FI81258C - FOERFARANDE FOER FRAMSTAELLNING AV EN PHARMACEUTISK KOMPOSITION FOER NASAL ADMINISTRATION. - Google Patents

Description

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This invention relates to a method of preparing a nasally administrable pharmaceutical composition.

The method of nasally administering pharmacologically active substances such as broncholytes and hormones to effect systemic absorption has long been known ["Pharmazeutische Technologie", ed. H. Sucker, P. Fuchs 10 and P. Speiser, Georg Thieme Verlag, Stuttgart (1978), p.

722 - 729]. Nasal systemic administration of pharmacologically active substances can have significant advantages over other routes of administration. For example, the active substance enters the bloodstream directly after passing through the nasal mucosa, which results in the immediate presence of the active substance in the blood and the rapid onset of the therapeutic effect. Nasal aerosol nebulizers are available which provide an accurate dose of the active agent as a liquid or powder spray with a droplet or particle size suitable for nasal administration and which are easy to use. However, systemic nasal administration of pharmacologically active substances is still rare.

GB Patent 1,592,563 describes that certain cyclic ergotpeptide alkaloids may be administered, preferably nasally. The publication describes nasal pharmaceutical dihydroergotamine compositions, especially in liquid and powder form, which can be suitably used as sprays.

A representative nasal pharmaceutical composition mentioned in the above publication is an aqueous solution containing 4 mg / ml of dihydroergotamine mesylate, 50 mg / ml of ethanol and 150 mg / ml of glycerin; this composition is hereinafter referred to as the "reference solution".

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Pharmaceutical compositions formulated for nasal administration often prove unsatisfactory in widespread clinical use. For example, they may be unstable when stored for a long time and are not well tolerated or used by patients. A significant reason for poor tolerability may be that some part of the composition, perhaps the active ingredient, impairs the function of the hairs.

The cilia of the airways are microscopic hair-like structures with a length of about 7 μm and a diameter of 1 to 3 μm. These cilia are present in the surface layer of the mucosa in the nose and trachea. The cilia make vibrations with a frequency of about 300 to 900 vibrations per minute at 37 ° C, which push the mucus together with 15 dust particles and other foreign substances towards the duct in the back of the nose, which is connected to the pharynx, or forward towards the nostrils. The particles and other substances then become either swallowed or soaked out. The mucus layer may move in some animals at a speed of no-20 at about 2-10 mm / min. In studies [I. B. Andersen et al., American Review of Respiratory Disease 106 (1977), p. 438] found an average mucus flow rate of 4.8 mm / min in a group of people. Individual flow rates ranged from 0 to 23.6 mm / min. It is easy to understand that any substance that impairs the function of the cilia will interfere with one of the body's most important defense mechanisms.

The extent to which a nasally administered substance reduces the function of the cilia can be detected by conventional means, for example in vitro using a trachea containing the cilia of animals.

One reproducible and sensitive test is as follows:

The guinea pig or rabbit trachea or nasal septum 35 is removed immediately after killing. The organ is immersed in physiological equilibrium serum (Dulbecco) at a temperature of 3 81258 23 ° C. A tubular piece, for example a piece the length of 3 tracheal rings, is removed and the epithelium containing the cilia is scraped off. The oscillation frequency of the cilia at a given point is measured by the microscopic imaging oscillography-5 method [L. Chevange et al .; Acta Otolaryng 70 (1970), ss. 16 - 28], in which the cilia are viewed at 500x magnification. A change in oscillation frequency indicates a change in the function of the cilia.

Some pharmaceutically active substances, in particular dihydroergotamine, impair the function of the cilia. Thus, upon administration (about 0.1 to 0.3 ml) of a "reference solution" or an aqueous solution containing 4 mg / ml of dihydro-ergotamine mesylate, the vibration of the cilia is irreversibly slowed down within 2 minutes of administration.

In addition, it has now been found that non-toxic substances which improve the function of the hair follicles, in particular xanthines, for example by increasing the oscillation frequency of the hair follicles in the above experiment, can be used to at least partially reverse the anti-hair loss effects of the other ingredients of the pharmaceutical composition. tolerable nasal pharmaceutical compositions.

Thus, the present invention relates to a process for the preparation of a pharmaceutical composition for nasal administration, which process is characterized in that xanthine is added to the ergotpeptide alkaloid-containing composition, preferably in solution, so that the weight ratio of xanthine to ergotpeptide alkaloid is 1: 0.1 to 1:10.

This method provides a composition containing a pharmacologically active substance, i.e., an ergotpeptide alkaloid capable of inducing a side effect of dysfunction, and a non-toxic substance, i.e., xanthine, capable of enhancing cilia. Such nasally administered pharmaceutical compositions are most preferably in the form of a liquid or powder.

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Substances which improve the function of the cilia can be determined by in vitro experiments, for example the above-mentioned experiment, and preferably provide a 20% or greater improvement in the function of the cilia after 20 to 5 minutes after administration. The amount of hair dye enhancing agent in the composition will, of course, depend on the amount, solubility and extent of the other hair dehydrating ingredients that impair the hair dye function. Preferred amounts of the color-promoting agent 10 in the nasal pharmaceutical composition can be determined by conventional methods, for example, using the above-mentioned in vitro test.

Xanthine is a particularly potent antagonist of the pharmacologically active substance-induced impairment of cilia function. In addition, it has now been found that such xanthines are well tolerated for nasal administration. In addition, nasal compositions containing such xanthines can be prepared as stable liquid solutions that do not decompose, precipitate, or lose color at acceptable osmolarity and pH, for example, and are easy to sterilize.

For example, the pharmacologically active ergotpeptide alkaloid 25 may be one that has the ability to be absorbed systemically through the nasal mucosa and into the bloodstream. It must, of course, be non-toxic.

This invention is particularly well suited for use with ergotpeptide alkaloids that significantly reduce cilia vibration in the in vitro assay described above and provide, for example, a 50% or greater retardation of cilia hair vibration 20 minutes after administration of a dose of active agent.

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As mentioned above, the pharmacologically active substance is preferably a cyclic ergotpeptide alkaloid product such as the compound of formula I in GB Patent 1,592,563, and is in particular dihydroergot-5-amine.

The active ingredient may be administered as the free base or as a pharmaceutically acceptable acid addition salt, for example as a mesylate. The activity of such salts is generally of the same order of magnitude as that of the active substance. For example, dihydroergotamine can be administered as a mesylate.

The therapeutic effect of a physiologically active substance is not decisive. Because the concentration of active ingredient in the blood increases rapidly after nasal administration, the nasal pharmaceutical compositions of the invention are particularly well suited for the treatment of conditions requiring rapid relief of active ingredients, such as orthostatic hypotension and especially migraine.

The dose of pharmacologically active substance to be administered will, of course, vary with the compound. In general, a satisfactory dose is one which achieves a blood concentration or therapeutic effect of the same order of magnitude as that which can be achieved by injection of a therapeutically effective amount of the active ingredient. For example, for frequent nasal administration, the dose may be, for example, about 0.5 to about 0.01 times the oral dose. For example, in the case of dihydroergotamine, 1 mg administered nasally results in approximately the same quantitative effect (as demonstrated by oral studies or contraction of the venous veins) as 10 mg dihydroergotamine administered orally. The preferred nasal amount of dihydroergotamine is in the range of about 0.25 to 5 mg.

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

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What xanthine is used is not critical, any xanthine can be used, for example xanthine of the formula ": wherein R 1, R 2 and R 3 are hydrogen or C 1-10 alkyl.

Such xanthines are well known. Examples of suitable xanthines include theophylline, and the preferred xanthine is caffeine.

The exact amount of xanthine or other substance capable of promoting the function of the cilia administered in a dose depends on e.g. how strongly the active substance and any other ingredients present in the nasal composition impair the function of the cilia. The ratio of active substance to xanthine or other cilia-enhancing agent can vary widely and can be determined by conventional experiments. A suitable ratio is from about 0.1: 1 to about 10: 1. It is preferable to use the lowest possible amount of xanthine or other hair promoter that restores the hair function to 50-100% of baseline (untreated hair function) within 20 minutes after administration in the above in vitro hair function test. Satisfactory results have been obtained using about 1 to about 5 mg of xanthine per dose.

The composition for nasal administration may contain, for example, about 0.1 to 2, more preferably 0.5 to 2% by weight of xanthine, for example in a solution containing, for example, 4 g of dihydroergotamine per liter of solution.

It is preferred to use a nasal spray that is isotonic or weakly hypertonic to the mucus surrounding the cilia. The solution from which the spray is made

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The engine pressure is preferably from 200 to 600 mOsm, in particular from 280 to 360 mOsm / Ι. The desired osmotic pressure can be achieved by the addition of any conventional isotonizing agent. For example, sodium chloride can be used. Preferably, non-toxic sugar, especially glucose, is used.

The exact amount of isotonizing agent depends on e.g. the osmotic potency of the isotonizing agent used and the osmotic pressure of the other 10 ingredients in the nasal composition.

The weight ratio of xanthine or other hair promoter to isotonizing agent may be, for example, from about 1: 0.5 to about 1:10.

In the case of sugar, the typical amount is about 15 to 50 mg / dose. The weight ratio between the color enhancer and the sugar is, for example, about 1: 1 to about 1:10. This may correspond to about 1 to about 10%, for example 2.5 to 5% in the case of liquid compositions. In the case of sodium chloride, a suitable weight ratio of hair color enhancer to sodium chloride is, for example, from about 1: 0.5 to about 1: 1. Liquid compositions have a suitable concentration of about 0.7 to about 1.2%.

The pharmaceutical composition prepared according to the invention may be liquid. 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%, for example 0.1 to 10%. The composition is preferably in the form of an aqueous solution.

The pharmaceutical composition prepared according to the invention may, if desired, be in the form of a powder. The powder is preferably designed to dissolve rapidly upon contact with the mucosa. The powder is preferably amorphous, and any crystals present are extremely small in size.

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Other pharmaceutical excipients for nasal administration may be present if desired. The exact choice of other excipients will depend on many factors, for example the stability and tolerability of the resulting pharmaceutical composition. The effect of several excipients has been described in the literature [e.g. H. J. M. van de Donk et al .; First European Congress of Biopharmacy and Pharmacokinetics 1-3 April 1981, ed. J. M. Aiache and J. Hirtz, Clermont Ferrand, ss. 406-413]. For example, an antioxidant or preservative such as sodium metabisulfate or methyl parahydroxybenzoate, or preferably benzalkonium chloride, cetylpyridinium chloride or phenyldodecinium bromide, sodium benzoate, sodium propionate or sodium sorbate, sodium sorbate, may be present.

The weight ratio between the antioxidant or preservative and the color promoter is preferably kept very low, for example from about 0.2: 1 to about 0.02: 1. The concentration of the antioxidant or preservative in the liquid may be, for example, 0.001 to 0.2%.

If desired, a surfactant such as sorbitan monooleate may be present. The amounts of pharmaceutical excipients are, of course, kept to a minimum, for example, in a liquid less than about 5% of the amount of xanthine or other hair promoter in the composition.

When the nasal pharmaceutical composition is in solid form, an inert carrier may be used, which may comprise about 97.5 to 85% of the composition. Alternatively, an inert carrier is not necessary.

The final pH of the 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.

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The desired pH can be obtained using a buffer system, for example acetic acid / sodium acetate, CO 2 / HCO 3® or HPO 4 / H 2 PO® and PBS buffer.

The pharmaceutical compositions according to the invention may be formulated in a conventional manner, for example by mixing the ingredients, for example, into an aqueous solution, followed, if desired, by filtration and / or sterilization under conventional conditions, for example by heating. If a powdered pharmaceutical composition is desired, the lyophilized product is preferably selected by subjecting a cooled solution of the nasal pharmaceutical composition under reduced pressure.

Nasal pharmaceutical compositions prepared in accordance with the invention are preferably Paka-15 in a conventional nasal spray applicator which is designed to provide a composition as a spray. If desired, a pressure of a compressed gas, for example air, nitrogen or a hydrocarbon such as freon, or an ultrasonic method can be used to provide the spray. The applicator 20 can be constructed to accommodate a unit dose; it may be, for example, an ampoule, capsule or the like containing a single dose-equivalent amount of a pharmaceutical composition for nasal administration. Alternatively, the ampoule may be large enough, for example 0.5 to 10 ml, to provide multiple doses of a pharmaceutical composition for nasal administration. Numerous suitable nasal spray applicators are known, for example "Microcompack", manufactured by Aerosol Services AG, CH-4313 Moehlin, Switzerland; or applicators manufactured by Valois S. A., BG G-26110 Le Neubourg, Rans-30 ka; both of which give liquid sprays.

The ampoule can be broken before it is placed in the liquid spray applicator.

When the nasal pharmaceutical composition prepared according to the invention is a liquid, the volume of the composition contained in a single dose can vary widely. A suitable volume is 0.1 to 0.2 ml. The particle size of the spray is preferably greater than 800, for example 800 to 1,000.

When the nasally administered pharmaceutical composition prepared according to the invention is solid, the volume and particle size of the composition to be administered in a single dose can also vary widely. The volume is preferably about 0.1 cm 3 and the particle size is about 800 to about 1,000 μm.

In the case of a preferred active agent, dihydroergotamine 10, the ratio of xanthine or other hair promoter to the active agent is preferably from about 1: 0.1 to about 1: 1. The pharmaceutical composition is preferably in the form of a liquid containing from about 0.2% to about 2% by weight of xanthine or other substance capable of improving the function of the hair follicles. Glucose is preferably present.

A particularly preferred nasal pharmaceutical composition according to the invention is an aqueous solution containing 0.4% dihydroergotamine mesylate-20, 5% glucose and 1% caffeine. This composition is hereinafter referred to as "composition A".

The effect of the caffeine contained in the nasally administered pharmaceutical compositions according to the invention on the mucosa and the iris hair can be determined conventionally by in vitro and in vivo experiments. One particularly suitable in vitro assay has been described above.

Another experiment can be performed by the method described by R. Guillerm [Il Farmaco, 1 (1972), p. 1 - 18]: 30 A piece of sheep's or rat's trachea containing cilia and mucus is applied to a plate maintained at 35 ° C by means of a thermostat. For nasal administration, the pharmaceutical composition is sprayed into the trachea with an ultrasonic aerosol device which sprays 1 ml of 35 solutions per liter of air per minute for 5 minutes. The diameter of the spray nozzle is 2 to 4 pm. The vibration frequency of the hair follicles li 81258 is measured by the photographic oscillographic method of R. Guillerm et al. [Physiol. 57 (1965), p. 725]. In this experiment, the composition A prepared according to the invention has a very small effect on the function of the cilia.

The following is an example of the results obtained according to the above-mentioned Chevance technique.

10 Time since administration (min)

Composition 0_5 10 20 30 60 90 j Frequency of oscillation of cilia; ____ (vibration per minute) _ 5% glucose 420 480 nt nt nt 420 nt 15 1% caffeine 340 380 nt 500 nt nt 520 1% caffeine + glucose 320 240 300 420 420 nt nt

Composition A 360 nt 380 300 nt nt_nt nt = not measured 20

In another in vitro experiment, the rate of movement across a piece of trachea containing sheep mucus was studied by the method of S. Battista [Screening methods in Pharmacology, ed. R. A. Turner and P. Heebborn, Vol. 2, Academic 25 Press, New York (1971), p. 167 - 202]:

The trachea is kept stretched in a temperature controlled chamber. The rate of movement of the particle across the mucosa is studied, including the rate of movement across the surface of the trachea sprayed with about 0.1 to 0.2 ml of the nasal pharmaceutical composition.

An example of the results obtained with composition A according to the invention is the following:

In Experiments 1 and 2, 130 μΐ of Composition A was sprayed (moment 0 min) onto a 1 cm wide zone about 12 to 35 min from the starting point of the particle. The following results were obtained from these tests: 12 81 258 _Test 1__Test 2_______

Time Traveled Speed Traveled Speed (min) __ distance (mm) (mm / min) __ distance (mm) (mm / min) 5 5 38 7.6 50 10 7 52 7 70 10 9 (a 70 9 90 10 12 (b 83 4.3 110 6.7 15 (c 110_ 9_ 140_10__ 10 a) entering the sprayed area b) crossing the sprayed area c) leaving the sprayed area

As can be seen, the velocity of the particle decreases only slightly as it crosses the belt zone treated with Composition A.

The effects of a nasally administered pharmaceutical composition prepared according to the invention on mucus and ciliary hair can also be monitored by in vivo experiments.

A clinical experiment was performed to measure nasal dryness by the method of I. Andersen et al. [Am. Rev. Respir. Dis. 110 (1974), ss. 301-305].

In one experiment, a saccharin crystal (0.4 to 0.6 mm in diameter) is placed on the nasal mucosa of healthy volunteers, in the area of the middle cortex in front of the upper ne-visual canal, where the nostrils are most permeable. The time taken by the subject to sense sweetness is recorded as mucosilary transport time.

Approximately 0.13 ml of the pharmaceutical composition for nasal administration is sprayed into the nose. The saccharin crystal is placed in the nose after 3 minutes. After 5 min, subjects are asked at 30 s intervals if they experience a sweet sensation.

The average results obtained for Il 13 81 258 12 subjects were as follows:

Test substance__Transport time (e (min) _ 5 Placebo (d 15.2 ± 4.7

Composition A__13.9 t 2.6_ d) 0.9% aqueous NaCl solution e) Time from spraying to sweet sensation 10 Composition A slightly but not significantly reduced the transport time. The composition was generally well tolerated. One person in 12 experienced mild motile stinging in the nasal mucosa when using placebo and 2 out of 12 people using Composition A.

In the second preliminary experiment, the reference solution mentioned on page 1 was used. The results were as follows:

Test substance__Transport time'8) (min)

Placebo '* 5 15.44 ± 3.86 20 Reference__22.50 t 10.12_ d) and e) as in the previous table

An undesirable 40-45% increase in transport time was observed. 4 out of ten subjects felt irritation-25. 3: 11a out of 10 subjects have vasomotor disorders (nasal irritation and congestion).

In addition, although sufficient amounts of the nasal pharmaceutical composition of the present invention to be administered to the nasal mucosa are administered to provide a therapeutic effect, the amount of xanthine absorbed may be small.

For example, in a double-blind clinical trial, nasal spray containing Composition A was administered to 10 healthy volunteers. The dose contained 2.6 mg of 35 caffeine. The caffeine concentration measured in the blood in one preliminary experiment was as follows: 14 81 258 Area under the curve (ng / ml / h) 22.29 ± 3.94

Maximum concentration (mg / ml) 2.34 ± 0.52

The amount of caffeine detected in the body was thus 10 -5 to 20 times lower than would be expected when drinking one cup of coffee (containing, for example, 50-100 mg of caffeine).

The efficacy of the compositions of the invention may be determined by conventional clinical trials. 10 For example, Composition A has been the subject of a clinical study in patients with migraine.

The study was performed using Composition A and placebo in 9 patients in double-blind, crossover experiments. Each patient was treated for one month with either Formulation A or 15 placebo.

Spray applicators designed to deliver 0.5 mg dihydroergotamine / dose of Composition A or an equivalent volume of placebo solution were used. At the onset of a migraine attack, each patient sprayed a dose of 20 into each nostril. Dosing was repeated at 30-min intervals if the seizure continued; the maximum number was 4 doses per day.

7 of 9 patients treated with Formulation A felt relief from a migraine attack. With Pla-25 sebo, only 1 patient experienced some relief. Other results obtained in this study were as follows:

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Treatment ________Composition A Plasebo

Total number of migraine attacks 5 41 26

Score

Facilitating the scene 22 0

Seizure Deterioration 5 6 10 No Effect _14_20 These results indicate a statistically significant alleviating effect of Composition A on a migraine attack.

According to the criteria used worldwide, the tolerability of Composition A was excellent in 8 patients and acceptable in 1 patient.

As mentioned above, the pharmaceutical compositions prepared according to the invention are stable. Stability can be measured by standard stress-stability tests, which measure the concentration of the active substance. For example, the results obtained for composition A and the reference solution are as follows: 25___

Reference solution__Composition A_

Time Active substance concentration Active substance concentration (weekly (%) at different temperatures __ (%) at different temperatures

chamber) 35 ° C 44 ° C 50 ° C__35 ° C 44 ° C 50 ° C

30 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 35 As can be seen from the above results, composition A is overall more stable than the reference solution.

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In further experiments, the stability of the lyophilized product was shown to be excellent even at a temperature of 50 ° C.

In the second stability test, a plunger-nasal spray applicator attached to a flask containing Composition A 5 or a reference solution (10 ml) was used to produce a 0.13 ml spray of soil 11, 21, 31, 61 and 91 days after filling. Once the dose has been sprayed out of the bottle, air is sucked in to replace the sprayed solution, and thus the air may promote disintegration.

The dihydroergotamine content of Composition A after 91 days was about 89% of baseline. The ergotamine content of the reference solution was 81% of baseline after 61 days and 66% of baseline after 91 days.

The stability of Composition A was significantly better than that of the reference solution.

All percentages and weight ratios are expressed as mass percentages except for percentages in liquids expressed as masses per mass volume.

The following example illustrates the invention.

20 Example 1 1.) Composition

Ingredients: / ml / 10 1 dihydroergotamine mesylate 0.004 g 40 g caffeine 0.010 g 100 g 25 glucose 0.050 g 500 g is made up to 1 ml with water to 10 l 2.) Preparation of the composition Saturate 9 l of water with carbon dioxide. 100 g of caffeine and then 40 g of dihydroergotamine mesylate are dissolved in water 30. Dissolve 500 g of glucose in the solution with stirring without stopping the impregnation with carbon dioxide. Make up to 10 l with water. The mixture is filtered in the presence of carbon dioxide through a filter (0.22 μm orifices).

17 81 258 3.) Filling the ampoules

The ampoules are filled with up to 1 ml of solution under carbon dioxide, sealed and then autoclaved at 121 ° C for 5 min. The pH is typically 4.38 -5 to 4.46 at 22 ° C.

4.) Operation

The ampoules are opened by breaking and placed in a conventional nasal spray. The nebulizer sprays approximately 0.13 ml of a solution containing 0.5 mg dihydroergotamine at a time.

10 The dose is taken through the nose 2-4 times a day for the treatment or prevention of migraines.

Claims (7)

18 81 258 A process for preparing a pharmaceutical composition for nasal administration, characterized in that xanthine is added to a composition containing ergotpeptide alkaloid, preferably in solution, so that the weight ratio of xanthine to ergotpeptide alkaloid is 1: 0.1 to 1:10. Process for the preparation of a composition according to Claim 1, characterized in that dihydroergotamine is used as the ergot peptide alkaloid as the free base or as its acid addition salt, preferably as the mesylate. Process for preparing a composition according to Claim 1 or 2, characterized in that theophylline is used as the xanthine. Process for preparing a composition according to Claim 1 or 2, characterized in that caffeine is used as the xanthine. Process for preparing a composition according to any one of claims 1 to 4, characterized in that a non-toxic isotonizing agent is used as an additive, wherein the ratio of xanthine to non-toxic isotonizing agent is about 1: 0.05 to 1:10. Process for preparing a composition according to Claim 5, characterized in that a sugar which is preferably glucose is used as the isotonizing agent. Process for preparing a composition according to any one of claims 1 to 6, characterized in that an aqueous solution containing 0.4% dihydroergotamine mesylate, 5% glucose and 1% caffeine is prepared. Il 19 81258