U.S. patent application number 11/376979 was filed with the patent office on 2006-07-06 for system and method for intranasal administration of lorazepam.
Invention is credited to Daniel P. Wermeling.
Application Number | 20060147386 11/376979 |
Document ID | / |
Family ID | 25149925 |
Filed Date | 2006-07-06 |
United States Patent
Application |
20060147386 |
Kind Code |
A1 |
Wermeling; Daniel P. |
July 6, 2006 |
System and method for intranasal administration of lorazepam
Abstract
A therapeutic composition of lorazepam and its pharmaceutically
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.
Inventors: |
Wermeling; Daniel P.;
(Lexington, KY) |
Correspondence
Address: |
MAYER, BROWN, ROWE & MAW LLP
P.O. BOX 2828
CHICAGO
IL
60690-2828
US
|
Family ID: |
25149925 |
Appl. No.: |
11/376979 |
Filed: |
March 16, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10418260 |
Apr 15, 2003 |
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11376979 |
Mar 16, 2006 |
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09790199 |
Feb 20, 2001 |
6610271 |
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10418260 |
Apr 15, 2003 |
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09569125 |
May 10, 2000 |
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09790199 |
Feb 20, 2001 |
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Current U.S.
Class: |
424/45 |
Current CPC
Class: |
A61K 31/485 20130101;
A61K 9/0043 20130101; A61K 31/55 20130101; A61P 25/22 20180101;
A61K 47/10 20130101; A61P 25/20 20180101 |
Class at
Publication: |
424/045 |
International
Class: |
A61L 9/04 20060101
A61L009/04 |
Claims
1. A pharmaceutical composition for intranasal administration to a
mammal in the form of a controlled unit-dose liquid spray to
produce a pharmacologically induced sedative-anxiolytic
physiological response in the mammal, the composition comprising:
lorazepam; a physiologically acceptable non-aqueous, organic liquid
solvent-carrier for the lorazepam; and a preservative, wherein the
liquid composition forming a spray when discharged from a manually
actuated spray device.
2. The composition of claim 1, wherein the solvent-carrier is
selected from the group consisting of polyethylene glycol,
propylene glycol, and mixtures thereof.
3. The sprayable composition of claim 1, wherein the
solvent-carrier constitutes a minor proportion of the
composition.
4. The composition of claim 2, wherein the solvent carrier
comprises polyethylene glycol having an average molecular weight of
about 400.
5. The composition of claim 2, wherein the polyethylene glycol
constitutes from about 15% to about 25% by volume and the propylene
glycol from about 75% to about 85% by volume of the liquid
composition.
6. The composition of claim 5, wherein the polyethylene glycol
constitutes about 20% by volume and the polpylene glycol about 80%
by volume of the liquid composition.
7. The composition of claim 6, wherein the solvent-carrier is
polyethylene glycol having an average molecular weight of about
400.
8. The composition of claim 6, wherein the lorazepam is present at
a concentration of 1.0 mg/0.1 mL of liquid.
9. The composition of claim 1 which further includes an additive
selected from the group consisting of preservatives, artificial
sweeteners, flavors, and combinations thereof.
10. A sprayable liquid pharmaceutical composition for the
controlled intranasal administration in the form of at least one
unit-dose to a mammal for the purpose of producing a
sedative-anxiolytic response in the mammal, the composition
comprising: lorazepam; a physiologically acceptable non-aqueous
solvent for the lorazepam; and a preservative, wherein the
lorazepam is present in the liquid composition at a concentration
of about 1.0 mg/0.1 mL.
11. The composition of claim 10 which further includes a
physiologically acceptable liquid solute for the lorazepam
solvent.
12. The composition of claim 11, wherein the solute for the
lorazepam solvent is propylene glycol water.
13. The composition of claim 12, wherein the lorazepam solvent is
polyethylene glycol having a number average molecular weight of
about 400.
14. The composition of claim 13, wherein the ratio of polyethylene
glycol to propylene glycol is about four-to-one.
15. The composition of claim 13, wherein the solvent constitutes
about 80% by volume and the propylene glycol about 18% by
volume.
16. The composition of claim 10 which further includes an
artificial sweetener selected from the group consisting of
saccharin and aspartame.
17. The composition of claim 16, wherein the sweetener is
saccharin.
18. The composition of claim 10 which further includes a
preservative.
19. The composition of claim 18, wherein the preservative is
butglated hydroxytokrene.
20. A method of treating a mammal exhibiting symptoms of
anxiety-related disorders, said mammal requiring treatment, the
method comprising the steps of: a. providing a controlled dose
intranasal spray delivery device; b. filling the delivery device
with a sprayable liquid composition, the liquid composition
comprising: lorazepam, a physiologically acceptable solvent-carrier
for the lorazepam; and c. administering a predetermined measured
dose of the liquid lorazepam--containing composition intranasally
to the mammal requiring treatment by spraying the liquid
composition droplets from the delivery device into at least one of
the mammal's nostrils.
21. The method of claim 20, wherein the dose is administered by
manually activating the delivery device.
22. The method of claim 20, wherein the predetermined dose is
administered by spraying the lorazepam-containing composition first
in one nostril and then in the other.
23. The method of claim 20, wherein the mammal is an adult human
and the predetermined dose is two mg. of lorazepam.
24. The method of claim 20, wherein the sprayable liquid
composition is prepared by dissolving lorazepam in an organic
solvent selected from the group consisting of polyethylene glycol
400, propylene glycol, and mixtures thereof, and adding the
lorazepam solution to the delivery device under aseptic
conditions.
25. The method of claim 20 which includes the further step of
sterilizing the delivery device before addition of the liquid
composition.
Description
FIELD OF THE INVENTION
[0001] The invention relates to pharmaceutical drug compositions
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
[0002] Lorazepam preparations for the treatment of anxiety-related
disorders and to induce sedation have been previously approved by
the U.S. Food and Drug Administration ("FDA") and have been
long-used for oral, intra-muscular 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.
[0003] It has been reported that, following oral administration,
peak plasma concentrations of approximately 25 ng/mL 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-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.)
[0004] The intranasal route of administration also provides
numerous advantages over intravenous (IV) and intramuscular (IM)
injections. One principal advantage of intranasal administration is
convenience. An injectable system requires sterilization of the
hypodermic syringe and in the institutional setting, leads to
concerns among medical personnel about the risk of contracting
disease if the they are accidentally 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 and the attending medical
personnel, and is far less burdensome on the institution than
injectables. There is no significant risk of infection of medical
personnel or others in the institutional setting that is associated
with nasal spray devices.
[0005] A second important advantage of intranasal administration
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 cases, the after-effects of the injection include
burning, edema, swelling, turgidity, hardness and soreness. In
contrast, intranasal administration is perceived as non-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 can self-administer the prescribed dosage(s) of
nasal spray. An empty nasal spray device, or one containing a
non-medicated solution can be given to the patient to practice the
technique for proper insertion, inhalation and activation for
self-administration.
[0006] 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 fact that
preparations for oral, IM and IV administration have been approved
for commercial use for many years.
[0007] 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 compounds are
commercially available to physicians to prescribe and dispense to
their patients in that form.
[0008] Furthermore, only one multiple-dose spray device has
apparently been approved by the FDA for intranasal administration
of an opiate solution that is categorized as a controlled
substance. The devices that are presently available 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 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 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.
[0009] 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, 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.
[0010] 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 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 containing an opiate compound classed as a
"controlled substance" by the FDA were found to be capable of
administering 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.
OBJECTS OF THE INVENTION
[0011] 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
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.
[0012] 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.
[0013] 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 anxiety to the patient occasioned by
administration.
[0014] It is another object of this invention to provide an
intranasal 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 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.
[0015] It is also an object of the invention to provide the novel
and improved combination of a device for intranasal administration
and a formulation for lorazepam that meet the requirements for FDA
approval.
[0016] Yet another object of the invention is to provide such novel
lorazepam compositions for intranasal administration in a
relatively small and inexpensive, manually operated, self-contained
hand-held disposable device that retains essentially no significant
quantity of the therapeutic composition after administration of the
one or more unit-doses as prescribed.
[0017] A further object of the invention is to provide a
comprehensive method for providing a novel therapeutic composition
for intranasal administration that contains lorazepam in a form
that exhibits the same pharmacological activity as lorazepam
compositions that are approved for oral, IM 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.
[0018] As used herein, the term "essentially no significant
quantity of the therapeutic composition" means none, or a trace
amount, or an amount that is so small that it cannot be recovered
for a subsequent unintended use or abuse after the prescribed
use.
[0019] As used herein, the term "spray" means the liquid
composition 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.
[0020] As used herein, "lorazepam" means lorazepam and its active
pharmaceutically acceptable derivatives and metabolites.
SUMMARY OF THE INVENTION
[0021] The improved lorazepam composition for intranasal spray
administration is prepared by dissolving lorazepam in polyethylene
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 80% propylene glycol 2 by volume.
[0022] The invention further comprehends the intranasal
administration 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 composition 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 sedation and
administration to children.
[0023] The lorazepam compositions administered in accordance with
the method and system of the invention exhibit systemic
pharmacological effects following absorption from the nasal mucosa.
As will be shown below, the novel pharmaceutical 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.
[0024] 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 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.
[0025] 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 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 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
preservatives 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.
[0026] The lorazepam composition of the invention is also
compatible with the delivery system. The lorazepam compositions 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 temperatures; and without exceeding the
internal pressure limits of the delivery system at higher
temperatures.
[0027] The predetermined therapeutic volume of the pharmaceutical
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 predetermined quantity of lorazepam to
classes of patients for 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.
[0028] Dispensing devices meeting the above criteria and technical
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 capability 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
operable 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.
[0029] 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 manufactured and filled
devices.
[0030] In accordance with the invention, the orifice of a
commercial 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 aerosol. The size of
the orifice is optimized in relation to the viscosity of the
lorazepam composition.
[0031] 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 for the liquid
lorazepam composition and metal components, preferably of stainless
steel, that form elements of the delivery system. Such devices are
compact, relatively inexpensive and can be discarded after the
prescribed use. In a preferred embodiment, the container and its
sealing means are sterilizable; most preferably, the entire device
is constructed from materials that can be sterilized.
[0032] 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
[0033] 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 following detailed
description and in conjunction with the accompanying drawings, in
which:
[0034] FIG. 1 is a graphic representation of the concentration of
lorazepam in blood plasma versus time for IV, IM and IN doses;
and
[0035] FIG. 2 is a graphic representation of the data of FIG. 1
over a longer time period.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0036] 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 provide the desired
unit-dose in a total sprayed liquid volume that can be delivered by
the device and accommodated and 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.RTM., includes 2 mg of
lorazepam in 0.18 mL of polyethylene glycol 400 in 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.
[0037] A suitable composition for use in the invention was prepared
as follows.
[0038] 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 polyethylene 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 artificial sweeter is also dissolved in the composition. The
final composition was as follows: TABLE-US-00001 lorazepam 10.0 mg
polyethylene glycol 400 0.18 mL propylene glycol 0.809 mL butylate
hydroxytolune 0.1 mg saccharin (powder) 1.0 mg
[0039] 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 actuation 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.
[0040] 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 substantially 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.
[0041] 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.
[0042] The lorazepam nasal spray applicators are preferably stored
at temperatures in the range of 2.degree.-8.degree. C.
(36.degree.-48.degree. F.) and are protected from light to provide
for maximum shelf life. If the applicator body is not transparent,
visual inspection 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 preservative
will serve to extend the shelf life, as will storage under
refrigeration. In the last case, the products and dispenser should
be brought to room temperature before administration. Any expired
product is discarded in the appropriate manner.
[0043] 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 of lorazepam in
0.1 mL. The composition was used to fill the required number of
single-dose, metered sprayers commercially 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.
[0044] 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 administration. The product was
Ativan.RTM. Injection for parental administration sold by Wyeth
Laboratories, (a Wyeth-Ayerst Company.) Each mL of Ativan.RTM.
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.
[0045] Each of the applicators was weighed prior to use and after
use. Qualified medical personnel took the respective applicators to
subjects in a clinical setting; one dose was administered up each
nostril, after which the applicator was 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
about five minutes. Syringes were weighed before and after
administration. Further details of the protocol, and the results of
these studies of the methods and system of the invention and the
comparative prior art method follow.
Unit-Dose:
[0046] A statistical comparison of dose 1 and dose 2 for the
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 statistically significant. (This
analysis excluded data from one of the devices that
malfunctioned.)
Investigational Methods
[0047] A clinical study was undertaken for the purposes of (1) to
assessing the absolute bioavailability of lorazepam by comparing
the pharmacokinetics of 2.0 mg lorazepam administered by intranasal
(IN) and intravenous (IV) routes; and (2) to compare
pharmacokinetic parameters via IN administration to intramuscular
(IM) and intravenous administration. This was undertaken as a
single-dose, open-label, three-way crossover, randomized, pilot
bioavailability study of lorazepam comparing intranasal
administration in healthy human volunteers.
[0048] 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 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.
[0049] The subjects were within .+-.20% of ideal body weight and no
history of allergies, acute or chronic nasal symptoms, significant
nasal surgery or abnormalities were reported.
[0050] Eleven of the twelve subjects completed the study according
to the protocol. Each of the subjects received 3 doses of 2 mg of
lorazepam on three separate occasions. No clinically significant
protocol violations occurred during this study. The inclusion
criteria mentioned abstinence from prescription 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 alcoholic and
caffeine-containing beverages for 48 hours before the dosing period
and during the study.
Clinical Trials
Study Drug Formulation
[0051] Lorazepam for intranasal administration was supplied by the
University of Kentucky College of Pharmacy. Lorazepam for
intravenous administration ("IV") was supplied as Ativan.RTM. 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") was supplied as Ativan.RTM. 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, the
dosages for each of the three routes of administration were as
follows:
[0052] Treatment A: 2.0 mg intravenous lorazepam;
[0053] Treatment B: 2.0 mg intramuscular lorazepam; and
[0054] Treatment C: 2.0 mg intranasal lorazepam solution
Study Drug Administration
[0055] 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
[0056] Weight, blood pressure, and pulse were measured prior to
dosing and at the end of the study. Blood pressure and pulse rate
were measured with the subjects seated in an upright position
before any corresponding blood sample was collected. 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.
[0057] The three treatments were separated by one-week washout
period. The subject (#02) whose doses were delayed received the
final dose within one month of the first dose, was dosed with the
other subjects during their first and third periods and received
the final treatment two weeks later. She was dosed in the treatment
order to which she was randomized.
Clinical Adverse Events
[0058] Spontaneously reported adverse events were recorded by the
subjects throughout the study; adverse events were also elicited by
nondirected interviews.
Sample Collection and Handling
[0059] Blood samples for the three treatments were collected from
each subject according to the following schedule: 0 (pre-dose), 5,
15, 30 and 45 minutes, and 1, 2, 3, 4, 8, 12, 18, 24 and 36 hours
following lorazepam administration. The beginning of the IV
administration was considered time zero. After collection, the
blood was centrifuged in a refrigerated centrifuge at 4.degree. C.
to separate the plasma and the cells, and the plasma was
transferred to polypropylene tubes. The plasma was stored at
approximately -70.degree. C. at the study site until shipped to an
independent analytical service. The plasma was maintained frozen
during shipping and upon arrival at the remote analytical facility,
the samples were stored at approximately -20.degree. C. until
analyzed.
Bioanalytical Methods
LC/MS/MS Assay for lorazepam
[0060] The sample analysis using an LC/MS/MS assay was performed by
an independent service in accordance with established protocols.
The analytic range for the lorazepam method was 0.10 ng to 25.00
ng/mL using 1.0 mL of human plasma. Concentrations less than 1.10
ng/mL were reported as below quantitation limit (BQL). Samples with
concentrations greater than 25 ng/mL were reanalyzed using a
dilution so that the assayed concentration was within the range of
0.10 ng to 25.00 ng/mL.
Pharmacokinetic Methods
[0061] Plasma concentration versus time date for lorazepam were
analyzed using noncompartmental pharmacokinetic methods.
Pharmacokinetic parameters were determined using standard
noncompartmental methods with log-linear least square regression
analysis to determine the elimination rate constants (WinNonlin,
Pharsight Corp., Palo Alto, Calif.). The areas under the
concentration versus time curves from time zero to infinity
(AUC.sub.0-.infin.) were calculated by a combination of the linear
and logarithmic trapezoidal rules,-with extrapolation to infinity
by dividing the last measurable serum concentration by the
elimination rate constant (.lamda..sub.Z) (Proost, 1985). Values
for the maximum concentration (C.sub.max) and time to
[0062] C.sub.max (T.sub.max) were determined by visual inspection
of concentration versus time data for each subject. The elimination
half-life was determined from 0.693/.lamda..sub.Z. The absolute
bioavailability (F) for the IN and IM dosage forms, assuming equal
2 mg doses, was determined by
F=AUC.sub.IN,0-.infin./AUC.sub.IV,0-.infin. for the IN dose and
F=AUC.sub.IM,0-.infin./AUC.sub.IV,0-/.infin. for the IM dose.
Clearance (CL for IV and CL/F for IN and IM doses) was determined
by dividing the dose by AUC.sub.0-.infin.. Volume of distribution
at steady state and for elimination (V.sub.SS and V.sub.Z) were
determined by moment curves (Gibaldi and Perrier, 1982).
TABLE-US-00002 TABLE 1 Mean (CV as a %) pharmacokinetic parameters
following administration of 2 mg intravenous (IV infusion over 5
min), intranasal (IN) and intramuscular (IM) lorazepam doses in 11
healthy volunteers. Parameter 2 mg IV 2 mg IM 2 mg IN T.sub.max
(hrs*) 0.1 3.0 0.5 (0.083 to 1.017) (0.5 to 8.017) (0.25 to 2)
C.sub.max (ng/mL) 47.57 (57.8) 22.58 (28.9) 21.38 (24.3) t.sub.1/2
(hr) 16.6 (27.3) 17.4 (38.1) 18.5 (28.3) AUC.sub.0-4 (ng hr/mL)
386.8 (19.4) 372.8 (16.4) 288.0 (25.4) AUC.sub.0-.infin. 500.8
(30.8) 506.2 (33.7) 393.5 (38.0) (ng hr/mL) CL or CL/F (L/hr) 4.3
(27.0) 4.3 (28.5) 5.7 (31.8) V.sub.ss (L) 93.2 (11.9) -- -- V.sub.z
or V.sub.z/F (L) 97.8 (15.2) 99.2 (10.8) 140.1 (16.8) F (%) assume
100% 100.9 (10.2) 77.7 (11.1) *median and range given for
T.sub.max
[0063] Table 1 is a summary of pharmacokinetic data for the three
doses. Absorption of lorazepam following IN administration was
rapid as indicated by the fact that concentrations were detected in
all subjects within five minutes after the IN administration. The
median T.sub.max values were 30 minutes and three hours for the IN
and IM doses, respectively. On average, 0.1091 g (CV 5.6%, n=21)
was dispensed from the individual spray pumps as determined by the
difference in the pre- and post-weights. (This data excludes one
malfuctioning device of the 22 devices used in this study.) The
mean plasma concentration versus time curve profiles for the IV, IM
and IN doses are shown in FIG. 1. Plasma concentrations were still
detectable 36 hours after administration.
[0064] FIGS. 1 and 2 are plots of the mean (n=11) plasma lorazepam
concentration versus time graphs following three treatments: (A)
2.0 mg lorazepam by five minutes IV infusion, (B) 2.0 mg lorazepam
IN dose and (C) 2.0 mg lorazepam IM dose. FIG. 1 shows the results
over the period following administration; FIG. 2 is the same data
for the 36 hours following administration.
Safety Results
[0065] Results of the clinical measurement of vital signs and body
weight exams were recorded and nasal exams were performed. A review
of this data failed to reveal any clinically significant safety
concerns. There were no serious adverse events and no subjects were
discontinued due to adverse effects. Subjects commented that they
experienced a mild bad taste immediately after the IN dose. Any
safety concerns associated with IN are similar to those associated
with IV administration.
[0066] Detailed nasal examination demonstrated no pathology of the
naso-pharynx after single administration of the lorazepam
formulations.
Pharmacokinetic Results
[0067] The plasma lorazepam concentrations and actual collection
times for each of the 11 subjects was tabulated and plasma
concentration-time curves for each of the 11 subjects were
prepared. The mean concentration-time curves of FIGS. 1 and 2 are
representative for most subjects (mean data tabulation). FIG. 1 is
a plot of the mean (n=11) lorazepam concentration versus time
graphs following IV, IM and IN doses of 2 mg lorazepam during the 4
hours after dose; FIG. 2 is the same data plotted for 36 hours
after the dose.
[0068] Noncompartmental pharmacokinetic analysis was used to
evaluate the plasma concentration versus time curves of lorazepam
following single 2.0 mg doses of lorazepam by intravenous (IV),
intramuscular (IM), and intranasal (IN) routes. Individual plasma
lorazepam concentration versus time profiles for all subjects were
recorded; number of time points used to estimate the elimination
rate constant were also recorded; and a complete listing of
individual and mean pharmacokinetic parameters for all 11 subjects
was recorded. Table 1 is a summary of the descriptive statistics
for lorazepam pharmacokinetic parameters.
[0069] Rapid absorption of lorazepam was observed after the IV and
IN doses. The T.sub.max values were approximately 9 and 18 minutes,
on average, for the IM and IN doses, respectively. The mean
T.sub.max for the IV infusion was not the first blood sample after
the end of the infusion for two reasons. The peak concentration
after the IV dose in one subject was not at the first blood sample
after the end of the IV infusion, but at the next time point. In
the case of Subject 4, acquiring the blood sample immediately
following the IV infusion was delayed resulting in the mean
T.sub.max being affected. As expected, the lorazepam C.sub.max and
AUCs were significantly higher after IM and IV administration
compared to IN administration. Mean plasma half-lives and clearance
after correcting for bioavailability, were similar for all three
treatments.
[0070] The arithmetic mean value of absolute bioavailability of
lorazepam (11 subjects) for the IN formulation is 78%. The plasma
levels were comparable to those of the IM dose.
[0071] From the above, it will be understood that a novel
composition and method is provided for the safe and controlled
intra-nasal administration of precise doses of lorazepam in
accordance with a medically prescribed regimen.
* * * * *