Note: Descriptions are shown in the official language in which they were submitted.
I ~ ~r~ 3
Improvemen~s in or relating to nasal pharmaceutical
compositions
This invention relates to nasal pharmaceutical
compositionsO
The practice of nasally administering some
pharmacologically active agents such as broncholytics and
hormones to a~tain systemic absorption has been known for a
long time [see pages 722-729 in "Pharmazeutische Technologie"
edi~ed by H. Sucker, P. Fuchs and P. Speiser, Georg Thieme
Verlag, Stuttgart, 1978]. Nasal systemic administration of
pharmacologically active agents may offer significant
advantages over other routes of administration. For example,
after passing through the nasal mucous membrane the active
agent enters the blood stream directly, thus leading to
immediate bioavailability of active agent in the blood and a
rapid onset of therapeutic action. Nasal aerosol applicators
capable of providing a precise dose of the active agent in
liquid or powder spray form of suitable droplet or particle
size for nasal administration are available which are easy to
use~ However, the nasal route of systemic administration of
pharmacologically active agents is still uncommon.
UK Patent Specification Number 1,592,563 discloses
that certain ergot cyclic peptide alkaloids may be beneficially
administered by the nasal route. Nasal pharmaceutical
compositions of dihydroergotamine, in particular in the form of
.p, ~. .
;,
- 2
liquids and powders, are disclosed which can be used to
provide a suitable spray. A representatlve nasal pharmaceutical
composition contemplated by the above mentloned Patent
Specification is an aqueous solution containiny per ml 4 mg
dihydroergotamine mesylate, 50 mg ethanol and 150 mg glycerine,
and this composition is hereinafter referred to as the
"reference" solution.
Often pharmaceutical compositions formulated for
nasal administration turn out to be unsatisfactory in wide-
spread clinical use. For example they may be unstable over along period of time, not well tolerated or not well accepted
by patientsc An important factor for bad tolerance may be
-that a constituent of the composition, perhaps the active
agent, depresses the ciliary function.
The aix passage cilia are microscopic hairlike
structures about 7 microns in length and 1 to 3 microns in
diameter. These cilia are on the surface layer of the mucus
membrane in the nose and in the trachea. The cilia perform
undulatory motions at a frequency beat of about 300-90~ cycles
per minute at 37~C that propel mucus together with dust particles
and other foreign matter towards the passages at the back of
the nose (choanae) which communicate with the pharanx or
forwards towards the nostril openings. The particles and
matter are thus either swallowed or sneezed away. The mucus
layer may move at a rate of about 2 to 10 mm per minute in
some animals. Studies made by I.B. Andersen et al in American
Review of Respiratory Disease 106, 438 (1977) an average mucus
flow rate of 4.8 mm per minute was found in a group of humans.
The individual flow rates varied from 0 to 23.6 mm per rninute.
It will readily be appreciated that any substance
that depresses the ciliary function in-terferes with one of the
major protective mechanisms of the body.
The extent to which a nasally administered agent
depresses the ciliary function may be observed in standard
tests, e.g. in vitro, using the ciliary trachea of animals.
One reproducible and sensi-tive test is as follows:-
J1.~2 ~1
The trachea or nasal sept~lm of a guinea piy orrabbit is removed immediately after sacrifice. The oryan is
immersed in physiological balance serum (Dulbecco) at 23C.
A tubular fragment, e.g. of 3 tracheal rings, is removed and
the ciliary epithelium is scraped therefrom The bea-ting
frequency of cilia at one particular point ls measured by
` microphoto-oscillographic techni~ues according to the principles
of L. Chevance et al, Acta Otolaryng, 70, 16~28, (1970) wherein
the cilia are observed and magnified 500 timesO A change in
beating frequency indicates a change in ciliary function.
Some pharmacologically ac-tive agents in particular
dihydroergotamine depress the ciliary function. Thus
application (about 0.1 to 0.3 ml) of the "reference" solution
or an aqueous solution containing 4 mg dihydroergotamine
mesylate per ml to the cilia results in an irreversible
depression of cilia beating within 2 minutes after application.
Moreover we have found that non-toxic agents which
increase the ciliary function, in particular xanthines, e.g.
which increase the ciliary beating frequency in the above
test, may be used to at ]east partially counteract the ciliary
function depressant effects of other constituents in a
pharmaceutical composition, and provide clinically well
tolerated nasal pharmaceutical compositions.
; The present invention accordingly provides a nasal
2S pharmaceutical composition incorporating a pharmacologically
active agent, the active agent or any other constituent present
being capable of inducing, as a side effect, the depression
of ciliary function and also containing a non-toxic agent
which is capable of increasing the ciliary functiorl.
The present invention furthermore provides nasal
; co-administration of a pharmacologically active agent which is
capable of depressing ciliary function and a non--toxic agent
which is capable of increasing the ciliary function. The
invention also provides a method of nasally adminis-tering a
pharmacologically active agent which is capable of
` depressing ciliary function characterised by nasal co-
administration with a non-toxic agen-t which is capable of
increasing the ciliary function, e.g. onto -the nasal mucus
:', .~;
~37'ô~3
membrane. Furthermore, the invention provides a nasal
pharmaceu-tical composition comprising dihydroergotamine and
a non-toxic agen-t which is capable of increasing the eiliary
function. Such nasal pharmaceutical compositions will be
most preferably in the form of a li~uid or a powder.
Agents whieh increase eiliary function may be
determined by in vitro tests, e.g. the above mentioned test,
and suitably produce a 20~ or greater increase in ciliary
function 20 minutes after administra-tion. The ehoice of agent
is not critical so long as it is pharmacologically acceptable.
The amount of ciliary function increasing agent present in
tne composition will naturally depend on the amounts of
other constituents whieh depress the ciliary function, the
solubility of the agent and the extent to which they depress
the ciliary function. Preferred amounts of ciliary
increasing agent in the nasal pharmaeeutieal eomposition may
be determined by routine experimentation, e.g. using the
above mentioned in vitro test.
A xanthine is especially e~fective in antagonising
the depression of eiliary funetion, eOg. indueed by a
pharmaeologieally aetive agent. We have also found tha-t sueh
xanthines are well tolerated on nasal administration. Further-
more nasal pharmaeeutical eompositions containing sueh
xanthines may be made which are liquid solutions stable against
e.g. deeomposition, precipitation ou-t or discolouration at an
aceeptable osmolarity and pH, and which may be sterilized
easily.
Accordingly in another aspect the present invention
provides nasal co-administration of a xanthine with a
pharmaceutieally active agent which is capable of depressing
eiliary function. In yet another aspect the present
invention provides a method of nasally systemically
administering a pharmaeologically active agent which is
capable of depressing ciliary function charaeterised by co-
administration with a xanthine. In a further aspect thepresent invention provides a nasal pharmaceutical composition
eomprising a pharmacologieally active agent which is capable of
depressing ciliary function, and a xanthine.
The pharmacologically active agent may be for
~.~ a~3~
example an active agent which is capable of being systemically
~sorbed thro~gh the nasal mucus membrane an~ passing into the
body circulation. The active agent should of course be non-
toxic.
The present invention is particularly suitable for
use with active agents which significantly depress ciliary
beating in the in vitro test as described above, e.g. show a
50% or greater reduction of ciliary beating 20 minutes after
application of the dose of active agent.
As indicated above the pharmacologically active
agent is preferably an ergot cyclic peptide al~aloid product
disclosed as formula I in UK Patent Specification Number
1,592,563, and is especially dihydroergotamine.
The active agent may be administered in free base
form or in pharmaceutically acceptable acid addition salt form,
e.g. the mesylate. Such salts in general have the same order
of activity as the active agent. For example dihydroergot-
amine may be administered in the form of the mesyla-te.
The particular therapeutic effect exhibited by the
pharmacologically active agent is not critical. In view of
the xapid increase in active agent concentration in the blood
after nasal administration, the nasal pharmaceutical
compositions of the invention are specially suitable for
administration of active agents for -the treatment of conditions
which require quick relief, e.g. particularly orthostatic hypo-
tension and especially migraine.
The dosage of pharmacologically active agent to be
administered will naturally vary from compound -to compound.
In general a satisfactory dosage is one which provides -the
same order of bioavailability or therapeutic effect as that
obtainable by injecting a therapeutically effec-tive amount of
the active agent. Often the nasal route requires smaller
dosages than the oral route to obtain the same effect e.g.
a nasal dosage may be from about 0.5 to about 0.01 times the
oral dose. For example with dihydroergotamine 1 mg
administered nasally produces the roughly same quantita-tive
effect (as indiaated by bioavailability studies or vaso-
contriction of hand veins) as 10 mg dihydroergotamine
, '
, ;~,
administered orally. For dihydroergotamine the preferxed
amount to be administered nasalLy is in the order of from
about 0.25 to 5 mg.
Naturally the dose of active agent should not be
so high or the dosage repea-ted so of-ten that ~ide effects
might occur.
The choice of xanthine is not critical. Any xanthine
may be used, for example a xanthine of formula
O R
~ 1 1
o~ N ~ N
R2
wherein Rl, R2 and R3 are chosen from hydrogen or alkyl
' :LO (Cl-10~-
Such xanthines are in general known. Examples of
suitable xanthines include theophylline and the preferred
xanthine is caffeine.
The exact amount of xanthine r or other agent
capable of increasing the ciliary function~ to be administered
in a dose will depend, inter alia, on the extent to which
the pharmacologically active agent and any other constituent
present in the nasal pharmaceutical composition depresses
the ciliary function. ~he ratio of active agent to
xanthine or other ciliary increasing agent may vary within
wide limits and may be determined by routine experimentation.
suitable ratio is from about 0.1:1 to about 10:1. It is
pre~erred to use the minimum amount of xanthine or other agent
capable of increasing the ciliary function to bring the ciliary
25 function to within 50 to 100% of the base value (of untreated
cilia) within 20 minutes after application in -the above
mentioned in vitxo ciliaxy function testO
, ,
3'~
Satisfactory results have been obtained with ~rom abou-t 1 mg
to about 5 mg xanthine per dose.
The nasal composition may contain, e.g. about 0.2 to
about 2%, more preferably 0.5% to 2%, by weigh-t of xanthine,
e.g. in a liquid of e.g. 4 g dihydroergotamine per litre.
It is preferred to administer a nasal spray which
is isotonic, or is slightly hypertonic, with respect to the
ciliary mucus. Convenien-tly the osmo-tic pressure of liquid
providing the spray is from about 200 ko 600 mOsm, especially
; 10 from 280 to 360 mOsm, per litre. The desired osmotic pressure
may be obtained by the addition of any conventional non--toxic
isotonizing agent.
Sodium chloride mayfor example be used. Preferably a non-
toxic sugar is used, especially glucose.
The exact amount of isotonizing agent to be present
depends, inter alia, on the osmotic power of the particular
isotonizing agent and the osmotic pressure of the o-ther
constituents in the nasal pharmaceutical composition.
The weight ratio of xanthine or other agent capable of
increasing the ciliary function to isotonizing agent may be,
for example, from abou-t 1:0.05 to about 1:10.
For a sugar, a typical amount is from about 5 mg
to 50 mg per doseO The weight ratio of ciliary function
increasing agent to sugar is for exarnple from about 1:1 to
about 1:10. This may correspond to about 1 to about 10%,
e.g. 2.5 to 5%, for liquid compositions. For sodium chloride
a suitable weight ratio of ciliary function increasing
agent to sodium chloride is for example from about 1:0.5 to
about 1:1. For liquid compositions a
~Db~7~
suitable concentration is from about 0.7 to about 1~2 per cent.
The nasal pharmaceutical composition of the invention may
be in liquid form. A solvent such as water may be used. A
co-solvent such as propylene glycol may be present, preferably
in a concentration of less than 10~ eOg. 0~1 to 10%. I~he com
position is preferably in the form of an aqueous solutionO
~lternatively it may be in the form of a suspension or an
oil-in-water emulsion.
If desired the nasal pharmaceutical composition of the
invention may be in powder form. Preferably the powder is
des;gned to dissolve rapidly on contact with the mucus membraneO
The powder is conveniently amorphous, any crystals being present
therein having an extremely small size.
If desired other nasal pharmaceutical excipiénts may be
present. The exact choice of other excipients present will
depend on a number of fac~ors, including stability and toler-
ability of the resultant pharmaceutical compositions. The
influence of severa~ excipients have been described in the
literature~ e.g. in H.J.M. van de Donk et al. First European
Congress of Biopharmacy and Pharmacokinetics 1-3 April 1981~
Editors J.M. Aiache and J.Hirtz, Clermont.Ferrant, p.406-413.
For example, an anti-oxidant or conserving agent such as sodium
metabisulphate or methyl parahydroxybenzoate or preferably
benzalkonium chloride~ cetylpyridinium chloride or phenododec-
inium bromide, sodium benzoate, sodium propionate or sodiumsorbate, or a protective gas such as carbon dioxide or nitrogen
may be present.
The weight ratio of anti-oxidant or conserving agent to
ciliary function increase agent is preferably kept very low,
e.g. from about 0.2:1 to about 0.02:1. The concentration of
antioxidant or conserving agent in a liquid may be for example
from 0.001~ to 0.2~.
If desired a tenside may be present, such as sorbitan mono-
oleate. Naturally the amounts of pharmaceutical excipients are
conveniently kept as low as possible, e.g. in liquid form less
than about 5% of the amount of xanthine or other agent capable
of increasing the ciliary function in the composition.
When the nasal pharmaceutical composition is in solid form
3~ g;~
then an iner-t carrier may be employed, which may comprise ~or
example from about 97.5 to ~5% of the composition. Alternatively
no inert carrier may be necessary.
The final pH of the nasal composi-tion of the
invention is preferably from abou-t 3.5 to about 9, conveniently
3.5 to 4.5 in the case of dihydroergotamine.
The desired pH may be achieved by means of the
presence of a buffer system~ e.g. acetic acid/sodium acetate,
C02/HC03~, or HPo~ 3/H2PO ~3 and PbS buffer.
The nasal pharmaceutical compositions of the
invention may be formulated in conventional manner, e.g. by
admixture of t~le constituents e.g. to form a solution in water,
if desired followed by filtering of the solution and/or
sterilizing under conventional conditions, e.g. by heating. If
lS a powder ph~maceutical composition is desired then preferably
a lyophilizàte is produced by exposing a chilled solution of
the nasal pharmaceutical composition to a vacuum.
~` ~he nasal pharmaceutical compositions of -the
~ invention in use are conveniently packaged in conventional
: 20 manner in a nasal spray applicator constructed to produce a
spray of the composition~ If desired pressure of a compressed
;gas, e.g. air, nitrogen or a hydrocarbon such as a freon or
ultrasonic means may be used to provide the spray. The
applicator may be constructed to receive a unit dosage form,
e.g. an ampoule, capsule or the like containing a sufficient
amount of the nasal pharmaceutical composition according to
the invention for a single dose. Alternatively the ampoule
may be of sufficient volumeJ e.g. 0.5 to 10 ml, to provide
several doses of the nasal pharmaceutical composition.
Numerous suitable nasal spray applicators are known, eOg.
"Microcompack" from Aerosol Services AG, CH-4313 Moehlin,
Switzerland, or applicators from Valois S.A., BG G-2~110
Le Neubourg, France, both of which provide liquid sprays.
The ampoule may be broken before being inserted into -the nasal
spray applicator.
~hen the nasal pharmaceutical composition of the invention is
liquid then the volume of composition to be dispensed in one
. .
:'
-- 10 --
dose may vary between wide limits. A suitable volume is from
0.1 to 0.2 mlO The particle size of the spray is preferably
greater than 800 microns, e.g. in -the range of from about 300
to 1000 microns.
When the nasal pharmaceutical composition of the
invention is solid, the volume and particle size of composi-tion
to be administered in a single dose may also vary within wide
limits. Prefexably the volume is in the range of about 0.1 ccm
and the particle size is from about 800 to about 1000 micronsO
For the preferred active agent dihydroergotamine
the ratio of xanthine or other agent capable of increasing
the ciliary function to active agent is conveniently from about
1:0.1 to about 1:1. Preferably the pharmaceutical composition
is in the form of a solution containing ~rom about 0.2 to about
2~, e.g. 0.5 to 2%, by ~eight of the xanthine or other agent
capable of increasing the ciliary function. Conveniently
glucose is present.
A particularly preferred nasal pharmaceutical
composition of the invention contains an aqueous solution of
0.4% dihydroergotamine mesylate, 5% glucose and 1% caffeine.
This composition is hereinafter referred to as composition A.
The muco ciliary effect of caffeine in the nasal pharmaceutical
compositions of the invention may be determined in conventional
manner in standard in vitro and in vivo tests. One par-ticularly
appropriate in vitro test has been described above. Another
test may be effected according to the principles of R. Guillerm,
Il Farmaco, 1, 1-13, (1972). A piece of a sheep or rat trachea
containing cilia and mucus is stretched on a thermostatically
controlled plate at 35~C. The nasal pharmaceutical composition
is sprayed onto the trachea by means of an ultrasonic aerosol
delivering 1 ml of solution per litre of air per minute over
a period of 5 minutes. The spray nozzle diameter is from 2 -to
microns. The ciliary beating frequency is measured by photo-
oscillographic techniques, according to the principles of
R. Guillerm et al., Physiol~ 57, 725, (1965). In this test
the composition A of the invention has a very small effect on
the ciliary function.
tj~3
An example of -the results according to the above mentioned
Chevance et al technique is:-
Time after administra-tion
Cbl~osition Omin 5min lOrnin 20min 30min 60min 90min
Ciliary beating frequency (cycles/minute)
5% glucose 420480 nt nt nt 420 n-t
1% caffeine 340 380 nt 500 nt nt 520
1% caffeine + 320 240 300 420 420 nt nt
glucose
10 ~osition A 360nt 380 300 nt nt nt
nt = not tested
In a further in vitro test the speed of movement
across a mucosal trachea piece from a sheep is studied
according to the principles of S.P. Battista in Screening
methods in Pharmacology, Editors R.A. Turner and P. Hebborn,
Vol. 2, Academic Press, New York, 1971, 167-202. The trachea
is maintained in a stretched condition in a thermoregulated
charnber. The speed of movement of a par~icle across the mucus
membrane is studied-including across an area of the trachea
20 where ca. 0.1 to 0. 2 ml of the nasal pharmaceutical
; composition has been sprayed.
An example of results obtained with composition A
of this invention is as follo~s:-
Time Run 1 Run 2
2 5 (minutes)
O Spray of 130 microlitres of composition A into a
zone 1 cm broad and crossed at about 12 minutes
after the start from which the particle departs
Distance speed Distance speed
` 30 travelled (mm/min) travelled (mm/min)
(mrn) (mm)
38 7. 6 50 10
~ 7 52 7 70 10
`` 91~ 70 9 90 10
` 35122) 83 ~ . 3 110 6. 7
153) 110 9 1~0 10
- 12 -
) approach to sprayed area, 2) crossing of sprayed area;
) departure away from sprayed area
~ s can be seen there is only a slight reduction in
speed of the particle when it is crossing over the zone treated
with composi-tion A.
The muco-ciliary properties of the nasal
pharmaceutical composition of the invention may also be
observed in in vivo tests.
A clinical test was effected to measure the nasal drainage
in accordance wlth the principles of I. Andersen et al; Am.
Rev.Respir.Dis~ 110, 301-305 (1974). In one trial a grain
-
of saccharin (0.~ to 0.6 mm in diameter) is placed on the
nasal mucus membrane of healthy volunteers, in the region of
the middle concha in front of the upper nasolacrinal duct
where the nostrils are the most permeable. ~he -time taken
for a subject to experience a sweet sensation is recorded as
the mucociliary transport time.
About 0~13 ml of- a nasal pharmaceutical composi-tion is sprayed
into the nose. The grain of saccharin is placed into the
nose 3 minutes later. 5 minutes later the subjects are as~ed
every 30 seconds whether a sweet sensation has been observed.
The mean results obtained in 12 subjects were as follows:-
Time of -transit )
~minutes)
Placebo4) 15.2 *~.7
Composition A 13.9 *2.6
) NaCl 9/oo aqueous solution
) Period from spraying un-til experience of sweetness
Composition A slightly decreased the transit time
but not significantly. The composi-tion was in general well
tolerated. A slight transitory prickling sensation in the
nasal mucosa was observed by one subject out of 12 on placebo
and 2 subjects out of 12 with composition A.
j
13 -
In another preliminary trial the "reEerence" solution was
used. Results obtained were:-
Time of transit )
(minutes)
Placebo ) 15.~4 ~3.86
Reference 22.50 +10.12
For meanings of ~) and 5) see above
An undesirable 40 to 45% increase in the transit time was
observed. 4 out of the -ten subjects experienced irritation.
3 out of 10 subjects experienced vasomotor disorders
(rhinorrhea and obstruc-tion~.
Moreover, even when the nasal mucus membrane is
challenged with a nasal pharmaceutical composition of the
invention in sufficient quantities to provide a therapeutic
effect the amount of xanthine absorbed may be low. For
example in one double-blind clinical trial, a nasal spray of
composition A was administered to ten healthy volunteers.
The equivalent of 2.6 mg caffeine was administeredO The
amount of caffeine detected in the blood in one preliminary
trial was as follows:-
Area Under Curve (nanogram/ml/hr) 22.29 ~ 3.94
Cmax (nanogram/ml) 2~34 + 0~52
The amount of caffeine detected in the body was thus ten to
twenty times less than that e~pected from drinking a cup of
coffee (containing e.g. 50 to 100 mg caffeine).
The efficacy of the compositions according to the
invention may be determined in conventional clinic therapeutic
trials. For example with composition A a clinical study
has been effected in patients suffering from migraine.
The study was effected with a composition A and
placebo in 9 patients according to a double blind cross over
plan. Each patient was treated for 1 month with either
composition A or placebo.
Spray applicators designed to administer a metered
dose of 0~5 mg dihydroergotamine in -the form of composition
A or a similar volume of placebo solution were used. A-t -the
- 14 -
beginning of a migraine attack each subjec-t administered a
metered dose into each nostril. Every 30 min~l-tes a further
dose is administered if the a-t-tack persists up to a maximum
of 4 doses within 24 hours.
7 subjects out of 9 when -treated with composition A
experienced a beneficial effect on the migraine a-ttack. With
placebo only 1 patient obtained some beneficial effect.
Further data obtained in this trial were:-
Treatment
Composition A Placebo
Total number of migraine 41 26
attacks
Results
Alleviation of attack 22 0
15 Decrease in intensi-ty of attack 5 6
No e~fect 14 20
; These results show a statistically significant
beneficial effect of composition A on the migraine attack.
On a global assessment, the tolerance of composition
A was excellent in 8 subjects and acceptable in 1 patient.
As indicated above the nasal pharmaceutical compositions of
the invention are stable. The stabili-ty can be measured in
standard stress stability tests wherein the active agent
concentration is determined. An example of results obtained
with composition A and the "reference"solution is as follows:-
Referenoe Solution Composition A
Temperature 35C44C 50C 35C 44c 50C
Weeks Concentration % Concentration %
0 104104 104 103103 103
3 99 96 92 10294 93
6 97.590.5 83.5 10392 88
9 93 86 76 10189 85
As indicated by the above results composition A isoverall significantly more stable -than the reference solution.
In further trials one lyophilisate was shown to have
excellent stability even at 50C.
In another stability trial a piston nasal spray
~3'~
appli~ator fitted to a bottle ~illed with 10 ml of composition
A or the reference solution was used to produce a nasal spray
of 0.13 ml, 11, 21, 31, 61 and 91 days after filling. After
a spray has been produced air is sucked into the bottle to
replace the sprayed solution, and hence the air ma~ induce
decomposition.
With composition ~ the concentration of dih~dro-
ergotamine was about 89% the original value after 91 days.
With the reference solution at 61 days the concen-tration of
dihydroergotamine was 31% the original value and at 91 days
66% the original value.
Thus the stability of composition A is significantly
better than the reference solution.
As used herein all percentages and weight ratios refer
to parts by weight except percen-tages referring to liquids
when they refer to weight per volume of liquid.
The following Example illustrates the invention:-
EXAMPLE 1:
1 D Composition
Constituents per 1 ml per 10 litres
Dihydroergotamine mesylate 0.004 g 40 g
Caffeine 0.010 g 100 g
Glucose 0-050 g 500 g
Water to 1 ml 10 1
2. Preparation of the composition
9 litres of water are saturated with carbon dioxide. lOOg
of caffeine are dissolved in the water and then 40 g
dihydroergotamine mesylate. 500 g Glucose are dissolved
in the stirred solution, without stopping sa-tura-tion with
carbon dioxide. Water is added to 10 litres. The
mixture is filtered in the presence of carbon dioxide
through a filter (0.22 micron holes).
3. Filling of ampoules
Ampoules are filled wi-th a maximum of 1 ml solution under
carbon dioxide, sealed and then are sterilized in an
autoclave at 121C for 5 minutes.
16 -
The pH is typically between 4.38 and 4.46 at 22C.
4. Use
The ampoules are broken open and then inserted :into a
conventional nasal dispenser. The dispenser sprays for
each dose ahout 0.13 ml of solution con-taining 0.5 mg of
dihydroergotamine. I'he dose is applied nasally 2 to 4
times a day in the prophylaxis or -treatment of migraine.
