(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2006/0198896 A1
`(43) Pub. Date:
`Sep. 7, 2006
`Liversidge et al.
`
`US 20060198896Al
`
`(54) AEROSOL AND INJECTABLE
`FORMULATIONS OF NANOPARTICULATE
`BENZODIAZEPINE
`
`(75) Inventors: Gary Liversidge, West Chester, PA
`(US); Scott Jenkins, DoWningtoWn, PA
`(Us)
`Correspondence Address:
`ELAN DRUG DELIVERY, INC.
`C/O FOLEY & LARDNER LLP
`3000 K STREET, N.W.
`SUITE 500
`WASHINGTON, DC 20007-5109 (US)
`
`(73) Assignee: Elan Pharma International Limited
`
`(21) Appl. No.:
`
`11/354,249
`
`(22) Filed:
`
`Feb. 15, 2006
`
`Related US. Application Data
`
`(60) Provisional application No. 60/ 653,034, ?led on Feb.
`15, 2005.
`
`Publication Classi?cation
`
`(51) Int. Cl.
`(2006.01)
`A61K 31/5513
`(2006.01)
`A61K 9/14
`(52) US. Cl. ......................... ..424/489;514/221;977/906
`
`(57)
`
`ABSTRACT
`
`Described are nanoparticulate formulations of a benZodiaZ
`epine, such as loraZepam, that does not require the presence
`of polyethylene glycol and propylene glycol as stabilizers,
`and methods of making and using such formulations. The
`formulations are particularly useful in aerosol and injectable
`dosage forms, and comprise nanoparticulate benZodiaZ
`epine, such as loraZepam, and at least one surface stabilizer.
`The formulations are useful in the treatment of status
`epilepticus, treatment of irritable boWel syndrome, sleep
`induction, acute psychosis, and as a pre-anesthesia medica
`tion.
`
`AQUESTIVE EXHIBIT 1022 page 0000
`
`

`

`US 2006/0198896 A1
`
`Sep. 7, 2006
`
`AEROSOL AND INJECTABLE FORMULATIONS
`OF NANOPARTICULATE BENZODIAZEPINE
`
`[0005] A. Droplet/Particle SiZe Determines Deposition
`Site
`
`FIELD OF THE INVENTION
`
`[0001] The present invention is directed to aerosol and
`injectable formulations of nanoparticulate benZodiaZepine,
`and preferably, nanoparticulate loraZepam. The composi
`tions of the invention are useful in treating status epilepticus,
`sleep induction, acute psychosis, irritable boWel syndrome,
`and for pre-anesthesia medication. Also encompassed by the
`invention are methods of making and using such composi
`tions.
`
`BACKGROUND OF THE INVENTION
`
`I. Administration Routes for Drugs
`
`[0002] The route of administration of a drug substance can
`be critical to its pharmacological effectiveness. Various
`routes of administration exist, and all have their oWn advan
`tages and disadvantages. Oral drug delivery of tablets,
`capsules, liquids, and the like is the most convenient
`approach to drug delivery, but many drug compounds are not
`amenable to oral administration. 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. Similarly, poorly Water soluble compounds Which do
`not dissolve rapidly enough to be orally absorbed are likely
`to be ineffective When given as oral dosage forms. Oral
`administration can also be undesirable because drugs Which
`are administered orally are generally distributed to all tissues
`in the body, and not just to the intended site of pharmaco
`logical activity. Alternative types of systemic administration
`are subcutaneous or intravenous injection. This approach
`avoids the gastrointestinal tract and therefore can be an
`effective route for delivery of proteins and peptides. HoW
`ever, these routes of administration have a loW rate of patient
`compliance, especially for drugs such as insulin Which must
`be administered one or more times daily. Additional alter
`native methods of drug delivery have been developed
`including transdermal, rectal, vaginal, intranasal, and pul
`monary delivery.
`
`[0003] Nasal drug delivery relies on inhalation of an
`aerosol through the nose so that active drug substance can
`reach the nasal mucosa. Drugs intended for systemic activity
`can be absorbed into the bloodstream because the nasal
`mucosa is highly vasculariZed. Alternatively, if the drug is
`intended to act topically, it is delivered directly to the site of
`activity and does not have to distribute throughout the body;
`hence, relatively loW doses may be used. Examples of such
`drugs are decongestants, antihistamines, and anti-in?amma
`tory steroids for seasonal allergic rhinitis.
`
`[0004] Pulmonary drug delivery relies on inhalation of an
`aerosol through the mouth and throat so that the drug
`substance can reach the lung. For systemically active drugs,
`it is desirable for the drug particles to reach the alveolar
`region of the lung, Whereas drugs Which act on the smooth
`muscle of the conducting airWays should preferentially
`deposit in the bronchiole region. Such drugs can include
`beta-agonists, anti cholinergics, and corticosteroids.
`
`[0006] In developing a therapeutic aerosol, the aerody
`namic siZe distribution of the inhaled particles is the single
`most important variable in de?ning the site of droplet or
`particle deposition in the patient; in short, it Will determine
`Whether drug targeting succeeds or fails. See P. Byron,
`“Aerosol Formulation, Generation, and Delivery Using
`Nonmetered Systems,”RespiraZ0ry Drug Delivery, 144-151,
`144 (CRC Press, 1989). Thus, a prerequisite in developing
`a therapeutic aerosol is a preferential particle siZe. The
`deposition of inhaled aerosols involves different mecha
`nisms for different siZe particles. D. SWift (1980); Parodi et
`al., “Airborne Particles and Their Pulmonary Deposition,” in
`Scientific Foundations ofRespiraZory Medicine, Scaddings
`et al. (eds.), pp. 545-557 (W. B. Saunders, Philadelphia,
`1981); J. Heyder, “Mechanism of Aerosol Particle Deposi
`tion,” Chest, 80:820-823 (1981).
`[0007] Generally, inhaled particles are subject to deposi
`tion by one of tWo mechanisms: impaction, Which usually
`predominates for larger particles, and sedimentation, Which
`is prevalent for smaller particles. Impaction occurs When the
`momentum of an inhaled particle is large enough that the
`particle does not folloW the air stream and encounters a
`physiological surface. In contrast, sedimentation occurs pri
`marily in the deep lung When very small particles Which
`have traveled With the inhaled air stream encounter physi
`ological surfaces as a result of random diffusion Within the
`air stream. For intranasally administered drug compounds
`Which are inhaled through the nose, it is desirable for the
`drug to impact directly on the nasal mucosa; thus, large (ca.
`5 to 100 um) particles or droplets are generally preferred for
`targeting of nasal delivery.
`[0008] Pulmonary drug delivery is accomplished by inha
`lation of an aerosol through the mouth and throat. Particles
`having aerodynamic diameters of greater than about 5
`microns generally do not reach the lung; instead, they tend
`to impact the back of the throat and are sWalloWed and
`possibly orally absorbed. Particles having diameters of
`about 2 to about 5 microns are small enough to reach the
`upper- to mid-pulmonary region (conducting airWays), but
`are too large to reach the alveoli. Even smaller particles, i.e.,
`about 0.5 to about 2 microns, are capable of reaching the
`alveolar region. Particles having diameters smaller than
`about 0.5 microns can also be deposited in the alveolar
`region by sedimentation, although very small particles may
`be exhaled.
`
`[0009] B. Devices Used For Nasal And Pulmonary Drug
`Delivery
`[0010] Drugs intended for intranasal delivery (systemic
`and local) can be administered as aqueous solutions or
`suspensions, as solutions or suspensions in halogenated
`hydrocarbon propellants (pressurized metered-dose inhal
`ers), or as dry poWders. Metered-dose spray pumps for
`aqueous formulations, pMDIs, and DPIs for nasal delivery
`are available from, for example, Valois of America or
`Pfeilfer of America.
`
`[0011] Drugs intended for pulmonary delivery can also be
`administered as aqueous formulations, as suspensions or
`solutions in halogenated hydrocarbon propellants, or as dry
`poWders. Aqueous formulations must be aerosoliZed by
`
`AQUESTIVE EXHIBIT 1022 page 0001
`
`

`

`US 2006/0198896 A1
`
`Sep. 7, 2006
`
`liquid nebuliZers employing either hydraulic or ultrasonic
`atomization, propellant-based systems require suitable pres
`suriZed metered-dose inhalers (pMDIs), and dry poWders
`require dry poWder inhaler devices (DPIs) Which are capable
`of dispersing the drug substance effectively. For aqueous and
`other non-pressurized liquid systems, a variety of nebuliZers
`(including small volume nebuliZers) are available to aero
`soliZe the formulations. Compressor-driven nebuliZers
`incorporate jet technology and use compressed air to gen
`erate the liquid aerosol. Such devices are commercially
`available from, for example, Healthdyne Technologies, Inc.;
`Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari
`Respiratory, Inc.; Mada Medical, Inc.; Puritan-Bennet;
`Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak, Inc.
`Ultrasonic nebuliZers rely on mechanical energy in the form
`of vibration of a pieZoelectric crystal to generate inhalable
`liquid droplets and are commercially available from, for
`example, Omron Heathcare, Inc. and DeVilbiss Health Care,
`Inc.
`
`[0012] A propellant driven inhaler (pMDI) releases a
`metered dose of medicine upon each actuation. The medi
`cine is formulated as a suspension or solution of a drug
`substance in a suitable propellant such as a halogenated
`hydrocarbon. pMDIs are described in, for example, NeW
`man, S. P., Aerosols and the Lung, Clarke et al., eds., pp.
`197-224 (ButterWor‘ths, London, England, 1984).
`[0013] Dry poWder inhalers (DPIs), Which involve
`deaggregation and aerosoliZation of dry poWders, normally
`rely upon a burst of inspired air that is draWn through the
`unit to deliver a drug dosage. Such devices are described in,
`for example, US. Pat. No. 4,807,814 to Douche et al., Which
`is directed to a pneumatic poWder ejector having a suction
`stage and an injection stage; SU 628930 (Abstract), describ
`ing a hand-held poWder disperser having an axial air ?oW
`tube; Fox et al., Powder and Bulk Engineering, pages 33-36
`(March 1988), describing a venturi eductor having an axial
`air inlet tube upstream of a venturi restriction; EP 347 779,
`describing a hand-held poWder disperser having a collaps
`ible expansion chamber, and US. Pat. No. 5,785,049 to
`Smith et al., directed to dry poWder delivery devices for
`drugs.
`[0014] C. Problems With Conventional Aerosol and Inject
`able Compositions and Methods
`
`[0015] Conventional techniques are extremely inef?cient
`in delivering agents to the lung for a variety of reasons. Prior
`to the present invention, attempts to develop inhalable
`aqueous suspensions of poorly Water soluble drugs have
`been largely unsuccessful. For example, it has been reported
`that ultrasonic nebuliZation of a suspension containing ?uo
`rescein and latex drug spheres, representing insoluble drug
`particles, resulted in only 1% aerosoliZation of the particles,
`While air-jet nebuliZation resulted in only a fraction of
`particles being aerosoliZed (Susan L. Tiano, “Functionality
`Testing Used to Rationally Assess Performance of a Model
`Respiratory Solution or Suspension in a NebuliZer,” Disser
`tation Abstracts International, 56/12-B, pp. 6578 (1995)).
`Another problem encountered With nebuliZation of liquid
`formulations prior to the present invention Was the long
`(4-20 min) period of time required for administration of a
`therapeutic dose. Long administration times are required
`because conventional liquid formulations for nebuliZation
`are very dilute solutions or suspensions of microniZed drug
`
`substance. Prolonged administration times are undesirable
`because they lessen patient compliance and make it di?icult
`to control the dose administered. Lastly, aerosol formula
`tions of microniZed drug are not feasible for deep lung
`delivery of insoluble compounds because the droplets
`needed to reach the alveolar region (0.5 to 2 microns) are too
`small to accommodate microniZed drug crystals, Which are
`typically 2-3 microns or more in diameter.
`
`[0016] Conventional pMDIs are also inef?cient in deliv
`ering drug substance to the lung. In most cases, pMDIs
`consist of suspensions of microniZed drug substance in
`halogenated hydrocarbons such as chloro?uorocarbons
`(CFCs) or hydro?uoroalkanes (HFAs). Actuation of the
`pMDI results in delivery of a metered dose of drug and
`propellant, both of Which exit the device at high velocities
`because of the propellant pressures. The high velocity and
`momentum of the drug particles results in a high degree of
`oropharyngeal impaction as Well as loss to the device used
`to deliver the agent. These losses lead to variability in
`therapeutic agent levels and poor therapeutic control. In
`addition, oropharyngeal deposition of drugs intended for
`topical administration to the conducting airWays (such as
`corticosteroids) can lead to systemic absorption With result
`ant undesirable side effects. Additionally, conventional
`microniZation (air-jet milling) of pure drug substance can
`reduce the drug particle siZe to no less than about 2-3
`microns. Thus, the microniZed material typically used in
`pMDIs is inherently unsuitable for delivery to the alveolar
`region and is not expected to deposit beloW the central
`bronchiole region of the lung.
`
`[0017] Prior to the present invention, delivery of dry
`poWders to the lung typically used microniZed drug sub
`stance. In the dry poWder form, microniZed substances tend
`to have substantial interpar‘ticle electrostatic attractive forces
`Which prevent the poWders from ?oWing smoothly and
`generally make them dif?cult to disperse. Thus, tWo key
`challenges to pulmonary delivery of dry poWders are the
`ability of the device to accurately meter the intended dose
`and the ability of the device to fully disperse the microniZed
`particles. For many devices and formulations, the extent of
`dispersion is dependent upon the patient’s inspiration rate,
`Which itself may be variable and can lead to a variability in
`the delivered dose.
`
`[0018] Delivery of drugs to the nasal mucosa can also be
`accomplished With aqueous, propellant-based, or dry poW
`der formulations. HoWever, absorption of poorly soluble
`drugs can be problematic because of mucociliary clearance
`Which transports deposited particles from the nasal mucosa
`to the throat Where they are sWalloWed. Complete clearance
`generally occurs Within about 15-20 minutes. Thus, poorly
`soluble drugs Which do not dissolve Within this time frame
`are unavailable for either local or systemic activity.
`
`[0019] As described beloW in the Background of Nano
`particulate Active Agent Compositions, several published
`US. patents and patent applications describe aerosols of
`nanoparticulate drugs. HoWever, none of these documents
`describe aerosols of a nanoparticulate benZodiaZepine, such
`as loraZepam.
`II. Background Regarding LoraZepam
`
`[0020] LoraZepam is a benZodiaZepine. It is also knoWn as
`7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,
`
`AQUESTIVE EXHIBIT 1022 page 0002
`
`

`

`US 2006/0198896 A1
`
`Sep. 7, 2006
`
`is
`formula
`molecular
`Its
`4-benzodiazepin-2-one.
`CISHIOCIZNZOZ, and it has a molecular Weight of 321.16.
`Lorazepam has only slight solubility in Water, i.e., 0.08
`mg/mL. US. Pat. No. 6,699,849 to Loftsson et al., Which is
`speci?cally incorporated by reference, refers to lorazepam
`and benzodiazepine. Lorazepam is a controlled substance.
`Merck Index, Thirteenth Ed., p. 999 (Merck & Co., White
`house Station, N]. 2001). As pharmaceutically acceptable
`salts including organic salts or esters of lorazepam can be
`employed as a substitute for lorazepam, the references beloW
`to lorazepam are also intended to include lorazepam salts
`and esters and mixtures thereof.
`
`[0021] Because of lorazepam’s loW Water solubility, it is
`generally formulated for oral administration. HoWever, oral
`administration of lorazepam has disadvantages. For
`example, lorazepam is susceptible to enzymatic degradation
`by glucuronyl transferase enzyme in the intestine or in the
`intestinal mucosa, as disclosed in US. Pat. No. 6,692,766 to
`Rubinstein et al., Which is incorporated by reference. Sterile
`lorazepam typically includes a preservative such as benzyl
`alcohol and requires refrigeration. Lorazepam delivered
`orally may have a sloW absorption and onset of action.
`
`[0022] Inj ectable formulations of lorazepam are preferable
`over oral administration doses because intravenous (IV) or
`intramuscular (IM) administration of a drug results in a
`signi?cantly shorter response time as compared to oral
`administration. Moreover, injectable formulations of pain
`medication are also preferable for post-operative health care,
`Where oral administration may not be feasible. Injectable
`formulations of lorazepam are particularly preferred, as
`lorazepam is not addictive, in contrast to other injectable
`formulations of drugs, such as morphine and ketorolac
`(Toradol®).
`[0023] HoWever, injectable lorazepam formulations are
`dif?cult to formulate due to the loW Water-solubility of
`lorazepam. Moreover, current injectable formulations of
`lorazepam are undesirable because the formulations must
`include polyethylene glycol and propylene glycol as solu
`bilizers, Which can result in pain at the injection site.
`III. Background Regarding Nanoparticulate Active Agent
`Compositions
`[0024] Nanoparticulate compositions, ?rst described in
`US. Pat. No. 5,145,684 (“the ’684 patent”), are particles
`consisting of a poorly soluble therapeutic or diagnostic agent
`having adsorbed onto or associated With the surface thereof
`a non-crosslinked surface stabilizer. The ’684 patent also
`describes methods of making such nanoparticulate compo
`sitions but does not describe compositions comprising a
`benzodiazepine, such as lorazepam, in nanoparticulate form.
`Methods of making nanoparticulate compositions are
`described, for example, in US. Pat. Nos. 5,518,187 and
`5,862,999, both for “Method of Grinding Pharmaceutical
`Substances,” US. Pat. No. 5,718,388, for “Continuous
`Method of Grinding Pharmaceutical Substances,” and US.
`Pat. No. 5,510,118 for “Process of Preparing Therapeutic
`Compositions Containing Nanoparticles.”
`[0025] Nanoparticulate compositions are also described,
`for example, in US. Pat. No. 5,298,262 for “Use of Ionic
`Cloud Point Modi?ers to Prevent Particle Aggregation Dur
`ing Sterilization,” US. Pat. No. 5,302,401 for “Method to
`Reduce Particle Size GroWth During Lyophilization,” U.S.
`
`Pat. No. 5,318,767 for “X-Ray Contrast Compositions Use
`ful in Medical Imaging,” US. Pat. No. 5,326,552 for “Novel
`Formulation For Nanoparticulate X-Ray Blood Pool Con
`trast Agents Using High Molecular Weight Non-ionic Sur
`factants,” US. Pat. No. 5,328,404 for “Method of X-Ray
`Imaging Using Iodinated Aromatic Propanedioates,” US.
`Pat. No. 5,336,507 for “Use of Charged Phospholipids to
`Reduce Nanoparticle Aggregation,” US. Pat. No. 5,340,564
`for “Formulations Comprising Olin 10-G to Prevent Particle
`Aggregation and Increase Stability,” US. Pat. No. 5,346,
`702 for “Use of Non-Ionic Cloud Point Modi?ers to Mini
`mize Nanoparticulate Aggregation During Sterilization,”
`US. Pat. No. 5,349,957 for “Preparation and Magnetic
`Properties of Very Small Magnetic-Dextran Particles,” US.
`Pat. No. 5,352,459 for “Use of Puri?ed Surface Modi?ers to
`Prevent Particle Aggregation During Sterilization,” US. Pat.
`Nos. 5,399,363 and 5,494,683, both for “Surface Modi?ed
`Anticancer Nanoparticles,” US. Pat. No. 5,401,492 for
`“Water Insoluble Non-Magnetic Manganese Particles as
`Magnetic Resonance Enhancement Agents,” US. Pat. No.
`5,429,824 for “Use of Tyloxapol as a Nanoparticulate Sta
`bilizer,” US. Pat. No. 5,447,710 for “Method for Making
`Nanoparticulate X-Ray Blood Pool Contrast Agents Using
`High Molecular Weight Non-ionic Surfactants,” US. Pat.
`No. 5,451,393 for “X-Ray Contrast Compositions Useful in
`Medical Imaging,” US. Pat. No. 5,466,440 for “Formula
`tions of Oral Gastrointestinal Diagnostic X-Ray Contrast
`Agents in Combination With Pharmaceutically Acceptable
`Clays,” US. Pat. No. 5,470,583 for “Method of Preparing
`Nanoparticle Compositions Containing Charged Phospho
`lipids to Reduce Aggregation,” US. Pat. No. 5,472,683 for
`“Nanoparticulate Diagnostic Mixed Carbamic Anhydrides
`as X-Ray Contrast Agents for Blood Pool and Lymphatic
`System Imaging,” US. Pat. No. 5,500,204 for “Nanopar
`ticulate Diagnostic Dimers as X-Ray Contrast Agents for
`Blood Pool and Lymphatic System Imaging,” US. Pat. No.
`5,518,738 for “Nanoparticulate NSAID Formulations,” US.
`Pat. No. 5,521,218 for “Nanoparticulate Iododipamide
`Derivatives for Use as X-Ray Contrast Agents,” US. Pat.
`No. 5,525,328 for “Nanoparticulate Diagnostic Diatrizoxy
`Ester X-Ray Contrast Agents for Blood Pool and Lymphatic
`System Imaging,” US. Pat. No. 5,543,133 for “Process of
`Preparing X-Ray Contrast Compositions Containing Nano
`particles,” US. Pat. No. 5,552,160 for “Surface Modi?ed
`NSAID Nanoparticles,” US. Pat. No. 5,560,931 for “For
`mulations of Compounds as Nanoparticulate Dispersions in
`Digestible Oils or Fatty Acids,” US. Pat. No. 5,565,188 for
`“Polyalkylene Block Copolymers as Surface Modi?ers for
`Nanoparticles,” US. Pat. No. 5,569,448 for “Sulfated Non
`ionic Block Copolymer Surfactant as Stabilizer Coatings for
`Nanoparticle Compositions,” US. Pat. No. 5,571,536 for
`“Formulations of Compounds as Nanoparticulate Disper
`sions in Digestible Oils or Fatty Acids,” US. Pat. No.
`5,573,749 for “Nanoparticulate Diagnostic Mixed Carboxy
`lic Anydrides as X-Ray Contrast Agents for Blood Pool and
`Lymphatic System Imaging,” US. Pat. No. 5,573,750 for
`“Diagnostic Imaging X-Ray Contrast Agents,” US. Pat. No.
`5,573,783 for “Redispersible Nanoparticulate Film Matrices
`With Protective Overcoats,” US. Pat. No. 5,580,579 for
`“Site-speci?c Adhesion Within the GI Tract Using Nano
`particles Stabilized by High Molecular Weight, Linear Poly
`(ethylene Oxide) Polymers,” US. Pat. No. 5,585,108 for
`“Formulations of Oral Gastrointestinal Therapeutic Agents
`in Combination With Pharmaceutically Acceptable Clays,”
`
`AQUESTIVE EXHIBIT 1022 page 0003
`
`

`

`US 2006/0198896 A1
`
`Sep. 7, 2006
`
`US. Pat. No. 5,587,143 for “Butylene Oxide-Ethylene
`Oxide Block Copolymers Surfactants as Stabilizer Coatings
`for Nanoparticulate Compositions,” US. Pat. No. 5,591,456
`for “Milled Naproxen With Hydroxypropyl Cellulose as
`Dispersion Stabilizer,” US. Pat. No. 5,593,657 for “Novel
`Barium Salt Formulations Stabilized by Non-ionic and
`Anionic Stabilizers,” US. Pat. No. 5,622,938 for “Sugar
`Based Surfactant for Nanocrystals,” US. Pat. No. 5,628,981
`for “Improved Formulations of Oral Gastrointestinal Diag
`nostic X-Ray Contrast Agents and Oral Gastrointestinal
`Therapeutic Agents,” US. Pat. No. 5,643,552 for “Nano
`particulate Diagnostic Mixed Carbonic Anhydrides as
`X-Ray Contrast Agents for Blood Pool and Lymphatic
`System Imaging,” US. Pat. No. 5,718,388 for “Continuous
`Method of Grinding Pharmaceutical Substances,” US. Pat.
`No. 5,718,919 for “Nanoparticles Containing the R(—)Enan
`tiomer of Ibuprofen,” US. Pat. No. 5,747,001 for “Aerosols
`Containing Beclomethasone Nanoparticle Dispersions,”
`US. Pat. No. 5,834,025 for “Reduction of Intravenously
`Administered Nanoparticulate
`Formulation Induced
`Adverse Physiological Reactions,” US. Pat. No. 6,045,829
`“Nanocrystalline Formulations of Human Immunode?
`ciency Virus (HIV) Protease Inhibitors Using Cellulosic
`Surface Stabilizers,” US. Pat. No. 6,068,858 for “Methods
`of Making Nanocrystalline Formulations of Human Immu
`node?ciency Virus (HIV) Protease Inhibitors Using Cellu
`losic Surface Stabilizers,” US. Pat. No. 6,153,225 for
`“Injectable Formulations of Nanoparticulate Naproxen,”
`US. Pat. No. 6,165,506 for “NeW Solid Dose Form of
`Nanoparticulate Naproxen,” US. Pat. No. 6,221,400 for
`“Methods of Treating Mammals Using Nanocrystalline For
`mulations of Human Immunode?ciency Virus (HIV) Pro
`tease Inhibitors,” US. Pat. No. 6,264,922 for “Nebulized
`Aerosols Containing Nanoparticle Dispersions,” US. Pat.
`No. 6,267,989 for “Methods for Preventing Crystal GroWth
`and Particle Aggregation in Nanoparticle Compositions,”
`US. Pat. No. 6,270,806 for “Use of PEG-Derivatized Lipids
`as Surface Stabilizers for Nanoparticulate Compositions,”
`US. Pat. No. 6,316,029 for “Rapidly Disintegrating Solid
`Oral Dosage Form,” US. Pat. No. 6,375,986 for “Solid Dose
`Nanoparticulate Compositions Comprising a Synergistic
`Combination of a Polymeric Surface Stabilizer and Dioctyl
`Sodium Sulfosuccinate,” US. Pat. No. 6,428,814 for “Bio
`adhesive Nanoparticulate Compositions Having Cationic
`Surface Stabilizers,” US. Pat. No. 6,431,478 for “Small
`Scale Mill,” US. Pat. No. 6,432,381 for “Methods for
`Targeting Drug Delivery to the Upper and/or LoWer Gas
`trointestinal Tract,” US. Pat. No. 6,582,285 for “Apparatus
`for Sanitary Wet Milling,” and US. Pat. No. 6,592,903 for
`“Nanoparticulate Dispersions Comprising a Synergistic
`Combination of a Polymeric Surface Stabilizer and Dioctyl
`Sodium Sulfosuccinate,” US. Pat. No. 6,656,504 for
`“Nanoparticulate Compositions Comprising Amorphous
`Cyclosporine,” US. Pat. No. 6,742,734 for “System and
`Method for Milling Materials,” US. Pat. No. 6,745,962 for
`“Small Scale Mill and Method Thereof,” US. Pat. No.
`6,811,767 for “Liquid droplet aerosols of nanoparticulate
`drugs,” and US. Pat. No. 6,908,626 for “Compositions
`having a combination of immediate release and controlled
`release characteristics,” all of Which are speci?cally incor
`porated by reference. In addition, US. patent application
`Ser. No. 20020012675 A1, published on Jan. 31, 2002, for
`“Controlled Release Nanoparticulate Compositions” and
`WO 02/098565 for “System and Method for Milling Mate
`
`rials,” describe nanoparticulate compositions, and are spe
`ci?cally incorporated by reference.
`[0026] In particular, documents referring to aerosols of
`nanoparticulate drugs include US. Pat. No. 5,747,001 for
`“Aerosols Containing Beclomethasone Nanoparticle Disper
`sions” and US. Pat. No. 6,264,922 for “Nebulized Aerosols
`Containing Nanoparticle Dispersions,” and documents refer
`ring to injectable compositions of nanoparticulate drugs
`include US. Pat. No. 6,153,225 for “Injectable Formulations
`of Nanoparticulate Naproxen,” and US. Pat. Nos. 5,399,363
`and 5,494,683, both for “Surface Modi?ed Anticancer
`Nanoparticles.” None of these documents describe inject
`able or aerosol compositions of a nanoparticulate benzodi
`azepine, such as lorazepam.
`[0027] Amorphous small particle compositions are
`described, for example, in US. Pat. No. 4,783,484 for
`“Particulate Composition and Use Thereof as Antimicrobial
`Agent,” US. Pat. No. 4,826,689 for “Method for Making
`Uniformly Sized Particles from Water-Insoluble Organic
`Compounds,” US. Pat. No. 4,997,454 for “Method for
`Making Uniformly-Sized Particles From Insoluble Com
`pounds,” US. Pat. No. 5,741,522 for “Ultrasmall, Non
`aggregated Porous Particles of Uniform Size for Entrapping
`Gas Bubbles Within and Methods,” and US. Pat. No.
`5,776,496, for “Ultrasmall Porous Particles for Enhancing
`Ultrasound Back Scatter” all of Which are speci?cally incor
`porated herein by reference.
`
`[0028] There remains a need in the art for improved
`dosage forms of benzodiazepines, such as lorazepam. The
`present invention satis?es this need.
`
`SUMMARY OF THE INVENTION
`
`[0029] The present invention is directed to the surprising
`and unexpected discovery of neW aerosol and injectable
`dosage forms of a nanoparticulate benzodiazepine, such as
`lorazepam. The formulations comprises a nanoparticulate
`benzodiazepine, such as nanoparticulate lorazepam, having
`an effective average particle size of less than about 2000 nm.
`The nanoparticulate benzodiazepine, such as lorazepam,
`preferably has at least one surface stabilizer either adsorbed
`onto or associated With the surface of the benzodizepine. In
`one embodiment of the invention, the surface stabilizer is a
`povidone polymer. Because lorazepam is practically
`insoluble in Water, signi?cant bioavailability can be prob
`lematic.
`
`[0030] In one embodiment there is provided an aerosol
`that delivers an optimal dosage of a benzodiazepine, such as
`lorazepam. The aerosols of the invention do not require a
`preservative such as benzyl alcohol, Which affects
`lorazepam stability.
`
`[0031] In another embodiment, a safe and effective inject
`able formulation of a benzodiazepine, such as lorazepam, is
`provided. The injectable formulation eliminates the need for
`propylene glycol and polyethylene glycol, such as polyoxyl
`60 hydrogenated castor oil (HCO-60), as solubilizers for
`injectable lorazepam compositions, and solves the problem
`of the insolubility of lorazepam in Water. This is bene?cial,
`as in convention non-nanoparticulate injectable benzodiaz
`epine formulations comprising polyoxyl 60 hydrogenated
`castor oil as a solubilizer, the presence of this solubilizer can
`lead to anaphylactic shock (i.e., severe allergic reaction) and
`
`AQUESTIVE EXHIBIT 1022 page 0004
`
`

`

`US 2006/0198896 A1
`
`Sep. 7, 2006
`
`death. The injectable dosage forms of the invention surpris
`ingly deliver the required therapeutic amount of the drug in
`vivo, and render the drug bioavailable in a rapid and
`constant manner, Which is required for effective human
`therapy. Moreover, the invention provides for compositions
`comprising high concentrations of a benZodiaZepine, such as
`loraZepam, in loW injection volumes, With rapid drug dis
`solution upon administration.
`
`[0032] The present invention is also directed to aqueous,
`propellant-based, and dry poWder aerosols of a nanoparticu
`late benZodiaZepine, such as loraZepam, for pulmonary and
`nasal delivery, in Which essentially every inhaled particle
`contains at least one nanoparticulate benZodiaZepine, such
`as loraZepam, nanoparticle. The nanoparticulate benZodiaZ
`epine, such as loraZepam, is highly Water-insoluble. Prefer
`ably,
`the nanoparticulate benZodiaZepine, such as
`loraZepam, has an effective average particle siZe of less than
`about 2 microns. Nanoparticulate aerosol formulations are
`described in Us. Pat. No. 6,811,767 to Bosch et al., spe
`ci?cally incorporated by reference. Non-aerosol prepara
`tions of submicron siZed Water-insoluble drugs are described
`in Us. Pat. No. 5,145,684 to Liversidge et al., speci?cally
`incorporated herein by reference.
`[0033] The invention also includes the folloWing embodi
`ments directed to aerosol formulations of a benZodiaZepine,
`such as loraZepam. One embodiment of the invention is
`directed to aqueous aerosols of nanoparticulate dispersion of
`a benZodiaZepine, such as loraZepam. Another embodiment
`of the invention is directed to dry poWder aerosol formula
`tions comprising a benZodiaZepine, such as loraZepam, for
`pulmonary and/or nasal administration. Yet another embodi
`ment of the invention is directed to a process and compo
`sition for propellant-based systems comprising a nanopar
`ticulate benZodiaZepine, such as loraZepam.
`[0034] The nanoparticulate benZodiaZepine, such as
`loraZepam, formulations of the invention may optionally
`include one or more pharmaceutically acceptable excipients,
`such as non-toxic physiologically acceptable liquid carriers,
`pH adjusting agents, or preservatives.
`[0035] In another aspect of the invention there is provided
`a method of preparing the nanoparticulate benZodiaZepine,
`such as loraZepam, injectable and aerosol formulations of
`the invention. The nanoparticulate dispersions used in mak
`ing aerosol and injectable nanoparticulate benZodiaZepine
`compositions can be made by Wet milling, homogeniZation,
`precipitation, or supercritical ?uid methods knoWn in the art.
`An exemplary method comprises: (1) dispersing a benZodi
`aZepine, such as loraZepam, in a liquid dispersion media;
`and (2) mechanically reducing the particle siZe of the
`benZodiaZepine to the desired effective average particle siZe,
`e.g., less than about 2000 nm. At least one surface stabiliZer
`can be added to the dispersion media either before, during,
`or after particle siZe reduction of the benZodiaZepine. In one
`embodiment for the injectable composition, the surface
`stabiliZer is a povidone polymer With a molecular Weight of
`less than about 40,000 daltons. Preferably, the liquid dis
`persion media is maintained at a physiologic pH, for
`example, Within the range of from about 3 to about 8, during
`the siZe reduction process. The nanoparticulate benZodiaZ
`epine dispersion can be used as an injectable formulation.
`[00