Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation or chromatography(including HPLC)of a diaster- eoisomeric mixture of a compoundof formula (I) or a suitable salt or derivative thereof.

Either type of coupling is conducted in a suitable solvent such as dichloromethaneor dimethylforma- mide, optionally in the presence of 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.

whenneither 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 text- books on organic chemistry orliterature precedent, from readily accessible starting materials using appropriate rea- gents and reaction conditions.

[0049] The biological activities of the compounds of the present invention were determined bythe following test meth- ods, which are based onthe ability of the compoundsto inhibit the cleavage of various fluorogenic peptides by MMPs 1,2, 3,9, 13 and 14.

The organic layer was dried (NapSO,), the solvent was evaporated under reduced pressure and the residue waspurified by flash chromatography onsilica gel (hex- ane/ethyl acetate 2:1 as eluent) to give the titled compound as a pale yellow low melting solid (230mg).

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.

As the topical medication for the treatment of acne, therefore, frequent use has been normally made of the creams or ointments having the sebum excretion depressant, and antimicrobial substances incorporated into them.

For example, hormones of the female type, which act as a sebum excretion depressant, suppress the growth of the epider mis and reduce excretion of the sebaceous gland, but the side-effects (e.g. estrogenic effect) brought about by the hormone of the female type are not desirable to males and females at puberty; and, the antimicrobial agents, such as hexachlorophene, trichlorocarbanilide and benzalkonium chloride, demonstrate in vitro exceed ingly high antimicrobial activity against Propionibacter ium acnes, an acne bacterium ordinarily found on the skin, but when being in practice incorporated into creams, ointments, etc. and used for the treatment of acne, mostly fail to produce the expected therapeutic effect.

chlorophene, trichlorocarbanilide, benzalkonium chlo As the pharmaceutically acceptable carrier which is ride, phenol, cetyl pyridinium chloride, undecylenic used in the present invention, there may be mentioned acid and bithionol.

A gelling agent and an alcohol in atoms; for example Brij (R)35,78 and 98, etc., produced proves poor solubility being so far regarded as the de by Kao Atlas Co., in Japan; hereinafter "ethyleneoxide' fect of the Compound I from the standpoint of pro is abbreviated as "EO”), polyoxyethylene fatty acid cessing it into preparations.

The properties of the preparation for topical applica tion according to the present invention may be those of any kind being applicable to the external skin, such as cream, ointment and lotion.

The reaction was worked up by partitioning between citric acid and ethyl acetate, drying the organic layer and solvent removal to give the crude product (1g).

Biochem., 99, procedure of Cawston and Barrett, 340-345, 1979), hereby incorporated by reference, 11. whereby a ImM solution of the inhibitor being tested or 12 dilutions thereof was incubated at 37° for 16 hours 13 with collagen and collagenase (buffered with 25mM 14 Hepes, pH 7.5 containing 5mM CaCly5, 0.05% Brij 35 and 0.02% NaN3).

Example 28° Stromelysininhibition activity The potency of compounds of general formula I to act as inhibitors of stromelysin was determined using the procedure of Cawston et al (Biochem.

J., 195, 159-165 1981), hereby incorporated by reference, whereby a 1mM solution of the inhibitor being tested or dilutions thereof was incubated at 37°C for 16 hours with stromelysin and 14, acetylate casein (buffered with 25mM Hepes, pH 7.5 containing 5mM CaCl5, 0.05% Brij 35 and 0.02% NaN3.

Armenia Austria Australia Barbados Belgium Burkina Faso Bulgaria Benin Brazil Belarus Canada Central African Republic Congo Switzerland Cite d'Ivoire Cameroon China Czechoslovakia Czech Republic Germany Denmark Estonia Spain Finland France Gabon Malawi Mexico Niger Netherlands Norway New Zealand Poland Portugal Romania Russian Federation Sudan Sweden Singapore Slovenia Slovakia Senegal Swaziland Chad Togo Tajikistan Trinidad and Tobago Ukraine Uganda United States of America Uzbekistan

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 .

: 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.

Neurelis, Inc. c/o Pacific Link Consulting, LLC Attention: Richard Lowenthal, MS, MSEL President, Pacific-Link Consulting 8195 Run of the Knolls Court San Diego, CA 92127 Dear Mr. Lowenthal: Food and Drug Administration Silver Spring MD 20993

We have reviewed your request and concluded that it meets the criteria for Fast Track designation.

Therefore, we are designating as a Fast Track development program the investigation of NRL-1 for the management of selected, refractory patients with epilepsy, on stable regimens of AEDs, who require intermittent use of diazepam to control bouts of increased seizures.

Please note that if the clinical development program you pursue does not continue to meet the criteria for Fast Track designation, the application will not be reviewed under the Fast Track program.

Sincerely, {See appended electronic signature page} Billy Dunn, MD Director Division of Neurology Products Office of Drug Evaluation I Center for Drug Evaluation and Research Reference ID: 4034029 Neurelis - EX. 2002 Aquestive Therapeutics, Inv. v. Neurelis, Inc. - IPR2019-00450

Edited by Raymond C Rowe BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MlnstP Senior Principal Scientist AstraZeneca Macclesfield, UK Paul J Sheskey BSc, RPh Technical Service Leader Water Soluble Polymers R&D The Dow Chemical Company Midland Ml, USA Paul J Weller BSc, MSc, CChem, MRSC Publisher - Science and Practice Royal Pharmaceutical Society of Great Britain London, UK

The publisher makes no representation, expre s or implied, with rega rd to the a curacy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omission that may be made.

Alpha-tocopherol is a highly lipophilic compound, and is an e cellent solvent for many poorly soluble drugs.Cl) Of wide spread regulatory acceptability, tocopherols are of value in oil or fat-based pharmaceutical product and are normally used in the concentration range 0.001--0.05% v/v.

Distilling range 1.538-1 .541 Refractive index Residue on ignition ..; 0.005% Nonvolatile matter Chlorinated compounds Benzaldehyde Peroxide value Organic volatile impurities Assay ;;;.

7 Applications in Pharmaceutical Formulation or Technology Benzyl alcohol is an antimicrobial preservative used in cos metic I foods, and a wide range of pharma eutical formula including oral and parenteral preparation , at tions,' -4) concentration up to 2.0% v/v.

“Pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Preferably the difference in AUC (e.g., absorption) of the nanoparticulate active agent composition of the invention, comprising atleast one peptide us a surface stabilizer, when administered in the fed versus the fasted state, is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%,less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%.

Examples of representative active agents useful in this invention include, but are not limited to, acyclovir, alprazolam,altretamine, amiloride, amiodarone, benztropine mesylate, bupropion, cabergoline, candesartan, ccrivastatin, chlorpromazine, ciprofloxacin, cisapride, clarithromycin, clonidine, clopidogrel, cyclobenzaprine, cyproheptadine, delavirdine, desmopressin, diltiazem, dipyridamole, dolasetron, enalapril maleate, enalaprilat, famotidine, felodipine, furazolidone, glipizide, irbesartan, ketoconazole, lansoprazole, loratadinc, loxapine, mebendazole, mercaptopurine, milrinonelactate, minocycline, mitoxantrone, nelfinavir mesylate, nimodipine, norfloxacin, clanzapine, omeprazole, penciclovir, pimozide, tacolimus, quazepam, raloxifene, rifabutin, rifampin, risperidone,rizatriptan, saquinavir, sertraline, sildenafil, acetyl-sulfisoxazole, temazepam, thiabendazole, thioguanine, trandolapril, triamterene, trimetrexate, troglitazone, trovafloxacin, verapamil, vinblastine sulfate, mycophenolate, atovaquone, atovaquone, proguanil, ceftazidime, cefuroxime, etoposide, terbinafine, thalidomide, fluconazole, amsacrine, dacarbazine, teniposide, and acetylsalicylate.

Exemplary COX-2 inhibitors that can be formulated in combination with the nanoparticulate nimesulide composition of the invention include, but are not limited to, celecoxib (SC-58635, CELEBREX®, Pharmacia/Searle & Co.), rofecoxib (MK- 966, L-748731, VIOXX®, Merck & Co.}, meloxicam (MOBIC®, co-marketed by Abbott Laboratories, Chicago, IL, and Boehringer Ingelheim Pharmaceuticals), valdecoxib (BEXTRA®, G.D.Searle & Co.), parecoxib (G.D. Searle & Co.),

The optimal amount of the individual components can depend, for example, upon the particular active agent selected, the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc.

[] Assignment Papers (cover sheet & document(s)) Specification [Total PagesS,j Nameof Assignee Both the claims and abstract must start on a new page (For information on thepreferred arrangement, see MPEP 608.01(a})

By way of non-limiting example, such active ingredients include: paraldehyde; aromatic allylic alcohols (suchasstiripentol); 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. 35401-716.201

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 combinationsthereof.

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, benzamidine, chymotrypsin and trypsin.

[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.