(12) United States Patent
`Wermeling
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006610271B2
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,610,271 B2
`Aug. 26, 2003
`
`(54) SYSTEM AND METHOD FOR INTRANASAL
`ADMINISTRATION OF LORAZEPAM
`
`(75)
`
`Inventor: Daniel P. Wermeling, Lexington, KY
`(US)
`
`(73) Assignee: University of Kentucky Research
`Foundation, Lexington, KY (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/790,199
`
`(22) Filed:
`
`Feb.20,2001
`
`(65)
`
`Prior Publication Data
`
`US 2001/0055571 A1 Dec. 27, 2001
`
`Related U.S. Application Data
`
`(51)
`
`(63) Continuation-in-part of application No. 09/569,125, filed on
`May 10, 2000, now abandoned.
`Int. Cl? .......................... A61N 25/02; A61K 9/00;
`A61K 1!55; A61L 9/04
`(52) U.S. Cl. .......................... 424/43; 514/219; 514/220
`(58) Field of Search ............................ 424/401, 44, 43;
`514/219, 220
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,950,664 A * 8/1990 Goldberg .................... 514/219
`
`5,132,114 A * 7/1992 Stanley eta!. .............. 424/440
`5,307,953 A * 5/1994 Regan ......................... 222/82
`5,397, 771 A * 3/1995 Bechgaard et a!.
`. . . . . . . . . . . . 514/2
`5,428,006 A * 6/1995 Bechgaard eta!. ............ 514/3
`5,693,608 A * 12/1997 Bechgaard eta!. ............ 514/2
`6,015,797 A * 1!2000 Camborde eta!. ............ 514/46
`RE36,744 E * 6/2000 Goldberg .................... 514/219
`6,193,985 B1 * 2/2001 Sonne ........................ 424/400
`6,228,383 B1 * 5/2001 Hansen et a!. .............. 424/407
`6,255,502 B1 * 7/2001 Penkler et a!. .............. 552!549
`6,274,635 B1 * 8/2001 Travis ........................ 514/885
`
`wo
`
`FOREIGN PATENT DOCUMENTS
`* 3/1990
`
`90/02737
`
`* cited by examiner
`
`Primary Examiner---Sreeni Padmanabhan
`Assistant Examiner-Lauren Q. Wells
`(74) Attorney, Agent, or Firm-Milton Springut; William
`D. Schmidt; Kalow & Springut LLP
`
`(57)
`
`ABSTRACT
`
`A therapeutic composition of lorazepam and its pharmaceu(cid:173)
`tically acceptable derivatives are provided for intranasal
`administration of at least one predetermined volumetric unit
`dose in the form of a spray by means that delivers one or
`more therapeutically prescribed unit doses that are highly
`accurate as to the volume discharged and which leave no
`significant quantity of the composition in the delivery
`means.
`
`28 Claims, 1 Drawing Sheet
`
`Neurelis - EX. 2014
`Aquestive Therapeutics, Inv. v. Neurelis, Inc. - IPR2019-00451
`
`

`

`

`

`US 6,610,271 B2
`
`1
`SYSTEM AND METHOD FOR INTRANASAL
`ADMINISTRATION OF LORAZEPAM
`
`This Application is a Continuation-in-Part of co-pending
`application Ser. No. 09/569,125, filed May 10, 2000, now 5
`abandoned.
`
`FIELD OF THE INVENTION
`
`The invention relates to pharmaceutical drug composi(cid:173)
`tions and preparations of lorazepam. This invention also
`relates to pharmaceutical drug delivery devices, specifically
`to devices for the intranasal administration of lorazepam.
`
`BACKGROUND OF THE INVENTION
`
`2
`contrast, intranasal administration is perceived as non(cid:173)
`invasive, is not accompanied by pain, has no significant
`after-effects and produces the gratification of prompt relief
`in the patient exhibiting the symptom. This is of particular
`advantage when the patient is a child. Most people have
`some familiarity with nasal sprays in the form of over-the-
`counter decongestants for alleviating the symptoms of colds
`and allergies that they or a family member have used
`routinely. Another important consideration is that the patient
`10 can self-administer the prescribed dosage(s) of nasal spray.
`An empty nasal spray device, or one containing a non(cid:173)
`medicated solution can be given to the patient to practice the
`technique for proper insertion, inhalation and activation for
`self-administration.
`In view of the aforementioned advantages and benefits
`afforded by the intranasal administration, it would be
`expected that a preparation of lorazepam exhibiting systemic
`pharmacological activity would presently be available for
`intranasal administration. This has not occurred, despite the
`20 fact that preparations for oral, IM and IV administration
`have been approved for commercial use for many years.
`Despite the remarkable commercial success that has been
`enjoyed by those drugs that have been made available in
`intranasal form, in fact, only a very limited number of
`25 compounds are commercially available to physicians to
`prescribe and dispense to their patients in that form.
`Furthermore, only one multiple-dose spray device has
`apparently been approved by the FDA for intranasal admin(cid:173)
`istration of an opiate solution that is categorized as a
`controlled substance. The devices that are presently avail-
`able exhibit several deficiencies. One spray device intended
`for multiple uses must be primed before use by expelling a
`portion of the liquid contents in order to assure that the pump
`mechanism and delivery tube are filled. Up to seven or eight
`activations are required to prime the device. It is also
`indicated that further priming to disperse one or two sprays
`is to be performed if the device is not used for 48 hours or
`longer. These procedures necessarily result in the dispenser
`being overfilled in order to assure that there will be sufficient
`liquid to deliver the labelled number of doses. It has been
`found that a substantial volume of the controlled substance
`often remains in the device, even after the labelled number
`of doses have been administered. In practice, it has also been
`45 found that medical personnel and workers at health care
`facilities routinely abscond with the dispensers, sometimes
`after the patient has had only one or a few of the prescribed
`doses in a multi-dose container. This improper use of
`controlled substances as so-called "recreational drugs" is
`50 well-known among medical facility managers and law
`enforcement authorities. So far as is presently known, no
`preventative measures have been reported that are effective
`in dealing with this problem.
`A further problem resides in dispensing to a patient
`intranasal spray devices with sufficient fluid contents for
`numerous doses for anxiety control purposes. Because a
`patient suffering from a disorder and exhibiting anxiety may
`not act rationally in self-administering a drug for relief of the
`symptom, there is a potential for overdosing. Moreover,
`60 because of the nature and construction of these multiple dose
`spray devices, medical personnel cannot easily determine
`the number of doses that have been administered by a simple
`visual inspection of the device.
`Another problem that has recently been identified in
`clinical studies is the relative inaccuracy of multi-dose
`intranasal delivery devices that are currently being marketed
`with opiate solutions for the control of pain. Not only does
`
`15
`
`30
`
`Lorazepam preparations for the treatment of anxiety-
`related disorders and to induce sedation have been previ(cid:173)
`ously approved by the U.S. Food and Drug Administration
`("FDA") and have been long-used for oral, intramuscular
`and/or intravenous administration. Lorazepam is currently
`marketed in injectable and tablet formulations. Marketers of
`these preparations have not sought regulatory approval from
`the FDA for liquid compositions of the same therapeutic
`compound for intranasal administration. This is surprising
`since it is well-known from the literature that the intranasal
`administration of a pharmacologically active compound
`generally results in a more rapid bioavailability of the
`compound, or of its desired active metabolite than if the
`compound is administered orally. Moreover, the time
`required to achieve the same concentration of the active
`compound in the bloodstream e.g., within a period of about
`thirty minutes after administration, is generally less via the
`intranasal route compared to oral administration.
`It has been reported that, following oral administration,
`peak plasma concentrations of approximately 25 ng/mL 35
`were not observed until approximately 2.4 hours after
`administration with a bioavailability of 99.8%. (Greenblat,
`et al., Journal of Pharmaceutical Sciences, Vol. 66, No. 1
`(1979).) It has also been reported that, following intranasal
`administration of lorazepam in a Cremophor EL, a non- 40
`aqueous vehicle, the time to peak plasma concentration was
`1.4 hours with a bioavailability of 51%. (Lau and Slattery,
`International Journal of Pharmaceuticals, 54 (1989)
`171-174.)
`The intranasal route of administration also provides
`numerous advantages over intravenous (IV) and intramus(cid:173)
`cular (IM) injections. One principal advantage of intranasal
`administration is convenience. An injectable system requires
`sterilization of the hypodermic syringe and in the institu(cid:173)
`tional setting, leads to concerns among medical personnel
`about the risk of contracting disease if the they are acciden(cid:173)
`tally stuck by a contaminated needle. Strict requirements for
`the safe disposal of the used needle and syringe must also be
`imposed in the institutional setting. In contrast, intranasal
`administration requires little time on the part of the patient 55
`and the attending medical personnel, and is far less burden(cid:173)
`some on the institution than injectables. There is no signifi(cid:173)
`cant risk of infection of medical personnel or others in the
`institutional setting that is associated with nasal spray
`devices.
`A second important advantage of intranasal administra(cid:173)
`tion over IM and IV is patient acceptance of the drug
`delivery system. Many, if not most, patients experience
`anxiety and exhibit symptoms of stress when faced with
`hypodermic injections via the IM or IV routes. In some 65
`cases, the after-effects of the injection include burning,
`edema, swelling, turgidity, hardness and soreness. In
`
`Neurelis - EX. 2014
`Aquestive Therapeutics, Inv. v. Neurelis, Inc. - IPR2019-00451
`
`

`

`US 6,610,271 B2
`
`3
`the average volume of liquid spray actually administered fall
`about 10% below the purported dosage appearing on the
`approved label for one such product, significant variations
`were also observed among a series of administrations by
`each patient in the study group. Thus, spray devices tested 5
`containing an opiate compound classed as a "controlled
`substance" by the FDA were found to be capable of admin(cid:173)
`istering only about 90% by volume of the prescribed dosage,
`on average, and the dosage actually received by each patient
`in repeated administrations exhibited substantial significant
`variations of from 60% to 130% of the claimed label dosage.
`
`10
`
`4
`amount, or an amount that is so small that it cannot be
`recovered for a subsequent unintended use or abuse after the
`prescribed use.
`As used herein, the term "spray" means the liquid com(cid:173)
`position expressed from the device under pressure in the
`form of an aerosol, a fine mist, liquid droplets, a fine stream,
`and combinations of two or more of the above forms. It will
`be understood that the precise form of the composition is
`dependent upon the viscosity and other physical properties
`of the composition and the manner in which the manual or
`other force is applied to the device to discharge the liquid
`composition. A heterogenous spray is acceptable so long as
`the sprayed volume is effectively adsorbed by the nasal
`mucosa.
`As used herein, "lorazepam" means lorazepam and its
`active pharmaceutically acceptable derivatives and metabo(cid:173)
`lites.
`
`SUMMARY OF THE INVENTION
`
`30
`
`35
`
`OBJECTS OF THE INVENTION
`Accordingly, it is a principal object of the invention to
`provide a novel therapeutic composition of lorazepam and
`its pharmaceutical by acceptable derivatives for intranasal 15
`administration of at least one predetermined volumetric unit
`dose in the form of a spray by means that delivers one or
`more therapeutically prescribed unit doses that are highly
`accurate as to the volume discharged and which leave no
`significant quantity of the composition in the delivery 20
`means.
`Another object of the invention is to provide a novel
`composition comprising lorazepam, a known compound that
`is approved for oral, IM and/or IV administration, for use in
`a highly accurate and reproducible intranasal spray delivery
`system in a single unit-dose or therapeutically prescribed
`multiple unit-dose.
`It is a further object of this invention to provide an
`improved intranasal dosage composition and method of
`administration of lorazepam that exhibits a relatively rapid
`onset, moderate duration of therapeutic activity, minimal
`side effects, improved bioavailability, ease and safety of
`administration, and minimal physical discomfort and anxi-
`ety to the patient occasioned by administration.
`It is another object of this invention to provide an intra(cid:173)
`nasal delivery system for one or more unit doses of novel
`therapeutic compositions containing lorazepam that permits
`administration of one or more therapeutically prescribed
`unit-doses in a medical care facility, such as a hospital, day 40
`clinic, or doctor or dentist's office in which the delivery
`system contains essentially no significant quantity of the
`therapeutic composition after administration of the single
`unit-dose or the prescribed number of multiple unit-doses.
`It is also an object of the invention to provide the novel 45
`and improved combination of a device for intranasal admin(cid:173)
`istration and a formulation for lorazepam that meet the
`requirements for FDA approval.
`Yet another object of the invention is to provide such
`novellorazepam compositions for intranasal administration 50
`in a relatively small and inexpensive, manually operated,
`self-contained hand-held disposable device that retains
`essentially no significant quantity of the therapeutic com(cid:173)
`position after administration of the one or more unit-doses as
`prescribed.
`A further object of the invention is to provide a compre(cid:173)
`hensive method for providing a novel therapeutic composi(cid:173)
`tion for intranasal administration that contains lorazepam in
`a form that exhibits the same pharmacological activity as
`lorazepam compositions that are approved for oral, IM 60
`and/or IV administration, the intranasal composition being
`available for delivery in highly accurate and reproducible
`predetermined unit-doses leaving essentially no significant
`quantity of the therapeutic composition after administration
`of the prescribed number of unit-doses.
`As used herein, the term "essentially no significant quan(cid:173)
`tity of the therapeutic composition" means none, or a trace
`
`The improved lorazepam composition for intranasal spray
`administration is prepared by dissolving lorazepam in poly(cid:173)
`ethylene glycol having an average molecular weight of 400,
`["PEG 400" ] and diluting the solution with propylene
`glycol to a final composition of about 20% PEG 400 and
`25 80% propylene glycol 2 by volume.
`The invention further comprehends the intranasal admin(cid:173)
`istration of the lorazepam composition in the form of a spray
`in a unit-dose of a predetermined therapeutic volume, where
`substantially all of the predetermined volume of the com(cid:173)
`position is sprayed from delivery means within a specified
`narrow range of accuracy, while leaving essentially no
`significant quantity of the therapeutic composition in the
`applicator from the unit-dose as administered. The dose is
`administered principally in the form of liquid droplets, that
`may be accompanied by a minor proportion of an atomized
`mist or an aerosol. Application to the nasal mucosa of a
`subject requiring treatment is consistent with the current
`therapeutic use of lorazepam for treatment of anxiety-related
`disorders, and especially useful when acute administration is
`indicated. Such indications include sedation of agitated
`and/or demented patients pre-operative surgical/dental sed a(cid:173)
`tion and administration to children.
`The lorazepam compositions administered in accordance
`with the method and system of the invention exhibit sys(cid:173)
`temic pharmacological effects following absorption from the
`nasal mucosa. As will be shown below, the novel pharma(cid:173)
`ceutical composition provide the lorazepam in a form that is
`readily absorbable by the nasal mucosa without damaging or
`irritating the mucosa, or producing an allergic, or other
`unacceptable reaction in the recipient.
`The lorazepam compounds for use in the practice of the
`invention comprise a pharmacologically acceptable carrier
`that can be nasally administered with safety over the entire
`55 reasonably foreseeable range of prescribed users of the
`composition. It has been found that the addition of water to
`the composition reduces the stability of the lorazepam. It is
`therefore preferred that the liquid composition be non-
`aqueous. Compatible organic solvents ar preferred.
`In one preferred embodiment, the lorazepam composition
`includes minor proportion of an artificial sweetener. The
`purpose of the artificial sweetener is to counteract or mask
`the otherwise bitter taste that the subject can experience if
`the composition reaches the taste buds. Flavor extracts can
`65 also be included in the composition, either in addition to or
`in place of an artificial sweetener to mask the after taste of
`the lorazepam composition. The composition preferably has
`
`Neurelis - EX. 2014
`Aquestive Therapeutics, Inv. v. Neurelis, Inc. - IPR2019-00451
`
`

`

`US 6,610,271 B2
`
`6
`The preparation of the lorazepam composition and its
`aseptic filling into containers and the assembly of the filled
`containers in the spray devices must be completed under
`aseptic conditions since the lorazepam cannot withstand
`terminal sterilization without decomposition. Spray devices
`can be sterilized before filing, along with the intended
`packaging, employing methods and technology that are well
`known in the art.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`5
`
`The novel features and other advantages of the present
`invention, in addition to those mentioned above, will
`become apparent to those skilled in the art from the follow-
`15 ing detailed description and in conjunction with the accom(cid:173)
`panying drawings, in which:
`FIG. 1 is a graphic representation of the concentration of
`lorazepam in blood plasma versus time for IV, IM and IN
`doses; and
`FIG. 2 is a graphic representation of the data of FIG. 1
`over a longer time period.
`
`20
`
`5
`a shelf life in the chosen delivery system of at least six
`months, and most preferably greater than two years.
`Optionally, the composition can include one or more pre(cid:173)
`servatives of the type approved for use in pharmaceutical
`compositions. The preservative is preferably an anti-
`oxidant. One preservative that has been found particularly
`suitable is butylate hydroxytolune, which can be added at the
`rate of 0.1 mg/mL.
`The lorazepam composition of the invention is also com(cid:173)
`patible with the delivery system. The lorazepam composi- 10
`tions for use in the invention are formulated to deliver the
`dose within the foreseeable temperature ranges of exposure,
`e.g., without becoming too viscous to be administered in the
`proper form by the device, or crystallizing at lower tem(cid:173)
`peratures; and without exceeding the internal pressure limits
`of the delivery system at higher temperatures.
`The predetermined therapeutic volume of the pharmaceu(cid:173)
`tical composition contained in the unit dose is delimited by
`several parameters, including the capability of the nasal
`passage to receive and absorb the volumetric quantity of
`spray; and the solubility of the particular lorazepam in the
`physiologically and pharmacologically acceptable carrier
`liquid at the concentration required to achieve the desired
`effect. The relative safety of administering a given prede(cid:173)
`termined quantity of lorazepam to classes of patients for 25
`anxiety-related disorders or for sedation, whose body
`weight, age, general health, use of other medications may
`vary widely and can be determined by methods well known
`in the art.
`Dispensing devices meeting the above criteria and tech(cid:173)
`nical specifications have been provided in accordance with
`the invention by modifying commercially available devices,
`such as those sold by Pfeiffer of America of Princeton, N.J.
`and Valois of America, Inc. of Greenwich, Conn. When
`modified as described below, such devices have the capa(cid:173)
`bility of consistently delivering a predetermined volumetric
`amount of a liquid composition intranasally via a unit-dose
`dispenser that is manually operable by the patient requiring
`such intranasal drug administration. These manually oper(cid:173)
`able devices are designed for delivery of a single unit-dose,
`after which there is essentially significant quantity of the
`therapeutic composition remaining in the device. The device
`can thereafter be discarded without concern that others may
`abuse the controlled substance.
`Commercial spray devices can be provided with enough
`pharmacologically active composition to administer one
`predetermined unit-dose or two unit-doses ("bi-dose"), each
`with a high degree of accuracy and reproducibility for the
`device and among a plurality of such commercially manu(cid:173)
`factured and filled devices.
`In accordance with the invention, the orifice of a com(cid:173)
`mercial spray applicator was enlarged and the swirl chamber
`is retained in order to produce a spray that is principally in
`the form of liquid droplets that coat the nares. A minor
`proportion of the product may be in the form of a mist or 55
`aerosol. The size of the orifice is optimized in relation to the
`viscosity of the lorazepam composition.
`Devices that are suitable for use in the practice of the
`invention are fabricated from a variety of polymeric
`materials, and can also include glass or polymer containers 60
`for the liquid lorazepam composition and metal components,
`preferably of stainless steel, that form elements of the
`delivery system. Such devices are compact, relatively inex(cid:173)
`pensive and can be discarded after the prescribed use. In a
`preferred embodiment, the container and its sealing means 65
`are sterilizable; most preferably, the entire device is con(cid:173)
`structed from materials that can be sterilized.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENT
`
`A suitable liquid composition for use in a spray device for
`intranasal administration includes a solvent in which the
`desired concentration of lorazepam can be attained to pro(cid:173)
`vide the desired unit-dose in a total sprayed liquid volume
`that can be delivered by the device and accommodated and
`30 absorbed by the subject's nasal mucosa. Lorazepam is
`insoluble in water. A commercially available injectable
`composition approved by the FDA and sold by Wyeth
`Laboratories under the brand name Ativan®, includes 2 mg
`of lorazepam in 0.18 mL of polyethylene glycol 400 in
`35 propylene glycol with 2.0% benzyl alcohol as a preservative.
`This composition was not acceptable for intranasal spray
`administration because benzyl alcohol is irritating to the
`mucosa.
`A suitable composition for use in the invention was
`prepared as follows.
`Lorazepam was formulated in a liquid composition for
`use in the practice of the invention. Since lorazepam is
`insoluble in water, the lorazepam was dissolved in polyeth-
`45 ylene glycol having an average molecular weight of about
`400 ("PEG400"), and the solution diluted with propylene
`glycol. In order to provide for shelf-life stability over a
`period of up to six-months under typical conditions, a
`preservative can be added. In a preferred embodiment, an
`50 artificial sweeter is also dissolved in the composition. The
`final composition was as follows:
`
`40
`
`lorazepam
`polyethylene glycol 400
`propylene glycol
`butylate hydroxytolune
`saccharin (powder)
`
`10.0 mg
`0.18 mL
`0.809 mL
`0.1 mg
`1.0 mg
`
`The lorazepam is preferably prepared in the form of a
`single or unit-dose nasal spray for intranasal administration
`by a precision dosage manually-activated pump. Each 1 ml
`of nasal spray solution is preferably formulated to contain 10
`mg lorazepam. In a preferred delivery system, each actua(cid:173)
`tion of the nasal spray pump delivers 0.1 ml of this 10 mg/ml
`hm solution constituting a 1 mg dose. A smaller dose of the
`lorazepam HCl can be administered to children.
`
`Neurelis - EX. 2014
`Aquestive Therapeutics, Inv. v. Neurelis, Inc. - IPR2019-00451
`
`

`

`US 6,610,271 B2
`
`7
`As will be understood by those familiar with the art,
`dosage forms at lower concentrations of lorazepam can be
`prepared for administration based upon the patient's lower
`body weight, as in the case of children or adults of substan(cid:173)
`tially smaller size. The nasal spray solution has a pH in the
`range of from about 3 to about 7, with a pH of about 5 being
`preferred.
`The lorazepam composition was placed in containers
`adapted for use with modified Pfeiffer dispensers identified
`by model/part numbers as 52020/BSK 7482. The intranasal
`applicators of the prior art are modified by increasing the
`size of the discharge orifice in nose piece to about 0.07 mm
`from about 0.05 mm in diameter (which is typical for an
`aqueous solution), i.e., a 40% increase in diameter. This
`increase is necessary to accommodate the higher viscosity of
`the composition of the invention. The swirl chamber of the
`prior art precision spray dispenser can be retained. The
`applicator components are sterilized by methods well known
`in the art. As will be understood by those of ordinary skill
`in the art, other changes in the design and/or construction of
`the spray dispenser can be made to accommodate and
`discharge the more viscous composition of the invention.
`The lorazepam nasal spray applicators are preferably
`stored at temperatures in the range of 2°-8° C. (36°-48° F.)
`and are protected from light to provide for maximum shelf
`life. If the applicator body is not transparent, visual inspec(cid:173)
`tion of the drug product for signs of deterioration is not
`possible and attention to the expiration date and storage
`conditions is important. The optional inclusion of a preser(cid:173)
`vative will serve to extend the shelf life, as will storage
`under refrigeration. In the last case, the products and dis(cid:173)
`penser should be brought to room temperature before admin(cid:173)
`istration. Any expired product is discarded in the appropriate
`manner.
`A formulation of lorazepam for intranasal administration
`was prepared as described above under aseptic conditions in
`the form of a liquid composition at a concentration of 1.0 mg
`oflorazepam in 0.1 mL. The composition was used to fill the
`required number of single-dose, metered sprayers commer(cid:173)
`cially produced and sold by Pfeiffer of America, Inc., each
`of which sprayers first having been modified as described
`above. The filling of the containers and their assembly is
`completed under aseptic conditions since the lorazepam
`composition cannot withstand the heat of sterilization.
`Each subject received a single spray in each nostril for a
`total of 2.0 mg. A 2.0 mg dose is preferred as being within
`common, safe and labeled doses prescribed. Commercially
`available lorazepam was purchased for IM and IV admin(cid:173)
`istration. The product was Ativan® Injection for parental
`administration sold by Wyeth Laboratories, (a Wyeth-Ayerst
`Company.) Each mL ofAtivan® Injection is formulated with
`2 mg of lorazepam in 0.18 mL PEG400 in propylene glycol
`with 2.0% benzyl alcohol as a preservative. The IV doses
`were diluted according to the label instructions by adding
`one mL of water.
`Each of the applicators was weighed prior to use and after
`use. Qualified medical personnel took the respective appli(cid:173)
`cators to subjects in a clinical setting; one dose was admin(cid:173)
`istered up each nostril, after which the applicator was 60
`recovered for weighing. Each subject used two Pfeiffer unit
`dose spray devices, both of which were discarded following
`the post-use weighing. The IV doses were administered
`through antecubital veins on the arm opposite to the arm
`from which samples were taken, injecting the solution over 65
`about five minutes. Syringes were weighed before and after
`administration. Further details of the protocol, and the
`
`8
`results of these studies of the methods and system of the
`invention and the comparative prior art method follow.
`Unit-Dose:
`A statistical comparison of dose 1 and dose 2 for the
`5 Pfeiffer unit dose delivery system was done using a paired
`t-test. Analysis of the data for normally functioning devices
`indicated that the difference between the mean sprays of the
`two applications using the Pfeiffer device was not statisti(cid:173)
`cally significant. (This analysis excluded data from one of
`10 the devices that malfunctioned.)
`Investigational Methods
`A clinical study was undertaken for the purposes of (1) to
`assessing the absolute bioavailability of lorazepam by com(cid:173)
`paring the pharmacokinetics of 2.0 mg lorazepam adminis-
`15 tered by intranasal (IN) and intravenous (IV) routes; and (2)
`to compare pharmacokinetic parameters via IN administra(cid:173)
`tion to intramuscular (IM) and intravenous administration.
`This was undertaken as a single-dose, open-label, three-way
`crossover, randomized, pilot bioavailability study of
`20 lorazepam comparing intranasal administration in healthy
`human volunteers.
`Twelve healthy non-smoking subjects (six male and six
`female) between the ages of 18 and 35 years were initially
`selected for this inpatient study. One subject left the study
`25 and one subject received delayed doses. Study participants
`were selected based on inclusion/exclusion criteria, history
`and physical exam, laboratory tests, and other customary
`procedures.
`The subjects were within ±20% of ideal body weight and
`30 no history of allergies, acute or chronic nasal symptoms,
`significant nasal surgery or abnormalities were reported.
`Eleven of the twelve subjects completed the study accord(cid:173)
`ing to the protocol. Each of the subjects received 3 doses of
`2 mg of lorazepam on three separate occasions. No clinically
`35 significant protocol violations occurred during this study.
`The inclusion criteria mentioned abstinence from prescrip(cid:173)
`tion and non-prescription drugs prior to and during the study,
`and any medications taken in the 14 days before the study
`and during the study were noted. Subjects abstained from
`40 alcoholic and caffeine-containing beverages for 48 hours
`before the dosing period and during the study.
`Clinical Trials
`Study Drug Formulation
`Lorazepam for intranasal administration was supplied by
`45 the University of Kentucky College of Pharmacy.
`Lorazepam for intravenous administration ("IV") was sup(cid:173)
`plied as Ativan® 1 mg/mL for subjects 1, 3, 8, and 9 on the
`first day and for subjects 2, 4, 5, 6, and 7 on the second study
`day. Lorazepam for intramuscular administration ("IM")
`50 was supplied as Ativan® 2 mg/mL for subjects 2, 4, 5, 6 and
`7 on first study day and for subjects 1, 3, 8 and 9 on the
`second study day. Free base content was 1.77 mg or 88.7%
`of stated lorazepam strength (from molecular weights:
`321.8-36.46=285.34, 285.34/321.8=88.7%) To summarize,
`55 the dosages for each of the three routes of administration
`were as follows:
`Treatment A: 2.0 mg intravenous lorazepam;
`Treatment B: 2.0 mg intramuscular lorazepam; and
`Treatment C: 2.0 mg intranasal lorazepam solution
`Study Drug Administration
`Drug administration occurred at approximately 0800
`hours following overnight fasting. Subjects were allowed up
`to 360 mL of juice or soft drink one hour before each dose,
`but were not allowed to eat for one hour after their dose.
`Safety Measures
`Weight, blood pressure, and pulse were measured prior to
`dosing and at the end of the study. Blood pressure and pulse
`
`Neurelis - EX. 2014
`Aquestive Therapeutics, Inv. v. Neurelis, Inc. - IPR2019-00451
`
`

`

`US 6,610,271 B2
`
`5
`
`10
`
`15
`
`9
`rate were measured with the subjects seated in an upright
`position before any corresponding blood sample was col(cid:173)
`lected. Blood pressure and pulse rate were measured and
`recorded on the same arm throughout the study at 0 (pre-
`dose) and 30 minutes, 1, 2, 4, 8, and 16 hours.
`The three treatments were separated by one-week wash(cid:173)
`out