SE454402B - NATIONAL ADMINISTRATIVE PHARMACEUTICAL COMPOSITION INCLUDING AN ERGOTPEPTIDALKALOID AND XANTIN - Google Patents

Description

454 402 2 cilia are found on the surface layer of the mucous membrane or mucous membrane of the nose and in the trachea or trachea. These cilia perform undulating movements or wave motions with a frequency range of about 300-900 cycles per minute at 37 ° C, which drive mucus together with dust particles and other foreign material towards the openings in the rear part of the nose (koans), which are in connection with the pharynx, or forward towards the nostril openings. This means that you either swallow or chew away these particles and this material. The mucosal layer can move at a rate of about 2 to 10 mm per minute in some animals. Studies by I.B., Andersen et al in American Review of Respiratory Disease Lgg, 438 (1977) led to an average mucosal flow rate of 4.8 mm per minute being observed in a group of people. The individual flow rates ranged from 0 to 23.6 mm per minute.

It is easy to realize that a substance that impairs ciliary function disrupts one of the body's main protective mechanisms.

The extent to which nasally administered agent reduces ciliary function can be observed in standard tests, e.g. in vitro, using ciliary trachea in animals.

A reproducible and susceptible test is performed as follows: The trachea or nasal septum of a guinea pig or rabbit is removed immediately after killing. The organ is immersed in physiological balance serum (Dulbecco) at 23 ° C. A tubular fragment, e.g. of three tracheal rings, is removed and the ciliary epithelium is scraped away therefrom. The frequency range of the cilia at a particular point is measured by microphotoscopic technique according to the principle of L. Chevance et al., Acta Otolaryng, 10, 16-28, (1970), where the cilia are observed and magnified 500 times. A change in the frequency range indicates a change in the ciliary function.

Certain pharmacologically active agents, especially dihydroergotamine, impair ciliary function. Thus, application (about 0.1 - 0.3 ml) of the "reference solution" or an aqueous solution containing 4 mg of dihydroergotamine mesylate per ml to the cilia results in an irreversible deterioration of the cilia frequency within 2 minutes after application.

More particularly, the present invention relates to a nasally administrable pharmaceutical composition which contains, as a pharmacologically active agent, an ergot peptide alkaloid. In connection with such a composition we have found that non-toxic agents, more specifically xanthines, increase ciliary function, e.g. the ciliary frequency rate in the above test, so they can be used to at least partially counteract the ciliary impairment effects of other ingredients in a pharmaceutical composition and provide clinically well tolerated nasal pharmaceutical compositions.

Accordingly, according to the present invention there is provided a nasal pharmaceutical composition which, as a pharmacologically active agent, contains an ergot peptide alkaloid, the composition being characterized in that it contains a xanthine of the formula: wherein R 1, R 2 and R 3 are selected from hydrogen and (C 1 -C 10) -alkyl, in an amount which antagonizes or increases the ciliary function-reducing effect shown by said ergot peptide alkaloid.

The xanthine that increases or increases ciliary function can be determined by in vitro experiments; for example the above test, and suitably gives an increase of 20% or more of the ciliary function minutes after administration. The choice of agent is not critical as long as it is pharmacologically acceptable. The amount of the ciliary function enhancing agent present in the composition is, of course, dependent on the amounts of other ingredients which reduce the ciliary function, the solubility of the agent and the extent to which they reduce the ciliary function. Preferred amounts of ciliary enhancing agents in the nasal pharmaceutical composition can be determined by routine experimentation, e.g. using the above in vitro tests.

In addition to the fact that xanthine is particularly effective in antagonizing the reduction in ciliary function, which reduction e.g. is caused by the pharmacologically active agent, we have also found that the xanthines are well tolerated by nasal administration. Furthermore, nasal pharmaceutical compositions containing xanthines can be prepared, which are liquid solutions which are stable against e.g. decomposition, precipitation or discoloration at acceptable osmolarity and acceptable pH and which can be easily sterilized.

The pharmacologically active ergot peptide alkaloid may e.g. be one that can be systemically absorbed through the nasal mucosa and that passes into the body's circulatory system. Of course, it should not be toxic.

The present invention is particularly suitable for use in connection with ergot peptide alkaloids which markedly lower the ciliary frequency in the in vitro test described above, and which e.g. shows an S0% or even greater reduction in ciliary frequency 20 minutes after application.

As mentioned above, the pharmacologically active agent is preferably a cyclic ergot peptide alkaloid product described by the formula I in GB-PS 1,592,563, the contents of which are hereby incorporated into the present text, and this product is especially dihydroergotamine.

The active agent may be administered in free base form or in the form of a pharmaceutically acceptable acid addition salt, e.g. næsyknßt.Such salts generally have an activity of the same order of magnitude as the active agent. For example, dihydroergotamine can be administered in the form of the mesylate.

The special therapeutic effect exerted by the pharmacologically active agent is not critical. In view of the rapid increase in the concentration of active agent in the blood after nasal administration, the nasal pharmaceutical compositions of the invention are particularly suitable for the administration of active agents for the treatment of conditions requiring rapid relief, e.g. especially orthostatic hypotension and in particular migraine.

The dose of pharmacologically active agent to be administered will, of course, vary from compound to compound. In general, a satisfactory dose is one which provides the same magnitude for bioavailability or therapeutic effect as that obtained by injecting a therapeutically effective amount of the active agent. Often the nasal route requires smaller doses than the oral route to obtain the same effect; for example, a nasal dose may be from about 0.5 to about 0.01 times the oral dose. Thus, e.g. with dihydroergotamine 1 mg administered nasally roughly the same quantitative effect (as shown by bioavailability studies or vasoconstriction of hand veins) 454 402 as 10 mg dihydroergotamine administered orally. For dihydroergotamine, the preferred nasally administered amount is on the order of about 0.25 to 5 mg.

Of course, the dose of the active agent should not be so high or the dose repeated so often that side effects may occur.

The xanthines used according to the invention are generally known. Examples of suitable xanthines are theophylline, and the preferred xanthine is caffeine.

The exact amount of xanthine to be administered in one dose depends, among other things, on to the extent to which the pharmacologically active agent and any other ingredient present in the nasal pharmaceutical composition reduces ciliary function. The ratio of active agent to xanthine or other ciliary enhancing agent can vary widely and can be determined by routine experimentation. A suitable ratio is from about 0.1: 1 to about 10: 1. It is advisable to use the minimum amount of xanthine or other agent capable of increasing ciliary function which brings the ciliary function to a value in the range from 50 to 100% of the base value (for untreated cilia) within 20 minutes after application in the above in vitro ciliary function test.

Satisfactory results have been obtained with from about 1 mg to about 5 mg of xanthine per dose.

The nasal composition may contain e.g. 0 to about 2% by weight, more preferably from 0.5 to 2% by weight, of from about 1%, of xanthine, e.g. in a liquid containing, for example, 4 g of dihydroergotamine per liter.

It is convenient to administer a nasal spray that is isotonic, or slightly hypertonic, with respect to ciliary mucosa. Suitably the osmotic pressure of the liquid used to give this spray is from about 200 to 600 mOsm, especially from 280 to 360 mOsm, per liter. The desired osmotic pressure can be obtained by the addition of any conventional non-toxic isotonizing agent. Sodium chloride can e.g. be used. Preferably, non-toxic sugar, especially glucose, is used.

The exact amount of isotonizing agent that must be present depends, among other things, on on the osmotic effect of the particular isotonizing agent and the osmotic pressure of the other constituents of the nasal pharmaceutical composition.

The weight ratio of xanthine or other agent capable of increasing ciliary function to isotonizing agents can e.g. be from about 1: 0.0S to about 1:10.

For a sugar, a typical amount is from about 5 mg to 50 mg per dose. The weight ratio between ciliary enhancing agent and sugar is e.g. from about 1: 1 to about 1:10. This can correspond from about 1 to about 10%, e.g. from 2.5 to 5%, for liquid compositions. For sodium chloride, a suitable weight ratio between ciliary enhancing agent and sodium chloride is e.g. from about 110.5 to about 1: 1. For liquid compositions, a suitable concentration is from about 0.7 to about 1.2%.

The nasal pharmaceutical composition of the invention may be in liquid form. A solvent such as water can be used. A co-solvent such as propylene glycol may be present, preferably in a concentration of less than 10%, eg from 0.1 to 10%. The composition is preferably in the form of an aqueous solution. Alternatively, 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 designed so that it dissolves quickly upon contact with the mucous membrane. The powder is suitably amorphous, with any crystals present therein being extremely small in size.

If desired, other nasal pharmaceutical excipients may be present. The exact choice of other excipients present depends on a number of factors, including the stability and tolerability of the resulting pharmaceutical compositions. The effects of a number of excipients have been described in the literature, e.g. and H.J.M. van de Donk et al, First European Congress of Biopharmacy and Pharmacokinetics, April 1-3, 1981, publisher J.M. Aiache and J, Hirtz, Clermont Ferrant, p. 406-413. For example, an antioxidant or preservative may be present, such as sodium metabisulfate or methyl parahydroxybenzoate or preferably benzalkonium chloride, cetylpyridinium chloride or phenododecinium bromide, sodium benzoate, sodium propionate or sodium bicarbonate or sodium bicarbonate. 454 402 ~ _1 The weight ratio between antioxidant or preservative and ciliary enhancing agent is preferably kept very low, e.g. from about 0.2: 1 to about 0.02: 1. The concentration of antioxidant or preservative in a liquid can e.g. be from 0.001 to 0.2 a. If desired, a surfactant may be present, such as sorbitan monooleate. Of course, the amounts of the pharmaceutical excipients are suitably kept as low as possible, e.g. in liquid form less than about S $ of the amount of xanthine or other agent capable of enhancing the ciliary function of the composition.

When the nasal pharmaceutical composition is in solid form, an inert carrier may be used, which e.g. may constitute from about 97.5 to 85% of the composition. Alternatively, an inert carrier may not be required.

The final pH of the nasal composition of the invention is preferably from about 3.5 to about 9, preferably from 3.5 to 4.5, in the case of dihydroergotamine.

The desired pH value can be obtained by the presence of a buffer system, e.g. acetic acid / sodium acetate, CO 2 / HCO 3 C :) or Hm? G3 / n2Po4 G3 / and Pas buffer.

The nasal pharmaceutical compositions of the invention may be formulated in conventional manner, e.g. by mixing the ingredients, for example to form a solution in water, if desired followed by filtration of the solution and / or sterilization under conventional conditions, e.g. by heating.

If a pharmaceutical powder composition is desired, a lyophilisate is preferably prepared by subjecting a cooled solution of the nasal pharmaceutical composition to vacuum.

The nasal pharmaceutical compositions of the invention, when used, are conveniently packaged in a conventional manner in a nasal spray applicator designed to give a spray of the composition. If desired, pressure from a compressed gas, e.g. air, nitrogen or a hydrocarbon, such as freon, or ultrasonic means are used to produce a spray. The applicator can be designed to receive a unit dosage form, e.g. an ampoule, capsule or the like containing a sufficient amount of the nasal pharmaceutical composition of the invention for a single dose. Alternatively, the ampoule may have a sufficient volume, e.g. from 0.5 to 10 ml, to give multiple doses of the nasal ZS - 454 402 pharmaceutical composition. Numerous suitable nasal spray applicators are known, e.g. "Microcompack" from Aerosol Services AG, CH-4313 Moehlin, Switzerland, or applicators from Valois S.A., BG G-26110 Le Neubourg, France, both of which provide liquid spray. The ampoule can be broken before being inserted into the nasal spray applicator.

When the nasal pharmaceutical composition according to the invention is liquid, the volume of the composition released in a dose can vary widely. A suitable volume is from 0.1 to 0.2 ml. The particle size of the spray in question is preferably larger than 800 μm, e.g. within the range of about 800 to 1000 μm.

When the nasal pharmaceutical composition of the invention is in solid form, the volume and particle size of the composition for administration in a single dose may also vary widely. Preferably, the volume in the range is from about 0.1 cms and the particle size is from about 800 to about 1000 microns.

For the preferred active agent dihydroergotamine, the ratio of xanthine to the active agent is suitably from about 110.1 to about 1: 1. Preferably, the pharmaceutical composition is in the form of a solution containing from about 0.2 to about 2% by weight, e.g. from 0.5 to 2% by weight, of the xanthine. Preferably glucose is present.

An especially preferred nasal pharmaceutical composition according to 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 mucociliary effect of caffeine in the nasal pharmaceutical compositions of the invention can be determined in a conventional manner by standard in vitro and in vivo tests. A particularly suitable in vitro test has been described above. Another test can be performed according to the principles described by R. Guillerm, Il parmaco, 1, 1-13 (1972). A piece of sheep or rat trachea containing cilia and mucus is stretched on a thermostatically controlled plate at 35 ° C. . The nasal pharmaceutical composition is sprayed on the trachea in question by means of an ultrasonic aerosol which delivers 1 ml of solution per liter of air per minute for a period d 454 402 of 5 minutes. The diameter of the spray nozzle is from 2 to 4 pm.

Ciliary frequency is measured by photo-oscillographic technique according to the principles described by R. Guillerm et al, Physiol. eel, 725 (1965). In this test, composition A according to the invention has very little effect on the ciliary function.

An example of the results according to the above Chevance technique is: Time after administration Composition Omin Smin 10min 20min 30min 60min 90min 90min Ciliary movement frequency (cycles / minute)% glucose 420 480 et et 420 et% caffeine 340 380 et 500 et et S20 1% caffeine + 320 240 300 420 420 et et glucose Composition A 360 et 380 300 et et et et = not tested In a further in vitro test, the speed of movement over a piece of mucosal trachea from a sheep is studied according to the principles described by SPBattista in Screening methods in Pharmacology, publishers RATurner and P.Hebborn, vol. 2, Academic Press, New York, 1971, 167-202. The trachea in question is kept in a stretched state in a thermoregulated chamber. The rate of movement or movement of a particle across the mucous membrane is studied over an area of the trachea in question where approximately 0.1 to 0.2 ml of the nasal pharmaceutical composition has been sprayed.

An example of results obtained with composition A according to the present invention are the following: 454 402 Time Experiment 1 Increase 2 (min) 0 Spray 130 microliters of composition A in a zone which is 1 cm wide and which is crossed about 12 minutes after the time when the particle begins to move Displacement Speed Displacement Speed distance (mm / min) distance (mm / min) (mm) (mm) 38 7.6 50 10 7 52 7 70 10 91) 10 9 90 10 122) ss 4, 3,110 6,7 193) 11o 9 140 10 1) entry into sprayed area; 2) crossing of sprayed area; 3) exit from sprayed area.

From the above it appears that there is only a slight reduction in the velocity of the particle when it passes over the zone treated with composition A.

The mucociliary properties of the nasal pharmaceutical composition of the invention can also be observed in in vivo tests.

A clinical test was performed to measure the nasal flow in accordance with the principles described by I. Andersen et al., Am.

Rev.Respir.Dis. 110, 301-305 (1974). In one experiment, a saccharin grain (0.4-0.6 mm in diameter) is placed on the nasal mucosal membrane of healthy subjects, in the area of the middle nasal mussel in front of the upper nasolacrinal canal where the nostrils are most permeable. The time it takes for a subject to perceive an odor sensation is recorded as the mucociliary transport time.

About 0.13 ml of a nasal pharmaceutical composition is sprayed into the nose. The saccharin grain is placed in the nose 3 minutes later. Minutes later, the subjects are asked every thirty seconds whether a sense of smell has begun to appear. The average results obtained on 12 subjects were as follows: fa 454 402 11 Passage time 5) (minutes) Zero sample) 15.2 1 4.7 Composition A 13.9 I 2.6 _ 4) NaCl 90 0 / oo aqueous solution ) period of time from spraying until a sweet odor appears.

Composition A reduced the passing time slightly but not significantly.

The composition was generally well tolerated. A certain transient stinging sensation in the mucous membrane of the nose was observed by a subject of twelve for the blank and by two subjects of twelve for composition A.

In another preliminary experiment, the "reference solution" was used. The results obtained were: Passage time 5] (minutes) No11pr0v43 1s, 44 1 3.86 Reference 22.50 110.12 For the meanings of 4) and 5) see above.

An undesirable 40 to 45% increase in passage time was observed. Four of the ten subjects felt irritated.

Three out of ten subjects felt vasomotor disorders (rinnorrhea and stuffy nose).

Furthermore, even when the nasal mucosal membrane is treated with a nasal pharmaceutical composition of the invention in sufficient quantities to produce a therapeutic effect, the amount of xanthine adsorbed may be low. For example, in a double-blind clinical trial, a nasal spray of composition A was administered to ten healthy subjects. The equivalent of 2.6 mg of caffeine was administered. The amount of caffeine detected in the blood during an initial experiment was as follows: Area under curve (nanogram / ml / h) 22.29 1 3.94 Cmax (nanogram / ml) 2.34 1 0.52 The amount of caffeine detected in the body was thus ten to twenty times smaller than that which can be expected when drinking a cup of coffee (containing eg SO to 100 mg of caffeine).

The efficacy of the compositions of the invention can be determined in conventional clinical therapeutic trials. For example, for composition A, clinical studies have been performed on patients suffering from migraines for '454 402 ll pelvis.

The studies were performed with a composition A and a zero sample of nine patients according to a double blind crossover plan. Each patient was treated for one month with either composition A or the null sample.

Spray applicators designed to administer a metered dose of 0.5 mg of dihydroergotamine in the form of composition A or an equivalent volume of blank are used. At the onset of a migraine attack, a measured dose was administered to each subject in each nostril. Every 30 minutes, an additional dose is administered if the attack lasts up to a maximum of four doses within 24 hours.

When treated with composition A, seven subjects experienced nine beneficial effects on the migraine attack. For the blank test, only one patient felt a certain soothing effect. Additional data obtained in this trial were: Treatment Composition A Zero sample _ Total number of migraine attacks 41 26 Results Eliminated symptoms 22 0 Reduction of the intensity of the attack 5 6 No effect _ 14 20 These results show a statistically significant beneficial effect for composition A on the migraine attack.

As a general evaluation, the tolerance for composition A was excellent in eight subjects and acceptable in one patient.

As mentioned above, the nasal pharmaceutical compositions of the invention are stable. The stability can be measured by standard tests regarding stress stability, where the concentration of the active agent is determined. An example of results obtained for composition A and the "reference solution" is as follows: / 15 f) b! 3 454 402 Reference solution Composition A temperature ss ° c 44 ° c so ° c ss ° c 44 ° c so ° c Weeks Concentration 1 Concentration 1 0 104 104 104 103 103 103 3 99 96 92 102 94 93 6 97.5 90, 5 83.5 103 92 88 9 93 86 76 101 89 85 As can be seen from the above results, composition A is overall more significantly more stable than the reference solution. In further experiments, a lyophilisate was found to have excellent stability even at 50 ° C.

In another stability test, a nasal spray plunger attached to a vial filled with 10 ml of composition A or the reference solution was used to produce a 0.13 ml nasal spray, 11, 21, 31, 61 and 91 days after filling. Once a spray has been prepared, air is sucked into the bottle to replace the sprayed solution, and consequently the air can cause decomposition.

For composition A, the concentration of dihydroergotamine was about 89% of the original value after 91 days. For the reference solution, the concentration of dihydroergotamine was 81% of the original value after 61 days and 66% of the original value after 91 days.

Thus, the stability of composition A is markedly better than that of the reference solution.

As used herein, all percentages and weight ratios refer to parts by weight with the exception of the percentages relating to liquids, as they refer to weight per volume of liquid.

The following examples illustrate the invention: EXAMPLE 1: 1. Composition _ Ingredients per ml per 10 liters Dihydroergotamine mesylate 0.004 g 40 g Caffeine 0.010 g 100 g Glucose 0.050 g 500 g Water to 1 ml 10 liters TJ U! 454 402 ll 2. Preparation of the composition 9 liters of water are saturated with carbon dioxide. 100 g of caffeine are dissolved in the water and then 40 g of dihydroergotamine mesylate. S00 g of glucose is dissolved in the stirred solution, without interrupting the saturation with carbon dioxide. Water is added up to 10 liters. The mixture is filtered in the presence of carbon dioxide through a filter (0.22 μm heel). 3. Filling ampoules Ampoules are filled with a maximum of 1 ml of solution under carbon dioxide, sealed and then sterilized in an autoclave at 121 ° C for minutes. The pH is typically between 4.38 and 4.46 at 22 ° C. 4. Use The ampoules are opened and then placed in a conventional nasal delivery device. This dispenser sprays for each dose approximately 0.13 ml of solution containing 0.5 mg of dihydroergotamine. The dose is applied nasally 2 to 4 times a day for prophylaxis or treatment of migraine. f;

Claims (13)

454 402 15 PATENT CLAIMS A nasally administrable pharmaceutical composition which, as a pharmacologically active agent, contains an ergot peptide alkaloid, characterized in that it contains a xanthine of the formula: R 3 \ (I) a] n N> in which R 1, R 2 and R 3 are selected from hydrogen and (C1-C10) -alkyl, in an amount which antagonizes or increases the ciliary function-reducing effect exhibited by said ergot peptide alkaloid. Composition according to Claim 1, characterized in that the ergot peptide alkaloid has the formula: wherein R 4 is hydrogen or halogen and R 4 is hydrogen or an alkyl group having 1 to 4 carbon atoms and either a) R 6 is isopropyl, sec-butyl or isobutyl, R 7 is methyl, ethyl or isopropyl and either R 8 is hydrogen and R 9 is hydrogen or methoxy or R 5 and R 9 together form an additional bond, or b) R 6 is benzyl, R7 is methyl, R8 is hydrogen and R9 is hydrogen or methoxy, the ratio of xanthine to ergot peptide alkaloid being from 1: 0, 1 to 1:10. Composition according to Claim 1 or 2, characterized in that the ergot peptide alkaloid is present in free base form or in the form of an acid addition salt. ' Composition according to any one of the preceding claims, characterized in that the ergot peptide alkaloid is dihydroergotamine. 5. A composition according to claim 4, characterized in that the dihydroergotamine is in the form of the mesylate. Composition according to any one of the preceding claims, characterized in that the xanthine is theophylline. Composition according to any one of Claims 1-S, characterized in that the xanthine is caffeine. Composition according to any one of the preceding claims, characterized in that it also contains a non-toxic isotonizing agent. The composition of claim 8, wherein the ratio of xanthine to non-toxic isotonizing agent is from about 1: 0.0S to about 1:10. 10. A composition according to any one of claims 8 and 9, characterized in that the isotonizing agent is a sugar. Composition according to Claim 10, characterized in that the sugar is glucose. Composition according to any one of the preceding claims, characterized in that it is present in solution. Composition according to any one of the preceding claims, characterized in that it comprises an aqueous solution containing 0.4% dihydroergotamine desylate, 5% glucose and 1% caffeine. IN\