(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2008/0070904 A1
`(43) Pub. Date:
`Mar. 20, 2008
`J amieson et al.
`
`US 20080070904Al
`
`(54) PHARMACEUTICAL COMPOSITIONS OF
`BENZODIAZEPINES AND METHOD OF USE
`THEREOF
`
`(75) Inventors: Gene Jamieson, Boulder Creek, CA
`(US); Michael Des Jardin, Sunnyvale,
`CA (US); Clark Allphin, Los Altos, CA
`(Us)
`Correspondence Address:
`JAZZ PHARMACEUTICALS
`3180 PORTER DRIVE
`PALO ALTO, CA 94304 (US)
`
`(73) Assignee: Jazz Pharmaceuticals, Palo Alto, CA
`(Us)
`
`(21) Appl. No.:
`
`11/897,028
`
`(22) Filed:
`
`Aug. 27, 2007
`
`Related US. Application Data
`
`(60) Provisional application No. 60/840,568, ?led on Aug.
`28, 2006.
`
`Publication Classi?cation
`
`(51) Int. Cl.
`(2006.01)
`A61K 31/5513
`(2006.01)
`A61K 31/5517
`(2006.01)
`A61P 25/00
`(52) Us. or. .......................................... ..514/220;514/221
`
`(57)
`
`ABSTRACT
`
`The present invention includes benZodiaZepine composi
`tions formulated for intranasal administration, comprising a
`binary solvent system comprising a ?rst solvent in Which the
`benZodiaZepine is soluble, the ?rst solvent capable of pen
`etrating nasal mucosal tissue, and a second solvent in Which
`the benZodiaZepine in less soluble. The compositions of the
`present invention may be used to treat a variety of disorders
`including, but not limited to, panic attacks, muscle spasms,
`anxiety, and seizures. In one aspect, the present invention
`relates to a fast-acting, clonaZepam composition for trans
`nasal administration that can be used for the treatment of
`seizure clusters.
`
`AQUESTIVE EXHIBIT 1012 page 0001
`
`

`

`Patent Application Publication Mar. 20, 2008 Sheet 1 0f 4
`
`US 2008/0070904 A1
`
`(g
`
`120
`
`3 10D _
`g
`a
`,é
`3
`
`8D _
`
`—Q—-L0razepam
`+Clonazepam
`.1
`mhmDlazepam
`
`3
`a
`.‘J
`O
`
`E,
`g
`‘a
`E!
`
`3
`
`90 -
`
`40 ‘
`
`20 ~
`
`é
`E
`
`* W
`0 W I
`I
`I
`l
`0
`1
`2
`3
`4
`5
`Time (h)
`
`I
`6
`
`I
`7
`
`9
`
`FIGURE 1
`
`PG/GF
`y=-0,6539x+66,185
`R2 = 0,9904
`
`80'
`
`7° ‘
`.51 60 _
`\m
`E 50 —
`.2
`i 40 -
`2
`'8 3o -
`TA/GF
`o
`J
`o 20 " y=-O,6229x+67,597
`2_
`R - 0,999
`
`10 _
`
`O
`
`0
`
`I
`
`20
`
`I
`
`40
`
`-
`
`I
`
`60
`
`i
`
`so
`
`l
`
`100
`
`% TA or PG in GF
`
`'
`
`'
`
`FIGURE 2
`
`AQUESTIVE EXHIBIT 1012 page 0002
`
`

`

`Patent Application Publication Mar. 20, 2008 Sheet 2 0f 4
`
`US 2008/0070904 A1
`
`140,0
`
`120,0
`
`
`
`lnteg ral
`
`80,0
`
`60,0
`
`40.0
`
`20,0 '
`
`—
`
`u
`
`0.0
`
`m E
`62
`
`FIGURE 3
`
`140
`
`120
`
`100
`
`80
`
`60
`
`Integral
`
`|
`
`|
`
`R
`
`Rw
`
`09%
`HOAc
`
`FIGURE 4
`
`v
`
`[i]
`1"“
`Saline (0.3% (0.9% Setron
`HOAc) HOAc)
`
`v
`
`AQUESTIVE EXHIBIT 1012 page 0003
`
`

`

`Patent Application Publication Mar. 20, 2008 Sheet 3 of 4
`
`US 2008/0070904 A1
`
`60 00
`
`‘
`
`5000
`
`40.00
`
`3000
`
`20.00
`
`10.00
`
`'
`
`-q- Formul l
`
`--- FormuL II
`
`-u--FormuL N
`
`' +MUBV8HOUS
`
`0.00
`
`10.00
`
`20.00
`
`3000 ."ml (mm .00
`
`50.00
`
`60.00
`
`70.00
`
`FIGURE 5'
`
`animals
`
`No of affected
`
`(control)
`
`Groups
`
`% Score 0 E Score 1 I Score 2
`
`FIGURE 6
`
`AQUESTIVE EXHIBIT 1012 page 0004
`
`

`

`Patent Application Publication Mar. 20, 2008 Sheet 4 0f 4
`
`US 2008/0070904 A1
`
`D
`
`O Q
`
`30
`20
`Vlscosity (cP)
`
`50
`
`FIGURE 7
`
`10
`
`20
`30
`Viscosity (cP)
`
`50
`
`FIGURE 8
`
`2
`5. 2
`
`.
`
`cmEoimEo
`
`D
`
`O
`0 0 0 n
`
`0
`
`5. o
`
`_
`
`0
`
`10
`
`20
`30
`Vlscoslty (cP)
`
`40
`
`50
`
`FIGURE 9
`
`AQUESTIVE EXHIBIT 1012 page 0005
`
`

`

`US 2008/0070904 A1
`
`Mar. 20, 2008
`
`PHARMACEUTICAL COMPOSITIONS OF
`BENZODIAZEPINES AND METHOD OF USE
`THEREOF
`
`TECHNICAL FIELD
`[0001] This application claims the bene?t of priority,
`under 35 U.S.C. 119(e), to US. Provisional Application Ser.
`No. 60/840,568, ?led Aug. 28, 2006 and is incorporated
`herein by reference.
`
`[0002] The present invention relates to formulations,
`including compositions and dosage forms of benZodiaZ
`epines. Described herein are compositions that are useful
`and ef?cacious for transmucosal delivery, including intra
`nasal delivery, as Well as methods of use and methods of
`manufacturing for such compositions.
`
`BACKGROUND OF THE INVENTION
`[0003] BenZodiaZepines are a class of antidepressants,
`anti-panic agents, and muscle relaxants used to ameliorate
`anxiety, treat panic disorders, induce sleep, relax muscles,
`and relieve seiZures and muscle spasms. BenZodiaZepine
`medications produce these e?fects by depressing the central
`nervous system. ClonaZepam, alpraZolam, chlordiaZep
`oxide, diaZepam, loraZepam, oxaZepam, estaZolam, mida
`Zolam, and triaZolam are examples of benZodiaZepine medi
`cations.
`[0004] ClonaZepam is marketed by Ho?‘man-La Roche
`under the trade names KLONOPIN® (Ho?fmann-La Roche
`Inc., NeW Jersey) in the United States and RIVOTRIL®
`(Ho?fmann-La Roche Inc., NeW Jersey) in Canada, South
`America, and Europe. The pharmacological pro?le of clon
`aZepam resembles that of other anxiolytic/ sedative benZo
`diaZepine medications, and its anticonvulsive characteristics
`are like those of other diaZepines. ClonaZepam can suppress
`the spike-Wave discharge accompanying absence seiZures
`(i.e., petit mal seizures) and reduce amplitude, frequency,
`duration, and discharge spreading in small-scale motor sei
`Zures.
`
`[0005] LoraZepam Was ?rst introduced in the late 1970’s
`by Wyeth Pharmaceuticals under the trade name Ativan®. It
`is noW manufactured by Wyeth Laboratories, Pennsylvania
`and distributed by Biovail Pharmaceuticals, NeW Jersey and
`is indicated for the management of anxiety disorders or for
`the short term relief of the symptoms of anxiety or anxiety
`associated With depressive symptoms. Injectable loraZepam
`is useful as an initial anticonvulsant medication for the
`control of status epilepticus.
`
`[0006] DiaZepam Was ?rst marketed as Valium® by Holf
`man-LaRoche in the l960’s. Valium is noW distributed by
`Roche Pharmaceuticals, NeW Jersey. Valium is indicated for
`the management of anxiety disorder and relief of symptoms
`of anxiety, for symptomatic relief of acute alcohol With
`draWal, adjunctively for relief of skeletal muscle spasm, and
`adjunctively in convulsive disorders.
`[0007] ClonaZepam is Well absorbed orally; maximum
`blood concentrations typically occur in one to tWo hours. It
`is metaboliZed by the liver and reduced to inactive metabo
`lites that are excreted primarily in the urine. The amount
`excreted unchanged in the urine is less than 0.5% of a dose.
`In addition, 9% to 27% of a dose of clonaZepam is excreted
`in the feces. ClonaZepam exhibits a half-life that varies from
`about 18 hours to 50 hours.
`
`[0008] LoraZepam is Well absorbed orally; maximum
`blood concentrations typically occur in one to four hours. It
`is metaboliZed by the liver and reduced to inactive metabo
`lites that are excreted primarily in the urine. LoraZepam
`exhibits a half-life that varies from about 8 hours to 24
`hours.
`[0009] DiaZepam is Well absorbed orally; maximum blood
`concentrations typically occur in one to tWo hours. It is
`metaboliZed by the liver and reduced to inactive metabolites
`that are excreted primarily in the urine. DiaZepam exhibits
`a half-life of about 100 hours.
`[0010] ClonaZepam exhibits strong anxiolytic properties
`and euphoric side effects; therefore, it is considered a
`“highly potent” benZodiaZepine. Speci?cally, 0.25 mg of
`clonaZepam is roughly equal to 1.0 mg of loraZepam and 5.0
`mg of diaZepam. ClonaZepam’s sedative effects are rela
`tively Weak in comparison With its strong anticonvulsant and
`anxiolytic elfects. The sedative e?fects of clonaZepam are
`also Weaker than that of other benZodiaZepines. ClonaZepam
`appears, to act by simulating the central nervous system
`actions of GABA, like other benZodiaZepines.
`[0011] ClonaZepam is commonly prescribed to treat epi
`lepsy, anxiety disorders, panic attacks, Restless Legs Syn
`drome (RLS), chronic fatigue syndrome, REM behavior
`disorder, night terrors, and Tourette’s Syndrome. In the
`treatment of anxiety disorders, loW-dose, long-term treat
`ment With clonaZepam may be required because of the
`chronic nature of anxiety. Although benZodiaZepines have
`some potential for abuse, the use of clonaZepam in long-term
`treatment of anxiety disorders is therapeutic and should not
`be confused With dependence or addiction. ClonaZepam also
`is used for the initial treatment of mania in combination With
`medications such as lithium, risperidone, or haloperidol. In
`addition, clonaZepam is prescribed to treat the symptoms of
`Parkinson’s disease and schiZophrenia and for tWitching and
`pain management. ClonaZepam has also been used to reduce
`and manage Tourette’s Syndrome motor tics. In another
`application, clonaZepam has been used to treat Hallucinogen
`Persisting Perception Disorder (HPPD). ClonaZepam is not
`typically used to treat insomnia because of its relatively
`Weak sedative elfects.
`[0012] For epilepsy patients, clonaZepam is indicated for
`use alone or as an adjunct therapy, and as primary therapy
`and for refractory patients. Epilepsy is a disorder character
`iZed by transient but recurrent disturbances of brain function
`that may or may not be associated With impairment or loss
`of consciousness and abnormal movements or behavior. The
`primary objective of caring for patients With epilepsy is to
`restore their functional capacity to its maximal potential. To
`do this, physicians use a stable regimen of anti-epileptic
`drugs (AED). Approximately 30% of patients continue to be
`refractory to AED treatment and often have recurrent sei
`Zures that may occur in clusters. Some of these patients may
`also experience continued seiZure activity Without regaining
`consciousness for a prolonged period of time, a condition
`called status epilepticus. In addition to being life threaten
`ing, recurrent seiZures and status epilepticus can impact
`cognition and permanently damage other brain function.
`[0013] Patients With refractory epilepsy including epi
`sodes of seiZure clusters and status epilepticus often present
`at the emergency room Where they are treated With IV
`benZodiaZepines, phenyloin and barbiturates. The goal of
`
`AQUESTIVE EXHIBIT 1012 page 0006
`
`

`

`US 2008/0070904 A1
`
`Mar. 20, 2008
`
`treatment in the ER is the prompt cessation of seizure
`activity. Prior to the ER, there are limited treatment options
`available to these patients and caregivers.
`[0014] Epileptic seizures are often classi?ed in tWo types:
`primary generalized seizures, (seizures that begin With a
`Widespread electrical discharge involving both sides of the
`brain) and partial seizures (seizures involving one area of the
`brain). Included among primary generalized seizures are:
`absence (also knoWn as petit-mal) seizures, myoclonic sei
`zures, atonic and tonic seizures, clonic and clonic-tonic (also
`knoWn as grand-mal) seizures. Included among partial sei
`zures are simple and complex seizures and secondary gen
`eralized seizures.
`
`[0015] Clonazepam has been used in the treatment many
`different epilepsy syndromes and for different types of
`seizures including Lennox-Gastaut syndrome (petit mal
`variant), akinetic and myoclonic seizures. Clonazepam is
`also useful in patients With absence seizures. In Europe,
`clonazepam, available in IV formulation, is also used in the
`acute treatment of seizures in the emergency setting. Often
`patients With history of cluster seizures and status epilepti
`cus Will present to the emergency room.
`[0016] A rectal gel formulation of diazepam is commer
`cially available (Diastat®) for outpatient treatment of
`increased seizure activity in patients on stable anti-epileptic
`drug regimen. Diastat® is administered to patients by car
`egivers and has been effective in aborting seizure activity
`and thereby reducing ER visits. However, due to the mode
`of administration, Diastat® has primarily been used in the
`pediatric population Where a parent can rectally administer
`to their child. Ideally, an outpatient rescue treatment for
`these epileptic patients Would have a quick onset of action
`terminating the ongoing seizure and prevent recurrence of
`seizure activity through a long enough duration of effect.
`The treatment should also be easily administered by car
`egivers in a culturally acceptable mode of administration
`that is easily accessible.
`
`[0017] The nasal mucosa offers an alternative to oral and
`parenteral administration; intranasal administration is a
`practical Way to achieve the therapeutic effect of many
`medications. Advantages of this method are that drugs can
`be administered readily and simply, and either a localized or
`a systemic effect can be achieved. Intranasal administration
`suffers from a signi?cant problem, hoWever: Most drug
`molecules di?‘use sloWly and poorly through the nasal
`mucosa. Therefore, therapeutic levels of the medication
`cannot be achieved or may not be achieved in time With the
`progression of the incidence. A further constraint is that the
`administration volume must be small; usually it is maxi
`mally about 150 pL per nostril. If a greater volume of
`medication is administered, it may drain into the pharynx
`and be sWalloWed.
`[0018] Various intranasal benzodiazepine compositions
`have been developed. HoWever, some of these compositions
`exhibit a delayed time to peak plasma concentration, poor
`absorption, or poor bioavailability. This is unacceptable for
`treatment or prevention of some disorders, illnesses and
`symptoms. Some intranasal midazolam formulations, for
`example, are produced at a pH that causes nasal irritation
`and burning in many patients.
`[0019] Accordingly, there is a need for intranasal benzo
`diazepine compositions With improved properties such as,
`
`for example, rapid absorption, time to peak concentration,
`and bioavailability. Further, a need exists for vehicles in
`Which the solubility of the drug is high but Which are
`non-damaging to the nasal mucosa. There also is a need for
`intranasal compositions that improve patient compliance.
`
`SUMMARY OF THE INVENTION
`[0020] In one aspect, the invention is directed to a phar
`maceutical composition for transmucosal administration to a
`mammal, comprising a solvent system comprising a ?rst
`solvent in Which a benzodiazepine is soluble, the ?rst
`solvent capable of penetrating nasal mucosal tissue, and a
`second solvent in Which the benzodiazepine is less soluble
`than in the ?rst solvent, Wherein the solvent system com
`prises 10% (Weight/Weight) or less of an aqueous bulfer
`solution With the caveat that the solvent system does not
`comprise free polyethylene glycol polymers; and a thera
`peutically effective amount of a benzodiazepine.
`
`[0021] In other embodiments, the pharmaceutical the sol
`vent system may be substantially a single phase and sub
`stantially homogeneous, may be substantially free of aque
`ous bulfer, the ?rst solvent may be diethylene glycol
`monoethylether (DEGEE) or tetrahydrofurfuryl alcohol
`polyethyleneglycol ether (glycofurol), the ?rst solvent may
`be present at a Weight percent of betWeen about 30% to
`about 70%, the second solvent may be glycerol triacetate or
`propylene glycol, and the benzodiazepine may be present at
`a Weight percent of betWeen about 0.1% to about 10%.
`
`[0022] In further embodiments, the ?rst and second sol
`vents may be present in equal Weight percents, the pH of the
`aqueous bulfer solution may be betWeen about pH 4 to about
`pH 7, the composition may further comprise one or more
`components selected from the group consisting of a surfac
`tant, anti-oxidant, pharmaceutically acceptable polymer,
`polyalcohol, lipid, mucosa penetration enhancing agent,
`colorant, ?avoring agent, anesthetic agent, co-solvent, and
`agent to adjust osmolarity, the composition may be formu
`lated to be sprayable and the composition may be sprayable
`at temperatures betWeen —l5° and 30° C.
`
`[0023] In another aspect, the invention is directed to a
`pharmaceutical composition for transmucosal administra
`tion to a mammal, comprising a solvent system comprising
`a ?rst solvent comprising one or more components selected
`from the group consisting of diethylene glycol monoethyl
`ether and tetrahydrofurfuryl alcohol polyethyleneglycol
`ether, and a second solvent comprising one or more com
`ponent selected from the group consisting of glycerol triac
`etate or propylene glycol, Wherein the solvent system com
`prises l0% (Weight/Weight) or less of an aqueous bulfer
`solution With the caveat that the solvent system does not
`comprise free polyethylene glycol polymers; and a thera
`peutically effective amount of a benzodiazepine Wherein the
`composition is a single phase and homogeneous.
`[0024] In further embodiments the composition may be
`used at a unit therapeutic dose of betWeen about 50 [LL and
`300 uL, or betWeen 25 and 150 uL.
`
`[0025] In another embodiment, the pharmaceutical com
`position of the invention comprises a benzodiazepine for
`intranasal administration to a mammal comprising an ethyl
`ether solvent and a therapeutically effective amount of the
`benzodiazepine, Wherein the composition is a single phase
`and homogeneous.
`
`AQUESTIVE EXHIBIT 1012 page 0007
`
`

`

`US 2008/0070904 A1
`
`Mar. 20, 2008
`
`[0026] In yet another aspect, the pharmaceutical compo
`sition of the invention comprises a benzodiazepine for
`transmucosal administration to a mammal, characterized by
`(i) a Tmax of a benzodiazepine, after a single intranasal
`administration, of no more than 2 hours, and (ii) a bioavail
`ability of the benzodiazepine, after a single intranasal
`administration, of no less than 30% of the bioavailability of
`an equivalent dose of the benzodiazepine delivered orally.
`[0027] In still another aspect, the pharmaceutical compo
`sition of the invention comprises a benzodiazepine for
`transmucosal administration to a mammal, characterized by
`(i) a Cmax of the benzodiazepine, after a single intranasal
`administration, of at least about 75% the Cmax of an equiva
`lent dose of the benzodiazepine delivered orally, and (ii) a
`bioavailability of the benzodiazepine, after a single intrana
`sal administration, of no less than 30% of the bioavailability
`of an equivalent dose of the benzodiazepine delivered orally.
`
`[0028] In a further aspect, the pharmaceutical composition
`of the invention comprises a benzodiazepine for intranasal
`administration to a mammal, characterized by (i) a ratio of
`the AUC of the benzodiazepine, after a single intranasal
`administration, (AUCin) to the AUC of an equivalent dose of
`the benzodiazepine delivered orally (AUComl) of at least
`about AUCin:AUCOm1=l:3.3, Wherein the AUC values are
`determined over the same time period.
`
`[0029] In other aspects, the invention is directed to a
`method for administering an active agent to a mammal in
`need thereof, the method comprising delivery of a benzo
`diazepine to the mammal’s bloodstream via the nasal
`mucosa of the mammal in a dosage form comprising the
`compositions described above, and the invention is directed
`to a method of treating a mammal suffering seizures, the
`method comprising delivery of the benzodiazepine to the
`mammal’s bloodstream via the nasal mucosa of the mam
`mal, Wherein the benzodiazepine is delivered in a dosage
`form comprising a composition described above.
`
`[0030] In other embodiments, delivery of the active agent
`occurs at the onset of the symptoms of seizures, and one or
`more unit doses may be administered.
`
`[0031] In yet another aspect, the invention is directed to a
`method of manufacturing a benzodiazepine composition, the
`method comprising mixing a solvent system and benzodi
`azepine to provide a single-phase, homogeneous solution
`suitable for intranasal administration of the benzodiazepine.
`
`[0032] Still another aspect, the invention is directed to a
`method of administering an active agent to a mammal in
`need thereof, Wherein a composition described above is
`administered to a mammal suffering from anxiety attacks
`selected from the group consisting of panic attacks, social
`phobia; social anxiety and performance anxiety.
`[0033] These and other embodiments of the present inven
`tion Will readily occur to those of ordinary skill in the art in
`vieW of the disclosure herein.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`[0034] FIG. 1 presents a graphic representation of the
`mean cumulative amount of diazepam, lorazepam and clon
`azepam permeated per unit area over a period of 7 hours (h).
`In the ?gure, the horizontal axis is Time given in hours (h)
`and the vertical axis is the mean permeated amount of
`
`permeated drug per unit area (ug/cmz). The legend for the
`plot of data is as folloWs: lorazepam, diamonds; clon
`azepam, squares; and diazepam, triangles.
`[0035] FIG. 2 presents the solubility of clonazepam in
`mixtures of triacetin or propylene glycol and glycofurol. In
`the ?gure, the vertical axis is CLO (clonazepam) solubility
`in mg/mL, and the horizontal axis is the percent (%) triacetin
`(TA) or propylene glycol (PG) and glycofurol (GF). In the
`?gure, the linear regression for PG/GF Was y=—0.6539x+
`66.185, With a correlation coef?cient of R2=0.9904; and the
`linear regression for TA/GF Was y=—0.6229x+67.597, With
`a correlation coefficient of R2=0.999.
`
`[0036] FIG. 3 presents irritation data for ?ve clonazepam
`formulations. Comparison of irritation values is given rela
`tive to acetic acid solutions and a setron formulation. In the
`?gure, the vertical axis is the blood pressure integrated as a
`function of time (Integral) and the horizontal axis is the
`formulations tested at 50 [LL doses, as folloWs: CLZ2080i
`10 mg/mL clonazepam, 20% Transcutol® (TC), 80% Poly
`ethylene Glycol (PEG); CLZ5050il0 mg/mL clonazepam,
`50% TC, 50% PEG; CLZ70G30Til0 mg/mL clonazepam,
`70% GF, 30% TA; CLZ20T80P02T, 10 mg/mL clonazepam,
`10% TC, 90% PEG 200 and 0.2% TWeen 20; Saline (nega
`tive control); Acetic Acid (HOAc) 0.3% (positive control);
`Acetic Acid (HOAc) 1.5% (positive control); Setron (posi
`tive control).
`[0037] FIG. 4 presents that data for irritation scores of
`eight clonazepam formulations and control formulations
`based on the mean blood pressure changes. The columns for
`saline, acetic acid solutions and a setron formulation (i.e.,
`the right-most four columns) represented data from previous
`experiments and Were inserted for comparison. In the ?gure,
`the vertical axis is the blood pressure integrated as a function
`of time (Integral) and the horizontal axis corresponds to the
`tested formulations (the formulations are set forth in Table
`11). Saline Was a negative control; 0.3% Acetic Acid
`(HOAc) and 0.9% HOAc Were positive irritation controls;
`and setron Was a positive irritation control.
`
`[0038] FIG. 5 presents pharmacokinetic data in a rabbit
`study. In the ?gure, the vertical axis is concentration of
`clonazepam (CLZ conc. (ng/mL)), and the horizontal axis is
`time in minutes (Time (min.)). The legend for the plot of
`data is as folloWs: Formulation I, closed circles; Formulation
`II, closed squares; Formulation III; upright triangles; and
`Formulation IV, light x’s. The top data line With dark x’s
`corresponds to the data for intravenous administration.
`
`[0039] FIG. 6 summarizes the histopathology results for
`the nasal cavities of test animals to Which clonazepam
`compositions of the present invention Were administered. In
`the ?gure, the vertical axis is the number of affected animals;
`and the horizontal axis are the test groups organized by
`groups of three bar graphs. In each bar graph the order of the
`vertical bars is as folloWs: Score 0; Score 1; and Score 2.
`
`[0040] FIG. 7 shoWs the correlation betWeen plume area at
`3 cm and viscosity of non-aqueous solvent matrices. Data
`for Water is shoWn for comparison (III). Composition of
`solvent matrices is presented in Table 19. In the ?gure, the
`vertical axis is plume area in cm and the horizontal axis is
`viscosity (cP).
`[0041] FIG. 8 shoWs the correlation betWeen spray angle
`and viscosity of non-aqueous solvent matrices. Data for
`
`AQUESTIVE EXHIBIT 1012 page 0008
`
`

`

`US 2008/0070904 A1
`
`Mar. 20, 2008
`
`Water is shown for comparison (El). Composition of solvent
`matrices is presented in Table 19. In the ?gure, the vertical
`axis is spray angle (in degrees) and the horizontal axis is
`viscosity (cP).
`[0042] FIG. 9 shoWs the correlation betWeen plume asym
`metry (DmaX/Dmin) and viscosity of non-aqueous solvent
`matrices. Data for Water is shoWn for comparison (El).
`Composition of solvent matrices is presented in Table 19. In
`the ?gure, the vertical axis is (DmaX/Dmin) and the horizontal
`axis is viscosity (cP).
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0043] All patents, publications, and patent applications
`cited in this speci?cation are herein incorporated by refer
`ence as if each individual patent, publication, or patent
`application Was speci?cally and individually indicated to be
`incorporated by reference in its entirety for all purposes.
`[0044] 1.0.0 De?nitions
`[0045] It is to be understood that the terminology used
`herein is for the purpose of describing particular embodi
`ments only, and is not intended to be limiting. As used in this
`speci?cation and the appended claims, the singular forms
`“a,”“an” and “the” include plural referents unless the context
`clearly dictates otherWise. Thus, for example, reference to “a
`solvent” includes a combination of tWo or more such sol
`vents, reference to “a compound” includes one or more
`compounds, mixtures of compounds, and the like.
`
`[0046] Unless de?ned otherWise, all technical and scien
`ti?c terms used herein have the same meaning as commonly
`understood by one of ordinary skill in the art to Which the
`invention pertains. Although other methods and materials
`similar, or equivalent, to those described herein can be used
`in the practice of the present invention, the preferred mate
`rials and methods are described herein.
`[0047] In describing and claiming the present invention,
`the folloWing terminology Will be used in accordance With
`the de?nitions set out beloW.
`
`[0048] The term “dosage form” as used herein refers to a
`pharmaceutical composition comprising an active agent,
`such as a benzodiazepine, and optionally containing inactive
`ingredients, e.g., pharmaceutically acceptable excipients
`such as suspending agents, surfactants, solvents, co-sol
`vents, permeation enhancers, binders, diluents, lubricants,
`stabilizers, anti-oxidants, osmotic agents, colorants, plasti
`cizers, coatings and the like, that may be used to manufac
`ture and deliver active pharmaceutical agents.
`
`[0049] The term “gel” as used herein refers to a semi-solid
`dosage form that contains a gelling agent in, for example, an
`aqueous, alcoholic, or hydroalcoholic vehicle and the gelling
`agent imparts a three-dimensional cross-linked matrix (“gel
`li?ed”) to the vehicle. The term “semi-solid” as used herein
`refers to a heterogeneous system in Which one solid phase is
`dispersed in a second liquid phase. In preferred embodi
`ments of the present invention, the benzodiazepine (e. g.,
`clonazepam) compositions formulated for intranasal deliv
`ery are not gelli?ed.
`
`[0050] The pH measurements for formulations and com
`positions described herein, Wherein the formulations or
`compositions do not comprise a predominantly aqueous
`
`environment, are more aptly described as “apparent pH”
`values as the pH values are not determined in a predomi
`nantly aqueous environment. In such cases, the in?uence of,
`for example, organic solvents on the pH measurement may
`result in a shift of pH relative to a true aqueous environment.
`
`[0051] The term “mucoadhesive” as used herein refers to
`adhesion to mucous membranes that are covered by mucus,
`for example, those in the nasal cavity.
`
`[0052] The term “carrier” or “vehicle” as used herein
`refers to carrier materials (other than the pharmaceutically
`active ingredient) suitable for administration of a pharma
`ceutically active ingredient, for example, transmucosal
`administration via nasal mucosa. A vehicle may comprise,
`for example, solvents, cosolvents, permeation enhancers, pH
`buffering agents, antioxidants, additives, or the like, Wherein
`components of the vehicle are nontoxic and do not interact
`With other components of the total composition in a delete
`rious manner.
`
`[0053] The term “transdermal” delivery, as used herein
`refers to both transdermal (or “percutaneous”) and transmu
`cosal administration, that is, delivery by passage of a drug
`through a skin or mucosal tissue surface and ultimately into
`the bloodstream. Transmucosal administration includes, but
`is not limited to, nasal, oral, rectal, and vaginal administra
`tion of a composition for delivery of an active drug (e.g.,
`clonazepam) to the blood stream of the subject to Which it
`is administered.
`
`[0054] The phrase “therapeutically effective amount” as
`used herein refers to a nontoxic but suf?cient amount of a
`drug, agent, or compound to provide a desired therapeutic
`effect, for example, one or more doses of benzodiazepine
`that Will be effective in treatment of seizures including
`seizure clusters and status epilepticus or for the treatment of
`anxiety states including but not limited to panic attacks,
`social phobia, social anxiety and performance anxiety, acute
`mania, psychosis, and drug WithdraWal, including but not
`limited to nicotine WithdraWal, opiate WithdraWal, and alco
`hol WithdraWal.
`
`[0055] The phrase “seizure clusters” as used herein refers
`to closely related groups of seizures in some epilepsy
`patients. Typically seizure cluster patients experience this
`increased frequency of seizures in unique patterns. It is not
`uncommon for some of these patients to experience 3 or
`more seizures in a 24-48 hour period.
`
`[0056] The term “benzodiazepine” as used herein refers to
`a class of drugs With sedative, hypnotic, anxiolytic, anticon
`vulsant, amnestic and/or muscle relaxant properties. Typi
`cally, benzodiazepines comprise a structure composed of a
`benzene ring fused to a seven-membered diazepine ring.
`Most of the important benzodiazepines contain an aryl
`substituent ring and a l,4-diazepine ring. Generally, benzo
`diazepine refers to aryl-l,4-benzodiazepines. The actions of
`benzodiazepines are usually the result of increased activa
`tion of receptors by gamma-aminobutyric acid (GABA).
`The term benzodiazepine includes benzodiazepines and
`pharmaceutically acceptable salts thereof.
`[0057] Benzodiazepines are commonly divided into three
`groups related to the period of time for Which the drug has
`an evident effect: short-acting benzodiazepines typically act
`for less than six hours; intermediate-acting benzodiazepines
`typically act for 6-10 hours; and long-acting benzodiaz
`
`AQUESTIVE EXHIBIT 1012 page 0009
`
`

`

`US 2008/0070904 A1
`
`Mar. 20, 2008
`
`epines have strong sedative effects that persist. The folloW
`ing list is a partial list of benZodiaZepines. The list is
`arranged in an approximate order of the shortest acting to the
`longest acting benZodiaZepine: alpraZolam; bromaZepam;
`chlordiaZepoxide; clobaZam; clonaZepam; cloraZepate; diaZ
`epam; estaZolam; ?unitraZepam; ?uraZepam; halaZepam;
`ketaZolam;
`lopraZolam;
`loraZepam;
`lormetaZepam;
`medaZepam; midaZolam;
`nitraZepam;
`nordaZepam;
`oxaZepam; praZepam; quaZepam; temaZepam; tetraZepam;
`and triaZolam.
`
`[0058] BenZodiaZepines typically have the folloWing
`effects, though some may be relatively stronger anxiolytics
`and others relatively stronger amnesics: anxiolytic (reduce
`anxiety, e.g., treatment of panic attacks); anticonvulsant
`(e.g., treatment of seizures); antispasmodic (e.g., muscle
`relaxant); sedative/hypnotic; antidepressant; and, amnesic
`(produce anterograde amnesia).
`
`[0059] The term “clonaZepam” as used herein includes
`clonaZepam and its active pharmaceutically acceptable
`derivatives and metabolites, as Well as pharmaceutically
`acceptable salts thereof. ClonaZepam’s pharmacological
`pro?le is similar to other anxiolytic/sedative benZodiaZ
`epines. Further, the basic anticonvulsive properties of clon
`aZepam are similar to those of other diaZepines. ClonaZepam
`is capable of suppressing the spike and Wave discharge in
`absence seiZures (petit mal) and decreasing the frequency,
`amplitude, duration and spread of discharge in minor motor
`seizures. ClonaZepam can be used for the treatment of
`seiZure clusters associated With epilepsy. Chemically, clon
`aZepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-l,4
`benZodiaZepin-2-one. It is a light yelloW crystalline poWder.
`ClonaZepam has a molecular Weight of 315.72 and the
`folloWing molecular formula: Cl5HlOClN3O3. The structure
`of clonaZepam is as folloWs:
`
`H
`\
`N
`
`O
`
`OZN
`
`/N
`
`C1
`
`[0060] The term “alkyl solvent” as used herein includes
`alkyl ethers of 2-5 carbo