JP2002512193A - Use of carbohydrate corticosteroids for the manufacture of a medicament for treating mild / early forms of COPD (chronic obstructive pulmonary disease) - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention is directed to treating chronic obstructive pulmonary disease (COPD) in patients having a FEV _1.0 value greater than 65% of the predicted value and a reversibility of less than 10% in a bronchodilation test. The use of carbohydrate corticosteroids for the manufacture of medicaments. The present invention further provides a method of treating COPD in a patient having an FEV _1.0 value greater than 65% of the predicted value and a reversibility of less than 10% in a bronchodilation test, wherein the patient in need of such treatment comprises: A method for administering a therapeutically effective amount of a carbohydrate corticosteroid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD). More particularly, the present invention relates to the use of carbohydrate corticosteroids for treating mild / early forms of COPD.

BACKGROUND OF THE INVENTION Chronic obstructive pulmonary disease (COPD) is a common disease in industrialized countries (
Approximately 6% of men and 4% of women aged 45 and older are affected in the UK), which is responsible for significant morbidity and mortality. The majority of patients are smokers. CO
The two most important conditions associated with PD are chronic bronchitis and emphysema.

[0003] Chronic bronchitis is a long-standing disease of the bronchi with an increased incidence of mucus and other mucosal changes. The symptoms are cough and expectoration of sputum, and the disease progresses to shortness of breath. Over the years, bronchial stenosis and occlusion cause dyspnea and eventually systemic disability. Annual reductions in airflow resistance are usually progressive and may be accompanied by airway hyperresponsiveness. However, in contrast to asthma, hyperresponsiveness mainly depends on baseline occlusion, which is hardly reversed by bronchodilation treatment.

[0004] Emphysema is a chronic lung disease that affects the alveoli and / or the ends of the smallest bronchi. The lung loses its elasticity, and the area of the lung becomes destroyed by the expansion of the air space. These expansion areas trap "stale" air and do not effectively replace it with fresh air. This can cause dyspnea and prevent enough oxygen from being delivered to the blood. The main symptom in patients with emphysema is shortness of breath.

[0005] Treatment of COPD is often unsatisfactory. Currently, COPD is treated only at its more advanced stages using various inhaled or orally administered bronchodilators or inhaled anticholinergics. In more severe COPD, if the patient demonstrates improvement during the first few weeks of treatment, oral or inhaled steroids, such as carbohydrate corticosteroids, should be continued . The problem with these procedures is that they are not all considered to be effective. A recent review of new therapies for COPD has only been published (Thorax, 53 (1998), 137-147). Here it is clearly stated that there is little evidence that glucocorticosteroids are beneficial in COPD. Inhaled fluticasone propionate has recently been compared to placebo in the treatment of patients with moderate COPD for 6 months (Lanc
et, 351 (1998), 773-780). A slight but statistically significant improvement was observed in some disease states, but the major COPD aspects, disease progression, were not mentioned in this study. To explain these data, the author speculates that in severe COPD, some degree of steroid-sensitive inflammation may contribute to the elimination of this group of patients.

[0006] With regard to mild-stage COPD when airway obstruction is slightly to moderately abnormal,
Anti-inflammatory therapies are considered ineffective, or the effects of drugs such as inhaled steroids are considered to be marginal or temporary (Eur. Resp. J., 5 (1992), 12).
54-1261; Lancet, 351 (1998), 766-767;
3 (1998), 137-147). Of greatest concern is the lack of therapy (excluding smoking cessation) to slow disease progression, i.e., to slow the rate of annual decline in maximum forced expiratory volume in 1 second (FEV _1.0 ). This lack of effective therapy is
Applicable to COPD patients regardless of disease stage. Smoking cessation has been shown to reduce the rate of decline in lung function in COPD, and is currently the only proven long-term therapeutic intervention in COPD. However, smoking cessation has proven to be very difficult for the majority of patients. At present, there are no known drug treatments that can reduce disease progression in patients suffering from only mild / early COPD, but their pulmonary function was so great that they could lead to severe destruction. The high risk of suffering a rapid decline in

[0007] It is known from Renkema et al., Chest, 109 (1996), 1156-1162 that corticosteroids can be used for long-term treatment of patients with COPD. However, when assessing the efficacy of corticosteroids in patients with COPD, it is essential to exclude patients with asthma, ie, patients with greater than 10% reversibility in bronchodilation studies. Is clearly stated. Furthermore, "The tests performed so far were CO
It shows that the beneficial effects of long-term treatment with corticosteroids in patients with PD are smaller and less pronounced than in patients with asthma. "

[0008] It is therefore an object of the present invention to provide mild / early CO
The purpose is to find compounds suitable for the manufacture of a medicament for the treatment of PD.

It is a further object of the present invention to provide a method of treating a patient suffering from mild / early COPD.

SUMMARY OF THE INVENTION [0010] According to the present invention, surprisingly, carbohydrate corticosteroids have been shown to reduce causal factors, especially cigarette smoking, despite mild exposure despite continuous exposure to smoking.
It has been found to be effective in treating early COPD. Mild COPD patients, the FEV _1.0 maximum forced expiratory volume (FEV _1.0) value in seconds is predicted 6
Defined as greater than 5% of patients and distinguished from asthma by having less than 10% reversibility in bronchodilation tests.

In accordance with the present invention, chronic obstruction in patients with FEV _1.0 values greater than 65% and reversibility less than 10% in the bronchodilator test (measurement of FEV _1.0 and reversibility using bronchodilators) Provided is the use of a carbohydrate corticosteroid for the manufacture of a medicament for treating an inflammatory lung disease.

According to a further aspect of the present invention, there is provided a method of treating chronic obstructive pulmonary disease in a patient having a FEV _1.0 value greater than 65% of the predicted value and a reversibility of less than 10% in a bronchodilation test. The method is characterized by administering a therapeutically effective amount of a carbohydrate corticosteroid to a patient in need of such treatment.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a linear change over time for all patients. FIG. 2 is a linear change over time for a patient that is less than 26 packs-year (as defined below). Treated patients have an annual decline in lung function that approximates the annual decline in lung function in some normal, healthy individuals. FIG. 3 is a linear change over time for a patient that is less than 36 packs-year (as defined below). FIG. 4 is a linear change over time for patients with more than 36 packs-years (as defined below). FIG. 5 shows the difference in linear change over time by pack-year (as defined below).

DETAILED DESCRIPTION OF THE INVENTION Successful results for the treatment of mild COPD with carbohydrate corticosteroids include:
Three years of treatment of a large group of patients has been demonstrated in the present invention. The patients were selected to meet the mild COPD criteria shown above, and they all
He was a smoker.

[0015] The results of clinical trials show that early use of glucocorticosteroids in mild, early COPD significantly improves the patient's situation, ie, the progressive course of the disease is significantly reduced by treatment Let me. The beneficial effect of steroid treatment on the annual reduction in FEV _1.0 is more pronounced for people with lower smoking exposure than for heavy smokers (FIG. 5). Patients with more than 36 packs-years enjoy little benefit, so some may benefit from the treatment, but are difficult to treat properly. However, and also based on new data, a category of patients exposed to this more severe smoking responds to the treatment of the present invention if they manage to reduce their smoking Can be something. Accordingly, the present invention provides a composition comprising less than 46 packs-years, suitably less than 36 packs-years, preferably less than 26 packs-years, more preferably less than 16 packs-
It may be a use for the manufacture of a medicament aimed at treating COPD in patients with years of smoking exposure.

As can be seen from the figure, the treatment period must be of a certain length before some effect is clearly noticed. A treatment period of at least one year is required. Preferably, the patient is treated for at least three years.

The carbohydrate corticosteroid used in the present invention is preferably an anti-inflammatory carbohydrate corticosteroid. Among the carbohydrate corticosteroids that can be used in the manufacture of the medicament according to the invention, the following may be listed: betamethasone (for example, as valerate), fluticasone (for example, as propionate), budesonide, tipredan, Dexamethasone, beclomethasone (e.g., as dipropionate), prednisolone, fluocinolone, triamcinolone (e.g., as acetonide), mometasone (e.g., as furoate), rofleponide (e.g., as palmitate), flumethasone, flunisolide, ciclesonide, α, cortisol, cortisol, 17α-butylidenedioxy-
6α, 9α-difluoro-11β, 21-dihydroxy-pregna-1,4-diene-3,20-dione, 6α, 9α-difluoro-11β-hydroxy-16α,
17α-butylidenedioxy-17α-methylthio-androst-4-ene-
3-one, S-methyl 16α, 17α-butylidenedioxy-6α, 9α-difluoro-11β-hydroxy-3-oxo-androsta-1,4-diene-1
7β-carbothioate, methyl 9α-chloro-6α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17α-carboxylate, 6α, 9α-carboxylate Difluoro-
11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid S-2- (2-oxotetrahydrofuran-3S-yl) ester, optionally In pure isomeric forms (if such forms exist) and their ester, acetal and salt forms. Preferably the use of budesonide, rofleponide, rofleponide palmitate, mometasone furoate, beclomethasone dipropionate or fluticasone propionate, more preferably budesonide, rofleponide or rofreponide palmitate, such as 21-palmitate, most preferably budesonide.

For administration, the drug is suitably administered from a nebulizer, from a pressurized metered dose inhaler, or from a dry powder inhaler such as the Turbuhaler ™ (Astra, Sweden).
As a trademark) or from a dry powder inhaler utilizing gelatin, plastic or other capsules, cartridges or blister packs.

According to the present invention, carbohydrate corticosteroids are: 1) aggregated particles comprising steroid particles having a particle size of less than 10 μm; 2) aggregated particles comprising steroid particles and a carrier, both of which are Has an average particle size of less than 10 μm; or 3) an ordered mixture comprising steroid particles having a size of less than 10 μm, and also coarse particles of a carrier, optionally carrier particles having a particle size of less than 10 μm.
ure). Coarse carrier particles can also be aggregates of small particles;

The amount of carbohydrate corticosteroid administered to the patient is preferably between 100 μg and 30 μg.
The dose is 00 μg / day, more preferably 200 μg to 1600 μg, and is administered 1 to 4 times / day as a single dose or divided dose. Highly preferred doses will give 200 μg twice daily or 400 μg twice daily.

The carbohydrate corticosteroid is preferably in an amount of 100 μg to 25 mg / dose, more preferably in an amount of 100 μg to 10 mg, most preferably in an amount of 100 μg to 2000 μg / dose.
It can be used in dosage amounts, in admixture with one or more pharmaceutically acceptable excipients, diluents or carriers. Examples of suitable diluents or carriers include lactose, dextran, mannitol or glucose. Preferably, lactose is used, especially as a monohydrate.

[0022] The one or more components are preferably in the form of a dry powder, more preferably a micronized dry powder. Most preferably, an agglomerated micronized dry powder is used. As an alternative to agglomeration, the micronized carbohydrate corticosteroid can be in the form of an ordered mixture with pharmaceutically acceptable additives, diluents or carriers. The order mixture may primarily comprise fine particles of a substance associated with the coarse particles of the pharmaceutically acceptable excipient, diluent or carrier, wherein, for example, at least about 70% by weight, suitably at least about 70% by weight. 90% by weight of the coarse particles have a particle size greater than about 20 μm. The components used in the present invention can be obtained in these preferred forms using methods known to those skilled in the art.

When the drug is adapted to be administered from a pressurized inhaler, it is preferably in finely divided form, for example in micronized form. It may be dissolved or preferably suspended in a liquid propellant mixture. Propellants that can be used include chlorofluorocarbons, hydrocarbons or hydrofluoroalkanes. Particularly preferred propellants are P134a (tetrafluoroethane) and P22
7 (heptafluoropropane), each of which can be used alone or in combination. They may optionally contain one or more other propellants and / or
Or it may be used in combination with one or more surfactants and / or one or more other excipients, for example, ethanol, lubricants, antioxidants and / or stabilizers.

When the drug is adapted to be administered by nebulizer, it may or may not have appropriate pH or tonicity adjustment, as a unit dose or multi-dose device.
It may be in the form of an atomized aqueous suspension or solution.

Examples The present invention will now be illustrated by the following examples, which are not intended to limit the scope of the invention.

In the examples, micronization is performed in a conventional manner so that the particle size range for each component is suitable for administration by inhalation.

Example 1 9 parts of budesonide and 91 parts of lactose monohydrate are separately micronized in a spiral jet mill under a pressure of about 6-7 bar to obtain a particle size of less than 3 μm, followed by Turbula Mix thoroughly with a mixer. Prior to mixing, the lactose monohydrate powder is conditioned according to the method described in US Pat. No. 5,709,884 to remove amorphous regions in their crystal structure. The mixture was micronized again with a spiral jet mill under a pressure of only about 1 bar to obtain a homogeneous mixture.
Next, the powder is supplied to a twin screw feeder (K-Tron), sieved with a vibrating sieve (mesh size: 0.5 mm), and spheroidized at a peripheral speed of 0.5 m / sec in a rotary tank for 4 minutes. And then sieved again using the same sieve, then spheroidized again for 6 minutes,
The powder was agglomerated by passing through a final sieve (mesh size: 1.0 mm) to obtain a powder having a bulk 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 method described in US Pat. No. 5,709,884. The mixture is then spheronized using the method of EP-A-721 331 and Turbuh
The storage compartment of aler ™ was filled.

Example 3 400 parts of budesonide was micronized with a spiral jet mill, and EP-A-7
21 331 and spheronized and filled into Turbuhaler ™ storage compartments.

Example 4-Clinical Trials Glucocorticorgic corticosteroids were used for three years of treatment of mild COPD in a large group of patients. The patients were selected to meet the criteria for mild COPD, and they were all smokers. Mild COPD patients are defined as those patients whose maximum forced expiratory volume in 1 second (FEV _1.0 ) values are greater than 65% of the predicted FEV _1.0 and have less than 10% reversibility in bronchodilation tests. , Is distinguished from asthma.

After the elapse of the second visit to the medical center, drug administration is started at the third visit to patients eligible for treatment (1277 patients who completed the study), or , (Half of the group) received placebo. They followed a regular visit to a medical center approximately every 2-3 months for 3 years. Turbuhaler ™
Carbohydrate corticosteroids were administered by inhalation of a dry powder formulation (400 μg twice daily) by using a respiratory dry powder inhaler. An equivalent amount of placebo was used.

The FEV _1.0 value for each patient was measured at each visit and changes in that value were recorded. The results are presented in FIGS. When presenting the result as a change in FEV _1.0, by using a linear mixed effects model, by calculating the slope of FEV _1.0 for each of the patient, then, formed to display an average slope in FIG. are doing. During the study period, each patient is normalized to one starting value so that meaningful comparisons of disease progression can be made to placebo. FIG. 1 shows that all patients were recruited together, and in FIGS.
Patients are separated by their smoking exposure. All values are averages. One pack-year is defined as a one year smoker of 20 cigarettes / day. Figure 2 shows that the disease was heavy smoker (less than 36 packs-Figure 3 for a year and more than 36 packs-
When not as advanced as for FIG. 4) for years, it shows a clear effect for patients with less than 26 packs-years of smoking exposure. The results are also summarized in FIG. 5, where patients with less than 26 packs-years have higher and / or higher
Alternatively, it has been shown to have a smaller decrease in FEV _1.0 as compared to individuals who have longer tobacco exposure.

[Brief description of the drawings]

FIG. 1 is a linear change over time for all patients.

FIG. 2 is a linear change over time for a patient that is less than 26 packs-year (as defined below).

FIG. 3 is a linear change over time for a patient that is less than 36 packs-year (as defined below).

FIG. 4 is a linear change over time for patients with more than 36 packs-years (as defined below).

FIG. 5 is the difference in linear change over time by pack-year (as defined below).

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] May 24, 2000 (2000.5.24)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Stephen Allson Sweden, S- 221 87 Lund, AstraZeneca R & D Lund F-term (reference) 4C086 AA01 AA02 DA12 EA19 MA01 MA02 MA03 MA04 MA05 NA14 ZA61

Claims (30)

[Claims] 1. FEV greater than 65% of predicted value in bronchodilation test _1.0 Obstructive pulmonary disease (COP) in patients with
D) The use of carbohydrate corticosteroids for the manufacture of a medicament intended for treating
use. 2. Use according to claim 1, intended for treatment for at least one year. 3. Use according to claim 2, intended for treatment for at least 3 years. 4. The use according to claim 1, wherein the carbohydrate corticosteroid is budesonide or an isomer or ester thereof. 5. Use according to claim 1, wherein the carbohydrate corticosteroid is rofleponide or an ester thereof. 6. Use according to any of the preceding claims, wherein the carbohydrate corticosteroid is mixed with one or more pharmaceutically acceptable excipients, diluents or carriers. 7. The method according to claim 6, wherein the carbohydrate corticosteroid is mixed with one or more pharmaceutically acceptable excipients, diluents or carriers in an amount of 100 μg to 25 mg per dose. use. 8. The method of claim 7, wherein the carbohydrate corticosteroid is mixed with one or more pharmaceutically acceptable excipients, diluents or carriers in an amount of 100 μg to 2000 μg per dose. use. 9. Use according to any of claims 1-8, wherein the carbohydrate corticosteroid is administered in the form of agglomerated steroid particles having a particle size of less than 10 μm. 10. The method of claim 1, wherein the carbohydrate corticosteroid is administered in the form of agglomerated particles comprising a steroid and a carrier, both of which have a particle size of less than 10 μm. Use of. 11. The use according to any of claims 1-8, wherein the carbohydrate corticosteroid is administered in the form of an ordered mixture comprising steroid particles having a diameter of less than 10 μm and coarse particles of a carrier. 12. The method of claim 1, wherein the amount of carbohydrate corticosteroid administered to the patient ranges from 100 μg to 3000 μg per day and is administered as a single or divided dose from 1 to 4 times per day. Use according to any of the clauses. 13. The use according to claim 12, wherein the amount of carbohydrate corticosteroid administered to the patient ranges from 200 μg to 1600 μg per day. 14. The amount of a carbohydrate corticosteroid administered to a patient is 200 μg given twice a day or 400 μg given twice a day.
Use as described in. 15. The patient has less than 36 packs-years, suitably less than 26 packs-.
15. Use according to any of the preceding claims, wherein the use has a smoking exposure of less than 16 years, preferably less than 16 packs. 16. An FE greater than 65% of the predicted value in a bronchodilation test.
Chronic obstructive pulmonary disease (CO2) in patients with _V1.0 values and less than 10% reversibility
A method of treating PD), comprising administering to a patient in need of such treatment a therapeutically effective amount of a carbohydrate corticosteroid. 17. The method according to claim 16, intended for at least one year of treatment. 18. The method according to claim 17, intended for at least 3 years of treatment. 19. The method according to any one of claims 16 to 18, wherein the carbohydrate corticosteroid is budesonide or an isomer or ester thereof. 20. The method according to any one of claims 16 to 18, wherein the carbohydrate corticosteroid is rofleponide or an ester thereof. 21. The method of any of claims 16-20, wherein the carbohydrate corticosteroid is mixed with one or more pharmaceutically acceptable excipients, diluents or carriers. 22. The method of claim 16-21, wherein the carbohydrate corticosteroid is mixed with one or more pharmaceutically acceptable excipients, diluents or carriers in an amount of 100 μg to 25 mg per dose. The method according to any of the above. 23. The method of claim 22, wherein the carbohydrate corticosteroid is mixed with one or more pharmaceutically acceptable excipients, diluents or carriers in an amount of 100 μg to 2000 μg. 24. The method according to any of claims 16-23, wherein the carbohydrate corticosteroid is administered in the form of agglomerated steroid particles having a particle size of less than 10 μm. 25. The method according to claim 16, wherein the carbohydrate corticosteroid is administered in the form of agglomerated particles comprising a steroid and a carrier, both of which have a particle size of less than 10 μm. the method of. 26. The method of any of claims 16-23, wherein the carbohydrate corticosteroid is administered in the form of an ordered mixture comprising steroid particles having a diameter of less than 10 μm and coarse particles of a carrier. 27. The amount of a carbohydrate corticosteroid administered to a patient ranges from 100 μg to 3000 μg per day and is administered as a single or divided dose from 1 to 4 times per day. -26. The method according to any of -26. 28. The method of claim 27, wherein the amount of carbohydrate corticosteroid administered to the patient ranges from 200 μg to 1600 μg per day. 29. The amount of a carbohydrate corticosteroid administered to a patient is 200 μg given twice a day or 400 μg given twice a day.
The method described in. 30. The patient has less than 36 packs-years, suitably less than 26 packs-
29. The method according to any of the claims 16-28, wherein the method has a smoking exposure of year, preferably less than 16 pack-years.