NL8502178A - NEW PHARMACEUTICAL PREPARATIONS. - Google Patents

Description

- 1 - * ‘a

New pharmaceutical preparations.

The present invention relates to new pharmaceutical preparations, in particular to new pharmaceutical preparations containing a) ketotifene and b) a xanthine effective against asthma in a fixed combination.

The compound ketotifene of formula 1 is a known therapeutically active agent with valuable antianaphylactic properties and in particular has a potent inhibitory effect on mediator systems responsible for anaphylactic reaction and has found wide application for the long term prevention or prophylaxis of all forms of bronchial asthma, allergic bronchitis and asthma symptoms associated with hay fever. This compound has also found use in the prevention and treatment of multi-system allergies, allergic rhinitis and allergic skin reactions. As already noted, its operation is mainly focused on mediator systems. It has almost no direct bronchodilator effect and, when administered, for example for the treatment of asthma, its practical utility is in principle preventive or prophylactic.

The xanthines effective against asth-25πia comprise a large and recognized class of compounds, the most commonly used representative of which is the usual anti-asthmatic drug theophylline of formula 2a.

As a class, the said xanthines are pharmacologically characterized by their relaxing effect on the smooth muscles and, unlike ketotifene, their use in asthma indication is consequently aimed at their bronchodilator effect, ie related to their ability to control bronchoconstriction during an asthma attack. prevent or terminate.

In view of its complex etiology, the treatment of asthma is generally performed using fetv zi7a * * * 2 - a mixed regimen and descriptions for the co-therapeutic application of ketotifene and theophylline in the treatment of asthma are abundant. found in the prior art. The main motive for the co-therapeutic application of ketotifene and theophylline has, of course, been the complementary beneficial effect inhibiting (prophylactic) effect of ketotifene and the direct bronchodilator effect of theophylline. In addition, numerous reports have drawn attention to the beneficial, compensatory effect obtained through the interaction of the central nervous system depressant action inherent with ketotifene and the central nervous system stimulant effect inherent with theophylline.

More recently, a limited number of reports have been published that hypothesize a possible effect of a joint therapeutic application of ketotifene and a low dose of theophylline, ie, normal doses of ketotifene together with lower doses of theophylline, for example doses as low as half of the usual theophylline doses are used, see for example: i) A. Franck, Wiener Med. Wochenschrift, 129 (Supp.

54), 6 (1979); ii) A.G. Palma-Carlos, Allerg. Immunol. (Paris) 14, (4), 46-64 (1982); iii) Celga et al., Allergolog. Immunopathol., Jj, 387 25 (1980) and iv) Stableforth and med., Orally at the Xlle conference of the European Academy of Allergology and Clinical Immulogy, Rome, September 1983.

If a joint therapeutic use of ketotifene and a low dose of theophylline was proposed, the main reason for this was the mutually compensatory CNS-depressant / CNS-stimulating effects of the two compounds / see references under i) and ii) above /, or an assumed "potentiation" of the direct bronchodilator activity of theophylline by ketotifene / see reference i) above 8502178. * 4 - 3 - ("synergistic" activity of theophylline on other agents with anti-asthma activity attributed to the phosphylesterase inhibitory activity of theophylline); reference ii) above ("potentiation of bronchial muscle relaxation); reference iii) above-5 (reduction of chronic obstructive pulmonary disease); and reference iv) above (ketotifene modulates the bronchodilator activity of theophylline).

However, a critical review shows that such references can be misleading and that the terms "synergy" and "potentiation" are used in cases where only one additive effect (broncholytic for theophylline plus a protective one for ketotifene) is intended. Moreover, the experimental design employed does not in fact generally allow demonstration of synergism, in contrast to the additive activity.

Although the usefulness of xanthines with an anti-asthma activity, for example theophylline, for the prevention of asthma has previously been attributed to their direct bronchodilator effect, data now available show that they actually also have a preventive (prophylactic) effect / Hamble- ton and med., Lancet J_, 381-385 (1977) 7. In addition, this effect may not be related to the bronchodilator effect, since, for example in the case of theophylline: a) in the hospital, the hyper-reactivity of airways can be reduced by using non-bronchodilator doses / Lopex - Vidriero and Med., Am. Rev. Respir. Disease, 129, 30 (1984) and b) a therapeutic effect can be observed in patients with subbronchodilator drug serum levels, eg, in the case of theophylline less than 10 µg / ml, and it is common, for example, when using theophylline to combining this with drug serum levels of sub-bronchodilator / Woodcock et al., Lancet ii, 610-613 (1983) 7.

35 However, in spite of the evidence, the preventive effect of the xanthines with anti-asthma activity, including theophylline, in asthma has so far found relatively little recognition and the reason for its therapeutic use in the treatment of these their disease has remained their direct bronchodilator effect, as appears from numerous review articles regarding the treatment of asthma, see, for example, Robertson et al., "Chest" 82 (1), 645-685 (1985).

The precise mechanisms by which ketotifene and the xanthines acting against asthma, for example theophylline, exert a preventive action against asthma remain the subject of extensive speculation. However, it is now known that the platelet activating factor (PAF) exhibits many properties that are a prerequisite for a mediator of both inflammation and asthma / Page and med., Trends Pharm. Sci. 5> 239-241 (1984) /. The action of PAF in reproducing most facets of an inflammatory response has been extended to human tissues using subcutaneous injection and tracheal instillation / Archer et al., Br. J. Dermatol. 110, 45-50 (1984) and Gatear et al., Am. Rev. Resp. Dis. 129, A320 (1984) /. In rabbits, PAF formation appears to be the central factor through which anaphylactic responses are expressed / Halons and med., Am. Rev. Respir. Dis., 122, 915-924 (1980); Henson et al., J. Immunol. 1977; and Shen and med., "Proceedings of the 1st World Conference on Inflammation: Anti-rheumatics, 25 Analgesics and Immunomodulations" Eds. Bertelli and Med., Bioscience Ediprint, Geneva, In press_ /. It is also known that the allergen-induced bronchospasm and spontaneous exacerbation of asthma are associated with decreased platelet reactivity for PAF, in an analogous manner to that observed in 30 rabbits / Thompson et al., Am. Rev. Resp. Dis., 129, A3 (1984) 7. This substantial evidence justifies assigning a role as a vital mediator of both asthma and inflammation to PAF, and indeed the evidence in favor of involvement of PAF in asthma as well as other inflammatory diseases is considerably more extensive than that to undermine. \ 0 1 7 ^ ♦% - 5 - support for the pathology associated with mast cells has been offered.

It has already been shown that both ketotifene and, for example, theophylline inhibit PAF-induced bronchospasm / Saunders enmed., Thrombos. Haemostas. 50, 1493 (1983) 5 and Medieros enmed., J. Pharmacology 14, 98 (1983) /. In connection with the present invention, it has now surprisingly and unexpectedly been found that in combination ketotifene and the anti-asthmatically active xanthines, for example theophylline, exert an inhibitory effect on the PAF-induced bronchospasm greater than the sum of their separate actions (super additive synergy). Thus, if we take theophylline as a representative of the xanthines with anti-asthma activity, it has now been found that the activity of ketotifene and theophylline in the mediator field, ie, their activity in relation to preventive or prophylactic utility, is mutually and synergistically potentiated. is. More importantly, it has been found that ketotifene synergistically enhances the preventative or prophylactic utility of, for example, theophylline, in theophylline dosages which are classically lower than therapeutic, ie, 20, dosages insufficient to induce bronchodilation. An equivalent synergistic interaction at the media level can also be demonstrated using ketotifene and other antiasthmatically effective xanthines, as will be explained, for example, below.

Based on this surprising and extraordinary finding of synergies related to the preventive (or prophylactic) utility, the present invention now provides: a pharmaceutical composition containing a) ketotifene and b) an antiasthmatically effective xanthine, in a fixed combination. .

By providing a fixed combination, the present invention allows for the full and practical, ie clinical, realization of the therapeutic benefit obtained from the mediator-synergistic interaction of the defined components a) and b), as discussed above.

8502178 0 t - 6 -

The particular advantage of the present invention will be apparent if one takes into account the fact, as discussed above, that in practice drug serum levels, for example of the antiasthmatically effective xanthine, theophylline, are insufficient for bronchodilation, inescapable feature of normal theophylline therapy. This is an unavoidable consequence of theophylline's known, extremely rapid excretion rate from the body and, consequently, of the theophylline "once daily dose", generally regarded as an important therapeutic goal of the slow-release theophylline treatment.

In addition, in the hospital, the synergistic interaction at the mediator level, as discussed above, obtained using the compositions of the invention may be beneficial to treated patients, not only in terms of preventive or prophylactic utility, but also expressed in the related mediator level systems, for example in synergistic reduction of airway hyper-reactivity and development of mucous membranes and inflammation, etc., as evidenced by an improved patient response, expressed for example in the degree of airway obstruction, particularly during an asthmatic attack. For example, an airway obstruction, to be determined by standard clinical study methods, as described, for example, hereinafter, can be synergistically reduced when administering the compositions of the invention containing the two components a) and b), compared to the results raging in patients receiving a) or b) alone. This interaction which occurs when using the compositions according to the invention can be particularly evident during the initial phase of the treatment of asthma, for example during the first 4-6 weeks after the start of the therapy.

Only the cotherapy cannot be anticipated for, reproduction.

cably providing the described medium level synergistic interaction obtained under 8502178% -7 use of the compositions of the invention in the hospital. In addition, despite the prior art reference regarding drug interactions, for example, between theophylline and ketotifene, as discussed above, no proposal for a fixed combination administration has previously been made.

Ingredient, a) ketotifene, may be present in the compositions of the invention in both free form and in the form of a pharmaceutically acceptable acid addition salt, for example, in the form of its hydrogen fumarate. Such salt forms are well tolerated. References to ketotifene in this specification are, therefore, to be construed as including both the free compound and its pharmaceutically acceptable acid addition salts unless otherwise indicated.

In the compositions of the invention, component a) is preferably present in the form of its hydrogen fumarate.

Suitable anti-asthmatically effective xanthines for use as constituent b) in the compositions of the present invention include those of formula 2 wherein i) R 1, R 1 and R 1 each represent a hydrogen atom and R 1 an n-propyl group, or ii) R 1 and R 1 each represents a methyl group, R 1 a group and R 1 a benzyl group, and iii) R 1 and R 1 each represent a methyl group, R 1 a hydrogen-25 atom, and R 1 represents the group of formula III.

The compounds i) to iii) above are known and, together with processes for their preparation, are described, for example, in i) European patent 0011609, ii) Belgian patent 602,888 and iii) European patent 30 0089028. Of these, the recommended compound for use in the compositions according to the invention i), which is also known and hereinafter referred to as enprofylline. The most recommended antiasthmatically effective xanthine for use in the compositions of the invention, however, is the compound theophylline 35 of formula 2a referred to above.

3502178 P \ - 8 -

The ingredients b) can be in the formulations of the invention in free form, in the form of any of their known mixtures with a pharmaceutically acceptable additive, especially pharmaceutically acceptable amines, such as choline, ethanol, diethanolamine, etc., or are in the form of a pharmaceutically acceptable acid addition salt thereof, including the pharmaceutically acceptable acid addition salts of such additive mixtures. Additive mixtures and salts thereof are, as already mentioned above, known in the art and generally have the advantage of greater solubility, compared to the free compound or its salts. In the case of the antiasthmatically effective xanthine theophylline, the products include, for example, theophylline calcium salicylate, theophylline diethanolamine, theophylline isopropanolamine and, in particular, aminophylline. / a 2: 1 (p.p.w.) combination of theophylline and ethylenediamine /. Such combinations and salts are also well tolerated, and references to antiasthmatically effective xanthines herein, as well as to specific xanthines of this class, such as theophylline, should therefore be understood to include both the free forms and the adjuvant mixtures and salts, such as mentioned above, unless otherwise indicated. Preferably, the xanthines effective against asthma, including those recommended, such as xanthine, theophylline, etc., are present as component b) in the compositions of the invention, present as the free compound, for example, as the free theophylline.

Pharmaceutical preparations according to the invention include any suitable form useful for administration, enterally or parenterally, containing components a) and b), in a fixed combination, ie together and each in a predetermined amount , for example, in a predetermined relative amount. Recommended compositions according to the invention are forms suitable for oral administration, including capsules, tablets, syrups, etc. Preferably, the compositions of the invention are a unit dosage form, for example, for oral administration, where each dosage will contain a predetermined amount of each of components a) and b).

Preparations according to the invention include both systems in which the components a) and b) are clearly separated, for example present or separately present in the preparation, and systems in which the said components are intimately mixed or both are almost uniformly dispersed in a conventional matrix . Preparations of the first type comprise 10 capsules, for example for oral administration, each of which a) and b) are in an independent, granulated, powdered, tableted or similar form (mixed together or not) or completely separated, for example in separate compartments of a separated capsule or in separate layers of a shell tablet. Preparations of the latter type include, for example, tablets or corresponding preparations, in which a) and b) are each distributed almost uniformly over the tablet mass or matrix. In such cases, the tablet mass or matrix will generally contain a substantially uniform matrix incorporating carriers, solid diluents and / or binders, etc., as commonly used in the art. Such compositions may be obtained by methods well known in the art, such as described in the examples below, for example.

It is further recommended that component b) is present in the compositions of the invention in a slow-release form, ie in a form that allows for a sustained release of component b) into the body or tissues, over prolonged periods of time or can maintain relatively constant blood serum levels of component b) for prolonged periods of time after administration.

Suitable slow release forms of component b) are known in the art and can be obtained by any of the methods known and conventional. 8502 1 7 8 - 10 - are used in the galenic field, particularly in connection with the slow release formulations containing xanthines, see for example European Patent 0122077, U.S. Patents 4,415,547 and 3,400,185 and PGT Patents Application WO 8300284. This includes slow release pellet molds in which, for example, individual particles of a granular product, powder or a corresponding product containing b) are provided with a (suitable) slow release coating. They can be obtained, for example, by coating a finely divided preparation, for example granular or powdered preparation, of the drug mass with a suitable resistant, for example resistant to gastric juice, but not visceral, layer. Specific examples of such slow release pellet molds are described below. The specific release properties of component b), which are obtained in such a manner, can be varied if desired, for example by selection of the coating material, by variation of the thickness of the applied coating layer and / or variation of the particle size of the coated material. Since the excretion rate of xanthine derivatives effective against asthma, for example theophylline, is very specific to the product, the blood-serum levels obtained using a special slow release preparation will inevitably vary considerably from individual to individual vary. Generally, however, in the case of, for example, slow release theophylline forms suitable for use in the compositions of the invention will be such that blood serum levels of the order of about 8 to about 20 ng / ml during periods of, for example, about 4 to about 8 hours or more, for example, periods up to about 6 hours, after administration are obtained.

In the case of theophylline, recommended slow release forms of component b) will be such that under laboratory conditions the following approximate theophylline-8502178-11-release properties are obtained: 1. When dissolved in an amount of about 200 mg in 1000 ml of 0.1 N HCl: a) the percentage of theophylline release after 3 hours = about 40-60%, preferably about 45-55%, for example about 50%; b) the percentage of theophylline release after 8 hours 55 about 70-90%, preferably about 75-85%, for example about 80%.

2. When dissolved in an amount of about 100 mg in 1000 ml of 0.1 N HCl: a) the percentage of theophylline release after 3 hours about 45-60%, preferably about 50-57%, for example about 53%; B) the percentage of theophylline release after 8 hours * about 80 to 100%, for example about 85-95%, for example about 90%.

The average theophylline release under the conditions mentioned under 1) above after 1 hour will preferably not exceed about 30%, in particular about 25%. Theophylline release for one hour under the aforementioned conditions 1) over an 8 hour period suitably ranges within the range of about 4 to 20%, preferably about 5-15% per hour.

Thus, such forms conveniently provide a maximum theophylline release of i) about 60%, preferably about 55% and ii) 100%, preferably about 90-95% after i) 3 hours and ii) 8 hours, under the standard conditions which previously indicated under 1 and 2, respectively (all measurements were made at ambient temperature with a paddle stirrer at a rate of about 90 rpm. The pH was adjusted appropriately after about 120 minutes).

If component b) is theophylline in free form, a recommended slow release form that can be used in the compositions of the invention is theophylline retard-8502178-12 pellets, commercially available as the BRONCHORE-TARD product from KLINGE AG. The manufacture of another recommended slow release form is described in Example 1a below.

In general, components a) and b) will be present in the compositions of the invention in a ratio of about 1:50 to 500 p.p.w., preferably about 1: 100 to 500 p.p.w. (a: b). In particular, in recommended embodiments, the compositions of the invention contain ingredients a) and b) in a ratio of about 1:50 to 350 ppw, especially about 1: 100 to 300 ppw, or about 1:50 to 300 ppw, in particular about 1: 100, 200 or 300 ppw, for example about 1: 200 or 300 ppw.

If the compositions of the invention contain a unit dosage form, the individual unit dosage forms will suitably contain from about 1 to about 2 mg, preferably about 1 mg, of component a). Suitably, in such unit dosage forms, up to about 500, preferably up to about 350, in particular about 300 mg, component b) will be present. Thus, recommended unit dose 20 will form about 1 mg to about 2 mg (but especially about 1 mg) of component a) and about 50 to about 500 mg, preferably about 100 to about 350 mg, e.g. about 100, 150, 175 200 or 300, especially about 175, 200 or 300 mg of component b), intended for 1 to 4 times, especially 1 to 2 times daily.

Such formulations will be suitable for use in the treatment of all conditions for which it is customary to use the ketotifene therapy, as well as for diseases in which a bronchodilator effect is required, for example in the treatment of active asthma and in the initiation of the asthma therapy. Once a daily dose is provided, or the bronchodilation is very important to the cure, the amounts of component b) will generally be greater, for example in the case of unit dose forms of the order of about 200 mg, or preferably 300 mg and 8302178-13 higher. The dosages should be administered 2 times a day or more often, or if bronchodilation is not very important for healing, for example in case of asthmaprophylaxis / maintenance therapy, or in the treatment of bronchitis, 5 the amounts of constituent b) those present in the compositions of the invention are lower, thus taking particular advantage of the synergistic interaction of the two components at the mediator level, as described and illustrated herein. For such purposes, the compositions of the invention may contain only about 50 to about 300 mg.

The aforementioned weight ratios and indicated mg values relate to the use of the components a) and b) in free form, ie to the amounts / relative amounts of free ketotifene and, for example, free theophylline. If salts / associated additives of components a) or b) are used, the amounts used will be those corresponding to the stated amounts of free a) or free b).

The beneficial effect of the preparations according to the present invention and in particular the synergistic interaction of ketotifene and the xanthines with an effective action against asthma, for example theophylline, for example with regard to the protective effect, as described above, can both clinically and using conventional animal models are demonstrated. Thus, the mutual synergistic interaction of ketotifene and theophylline in the mediator field, for example with regard to the PAF-induced bronchospasm, can be demonstrated for example as follows:

Methodology.

The spontaneously breathing, anesthetized guinea pig 35 responds to an intravenous injection of PAF with a toe. Γ. o -J 7 o -14 - decrease in airway resistance and decrease in dynamic elasticity. The use of PAF for drug activity studies is complicated by differences in susceptibility between animals, by a very large dose-effect relationship, and by potential interaction between doses. However, it is possible to establish a protocol in which up to four consecutive intravenous injections of a constant dose of PAF, at 10 minute intervals, will elicit closely related responses. This allows the use of such preparations for a routine evaluation of drug effects. Such animals are administered the PAF injection intravenously 5 minutes before (ketotifene or saline) or 1 minute before (aminophylline - the theophylline combination specifically described above - or a saline solution). Inhibition is determined by comparing the post-treatment response with that immediately / immediately before the drug treatment. The paired difference between the two responses is appropriately expressed in a percentile of the response immediately prior to treatment with the drug.

In order to investigate the synergism between ketotifene and aminophylline, the isobolic method was adopted as a rigorous test / Berenbaum, Clin. Exp. Immunol., 28, 1-18 C1977). Doses of ketotifene between 0.56 µg / 25 kg and 18 µg / kg were used either alone or in combination with doses of aminophylline between 0.01 mg / kg and 0.32 mg / kg. Responses were determined for at least five animals for each dose or dose combination, except for salt-treated animals (nine) and animals receiving 0.32 mg / kg aminophylline (ten) or 1.8 µg / kg ketotifene (seven ) if additional animals were used. A total of 86 animals were used for the study.

Results.

35 8502178 - 15 -

Treatment of the animals with two doses of salt caused an insignificant decrease (4%) in the response to PAF. Treatment with ketotifene caused a dose-dependent decrease, with inhibition evident at the lowest dose. Also, treatment with aminophylline caused a dose-dependent inhibition, but with a flatter slope than was observed with ketotifene. These values, along with those of drug combinations, are graphically depicted in the accompanying Figure I. Herein, the inhibitory effects of each dose in addition to the axes are indicated. The inhibitory effects of drug combinations are indicated at the appropriate intersections. From this data, it is possible to construct two isobols for the inhibition responses for aminophylline. Both isobols are concave, which is characteristic of a synergistic interaction.

15

Conclusion.

There is clear synergism between ketotifene at a near therapeutic dose and aminophylline at a dose which may be considered lower than the therapeutic dose for a bronchodilator effect, but produces drug concentrations that usually occur in both asthma and bronchitis during aminophylline therapy.

The beneficial effect of the compositions of the present invention can be demonstrated by clinical trials, conducted, for example, as follows:

The test conditions.

The trial was conducted on a group of 12 patients, both men and women, aged between 16 and 65 years. The selected patients show both seasonal and persistent chronic bronchial asthma (with reversible, allergic or mixed form tronchospasm), such as anamnesis-35 diagnosed by a skin test or determination of the allergen λ iu λ «4“ 7 w i - »* * 'j» Ψ κ - 16 - no specific IgE and, if necessary, confirmed by challenge by inhalation. The mild to moderate severities are characterized by mild to moderate bronchial obstruction with repeated assessment of seizure / duration symptomatology.

5 The following exclusion parameters were used: pregnancy, severe liver or kidney disorders, after a myocardial infarction (no more than 6 months), difficult to control diabetes mellitus, gastrointestinal disorders prone to influencing resorption, metabolism or excretion of the test 10 compound, for example, chronic diarrhea, malasorption syndrome, etc., heart rate disorders, gastric and intestinal ulcers, patients known to be unreliable or psychologically unstable.

As far as possible, patients received only 15 additional ath -symathomimetic or anticholinergic drugs if essential for ending the asthma attack. If absolutely necessary, other drugs, for example corticosteroids or antibiotics, were allowed, registering the nature of such treatment, duration and dosage used. In the event that patients were already receiving continuous bronchodilator, steroidal, or theophylline therapy, this was gradually reduced over the first two to three weeks of the trial.

For the test the following preparations were used: v 25 a) tablets containing 1 mg ketotifene + 200 mg slow-release theophylline in a fixed combination and prepared according to Example I below, b) tablets containing 1 mg ketotifene + 300 mg slowly-released theophylline in a fixed combination and prepared according to Example 2 below, c) tablets containing only 1 mg ketotifene and manufactured according to Example Ib below, but with the exception of component a), d) tablets containing 200 mg slow-release theophylline-35 which, according to Example Ib below, but 8502178 * - 17 - were produced with the omission of component b), e) Tablets containing 300 mg of slow-release theophylline, manufactured according to the following following Example II, but omitting component b).

5 Each patient received 420 tablets. The test preparations were distributed to the patients in a random, double-blind manner, whereby patients weighing ≥ 50 kg receiving theophylline (alone or in combination with ketotifene) were provided with a 200 mg theophylline preparation / i.e. 10 according to a) or d) above_ /, while patients weighing> 50 kg receiving theophylline (alone or in combination with ketotifene) were provided with a preparation containing 300 mg theophylline / i.e. according to b) or e) above_ /. All tablets had an almost identical appearance, with the tablets c) being provided in two sizes, small (for administration to patients with ^ 50 kg) corresponding to alternative tablets containing 200 mg theophylline, while the larger (for administration to patients of > 50 kg) correspond to alternative tablets containing 300 mg theophylline.

20 During the course of the study, each patient took two tablets orally daily (morning and evening). The duration of the study was 6 months for each patient.

Clinical monitoring was performed for each patient 2, 4, 6 and 8 weeks after the start of the trial and then at 25 4-week intervals thereafter. The following parameters were determined during each check: - Vital capacity - Expirator spare volume - Functional residual air capacity 30 - Total resistance - Closing volume - Current volume.

Details of the number and severity of the symptoms occurring, the occurrence of difficulty breathing, coughing, giving up, reported by the test patients 8502 1 7 8-18, were recorded.

At the start of the test, 5 ml of blood was taken from each patient, which was also done 1 month later to determine the theophylline. The second sample was taken 4-8 hours after the administration of the test preparation.

Results.

Patients receiving ketotifene + theophylline in a fixed combination were shown to show a significantly improved response, for example, for the following parameters listed, compared to patients receiving ketotifene or theophylline alone: 1-second capacity as percentage of vital capacity, flow volume 25 , total resistance and "closing volume".

A significant improvement was also observed in patients receiving ketotifene + theophylline in a fixed combination for the following listed parameters: vital capacity? expirator reserve volume, flow volume 25, 50 and 75 and the functional residual air capacity. In particular, the results obtained during the first 4 to 6 weeks following the start of the trial for the individually measured parameters, in particular total resistance, indicate that the registered activity for patients receiving ketotifene + theophylline in a fixed combination was greater than expected from the results obtained for patients receiving ketotifene or theophylline alone, ie, indicative of greater activity than additive activity.

According to the foregoing, the present invention also provides a pharmaceutical composition for the treatment of asthma which exhibits or provides a superadditive or synergistic activity against asthma, especially at the mediator level, or exhibits a superadditive or synergistic, preventive or prophylactic activity against asthma or provides, in particular at the mediator level, as evidenced, for example, by a reduction in airway obstruction, for example as a result of, inter alia, U2173 - 19 - a hyperreactivity of the airways, development of mucus, inflammation, etc., which preparation a) ketotifene and b ) contains a xanthine effective against asthma in a fixed combination (eg, as described herein).

According to an alternative embodiment of the invention, a method for the treatment, in particular for the preventive or prophylactic treatment, of asthma, in particular at the media level, or for the reduction of the obstruction of the airways, for example as a result of a respiratory hyperreactivity, mucus development, inflammation, etc., particularly during the preventive or prophylactic treatment of asthma, provided to a patient in need of such treatment, which method comprises administering a pharmaceutical composition comprising a) ketotifene and b ) a xanthine having an effective anti-asthma activity, in a fixed combination (eg, as described herein) to a patient, or the use of a pharmaceutical composition, (eg, as described herein) that a) ketotifene and b) a xanthine with an effective action against asthma, in a fixed combination, for the above defined the treatment, or the use of a) ketotifene and b) a xanthine effective for the treatment of asthma for the preparation or manufacture of a pharmaceutical preparation, (eg as described herein), which a) and b) in a fixed combination for use in the above-described treatment method.

35 3532178 - 20 -

Example I:

Manufacture of tablets containing 200 mg of free theophylline in a slow release form and 1 mg of free ketotiphene.

Ia) Manufacture of pellets from which theophylline is slowly released.

10 4.135 kg of ethyl cellulose, 0.37 kg of hydroxypropylmethyl cellulose and 0.53 kg of di-n-butyl phthalate were dissolved in a mixture containing 30 kg of isopropanol, 3 kg of ethanol and 10 kg of water, yielding a coating solution with a viscosity of 170 -230 cP was obtained.

49.5 kg of regular theophylline press grains (for example, those which can be supplied directly by Boehringer) were introduced, with about 9-10% of the grains having a diameter> 0.71 mm and about 60-70% of the grains having a diameter> 0, 50 mm) in the holder of a Glatt W56-60 spray coating device fitted with 2.5 mm diameter Schlick nozzles. The granular product was spray-coated with the coating solution described above, the coating taking place under the following conditions:

Distance between the bottom and the sprinkler: 50 cm 25 Vibration interval: 60 seconds

Duration of the vibration: 10 seconds

Spray solution temperature: 22-27 ° C

Spray pressure: 3.8 bar

Feeding capacity of the pump: approx. 20 1 / g

30 Temperature at the air inlet: 27-31 ° C

Temperature in the granulated mass: 25-27 ° C

Applied air volume: 2600-4600 m3 / h

After completion of the spraying process, the resulting spray coated product was dried for 10 minutes at a temperature between 45 and 55 ° C.

8502173 - 21 -

The entire spray coating process was carried out such that the total processing time was about 200 minutes to obtain a product in which the coating to theophylline ratio was about 1: 100 (p.p.w.).

Ib) Manufacture of tablets of the product.

Components * Relative quantity in mg_ a) Press pieces from which theophylline is slowly released, manufactured according to Ia) previously 220.30 * b) Ketotiphenium hydrogen fumarate 1.38 ** 15 c) Lactic acid 90.00 d) Cellulose granules 60.00 e) Cellulose powder 58.32 f) Stearic acid 100.00 20 * = 200 mg uncoated, free theophylline.

** »1 mg free ketotifene.

The ingredients were intimately mixed in a conventional manner and compressed into individual tablets having a total weight of 530.00 mg, each containing 200 mg of free theophylline and the equivalent of 1 mg of free ketotifene.

Theophylline release rate characteristics of the sample of the tablets were determined under standard laboratory conditions for 8 hours / 6 tablets in 500 ml simulated gastric acid (0.1N hydrochloric acid to pH 7.5 with a pH adjustment after 1, 2 and 3 hours) / . Using paddle stirring at 50 rpm, the results were: 35 8502178 - 22 -

Time elapsed Percentage released theophylline 1 hour approximately 12% 2 hours approximately 22% 3 hours approximately 34% 5 5 hours approximately 64% 8 hours approximately 87%

Example II

10 Manufacture of tablets containing 300 mg of free theophylline in a slow-release form and 5 mg of free ketotifene.

The procedure of Example 1 was repeated, but now the following relative amounts (in mg) of the components a) -f) were used in step Ib): a) 330.50 / = 300 mg uncoated, free theophylline_7, b) 1.38 (= 1 mg of free ketotifene).

c): 80. d): 60.00. e): 57.12. f): 100.00.

The product tablets each weigh 630.00 mg and contain 300 mg of free theophylline and the equivalent of 1 mg of free ketotifene.

Theophylline release rate characteristics for the tablets of the product, determined under standard laboratory conditions as described in Example I, are: 25 Time elapsed Percentage released theophylline 1 hour approximately 11% 2 hours approximately 21% 3 hours approximately 31% 5 hours approximately 65% 30 8 hours approximately 89%

Example III

The manufacture of capsules containing 150 mg of free theo-35 phylline and 1 mg of free ketotifene.

8502178 - 23 - lila) Preparation of the ketotifene tablet mass.

Components Relative amount in mg_ 5 a) Ketotiphenium hydrogen fumarate: 1.38 * b) Talc: 0.16 c) Calcium hydrogen phosphate: 35.26 d) Corn starch: 5.26 e) Dried corn starch 2.6 10 f) Magnesium stearate 0, 5 * = 1 mg of free ketotifene.

The ingredients were mixed in a conventional manner and compressed into individual tablets, each weighing about 45.00 mg and containing the equivalent of 1 mg of free ketotifene.

Illb) Manufacture of product capsules.

20

A hard gelatin capsule was filled with 162.9 mg of theophylline retard press-pieces from Klinge AG, as described above (= 150 mg uncoated, free theophylline (1 tablet obtained according to the step 11a) described above) and the capsule was closed.

Example IV

Manufacture capsules containing __ = 1 mg of free ketotifene and free theophylline in varying amounts.

In an analogous manner as described in Example III, hard gelatin capsules were obtained, which obtained 1 tablet according to Example III) and theophylline retard pellets from Klinge AG, as described in Example Illb), in the following 8502178

ν 'V

- 24 - stated amounts contain: IVa) 54.3 mg = 50.00 mg free, uncoated theophylline.

IVb) 108.6 mg = 100.00 mg free uncoated theophylline.

IVc) 190.05 mg = 175.00 mg free uncoated theophylline.

IVd) 217.2 mg = 200.00 mg of free, uncoated theophylline.

10 IVe) 325.8 mg = 300.00 mg free, uncoated theophylline.

IVf) 380.1mg = 350.00mg free uncoated theophylline.

Press pieces from which theophylline is slowly released of the general type described above in Example 1a, ie containing a theophylline granular product as core material and a described coating layer, are also new.

According to another aspect, the present invention also provides: I. Theophylline in a slow release pellet form, containing granular product consisting mainly of free theophylline as pellet core material, provided with a coating for the pellet incorporating ethyl cellulose and hydroxypropyl methyl cellulose.

Preferably, the coating is effected, for example in the manner described in example I, such that almost all the granules containing the core material are individually coated. Suitably, the granules containing the core material meet the dimensional characteristics described for the theophylline granular starting material in Example 1a. Suitably, the coating is effected such that the core material and the coating layer in the obtained pellets are present in a ratio of about 1: 0.5 to 0.2 ppw, preferably about 8502178, - 25 - 1: 0, 1 ppw. The obtained pellets preferably have a maximum diameter of about 2.0 mm and a minimum diameter of about 0.3 mm. Suitably, about 55 to about 85%, preferably about 50 to about 80%, of the pressed pieces obtained have a diameter> 0.71 mm. It is further suitable that no more than about 1.0%, preferably no more than about 0.5%, of the pellets obtained have a diameter> 1.4mm and no more than about 15%, preferably no more than about 10-12%, has a diameter> 1.0 mm.

The ratio of hydroxypropylmethylcellulose to ethylcellulose, in the applied coating, is suitably about 1: 6 to 14 ppw, preferably about 1: 8 to 12 ppw, especially preferably about 1: 9 to 11 ppw. Suitably, the coating contains also an emollient such as di-n-15 butyl phthalate. If present, the amount of emollient is between about 8 and 15%, and is preferably about 12% (wt, based on the total weight of the coating material).

The invention further provides: II. A method of making theophylline-20ne in a pellet form from which the active material is slowly released, as defined under I above, which method comprises spray-coating a granular theophylline product with a coating mixture containing a solution of ethyl cellulose and hydroxypropylmethyl cellulose in methanol 25 contains. Suitably, this method is performed using individual parameters and / or conditions, as described in Example 1a above.

In addition, the present invention also provides: III. A pharmaceutical composition containing a) ketotifene, preferably in the form of its hydrogen fumarate, and b) theophylline in the form of pellets, as defined under I above, in a fixed combination, in particular a pharmaceutical preparation as above disclosed that contains a tablet or a similar product, wherein a) and b) are each distributed almost uniformly throughout the tablet mass or matrix.

8502178

V V

- 26 -

The invention also provides: IVa) A method of preparing or manufacturing a pharmaceutical composition, as defined above, with improved treatment efficiency, especially in the preventive or prophylactic treatment of asthma or improved effectiveness in reducing of airway obstruction, especially during the preventive or prophylactic treatment of asthma, the method comprising introducing a) ketotifene, preferably in the form of its hydrogen fumarate, in association with a xanthine effective against asthma, in a fixed combination, as well as IVb) A method of preparing or manufacturing a pharmaceutical preparation as defined under III above, which method comprises introducing components 15 a) and b) into a fixed combination, in particular the intimately mixing the components a) and b) together with a solid, pharmaceutically acceptable, diluent mixture part or carrier therefor, to obtain a mass which can be processed into tablets or a corresponding product and to process this mass into 20 tablets or a corresponding form.

Suitable release characteristics for theophylline for the compositions as defined under III above in a tablet form or a similar form, for example of the type described above in Examples I and II, under standard laboratory conditions as described in Example I are, for example, as follows :

Elapsed time The percentage of theophylline released 1.1 hours (20%, preferably about 15% or 30 less.

2. 2 hours (30%, preferably about 25% or less.

3.3 hours <40%, preferably about 35% or less.

4.5 hours <70%, preferably about 65% or 8502178,3? - 27 - less.

5.8 hours <95%, preferably about 90% or less.

5 8p0 2 178

Claims (10)

A pharmaceutical composition containing a) ketotifene and b) a xanthine effective against asthma in a fixed combination. A pharmaceutical composition according to claim 1, which contains as a) ketotifene hydrogen fumarate. A pharmaceutical composition according to claim 1, which contains as b) theophylline. 4. A pharmaceutical composition according to any one of claims 1-3, wherein b) is in a form from which the active material is slowly released. A pharmaceutical composition according to any one of claims 1-4, wherein a) and b) are present in a ratio of about 1:50 to 500 p.p.w. / free a): free b) _7. 6. A method of preparing or manufacturing a pharmaceutical composition according to any one of claims 1 to 5 having an improved effectiveness in the treatment, in particular the preventive or prophylactic treatment of asthma, or with an improved effectiveness in the reduction of the respiratory tract obstruction, particularly during the preventive or prophylactic treatment of asthma, characterized in that a) ketotifene, preferably in the form of its hydrogen fumarate, is associated with an xanthine having an effective action against asthma, in fixed combination. 7. The use of a pharmaceutical preparation according to any one of claims 1 to 5 for the treatment, in particular preventive or prophylactic treatment of asthma or for the reduction of airway obstruction, especially during the preventive or prophylactic treatment of asthma . 8. Theophylline in the form of pellets from which the active material is slowly released containing a granular 8502178-29 product mainly consisting of free theophylline as the core material for the pellets, provided with a coating for the pellets in which ethyl cellulose and hydroxypropyl Methyl cellulose are included. Process for the production of theophylline in the form of pellets from which the active material is slowly released, as defined in claim 8, characterized in that a theophylline product in the form of pellets is spray coated with a coating mixture in which a solution of ethyl cellulose and hydroxypropylmethyl cellulose in methanol is included. 10. Compositions and methods as described in the description and / or examples. 15 or '50 2 1 7 8