Abstract:
In one aspect, the present invention is concerned with a treatment where it is desired that an active agent is designed to be released in a pulse 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 whilst a subject is sleeping. As well as treating certain conditions by a particular regime, the invention also provides novel formulations for a delayed, followed by a pulsed release of drug.

Description:
FIELD OF INVENTION 
       [0001]    In one aspect, the present invention is concerned with a treatment where it is desired that an active agent is designed to be released in a pulse 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 whilst a subject is sleeping. As well as treating certain conditions by a particular regime, the invention also provides novel formulations for a delayed, followed by a pulsed release of drug. 
       BACKGROUND TO THE INVENTION 
       [0002]    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)) 
         [0003]    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. 
         [0004]    It is amongst the objects of the present invention to obviate and/or mitigate at least one of the aforementioned disadvantages. 
         [0005]    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 in a short pulse, following a period of delay following administration. 
       SUMMARY OF INVENTION 
       [0006]    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 a delayed release of the pharmaceutically active ingredient could be achieved, followed by a pulsed delivery of the agent. 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. 
         [0007]    One particularly preferred embodiment relates to treating subjects who wake during the night, but have no or little difficulty in initially falling asleep, commonly termed sleep maintenance insomnia. In a preferred embodiment therefore, the formulations of the present invention are for treating sleep maintenance insomnia. Such formulations therefore comprise a pharmaceutically active agent for inducing and/or facilitating sleep. Typically this may be a sedative or hypnotic agent, such as a benzodiazepine, chloral hydrate, melatonin and analogues thereof, zolpidem, zopiclone or zaleplon. 
         [0008]    Thus, in a first aspect, the present invention provides a sleep inducing and/or maintaining formulation agent such as a sedative or hypnotic agent, formulated as a component of a press-coated tablet for treating sleep maintenance insomnia, wherein the formulation 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 the hypnotic agent is substantially not released from the formulation for a period between 1-8 hours, such as 1.5-4 hours after administration of the formulation to the subject and thereafter the agent is released from the formulation as a pulse such that at least 70-90%, for example 80% of the agent within the formulation is released within 5-80 mins, such as 10-45, or 10-30 mins. 
         [0009]    In a further aspect there is provided a method of treating sleep maintenance insomnia, the method comprising administering a press-coated tablet comprising a sleep inducing agent, such as a sedative or hypnotic agent to a subject, immediately before the subject intends sleeping, wherein the formulation substantially delays release of the drug for 1-8 hours, such as 1.5-4 hours following administration of the formulation and thereafter the drug is released in a pulse over a period of 5-80 mins, such as 10-45 or 10-30 mins. 
         [0010]    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 a low-substituted hydroxypropyl cellulose (L-HPC), such as LH-11, or LH-21. 
         [0011]    In a further aspect, the present invention provides a press-coated tablet formulation for a delayed, followed by a pulsed release of an active agent, the tablet comprising 
         [0000]    (a) a core comprising the active agent(s) together with an excipient(s); and
 
(b) a delayed release layer surrounding the core and comprising a wax and L-HPC 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 1-8 hours, such as 1.5-4 hours after administration of the tablet by 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 5-80 mins, such as 10-40 or 10-30 mins.
 
         [0012]    The active agents of the above aspect 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). 
         [0000]    The press-coated tablets of the present invention may be used to treat one or more of the following conditions/disorders or diseases: 
         [0013]    Central Nervous System disorders, e.g. Neurogenic pain, stroke, dementia, Alzheimer&#39;s disease, Parkinson&#39;s disease, neuronal degeneration, meningitis, spinal cord injury, cerebral vasospasm, amyotrophic lateral sclerosis 
         [0000]    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&#39;s disease, Hypoaldosteronism, cushing&#39;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&#39;s Disease, Alopecia greata, Amyotrophic Lateral Sclerosis, Ankylosing Spondylitis, polyarticular Arthritis, Atopic allergy, topic Dermatitis, Autoimmune hepatitis, Celiac disease, Chagas disease, Coeliac Disease, Cogan syndrome, Crohns Disease, Cushing&#39;s Syndrome, Diabetes mellitus type 1, Endometriosis, Eosinophilic fasciitis, Fibromyalgia/Fibromyositis, Gastritis, Glomerulonephritis, Graves&#39; disease. Guillain-Barrë syndrome (GBS), Hashimoto&#39;s encephalitis, Hashimoto&#39;s thyroiditis, Haemolytic anaemia, Idiopathic Inflammatory Demyelinating Diseases, Idiopathic pulmonary fibrosis, interstitial cystitis, Juvenile idiopathic arthritis, Juvenile rheumatoid arthritis, Kawasaki&#39;s Disease, Lichen sclerosus, Lupus erythematosus, Ménière&#39;s disease, Myasthenia gravis, myositis, Narcolepsy, Pernicious anaemia, Perivenous encephalomyelitis, Polymyalgia rheumatica, Primary biliary cirrhosis, Psoriatic Arthritis, Reiter&#39;s syndrome, Rheumatoid fever, Sarcoidosis, Schizophrenia, Sjögren&#39;s syndrome, Spondyloarthropathy, Ulcerative Colitis
 
Musculoskeletal disorders: osteoarthritis, osteoporosis, Osteonecrosis, Arthritis, Paget&#39;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&#39;s disease, labyrinthitis,
 
Others: acute and chronic pain, viral infection, cancer, laryngitis, mastoiditis, myringitis, otitis media, rhinitis, sinusitis, Sialadenitis, Retropharyngeal Abscess, Tonsillopharyngitis,
 
       Gastro-Intestinal Disorders 
       [0014]    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&#39;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, Whipples Disease
 
Exemplary active agents for use in the pharmaceutical and veterinary applications of the invention include analgesics, 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.
 
Said Active Agent or Agents May be Selected from the Following:
 
       Gastro Drugs 
       [0015]    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, Chlorbenzoxamine, 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 
       [0016]    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 
       [0017]    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 
       [0018]    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 hydrochloride, triamterene, weplerenone, spironolactone,
 
Osmotic diuretics&#39;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, 
       [0019]    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, 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, MefloquinePrimaquine, Proguanil, Pyrimethamine, Quinine, Doxycyclin, Diloxanide Furoate, Metronidaziole, Tinidazole, MepacrineSodium Stibogluconate, Atovaquone, Pentamidine Isetionate, Mebendazole, Piperazine,
 
       Other: 
       [0020]    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, 
         [0021]    In a particularly preferred embodiment the active agent is designed to treat sleep maintenance insomnia and as such the active agent is a sedative or hypnotic, such as zolpidem, Zaleplon or Zopiclone. 
         [0022]    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”. 
         [0023]    In accordance with the invention, formulations are provided which are to be taken by a subject and which do not initially administer the active agent when the subject first takes the formulation. However, at a later time point the agent is administered to the subject as a “pulse” of agent. 
         [0024]    In relation to the treatment of sleep maintenance insomnia, the subject takes a formulation in accordance with the invention and which comprises a sleep inducing/maintaining agent. Initially, the agent is substantially not released from the formulation, but after a period of time, for example, when a subject suffering from sleep maintenance insomnia may be expected to wake up, the agent is released in a pulse, so as to treat the subject and reduce the likelihood of them waking up through the night. It is desired that the agent is released in a pulse like manner so that the drug does not remain in the subject&#39;s system for a long period of time, in order to ensure that the subject is able to wake up at a suitable time in the morning and not to feel drowsy, a common side-effect of sleep inducing/maintaining agents. 
         [0025]    The L-HPC is preferably LH-11 or LH-21, especially LH-11. LH-11 and LH-21 are particular types of 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-11 is mostly fibrous and has a mean particle size of 55 μm. LH-11 has a hydroxypropyl content of around 11% and a molecular weight of around 130,000. LH-21 is moderately fibrous and has a mean particle size of 45 μm. LH-21 has a molecular weight of around 120,000 and a hydroxypropyl content of around 11% 
         [0026]    The wax may be any suitable wax such beeswax, carnuba wax, microcrystalline wax, hydrogenated castor oil. A particularly preferred wax is a glyceryl ester, such as glycerol behenate. 
         [0027]    In a preferred formulation of the present invention as defined herein above, the wax and L-HPC 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-11 as the L-HPC employed as a delayed release layer in accordance with the present invention, is observed to provided a delayed release of approximately 3 hours. However, the same ratio with LH-21 as the L-HPC provides a delay in release of only 2 hours. Also reducing the amount of wax in comparison to the L-HPC is observed to reduce the delay significantly and conversely increasing the amount of wax to L-HPC ratio results in a significant increase in the delay of release. 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. 
         [0000]    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 which is designed to be released during dissolution/disintegration of the delayed release layer. 
         [0028]    The subject to be treated is an animal, e.g. a mammal, especially a human. 
         [0029]    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. 
         [0030]    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. 
         [0031]    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. 
         [0032]    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. 
         [0033]    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. 
         [0034]    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. 
         [0035]    Compressed tablets may be prepared by compressing the core tablet 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. The core tablet is subsequently coated with the materials for forming the delayed release layer. Tablets may be optionally coated, for example, by way of a further gastro-resistant coating. 
         [0036]    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. 
         [0037]    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. The core may be formed by dispersing one or more active agents with one or more excipients, such as a cellulose ether, typically a L-HPC, such as LH-21. 
         [0038]    The delayed release layer may be formed by melting the wax component and subsequently admixing the other components including the L-HPC. 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 μm-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. 
         [0039]    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. 
         [0040]    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. 
         [0041]    The core and/or delayed release 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. 
         [0042]    The filler in the delayed release layer can be the same or different as the filler in the core composition, if any. For example, the core composition can include a water soluble filler while the press coat composition can include a water insoluble filler. 
         [0043]    Other excipients can also be present in the core and/or delayed release 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. 
         [0044]    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. 
         [0045]    The tablet can be further coated with optional additional coatings. The additional coatings can be pH-dependent on pH-independent, aesthetic or functional; where the coating is a gastro-resistant coating (intended to prevent release in the stomach), the ‘clock’ or time for delayed release, as defined herein, will not start until gastric emptying occurs and dissolution of the gastro-resistant coating takes place (as can be determined, for example, by employing scintigraphy studies). The time taken for dissolution of the gastro-resistant coating together with the delay from the time-delay layer will ensure drug release in the lower reaches of the intestine, particularly the distal ileum and/or colon. Such additional coatings preferably include film forming materials. For subjects who may additionally find it difficult to go to sleep, the delayed release layer and/or additional coating may include a sleep inducing agent for immediate release. 
     
    
     
       DETAILED DESCRIPTION 
         [0046]    The present invention will now be further described by way of example and with reference to the figure which show: 
           [0047]      FIG. 1  shows the release profile of a drug from a tablet comprising glycerol behenate and LH-11 in a 50/50 w/w ratio in a delayed release layer; 
           [0048]      FIG. 2  shows the release profile of a drug from a tablet comprising glycerol behenate and LH-21 in a 50/50 w/w ratio in a delayed release layer; 
           [0049]      FIGS. 3 and 4  show the release profile of a drug from a tablet comprising glycerol behenate and LH-11 ( FIG. 3 ) and LH-21 ( FIG. 4 ) in 30:70 w/w ratio, in a delayed release layer; 
           [0050]      FIG. 5  shows Gamma Scintigraphy Images showing release of delayed release formulation of Zolpidem; 
           [0051]      FIG. 6  shows Pharmacokinetic analysis of drug levels in plasma, in 6 subjects; and 
           [0052]      FIG. 7  shows the release profile of a tablet comprising a delayed release layer of 50/50 w/w glycerol behenate/LH32. 
       
    
    
     FORMULATION FOR TREATING SLEEP MAINTENANCE INSOMNIA 
     1. Clinical Need 
       [0053]    This formulation profile was designed as a treatment for people that fall asleep initially, then reawaken and are unable to sleep 2-3 hours later. 
       2. Methods 
     2.1. Core Tablet Blend and Core Tablet Compression 
       [0000]    
       
         
           
             (i) 1 g Zolpidem tartrate, 5.1 g ac-di-sol, 2.0 g lactose and 0.9 g magnesium stearate. Powder mix of the above, except magnesium stearate, for 10 min in turbula mixer, then magnesium stearate added and all mixed for further 5 min. 
             (ii) 90 mg core tab blend-compressed in a 6.9 mm die/punch set at 1 ton for 10 seconds. 
             (iii) Tablets are stored in amber glass bottle until use. 
           
         
       
     
       2.2. Granules (to Surround Core Tablet) 
       [0000]    
       
         
           
             (i) Glycerol behenate (GB) and LH-11 weighed into tared weigh boats according to Table 1: 
           
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 Excipient 
                 Weight (g) 
               
               
                   
                   
               
             
             
               
                   
                 GB 
                 10 
               
               
                   
                 LH-11 
                 10 
               
               
                   
                   
               
             
          
         
       
       
         
           
             (ii) GB placed in a glass beaker on a hot plate set at 100° C. Once the GB melted, LH-11 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. 
           
         
       
     
       2.3. Formulation Compression 
       [0000]    
       
         
           
             (i) A 13 mm die and matching flat-faced punches 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, the core tablet dropped on and centralised (centralising tool) before placing the other 250 mg granules on top. 
             (iii) The formulation is compressed at 5 ton for 2 minutes in a 13 mm die/punch set. 
           
         
       
     
       2.4. Dissolution 
       [0065]    Dissolution performed in 900 ml sodium phosphate buffer (0.01 M, at pH7) at 37° C., with UV analysis at 242 nm. 
       3. Results (50:50, GB:LH-11) 
       [0066]    As can be seen from  FIG. 1 , a delay of approximately 3 hours is observed, followed by a rapid pulsed release of drug. 
       4. Supporting Data 
       [0067]    4.1. LH-21 instead of LH-11 (50:50, GB:LH-21)
 
As can be seen in  FIG. 2 , substituting LH-11 for LH-21, results in a decrease in the delay of release time. Such a decrease may not be desired for all envisaged applications.
 
       4.2. 80:20, GB:LH-11 
       [0068]    No release of zolpidem core tablet over 12 hours, data not shown. 
       4.3. 80:20, GB:LH-21 
       [0069]    No release of zolpidem core tablet over 12 hours, data not shown. 
       4.4. 30:70, GB:LH-11 
       [0070]    As can be seen in  FIG. 3 , reducing the glycerol behenate to LH-11 ratio results in a significant decrease in the delay of release time. 
       4.5. 30:70, GB:LH-21 
       [0071]    As can be seen in  FIG. 4 , reducing the glycerol behenate to LH-21 ratio results in a significant decrease in the delay of release time.
 
Using LH-21 in the outer granules instead of LH-11 releases the core tablet approximately 30 min earlier in both examples shown above.
 
       Extraction Method/Analysis of Plasma Levels of Zolpidem 
     Materials 
       [0072]    Human plasma, lithium heparin, origin USA: Sera laboratories international Ltd, Bx H911239 Zolpidem tartrate
 
DEE: Fisher laboratory reagent grade Bx 1097413
 
NaOH: prepared using Q3 water and NaOH: Sigma Aldrich, reagent grade beads, 97% Bx 01209BH
 
       Method 
       [0073]    vortex blank plasma
 
add 400 ul blank plasma to glass screw cap tubes
 
       Calibration 
       [0074]    Blank preparation—to be prepped before standards
 
add 100 ul mobile phase to 400 ul blank plasma
 
vortex 10 secs
 
       add 50 ul 1M NaOH 
       [0075]    vortex 10 secs
 
add 4 mL DEE and vortex 3 mins (note: DEE decanted from bottle fresh every day)
 
pipette tips changed after every addition of mobile phase/DEE
 
       Standard Preparation 
       [0076]    Starting with lowest concentration standard, vortex standard
 
Add 100 ul standard to 400 ul blank plasma
 
Vortex 10 secs
 
       Add 50 ul 1M NaOH 
       [0077]    Vortex 10 secs
 
Add 4 mL DEE and vortex 3 mins (note: DEE decanted from bottle fresh every day)
 
Pipette tips changed after every addition of standard/DEE
 
Centrifuge samples 3 mins at 2000 rpm
 
Remove top layer into clean labelled glass screwtop tube using glass pipette
 
Evaporate to dryness under nitrogen at 40° C. (also used RVC to evaporate, 40° C., 100 mbar, 25 mins)
 
Reconsititute in 100 ul mobile phase. Allow to stand for 30 mins and then vortex 3 mins
 
Transfer to HPLC vial with insert
 
       Sample Preparation 
       [0078]    Vortex samples to mix
 
Add 500 ul sample to glass screwtop tube
 
       Add 50 ul 1M NaOH 
       [0079]    Vortex 10 secs
 
Add 4 mL DEE and vortex 3 mins (note: DEE decanted from bottle fresh every day)
 
Pipette tips changed after every addition of standard/DEE
 
Centrifuge samples 3 mins at 2000 rpm
 
Remove top layer into clean labelled glass screwtop tube using glass pipette
 
Evaporate to dryness under nitrogen at 40° C. (also used RVC to evaporate, 40° C., 100 mbar, 25 mins)
 
Reconsititute in 100 ul mobile phase. Allow to stand for 30 mins and then vortex 3 mins
 
Transfer to HPLC vial with insert
 
       Mobile Phase Preparation 
     Materials 
       [0080]    Potassium phosphate monobasic, SAFC lot 1370660
 
NaOH: Sigma Aldrich, reagent grade beads, 97% Bx 01209BH
 
Acetonitrile: Fisher HPLC gradeBx 1095614
 
20 mM potassium phosphate buffer prepared with Q3 water, adjusted to pH 6 with NaOH
 
Buchner filtered through 0.2 um 47 mm nylon membrane
 
       Chromatographic Conditions 
       [0081]    Gynkotek HPLC system with Perkin Elmer LS 40 fluorescence detector
 
Column: phenomenex Lichrospher RP-18 100A 125×4.00 mm 5 micron with guard column
 
Detection: excitation: 251 nm emission: 289
 
Gradient: starting conditions 60% buffer 40% acetonitrile flowrate 1 mL/min
 
Increase from 40-80% acetonitrile over 10 mins, hold at 80% for 4 mins
 
Return to starting conditions for 2 mins prior to next injection
 
Injection volume 20 uL
 
       Spiked Standard Range 
       [0082]    1-150 ng/mL plasma
 
Clinical Trial Protocol—Zolpidem 10 mg delayed-release (2 hour time-delay)
 
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/m 2 .
 
Gastrointestinal transit of the delayed-release tablets was characterised by inclusion of a radiolabel marker, technetium-99m ( 99m Tc), 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 99 mTc-DTPA and administered with 240 ml of water at bedtime.
 
Subjects received a standard dinner comprising roast chicken with salad, low fat yoghurt and one cup of decaffeinated tea, coffee or juice 4 hours prior to dosing.
 
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.
 
The following imaging schedule was used:
 
Anterior static acquisitions of 25-second duration each were collected immediately after dosing 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 according to the following schedule:
 
Every 15 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 (9 hours post-dose). See  FIG. 5 .
 
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. 6 .
 
 FIG. 7  shows the release profile of a tablet formulation comprising a delayed release layer of 50/50 w/w glycerol behenate/LH32 demonstrating the ability to vary the period of delay before pulsed drug release.