A new method and preparation for intranasal delivery of scopolamine provides a safe and effective treatment for motion sickness and other conditions requiring anticholinergic therapy. The preparation can be in the form of aqueous nasal drops, mist spray, gel or oinment. Intranasal delivery of scopolamine has similar bioavailability and effect of intravenous delivery and is far superior to oral dosage. Scopolamine is prepared in a buffered saline solution at the desired dosage rate for effective anticholinergic response

Cintron, Nitza M.

Putcha, Lakshmi

English

NASA Technical Reports Server

./
NASA CASE NO.:
PRINT FIG: I
MSC-21858-I
NOTICE
The invention disclosed in this document resulted from research in
aeronautical and space activities performed under programs of the National
Aeronautics and Space Administration. This invention is owned by NASA and is,
therefore, available for licensing in accordance with the NASA Patent Licensing
Regulations (14 CFR 1245.2).
In encourage commercial utilization of NASA-owned inventions, it is NASA
policy to grant licenses to commercial concerns. Although NASA encourages
nonexclusive licensing to promote competition and achieve the widest possible
utilization, NASA will consider the granting of a limited exclusive license,
pursuant to the NASA Patent Licensing Regulations, when such a license will
provide the necessary incentive to the licensee to achieve early practical
application of the invention.
Address inquiries and all applications for license for this invention to
NASA Patent Counsel, Lyndon B. Johnson Space Center, Code AL3, Houston, TX 77058.
Approved NASA forms for application of nonexclusive or exclusive license
are available from the above address.
Serial Number:
Date Filed:
07/765,615
September 25, 1991
JSC
(NASA-Case-v_SC-21:_f ip-] ) I,IP,_,,A]AL
SCIPCILA_!I_;F PRLPARATI !_ ANL _. T _'CF_ P-)t,=nt
Appl ic_tion (_A3A) 1l "- C_CL O:_i
https://ntrs.nasa.gov/search.jsp?R=19920002410 2020-03-17T15:18:42+00:00Z
AWARDS ABSTRACT
MSC-21858-I
Serial Number: 07/765,615
Filed: 9/25/91
MSC-21858-I
INTRANASAL SCOPOLAMINE PREPARATION AND METHOD
This invention relates to a new method and preparation for intranasal
delivery of scopolamine and provides a safe and effective treatment for motion
sickness and other conditions requiring anticholinergic therapy.
The new method and preparation has been found superior to the prior alter-
native drug delivery systems. The intranasal delivery is usually by nose drops,
nasal mist spray as a metered dosage delivery, or aerosol mist, although gel or
ointment preparations can be made. The intranasal delivery provides high bio-
availability without the drawback of drug induced amnesia by intravenous
delivery. The intranasal delivery can be performed by the patient without the
necessity for an invasive intravenous administration, The intranasal preparation
is inexpensive to formulate in multiple dose quantities as needed by the patient.
Scopolamine is prepared in a buffered saline solution at the desired dosage
rate for effective anticholinergic response. A dose of 0.4 mg is a satisfactory
rate. Doses up to at least 0.6 mg may be used. The solution is adjusted to pH
4±0.2. This formulation may be modified into other forms by adaptations known
by those skilled in the art of pharmaceutical preparations. The scopolamine
formulation is a nonirritant solution to the nasal cavity. The preparation
requires no special storage conditions or formulation equipment.
Inventors:
Employer:
Evaluator:
Lakshmi Putcha and Nitza M. Cintron
NASA Johnson Space Center
Deborah L. Harm, Ph.D.
MSC-21858-I PATENT APPLICATION
INTRANASAL SCOPOLAMINE PREPARATION AND METHOD
Origin of the Invention
The invention described herein was made by employees
of the United States Government and may be manufactured
and used by and for the Government of the United States of
America for governmental purposes without payment of any
royalties thereon or therefor.
Field of the Invention
The invention is a highly effective preparation and
i0 method of administering scopolamine with an intranasal
dosage. Scopolamine is an anticholinergic and is used as
a treatment for motion sickness, as a pre-operative drug
to inhibit body secretions and for other disorders re-
quiring anticholinergic therapy. The intranasal dosage is
15 more effective than oral doses and safer and easier to
administer than intravenous doses.
Background of the Invention
Scopolamine is an anticholinergic agent which affects
the parasympathetic nervous system. Anticholinergics are
20 well known and understood by pharmacologists and are sub-
stances that inhibit and have a highly selective blocking
action on effector organs innervated by postganglionic
cholinergic nerves. This nervous system controls bodily
secretions such as saliva and digestive juices. Scopoi-
25 amine has known antiemetic and antinausent properties and
has been used to treat motion sickness by oral administra-
tion and topical patch. Also, scopolamine is used as a
preoperative treatment, generally administered intrave-
nously, to inhibit secretions during anesthesia and sur-
30 gery.
1
MSC-21858-I PATENT APPLICATION
When administered orally, the bioavailability of sco-
polamine is significantly diminished because it is broken
down by the liver. The intravenous administration of sco-
polamine has drawbacks, because although the bioavailabil-
5 ity is high, the large dose can cause drug induced amnesia
in the patient. Alternative routes of scopolamine admin-
istration have been explored including skin patches and
buccal absorption. The skin patch technique is exempli-
fied in U. S. Patent Nos. 4,262,003 and 4,436,741, both
i0 issued to Urquhardt et al. on April 14, 1981 and March 13,
1984, respectively. The patch effects transdermal absorp-
tion of the drug, and the patient is recommended to apply
the patch about 3 hours prior to need. However, some
studies have indicated that transdermal scopolamine must
15 be used 8 hours prior to need. The manufacture of the
patch is expensive adding cost to the administration of
the drug. Buccal administration has also been used and,
although individual absorption rates of scopolamine vary
greatly, the individual adsorption by buccal and oral
20 ingestion is not significantly different.
Summary of the Invention
A new method and preparation for scopolamine for
intranasal delivery has been developed and found superior
to the prior alternative drug delivery systems. The
25 intranasal delivery is usually by nose drops, nasal mist
spray as a metered dosage delivery, or aerosol mist,
although gel or ointment preparations can be made. The
intranasal delivery provides high bioavailability without
the drawback of drug induced amnesia by intravenous deliv-
30 ery. The intranasal delivery can be performed by the
patient without the necessity for an invasive intravenous
MSC-21858-I PATENT APPLICATION
i0
15
administration. The intranasal preparation is inexpensive
to formulate in multiple dose quantities as needed by the
patient.
Scopolamine is prepared in a buffered saline solution
at the desired dosage rate for effective anticholinergic
response. A dose of 0.4 mg is a satisfactory rate. Doses
up to at least 0.6 mg may be used. The solution is ad-
justed to pH 4 ± 0.2. This formulation may be modified
into other forms by adaptations known by those skilled in
art of pharmaceutical preparations. The scopolamine
formulation is a nonirritant solution to the nasal cavity.
The preparation requires no special storage conditions or
formulation equipment.
Brief Description of the Drawing
Figure 1 is a comparison of bioavailability and
effect of scopolamine by intranasal and oral dosage.
Detailed Description of the Invention
The scopolamine or the salts of scopolamine are mixed
in an aqueous buffered solution. The formulation can be
20 used directly as nasal drops or packaged as a spray mist
with a metered delivery dosage with an appropriate vehi-
cle. Also, the formulation can be adapted for use as an
ointment, gel, or any other viscous delivery systems for
intranasal use. The invention generally involves the
25 effective delivery of scopolamine to the intranasal tis-
sue. Other intranasal preparations may be known and
developed by those skilled the art and not depart from the
disclosure, method or preparation of this invention.
An exemplary formulation includes the following
30 ingredients, prepared in the following manner. There are
known substitutions and equivalents to the ingredients
that may be used. A methylcellulose vehicle was prepared
by dissolving 20 mg of the methylcellulose in 800 ml of
3
MSC-21858-I PATENT APPLICATION
sterile sodium chloride 0.9% and stirred until dissolved.
To the methylcellulose vehicle 75 ml of the bacteriocide
benzalkonium chloride 1:750 aqueous solution was added.
Then 4000 mg of scopolamine hydrobromide was added by
5 stirring until dissolved. The pH was adjusted to 4 ± 0.2
with i:I00 phosphoric acid buffer. The final volume was
made up to i000 ml with 0.9% sodium chloride. The dose
amount is 0.4 mg scopolamine HBr per 0.1 ml 0.9% NaCI.
This preparation has a long shelf life and does not te-
l0 quire special storage conditions.
The formulation may be prepared with a dosage of 0.4
mg to at least 0.6 mg. The aqueous formulation may be
used directly as nose drops and are nonirritant to intra-
nasal tissue.
15 The therapeutic effectiveness of a medication is a
function of its bioavailability after administration. The
bioavailability of scopolamine by oral dosage was compared
to intranasal dosage. In addition, scopolamine was admin-
istered intravenously. For the test, 0.4 mg of scopol-
20 amine was administered intravenously, orally, and intra-
nasally to 12 healthy male subjects in a randomized cross-
over design test. Each treatment was two weeks apart.
Subjects fasted for i0 to 12 hours before scopolamine
administration. Water was allowed ad libitum except for
25 the period from three hours before to one hour after
dosing. An Intracath® I.V. was placed in the antecubital
vein of the subjects for blood sampling. Saliva samples
were collected using Sarstedt salivettes. The samples
were collected 2.5, 5, 10, 20, 30, 45, 60, 120, 240, 300,
30 360, 480, 600, and 720 minutes after administration of the
designated dosage form.
Plasma levels of scopolamine were determined by com-
bined reverse-phase liquid chromatography and
radioreceptor assay. Area Under the Concentration Curve
35 (AUC) was calculated from plasma concentration - time
4
MSC-21858-I PATENT APPLICATION
data. Salivary volume and pH were measured, and salivary
flow rate (SFR) was calculated for each sample. The
salivary gland secretions are inhibited by anticholinergic
agents. Percent suppression of control effect and Area
5 Under the Effect Curve (AUEC) were calculated from SFR -
time data. Absolute bioavailability of intranasal and
oral doses were calculated from the respective AUCs and
AUECs.
TABLE 1 below is a summary of the data for each of
i0 the subject's scopolamine bioavailability calculated from
plasma data showing the significant contrast between oral
delivery characterized by low to negligible
bioavailability and intranasal with high bioavailability.
The data is summarized with mean and the standard error of
15 the mean.
TABLE 1
AREA UNDER PLASMA CONCENTRATION (AUC)
Time Curve of Scopolamine
After Administration of a 0.4mg Dose
20 Subject # Intravenous Intranasal Oral
25
30
1 9515 920
2 1814 2119
3 2854 1905
4 3823 4196
5 4732 2602
6 3013 2098
7 3659 2146
8 2420 3221
9 3520 2345
i0 1676 2000
ii 4016 2301
12 4107 3114
126.9
92.7
65.3
329.2
135.7
35 Mean ±
Standard Error
3762 ± 588 2414 ± 235 72.0 +_ 26.2
TABLE 2 below is a summary of the data for saliva
flow which is inhibited by scopolamine. The data shows
comparable saliva flow decrease for intravenous and
5
MSC-21858-I PATENT APPLICATION
intranasal delivery with significantly lower effect by
oral delivery. The data is summarized with the means and
standard error of the mean.
TABLE 2
AREA UNDER PERCENT OF CONTROL (AUEC) SALIVARY FLOW RATE
AFTER SCOPOLAMINE (0.4 MG) ADMINISTRATION
Subject # Intravenous Intranasal Oral
1 276.8 195.8 0
I0 2 440.4 321.9 237.5
3 352.8 284.7 73.2
4 329.5 316.5 105.7
5 373.8 413.5 362.1
6 338.5 336.5 100.3
15 7 149.0 211.6 27.0
8 191.2 284.9 0
9 400.1 405.5 219.6
I0 452.9 409.9 326.6
II 474.0 426.4 291.5
20 12 400.4 249.3 74.3
Mean ± 348.3 ± 19.0 321.4 ± 23.1 151.5 ±
43.7
Standard Error
25 Figure 1 is a summary comparison of the
bioavailability (AUC) of intranasal and oral scopolamine
from plasma levels of each dosage type. Figure 1 also
shows a comparison of the saliva suppression (AUEC) data.
The oral dose had lower than 10% bioavailability ex-
30 hibiting less than 40% saliva suppression as compared to
90% bioavailability and 95% suppression of saliva for
intranasal dosage. The standard deviation is represented
by the "I" above each box of the graph.
Plasma concentration-time profiles of scopolamine
35 after intravenous and intranasal administration were
similar with comparable AUC values. Scopolamine plasma
concentrations after oral dosage were significantly lower
than intravenous or intranasal doses. The data showed
MSC-21858-I PATENTAPPLICATION
high bioavailability of intranasal as compared to oral
scopolamine. Both intranasal and oral absorption of
scopolamine was rapid with peak concentrations occurring
within one hour after dosing. However, the percent
5 bioavailability was drastically different with 90% of the
intranasal dose bioavailable as compared to less than 10%
of the oral dose bioavailable.
The pharmacodymanic effect as a function of route of
administration was determined from saliva flow rate (SFR)
i0 measurements after dosing. The intranasal dose produced a
maximum effect of 95% inhibition of SFR as compared to
99.7% produced by the intravenous route with similar
duration and effect. The maximum inhibition by the oral
dose was less than 40%. The maximum effect was 1.05 hours
15 after intranasal dosage which correlates to its plasma
concentration peak.
Results show that intranasal scopolamine is a highly
bioavailable and effective source of scopolamine. It may
be administered as a noninvasive, reliable, fast and
20 effective treatment for motion sickness and for other
disorders or conditions requiring anticholinergic therapy.
7
MSC-21858-I PATENT APPLICATION
ABSTRACT
5
A new method and preparation for intranasal delivery
of scopolamine provides a safe and effective treatment for
motion-sickness and other conditions requiring
anticholinergic therapy. The preparation can be in the
form of aqueous nasal drops, mist spray, gel or oinment.
Intranasal delivery of scopolamine has similar
bioavailability and effect of intravenous delivery and is
far superior to oral dosage.
AUEC (%)
0 0 0 0 0 0 0 0 0 0 0 0
,- 0 O_ O0 I'.- (9 I_ _I" rO o4 ,,-
I I I I I I I I I I I" '
I"--
I I I I I I I I I !
0 0 0 0 0 0 0 0 0 0
0 O_ _ I'.- (9 I_ _" I'O o,I ,-"
Z
0
I
W
a.
A
--W
JC)
'_ 03....
0
-5
d
m
_z
0
AUC (%)


Intranasal scopolamine preparation and method

Abstract

Similar works

Full text

Available Versions

NASA Technical Reports Server