GB2163957A - Anti-asthma compositions containing ketotifen - Google Patents

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

SPECIFICATION Novel pharmaceutical preparations The present invention relates to novel pharmaceutical preparations, in particular to novel pharmaceutical preparations comprising a) ketotifen and b) an anti-asthmatically effective xanthine in fixed combination.

The compound ketotifen, which has the formula I

is a known therapeutically active agent having valuable antianaphylactic properties in particular it has a profound inhibitory effect on mediator systems responsible for anaphylactic reaction and has found extensive application in the long term prevention or prophylaxis of all forms of bronchial asthma, allergic bronchitis and asthmatic symptoms associated with hay fever. It has also found application in the prevention and treatment of multi-system allergies, allergic rhinitis and allergic skin reactions. As noted, its action is primarily upon mediator systems. It is essentially devoid of significant direct bronchodilatator activity and, in its application e.g. to the treatment of asthma, its practical utility is essentially preventive or prophylactic.

The anti-asthmatically effective xanthines comprise a large and recognised compound class of which the most commonly employed representative is the conventional anti-asthmatic drug theophylline of formula lla

As a class, the said xanthines are characterised pharmacologically by their smooth muscle relaxant activity and unlike ketotifen their use in the asthma indication has been consequential to their bronchodilatator activity, i.e. in relation to their ability to prevent or abort bronchoconstriction during asthma attack.

In view of its complex aetiology, treatment of asthma is generally carried out employing a mixed therapy regime, and reports for co-therapy employing ketotifen and theophylline in the treatment of asthma abound in the art. The prime motivation for ketotifen/theophylline co-therapy has of course been the complementary benefit of the inhibitory (prophylactic) effectiveness of ketotifen and the direct bronchodilatatory effectiveness of theophylline. In addition, numerous reports have drawn attention to the advantageous compensatory effect achieved via interaction of ketotifen's inherent CNS-depressant and theophylline's inherent CNS-stimulant activities.

More recently there have been a limited number of reports suggesting possible efficacy for a ketotifen/low dose theophylline co-therapy, i.e. in which regular dosages of ketotifen are employed in conjunction with sub-regular theophylline dosages, e.g. dosages to as little as 1/2 regular theophylline dosage levels - 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., 8,387(1980); andiv) Stableforth et al., oral disclosure at XII Congress of the European Academy of Allergology and Clinical Immunology, Rome, September 1983.

Where a ketotifen/low dose theophylline co-therapy has been proposed, the rational has either been the mutually compensatory CNS-depressant/CNS-stimulant activities of the two compounds [c.f. references i) and ii) above] or alleged "potentiation" of direct bronchodilatatory activity of theophylline by ketotifen [c.f.

reference i) above ("synergistic" interaction of theophylline with other anti-asthmatic agents attributed to the phosphodiesterase inhibitory activity oftheophylline); reference ii) above ("potentiation" of bronchial muscle relaxation); reference iii) above (reduction of chronic-obstructive lung disease); and reference iv) above (ketotifen modulates the bronchodilatatory effect of theophylline).

Critical evaluation however indicates that such references may be misleading, the terms "synergism" and "potentiation" being applied where only additive effect (broncholytic for theophylline plus protective for ketotifen) is meant. Moreover the experimental designs applied do not in fact generally allow demonstration of synergism as opposed to additive efficacy.

Although utility of the anti-asthmatic xanthines, e.g. theophylline, in asthma prophylaxis has classically been attributed to their direct bronchodilatatory activity, evidence now available indicates that they in fact also exhibit a preventive (prophylactic) effect [Hambleton et al., Lancet 1,381 -385(1977)]. Moreover this effect may be unrelated to bronchodilatatory action since, e.g. in the case of theophylline: a) In clinic airway hyperreactivity can be reduced by use of non-bronchodilatatory doses [Lopez - Vidriero etal.,Am. Rev. Respir.Disease, 129,30(1984)]; and b) Therapeutic efficacy can be observed in patients with sub-bronchodilatatory drug serum levels, e.g. in the case oftheophylline of less than 10 Fg/ml, and it is commonplace for e.g. theophylline usage to be associated with drug serum levels of sub-bronchodilatatory order [Woodcock petal., Lancet ii, 610 - 613 (1983)].

Despite the evidence however, the preventive efficacy of the anti-asthmatic xanthines, including theophylline, in asthma has so far gained relatively little recognition and the rational for therapeutic application in the treatment of this disease has remained their direct bronchodilatatory effect as evidenced by numerous review articles on asthma treatment, see e.g. Robertson et al. "Chest" 87(1), 645 - 685 (1985).

The precise mechanisms by which ketotifen and the anti-asthmaticxanthines, e.g. theophylline, exert preventive activity in asthma remain the subject of extensive speculation. However, it is now known that platelet activating factor (PAF) exhibits many of the properties that are prerequisite for a mediator of both inflammation and asthma [Page et al., Trends Pharm. Sci. 5,239 - 241(1984)]. The efficacy of PAF in reproducing most facets of an inflammatory reaction have been extended to human tissues by use of intradermal injection, and tracheal instillation [Archer et al., Br. J. Dermatoi. 110, 45 - 50 (1984) and Gatear et al., Am. Rev. Resp. Dis. 129, A3 (1984)]. In the rabbit, PAF formation appears to be the central agency whereby anaphylactic responses are expressed [Halonen et al., Am. Rev. Respir.Dis., 122,915 - 924(1980); Henson etal.,J. Immunol. 1977; and Shen etal. "Proceedingsofthe 1stWorld Conference on Inflammation: Antirheumatics, Analgesics and Immunomodulations" Eds. Bertelli et al., Bisoscience Ediprint, Geneva, In press]. It is also known that allergen-induced bronchospasm and spontaneous exacerbation of asthma are accompanied by impaired platelet reactivity to PAF in a manner analogous to that observed in the rabbit [Thompson et al., Am. Rev. Resp. Dis., 129, A3 (1984)].This substantial body of evidence justifies the assignment to PAF of a rôle as a vital mediator of both asthma and inflammation, and indeed the evidence favouring PAF involvement in asthma as well as other inflammatory disease is considerably more extensive than that which has been presented in support of mast cell-related pathology.

It has already been shown that both ketotifen and e.g. theophylline inhibit PAF-induced bronchospasm [Saunders et al., Thrombos. Haemostas. 50, 1493 (1983) and Medieros et al., J. Pharmacology 14, 98 (1983)].

In relation to the present invention it has now surprisingly and unexpectedly been found that in combination, ketotifen and the anti-asthmatically active xanthines, e.g. theophylline, have an inhibitory effect on PAF-induced bronchospasm which is greater than the sum of their individual potencies (superadditive synergism). Thus taking theophylline as representative of the anti-asthmatic xanthines it has been found, thatthe action of ketotifen and theophylline at the mediator level, i.e. their activity in relation to preventive or prophylactic utility is mutually and synergistically potentiated. More importantly it has been found that ketotifen synergistically augments the preventive or prophylactic utility of e.g. theophylline, attheophylline dosages which are classically sub-therapeutic, i.e. dosage levels which are insufficient to produce bronchodilatation.Equivalent synergistic interaction at mediator level may also be demonstrated employing ketotifen and other anti-asthmatically effective xanthine, e.g. as specified hereinafter.

Based on this surprising and unexpected finding of synergism in relation to preventive (or prophylactic utility, there is, in accordance with the present invention now provided: A pharmaceutical preparation comprising a) ketotifen and b) an anti-asthmatically effective xanthine in fixed combination.

By provision of a fixed combination, the present invention permits full and practical, i.e. clinical, realisation oftherapeutic advantage obtainable from mediator level synergistic interaction of the defined components a) and b) as discussed above.

The particular advantage of the present invention will be apparent having regard to the fact, already discussed above, that in practice drug serum levels, e.g. for the anti-asthmatically effective xanthine, theophylline, which are insufficient for bronchodilatation, are an inescapable feature of regular theophylline therapy. This is an inevitable consequence oftheophyllines' known, exceedingly rapid clearance rate from the body and corollary to theophylline "once a day dosaging", currently a major therapeutic objective of sustained release theophylline treatment.

Furthermore, in clinic, synergistic interaction at mediator level as discussed above, obtained employing the preparations of the invention may bring benefit to subjects treated not only in terms of preventive or prophylactic utility, but also in its expression in related mediator level systems, e.g. in a synergistic reduction of airways hyperreactivity, and development of mucous and inflammation etc... as evidenced by improved patient response, e.g. in terms of degree of airways obstruction, in particular during an asthmatic event.

Thus airways obstruction determinable in standard clincial trials, for example as hereinafter described, may be shown to be synergistically reduced on administration of preparations in accordance with the invention and comprising both components a) and b) as compared with results obtained for subjects receiving a) or b) alone. This interaction obtained using the preparations of the invention may be specially evident during the initial phase of asthma treatment, e.g. during the initial 4to 6 weeks following commencement of therapy.

Mere co-therapy may not be anticipated to provide reproducibly the disclosed, mediator level, synergistic interaction obtained employing the preparations of the invention in clinic. Moreover until now, and despite reference in the artto drug interaction, e.g. between theophylline and ketotifen, as discussed above, no proposal for administration in fixed combination has previously been made.

Component a), ketotifen, may be present in the preparations of the invention either in free form or in pharmaceutically acceptable acid addition salt form, e.g. in the form of its hydrogen fumarate. Such salt forms are well tolerated. References to ketotifen herein are accordingly to be understood as embracing both the free compound as well as its pharmaceutically acceptable acid addition salts unless otherwise specified.

Component a) is preferably present in the preparations of the invention in the form of its hydrogen fumarate.

Suitable anti-asthmatically effective xanthines for use as component b) in the preparations of the present invention include those of formula il

wherein i) R1, R3 and R4 are each hydrogen and R2 is n-propyl; or ii) R1 and R2 are each methyl, R3 is -(CH2)2N(C2H5)CH2CH2OH and R4 is benzyl; ii) R1 and R2 are each methyl, R4 is hydrogen and R3 is

The compounds into iii) above are known and are described, together with processes for their production, e.g. in i) European Patent No. 0011 609, ii) Belgian Patent No. 888 and iii) European Patent No. 0089028.

Of these the preferred compound for use in the preparations of the invention is i), also known and hereinafter referred to as enprophylline. The most preferred anti-asthmatically effective xanthine for use in the preparations of the invention is however the compound theophylline of formula Ila, previously referred to.

Components b) may be present in the preparations of the invention in free form, in the form of any one of their known admixtures with a pharmaceutically acceptable adjunct, in particular pharmaceutically acceptable amines, such as choline, ethanolamine, diethanolamine etc..., or in the form of a pharmaceutically acceptable acid addition salt thereof, including the pharmaceutically acceptable acid addition salts of such adjunct admixtures. Adjunct admixtures and salts thereof as aforesaid are well known in the art and generally have the advantage of increased solubility as compared with the free compound or its salts.In the case of the anti-asthmatically efective xanthine theophylline, they include e.g. the products theophylline calcium salicylate, theophylline diethanolamine, theophylline isopropanolamine and, in particular, aminophylline. [a 2:1 (p.p.w.) adjunct oftheophylline and ethylenediamine]. Such adjuncts and salts are also well tolerated and references to anti-asthmatically effective xanthines herein, as well as to specific xanthines of this class such as theophyllin, are accordingly to be understood as embracing both free forms as well as adjunct admixtures and salts as aforesaid, unless otherwise specified. Preferably anti-asthmatically effective xanthines, including the preferred such xanthine, theophylline, present as component b) in the preparations of the invention are present as the free compound, e.g. as free theophylline.

Pharmaceutical preparations in accordance with the invention include any appropriate form suitable for administration either enterally or parenterally and comprising components a) and b) in fixed combination, i.e. together and each in a predetermined amount, e.g. in predetermined relative proportion. Preferred preparations in accordance with the invention are forms suitable for oral administration, including capsules, tablets, syrups or the like. Preferably the preparations of the invention constitute a unit dosage form, e.g. for oral administration, whereby each unit dosage will comprise a predetermined amount of each of components a) and b).

Preparations in accordance with the invention include both systems wherein components a) and b) are evidently separate, e.g. present or contained apart within the preparation, as well as systems wherein the said components are present in intimate admixture or both substantially evenly dispersed throughout a common matrix. Preparations of the former type include capsules, e.g. for oral administration, containing a) and b) each in independent granulated, powder, tabletted or like form (whether mixed together or not) or quite separately, e.g. in individual compartments of a split capsule or in separate layers of a mantle tablet.

Preparations of the latter type include e.g. tablets or the like in which a) and b) are each substantially evenly distributed throughout the tablet mass or matrix. In such cases the tablet mass or matrix will generally comprise a substantially uniform matrix e.g. comprising carriers, solid diluents and/or binding agents etc. as commonly employed in the art. Such preparations can be manufactured in accordance with techniques generally known in the art, for example as hereinafter described in the accompanying examples.

It is further preferred that component b) is present in the preparations of the invention in sustained release form, i.e. in a form enabling continued release of component b) within the body, or to the body tissues, over prolonged periods oftime, or enabling maintainance of relatively constant component b)- blood serum levels over prolonged periods of time, subsequent to administration.

Suitable sustained release forms for component b) are known in the art and may be obtained by any of the techniques known and commonly employed in the galenic art, in particular in relation to sustained release formulation of xanthines, see e.g. European Patent Publication No.0 122077, US Patents Nos. 4,415,547 and 3,400,185 and PCT Application No, WO 8300284. They include sustained release pellet forms e.g. in which individual particles of a granulate, powder or the like comprising b) are provided with an (appropriate) sustained release coating. They may for example be obtained by providing a finely divided preparation, e.g.

granulate or powder preparation of the drug substance, with an appropriate resistant, e.g. enterically resistant, coating. Specific examples of such sustained release pellet forms are described hereinafter. The specific release properties of component b) obtained in such manner may be varied as desired, e.g. through choice of coating material, by variation of thickness of the coating applied and/or variation of the particle size of the material coated. Since clearance rate for anti-asthmatically effective xanthine derivatives, e.g.

theophylline, is highly subject specific, blood serum levels achieved employing any particular sustained release preparation will inevitably vary considerably from individual to individual. In general however, in the case of e.g. theophylline, sustained release forms suitable for use in the preparation of the invention will be such as to provide blood serum levels of the order of from ca. 8 to ca. 20 ng/ml over periods of from e.g. from ca. to ca. 8 hours or more, e.g.for periods of up to ca. 6 hours, subsequent to administration.

In the case of theophylline preferred sustained release forms for component b) will be such as to provide the following approximate theophylline release characteristics under laboratory conditions: 1. On dissolution in an amount of ca. 200 mg in 1000 ml 0.1 N HCI: a) % theophylline release after 3 hrs. = ca. 40 - 60%, preferably ca. 45 - 55%, e.g. ca. 50%; b) % theophylline release after 8 hrs. = ca. 70 - 90%, preferably ca. 75 - 85%, e.g. ca. 80%.

2. On dissolution in an amount ofca. 100 mg in 1000 ml 0.1 N HCI: a) %theophylline release after 3 hrs. = ca. 45 - 60%, preferably ca. 50 - 57%, e.g. ca. 53%; b) %theophylline release after8 hrs. = ca. 80to 100%, e.g. ca. 85-95%, e.g. ca. 90%.

Average theophylline release under conditions 1) above after 1 hour preferably does not exceed ca. 30%, more preferably ca. 25%. Hourlytheophylline release under conditions 1) above over an 8 hour period suitably varies within the range of from ca. 4 - 20%, preferably ca. 5 - 15%/hour.

Such forms thus suitably provide a maximum theophylline release of i) ca. 60%, preferably ca. 55% and ii) 100%, preferably ca. 90 - 95% after) 3 hrs. and ii) 8 hrs. under the standard conditions recited under 1. and 2.

above respectively. (All measurements at ambient temperature with paddle stirring at ca. 90 r.p.m.. The pH is suitably adjusted atca. cm.120 mins.).

When component b) is theophylline in free form, a preferred sustained release form for use in the preparations of the invention is theophylline retard pellets as supplied in the commercially available product BRONCHORETARD from the company KLINGE AG. Preparation of an alternative preferred sustained release form is hereinafter described in example la.

In general components a) and b) will be present in the preparations of the invention in a ratio of ca. 1:50 to 500 p.p.w., preferably ca. 1:100 to 500 p.p.w. (a:b). In particular and preferred embodiments the preparations of the invention comprise components a) and b) in a ratio of ca. 1:50 to 350 p.p.w., especially ca. 1:100 to 300 p.p.w, or ca 1:50 to 300 p.p.w., especially ca. 1:100, 200 or 300 p.p.w. e.g. ca. 1:200 or 300 p.p.w..

Where the preparations of the invention comprise a unit dosage form individual unit dosages will suitably comprise from about 1 to about 2 mg, preferably about 1 mg of component a). Suitably, such unit dosages will comprise maximally about 500, preferbly maximally about 350, more preferably about 300 mg of component b). Thus preferred unit dosages will comprise 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 e.g.

about 100, 150, 175, 200 or 300, especially about 175,200 or 300 mg of component b), intended for administration lx to 4x, in particular lx or 2x/daily.

Such compositions will be suitable for use in the treatment of all conditions for which ketotifen therapy is currently applied, as well as for conditions where bronchodilatatory effectiveness is required, e.g. in the treatment of active asthma and in initiating, asthma therapy. Where once a day dosaging is foreseen, or bronchodilatation is crucial to therapy, amounts of component b) present will generally be higher, e.g. in the case of unit dosage forms, of the order of ca. 200 mg, or preferably 300 mg upwards.Where dosages are to be administered 2x daily or more, or where bronchodilatation is not crucial to therapy, e.g. in the case of asthma prophylaxis/maintainance therapy, or in the treatment of bronchitis, amounts of component b) present in the preparations of the invention may be lower, thus taking special benefit of the synergistic interaction of the two components at the mediator level as herein disclosed and discussed. For such purposes the compositions of the invention may comprise from as little as about 50 to about 300 mg.

[The above weight ratios and recited mg values are to be understood as applying to components a) and b) in free form, i.e. to the amounts/relative proportions of free ketotifen and e.g. free theophylline. Where salts/adjuncts of components a) or b) are employed, amounts employed will be those corresponding to the indicated amounts of free a) or free b)].

The beneficial utility of compositions in accordance with the present invention, and in particular synergistic interaction of ketotifen and anti-asthmatically effective xanthines, e.g. theophylline, e.g. with respect to protective activity as discussed above, may be demonstrated in clinic as well as in conventional animal models. Thus mutual synergistic interaction of ketotifen and theophylline at mediator level, e.g. with respect to PAF induced bronchospasm can for example be demonstrated as follows: Methodology The spontaneously breathing, anaesthatised guinea-pig responds to an intravenous injection of PAF by an increase of airways resistance and a reduction of dynamic compliance. Use of PAF to test for drug efficacy is made difficult by differences in sensitivity between animals, by a steep dose-effect relationship and by potential interaction between doses.However, it is possible to establish a protocol whereby up to four successive intravenous injections of a constant dose of PAF, at 10-minute intervals, will elicit closely similar responses. This permits use of such preparations for routine evaluation of drug effects. In such animals, drugs are administered intravenously 5 minutes before (ketotifen or saline) or 1 minute before (aminophylline - the theophylline adjunct hereinabove specifically described - or saline) a PAF injection.

Inhibition is estimated by comparison of response post-treatment with response immediately prior to drug treatment. The paired-difference between the two responses is conveniently expressed as a percentile of the response immediately prior to drug treatment.

In order to test for synergism between ketotifen and aminophylline the isobole technique is adopted as a rigoroustest [Berenbaum,Clin. Exp. lmmunol.,28, 1 - 18(1977)]. Doses of ketotifen between 0.56 g/kg and 18 wg/kg are employed either alone or in combination with doses of aminophylline between 0.01 mg/kg and 0.32 mg/kg. Responses are determined for at least five animals at each dose or dose combination, excepting for saline-treated animals (nine) and for animals receiving 0.32 mg/kg of aminophylline (ten) or receiving 1.8 llg/kg of ketotifen (seven), when additional animals are used. A total of eighty-six animals are used for the study.

Results Treatment of animals with two doses of saline causes insignificant reduction (4%) of the response to PAF.

Treatment with ketotifen causes a dose-related reduction, with inhibition being evident at the lowest dose.

Treatment with aminophylline also causes a dose-related inhibition but with a shallower slope than is observed with ketotifen. This data, together with the data for drug combinations, is presented graphically in Figure I attached. In Figure I, inhibitory effects of each dose is depicted adjacent to the axes. Inhibitory effects of drug combinations is assigned to the appropriate intersection. From this data, it is possible to construct two isoboles for inhibitory responses to aminophylline. Both isoboles exhibit concavity, which is characteristic of synergistic interaction.

Conclusion Synergy is evident between ketotifen at a rear therapeutic dose and aminophylline at a dose which would be considered sub-therapeutic for bronchodilatator efficacy, but which produces drug concentrations that occur commonly in both asthma and bronchitis, during aminophylline therapy.

Beneficial utility of compositions in accordance with the present invention may also be demonstrated in clinical trials, for example performed as follows: Trial conditions The trial is carried out employing groups of 12 patients, male and female, between the ages of 16 and 65 years. Patients selected exhibit both seasonal or perennial, chronic bronchial asthma (with reversible, allergic- or mixed-form bronchospasm) as diagnosed anamnesically by skin test or determination of allergen specific IgE and, where necessary, confirmed by inhalative provocation. Light to medium-severe forms are characterised by light to medium grade bronchial obstruction in repeated determination of attack-/ duration-symptomatology.

The following exclusion parameters are applied: pregnancy; severe liver or kidney disease; condition subsequent to myocardial infarct (not more recent than 6 months); difficulty regulatable Diabetes mellitus; gastro-intestinal disease liable to influence resorption, metabolism or excretion of test substance, e.g.

chronic diarrhea, malasorption syndrome etc...; disturbance of heart rate; stomach or intestinal ulcus; subjects known to be unreliable or psychologically labile.

As far as possible, subjects only receive additional (3-symathikomimetic or anti-cholinergic medication where this is essential in aborting asthma attack. Where absolutely essential other medication, e.g corticosteroid or antibiotic treatment is permitted, the nature of such treatment, duration and applied dosaging being recorded. In the event that patients are already receiving continued bronchodilatatory, steroidal ortheophylline therapy, this is reduced step-wise only during the first 2 to 3 weeks of the trial.

The following trial preparations are employed: a) Tablets comprising 1 mg ketotifen + 200 mg sustained release theophylline in fixed combination and prepared in accordance with example 1 hereinafter.

b) Tablets comprising 1 mg ketotifen + 300 mg sustained release theophylline in fixed combination and prepared in accordance with example 2 hereinafter.

c) Tablets comprising 1 mg ketotifen only and prepared in accordance with example 1 b hereinafter but with omission of component a).

d) Tablets comprising 200 mg sustained release theophylline, prepared in accordance with example 1 b hereinafter but omitting component b).

e) Tablets comprising 300 mg sustained release theophylline, prepared in accordance with example 2 hereinafter, but omitting component b).

Each patient receives 420 tablets. The trial preparations are distributed to the patients in randomised double-blind fashion, whereby subjects weighing S 50 kg and receiving theophylline (alone or in combination with ketotifen) are provided with a 200 mg theophylline preparation [i.e. in accordance with a) or d) above] and subjects weighing > 50 kg and receiving theophylline (alone or in combination with ketotifen) are provided with a 300 mg theophylline preparation [i.e. in accordance with b) ore) above].All tablets are of essentially identical appearance, with tablets c) being provided in two sizes, the smaller size (for administration to subjects of S 50 kg) corresponding to alternative tablets comprising 200 mg theophylline, the larger (for administration to subjects of > 50 kg) corresponding to alternative tablets comprising 300 mg theophylline.

During the course of the study each patient takes 2 tablets daily (mornings and evenings) orally. Study duration for each patient is 6 months.

Clinical control is effected for each subject 2,4, 6 and 8 weeks after commencement of the trial and then subsequently at 4 week intervals. At each control the following parameters are measured: - Vital capacity - Expiratory reserve volume - Functional residual air capacity - Total resistance - Closing volume - Flow volume Details of number and severity of occurring symptoms - occurrence of difficulty in breathing, coughing, expectoration - reported by the trial patients is recorded.

5 ml blood is taken from each patient at entry into the trial and 1 month later for determination of theophylline. The second sample is taken 4 - 8 hours after administration of the trial preparation.

Results Patients receiving ketotifen + theophylline in fixed combination are found to exhibit significantly improved response, e.g. for the following listed parameters, in comparison with subjects receiving ketotifen ortheophylline alone: 1-Sec.-capacity as % of vital capacity; flow volume 25; total resistance; and closing volume. Significant improvement is also recorded for subjects receiving ketotifen + theophylline in fixed combination for the following listed parameters: Vital capacity; expiratory reserve volume; flow volume 25, 50 and 75; and functional residual air capacity. In particular results obtained during the first four to six weeks following commencement of the trial for individual parameters measured, in particular total resistance, indicate that efficacy recorded for subjects receiving ketotifen + theophylline in fixed combination is greater than may be projected from results obtained for subjects receiving ketotifen or theophylline alone, i.e. are indicative of super-additive effectiveness.

In accordance with the foregoing the present invention also provides a pharmaceutical preparation for the treatment of asthma and exhibiting or providing superadditive or synergistic anti-asthmatic effectiveness, in particular at mediator level; or exhibiting or providing superadditive or synergistic, preventive or prophylactic anti-asthmatic effectiveness, in particular at mediator level, e.g. as evidenced by reduction of airways obstruction, e.g. consequential to airways hyperreactivity, development of mucus, inflammation etc...: said preparation comprising a) ketotifen and b) an anti-asthmatically effective xanthine in fixed combination (e.g. as herein described).

In an alternative embodiment the invention provides a method for the treatment, in particular for the preventive or prophylactic treatment, of asthma, in particular at mediator level; or for the reduction of airways obstruction, e.g. consequential to airways hyperreactivity, development of mucus, inflammation etc..., in particular during the preventive or prophylactic treatment of asthma: in a subject in need of such treatment, which method comprises administering to said subject a pharmaceutical preparation comprising a) ketotifen and b) an anti-asthmatically effective xanthine in fixed combination (e.g. as herein described); or The use of a pharmaceutical preparation (e.g. as herein described) comprising a) ketotifen and b) and anti-asthmatically effective xanthine in fixed combination for treatment as defined above; or The use of a) ketotifen and b) an anti-asthmatically effective xanthine for the manufacture of a pharmaceutical preparation (e.g. as herein described) comprising a) and b) in fixed combination, for use in a method of treatment as defined above.

The following examples are illustrative of the preparations of the present invention and of their manufacture: Example 1 Preparation of tablets comprising 200 mg free theophylline in sustained release form and 1 mg free ketotifen 1 a) Preparation of theophylline sustained release pellets 4.135 kg ethylcellulose, 0.37 kg hydroxypropylmethylcellulose and 0.53 kg di-n-butylphthalate are dissolved in a mixture comprising 30 kg isopropanol, kg ethanol and 10 kg H2O,to provide a coating solution having a viscosity of 170-230 cP.

49.5 kg regulartheophylline granulate (e.g. as directly supplied by the company Boehringer - ca. 9 - 10% of granules having a diameter > 0.71 mm, ca. 60 - 70% of granules having a diameter > 0.50 mm) are filled into the container of a Glatt W56-60 spray coating apparatus fitted with Schlick nozzles of 2.5 mm diameter. The granulate is spray coated with the aforementioned coating solution, coating being effected under the following conditions: Nozzle-floor spacing; 50 cm Vibration interval: 60 secs.

Duration of vibration: 10 secs.

Temperature of spray solution: 22 - 27"C Spray pressure: 3,8 bar.

Pump-supply capacity: ca. 20 l/g Temperature at air-input: 27 - 31"C Temperature in granulate mass: 25 - 27"C Air volume employed: 2600-4600 m3/h On completion of the spray procedure the obtained spray-coated product is dried for 10 mins. at 45 - 55"C.

The whole spray coating procedure is conducted to give a total processing time of ca. 200 mins, providing a product in which the coating: theophylline ratio is ca. 1:100 (p.p.w.).

1b) Preparation of product tablets Ingredients Relative proportion in mg a) Theophylline sustained release pellets obtained in accordance with 1a) above 220.30 * b) Ketotifen hydrogen fumarate 1.38** c) Lactic acid 90.00 d) Cellulose granulate 60.00 e) Cellulose powder 58.32 f) Stearic acid 100.00 * = 200 mg uncoated, free theophylline ** = 1 mg free ketotifen The ingredients are thoroughly mixed in conventional fashion and pressed into individual tablets having a total weight of 530.00 mg and each comprising 200 mg free theophylline and the equivalent of 1 mg free ketotifen.

Sampletheophylline release rate characteristica for product tablets as determined under standard laboratory conditions [6 tablets in 500 ml simulated gastric juice (0.1 N HCI to pH 7.5 with pH adjustment at 1,2 and 3 hrs), over 8 hrs.. With paddle-stirring at 50 R.p.m.] are as follows: Elapsed time % Theophylline released 1 hr..................................... hr ca. 12% 2 hrs ca.22% 3 hrs ca.34% 5 ca.64% 8 hrs ca.87% Example 2 Preparation of tablets comprising 300 mg free theophylline in sustained release form and = 1 mg free ketotifen The procedure of example 1 is repeated, but employing the following relative proportions (in mg) of ingredients a)through f) at step 1b): a): 330.50 [= 300 mg uncoated,freetheophylline]. b): 1.38(= 1 mgfree ketotifen). c): 80. d): 60.00. e): 57.12. f): 100.00.

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

Sample theophylline release rate characteristica for product tablets as determined under standard laboratory conditions as set forth in example 1 are as follows: Elapsed time % Theophylline released lhr ca.11% 2hrs ca.21% 3hrs .................................. ca.31% 5 hrs ca.65% 8 hrs ca.89% Example 3 Preparation of capsules comprising ?50 mg free theophylline and 1 mg free ketotifen 3a)Preparation of ketotifen tablet mass Ingredients Relative proportion in mg a) Ketotifen hydrogen fumarate: 1.38 * b)Talc: 0.16 c) Calcium hydrogen phosphate water-free: 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 in conventional fashion and pressed into individual tablets each weighing ca. 45.00 mg and containing the equivalent of 1 mg free ketotifen.

S Preparation ofproduct capsules 162.9 mg theophylline retard pellets from the company Klinge AG as hereinbefore described [= 150 mg uncoated, free theophylline] and 1 tablet obtained in accordance with step 3a) above, are filled into a hard gelatin capsule and the capsule sealed.

Example 4 Preparation of capsules comprising 1 mg free ketotifen and free theophylline in varying amounts Hard gelatin capsules are prepared analogously to example 3, containing 1 tablet obtained in accordance with example 3a) and theophylline retard pellets from the company Klinge AG as specified in example 3b) in the following specified amounts: 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 free, uncoated theophylline 4f) 380.1 mg = 350.00 mg free, uncoated theophylline Theophylline sustained release pellets of the general type described above in example la, i.e. comprising a theophylline granulate as core material and a coating as set forth, are also new.

Accordingly in a further aspect the present invention also provides: I. Theophylline in sustained release pellet form and comprising a granulate consisting essentially of free theophylline as pellet core material, provided with a pellet coating comprising ethylcellulose and hydroxypropylmethylcellulose.

Preferably coating is effected, e.g. as described in example 1, such that substantially all of the granules comprising the core material are individually coated. Suitably the granules comprising the core material conform to the size characteristica described for the theophylline granulate starting material in example 1 a.

Suitably the coating is applied such that the core material and coatihg are present in the obtained pellets in a ratio of ca. 1:0.5 to 0.2 p.p.w., preferably ca. 1:0.1 p.p.w. The obtained pellets preferably have a maximum diameter of ca. 2.0 mm and a minimum diameter of ca. 0.3 mm. Suitably ca. 55 to ca. 85%, preferably ca. 50 to ca.80%, of the obtained pellets have a diameter > 0.71 mm. Suitably not more than ca. 1.0%, preferably not more than ca. 0.5% of the obtained pellets have a diameter > 1.4 mm, and not more than ca. 15%, preferably not more than ca. 10 - 12% have a diameter > 1.0 mm.

The ratio of hydroxypropylmethylcellulose to ethylcellulose in the applied coating is suitably ca. 1:6 to 14 p.p.w., preferably ca. 1:8 to 12 p.p.w., more preferably ca. 1:9 to 11 p.p.w.. Suitably the coating also comprises a softening agent such as di-n-butylphthalate. When present the softening agent is suitably present in an amount of from about 8 to 15%, preferably about 12%, by weight based on the total weight of coating material.

The invention further provides: II. A process for the production of theophylline in sustained release pellet form as defined under I. above, which process comprises spray-coating a theophylline granulate with a coating mixture comprising a methanolic solution of ethylcellulose and hydroxypropylmethylcellulose. Suitably said process is carried out employing individual parameters and/or conditions as hereinbefore described in example 1a.

In addition to present invention also provides: III. A pharmaceutical preparation comprising a) ketotifen preferably in the form of its hydrogen fumarate, and b) theophylline in pellet form as defined under I. above, in fixed combination, in particular a pharmaceutical preparation as aforesaid comprising a tablet or the like in which a) and b) are each substantially evenly distributed throughout the tablet mass or matrix.

The invention also provides: IVa. A process for the manufacture of a pharmaceutical preparation as hereinbefore defined, having improved effectiveness in the treatment, in particular in the preventive or prophylactic treatment of asthma; or improved effectiveness in the reduction of airways obstruction, in particular during preventive or prophylactic treatment of asthma: which process comprises bringing a) ketotifen, preferably in the form of its hydrogen fumarate, into association with an anti-asthmatically effective xanthine in a fixed combination; as well as IVb.A process for the manufacture of a pharmaceutical preparation as defined under III above, which process comprises bringing components a) and b) into fixed combination, in particular intimately admixing components a) and b) together with a solid, pharmaceutically acceptable diluent or carrier therefor, to produce a mass capable of being formed into tablets or the like and processing said mass into tablets or like form.

Suitable theophylline release rate characteristica for preparations as defined under Ill above in tablet or like form, e.g. of the kind hereinbefore described in examples 1 and 2, under standard laboratory conditions as set forth in example 1, are e.g. as follows: Elapsed time % Theophylline released 1. hour................................. 1 hour < 20%, pref ca.15% or less.

2. 2 hrs ................................... < 30%, prefca. 25% or less.

3. 3 hrs .................................. < 40%, pref ca.35% or less.

4. 5 hrs .................................. < 70%, pref ca.65% or less.

5. 8 hrs .................................. < 95%, prefca. 90% or less.

Claims (38)

1. A pharmaceutical preparation comprising a) ketotifen and b) and anti-asthmatically effective xanthine in fixed combination.

2. A pharmaceutical preparation according to claim 1 comprising ketotifen hydrogen fumarate as a).

3. A pharmaceutical preparation according to claim 1 or 2 comprising enprophylline as b).

4. A pharmaceutical preparation according to claim 1 or 2 comprising theophylline as b).

5. A pharmaceutical preparation according to claim 4 comprising free theophylline as b).

6. A pharmaceutical preparation according to any one of claims 1 to 5 wherein b) is in sustained release form.

7. A pharmaceutical preparation according to claim 6 wherein b) is in sustained release pellet form.

8. A pharmaceutical preparation according to any one of claims 1 to 7 in unit dosage form.

9. A pharmaceutical preparation according to claim 8 in unit dosage form appropriate for oral administration.

10. A pharmaceutical preparation according to claim 9 comprising a capsule or the like in which a) and b) are contained independently.

11. A pharmaceutical preparation according to claim 9 comprising a tablet or the like in which a) and b) are each substantially evenly distributed throughout the tablet mass or matrix.

12. A pharmaceutical preparation according to any one of claims 1 to 11 wherein a) and b) are present in a ratio of ca. 1:50 to 500 p.p.w. [free a): free b)].

13. A pharmaceutical preparation according to claim 12 wherein a) and b) are present in a ratio of ca. 1:50 to 350 p.p.w..

14. A pharmaceutical preparation according to claim 13 wherein a) and b) are present in a ratio of ca.1: 100 to 300 p.p.w..

15. A pharmaceutical preparation according to claim 12 wherein a) and b) are present in a ratio of ca. 1:50 to 300 p.p.w..

16. A pharmaceutical preparation according to any one of claims 8 to 11 comprising ca. 1 to ca. 2 mg a) [based on free compound] and from ca. 50 to ca. 500 mg of b) [based on free compound].

17. A pharmaceutical preparation according to claim 16 comprising ca. 1 mg of a).

18. A pharmaceutical preparation according to claim 16 or 17 comprising ca. 100 to ca. 350 mg of b).

19. A pharmaceutical preparation according to claim 18 comprising ca. 175,200 or 300 mg of b).

20. Theophylline in sustained release pellet form and comprising a granulate consisting essentially of free theophylline as pellet core material, provided with a pellet coating comprising ethylcellulose and hydroxypropylmethylcel lu lose.

21. Theophylline in pellet form according to claim 20 wherein substantially all the granules of the granulate have an individual coating.

22. Theophylline in pellet form according to claim 21 wherein the pellets have a minimum diameter of ca.

0.3 mm and a maximum diameter of ca. 2.0 mm and an average diameter of ca. 0.7 mm.

23. Theophylline in pellet form according to any one of claims 20 to 22 wherein the core material and coating are present in a ratio of ca. 1:0.02 to 0.3 p.p.w.

24. Theophylline in pellet form according to claim 23 wherein the core material and coating are present in a ratio of ca.1:0.05 0.2 p.p.w..

25. Theophylline in pellet form according to claim 24 wherein the core material and coating are present in a ratio of ca. 1:0.1 p.p.w..

26. Theophylline in pellet form according to any one of claims 20 to 25 wherein the ratio of hydroxypropylmethylcellulose to ethylcellulose in the coating is ca. 1:6 to 14 p.p.w..

27. Theophylline in pellet form according to claim 26 wherein the ratio of hydroxypropylmethylcellulose to ethylcellulose in the coating is ca. 1:8 to 12 p.p.w..

28. Theophylline in pellet form according to claim 27 wherein the ratio of hydroxypropylmethyicellulose to ethylcellulose in the coating is ca. 1:9 to 11 p.p.w..

29. Theophylline in pellet form according to any one of claims 20 to 28 wherein the coating additionally comprises di-n-butylphthalate.

30. Theophylline in pellet form according to claim 29 wherein the di-n-butylphthalate is present in an amount of from about 8 to 15% by weight based on the total weight of coating material.

31. Theophylline in pellet form according to claim 30 wherein the di-n-butylphthalate is present in an amount of from about 10 to about 12% by weight based on the total weight of the coating material.

32. A pharmaceutical preparation according to any one of claims 7 to 19 wherein b) comprises free theophylline in pellet form as defined in any one of claims 20 to 31.

33. A method for the treatment, in particular for the preventive or prophylactic treatment of asthma, or for the reduction of airways obstruction, in particular during preventive or prophylactic treatment of asthma, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a pharmaceutical preparation according to any one of claims 1 to 19 or 32.

34. The use of a pharmaceutical preparation according to any one of claims 1 to 19 or 32 for the treatment, in particular preventive or prophylactic treatment of asthma, or for the reduction of airways obstruction, in particular during preventive or prophylactic treatment of asthma.

35. The use of a) ketotifen and b) and anti-asthmatically effective xanthine for the manufacture of a pharmaceutical preparation according to any one of claims 1 to 19 or 32 for use in a method of treatment as defined in claim 33.

36. A processforthe manufacture of a pharmaceutical preparation having improved effectiveness in the treatment, in particular in the preventive or prophylactic treatment of asthma, or improved effectiveness in the reduction of airways obstruction, in particular during preventive or prophylactic treatment of asthma, which process comprises bringing a) ketotifen, preferably in the form of its hydrogen fumarate, into association with an anti-asthmatically effective xanthine in fixed combination.

37. Process for the production of theophylline in sustained release pellet form as defined in any one of claims 20 to 31 which process comprises spray-coating a theophylline granulate with a coating mixture comprising a methanolic solution of ethylcellulose and hydroxypropylmethylcellulose.

38. A pharmaceutical preparation according to claim 1; pellet form according to claim 20; method of treatment, or use according to any one of claims 33 to 35; or process according to claim 36 or 37, substantially as hereinbefore described with reference to the accompanying examples.