Polar drugs with molecular weights below 1000 Da will generally pass the membrane using the latter route, since, although tight junctions are dynamic structures and can open and close to a certain degree, when needed, the mean size of the channels is in the order of less ˚ than 10 A and the transport of larger molecules is considerably more limited [5,6].

Apart from the small molecular weight drugs, the chitosan delivery system, whether in the form of a solution or a powder, has also been shown to be very effective in delivering peptides such as leuprolide (1300 Da), salmon calcitonin (S-CT) (3500 Da) and parathyroid hormone (PTH) (4000 Da) across the nasal membrane.

Reports in the literature of studies in animal models and in man have shown this to be a distinct possibility with results showing the uptake of drugs into the cere- brospinal fluid and the brain tissue being dependent upon molecular weight and the lipophilicity [24–28].

As an example, Piet- rowsky [30] administered cholecystokinin-8 (CCK) to 20 healthy volunteers in a placebo controlled, double blind, cross-over study by the nasal and the intravenous route and recorded the auditory event- related potentials (AERP) during the volunteer’s performance of an oddball task.

We have exploited this concept for the nasal delivery of DNA plasmid expressing epitopes of respiratory syncytial virus (RSV) in order to produce an effec- tive vaccine for this severe illness of new born and young children [41].

Canada Central African Republic Congo Swiwerland Céte dIvoire Cameroon Czechoslovakia Germany Denmark Madagascar Mali Mongolia Mauritania Malawi Netherlands Norway Poland Romania Sudan Swedea Senegal Sovict Union Chad Togo

Thus, the preferred exemplary embodiments exhibit significant increases in viscosity in response to substantially simultaneous upshifts in both temperature and pH to those conditions encountered in the ocular milieu those skilled or at typical injectable drug delivery sites.

Thus, an exemplary composition of the present invention comprises a homogeneous association complex of a macromolecular mixture of methylcellulose, a polysaccharide available from Dow Chemical under the trade name Methocel, and a cross-linked polyacrylic acid such as Carbopol 940, a hydrophilic acrylic polymer available from the B. F. Goodrich Company.

such as cefoxitin, n~formamidoyl-thienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, carbenicillin, colistin, penicillin G, polymyxin B, vancomycin, cefazolin, cephalori- dine, chibrorifamycin, gramicidin, bacitracin, sulfonamides: amino— glycoside antibiotics such as gentamycin, kanamycin, amikacin, sisomicin and tobramycin; nalidixic acid and analogs such as norfloxacin and the antimicrobial combination of flucalanine/pentizidone: nitrofurazones, and the like;

anti-inflammatorics such as cortisone, hydrocortisone, hydrocortisone acetate, betamethasone, dexamethasone, dexamethasone sodium phosphate, prednisone, methylpredinisolone, medrysone, fluoro-— metholone, fluocortolone, prednisolone, prednisolone sodium phosphate, triamcinolone, indomethacin, sulindac, its salts and its corresponding sulfide, and the like; (4) miotics as_echothiophate,and anticholinergics such pilocarpine, physostigmine salicylate, diisopropylfluorophosphate, epinephrine, dipivolyl epinephraine, neostigmine, echothiophate iodide, demecarium bromide, carbachol, methacholine, bethanechol, and the like; (5) mydriatics such as atropine, homatropine, scopolamine, hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, oxyphenonium, eucatropine, and the like; and other medicaments used in the treatment of eye conditions or diseases such as

Its use, however, is limited by its short duration of action and occasional reports of cardiovascu¬ lar and/or respiratory complications.2 Recent literature suggests that loraze¬ pam, a new longer-acting benzodiaze- pine, is both effective and safe in the management of status epilepticus in adults and older children.35 To our knowledge, comparative data docu¬ menting the safety and efficacy in neo¬ nates are unavailable to date.

Electroencephalographic monitor¬ ing before lorazepam administration in patients 3, 5, and 6 demonstrated burst suppression patterns and elec¬ trographic seizures in the form of rhythmic theta and delta activity or multifocal sharp waves.

In all patients, serum electrolyte, cal¬ cium, glucose, albumin, globulin, cho¬ lesterol, and triglycéride levels, and hepatic and renal functions remained improved following unchanged or lorazepam administration.

The former has caused hyperosmolality in infants receiving 10 mL of a multi¬ vitamin preparation containing 30% propylene glycol.9 The largest dose of lorazepam used in this study, 0.20 mg, required 0.1 mL of the solution, con¬ taining 0.018 mL of the solubilizer, approximately 1/500 the volume in the above-mentioned report.

Other than in vitro data, there is no documenta¬ tion that benzoate enhances this risk in the human newborn.12 Furthermore, the dose of benzyl alcohol was so small in our study (0.5 mg/kg) that the effect of bilirubin displacement was consid¬ ered insignificant.

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Application/Control Number: 12/413,439 Art Unit: 1612 Page 6 The instant claims recite a method of treating...comprising...administering... a pharmaceutical solution... consisting of... 1 to 20 mg of a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols... one or more alcohols or glycols, ... and one or more alkyl glycosides.

Shim and Kim, "Administration Route Dependent Bioavailability of Interferon-o and Effect of Bile Salts on the Nasal Absorption", Drug Developmentand Industrial Pharmacy, 19(10):1183-1199 (1993) Stevens and Guillet, "Use of Glucagon to Treat Neonatal Low-Output Congestive Heart Failure after Maternal Labetalol Therapy", The Journal of Pediatrics, July 1995, pp. 151-153, Volume 127, Issue 1 Swarbrick et al., Encyclopedia of Pharmaceutical Technology, Informa Health Care, 2nd edition, Vol.

13/495,942 Non-Final Office Action issued October1, P| Vidaletal., "Makingsenseofantisense",EuropeanJournalofCancer,41:2812-2818, 2013 2005 Watanabeet al., "Antibacterial Carbohydrate Monoesters Suppressing Cell Growth of Streptoccus mutans in the Presence of Sucrose", Current Microbiology, September 2000, pp. 210-213, Vol.

(Original) The method of claim 20, wherein the benzodiazepine drugis selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,diazepam, flumazenil, flurazepam, halazepam,

Application No. 12/413,439 Response to June 19, 2014 Office Action Attorney Docket No.: 35401-716.201 Sonne fails to provide motivation to prepare the claimed nasal solutions, which do not require oil.

Microbial challenge with 5 organisms (staphylococcus aureas, pseudomonasaeruginosa, escherichia coli, candida albicans and aspergillus niger) showed a log plate count of less than 1/mL observed after a period of 28 days,indicating that the liquid formulation itself is microcidal and therefore a non- sterile productis likely acceptable.

Because a slightly irritating profile would be tolerated for an intranasal formulation against seizure clusters and other the major concern wasthat volunteers acute indications such as panic attacks, participating in a Clinical Phase I trial would not suffer unnecessary pain.

[00238] In addition to the PK parameters discussed above, the experiments performed in support of the present invention evaluated the local tolerance in the upper and lower respiratory tract of formulations I-IV containing clonazepam asactive drug.

[00258] In conclusion, the results of necropsy and histopathological examination, including comparison of severity scores, suggested that the clonazepam compositions of the present invention comprising formulations for intranasal delivery have acceptable tolerability for pharmaceutical use.

(57) Abstract; The invention concerns a micronized pharmaceutical or nutraceutical powder with immediate release having a grain size distribution of not more than 100 um, and comprising the combination of at least an active substance, at least a wetting agent and at least a diluent.

Estimates of the prevalence and incidence of epi- lepsy worldwide vary considerably, likely reflecting differences in measurement and reporting, along with clinical characteristics such as etiology and seizure type.

Articles were included if they met the following criteria: (1) original research, (2) population-based (selecting the entire population or using probability-based sampling methods), (3) reported a prevalence or incidence of epilepsy (or raw numbers that allowed the calculation of an estimate).

Epilepsy prevalence or incidence estimates, raw numbers, and confidence in- tervals (CIs) (when provided) were recorded along with any strati- fied results by age, sex, or year of data collection.

Congruent with pre- the vious descriptive reports,35 we found that incidence of epilepsy was generally higher in the youngest and oldest age groups; however, there were insufficient studies to perform a meta-analysis.

Ideally, a multivariable meta- regression would have been employed to deal with the possible confounding effects of variables such as age and location, though this would have required a very large number of studies, and as such only strat- ified estimates are provided.

[0013] The nasal administration of such large volumes of solution also accounts for a number of unpleasant side effects sometimes experienced by patients, including lacri mation, burning sensations, irritation in the nose and throat, and general discomfort (Lugo et al., 1993; Burstein et al., 1997; Kogan 2002).

[0025] The use of this formulation for intranasal mida Zolam administration in healthy volunteers and in epilepsy patients, providing a dose of 5 mg or 10 mg (90-180 pl in each nostril), causes nasal irritation, lacrimation and irrita tion of the throat in almost all subjects, as Well as a bitter taste (Knoester et al., 2002; Tenk et al., 2003).

The drug is subse quently eliminated from the blood circulation With half-lives ranging betWeen 1 and 2.4 hours in children and healthy adults, Which are not substantially different from that after intravenous injection of midaZolam (Rey et al., 1991; Bjork man et al., 1997; Burstein et al., 1997; Loftsson et al., 2001; Knoester et al., 2002; Tenk 2003).

14, 2005 [0096] According to a second aspect of the present inven tion, the compositions according to the ?rst aspect may be used in the following situations: [0097] 1) as sedative and anXiolytic agents for children undergoing diagnostic and surgical procedures; [0098] 2) as sedative and anXiolytic agents for adults undergoing gastrointestinal endoscopy and other diag nostic procedures; [0099] 3) as treatment of acute epileptic and febrile seiZures in children in medical centres and at home; and [0100] 4) as acute management to treat seiZures in adults With severe epilepsy in medical centres and at home.

[0102] A good correlation betWeen plasma levels and pharmacodynamic responses has been established for mida Zolam in a clinical study in Which patients, undergoing abdominal surgery, received an intravenous midaZolam infu sion (Persson et al., 1988).

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.

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 insulin, 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 gene related 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 weight from 1000 to 300000), secretin, bradykinin antagonists, GRF (Growth releasing factor), THF, TRH WSGR Docket No. 35401-716.102

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); 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.

[0194] Those skilled in the art will be aware that a systematic, therapeutically effective amount of benzodiazepine drugs for treating the aforementioned disorders will vary with age, size, weight, and general physical condition of the patient as well as the severity of the disease.

OMB 0651-0032 U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE Underthe Paperwork Reduction Act of 1995, no personsare required to respond to a collection of information unlessit displays a valid OMBcontrol number.

They are thought to be useful in preventing, treating, or ameliorating the symptomsof anxiety, insomnia, agitation, seizures (such as those caused by epilepsy), muscle spasmsandrigidity, the symptoms of drug withdrawal associated with the continuous abuse of central nervous system depressants, and exposure to nerve agents.

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.

[043] In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam,triazolam, temazepam, loprazolam, any pharmaceutically- acceptable salts thereof, and any combinationsthereof.

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

A synthetic analogue of calcitonin, a hypocalcemic pep tide has been shown to be elfectively absorbed percutane ously in the rat by applying it in transdermal dosage form as a gel containing a combination of bile salts and the alkyl glycosides octylglucoside or octylthioglucoside (Ogiso, T. et al., Chem.

We had previously shown that systemic delivery of insu lin via the ocular and nasal-lacrimal route in amounts sufticient to lower blood sugar in experimentally diabetic rats was made possible by including 1% saponin in the eye drops with the insulin (Pillion, D. J. et al., Invest.

The major limiting factors which have prevented the practical development of this route for general use is the low e?iciency of absorption across the nasal mucosa and the local and systemic toxicity of the penetration-enhancing agents used (Moses et al., Gordon et al., Salzmann et al and Chadwick, U.S. et al., Gut, 17:10-17 (1976)).

Dodecylmaltoside and other alkyl glycosides can readily be obtained in pure form and have well de?ned, simple AQUESTIVE EXHIBIT 1020 page 0002 structures (Neugebauer, J.. “A Guide to the Properties and Uses of Detergents in Biology and Biochemistry,” Calbio chem Corporation (1988)).

rats were anesthetized with sodium pentobar bital rather than xylaZine/ketamine; this modi?cation of the procedure resulted in basal blood glucose levels in the normoglycemic range and made it possible to readily moni tor the hyperglycemic action of any glucagon absorbed from the eye.

Pharm. Bull, 22(4) 425-—427 (1999) Intranasal Administration of Diazepam Aiming at the Treatment of Acute Seizures: Clinical Trials in Healthy Volunteers Sveinbjérn Gizurarson,*”” Fridrik K. GupsraNnpsson,” Helgi Jonsson,‘ and Erik BECHGAARD?

intranasal administration; diazepam; volunteers; bioavailability Key words Treatment of epileptic seizures should be controlled with- out causing adverse reactions and in such a way that it pro- motes a good quality of life.

adminis- tration of these drugs to a patient in seizure requires skilled personnel and an acute care facility, since the treatment may be associated with hypotension, cardiac dysrhythmiasor cen- tral nervous system depression.

Nine healthy volunteers, between 20—30 years old (weigh- ing 58—80kg), were chosen among 20 caucasian students who applied for participation, on the basis of normal liver and kidney function and no sign of a cold within the last two weeksprior to the first experimental day.

Studies on rectal administration of diazepam show that 12 min onset timeis sufficient for improving qual- ity of life and effective in controlling seizures in the majority ofpatients, suffering from multiple seizures.” Even after i.v.

[047) In some embodiments, the composition contains a benzodiazepine drug that at least partially in a particulate form suspended in 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 member of the group consistiog of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.

By way of non-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); propionate& (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.

Peptide inhibitors include actinonin, amastatin, bestatin, chloroacetyl-HOLeu-Ala-Gly-NH.sub.2, diprotin A and B, ebelactone A and B, E-64, leupeptin, pepstatin A, phisphoramidon, H-Thr-(tBu)-Phe-Pro-OH, aprotinin, kallikrein, chymostatin, WSGR Docket No. 35401-716.601 AQUESTIVE EXHIBIT 1009 page 0042

[0193) Those skilled in the art will be aware that a systematic, therapeutically effective amount of benzodiazepine drugs for treating the aforementioned disorders will vary with age, size, weight, and general physical condition of the patient as well as the severity of the disease.

In some embodiments, ments, the benzodiazepine drug is fully dissolved in a single 5 the pharmaceutical composition is in a pharmaceutically- phase comprising one or more one or more natural or 1 acceptable spray formulation having volume from about 100 synthetic tocopherols or tocotrienols and one or more alco- µL to 200 µL.

In some embodiments, the carrier system selected from the group consisting of: alprazolam, brotizo- comprises one or more natural or synthetic tocopherols or lam, chlordiazepoxide, clobazam, clonazepam, clorazepam, 60 tocotrienols, or any combinations thereof, in an amount from demoxazepam, diazepam, flumazenil, flurazepam, halaze- about 60% to about 75% (w/w).

In some embodiments, the pam, midazolam, nordazepam, medazepam, nitrazepam, carrier system comprises one or more natural or synthetic oxazepam, lorazepam, prazepam, quazepam, triazolam, tocopherols or tocotrienols, or any combinations thereof, in temazepam, loprazolam, any pharmaceutically-acceptable an amount of about 70% (w/w).

In some embodiments, the composition about 40%, about 10% to about 35%, about 12% to about consists of a benzodiazepine dissolved in a solvent consist- 55%, about 12% to about 40%, about 12% to about 35%, ing of one or more natural or synthetic tocopherols or about 15% to about 55%, about 15% to about 40%, about 10 tocotrienols, one or more alcohols or glycols, and optionally 15% to about 35%, about 10%, about 12.5%, about 15%, one or more alkyl glycosides, wherein the solution is at least about 17.5%, about 20%, about 22.5%, about 25%, about substantially free of water.

In some demoxazepam, diazepam, flumazenil, flurazepam, halaze- embodiments, the carrier system comprises one or more pam, midazolam, nordazepam, medazepam, nitrazepam, alcohols or glycols, or any combinations thereof, in an oxazepam, lorazepam, prazepam, quazepam, triazolam, amount from about 25% to about 40% (w/w).

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.

, [013] In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam,nitrazepam, oxazepam, lorazepam, prazepam, triazolam, quazepam, combinations thercof.

essentially of a benzodiazepine drugthatis fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides wherein the solution is at least substantially free of water.

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

the invention provides a pharmaceutical composition for nasal in some embodiments, [9148] Thus, administration comprising: a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amountfrom about 30% to about 95% (w/w); one or more alkyl glycosides; and one or more alcohols or glycols, or any combinationsthereof, in an amount from about