In this context, it is intended that bioavailability be determined by a suitable pharmacodynamic method, such as comparison of area under the blood plasma concentration curve (AUC)for the nasally and intravenously administered drug.

[052] In some embodiments, the composition contains a benzodiazepine drug that at least partially in a particulate form suspendedin a carrier system containing a natural or synthetic tocopherol or tocotrienol, one or more alcohols or glycols, and an alkyl glycoside.

In some embodiments, benzodiazepine comprises a memberof the group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinationsthereof.

By way of non-limiting example, such active ingredients include: paraldehyde; aromatic allylic alcohols (such asstiripentol); barbiturates (e.g. phenobarbitol, primidone, methylphenobarbital, metharbital and barbexaclone); bromides (such as potassium bromide); carbamates (such as felbamate); carboxamides (such as carbamazepine and oxcarbazepine); fatty acids (such as valproic acid, sodium valproate, and divalproex sodium, vigabatrin, progabide, tiagabine); fructose, topiramate, Gaba analogs(e.g. gabapentin and pregabalin); hydantoins(e.g. ethotoin, phenytoin, mephenytoin and fosphenytoin); oxazolidinediones (such as paramethadione, trimethadione, ethadione); propionates(e.g. beclamide), pyrimidinediones (e.g. primidone); pyrrolidines (e.g. brivaracetam, levetiracetam and seletracetam); WSGRDocket No. 35401-716.103

succinimides (e.g. ethosuximide, phensuximide and mesuximide); sulfonamides (e.g. acetazolamide, sulthiame, methazolamide and zonisamide); triazines (such as lamotrigine); ureas (such as pheneturide, phenacemide); valproylamides (such as valpromide and valnoctamide); as well as other anticonvulsants or pharmaceutically acceptable salts or combinations thereof.

Definitions [050] As used herein the phrase “therapeutically effective amount” (or more simply “effective amount”) includes an amount sufficient to provide a specific therapeutic response for which the drug is administered to a patient in need ofparticular treatment.

In some embodiments, benzodiazepine comprises a memberofthe group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinationsthereof.

By way of non-limiting example, such active ingredients includeinsulin, calcitonins (for example porcine, human, salmon, chicken,or eel) and synthetic modifications thereof, enkephalins, LHRH and analogues (Nafarelin, Buserelin, Zolidex), GHRH (growth hormonereleasing hormone), nifedipin, THF (thymic humoral factor), CGRP (calcitonin generelated peptide), atrial natriuretic peptide, antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines (particularly HIV vaccines, measles, rhinovirus Type 13 and respiratory syncitial virus), pentamidine, CCK (Cholecystikinine), DDVAP,Interferons, growth hormone(solatotropir polypeptides or their derivatives (preferably with a molecular WSGR Docket No. 32103-716.101

By way ofnon-limiting example, such active ingredients include: paraldehyde; aromatic allylic alcohols (such as stiripentol); barbiturates(e.g. phenobarbitol, primidone, methylphenobarbital, metharbital and barbexaclone), bromides (such as potassium bromide); carbamates (such as felbamate); carboxamides (such as carbamazepine and oxcarbazepine); fatty acids (such as valproic acid, sodium valproate, and divalproex sodium, vigabatrin, progabide, tiagabine); fructose, topiramate, Gaba analogs(e.g. gabapentin and pregabalin); hydantoins(e.g. ethotoin, phenytoin, mephenytoin and fosphenytoin); oxazolidinediones (such as paramethadione, trimethadione, ethadione);, propionates(e.g. beclamide), pyrimidinediones(e.g. primidone); pyrrolidines(e.g. brivaracetam,levetiracetam and seletracetam); succinimides(e.g. ethosuximide, phensuximide and mesuximide); sulfonamides (e.g. acetazolamide, sulthiame, methazolamide and zonisamide); triazines (such as lamotrigine); ureas (such as pheneturide, phenacemide), valproylamides (such as valpromide and valnoctamide); as well as other anticonvulsants or pharmaceutically acceptable salts or combinations thereof.

[171]|Those skilled in the art will be aware that a systematic, therapeutically effective amount of benzodiazepine drugs for treating the aforementioned disorders wili vary with age, size, weight, and general physical condition ofthe patient as well as the severity of the disease.

The compositions of the present invention are particu larly suited for application to mucous membranes in animals or humans, to deliver systemically substantially insoluble or sparingly soluble biologically active agents in a manner Which ensures that a clinical effect is reached at least as rapidly as by conventional oral administration, With for instance tablets.

Hormones and hormone-like substances of the steroid group: Corticosteroids such as cortisone, hydrocortisone, prednolone, prednisolone, triamcinolone acetonide, dexamethasone, ?unisolide, budesonide, toxicorole pivalate, betametasone, beclomethasone dipropionate, ?uticasone etc; Sex-hormones such as: estradiol, progesterone, testosterone etc; Antibiotics: Tetracyclines such as tetracycline, doxycycline, oxytetracycline, chloramphenicol etc; Macrolides such as erythromycin and derivatives, etc; Antivirals: such as acyclovir, idoxuridine, tromantadine etc; Antimycotics: MiconaZole, ketoconaZole, ?uconaZole, itraconaZole, econaZole, terconaZole, griseofulvin, and polyenes such as amphotericin B or nystatine etc; Anti-amoebics: MetronidaZole, metronidaZole benZoate and tinidaZole etc; Anti-in?ammatory drugs: NSAID’s such as indomethacin, ibuprofen, piroxicam, diclofenac etc; Anti-allergics: Disodium cromoglycate etc; Immunosuppressive agents: cyclosporins etc; Coronary drugs: including vasodilators such as nitroglycerin, isosorbide dinitrate, Calcium-antagonists such as verapamile, nifedipine and diltiaZem, Cardiac glycosides such as digoxine.

lidocaine, etc; Anxiolytics, sedatives & hypnotics: diaZepam, nitraZepam, ?uraZepam, estaZolam, ?unitraZepam, triaZolam, alpraZolam, midaZolam, temaZepam, lormetaZepam, brotiZolam, clobaZam, clonaZepam, loraZepam, oxaZepam, buspirone, etc; Migraine relieving agents: sumatriptan, ergotamines and derivatives etc; Drugs against motion sickness: eg.

A composition as claimed in claim 1 Wherein the active agent is selected from the group consisting of tetracycline, doXycycline, oXytetracylcline, chloramphenicol, erythromycin, acyclovir, idoXuridine, tromantadine, miconaZole, ketoconaZole, ?uconaZole, itraconaZole, econaZole, griseofulvin, amphotericin B, nystatine, metronidaZole, metronidaZole benZoate, tinidaZole, indomethacin, ibuprofen, piroXicam, diclofenac, disodium cromoglycate, nitroglycerin, isosorbide dinitrate, verapamile, nifedipine, diltiaZem, digoXine, morphine, cyclosporins, buprenorphine, lidocaine, diaZepam, nitraZepam, ?uraZepam, estaZolam, ?unitraZepam, triaZolam, alpraZolam, midaZolam, temaZepam lormetaZepam, brotiZolam, clobaZam, clonaZepam, loraZepam, oXaZepam, busiprone, sumatriptan, ergotamine derivatives, cinnariZine, anti-histamines, ondansetron, tropisetron, granisetrone, metoclopramide, disul?ram, and vitamin K. 6.

A composition as claimed in claim 23 Wherein the active agent is selected from the group consisting of tetracycline, doXycycline, oXytetracycline, chloramphenicol, erythromycin, acyclovir, idoXuridine, tromantadine, miconaZole, ketoconaZole, ?uconaZole, itraconaZole, econaZole, griseofulvin, amphotericin B, nystatine, metronidaZole, metronidaZole benZoate, tinidaZole, indomethacin, ibuprofen, piroXicam, diclofenac, Disodium cromoglycate, nitroglycerin, isosorbide dinitrate, verapamile, nifedipine, diltiaZem, digoXine, morphine, cyclosporins, buprenorphine, lidocaine, diaZepam, nitraZepam, ?uraZepam, estaZolam, ?unitraZepam, triaZolam, alpraZolam, midaZolam, temaZepam, lormetaZepam, brotiZolam, clobaZam, clonaZepam, loraZepam, oXaZepam, busiprone, sumatriptan, ergotamine derivatives, cinnariZine, anti-histamines, ondansetron, tropisetron, granisetrone, metoclopramide, disul?ram, and vitamin K. 25.

Solid compositions of a similar type may also be empioyed asfillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.

The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to a brownoil, from which the title compound (1.42 grams, 51%, a 3:1 mixture of exo/endo diastereomers) was isolated by chromatography onsilica gel (20% ethyl acetate in hexaneas eluant).

Ethyl acetate was added and, afterstirring for 20 minutes, the insoluble material was removed byfiltration through Celite™M Thefiltrate was washed with brine, dried over magnesium sulfate and concentrated to afford the title compound (5.1 grams, 80%) as a clear oil.

Either type of coupling is conducted ina suitable solvent such as dichloromethane, N-methylpyrrolidine (NMP)or dimethylformamide (DMF), optionally in the presence of pyridine or a tertiary amine such as N-methylmorpholine or N- ethyldiisopropylamine (for example wheneither the hydroxylamine or the activating reagent is presented in the form of an acid addition salt), at from about 0°C to about room temperature.

Other amines of formula(III), when neither commercially available nor subsequently described, can be obtained either by analogy with the processes described in the Preparations section below or by conventional synthetic procedures, in accordance with standard textbooks on organic chemistry or literature precedent, from readily accessible starting materials using appropriate reagents and reaction conditions.

Many important contributions can be found in literature on the subject, focusing on different aspects of interest to researchers, such as the Proctor edited book (1), the edited and directly contributed books of Chien (2,3), and the reviews of Mum (4), Wilson (5), Edman (6), Merkus (7), Gizurarson (8), Duchene (9), Harris (10), Buri (11), and Alpar (12), A Nasal Drug Delivery Focus Group, organized in an American Association of Pharmaceutical Scientists section (13), has also been constituted as well as an Open Forum for free exchange and information in all R and D areas ranging from the formulation to the marketing of nasal preparations.

An instructive behavioral employment of the nose for drug absorption, usually in order to have hallucinations or more general mental effects, is the religious rite of the Amazo- nian population of Yanomamo to assume epeiza , that, is a Powdered mixture of different plant parts like Mimosa aca- cioides , Piptadenia peregrina, and others not identified (14).

However, from a technological point of view, the liquid preparations present problems linked to formula stability, low drug concentration at the absorption site, and short residence time in nasal cavity.

Pumps and squeeze bottles operate by mechanical actuation to sample a liquid volume from a reservoir and to produce a mist cloud having the shape of alt inverse cone or of a sagittal plume.

Thereafter, the primed lymphocytes migrate from the original MALT (e.g., the nasal associated lymphoid tissue) to the regional lymph nodes; here they get into further differentiation and then reach, by means of the systemic circulation, all the other mucosal surfaces, where both humoral and cellular immunity is provided.

The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in thig book and cannot accept any legal responsibility ot liability for any errors or omissions that may be made.

Managing Editor: Melanie Segala Copyeditor: Paul Gettehrer Indexer: Lillian Rodberg Compositor: Roy Barnhill - Cover Designer: Tim Kaage

Regulatory Status Included in the FDA Inactive Ingredients Guide (dental prep- arations, inhalations, IM and IV injections, nasal and oph- thalmic preparations, oral capsules, solutions, suspensions, syrups and tablets, rectal, topical, and transdermal prepara- tions).

Applications in Pharmaceutical Formulation or Technology Alpha tocopherol is primarily recognized as a source of vi- tamin E and the commercially available materials and speci- fications reflect this purpose.

The fatal toxic syndrome in low-birth-weight neonates, which includes symptoms of metabolic acidosis and respiratory de- pression, was attributed to the use of benzyl alcohol as a preservative in solutions used to flush umbilical catheters.

4/19/2019 Harvard Health Blog Quick injection helps stop epileptic seizures - Harvard Health Blog - Harvard Health Blog - https://www.health.harvard.edu/blog - Quick injection helps stop epileptic seizures Posted By Howard LeWine, M.D.

A study published last week in the New England Journal of Medicine indicates that a hand-held auto-injector—much like the epi pens used by people with life-threatening allergies—could be used to treat seizures that don’t stop on their own.

Muscle trumps vein For the trial, more than 4,000 emergency medical technicians were trained to administer seizure-stopping drugs called benzodiazepines two ways: through an intravenous line inserted into a vein in the arm (the current standard treatment), and with a device that automatically injects the drug into the thigh.

Looking ahead This one study isn’t the green light for doctors to give auto-injectors filled with anti-seizure medication to all of their patients who have seizures.

This could spare these people and their families the agonizing wait for an ambulance to arrive in order to halt the seizure.

Some of these epilepsy self-management programs are available by phone, online, and on other electronic devices, eliminating barriers to care, such as lack of access to transportation, functional limitations, and stigma.

As with any chronic condition, many people with epilepsy can benefit f om learning skills and techniques that help them better manage their disorder and its effects on daily life.

/11/11 HOBSCOTCH (Home-Based Self-Management and Cognitive Training Changes Lives) is a program led by Dartmouth College that is designed to address memory and attention problems among people with epilepsy through a combination of in-person visits and phone calls that provide coaching.

It is also testing a web-based group format approach designed to reach people at high risk of negative health events, such as seizures, hospitalizations, accidents or traumatic injuries, or self-harm attempts.

Blixen C, A Perzynski, Kanuch S, et al. Training peer educators to promote self-management skills in people with serious mental illness (SMI) and diabetes (DM) in a primary health care setting.

4/9/2019 Epilepsy Fast Facts | CDC Tire Centers for Disease Control and Prevention .

Some people may have multiple types of seizures or other medical conditions in addition to epilepsy.

These factors play a major role in determining both the severity of the person’s condition and the impact it has on his or her life.

Learn more about active epilepsy and find state-specific prevalence estimates on our Data and Statistics page.

Russ SA, Larson K, Halfon N. A national profile of childhood epilepsy and seizure disorder.

[0082] Before describing the present invention in detail, it is to be understood that this invention is not limited to particular embodiments described herein, for example, par ticular benZodiaZepines (including, Without limitation, clon aZepam, diaZepam and loraZepam), solvent(s), cosolvent(s), hydrophilic polymer(s), surfactant(s) (including, ionic and non-ionic surfactant(s)), polyalchohol(s), solubliZing agent(s), antioxidant(s), penetration enhancer(s), and/or buffering agent(s), and the like, as use of such particulars may be selected in vieW of the teachings of the present speci?cation by one of ordinary skill in the art.

The results of necropsy and histopathological examination, including comparison of severity scores, sug gested that clonaZepam compositions of the present inven tion have acceptable tolerability for pharmaceutical use for administration to nasal mucosal tissue.

Exemplary carrier particle substances include, but are not limited to, carbohydrates, such as sugar, mannitol and lactose, or pharmaceutically acceptable inorganic salts, such as sodium chloride or calcium phosphate, or mixtures thereof.

Invest Dermatol 64:190-195 (1975); Franz, T. 1., “The ?nite dose technique as a valid in vitro model for the study of percutaneous absorption in man,” In: Skin: Drug Application and Evaluation of Environmental Hazards, Cur rent Problems in Dermatology, vol.

The CDR system is a Widely used computeriZed cognitive assessment system (see, for example, Ebert U, et al., “Pharmacokinetics and phar macodynamics of scopolamine after subcutaneous adminis tration,”Journal of Clinical Pharmacology 38: 720-726 (1998); Harrington F, et al., “Cognitive Performance in Hypertensive and Normotensive Older Subjects,”HyperZen sion 36: 1079-1082 (2000); Preece AW, et al., “Effect ofa 915-MHZ simulated mobile phone signal on cognitive func tion in man,”lnlernalional Journal ofRadiaZion Biology 75: 447-456 (1999); and Walker M P, et al., “Quantifying ?uctuation in Dementia With LeWy Bodies, AlZheimer’s disease and vascular dementia,”Neurology 54: 1616-1625 (2000)) and has been used to evaluate a diverse range of pharmaceutical compounds.