MXPA00009981A - Use of a glucocorticosteroid for the manufacture of a medicament for treating mild/early forms of copd (chronic obstructive pulmonary disease) - Google Patents

Abstract

The invention relates to the use of a glucocorticosteroid for the manufacture of a medicament for treating chronic obstructive pulmonary disease (COPD) in patients having an FEV1.0 value>65%of predicted value and<10%reversibility in bronchodilator test. The invention further relates to a method for treatment of COPD in patients having an FEV1.0 value>65%of predicted value and<10%reversibility in bronchodilator test, where a therapeutically effective amount of a glucocorticosteroid is administered to a patient in need of such treatment.

Description

USE OF A G UCOCORTICOESTEROIDE FOR THE MANUFACTURE OF A MEDICATION TO TREAT MODERATE / INITIAL FORMS OF THE CHRONIC OBSTRUCTIVE PULMONARY DISEASE FIELD OF THE INVENTION The present invention relates to the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD). More particularly, the invention relates to the use of a glucocorticosteroid to treat the moderate / initial form of COPD.

BACKGROUND OF THE INVENTION Chronic obstructive pulmonary disease (COPD) is a common disease in industrialized countries (approximately 6% of men and% of women over 45 years old in the UK are affected) and is responsible for morbidity and considerable mortality The majority of patients are smokers. The two most important conditions associated with COPD are chronic bronchitis and emphysema. Chronic bronchitis is a bronchial disease that lasts a long time, involving increased mucosal production and other mucous changes. The symptoms are cough and expectoration of sputum and, as the disease progresses, respiratory failure. Chronic bronchitis presents exacerbations frequently due to recurrent infections. For many years Ref: 123700 Narrowing and obstruction of the bronchi cause respiratory distress and eventually general disability. The annual decay of airflow resistance is usually progressive and could be accompanied by hyper reactive airway. However, in contrast to asthma the hyper reaction is largely dependent on the obstruction of the baseline, and the obstruction of the baseline is reversed somewhat by bronchodilator treatment. Emphysema is a chronic disease of the lung that affects the alveoli and / or the ends of the smaller bronchi. The lung loses its elasticity and areas of the lungs get destroyed with large air spaces. These large areas trap "spent" air and do not effectively exchange it with fresh air. This results in difficulty in breathing and could result in insufficient oxygen being released into the blood. Respiratory failure is the predominant symptom in patients with emphysema.

The treatment of COPD is often unsatisfactory. Currently COPD is treated only in its most developed stages using a variety of inhaled or orally administered bronchodilators or inhaled anti-cholinergic agents. In the most severe COPD, orally administered steroids and inhaled steroids, such as glucocorticosteroids, could be continued if patients show improvement during the first weeks of treatment. The problem with these treatments is that none of them it has been observed so ^ gSTective. A recent review of new therapies for COPD has been published (Thorax, 53 (1998), 137-147). Here it is clearly established that there is almost no evidence that glucocorticosteroids are beneficial in COPD. Inhaled fluticasone propionate has recently been compared with placebo and the treatment of patients with moderate COPD during 6 months (Lancet 351 (1998), 773-780). Marginal but statistically significant improvement was observed in some variable diseases but with main reference to COPD, the progression of the disease was not addressed in this study. To explain their results, the authors speculate that in severe COPD some degree of steroid-sensitive inflammation could contribute to the disability of this group of patients. With respect to the moderate stages of COPD when the airway obstruction is marginal to moderately abnormal, anti-inflammatory therapy is considered to be without effect or the effect of drugs such as inhaled steroids are small and transient (Eur. Resp. J. 5 (1992), 1254-1261; Lancet, 351 (1998), 766-767; Thorax 53 (1998), 137-147). Of greater importance is the lack of therapy (except the suspension of smoking) that can reduce the progression of the disease, i.e. to decelerate the rate of annual decay in forced expiratory volume by 1 second (VEFj 0). This lack of effective therapy applies to patients with COPD without taking tells the stage of the disease. The cessation of smoking has been shown to decrease the rate of decline of lung function in COPD and is, at this time, the only successful long-term therapeutic intervention in COPD. However, it has been proven that V. "Quitting smoking is very difficult for most patients." It seems particularly unfortunate that there is currently no known drug treatment that can reduce the progression of the disease in patients who only have moderate COPD. / initial, but are at high risk of suffering rapid decline in lung function, leading to severe disability.It is known from Renkema et al, Chest 109 (1996), 1156-1162 that corticosteroids can be used in long-term treatment Patients with COPD However, it is clearly established that when assessing the efficacy of corticosteroids in patients with COPD, it is essential to exclude patients with asthma, ie to exclude patients who have reversibility> 10% in bronchodilator tests. It is established that far from that "studies carried out far from showing the beneficial effects of long-term treatment with corticosteroids in Patients with COPD are few and less prominent than in patients with asthma. " It is therefore an object of the present invention to find suitable compounds for the manufacture of a medicament for the treatment of moderate / initial COPD, which include the attenuation of decay in lung function. It is a further objective of the invention to present a method for the treatment of patients suffering from moderate / initial COPD.

BRIEF DESCRIPTION OF THE INVENTION According to the present invention it has surprisingly been found that glucocorticosteroids are effective in the treatment of moderate / initial COPD, instead of continuous exposure to occasionally related factors, in particular tobacco smoking e.g. To smoke cigarettes. Patients with moderate COPD are defined as patients who have forced expiratory volume values in 1 second (VEFj 0) > 65% predicted VEFj 0 and are distinguished from asthma because they have reversibility < 10% in bronchodilator tests. According to the invention there is provided the use of a glucocorticosteroid for the manufacture of a medicament for treating chronic obstructive pulmonary disease in patients having a FEV value! 0 > 65% of the predicted value and reversibility < 10% in bronchodilator tests (VEFI 0 measurements and reversibility use a bronchodilator).

According to a further aspect of the invention there is provided a method of treating chronic obstructive pulmonary disease in patients having a VEFj value of 0 > 65% of the predicted value and reversibility < 10% in tests of bronchodilator The method is characterized by administration to the patient in need of treatment of a therapeutically effective amount of a glucocorticosteroid.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 Linear change over time for all patients. Fig. 2 Linear change over time for patients with < 26 packages per year (as defined later). The treated patients have an annual decline in lung function that approximates that of some individuals with normal health.

Fig. 3 Linear change over time for patients with < 36 packages per year (as defined later). Fig. 4 Linear change over time for patients with > 36 packages per year (as defined later). Fig. 5 Difference in linear change over time, per packet per year (as defined later).

DETAILED DESCRIPTION OF THE INVENTION The successful outcome of the treatment of moderate COPD with glucocorticosteroids has been demonstrated in the present invention by the treatment of a large group of patients over a period of three years. Patients were selected to meet the moderate COPD criteria as established before and all were smokers. The results of the clinical trials showed that the Early use of a glucocorticosteroid in moderate / initial COPD will improve the patient's situation, i.e. the progressive course of the disease has been significantly decreased by treatment. The beneficial effect of e-steroid treatment on the annual decline in VEFi "is more pronounced for people who have lower exposure to smoke than for chronic smokers (Figure 5). Patients who have more than 36 packs per year benefit them less and in this way it will be difficult to treat them adequately although some may receive treatment benefits. However, based on the new results also this category of patients more severely exposed to smoke could respond more to the treatment of the present invention if they are led to reduce their smoking. Therefore, the present invention can be used for the manufacture of a medicament for treating COPD in patients having an exposure in the manner of smoking of less than 46 packs per year, suitably less than 36 packs per year, preferably less than 26 packages per year and more preferably less than 16 packages per year. As can be seen from the Figures, the treatment period must be of a certain duration before any effect is distinguished. A treatment period of at least one year is necessary. Preferably patients are treated for at least three years. The glucocorticosteroid used in the invention is , t. * preferably an anti-inflammatory glucocorticoid. Among the glucocorticoesters that can be used for the manufacture of medicaments according to the present invention, the following can be mentioned: betamethasone (eg as valerate), fluticasone (eg as propionate), budesonide, tipredane, dexamethasone, beclomethasone (eg as dipropionate) , prednisolone, fluocinolone, triamcinolone (eg as acetonide), mometasone (eg as furoate), rofleponide (eg as palmitate), flumethasone, flunisolide, ciclesonide, deflazacort, corticazole, 16 ?, 17? -butilidenedioxy-6 ?, 9? difluoro-ll ?, 21-dihydroxy-pregna-l, 4-dien-3, 20-dione, 6 ?, 9? -difluoro-ll? -hydroxy-16 ?, 17? -butylidenedioxy-17? -methylthio-androsta -4-on-3-one, 16, 17? -butylidenedioxy-6 ?, 9? -difluoro-ll? Hydroxy-3-oxo-androsta-1,4-dien-17? -s-methylcarbothioate, 9 ? -chloro-6? -fluoro-ll? -hydroxy-16? -methyl-3-oxo-17? -propionyloxy-androsta-1,4-dien-17? -methylcarboxylate, ester S-2 (-oxo) -tetrahydrofuran-3S-yl) of 6? 9 -difluoroyl? -hydroxy-16? -methyl-3-oxo-17? -pro pionyloxy-androsta-l, 4-dien-17? -carbothioic, optionally in their pure isomeric forms (where such forms exist) and in the forms of their esters, acetals and salts. Preferably, use is made of budesonide, rofleponide, rofle-ponid palmitate, mometasone furoate, beclomethasone dipropionate or fluticasone propionate, more preferably budesonide, rofleponide or palmitate. rofleponide, e.g. such as 21-palmitate, and more preferably budesonide. For administration, the medicament is suitably inhaled from a nebulizer, from a metered dose pressurized inhaler or as a dry powder inhaler, e.g. Turbuhaler® (registered trademark of Astra of Sweden) or of a dry powder inhaler that capsules, cartridges or packages of gelatin, plastic or other types of ampules. The administration of the drug could be by nasal or preferably oral inhalation. According to the invention, the glucocorticosteroid is preferably administered in the form of any of 1) agglomerated particles comprising steroid particles of particle size less than 10 μm, 2) agglomerated particles comprising steroid particles and a carrier, both having a particle size less than 10 μm, or 3) an ordered mixture which comprises steroid particles of a size less than 10 μm and coarse particles of a vehicle, also optionally the particles of the vehicle of a particle size of less than 10 μm. The coarse vehicle particles could also be agglomerated with small particles. The amount of glucocorticosteroid administered to the patient is preferably from 100 μg to 3000 μg per day, more preferably from 200 μg to 1600 μg administered as a single or divided dose of one to four times per day. Highly preferred doses are 200 μg given twice a day or 400 μg given twice a day. The glucocorticosteroids can be used in admixture with one or more pharmaceutically acceptable additives, diluents or vehicles, preferably in an amount of 100 μg to 25 mg per dose, more preferably in an amount of 100 μg to 10 mg, more preferably in an amount of 100 μg to 10 mg. ? ga 000? g per dose. Examples of suitable diluents or vehicles include lactose, dextran, mannitol or glucose. Lactose is preferably used, especially as monohydrate. One or more of the ingredients is preferably in the form of a dry powder, more preferably a dry micronized powder. More preferably an agglomerated micronised dry powder is used. As an alternative to agglomeration, the finely divided glucocorticosteroid could be in the form of an ordered mixture with the pharmaceutically acceptable additive, diluent or carrier. An ordered mixture comprises fine particles of the substance in association with mainly thick particles of the pharmaceutically acceptable additive, diluent or carrier, e.g. wherein at least about 70% by weight, suitably at least 90% by weight, of the coarse particles have a particle size of more than about 20 μm. The ingredients used in the In accordance with the invention, preferred forms can be obtained using methods known to those skilled in the art. When the medicament is adapted to be administered from a pressurized inhaler, it is preferably in finely divided form e.g. micronized Podj'Sa dissolves or, preferably suspended in a mixture of liquid propellant. The propellants that can be used include chlorofluorocarbons, hydrocarbons or hydrofluoroalkanes. Especially preferred propellants are P134a (tetrafluoroethane) and P 27 (heptafluoropropane), each of which could be used alone or in combination. They are optionally used in combination with one or more propellants and / or one or more surfactants and / or one or more excipients, for example ethanol, a lubricant, an antioxidant and / or stabilizing agent. When the medicament is adapted to be administered via a nebulizer it could be in the form of a slurry or nebulized aqueous solution, with or without an adequate pH or tonicity adjustment, either as a unit dose or multidose device.

EXAMPLES The invention will now be illustrated by means of the following Examples, which are not intended to limit the scope of the invention. The micronization examples are carried out in such a way that the particle size range is suitable for the administration by inhalation. Example 1 * "* 9 parts of budesonide and 91 parts of lactose monohydrate were micronized separately in a spiral jet mill at a pressure of about 6-7 bar to give a particle size of less than 3 [mu] m, before to mix thoroughly in a Turbula mixer Before mixing, the lactose monohydrate powder was conditioned according to the method described in US Pat. No. 5,709,884 to remove amorphous regions in its crystalline structures The mixture was remichronized in a spiral jet mill at a pressure of only about 1 bar to obtain a uniform mix, then the powder was agglomerated to feed the powder into a twin screw feeder (K-Tron), sifting on an oscillating screen (0.5mm mesh size), which spheronized in a rotating vessel with a peripheral speed of 0.5 m / s for 4 minutes, and then sieved again using the same sieve, after spheronizing once again last 6 minutes before the final sieve (1.0 mm mesh size) to give a powder with a total density of 0.35 g / ml.

Example 2 200 parts by weight of micronized budesonide were mixed with 800 parts of lactose monohydrate. The mixture was micronized using a high pressure air jet mill and then conditioned using the process of US 5,709,884. The mixture then spheronized using the process of EP-A-721 331 and filled into the Turbuhaler® storage compartment.

Example 3 400 parts of budesonide were micronized in a spiral jet mill, spheronized using the process of EP-A-721 331 and filled into the storage compartment of Turbuhaler®.

Example 4-Clinical Trials A glucocorticosteroid was used for the treatment of moderate COPD in a large group of patients over a period of three years. Patients were selected to meet the criteria for moderate COPD and all were smokers. Patients with moderate COPD were defined as patients who had a forced expiratory volume value in 1 second (FEV 0) > 65% of predicted VEFj 0 and were distinguished from asthma because they had reversibility < 10% in the bronchodilator test. After a run-in period of two visits to the medical center, the patients (1277 patients completed the test) suitable for the treatment started their medication or alternatively they were given a placebo (half the group) on their third visit. They were followed closely during the three-year period by regular visits to the medical center, approximately every 2-3 months! * The glucocorticosteroid was administered by inhalation of a dry powder formulation using a dry powder inhaler that acts on the Turbuhaler® breath (budesonide, 400 μg twice a day). One equivalent of placebo was used. The VEFj 0 value of each patient was measured at each visit and the change in value was observed. The results are presented in Figures 1-4. When the results are presented as change in VEFi 0 the VEFX 0 slope for each patient was calculated using a linear mixing effect model and thereafter the average slopes have been formed as shown in the figures. Each patient has been standardized to an initial value in order to make a meaningful comparison of the progression of the disease against the placebo values during the study period. Figure 1 represents all the patients taken together and in Figures 2-4 the patients have been divided according to their exposure to smoking. All values are average values. One package per year is defined as a smoker of 20 cigarettes per day for one year. Figure 2 shows the cleaning effect in patients who have a smoking exposure of less than 26 packs per year, where the disease has not progressed as much as for chronic smokers (Fi 3 for less than 36 per year and Figure 4 for less than 36 per year). The results have been summarized in Figure 5 which shows patients with < 26 packages per year that have a lower decline in VEFi "compared to the Individuals with a higher and / or longer exposure to the cigar.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (30)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The use of a glucocorticosteroid for the manufacture of a medicament for treating chronic obstructive pulmonary disease (COPD) in patients who have a smoking exposure of less than 46 packs per year and who have a value of VEFj "> 65% of the predicted value and reversibility < 10% in the bronchodilator test.

2. Use according to claim 1 for treatment for a period of at least one year.

3. The use according to claim 2 for the treatment for a period of at least three years.

4. The use according to claim 1, characterized in that the glucocorticosteroid is budesonide or an isomer or ester thereof.

5. The use according to claim 1, characterized in that the glucocorticosteroid is rofleponide or an ester thereof.

6. The use according to any of the preceding claims, characterized in that the glucocorticosteroid is mixed with one or more pharmaceutically acceptable additives, diluents or vehicles.

7. The use according to claim 6, characterized in that the glucocorticosteroid is mixed with one or more pharmaceutically acceptable additives, diluents or vehicles, in an amount of 100 μg to 25 mg per dose.

The use according to claim 6, characterized in that the glucocorticosteroid is mixed with one or more pharmaceutically acceptable additives, diluents or vehicles in an amount of 100 μg to 2000 μg per dose.

9. The use according to any of claims 1-8, characterized in that the glucocorticosteroid is administered in the form of agglomerated steroid particles with a particle size of less than 10 μm.

The use according to any of claims 1-8, characterized in that the glucocorticosteroid is administered in the form of agglomerated particles comprising the steroid and a carrier, both having a particle size of less than 10 μm.

The use according to any of claims 1-8, characterized in that the glucocorticosteroid is administered in the form of an ordered mixture comprising steroid particles of size less than 10 μm and coarse particles of a vehicle.

12. The use according to any of the preceding claims, characterized in that the amount The glucocorticosteroid administered to the patient falls in the range of 100? g to 3000? g per day, administered as a single or divided dose of one to four times per day.

13. The use according to claim 12, characterized in that the administered amount of glucocorticosteroid to the patient falls in the range of 200? G to 1600? G per day.

The use according to claim 12 or 13, characterized in that the amount of glucocorticosteroid administered to the patient is 200 μg given twice a day or 400 μg given twice a day.

15. The use according to any of claims 1-14, characterized in that patients have a smoking exposure of less than 36 packs per year, suitably less than 26 packs per year, preferably less than 16 packs per year.

16. A method for treating chronic obstructive pulmonary disease (COPD) in patients having a VEFj value of 0 > 65% of the predicted value and reversibility < 10% in the bronchodilator test, characterized in that an effective amount of a glucocorticosteroid is administered to a patient in need of such treatment.

17. The method according to claim 16 for the treatment for a period of at least one year.

18. The method according to claim 17 for the treatment for a period of at least three years.

19. The method according to any of claims 16-18, characterized in that the glucocorticosteroid is budesonide or an isomer or an ester thereof.

20. The method according to any of claims 16-18, characterized in that the glucocorticosteroid is rofleponide or an ester thereof.

21. The method according to any of claims 16-20, characterized in that the glucocorticosteroid is mixed with one or more pharmaceutically acceptable additives, diluents or vehicles.

The method according to any of claims 16-21, characterized in that the glucocorticosteroid is mixed with one or more pharmaceutically acceptable additives, diluents or vehicles in an amount of 100 μg to 25 mg per dose.

23. The method according to claim 22, characterized in that the glucocorticosteroid is mixed with one or more pharmaceutically acceptable additives, diluents or vehicles in an amount of 100 μg to 2000 μg per dose.

24. The method according to any of claims 16-23, characterized in that the glucocorticosteroid is administered in the form of agglomerated steroid particles with a particle size of less than 10 μm.

25. The method according to any of claims 16-23, characterized in that the glucocorticosteroid is administered in the form of agglomerated particles comprising the steroid and a vehicle, both having a particle size of less than 10 μm.

26. The method according to any of claims 16-23, characterized in that the glucocorticosteroid is administered in the form of an ordered mixture comprising steroid particles of size less than 10 μm and coarse particles of a vehicle.

The method according to any of claims 16-26, characterized in that the amount of glucocorticosteroid administered to the patient falls in the range of 100 μg to 3000 μg per day, administered as a single or divided dose of one to four times per day.

28. The method according to claim 27, characterized in that the administered amount of glucocorticosteroid to the patient falls in the range of 200? G to 1600? G per day.

29. The method according to claim 27 or 28, characterized in that the amount of glucocorticosteroid administered to the patient is 200 μg given twice a day or 400 μg given twice a day.

30. The method of compliance with any of the claims 16-28, characterized in that patients have a smoking exposure of less than 36 packs per year, suitably less than 26 packs per year, preferably less than 16 packs per year.