Of particular interest is the delivery of peptides and proteins through these routes, as it is known that peptidase activity is reduced or mini mired in the nasal cavity or the eyes [5], thus allowing a significant absorption of the bioactive agent.

I Journal of Controlled Release 49 (I997) 185— 192 possible methods of deciding the administration route and type of formulation by obtaining indepen- dent values of drug permeability coefficients.

Rogers, E. Shefter, Comparison of nasal, rectal, sublingual and intramuscular insulin efficacy and the effects of a bile salt absorption promoter, Exp.

[9] Y. Maitani, T. Yamamoto, K. Takayama, T. Nagai, The effect of soybean-derived sterol and its gincoside as an enhancer of nasai absorption of insulin in rabbits in vitro and in vivo, Int.

[10] N. Uchida, Y. Maitani, Y. Machida, M. Nakagaki, T. Nagai, Influence of bile salts on the permeability of insulin through the nasal mucosa of rabbits in compatison with dcxtran derivatives, Int.

In some embodiments, the composition consists essentially of a benZodiaZepine drug that is fully dissolved in a solvent con sisting 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, the composition consists essentially of a benZodiaZepine drug that is fully dissolved in a solvent con sisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides.

In some embodiments, the composition con sists of a benZodiaZepine drug in a form including benZodi aZepine microparticles and/or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and Water.

[0049] 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, benzo diazepine comprises a member of the group consisting of alprazolam, diazepam, ?urazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.

How ever, the treatment of conditions involving physiolog ical mechanisms within the eye (e. g., glaucoma, diabetic retinopathy, cataracts, etc.) generally does require the permeation of topically applied ophthalmic drugs pri marily through the cornea.

It has been reported that benzalkonium chloride (BAC), bile salts, dimethyl sulfoxide (DMSO), ethylenediamine tetraace tate (EDTA) and l-dodecylazayl-cycloheptan-2-one (AZONE ®) enhance the corneal penetration of cer tain drugs.

A principal objective of the present invention is to provide for a method of enhancing drug delivery across mucus covered epithelial tissues, particularly those of the cornea, sclera and conjunctiva of humans and ani mals.

Higher order saccharides being covalently linked in any of a number of ways to form different isomeric structures include for example disaccharides such as maltose, cellobiose, sucrose and lactose and trisaccharides, such as raffmose.

The method of claim 6 wherein the composition comprises a viscosity enhancing polymer selected from the group consisting of: alginates, carrageenan, gar, karaya, locust beans, tragacanth, zanthan, carbomer, hydroxyethylcellulose, hydroxypropylcelluiose, hy droxypropylmethylcellulose, methylcellulose, polyvi nyl alcohol, polyvinyl pyrrolidone, carboxymethylcel lulose and agarose.

[048] 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.

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 hormone releasing 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—716102

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); 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 [0171] Additionally, some embodiments of the compositions and methods of using the compositions comprise an additional ingredient in the composition selected from other anticonvulsants.

Suitably mucolytic agents are thiol-containing compounds such as N—acetylcysteine and derivatives 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, WSGR Docket No. 35401—716102

[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.

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.

For the treatment of rheumatoid arthritis, the compounds of the invention may be combined with agents such as TNF-a inhibitors such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel®), low dose methotrexate, lefunimide, hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold.

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.

Solid 3',8- dioxaspiro[bicycio[3.2.1 Joctane-3, 1'-cyclobutane]-2'-one (1.04 grams, 6.2 mmole) was added and the reaction wasstirred at room temperature overnight The mixture was quenched with aqueous 1N hydrochloric acid solution and extracted twice with methylene chloride.

For example, modern pro tein drugs Which are unstable in the acidic gastric environ ment or Which are rapidly degraded by proteolytic enZymes in the digestive tract are poor candidates for oral adminis tration.

Sep. 7, 2006 maximum advantage of the extensive surface area presented in the alveolar regionithus producing more favorable ben ZodiaZepine, such as loraZepam, delivery pro?les, such as a more complete absorption and rapid onset of action.

[0105] “Pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or dosage forms Which are, Within the scope of sound medical judgment, suitable for use in contact With the tissues of human beings and animals Without excessive toxicity, irri tation, allergic response, or other problem or complication, commensurate With a reasonable bene?t/risk ratio.

Sep. 7, 2006 and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylace tic, glutamic, benZoic, salicylic, sulfanilic, 2-acetoxyben Zoic, fumaric, toluenesulfonic, methanesulfonic, ethane dis ulfonic, oxalic, isethionic, and the like.

[0109] Representative examples of surface stabiliZers include hydroxypropyl methylcellulose (noW knoWn as hypromellose), hydroxypropylcellulose, polyvinylpyrroli done, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, choles terol, tragacanth, stearic acid, benZalkonium chloride, cal cium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying Wax, sorbitan esters, polyoxyeth ylene alkyl ethers (e.g., macrogol ethers such as cetomac rogol 1000), polyoxyethylene castor oil derivatives, poly oxyethylene sorbitan fatty acid esters (e.g., the commercially available TWeens® such as e.g., TWeen 20® and TWeen 80® (lCl Speciality Chemicals)); polyethylene glycols (e.g., CarboWaxes 3550® and 934® (Union Car bide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymeth ylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magne sium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,l,3,3-tetramethylbutyl)-phenol polymer With ethylene oxide and formaldehyde (also knoWn as tyloxapol, superione, and triton), poloxamers (e. g., Pluronics F68® and Fl08®, Which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908®, also knoWn as Poloxamine 908®, Which is a tetrafunctional block copolymer derived from sequential addition of pro pylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic l508® (T-l508) (BASF Wyandotte Corporation), Tritons X-200®, Which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-ll0®, Which is a mixture of sucrose stearate and sucrose distearate (Croda lnc.

Introduction The most desirable and convenient method of drug administration is the oral route and the most favored dosage forms include tablets, capsules and solutions because of their ease of manufacture and administra- tion.

In addition, the olfactory region provides a potential advantage where by a drug may be exposed to neurons that may facilitate its access into the cerebral spinal fluid when administered intranasally.

Relationship between the rate constants of mucosal absorption following nasal (d), rectal (s), and vaginal (y) delivery, and the log (octanol/ water) partition coefficients of the progestins.

For example, a Cyanocobalamin (Vita- min B12) Gel has been developed by Nastech Pharmaceutical Company for systemic adminis- tration to patients who are suffering from Vitamin B12 deficiency anemia (Table 4).

Drugs which are not absorbed from such dosage forms, stand better chance for absorption when formulated in ‘gelling’ microspheres made by using biocompat- ible materials e.g. starch, gelatin, albumin and dex- tran.

: 00354 5112020; E-mail: sg@lyf.is Received 16 October 2000, accepted 22 June 2001. has poor water solubility, but polyethylene glycol 300 (PEG300), a vehicle causing relatively little local irritation, has been found to solubilize an expected clinically relevant dose (4–10 mg) of diazepam in the limited volume necessary for nasal administration [2].

A two-factor ANOVA was used to compare P300, P300-N100 amplitude differences and b-activity effects Time (min) AQUESTIVE EXHIBIT 1025 page 0003 10000 1000 Serum diazepam concentration (ng ml–1) Figure 1 Mean (ts.d.)

A more likely explanation is that diazepam, which is a very lipophilic substance, progressively dis- tributes into the fatty tissue of the brain as the serum concentration falls, resulting in a delayed pharmaco- dynamic effect.

2 Gizurarson S, Gudbrandson FK, Jo´ nsson H, Bechgaard E. Intranasal administration of diazepam aiming at the treatment of acute seizures: Clinical trial in healthy volunteers.

4 Engelhardt W, Friess K, Hartung E, Sold M, Dierks T. EEG and auditory evoked potential P300 compared with psychometric tests in assessing vigilance after benzodiazepine sedation and antagonism.

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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].

The present invention pro vides a significant improvement over the type of com positions disclosed in the aforementioned patent by reducing the amount of inhibited phenol required to produce the same ameliorative effect.

Some are a con sequence of a local effect (such as a laceration, or cut) while others may reflect underlying constitutional dis orders (such as the yellowing of skin that may occur in liver diseases).

The objectionable external appear ance caused by these disorders may be minimized or corrected in a non-surgical fashion by the application of a composition, such as that disclosed herein, which is not harmful to one's health and which produces two fundamental and simultaneous reactions, one in the epidermis and another in the dermis.

These responses, in turn, are manifest by a peeling of the outermost skin layer and the consequent removal of surface irregularities, blem ishes and discolorations, and by a strengthening of the underlying dermis which results from an increase in the numbers of connective tissue cells which surround and support the hair follicles, glands and vessels.

Moreover, this same response may cause the obliteration or collapse of certain poorly formed blood vessels in the dermis and result in the disappearance or fading of certain types of birth marks.

For example, the amount of time required for an orally administered benzodiazepine drug to reach therapeutically relevant concentrations in blood plasma may be rather long, such as an hour or more.

Furthermore, due to the nature of seizures and muscle spasms, it can be extremely difficult for either a patient or a care-giver to administer the benzodiazepine drug orally and care-givers may bereluctant to place their hands in patients’ mouths.

10> 11 drug that is fully dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol, and ethanol and benzyl alcohol as defined in the claims, wherein the solutionis at least substantially free of water.

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

[074] For example, most benzodiazepines are so slightly soluble in water that a therapeutically effective amount cannot be dissolved in a volume of aqueous solvent that is amenable to application to a mucosal membrane.

A drug product is defined as a finished dosage form ; this means a tablet, capsule, solution, sup­ pository, etc. that contains the active dru g in­ gredient generally, but not necessarily in associa­ tion witl1 inactive ingredients.

are drug products Pharmaceutical alternatives that contain the identical therapeutic moiety or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester.

It AQUESTIVE EXHIBIT 1023 page 0027 is not advisable to take trough levels of two con­ secutive dosing intervals (if <24 h) because a dif­ ference may occur due to circadian rhythm even when steady state is reached.

In this case it is indicated to estimate whether or not a given drug product results at steady state in a blood level at the end of eacl1 dosing interval above the required M IC.

Smolen, V. F.: Pharmacokinetic Engineering Approach to D rug D elivery System D esign and the Optimization of Drug Ef­ fects, Proceedings of the I nternational Conference on Cybernetics, Washington, D .C .

Al- though recent efforts in using chemical enhancers have fo- cused on substances categorized as generally recognized as safe (GRAS), early work included a wide range of materi- als.

Penetration of Guinea Pig Skin by Acyclovir in Different Vehicles and Correlation with the Efficacy of Topical Therapy of Experimental Cutaneous Herpes Simplex Virus Infection.

Penetration Enhancement in Human Skin; Effect of 2- Pyrrolidone, Dimethylformamide, and Increased Hydration on Finite Dose Permeation of Aspirin and Caffeine.

Effect of Azone and Propylene Glycol on Penetration of Trifluorothymidine Through Skin and Efficacy of Different Topical Follnulations Against Cutaneous Herpes Simplex Virus Infections in Guinea Pigs.

Effect of Penetration Enhancers on the in vitro Transport of Ephedrine Through Rat Skin and Human Epidermis from Matrix Based Trans dermal Foi inulations .