MXPA02007688A - Method and compositions for treating an inflammatory disease. - Google Patents

Abstract

This invention relates to treating an inflammatory disease by administering a phosphodiesterase 4 inhibitor in combiantion with an inhibitor of prostaglandin synthesis, NSAIDs being exemplary.

Description

METHOD AND COMPOSITIONS TO TREAT AN ANTI-INFLAMMATORY DISEASE FIELD OF THE INVENTION This invention relates to compositions and methods for preventing or treating inflammatory diseases by administering a phosphodiesterase 4 inhibitor in combination with a prostaglandin synthesis inhibitor, wherein NSAIDs are exemplary.

BACKGROUND OF THE INVENTION The identification of novel therapeutic agents to treat lung diseases is complicated by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator could have a substantial effect on the three components of chronic asthma. An alternative to the "mediating method" is to regulate the activity of the cells responsible for the pathophysiology of the disease. One way is by raising the levels of cAMP (3 ', 5'-cyclic adenosine monophosphate). Cyclic AMP has been shown to be a second messenger that mediates biological responses on a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg + 2-ATP into cAMP at an accelerated rate. Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects that include: 1) smooth muscle relaxation of the air passage, 2) inhibition of mastoid cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation , and 5) inhibition of monocyte and macrophage activation. Therefore, compounds that activate adenylate cyclase or inhibit phosphodiesterase must be effective in suppressing inadequate activation of airway smooth muscle and a wide variety of inflammatory cells. The main cellular mechanism for the inactivation of cAMP is the hydrolysis of 3'-phosphodiester linked by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs). It has been shown that a cyclic nucleotide phosphodiesterase isozyme (PDE) PDE IV is responsible for the breakdown of cAMP in smooth muscle of the passage of air and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that the inhibition of this enzyme not only results in smooth muscle relaxation of the air passage, but also suppresses the f -f._f.-fr.-f- fofflfff "f - -? ^ * - < - ------ ----- ai- .... .., -t. --it ^. t. - > __ degranulation of mastoid, basophil and neutrophil cells together with the inhibition of monocyte and neutrophil activation. In addition, the beneficial effects of PDE IV inhibitors are markedly enhanced when the adenylate cyclase activity of target cells is elevated through suitable hormones or autocoids, as would be the case in vivo. In this way, PDE IV inhibitors would be effective in the lung, where the levels of prostaglandin E2 and prostacyclin (adenylate cyclase activators) are high. These compounds would offer a unique method towards the pharmacotherapy of bronchial asthma and have significant therapeutic advantages over agents currently on the market. In addition, it may be useful to combine therapies in view of the fact that the etiology of many lung diseases involves multiple mediators. In this invention, the combination of a PDE 4 inhibitor and a non-spheroidal anti-inflammatory to treat an inflammatory disease or a treatable condition by a selective inhibitor of PDE4 which has an inflammatory component associated with the synthesis of prostaglandins is associated therewith. .

BRIEF DESCRIPTION OF THE INVENTION In a first aspect, this invention relates to a method for treating an inflammatory disease in a mammal by administering to a patient in need thereof an effective amount of an inhibitor. f-tili-t ililí t-fí * É i Í ---- i .í - ¿k? &? specific of PDE 4 and an effective amount of a non-spheroidal inflammatory agent wherein the drugs are administered concomitantly, or separately and consecutively when the consecutive administration is close in time or remote in time.

DETAILED DESCRIPTION OF THE INVENTION The combination therapy contemplated by this invention comprises administering a PDE 4 inhibitor with a non-spheroidal anti-inflammatory agent to treat an inflammatory disease. The compounds can be administrable together in a single dosage form. Or they can be administrable as different formulations. To illustrate, both drugs may be provided separately as oral formulations, or one may be an oral preparation or a suppository or by injection or as an intravenous drip. They can be administrable at the same time. Or they may be administrable close in time or remotely, such as when a drug is administrable in the morning and the second drug is administrable in the afternoon. The specific PDE4 inhibitor useful in this invention can be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which is not only PDE4 inhibitor, nor compounds that inhibit other elements of the PDE family, as well as PDE4. Generally, it is preferred to use antagonists of PDE4 having an IC50 ratio of about 0.1 or more in reference to IC50 for the catalytic form of PDE IV which binds to rolipram with a high affinity divided by IC50 for the form which joins rolipram with a low affinity. PDE inhibitors such as theophylline and pentoxifylline inhibit all or most of the PDE isozymes indistinctly in all tissues. These compounds have side effects, apparently because they inhibit non-selectively all classes of PDE isozyme in all tissues. The target disease can be effectively treated through such compounds, but unwanted side effects can occur which, if they could be avoided or minimized, would increase the overall therapeutic effect of this method to treat certain diseases. For example, clinical studies with the rolipram of PDE 4 inhibitor, which was developed as an antidepressant, indicate that it has psychotropic activity and produces gastrointestinal effects, for example, heartburn, nausea and emesis. For purposes of this description, the catalytic site of cAMP which binds rolipram R and S with a low affinity, is termed the "low affinity" binding site (LPDE 4) and the other form of this catalytic site which binds to rolipram with a high affinity, is called the "high affinity" binding site (HPDE 4). This term HPDE 4 should not be confused with the term "hPDE4" which is used to denote human PDE4.

Initial experiments were performed to establish and validate a binding test to [3HjR-rolipram. The details of this work are given in example 1 below. To determine whether the high affinity binding activity and the low affinity binding activity reside in the same gene product, yeast was transformed by known methods and the expression of recombinant PDE4 was followed for a fermentation period of 6 hours. Western blot analysis using an antibody directed against PDE4, indicated that the amount of expressed PDE4 increased with time, reaching a maximum after 3 hours of growth. In addition, more than 90% of the immunoreactive product was in the high-speed supernatant (100,000 x g) of yeast lysates. The binding of [3 H] R-Rolipram and PDE activity were monitored together with protein expression. The activity of PDE4 was co-expressed with binding activity to rolipram, indicating that both functions exist in the same gene product. Similar to the results with the Western blot analysis, more than 85% of the PDE activity capable of inhibition by rolipram and the binding activity to [3H] -rolipram was found present in the fraction of the yeast supernatant. In general, most of the recombinant PDE4 expressed in this system exists as LPDE4 and only a small fraction as HPDE4. Accordingly, the inhibition of catalytic activity of recombinant PDE4 mainly reflects the actions of compounds in LPDE4. The inhibition of PDE4 catalytic activity can then be used as an index of the potency of the compounds in LPDE4. The potency of the compounds in HPDE4 can be assessed by examining their ability to compete for [3H] R-rolipram. To develop SAR for both high affinity and low affinity rolipram binding sites, the potencies of selected compounds were determined in two test systems. Results of experiments were tabulated using standard compounds. As expected, certain compounds were clearly more potent in competing with [3 H] R-rolipram at the site for which rolipram demonstrated high affinity binding compared to the other site, that in which rolipram is a low binding agent. affinity. The SAR correlation between high affinity binding and low affinity binding was poor and it was concluded that the SAR for inhibition of binding of high affinity [3H] R-rolipram was different from SAR for binding to the binding site of rolipram of low affinity. It is now known that there are at least two binding forms in recombinant human monocyte PDE4 (hPDE4) with which the inhibitors interact. One explanation for these observations is that hPDE4 exists in two different forms. One binds to the similar ones of rolipram and denbufilin with a high affinity, while the other binds to these compounds with a low affinity. Preferred PDE4 inhibitors for use in this invention will be those compounds which have a healthy therapeutic relationship, i.e., compounds which preferably inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thus reducing the side effects that ....... .. - (-.- ».«. »-f A-.,.". «. ^. T * íft * .Mm tM? T? M ^^ apparently they are related to the inhibition of the form which joins rolipram with a high affinity. Another way to establish this is that the preferred compounds will have an IC50 ratio of about 0.1 or more with respect to IC50 for the catalytic formula of PDE4 which binds rolipram with a high affinity divided by IC50 for the form which joins rolipram with a low affinity. A further perfection of this standard is that wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or more; said ratio is the ratio of the IC50 value to compete with the binding of InM from [3H] R-rolipram to a form of PDE4 which binds rolipram with a high affinity on the IC50 value to inhibit the catalytic activity of PDE IV in a way which binds rolipram with a low affinity using 1 microM of [3 H] -cAMP as the substrate. An explanation of further review of this test can be found in the patent of E.U.A. No. 5,998,428, the text of which is incorporated herein by reference to the extent that the text is necessary for the practice of this invention. Preferred are those PDE4 inhibitors which have an IC50 ratio of more than 0.5, and particularly those compounds that have a ratio of more than 1.0. A preferred compound is cis-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexane-1-carboxylic acid (Ariflo®).

In addition, the following PDE4 inhibitors may be useful in the practice of this invention: AWD-12-281 from Astra (Hofgen, N. e.al., 15th EFMC Int Symp Med Chem (Sept. 6-10, Edinburgh) 1998, Abst P .98); a derivative of 9- HLA? J ** Jt * L + - mu .. * J? - ^ * l ^^ »- - ^ - ^ ~ * L ~. ... ~ .. * --_-_ «Myth» 11 end TTÍ? Ü i Nominated benzyl adenine NCS-613 (INSERM); D-4418 of Chiroscience and Schering-Plow; a PDE4 inhibitor of benzodiazepine identified as CI-1018 (PD-168787; Parke-Davis / Warner-Lambert); a Kyowa Hakko benzodioxole derivative described in WO 9916766; V-11294a by Napp (Landells, L. J. et al., Resp. [Annu Cong Eur Resp Soc (Sept 19-23 Geneva) 1998] 1998, 12 (Suppl 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a phthalazinone (WO 9948505) from Byk-Gulden; or a compound identified as T-440 (Tanabe Seiyaku, Fuji, K. et al., J Pharmacol ExpTher, 1998, 284 (1): 162). Non-spheroidal anti-inflammatory drugs (NSAIDs) that may be useful in this invention are those which present prostaglandin synthesis. It is considered that NSAIDs act through inhibition of cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2). Numerous drugs are in this category. By way of example, one or more of the following NSAIDs may be used herein: aspirin, carprofen, choline salicylate, ketoprofen, Mg salicylate, salicylamine, salsalate, sodium salicylate, sodium thiosalicylate, meclofenamate sodium, oxyphenbutazone, phenylbutazone, indomethacin, piroxicam, sulindac, tolmetin and sodium tolmetin, mefenamic acid, zomerpirac, ibuprofen, fenoprofen, naproxen and naproxen sodium, diclofenac, flurbiprofen, ketoprofen, ketorolac, trometamol, celecoxib, diflunisal, and nabumatone. All are available from commercial sources or are described in medical and other scientific literature.

The combined antiinflammatory and analgesic effects of PDE4 and specific inhibitors of NSAIDs make this combination particularly useful for the symptomatic relief of pain and / or inflammatory conditions including rheumatic disorders such as rheumatoid arthritis, osteoarthritis, and spondyloarthropathies, and also in periarticular disorders, and soft tissue rheumatism. The combination may also be useful for treating lung diseases that involve an inflammatory condition. It is contemplated that both active agents may be administrable at the same time, or very close in time. Alternatively, a drug can be taken in the morning and one later in the day. Or in other circumstances, a drug can be taken twice a day and the other once a day, either at the same time as one of the dosages occurs twice a day or separately. Preferably, both drugs would be taken together at the same time. The compounds and pharmaceutically acceptable salts of the present which are active when given orally can be formulated as syrups, tablets, capsules, controlled release preparation or troches. A syrup formulation will generally consist of a suspension or solution of compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerin or water with a flavoring or coloring agent. When the composition is in the form of a tablet, any pharmaceutical carrier used routinely to prepare solid formulations can be used. Examples of said vehicles include magnesium stearate, magnesia, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned vehicles in a hard gelatin capsule shell. When the composition is in form in a soft gelatin shell capsule, any pharmaceutical carrier used routinely to prepare dispersions or suspensions, for example aqueous gums, celluloses, silicates or oils, can be considered and incorporated into a capsule shell of soft gelatin Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous vehicle optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, or sesame oil. Typical compositions for inhalations are in the form of a solution, suspension or emulsion which may be administrable as a dry powder or in the form of an aerosol using a conventional propellant such as fluorinated hydrocarbons such as for example trichlorofluoromethane. Preferably, the composition for PDE4 inhibitors is a unit dosage form such as a tablet or capsule, or a controlled release preparation. Although NSAIDs are usually taken orally, some of them such as diclofenac, ketoprofen, ketorolac, piroxicam, and tenoxicam can be given through _a * a a -tAJM. ___________ _, ..-.-- J -. ^ A, ... .--. ..t ^,., .-., ^ .. ^^ .. ^ - ü. ^ --- »- ,. ---- *. - intramuscular injection. Cetorolac and tenoxicam can also be given by intravenous injection. The active ingredient may be administrable 1 to 6 times a day, sufficient to present the desired activity. Preferably, the active ingredient is administrable about once or twice a day, preferably twice a day. As for the amount of drug administered, it is considered that for PDE4 inhibitors, it will be administrable in an amount between 1 to 200 micrograms per day per adult human. NSIADs are administrable in accordance with approved labels.

EXAMPLE 1 Phosphodiesterase and rolipram binding assays EXAMPLE 1A It was determined that the isolated human monocyte PDE4 and hrPDE (recombinant human PDE4) exists mainly in the low affinity form. Therefore, the activity of test compounds against the low affinity form of PDE4 can be assessed using standard tests for PDE4 catalytic activity using 1 microM of [3 H] cAMP as a substrate (Torphy et al., J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992).

MHH-lttW I * "*» Jfc * ~ "• * - ** .-.-.----- i ------ .. _.- .. *.» ..---- --.- > * -to.-.-.

High rat supernatants of rat brain were used as a protein source and both enantiomers of [3 H] -rolipram were prepared at a specific activity of 25.6 Ci / mmol. The standard test conditions were modified from the published procedure to be identical to the PDE test conditions, except for the latter of the cAMP: 50mM Tris HCl (pH 7.5), 5mM MgCl2, and 1 nM of [ 3H] -rolipram (Torphy et al., J. Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992). The test was performed for 1 hour at 30 ° C. The reaction was terminated and bound ligand was separated from the free ligand using a Brandel cell harvester. The - * »10 competition for the high affinity binding site was evaluated under conditions that are identical to those used to measure low affinity PDE activity, except that [3H] -cAMP and 5'AMP were not present.

EXAMPLE 1B _ 15 Measurement of phosphodiesterase activity The PDE activity was analyzed using a scintillation proximity analysis (SPA) enzyme test of [3 H] cAMP or [3 H] cGMP as described by the supplier (Amersham Life Sciences). The reactions were performed in 96-well plates at room temperature, in 0.1 ml of reaction pH buffer containing (final concentrations): 50 mM Tris-HCl, pH 7.5, 8.3 mM MgCl 2, 1.7 mM EGTA, [3H] cAMP or [3H] cGMP (approximately 2000 dpm / pmol), enzyme and various .1 tü 1 ttMti --._ h < t.-. concentrations of the inhibitors. The test was allowed to continue for 1 hour and was terminated by adding 50 μl of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 minutes. The formation of radiolabeled product was evaluated by scintillation spectrometry. The activities of PDE3 and PDE7 were evaluated using 0.05 μM of [3H] cAMP, while PDE4 was evaluated using 1uM of [3H] cAMP as a substrate. The activities of PDE1 B, PDE1C, PDE2 and PDE5 were evaluated using 1 μM of [3H] cGMP as a substrate.

F3H] R-rolipram binding test The [3H] R-rolipram binding assay was performed through modification of the method of Schneider et al., See Nicholson, et al., Trends Pharmacol, Sci., Vol. 12, pp. 19-27 (1991) and McHale et al., Mol. Pharmacol., Vol. 39, 109-113 (1991). R-rolipram binds to the catalytic site of PDE4, see Torphy et al., Mol. Pharmacol., Vol. 39, pp. 376-384 (1991). Consequently, competition for binding to [3H] R-rolipram provides independent confirmation of the PDE4 inhibitor potencies of unlabeled competitors. The test was performed at 30 ° C for 1 hour in 0.5 μl of pH buffer containing (final concentrations): 50 mM Tris-HCl, pH 7.5, 5 mM MgCl2, 0.05% bovine serum albumin, 2nM of [3 H] R-rolipram (5.7 x 104 dpm / pmol) and various concentrations of non-radiolabelled inhibitors. The reaction was stopped with the addition of 2.5 ml of -. ji ice-cooled reaction pH buffer (without [H] -R-rolipram) and rapid vacuum filtration (Brandel cell harvester) through Whatman GF / B filters that were immersed in 0.3% polyethylenediemine. The filters were washed with an additional 7.5 ml of cold pH regulator, dried and dried. 5 counted through liquid scintillation spectrometry.

EXAMPLE 2 Preparation of a controlled release tablet 0 A controlled release formulation was prepared using the ingredients set forth in Table 1.

TABLE 1 Table of ingredients 5 0 Mixing and compression techniques: Mixture The excipients and the drug were placed in a mixer and mixed. The magnesium stearate was then added and mixed for an additional 3 minutes. During the mixing process, the excipients and the drug were combined, passed through a screen and then mixed again.

Compression Approximately 350 mg of each mixture was compressed into tablets. A target tablet power of 10 kp was used. Opadry White was suspended in the purified water and that suspension was used to coat the tablets; Water was removed during the coating process and was not part of the final product.

EXAMPLE 3 Preparation of an immediate release tablet Immediate-release tablets were prepared by standard means and contained the ingredients indicated in Table 2. .t -_-_- S-lm .... l ..- * -,. .....-_.-_-.-- t. . ^ ?? k ^^^^^? í?! l¡ ^ í? ^^. ^ .. ^ ¿...? ^ ..-. -.¡ -, - hjU TABLE 2 Immediate-release tablets EXAMPLE 4 Treatment of arthritis A patient diagnosed with arthritis and experiencing pain due to an inflammation of a joint, is given a controlled release tablet containing 30 mg of Ariflo® prepared according to example 2 and a 500 mg tablet of Relafen (nabumetone) twice perday. Treatment continues until the inflammation decreases. _-_ *. -_ --- .--. J. -w-t-í--. ^ ... «. - .-, ------ t - á», -. J «---..-. ..-- s-A - ».- .. - rt..i¿se & - -I-I .--. I

Claims (12)

NOVELTY OF THE INVENTION
1. CLAIMS 5 1.- The use of a PDE 4 inhibitor and an anti-inflammatory drug
2. Non-spheroidal (NSAID) in a combined form, separately, or separately and consecutively to prepare a medication to treat a inflammatory disease, where the consecutive administration is close in time or remote in time. "10 2. The use as claimed in claim 1, wherein f the PDE4 inhibitor is cis 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, the NSAID it is selected from the group consisting of aspirin, carprofen, choline salicylate, ketoprofen, Mg salicylate, salicylamine, salsalate, sodium salicylate, sodium thiosalicylate, 15 meclofenamate sodium, oxifenbutazone, phenylbutazone, indomethacin, piroxicam, sulindac, tolmetin and sodium tolmetin, mefenamic acid, zomerpirac, ibuprofen, fenoprofen, naproxen and naproxen sodium, diclofenac, flurbiprofen, ketoprofen, ketorolac, trometamol, celecoxib, diflunisal, and nabumatone.
3. 3. - A pharmaceutical formulation comprising an inhibitor of PDE 4 and a non-steroidal anti-inflammatory drug (NSAID) in a combined form, separately, or separately and consecutively, wherein consecutive administration is close in time or remote in time.
4. 4. - The pharmaceutical formulation according to claim 3, further characterized in that the PDE4 inhibitor is cis 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, the NSAID is selected from the group consisting of of aspirin, carprofen, choline salicylate, ketoprofen, salicylate, salicylamine, salsalate, sodium salicylate, sodium thiosalicylate, meclofenamate sodium, oxifenbutazone, phenylbutazone, indomethacin, piroxicam, sulindac, tolmetin and sodium tolmetin, mefenamic acid, zomerpirac, ibuprofen, fenoprofen, naproxen and naproxen sodium, diclofenac, flurbiprofen, ketoprofen, ketorolac, trometamol, celecoxib, diflunisal, and nabumatone.
5. 5. The pharmaceutical formulation according to claim 3, further characterized in that the PDE4 inhibitor is roflumilast and the NSAID is selected from the group consisting of aspirin, carprofen, choline salicylate, ketoprofen, Mg salicylate, salicylamine, salsalate, sodium salicylate, sodium thiosalicylate, sodium meclofenamate, oxyphenbutazone, phenylbutazone, indomethacin, piroxicam, sulindac, tolmetin and sodium tolmetin, mefenamic acid, zomerpirac, ibuprofen, fenoprofen, naproxen and naproxen sodium, diclofenac, flurbiprofen, ketoprofen, ketorolac, trometamol, celecoxib, diflunisal, and nabumatone.
6. 6. The formulation according to any of claims 3-5, further characterized in that the formulation is adapted for oral use. m- -kj ^^ jj i
7. 7. - The use of a PDE4 inhibitor and a non-spheroidal anti-inflammatory drug for the preparation of a medicament for use in the treatment of an inflammatory disease.
8. 8. The use as claimed in claim 7, wherein the PDE4 inhibitor is cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, the NSAID is selected of the group consisting of aspirin, carprofen, choline salicylate, ketoprofen, Mg salicylate, salicylamine, saisalate, sodium salicylate, sodium thiosalicylate, sodium meclofenamate, oxyphenbutazone, phenylbutazone, indomethacin, -r 10 piroxicam, sulindac, tolmetin and sodium tolmetin, mefenamic acid, zomerpirac, ibuprofen, fenoprofen, naproxen and naproxen sodium, diclofenac, flurbiprofen, ketoprofen, ketorolac, trometamol, celecoxib, diflunisal, and nabumatone.
9. 9. The use as claimed in claim 7 or 8, wherein the PDE4 inhibitor is roflumilast and the NSAID is selected from the group * 15 which consists of aspirin, carprofen, choline salicylate, ketoprofen, salicylate of i »Mg, salicylamine, salsalate, sodium salicylate, sodium thiosalicylate, sodium meclofenamate, oxyphenbutazone, phenylbutazone, indomethacin, piroxicam, sulindac, tolmetin and sodium tolmetin , mefenamic acid, zomerpirac, ibuprofen, fenoprofen, naproxen and naproxen sodium, diclofenac, flurbiprofen, ketoprofen, ketorolac, trometamol, celecoxib, diflunisal, and nabumatone.
10. 10. The use as claimed in any of claims 7-9, wherein the medicament is adapted to lllilÉiittriliÜitff ^ if-'tí-rir ^ Oral administration and inflammatory disease is a respiratory disease.
11. 11. The use as claimed in any of claims 7-9, wherein the formulation is adapted for oral use and the disease is chronic obstructive pulmonary disease.
12. 12. The use as claimed in claim 8, wherein the PDE4 inhibitor is present at 15 mg per dose. - Íl * _táltitl Ét-É_i_lMÍr MG "» »- * -" - * -. ~~ »- ** ^ -. ~ * R m -m + tt? Mr,,, .t *« _ * «1