WO1986001108A1

WO1986001108A1 - New pharmaceutical composition

Info

Publication number: WO1986001108A1
Application number: PCT/CH1985/000120
Authority: WO
Inventors: Joseph Agius; John Morley; Wolf-Dieter Roth; Karl-Heinz Hahn
Original assignee: Sandoz Ag
Priority date: 1984-08-16
Filing date: 1985-08-06
Publication date: 1986-02-27
Also published as: SE8503771D0; NL8502178A; IT1200102B; GB2163957A; PT80961A; AU4617185A; DK370085D0; FR2569109A1; DK370085A; IT8548441A0; LU86044A1; BE903065A; SE8503771L; HUT40568A; DE3528481A1; GB8520189D0; GR851988B; IL76089A0; PT80961B

Abstract

The composition contains: a) ketotiphene and b) xanthine having an anti-asthmatic activity, particularly theophylline in the form of a stable combination appropriate for the treatment, particularly for the preventive or prophylactic treatment of asthma or for reducing a respiratory tract resistance in particular during the preventive or prophilactic treatment of asthma.

Description

NEW PHARMACEUTICAL PREPARATION

The present invention relates to a new pharmaceutical preparation, in particular a new pharmaceutical preparation in the form of a fixed combination, containing a) ketotifen and b) an anti-asthmatic xanthine.

The compound ketotifen, which has the formula I

is a known therapeutically active compound that has valuable anti-anaphylactic properties. In particular, it has a strong inhibitory effect on the transmission systems responsible for the anaphylactic reaction and has been widely used in the long-term prevention or prophylaxis of all forms of bronchial asthma, allergic bronchitis and asthmatic symptoms associated with hay fever. The compound is also used in the prevention and treatment of multi-system allergy, allergic rhinitis and allergic skin reactions. As already mentioned, it mainly affects the transmission systems. It is essentially free of any noticeable direct bronchodilator effect when used, for example, to treat asthma and in practical use, it is essentially preventive or prophylactic.

The anti-asthmatic xanthines comprise a wide and recognized class of compounds, of which the most widely used representative is the anti-asthmatic compound theophylline, which has the formula II a

II a

owns, is. The xanthines are pharmacologically characterized by a relaxing effect on smooth muscles, which, in contrast to ketotifen, on their bronchodilator effect, i.e. is based on their ability to prevent or prevent bronchoconstriction during an asthma attack.

In view of the complex aetiology of asthma, its treatment is generally carried out using mixed therapy, and reports of co-therapy using ketotifen and theophylline are abundant in the prior art. The first incentive for ketotifen / theophylline co-therapy was, of course, the complementary benefit that could be drawn from the preventive (prophylactic) effectiveness of ketotifen in bronchial asthma and the direct bronchodilator effect of theophylline. In addition, numerous reports have drawn attention to the advantageous compensatory effect resulting from the interaction of the ketotifen inherent CNS depressive and the theophylline inherent CNS stimulating effect. A limited number of reports have recently emerged that mention the potential effectiveness of co-therapy of ketotifene and a low dose of theophylline, i.e., a co-therapy in which conventional doses of ketotifen are used together with less than the usual doses of theophylline , for example cans that correspond up to half the usual theophylline doses, s. for example i) A. Frank, Wiener Med. Wochenschrift 129 (Suppl. 54), 6 (1979) ii) AG Palma-Carlos, Allerg. Immunolog. (Paris) 14, (4) 46-64 (1982) iii) Celga et al., Allergolog. Immunopathologist. 8, 337 (1980) and iv) Stableforth et al., Oral report at the XII Congress of Europ. Academy of Allergology and Clin. Immunology, Rome in September 1983.

The proposal for co-therapy of ketotifen and low-dose theophylline was based on the mutually compensating CNS depressive / CNS stimulating effect of the two components [see references i) and ii)] above or an alleged "potentiation" of the classic bronchodilate effect Theophylline made by ketotifen [see reference i) above ("synergistic" interaction of theophylline with other anti-asthmatic agents attributed to the phosphodiesterase inhibitory activity of theophylline); the above reference ii) - ("potentiation" of bronchial muscle relaxation); the above reference iii) - (alleviation of chronic obstructive pulmonary disease); unα the above reference iv) - (ketotifen changes the bronchidilatory effect of theophylline)]. A critical assessment shows, however, that such a reference can be misleading and that the terms "synergism" and "reinforcement" are used where only an additive effect (broncholytic for theophylline and protective for ketotifen) is meant. In addition, the experimental test arrangements do not allow a synergism to be shown in contrast to the additive effect.

Although the usability of anti-asthmatic xanthines, for example theophylline in asthma prophylaxis, has hitherto been attributed to their direct bronchodilator effect, available evidence now also shows a preventive (prophylactic) effect [Hambleton et al., Lancet 1, 381-385 (1977) ]. However, this effect does not appear to be related to the bronchodilator effect, because, for example in the case of theophylline a), in the clinic the hypersensitivity of the respiratory tract can be reduced by using non-bronchodilator doses of theophylline [Lopez- Vidriero et al., Am.Rev. Respir. Disease, 129, 30 (194)] and b) the therapeutic efficacy in patients with sub-bronchodilator blood levels can be observed, for example, in the case of theophylline of less than 10 μggml and it is common practice in theophylline use that these are less than the bronchodilatatori see plasma levels [Woodcock et al., Lancet ii, 610-613 (1983)].

Despite these signs, the preventive effects of the anti-asthmatic xanthines, including theophylline, have received little recognition in asthma, and the reason for their therapeutic use for the treatment of this disease has so far been their classic bronchodilator effect, as has been proven in numerous articles regarding asthma treatment, see for example, Robertson et al., "Chest" 87 (1), 645-685 (1985).

The exact mechanism by means of which ketotifen and the anti-asthmatic xanthines, for example theophylline, have a bypassing effect in asthma remains the subject of extensive speculation. However, it is known that the platelet activating factor (PAF) has many of the properties which are the precondition for an inflammatory and asthma transmitter [Page et al., Trends Pharm. 5, 239-241 (1984)]. The efficacy of PAF in reproducing most symptoms of an inflammatory response has been extended to human tissue using intradermal injection and tracheal infusion [Archer et al., Br.J. Dermatol. 110, 45-50 (1984) and Gatear et al., Am.Rev.Resp.Dis. 129, AB (1984)]. In rabbits, PAF formation appears to be the central transmitter for triggering anaphylactic reactions. [Halonen et al., Am.Rev.Respir.Dis. 122, 915-924 (1980); Hensen et al., J. Immunol. 119, 2179-2184 (1977) andehen et al., Proceedings of the 1 ^st world Conference on inflammation, antirheumatics, analgesics and immunomoderlators, and Bartelli et al., Bioscience Ediprint, Geneva, in press]. It is also known that allergen-induced bronchospasm and the spontaneous deterioration of asthma are accompanied by impairment of platelet reactivity to PAF in a manner analogous to that observed in rabbits [Thompson et al., Am.Rev.Resp. Dis. 129, AB (1984)]. This essential indication justifies PAF's role as an important transmitter of both asthma and inflammation, and the evidence that PAF is involved in asthma as well as other inflammatory diseases is much broader than what has been shown to support mast cells -Pathology. It has also been shown that both ketotifen and, for example, theophylline inhibit bronchospasm caused by PAF [Saunders et al., Thrombos.Haemastas. 50, 1493 (1983) and Medieras et al., J. Pharmacology 14, 98 (1983)].

According to the present invention, it has now surprisingly been found that a combination of ketotifen and the anti-asthmatic xanthines, for example theophylline, has an inhibitory effect on the bronchospasm caused by PAF that is greater than the sum of the individual effects (superadditive synergism). Using theophylline as a characteristic representative of the anti-asthmatic xanthine, it was found that the combination of the effect of ketotifen and theophylline on the transmitter level, i.e. in terms of their preventive or prophylactic effects, is mutual and synergistically enhanced. It was found to be of particular importance that ketotifen has the preventive or prophylactic anti-asthmatic activity of, for example, theophylline at theophylline doses which are classically below the therapeutically effective, i.e. in doses insufficient to effect bronchodilation, synergistically enhanced. An equivalent synergistic interaction at the transmitter level can also be demonstrated if ketotifen and another anti-asthmatic xanthine are used, as described below, for example.

In view of this surprising and unpredictable finding of a synergism with regard to a preventive (or a prophylactic) effect, a pharmaceutical composition is presented according to the present invention which comprises a) ketotifen and b) an anti-asthmatic xanthine in a fixed combination . Under the condition of a fixed combination, the present invention allows a full and practical, ie clinical realization of the therapeutic advantage of a synergistic interaction at the transmitter level of the components a) and b) defined above, as discussed above.

The particular advantage of the present invention is particularly clear when one takes into account the fact that it has already been pointed out above that in practice drug serum levels are essential, for example for the anti-asthmatic xanthines, theophyllines, which are insufficient for bronchodilation Characteristic of a regular theophylline therapy.

This is the result of the known rapid rate of excretion of theophylline from the body and results from the "once-daily dosage" of theophylline, usually an essential therapeutic goal which is aimed at when theophylline is used in sustained release form.

Moreover, in the clinic, the synergistic interaction at the transmitter level, as discussed above, which is obtained using the composition according to the invention, can bring advantages to the treated patient not only with regard to the preventive or prophylactic effect, but also in related transmitter level systems, for example a synergistic reduction in airway overreaction and development of mucus secretion and inflammation, etc., as evidence of an improved patient response, for example according to the degree of airway obstruction, particularly during an asthma attack. It can be shown that this airway obstruction, which can be determined according to the usual clinical standard, for example as described below, can be reduced synergistically by administration of compositions according to the invention which contain both component a) and component b), as compared to results obtained in patients who have only received component a) or component b). This interaction obtained when using the compositions according to the invention is particularly evident during the initial phase of the asthma treatment, for example during the first 4 to 6 weeks after the start of the therapy.

The occurrence of the desired synergistic interaction at the carrier level of the two mixture components could not be expected in practice (for example in the clinic) with a mere co-therapy and it is worth mentioning that despite the reference to a possible interaction between ketotifen and theophylline in the state of the Technology (for example, as discussed above), no proposal for a fixed combination has yet been made.

Component a) ketotifen can be present in the preparation according to the invention in free form or 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 and have a potency that corresponds to that of the free form. The term ketotifen in the present context means both the free form and the pharmaceutically acceptable acid addition salt form, unless stated otherwise. Component a) is preferably present in the compositions in the form of its hydrogen fumarate.

Suitable anti-asthmatic xanthines for use as component b) in the compositions of the present invention include those of Formula II

wherein i) R ₁ , R ₃ and R _{4 are} each hydrogen and R _{2 is} n-propyl, or ii) R ₁ and R _{2 are} each methyl, R _{3 is} - (CH ₂ ) ₂ N (C ₂ H ₅ ) CH ₂ CH ₂ OH and R _{4 are} benzyl, iii) R ₁ and R ₂ are each methyl, R _{4 is} hydrogen and R _{3 is}

The compounds i) to iii) are known and described together with the process for their preparation, for example i) in Europ. Patent No. 0011 609, ii) in Belgian Patent No. 602888 and iii) in European Patent No. 0089028. Of these, the preferred compound for use in the compositions according to the invention is also known compound i) and hereinafter referred to as enprophylline . However, the most preferred anti-asthmatic xanthine for use in the composition of the present invention is the compound theophylline of Formula IIa, which was previously indicated. Component b) can be used in the preparation according to the invention as such or in the form of one of the various known mixtures with pharmaceutically acceptable additives, in particular pharmaceutically acceptable amines, in particular choline, diethanolamine, ethanolamine etc. or in the form of pharmaceutically acceptable acid addition salts including the pharmaceutically acceptable acid addition salts thereof Mixture can be used. Such forms are known in the art and generally have the advantage of improved solubility compared to the free compound or its salts. In the case of the anti-asthmatic xanthine theophylline, they include the compounds theophylline calcium salicylate, theophylline diethanolamine, theophylline isopropanolamine and especially aminophylline, a 2: 1 (weight ratio) mixture of theophylline and ethylenediamine. Such mixtures and salts are also well tolerated and references to antistatic xanthines and specific xanthines of this class, such as theophylline, include both the free forms and the mixed forms and their salts, unless stated otherwise. Preferred anti-asthmatic xanthines, including the preferred xanthine theophylline, which are present as component b) in the composition according to the invention are contained therein as free compounds, for example as free theophylline.

Pharmaceutical compositions according to the invention comprise any form which is suitable for administration either enterally or parenterally and comprise components a) and b) in the form of a fixed combination, which together and each in a predetermined amount, for example in predetermined relative ratios. Preferred compositions according to the invention are forms suitable for oral administration, including capsules, tablets, syrups or the like. The compositions according to the invention preferably form a unit dose form, for example for oral administration, each unit dose containing a predetermined amount of each of components a) and b). Compositions according to the invention include systems in which components a) and b) are obviously separate, for example present or kept separate within the composition, and systems in which the specified components are intimately mixed or both are uniformly dispersed within a common matrix . Compositions of the former type include capsules, for example for oral administration, containing a) and b) each in independent granulated, powdered, tableted or similar form (whether mixed or not) or separately, for example in individual independent compartments of a two-part capsule or in separate layers a coat tablet. Compositions of the latter type include, for example, tablets or the like, in which a) and b) are each substantially uniformly distributed within the tablet mass or matrix. In such cases, the tablet mass or matrix becomes an essentially uniform matrix, for example containing a carrier, solid diluent! and / or binders, etc., as commonly used in the art. Such compositions can be prepared according to methods known in the art, for example as described below in the accompanying examples.

It is further preferred that component b) in the composition according to the invention is in a form with a delayed onset of action, i.e. in a form which enables component b) to be released continuously within the body or the body tissues over a longer period of time or which allows a relatively constant component b) to be present in the blood serum level for a longer period of time following the administration,

Suitable forms with delayed onset of action of component b) are known in the prior art and can be made using any known technique which is usually used in galenics, are obtained, in particular based on formulations with delayed release of xanthines, see. for example Europ. Patent Publication No. 0 122077, US Pat. Nos. 4415 547 and 3400 185 and PCT Application No. WO 83 00 284. They include sustained release pellet forms, for example in which individual particles of granules, powder or the like. containing b) are provided with a suitable coating for delayed release. They can be obtained, for example, by coating a finely divided form, for example granules or a powder form of the medicament, with a suitable resistant, for example enterally resistant, coating. Specific examples of such sustained release pellet forms are described below. The specific release characteristics of component b) obtained in this way can be changed as desired, for example by selecting the coating material, by changing the applied coating and / or by changing the particle size of the coated material. Since the release rate of the anti-asthmatic xanthine derivatives, for example theophylline, is strongly subject-specific, the blood serum levels obtained using the respective composition with delayed release will inevitably fluctuate greatly from one substance to another. In general, however, in the case of, for example, theophylline, the forms with delayed release can be used in the composition according to the invention, for blood serum levels in the order of magnitude of approximately 8 to approximately 20 μg / ml over time periods of approximately 4 to approximately 8 hours and more , for example over periods of up to about 6 hours after administration. In the case of theophylline, the preferred sustained release form of component b) is such that it gives the following approximate theophylline release characteristics under laboratory conditions:

1. An amount of about 200 mg is dissolved in 1000 ml of 0.1N HCl: a)% theophylline release after 3 hours = 40 to 60%, preferably about 45 to 55%, for example about 50%; b)% theophylline release after 8 hours = approx. 70 to 90%, preferably approx. 75 to 85%, for example approx. 80%.

2. A quantity of approximately 100 mg is dissolved in 1000 ml of 0.1N HCl: a)% theophylline release after 3 hours = approximately 45 to 60%, preferably approximately 50 to 57%, for example approximately 53%; b)% theophylline release after 8 hours = approx. 80 to 100%, for example approx. 85 to 95%, for example approx. 90%.

The average theophylline release under the above conditions 1) after 1 hour preferably does not exceed approximately 30%, in particular approximately 25%. Hourly theophylline release under the above conditions 1) during an 8 hour period varies within a range of about 4 to 20%, preferably about 5 to 15% / hour.

Such forms provide a maximum theophylline release of i) about 60%, preferably about 55% and ii) 100%, preferably about 90% to 95%, after i) 3 hours and ii) 8 hours under the standard conditions discussed above under 1. and 2. (All measurements are carried out at room temperature with stirring at 90 revolutions / minute. The pH value is expediently set after about 120 minutes.) If component b) is theophylline in free form, the preferred sustained release form for use in the composition according to the present invention is a theophylline retard pellet, as supplied by Klinge AG. is offered in the commercial preparation BRONCHORETARD. The production of a likewise preferred form with delayed release is described in Example la below.

In general, components a) and b) will be present in the composition according to the invention in a ratio of about 1:50 to 500 parts by weight, preferably about 1: 100 to 500 parts by weight (a: b). A special and preferred constituent of the composition according to the invention relates to components a) and b) in a ratio of approx. 1:50 to 350 parts by weight, in particular approx. 1: 100 to 300 parts by weight or approx. 1:50 to 300 parts by weight, in particular approx 1: 100, 200 or 300 parts by weight, for example approximately 1: 200 or 300 parts by weight.

If the compositions according to the invention comprise a unit dose form, the individual unit doses contain from about 1 to about 2 mg, preferably 1 mg, of component a). Such unit doses appropriately contain at most about 500, preferably at most about 350, particularly preferably about 300 mg of component b). Thus, preferred unit doses contain about 1 mg or about 2 mg (but especially about 1 mg) of component a) and from about 50 to about 500 mg, preferably from about 100 to about 350 mg, for example about 100, 150, 175, 200 or 300, in particular approximately 175, 200 or 300 mg of component b) which are intended for administration once to four times, in particular once or twice a day. Such compositions are ηeei.gnet for use in the treatment of all conditions for which a ketotifen therapy is usually used, as well as in conditions where bronchodilator activity is desired, for example in the treatment of active asthma or when triggering an asthma. Therapy. If a once-daily dosage is provided or bronchodilation is critical for the therapy, the proportions of component b) will generally be higher, for example in the case of unit dosage forms in the order of approximately 200 mg, or preferably 300 mg or more. If doses are to be administered twice a day or more, or if bronchodilation is not critical for the therapy, for example in the case of asthma prophylaxis / maintenance therapy or in the treatment of bronchitis, the proportions of the component b) present in the compositions can be lower and thereby take special advantage of the synergistic interaction of the two components at the transmitter level, as disclosed and discussed here. For such purposes, the compositions according to the invention may contain as little as about 50 to 300 mg.

[The above weight ratios and mg values discussed relate to components a) and b) in free form, i.e. on the proportions / relative ratios of the free ketone and, for example, the free theophilin. If salts / mixtures of components a) or b) are used, the proportions used correspond to the stated amounts of free components a) or b)].

The advantageous action of the compositions according to the invention and in particular the synergistic interaction of ketotifene anti-asthmatic xanthines, for example theophylline, for example in relation to the protective effect, as discussed above, can be shown both in the clinic and in conventional animal models. Accordingly, the mutual synergistic interaction of ketotifen and theophylline at the transmitter level can be shown, for example, in relation to brochospasm caused by PAF, for example as described below:

methodology

The spontaneous breathing of anesthetized guinea pigs responds to an IV injection of PAF by increasing the airway resistance and reducing the "dynamic compliance". The usability of PAF in testing the effectiveness of the active substances is complicated by the differences in the sensitivity of the animals a steep dose response curve and a potential interaction between doses. However, it is still possible to create an experimental protocol where almost up to four consecutive i.v. injections of a constant dose of PAF at 10 minute intervals produce almost similar reactions. This allows the use of the method for a routine assessment of drug effects. Such animals are given medicinal products 5 minutes before (ketotifen or saline) or 1 minute before (aminophylline - the theophylline mixture as specifically described above - or saline) given a PAF injection. Inhibition is assessed by comparing the response after treatment with the response just before drug administration. The difference found between the two reactions can expediently be expressed as a percentage of the reaction immediately before the treatment with the active ingredient.

In order to measure the synergism between ketotifen and aminophylline, the isobol technique is used as a strict test [Berenbaum, Clin.Exp.Immunol., 28, 1-18 (1977)]. Doses of ketotifen between 0.56 µg / kg and 18 µg / kg are used either alone or in combination with aminophylline in doses between 0.01 mg / kg and 0.32 mg / kg. Responses are determined in at least 5 animals for each dose or combination of doses, except for saline-treated animals (9) and animals containing 0.32 mg / kg aminophylline (10) or 1.8 μg / kg ketotifen (7) obtained if additional animals are used. A total of 86 animals are used for the study.

Results

Treatment of animals with 2 doses of saline resulted in only an insignificant reduction (4%) in the response to PAF. Treatment with ketotifen causes a dose-dependent reduction, whereby the inhibition is shown at the lowest dose. Treatment with aminophylline causes dose-dependent inhibition, but with a flatter curve than that seen with ketotifen. These data together with the data of the drug combination are visible in the attached FIG. 1. In Figure 1, the inhibitory effects of each dose are drawn near the axes. The inhibitory effects of the drug combination are accordingly assigned to the intersections. With the help of this data it is possible to construct two isoboles for inhibition reflexes on theophylline. Both isoboles have a concave shape, which is characteristic of synergistic interaction.

conclusion

A synergism between ketotifen at almost therapeutic doses and aminophylline at doses which are considered to be sub-therapeutic for a bronchodilator effect, but which are active ingredients Concentrations that usually occur during aminophylline therapy in both asthma and bronchitis have been proven.

The advantageous effect of the composition according to the invention can also be shown in clinical tests which are carried out, for example, as described below:

Examination conditions

An examination is carried out using a group of 12 patients, male or female, with an age range of 16 to 65 years. The selected patients show both seasonal and year-round chronic bronchial asthma (with reversible, allergic or mixed forms of bronchospasm) how anamnesis is determined with the help of skin tests or determination of allergen-specific IgE and, if necessary, confirmed by inhalation provocation. Mild or moderately severe forms are characterized by mild or moderate obstruction of the bronchi with repeated determination of an infestation or permanent symptomatology.

The following imposition parameters are used: pregnancy, severe liver or kidney diseases, conditions following a myocardial infarction (not later than 6 months), diabetes mellitus that is difficult to control, gastrointestinal disorders that are related to influence absorption, metabolism or Elimination of test substance such as chronic diarrhea, malabsorption syndrome, etc., heartbeat disorders, gastric or intestinal ulcers, individuals known to be unreliable or physiologically unstable. As far as possible, patients will only receive additional sympathomimetic or anti-cholinergic treatment if this is essential to avert asthma attacks. If absolutely necessary, another treatment, for example with corticosteroids or antibiotics, is also permitted. The type of such treatment, duration and the dose used are recorded. In the event that the patients are already receiving continuous bronchodilator, steroidal or theophylline therapy, this is gradually reduced only during the first 2 to 3 weeks of the trial.

The following experimental preparations are made:

a) Tablets containing 1 mg of ketotifen and 200 mg of theophylline in a delayed release form in a fixed combination and prepared according to Example 1 below.

b) tablets containing 1 mg of ketotifen and 300 mg of theophylline in a delayed release form in a fixed combination and prepared according to Example 2 below.

c) Tablets containing only 1 mg of ketotifen and prepared according to Example 1b below, but with the omission of component a).

d) tablets containing 200 mg of theophylline in a delayed release form, prepared according to the following example lb), but with the omission of component b).

e) tablets containing 300 mg of theophylline in a delayed release form, prepared according to Example 1 below, but with the omission of component b). Each patient receives 420 tablets. The test preparations are distributed to each patient in a randomized, double-blind manner, with individuals weighing - 50 kg receiving theophylline (alone or together with ketotifen) in a dose of 200 mg of a preparation [di according to a) or d)] above and individuals who

^ Weigh 50 kg, receive theophylline (alone or together with ketotifen) in a dose of 300 mg of a theophyl 1 in composition [di according to b) or e)] above. All tablets are essentially identical in appearance, with tablets c) being offered in 2 sizes, the smaller size (for administration to individuals with ≤ 50 kg) corresponding to the tablets containing 200 mg of theophylline, the larger (for administration to Individuals weighing more than 50 kg correspond to the other tablets containing 300 mg of theophylline.

During the study, each patient took 2 tablets daily (morning and evening) orally. The duration of the examination is 6 months for each patient.

The clinical examination is carried out for each individual 2, 4, 6 and 8 weeks after the start of the examination and thereafter in a 4-week interval. The following parameters are measured for each check:

- Vital capacity

- Exhale reserve volume

- Functional residual air capacity

- total resistance

- final volume

- flow volume Details of the number and severity of the symptoms that occur, the occurrence of difficulty breathing, coughing, expectorating, reported by the examination patients are recorded.

5 ml of blood is drawn from each patient upon entry into the study and 1 month later for theophylline determination. The second sample is taken 4 to 8 hours after the test composition is administered.

Results

Patients who received ketotifen and theophylline in a fixed combination showed a significantly improved response, for example to the parameters stated below, compared to individuals who received ketotifen or theophylline alone: 1-second capacity as% of vital capacity; Flow volume 25; total resistance; and final volume. A significant improvement is also registered in individuals who receive ketotifen and theophylline in a fixed combination with the following parameters: vital capacity; Exhalation reserve volume; Flow volume 25, 50 and 75, and functional residual air capacity. In particular, results obtained during the first 4 to 6 weeks following the start of the tests with individually measured parameters, in particular the total resistance, the effectiveness in individuals who received ketotifen and theophylline in a fixed combination, show that this is greater than can be expected from studies on individuals receiving ketotifen or theophylline alone, ie that these are indicative of super-additive effectiveness. Together with the foregoing, the present invention also relates to a pharmaceutical composition for the treatment of asthma which also shows a super-additive or synergistic anti-asthmatic activity, in particular at the transmitter level, or which is a super-additive or synergistic preventive or prophylactic anti-asthmatic Efficacy shows, in particular at the transmitter level, for example as proven by a reduction in airway resistance, for example as a result of airway overreactivity, development of the mucous membrane, inflammation etc. Such a composition contains a) ketotifen and b) an anti-asthmatic xanthine in a fixed combination (e.g. as discussed above).

Furthermore, the invention relates to a method for the treatment, in particular for the preventive or prophylactic treatment of asthma, in particular at the transmitter level or for reducing the airway resistance, for example as a consequence of airway overreactivity, development of the mucous membrane, inflammation etc., in particular during the preventive or prophylactic treatment of asthma: in an individual in need of such treatment, the method comprising the administration to such individuals of a pharmaceutical composition comprising a) ketotifen and b) an anti-asthmatic xanthine in a fixed combination (for example as described here) , or

the use of a pharmaceutical composition (for example as described here) containing a) ketotifen and b) an antiasthmatic xanthine in a fixed combination for treatment as defined above or

the use of a) ketotifen and b) an anti-asthmatic xanthine for the preparation of a pharmaceutical composition (for example as described here) containing a) and b) in a fixed combination for use in a method of treatment as discussed above. The following examples describe the composition according to the present invention and its preparation:

example 1

Production of tablets containing 200 mg free theophylline in delayed release form and = 1 mg free ketotifen

1a) Production of delayed release pellets of theoghylline

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

49.5 kg of regular theophylline granules (for example as supplied directly by Boehringer - approx. 9 to 10% of the particles have a diameter of 0.71 mm, approx. 60 to 70% of the particles have a diameter of 0, 50 mm) are filled in a container of the Glatt W-56-60 spray coating device, which is equipped with Schlick spray nozzles with a diameter of 2.5 mm. The granules are spray-coated with the above-mentioned coating solution, the coating being carried out under the following conditions:

Distance from the nozzle base 50 cm

Vibration interval 60 seconds

Duration of the vibration 10 seconds

Temperature of the spray solution 22 to 27 ° C

Spray pressure 3.8 bar

Pump capacity approx. 20 1 / g

Incoming air temperature 27 to 31 ° C

Temperature in the granulate mass 25 to 27 ° C used air volume 2600 to 4600 m ³ / h After the spraying process has ended, the spray-coated product obtained is dried at 45 to 55 ° C. for 10 minutes.

The entire spray drying process is carried out in such a way that it takes approximately 200 minutes to obtain a product in which the ratio of the coating to theophylline is approximately 1: 100 (parts by weight). 1b) Manufacture of tablets

Components Relative ratios in mg

a) Pellets with delayed release of theophylline are obtained * according to la) 220.30 above

** b) Ketoti fen hydrogen fumarate 1, 38 c) lactic acid 90, 00 d) cel l ulose granules 60, 00 e) cel l ulose powder 53, 32 f) stearic acid 100, 00

* = 200 mg uncoated, free theophylline ** = 1 mg free ketotifen

The constituents are mixed intensively in a manner known per se and pressed to give individual tablets, each having a total weight of 530.00 mg and each containing 200 mg of free theophylline and an equivalent of 1 mg of free ketotifen. The same theophylline release characteristics for the tablets as determined under standard laboratory conditions, [6 tablets in 500 ml simulated gastric juice (0.1N HCl to pH 7.5 with pH correction after 1.2 and 3 hours) during 8 hours with paddle stirring at 50 revolutions / minute] are the following:

Elapsed time% theophylline released

1 hour approx. 1 2%

2 hours approx. 22%

3 hours approx. 34% 5 hours approx. 64% 8 hours approx. 87%

Example 2:

Production of tablets containing 300 mg free theophylline in delayed release form and 1 mg free ketotifen

The procedure of Example 1 is repeated, but using the following relative ratios (in mg) of components a) to f) in step 1b): a): 330.50 [= 300 mg of uncoated, free theophylline]. b): 1.38 (= 1 mg free ketotifen). c): 80. d): 60.00. e): 57.12. f): 100.00.

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

The theophylline release characteristics of the tablet samples as determined under standard laboratory conditions as described in Example 1 are as follows: Elapsed time% released theophylline

1 hour approx. 11%

2 hours approx. 21%

3 hours approx. 31% 5 hours approx. 65% 8 hours approx. 89%

Example 3

Production of capsules containing 150 mg free theophylline and 1 mg free ketotifen

3a) Preparation of a ketotifen tablet mass

Components Relative ratio in mg

* a) Ketotifen hydrogen fumarate 1, 38 b) talc 0, 16 c) calcium hydrogen phosphate anhydrous 35, 26 d) corn starch 5, 26 e) dried corn starch 2, 6 f) magnesium stearate 0, 5

* = 1 mg free ketotifen

The ingredients are thoroughly mixed together in the usual way and pressed into individual tablets weighing 45.00 mg each, each containing an equivalent of 1 mg of free ketotifen. 3b) Manufacture of capsules

162.9 mg of theophylline sustained release pellets from Klinge AG., As described above [= 150 mg of uncoated, free theophylline] and 1 tablet obtained according to step 3a above) are placed in a hard gelatin capsule! filled and the capsule closed.

Example 4

Production of capsules containing 1 mg of free ketotifen and free theophylline in various proportions

Hard gelatin capsules are produced analogously to Example 3, containing a tablet obtained according to Example 3a) and theophylline sustained release pellets from Klinge AG., As described in Example 3b) in the proportions listed below:

4a) 54.3 mg = 50.00 mg free, uncoated theophylline

4b) 108.6 mg = 100.00 mg free, uncoated theophylline

4c) 190.05 mg = 175.00 mg free, uncoated theophylline

4d) 217.2 mg = 200.00 mg free, uncoated theophylline

4e) 325.8 mg = 300.00 mg of free, uncoated theophylline

4f) 380.1 mg = 350.00 mg free, uncoated theophylline

Theophylline pellets with a delayed release rate of the general type, described above in Example la), containing di theophylline granules as the core material and a coating, as described, are also new. Accordingly, another aspect of the present invention also relates to:

I. Theophylline in the form of a sustained release pellet containing granules consisting essentially of free theophylline as the pellet core material, provided with a pellet coating containing ethyl cellulose and hydroxypropyl methyl cellulose.

The coating is preferably applied as described, for example, in Example 1, in such a way that essentially all of the particles which contain the core material are coated individually. The particles expediently contain the core material in accordance with the dimensional characteristics, as described, for the theophylline granules used as starting material in Example 1a). The coating is expediently applied in such a way that the core material and the coating are present in the pellets obtained in a ratio of approximately 1: 0.5 to 0.2 parts by weight, preferably approximately 1: 0.1 parts by weight. The pellets obtained preferably have the largest diameter of approximately 2.0 mm and the smallest diameter of approximately 0.3 mm. Advantageously, about 55 to about 85%, preferably about 50 to about 80% of the pellets obtained have a diameter of> 0.71 mm. Advantageously, no more than about 1.0%, preferably no more than about 0.5% of the pellets obtained have a diameter of> 1.4 mm and no more than about 15%, preferably no more than about 10 to 12% have a diameter of> 1.0 mm.

The ratio of hydroxypropylmethyl cellulose to ethyl cellulose in the applied coating is advantageously about 1: 6 to 14 parts by weight, preferably about 1: 8 to 12 parts by weight, more preferably about 1: 9 to 11 parts by weight, the coating advantageously also contains a plasticizer and di-n-butyl phthalate. If present, the plasticizer is present in a proportion of 8 to 15%, preferably approx. 12%, by weight based on the total coating material.

The invention further relates to:

II. A process for the production of theophylline in pellet form with a delayed release rate, as indicated above under I., the process comprising spray coating a theophylline granulate with a coating mixture containing a methanolic solution of ethyl cellulose and hydroxypropyl methyl cellulose. The method is expediently carried out using individual parameters and / or conditions, as described above in Example la).

In addition, the present invention also relates to:

III. a pharmaceutical composition containing a) ketotifen, preferably in the form of its hydrogen fumarate and b) theophylline in pellet form, as stated above under I., in the form of a fixed combination, in particular a pharmaceutical composition, as stated above, containing a tablet or the like, wherein a) and b) are distributed substantially uniformly in the tablet mass or matrix.

The invention also relates to:

IVa. a method of making a pharmaceutical composition as set out above which has improved efficacy in the treatment, particularly in the preventive or prophylactic treatment of asthma, or improved efficacy in reducing airway resistance, particularly during the preventive or prophylactic treatment of asthma, this method combining a) ketotifen preferably in the form of its hydrogen fumarate with b) an anti-asthmatic xanthine in a fixed combination as well

IVb. a process for the preparation of a pharmaceutical composition as described under III. specified, the method consisting in that components a) and b) are brought into the form of a fixed combination, in particular by intimately mixing components a) and b) together with a solid, pharmaceutically acceptable diluent or carrier, in order to obtain a Produce mass, which is suitable for being pressed into tablets or the like and process this mass into tablets or similar forms.

Suitable theophylline release characteristics for the compositions as described in III above. For example, in tablets or other forms, for example of the type described above in Examples 1 and 2, under laboratory conditions as described in Example 1 are the following:

Elapsed time% released theophylline

1. 1 hour <20%, preferably about 15% or 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 less

5. 8 hours <95%, preferably about 90% or less

Claims

Claims:

1. A pharmaceutical composition consisting of a) ketotifen and b) an anti-asthmatic xanthine in the form of a fixed combination.

2. A pharmaceutical composition according to claim 1 containing as component a) ketotifen hydrogen fumarate.

3. A pharmaceutical composition according to claim 1 containing as component b) theophylline.

4. A pharmaceutical composition according to claims 1 and 4 containing theophylline in a form with a delayed release rate.

5. A pharmaceutical composition according to any one of claims 1 to 4 containing components a) and b) in a ratio of about 1 to 50 to 500 parts by weight [free a) to free b)].

6. Process for the preparation of a pharmaceutical composition which has an improved effect in the treatment, in particular in the preventive or prophylactic treatment of asthma, or an improved effect in the reduction of airway resistance, in particular during the preventive or has prophylactic treatment, characterized in that a) ketotifen, preferably in the form of its hydrogen fumarate, is combined with b) an anti-asthmatic xanthine in a fixed combination.

7. Use of a pharmaceutical Zusairnensetzunq according to one of claims 1 to 5 for the treatment, in particular a preventive or prophylactic treatment of asthma or for reducing airway resistance, in particular during the preventive or prophylactic treatment of asthma.

8. Use of a) ketotifen and b) an anti-asthmatic xanthine for the production of a pharmaceutical composition for the treatment, in particular for the preventive or prophylactic treatment of asthma or for reducing the airway resistance, in particular during the preventive or prophylactic treatment of asthma.

9. Theophylline in a form with a delayed release rate, containing a granulate consisting essentially of free theophylline as a pellet core material with a coating containing ethyl cellulose and hydroxypropyl methyl cellulose.

10. A process for the production of theophylline in the form of a pellet with a delayed release rate according to claim 9, characterized in that a theophylline granules are coated with a coating mixture consisting of a methanol solution of ethyl cellulose and hydroxypropylmethyl cellulose in a fluidized bed apparatus.