CA1197783A

CA1197783A - Nasal pharmaceutical compositions

Info

Publication number: CA1197783A
Application number: CA000420539A
Authority: CA
Inventors: Jean-Rene Kiechel; Danielle Plas; Francoise Acezat-Mispelter
Original assignee: Sandoz AG
Current assignee: Novartis AG
Priority date: 1982-02-01
Filing date: 1983-01-31
Publication date: 1985-12-10
Also published as: IL67822A; NL192325B; DK38183D0; NZ203117A; NL8300325A; JPS58134017A; IT1197558B; ES8502865A1; FI830245L; DE3302949A1; ZA83673B; PH22198A; FI81258C; DE3302949C2; IT8347646A0; AT385656B; SE8300495L; HK59989A; IE54532B1; JPH0253406B2

Abstract

Abstract:
A nasal pharmaceutical composition incorporates a non-toxic agent which is capable of increasing the ciliary function e.g. caffeine and at least partially antagonising the ciliary function depressant effect of the active agent e.g. dihydroergotamine or any other constituent present in the composition.

Description

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

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 . .

:' 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 ) 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 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 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 %

6 97.590.5 83.5 10392 88 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.

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.

Claims

Claims:

1. A nasal 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 function.

2. A nasal pharmaceutical composition according to claim 1 wherein the active agent is capable of depressing the ciliary function.

3. A composition according to claim 1 or 2 wherein the active agent is systemically active.

4. A nasal pharmaceutical composition containing as an active agent dihydroergotamine and a non-toxic agent which is capable of increasing the ciliary function.

5. A composition according to claim 4 wherein the dihydroergotamine present is in the form of the mesylate.

6. A composition according to claim 1, 2 or 4 wherein the weight ratio of active agent to ciliary function increasing agent is from 0.1:1 to 10:1

7. A composition according to claim 1 wherein the ciliary function increasing agent is xanthine.

8. A composition according to claim 7 wherein the xanthine is of formula I

wherein R1, R1 and R3 are chosen from hydrogen or alkyl (C1-10).

9. A composition according to claim 8 wherein the xanthine is theophylline.

10. A composition according to claim 8 wherein the xanthine is caffeine.

11. A composition according to claim 1 containing a non-toxic isotonizing agent.

12. A compositiion according to claim 11 wherein the weight ratio of agent capable of increasing the ciliary function to isotonizing agent is from 1:0.05 to 1:10.

13. A composition according to claim 12 wherein the isotonizing agent is a sugar.

14. A composition according to claim 13 wherein the sugar is glucose.

15. A composition according to claim 14 wherein the weight ratio of ciliary function increasing agent to glucose is from 1:1 to 1:10.

16. A nasal pharmaceutical composition comprising dihydroergotamine mesylate and caffeine in a weight ratio of 1:0.1 to 1:1, and glucose.

17. A composition according to claim 1 in the form of a powder

18. A composition according to claim 17 having a mean particle diameter of 800 to 1000 microns.

19. A composition according to claim 1 in unit dosage form.

20. A composition according to claim 1 in a nasal spray applicator.

21. A composition according to claim 1 in the form of a liquid.

22. A composition according to claim 21 in the form of a solution.

23. A composition according to claim 21 or 22 wherein the osmotic pressure is from 280 to 360 mOsm per litre.

24. A composition according to claim 21 or 22 in unit dosage form saturated with carbon dioxide gas.

25. A composition according to claim 21 in a nasal spray applicator.

26. A composition according to claim 25 wherein the spray applicator is designed to produce a spray of droplet size 800 to 1000 microns in diameter.