In some embodiments, the nanoparticulate benZodiaZepine particles comprise at least one member of the group consisting of alpraZolam, brotiZolam, chlordiaZepoxide, clobaZam, clon aZepam, cloraZepam, demoxaZepam, ?umaZenil, ?uraZepam, halaZepam, midaZolam, nordaZepam, medaZepam, diaZ AQUESTIVE EXHIBIT 1015 page 0006

In some embodiments, the nanoparticulate benZodi aZepine particles comprise at least one member of the group consisting of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, midaZolam, temaZepam and phar maceutically acceptable salts and combinations thereof.

In some embodiments, the benZodiaZepine particles comprise at least one member of the group consist ing of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, midaZolam, temaZepam and phar maceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benZodiaZepine particles comprise at least one member of the group consisting of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, mida Zolam, temaZepam and pharmaceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benZodiaZepine particles comprise at least one member of the group consisting of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, mida Zolam, temaZepam and pharmaceutically acceptable salts and combinations thereof.

The questionnaire was given to nurses viewing posters regarding epilepsy and treat- ment and to those attending a breakfast symposium discussing the treatment of seizures in the school.

Rectal diazepam gel is an FDA-approved therapy for the treatment of prolonged and repetitive seizures that has been developed to be given not only inside the hospital setting, but also outside of a health care fa- cility by laypersons (Valeant Pharmaceuticals, 2005).

The route of adminis- tration, identification of the seizure emergency, fear of side effects, and the training of personnel other than a nurse to administer this medication are reasons mentioned.

Education of school nurses regarding epilepsy and current treatment, as well as the preparation of a sei- zure action plan, is the cornerstone of care for the stu- dent with seizures.

The results of this survey indicate that discrepancies exist among school nurses about the scope of practice and the delegation of administration of rectal medi- cation by nonnurse personnel in the event of a seizure emergency.

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 some embodiments, the nanoparticulate benZodiaZepine particles comprise at least one member of the group consisting of alpraZolam, brotiZolam, chlordiaZepoxide, clobaZam, clon aZepam, cloraZepam, demoxaZepam, ?umaZenil, ?uraZepam, halaZepam, midaZolam, nordaZepam, medaZepam, diaZ AQUESTIVE EXHIBIT 1015 page 0006

In some embodiments, the nanoparticulate benZodi aZepine particles comprise at least one member of the group consisting of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, midaZolam, temaZepam and phar maceutically acceptable salts and combinations thereof.

In some embodiments, the benZodiaZepine particles comprise at least one member of the group consist ing of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, midaZolam, temaZepam and phar maceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benZodiaZepine particles comprise at least one member of the group consisting of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, mida Zolam, temaZepam and pharmaceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benZodiaZepine particles comprise at least one member of the group consisting of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, mida Zolam, temaZepam and pharmaceutically acceptable salts and combinations thereof.

Solid compositions of a similar type may also be employed as fillers 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 brown oil, from which the title compound (1.42 grams, 51%, a 3:1 mixture of exo/endo diastereomers) was isolated by chromatography on silica gel (20% ethyl acetate in hexane as eluant).

Either type of coupling is conducted in a suitable solvent such as dichloromethane, N-methylpyrrolidine (NMP)or dirnethylformamide (DMF), optionally in the presence of pyridine or a tertiary amine such as N-methylmorpholine or N- ethyldiisopropylamine (for example when either 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.

Moreover, persons skilled in the art will be aware of variations of, and alternatives to, those processes described herein, including in the Examples and Preparations sections, which allow the compounds defined by formula (I) to be obtained, such as carrying out certain bond-forming or functional group interconversion reactions in different sequences.

PCTIUSZ004l’036337 “Pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, andfor 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, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefitfrisk ratio.

Accordingly, the present invention is directed to the surprising discovery that a peptide, used as a nanopartieulate surface stabilizer, yields stable nanoparticulate active agent compositions that exhibit low degrees of aggregation.

Exemplary nutraceutioals and dietary supplements are disclosed, for example, in Roberts et a1., Nutmceuticais: The Complete Encyclopedia ofSupplements, Herbs, Vitamins, and Healing Foods (American Nutraceutical Association, 2001), which is specifically incorporated by reference.

Exemplary COX-2 inhibit01s that can be formulated in combination with the nanoparticulate niniesulide composition of the invention include, but are not limited to, celecoxib (SC-58635, CELEBREX®, PhannaciaJ’Searle & C0,), rofecoxib (MK— 966, b748731, VIOXX®, Merck & C0,), meloxicam (MOBIC®, co-marketed by Abbott Laboratories, Chicago, IL, and Boehringer Ingelheim Pharmaceuticals), valdecoxib (BEXTRA®, GD.

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.

Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lac- rimation, clonic convulsions, depressed respiration, saliva- tion, miosis, tremors, fasciculation and lower body surface temperature.

Although Diastat is indicated for use solely on an intermit- tent basis, the potential for a synergistic CNS-depressant effect when used simultaneously with alcohol or other CNS depressants must be considered by the prescribing physi- cian, and appropriate recommendations made to the patient aadlor caregiver.

The prescriber should be aware that these figures, obtained when Diastat was added to concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those pre- vailing during clinical studies.

Concomitant Medication Although Diastat is indicated for use solely on an intermit- tent basis, the potential for a synergistic CNS-depressant effect when used simultaneously with alcohol or other CNS- depressants must be considered by the prescribing physi- cian, and appropriate recommendations made to the patient and/or caregiver.

The findings suggest that calcitonin-salmon reduced the la- tency period for development of pituitary adenomas that do not produce hormones, probably through the perturba- tion of physiologic processes involved in the evolution of this commonly occurring endocrine lesion in the rat.

- through the head of the punch allows insertion of the metal red It facilitate removal from the die afier the test] A compacted Pellet it, the material is formed in the cavity with a single face of defined “f” .

Additional physicochemical information may be needed on poly- morphism, particle siZe distribution, solubility, dissolution rate, sta— bility, and other release—controlling variables of the active dmg entity under conditions that may react to the extremes of the physiologic environment experienced by the dosage form.

Regardless ofwhether a drug ex- hibits linear ornonlinear pharmacokinetics, the basis for characteriza- tion is equivalence ofAUC and ofthe relative degree offluctuation cf concentrations of the modified-release and immediate-release dosage forms.

2338 (1088) In Vitro and In Vivo Evaluation / General Information USP";fl tion, special studies may be necessary to assess specific risk factors related to the dosage form (e.g., irritation and/or sensitization at the site of application).

Unlike immediate-release dosage forms, modified-re- lease products cannot be characterized using a single-time point dis- solution test Furthermore, with a modified—release producta patient is to experience a specific plasma level curve covering a finite time period, usually 12 to 24 hours.

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—74873 1, VIOXX®, Merck & Co.), meloxicam (MOBIC®, co—marketed by Abbott Laboratories, Chicago, IL, and Boehringer Ingelheim Pharmaceuticals), valdecoxib (BEXTRA®, GD.

the alkylating agent is selected from the group consisting of chlormethine, chlorambucile, melphalan, uramustine, mannomustine, extramustinephoshate, mechlore-thaminoxide, cyclophosphamide, ifosfamide, trifosfamide, tretamine, thiotepa, triaziquone, mitomycine, busulfan, piposulfan, piposulfam, carmustine, lomustine, semustine, streptozotocine, mitobronitole, dacarbazine and procarbazine; or

the natural product is selected from the group consisting of Vinblastine, Vincristine, etoposide, teniposide, adriamycine, daunomycine, doctinomycin, daunorubicin, doxorubicin, mithramycin, bleomycin, mitomycin, L—asparaginase, alpha-interferon, camptothecin, taxol, and retinoic acid; or

The composition of claim 13, wherein the NSAID is selected from the group consisting of nabumetone, tiaramide, proquazone, bufexamac, flumizole, epirazole, tinoridine, timegadine, dapsone, aspirin, diflunisal, benorylate, fosfosal, diclofenac, alclofenac, fenclofenac, etodolac, indomethacin, sulindac, tolmetin, fentiazac, tilomisole, carprofen, fenbufen, flurbiprofen, ketoprofen, oxaprozin, suprofen, tiaprofenic acid, ibuprofen, naproxen, fenoprofen, indoprofen, pirprofen, flufenamic, mefenamic, meclofenamic, niflumic, oxyphenbutazone, phenylbutazone, apazone, feprazone, piroxicam, sudoxicam, isoxicam, and tenoxicam.

The composition of claim 13, wherein the COX—2 inhibitor is selected from the group consisting of nimesulide, celecoxib, rofecoxib, meloxicam, valdecoxib, parecoxib, etoricoxib, flurbiprofen, nabumetone, etodolac, iguratimod, flosulide, piroxicam, diclofenac, lumiracoxib, monteleukast, pranlukast, heptinylsulfide, SC-