-1 mm. Vortex 10 secs US 9,283,192 B2 13 14 add 4 mL DEE and vortex 3 mins (note: DEE decanted from A5 mL pre-dose blood sample was taken from each subject bottle fresh every day 15 minutes before dosing. Following dosing blood samples pipette tips changed after every addition of mobile phase/ were taken every 30 minutes until burst release observed by DEE scintigraphy then every 15 minutes for 2 hours then every 30 Standard Preparation: minutes for 1 hour then hourly until end of study day (15 starting with lowest concentration standard, Vortex standard hours post-dose). See FIG. 3. 10 secs to mix Blood samples were centrifuged at 2000 g for 10 minutes add 100 ul standard to 400 uL blank plasma and the plasma fraction removed and stored at -20° C. for Vortex 10 secs subsequent analysis. See FIGS. 4 and 5. 10 add 4 mL DEE and vortex 3 mins (note: DEE decanted from The invention claimed is: bottle fresh every day) 1. A press-coated tablet formulation for a delayed, fol pipette tips changed after every addition of standard/DEE lowed by a prolonged release of an active agent, the press centrifuge samples 3 mins at 2000 rpm coated tablet formulation comprising: remove top layer into clean labelled glass screwtop tube using 15 (a) a core comprising the active agent together with a wax glass pipette and optionally one or more fillers; and evaporate to dryness under at 40°C. (b) a delayed release layer Surrounding the core and com reconstitute in 100 ul mobile phase. Allow to stand for 30 prising a wax and a low Substituted hydroxypropyl cel mins and then Vortex 3 mins lulose in a ratio of 20:80 to 50:50 w/w; wherein the transfer to HPLC vial with insert delayed release layer delays release of the active agent Mobile Phase Preparation: within the core for between 2-8 hours after administra Materials tion of the press-coated tablet formulation to a subject potassium phosphate monobasic, SAFC lot 1370660 and thereafter a prolonged release of the active agent acetonitrile. Fisher HPLC gradeBX 1095614 from the core occurs, such that the active agent in the orthophosphoric acid: Analar normapur Bx 08.J170519 25 core is continuously released over a period of 2 up to 8 25 mM potassium phosphate buffer prepared with Q3 water, hours and wherein the low substituted hydroxypropyl adjusted to pH 2.5 with orthophosphoric acid cellulose is micronised with a mean particle diameter of Buchner filtered through 0.2 um 47 mm nylon membrane 20 um and has a molecular weight of 115,000 and a Chromatographic Conditions hydroxypropyl content of 8%. Gynkotek HPLC system with perkin elmer LS 40 fluores 30 2. The press-coated tablet formulation according to claim cence detector 1, further comprising: Column: phenomenex Gemini C6-Phenyl 110A 250x4.6 mm (c) a top-coating layer comprising an active agent together 5 micron with guard column with one or more excipients, wherein at least 70% of the Detection: excitation: 280 nm emission:313 nm. active agent in the top-coating layer is released within Isocratic 30.5% acetonitrile 69.5% phosphate buffer, flow 35 5-45 minutes following administration to the subject of rate 1 mL/min, run time 20 mins the press-coated tablet formulation. Injection volume 20 uL 3. The press-coated tablet formulation according to claim2 Standard Range: further comprising an amount of an active agent, which is the Verapamil 10-500 ng/mL plasma same or different to the active agent in the core and/or top norVerapamil 8.6-428 ng/mL plasma 40 coating layer, in the delayed release layer. Clinical Trial Protocol Verapamil 180 mg sustained-release 4. The press-coated tablet formulation according to claim2 over 6-8 hours (3 hour time-delay) wherein at least 80% of the active agent in the top-coating Clinical studies were carried out in Healthy male volun layer is released within 5-45 minutes following administra teers aged between 18-65 years inclusive with a body mass tion to the subject of the press-coated tablet. index (BMI) between 18.0 and 29.9 kg/m. Each subject 45 5. The press-coated tablet formulation according to claim received the following delayed-release tablets: Each tablet 4, wherein at least 80% of the active agent in the top-coating was radiolabelled with 4MBq 99mTc-DTPA and adminis layer is released within 10-30 minutes following administra tered with 240 ml of water at bedtime. tion to the subject of the press-coated tablet formulation. Subjects received a standard dinner comprising roast 6. The press-coated tablet formulation according to claim chicken with Salad, low fatyoghurt and one cup of decaffein 50 2, wherein at least 90% of the active agent in the top-coating ated tea, coffee or juice 2 hours prior to dosing. layer is released within 5-45 minutes following administra Gastrointestinal transit of the delayed-release tablets was tion to the subject of the press-coated tablet formation. characterised by inclusion of a radiolabel marker, techne 7. The press-coated tablet formulation according to claim tium-99m ("Tc), complexed with diethylenetriaminepen 6, wherein at least 90% of the active agent in the top-coating taacetic acid (DTPA) which prevents absorption from the 55 layer is released within 10-30 minutes following administra . The radiolabel is incorporated into the tion to the subject of the press-coated tablet formulation. core tablet. Each tablet was radiolabelled with 4 MBq. 8. The press-coated tablet formulation according to claim 99mTc-DTPA and administered with 240 ml of water at bed 2, wherein at least 70% of the active agent in the top-coating time. layer is released within 10-30 minutes following administra Scintigraphic imaging was performed using a Siemens 60 tion to the subject of the press-coated tablet formulation. E-Cam gamma camera fitted with a low-energy high-resolu 9. The press-coated tablet formulation according to claim 1 tion collimator. Subjects were imaged in a standing position wherein the active agent is designed to treat cardiovascular except during periods of sleep where the Subjects were conditions selected from the group consisting of hyperten imaged lying down. Anterior static acquisitions of 25-second Sion, angina pectoris and cardiac arrhythmia. duration each were collected immediately after dosing then 65 10. The press-coated tablet formulation according to claim every 30 minutes until 1 hour post-dose then every 15 minutes 9 wherein the press-coated tablet formulation comprises until complete release of radiolabel marker. Verapamil. US 9,283,192 B2 15 16 11. The press-coated tablet formulation according to claim Mepenzolate, Pipenzolate, Glycopyrronium, Oxyphe 1 wherein the wax for use in the core and the delayed release nonium, Penthienate, Methantheline, Propantheline, layer is independently selected from beeswax, carnuba wax, Otilonium bromide, Tridihexethyl, , microcrystalline wax, hydrogenated castor oil and a glyceryl Hexocyclium, Poldine, Bevonium, Diphemanil, Tiemo ester. nium iodide, Prifinium bromide, , 12. The press-coated tablet formulation according to claim Fenpiverinium, Papaverine, Drotaverine, , 11 wherein the glyceryl ester is glycerol behenate. 5-HT3 antagonists, 5-HT4 agonists, , Diiso 13. The press-coated tablet formulation according to claim promine, Chlorbenzoxamine, Pinaverium, Fenoverine, 11 wherein the wax in the core and the delayed release layer Idanpramine, Proxazole, Alverine, , is the same or different. 10 Isometheptene, Caroverine, Phloroglucinol, Silicones, 14. The press-coated tablet formulation according to claim Trimethyldiphenylpropylamine, Atropine, Hyos 1 wherein the wax in the delayed release layer and the low cyamine, Scopolamine, Butylscopolamine, Methylsco substituted hydroxypropyl cellulose are present in a ratio of polamine, Methylatropine, Fentonium, Cimetropium 25:75 to 40:60 W/w. bromide, and primarily dopamine antagonists; 15. The press-coated tablet formulation according to claim 15 Proton pump inhibitors selected from the group consisting 1 further comprising one or more pH-dependent, pH-inde of Omeprazole, lanSoprazole, pantoprazole, esomepra pendent, aesthetic or functional coatings. Zole, and rabeprazole sodium; 16. The press-coated tablet formulation according to claim Opioids and receptor antagonists; 15 wherein the coating is a gastro-resistant coating. Analgesics selected from the group consisting of Acetami 17. The press-coated tablet formulation according to claim nophen, Diclofenac, Diflunisal, Etodolac, Fenoprofen, 1 wherein the active agent in the core is continuously released Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, over a period of 3-6 hours. Ketorolac, Meclofenamate, Mefenamic Acid, Meloxi 18. The press-coated tablet formulation according to claim cam, Nabumetone, Naproxen, Oxaprozin, Phenylbuta 1 wherein less than 10% of the active agent within the core is Zone, Piroxicam, Sulindac, Tolimetin, Celecoxib, released for between 2-8 hours after administration of the 25 Buprenorphine. Butorphanol, Codeine, Hydrocodone, press-coated tablet formulation tablet to the subject. Hydromorphone, Levorphanol, Meperidine, Metha 19. The press-coated tablet formulation according to claim done, Morphine, Nalbuphine, Oxycodone, Oxymor 18 wherein less than 5% of the active agent within the core is phone, Pentazocine, Propoxyphene, and Tramadol; released for between 2-8 hours after administration of the Sleep drugs selected from the group consisting of press-coated tablet formulation tablet to the subject. 30 Nitrazepam, Flurazepam, Loprazolam, Lorimetazepam, 20. The press-coated tablet formulation according to claim Temazepam, Zaleplon, Zolpidem, , Chloral 18 wherein less than 1% of the active agent within the core is Hydrate, Triclofos, Clomethiazole, Quazepam, triaz released for between 2-8 hours after administration of the olam, EstaZolam, Clonazepam, , ESZopi press-coated tablet formulation tablet to the subject. clone, RoZerem, Trazodone, Amitriptyline, Doxepin, 21. The press-coated tablet formulation according to claim 35 Benzodiazepine drugs, melatonin, , 1, comprising one or more of the following active agents: and herbal remedies; Antacids selected from the group consisting of aluminium Cardiac glycosides selected from the group consisting of hydroxide, magnesium carbonate, magnesium trisili Digoxin and digitoxin; cate, hydrotalcite, and simeticonealginates; Phosphodiesterase Inhibitors selected from the group con Antispasmodics selected from the group consisting of atro 40 sisting of enoXimone and milrinone; pine Sulphate, dicycloverine hydrochloride, hyoscine Thiazides and related diuretics selected from the group butylbromine, , alverine citrate, consisting of bendroflumethiazide, chlortalidone, cyclo and mebeverine hydrochloride; penthiazide, inapamide, metolaZone, and Xipamide; Motility stimulants selected from the group consisting of Diuretics selected from the group consisting of furo metoclorpramide and domperidone; 45 semide, bumetanide, and torasemide; H2-Receptor antagonists selected from the group consist Potassium sparing diuretics and aldosterone antagonists ing of Cimetidine, famotidinenizatidine, and ranitidine; Selected from the group consisting of amiloride hydro Antimuscarinics; chloride, triamterene, weplerenone, and spironolactone; Chelates selected from the group consisting of Tripotas Osmotic diuretics; sium dicitratbismuthate and Sucralfate; 50 Drugs for arrhythmias selected from the group consisting Prostaglandin analogues; ofadenosine, amiodarone hydrochloride, disopyramide, Aminosalicylates selected from the group consisting of flecainide acetate, propafenone hydrochloride, and balsazide Sodium, mesalazine, olsalazine, and Sul lidocaine hydrochloride: phasalazine; Beta adrenoreceptor blocking drugs selected from the Corticosteroids selected from the group consisting of 55 group consisting of , atenolol, acebutolol, beclometaSone dipropionate, budenoside, hydrocorti fumarate, carvedilol, celiprolol, esmolol, Sone, and prednisolone; lebatolol, metoprolol tartrate, nadolol, nebivolol, Oxpre Affecting immune response selected from the group con nolol, pindolol, solatol, and timolol; sisting of ciclosporin, mercaptopurine, methotrexate, Hypertension drugs selected from the group consisting of adalimumab, and infliximab; 60 ambrisentan, bosentan, diaZoxide, hydralazine, iloprost, Stimulant laxatives selected from the group consisting of minoxidil, sildenafil. Sitaxentan, Sodium nitroprus side, bisacodyl, dantron, docusate, and sodium picosulfate; clonidine, methyldopa, moXonidine, guanethidine Drugs affecting biliary composition and flow: monosulphate, doxazosin, indoramin, , tera Bile acids sequestrants selected from the group consisting Zosin, phenoxybenzamine, and phentolamine mesilate; of colestyramine, Oxyphencyclimine, Camylofin, 65 Drugs affecting the renin-angiotensin System selected Mebeverine, Trimebutine, Rociverine, Dicycloverine, from the group consisting of Captropril, CilaZapril, . Difemerine, Piperidolate, Benzilone, Enalapril Maleate, Fosinopril, Imidapril, Lisinopril, US 9,283, 192 B2 17 18 Moexipril, Perindopril Erbumine, Quinapril, Ramipril, Co-Fluampicil, Piperacillin, Ticarcillin, Pivmecillinam, Trandolapril, Candesartan Cilexetil, Eprosartan, Irbe Cephalosporins, Cefaclor, Cefadroxil, Cefalexin, Sartan, Losartan, Olmesartan Medoxomil. Telmisartan, Cefixime, Cefotaxime, Cefradine, Ceftazidime, Valsartan, and Aliskiren: Cefuroxime, Ertapenem, Imipenem, Meropenem, Nitrates, calcium channel Blockers, and antianginal drugs Aztreonam, Tetracycline, Demeclocycline. Doxocy Selected from the group consisting of Glyceryl trinitrate, cline, Lymecycline, Minocycline, Oxytetracycline, Isosorbide Dinitrate. Isosorbide Mononitrate, Amlo Tigecycline, Gentamicin, Amikacin, Neomycin, Tobra dipine, Diltiazem, Felodipine, Isradipine, Lacidipine, mycin, Erythromycin, Azithromycin, Clarithromycin, Lercanidipine, Nicardipine, Nifedipine, Nimodipine, Telithromycin, Clindamycin, Chloramphenicol, Fusidic Verapamil, Ivabradine, Nicorandil, and ; 10 Acid, Vancomycin, Teicoplanin, Daptomycin, Lin Peripheral Vasodilators and related drugs selected from the eZolid, Quinupristin, Colistin, Co-Trimoxazole, Sulpa group consisting of Cilostazol. Nicotinate, diazine, Trimethoprim. Capreomycin, Cycloserine, Moxisylyte, Naftidrofuryl Oxalate, and ; Sympathomimetics selected from the group consisting of Ethambutol, Isoniazid, Pyrazinamide, Rifabutin, Dopamine, Dopexamine, Ephedrine, Metaraminol, Rifampicin, Streptomycin, Dapsone. Clofazimine, Met Noradrenaline Acid Tartrate, Norephidrine Bitartrate, 15 ronidazole, Tinidazole, Ciproflaxacin, Levoflaxacin, and Phenylephidrine; Moxifloxacin, Nalidixic Acid, Norflaxine, Orflaxacin, Anticoagulants and Protamine selected from the group Nitrofurantoin, Methenamine Hippurate, Amphotericin, consisting of Heparin, Bemiparin, Dalteparin, Enox Anidulafungin, Caspofungin, Fluconazole, Flucytosine, aparin, Tinzaparin, Danaparoid, Bivalirudin, Lepirudin, Griseofluvin, Itraconzole, Ketoconazole, Micafungin, Epoprostenol, Fondaprinux, Warfarin, Acenocoumarol, Nystatin, , Terbinafine, Voriconazole, Phenindione, Dabigatran Etexilate, Rivaroxaban, and Abacavir, Didanosine, Emtricitabine, Lamivudine, Sta Protamine Sulphate: Vudine, Tenofovir Disoproxil, Zidovudine, Atazanavir, Antiplatelet Drugs selected from the group consisting of Darunavir, Fosamprenavir, Indinavir, Lopinair, Nelfi Abciximab, Asprin, Clopidogrel, , Eptifi navir, Ritonavir, Saquinavir, Tipranavir, Efavirenz, batide, Prasugrel, and Tirofiban: 25 Etravirine, Nevarapine, Enfuvirtide, Maraviroc. Ralte Fibrinolytic and antifibrinolytic drugs selected from the gravir, Aciclovir, Famciclovir, Inosine Pranobex, Valaci group consisting of Alteplase. Reteplase, Streptokinase, clovir, Cidofovir, Gangciclovir, Foscarnet, Valgangci Tenecteplase, Urokinase, Etamsylate, and Tranexamic clovir, Adefovir Dipivoxil, Entecavir, Telbivudine, Acid; Amantadine, Oseltamivir, Zanamivir, Palivizumab, Rib Lipid regulating drugs selected from the group consisting avirin, Artemether, Chloroquine, , Pri of Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, 30 maquine, Proguanil, Pyrimethamine, Quinine, Doxycy Simvastatin, Colesevam, Colestyramine, Colestipol, EZetimibe, Bezafibrate, Ciprofibrate, Fenofibrate, Gem clin, Diloxanide Furoate, Metronidaziole, Tinidazole, fibrozyl, Acipmox, Nictotinic Acid, Omega three fatty , Sodium Stibogluconate, Atovaquone, Pen acid compounds, Ethanolamine Oleate, and Sodium Tet tamidine Isetionate, Mebendazole, and Piperazine; and radecyl Suphate: 35 other drugs selected from the group consisting of Benz CNS Drugs selected from the group consisting of Benperi tropine, procyclidine, biperiden, Amantadine, Bro dol, Chlorpromazine, Flupentixol, Haloperidol, mocriptine, Pergolide. Entacapone, Tolcapone, Selege Levomepromazine, Pericyazine, , line, Pramipexole, budesonide, formoterol, quetiapine Pimozide, Prochlorperazine, Promazine, Sulpiride, Tri fumarate, olanzapine, pioglitazone, montelukast, fluoperazine, Zuclopenthixol, Amisulpride, Aripipra Zoledromic Acid, Valsartan, latanoprost, Irbesartan, Zole, Clozapine, Olanzapine, Paliperidone, Quetiapine, 40 Clopidogrel, Atomoxetine, Dexamfetamine, Meth Riperidone, Sertindole, Zotepine, Flupentixol, ylphenidate, Modafinil, Bleomycin, Dactinomycin, , Olanzapine Embonate, Pipotiazine Daunorubicin, Idarubicin, Mitomycin, Mitoxantrone, Palmitate, , Zuclopenthixol Decanoate, Azacitidine, Capecitabine, Cladribine, Clofarabine, Carbamazepine, Valproate, Valproic acid, Lithium Car Cytarabine, Fludarabine, Flourouracil, Gemcitabine, bonate, Lithium Citrate. Amitriptyline. Clomipramine, 45 mercaptopurine, methotrexate, Nelarabine, Pemetr DoSulepin, , Lofepramine, Nortriptyline, exed, Raltitrexed. Thioguanine, , Trimipramine, mianserin, Trazodone, Phenelzine, Iso Betamethasone, Cortisone, Deflazacort, Dexam carboxazid, , Moclobemide, Citalo ethosone, Hydrocortisone, Methylprednisolone, Pred pram, Escitalopram, , Fluvoxamine, Paroxet nisolone, Triamcinolone. Ciclosporine, Sirolimus, Tac ine, Sertraline, , Duloxetine, Flupentixol, 50 rolimus, Interferon Alpha, and Interferon Beta. Mirtazapine, Reboxetine, Trytophan, Venflaxine, Atom 22. The press-coated tablet formulation according to claim oxetine, Dexametamine, Methylphenidate, Modafinil, 21, comprising one or more of the following active agents: Eslicarbazepine, Ocarbazepene, Ethosuximide, Gabap pirenzepine, misoprostol, ursodeoxycholic acid, Alos entin, Pregabalin, Lacosamide, Lamotrigine, Levetirac etron, Cilansetron, Mosapride, Prucalopride, Tegaserod, etam, Phenobarbital, Primidone, Phenytoin, Rufina 55 mide, Tiagabine, , Vigabatrin, Zonisamide, Metoclopramide, Bromopride, Clebopride, Domperi ropinirole, Rotigotine, Co-Beneldopa, Levodopa, Co done, Alizapride, Cinitapride, Cisapride, codeine, mor Careldopa, Rasagiline, , Entacapone, Tolca phine, loperamide, diphenoxylate, methylnaltrexone pone, Amantidine, Orphenadrine, Procyclidine, Trihex bromide, Valerian, and mannitol. yphenidyl, Haloperidol, Piracetam, Riluzole, 23. A method of treating a cardiovascular condition, the Tetrabenazine, Acamprosate, Disulfiram, Bupropion, 60 method comprising administering the press-coated tablet for Vareniciline, Buprenorphine, Lofexidine, Donepezil, mulation according to claim 1 to a subject in need thereof, Galantamine, Memantine, and Rivastigimine; wherein the active agent is a cardiovascular agent. Anti-Infectives selected from the group consisting of Ben 24. The method according to claim 23 wherein the cardio Zylpenicillin, Phenoxymethylpenicillin, Flucloxacillin, Vascular agent is Verapamil. Temocillin, Amoxicillin, Ampicillin, Co-Amoxiclav, ck k k k k