Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/10—Expectorants

Definitions

• 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 glucocorticosteriod for treating mild/early form of COPD.
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• Chronic bronchitis is a long-standing disease of the bronchi involving increased production of mucous and other mucosal changes. The symptoms are cough and expectoration of sputum and as the disease progresses shortness of breath. Chronic bronchitis exhibits exacerbations frequently due to recurrent infections. Over many years narrowing and plugging of the bronchi cause difficult breathing and eventually general disability. The annual decline in airflow resistance is normally progressive and may be accompanied by airway hyper-responsiveness. However, in contrast to asthma the hyper-responsiveness is largely dependent on the baseline obstruction and the baseline obstruction is little reversed by bronchodilator treatment.
• Emphysema is a chronic lung disease which affects the alveoli and/or the ends of the smallest bronchi.
• the lung loses its elasticity and areas of the lungs become destroyed with enlarged air spaces. These enlarged areas trap 'stale' air and do not effectively exchange it with fresh air. This results in difficult breathing and may result in insufficient oxygen being delivered to the blood.
• the predominant symptom in patients with emphysema is shortness of breath.
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• steroids and inhaled steroids such as glucocorticosteroids
• glucocorticosteroids may be continued if the patients demonstrate improvement during the first few weeks of treatment.
• the problem with these treatments is that none of them has been regarded as effective.
• a recent review of new therapies for COPD has just been published (Thorax, 53 (1998), 137-147). Here it is clearly stated that there is scarcely no evidence that glucocorticosteroids are beneficial in COPD.
• corticosteroids can be used in long-term treatment of patients with COPD. It is, however, clearly stated that when assessing the effectiveness of corticosteroids in patients with COPD, it is essential to exclude patients with asthma, i.e. to exclude patients having > 10 % reversibility in bronchodilator test. Furthermore, it is stated that "studies performed thus far show that the beneficial effects of long-term treatment with corticosteroids in patients with COPD are small and less prominent than in patients with asthma".
• glucocorticosteroids are effective in treating mild/early COPD in spite of continuous exposure to causally- related factors, in particular tobacco smoking e.g. cigarette smoking.
• Mild COPD patients are defined as patients having a forced expiratory volume in 1 second (FEVi . o) values > 65 % of predicted FEVi . o, and they are distinguished from asthma by having ⁇ 10 % reversibility in bronchodilator test.
• a glucocorticosteroid for the manufacture of a medicament for treating chronic obstructive pulmonary disease in patients having a FEVi.o value > 65 % of predicted value and ⁇ 10 % reversibility in bronchodilator test (measurements of FEVi.o and reversibility using a bronchodilator).
• a method of treatment of chronic obstructive pulmonary disease in patients having a FEVi.o value > 65 % of predicted value and ⁇ 10 % reversibility in bronchodilator test is provided.
• the method is characterized by administration to the patient in need of such treatment of a therapeutically effective amount of a glucocorticosteroid.
• Fig. 1 Linear change over time for all patients.
• Fig. 2 Linear change over time for patients with ⁇ 26 pack-years (as defined below).
• the treated patients have an annual decline in lung function that approaches that of some normal health individuals.
• Fig. 3 Linear change over time for patients with ⁇ 36 pack-years (as defined below).
• Fig. 4 Linear change over time for patients with > 36 pack-years (as defined below).
• Fig. 5 Difference in linear change over time, by pack-year (as defined below).
• the present invention can be used for the manufacture of a medicament for treating COPD in patients having a smoking exposure of less than 46 pack-years, suitably less 36 pack-years, preferably less than 26 pack-years and more preferably less than 16 pack-years.
• the treatment period must be of a certain length before any effect will be distinguished.
• a treatment period of at least one year is necessary.
• the patients are treated for at least three years.
• the glucocorticosteroid used in the invention is preferably an anti-inflammatory gluco- corticosteroid.
• glucocorticosteroids which can be used for the manufacture of the medicaments according to the present invention the following can be mentioned: betamethasone (e.g. as valerate), fluticasone (e.g. as propionate), budesonide, tipredane, dexamethasone, beclomethasone (e.g. as dipropionate), prednisolone fluocinolone, triamcinolone (e.g. as acetonide), mometasone (e.g. as furoate), rofleponide (e.g.
• flumethasone flunisolide, ciclesonide, deflazacort, corticazol, 16 ⁇ ,17 ⁇ - butylidenedioxy-6 ⁇ ,9 ⁇ -difluoro- 11 ⁇ ,21 -dihydroxy-pregna- 1 ,4-diene-3,20-dione, 6 ,9 ⁇ - difluoro- 11 ⁇ -hydroxy- 16oc, 17 ⁇ -butylidenedioxy- 17 ⁇ -methylthio-androsta-4-ene-3-one, S- methyl 16 ⁇ , 17 ⁇ -butylidenedioxy-6 ,9 ⁇ -difluoro- 11 ⁇ hydroxy-3-oxo-androsta- 1 ,4-diene 17 ⁇ -carbothioate, methyl 9 ⁇ -chloro-6 ⁇ -fluoro- 11 ⁇ -hydroxy- 16 ⁇ -methy 1-3 -oxo-17 ⁇ - propionyloxy-androsta- 1 ,4-diene- 17 ⁇ -carboxylate, 6
• budesonide Preferably, use is made of budesonide, rofleponide, rofle-ponide palmitate, momethasone furoate, beclomethasone dipropionate or fluticasone propionate, more preferably of budesonide, rofleponide or rofleponide palmitate, e.g. as the 21 -palmitate, and most preferably of budesonide.
• the medicament is suitably inhaled from a nebulizer, from a pressurized metered dose inhaler or as a dry powder inhaler, e.g. Turbuhaler® (trademark of Astra of Sweden) or from a dry powder inhaler utilizing gelatin, plastic or other capsules, cartridges or blister packs.
• a nebulizer for administration, the medicament is suitably inhaled from a nebulizer, from a pressurized metered dose inhaler or as a dry powder inhaler, e.g. Turbuhaler® (trademark of Astra of Sweden) or from a dry powder inhaler utilizing gelatin, plastic or other capsules, cartridges or blister packs.
• a dry powder inhaler e.g. Turbuhaler® (trademark of Astra of Sweden) or from a dry powder inhaler utilizing gelatin, plastic or other capsules, cartridges or blister packs.
• the administration of the medicament may be by nasal or preferably oral inhalation.
• the glucocorticosteroid is preferably administered in the form of either
• agglomerated particles comprising particles of the steroid of the particle size of less than 10 ⁇ m
• agglomerated particles comprising particles of the steroid and a carrier, both of which have a particle size of less than 10 ⁇ m, or
• an ordered mixture comprising steroid particles of a size less than 10 ⁇ m and coarser particles of a carrier, optionally also particles of the carrier of a particle size less than 10 ⁇ m.
• the coarser carrier particles could also be agglomerates of small particles.
• the amount of glucocorticosteroid administered to the patient is preferably from 100 ⁇ g to 3000 ⁇ g per day, more preferably from 200 ⁇ g to 1600 ⁇ g administered as a single or divided dose/s one to four times per day. Highly preferred doses are 200 ⁇ g given twice a day or 400 ⁇ g given twice a day.
• the glucocorticosteroids can be used in admixture with one or more pharmaceutically acceptable additives, diluents or carriers, preferably in an amount of from 100 ⁇ g to 25 mg per dose, more preferably in an amount of from 100 ⁇ g to 10 mg, most preferably in an amount of from 100 ⁇ g to 2000 ⁇ g per dose.
• suitable diluents or carriers include lactose, dextran, mannitol or glucose.
• lactose is used, especially as the monohydrate.
• One or more of the ingredients is preferably in the form of a dry powder, more preferably a micronized dry powder. Most preferably an agglomerated micronized dry powder is used.
• the finely divided glucocorticosteroid may 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 coarse 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 ⁇ m.
• the ingredients used in the in- vention can be obtained in these preferred forms using methods known to those of skill in the art.
• the medicament When the medicament is adapted to be administered from a pressurized inhaler, it is preferably in finely divided e.g. micronized form. It may be dissolved or, preferably suspended in a liquid propellant mixture.
• the propellants which can be used include chlorofluorocarbons, hydrocarbons or hydrofluoroalkanes.
• Especially preferred propellants are PI 34a (tetrafluroethane) and P227 (heptafluoropropane) each of which may be used alone or in combination. They are optionally used in combination with one or more other propellants and/or one or more surfactants and/or one or more other excipients, for example ethanol, a lubricant, an anti-oxidant and/or stabilizing agent.
• the medicament When the medicament is adapted to be administered via a nebulizer it may be in the form of a nebulized aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a unit dose or multi-dose device.
• a nebulizer When the medicament is adapted to be administered via a nebulizer it may be in the form of a nebulized aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a unit dose or multi-dose device.
• micronization is carried out in a conventional manner such 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 were micronized separately in a spiral jet mill at a pressure of about 6-7 bars to give a particle size of less than 3 ⁇ m before being mixed thoroughly in a Turbula mixer. Before mixing, the lactose monohydrate powder was conditioned according to the method described in US patent 5,709,884 to remove amorphous regions in their crystal structure. The mixture was remicronized in a spiral jet mill at a pressure of only about 1 bar to obtain a uniform mixture.
• the powder was then agglomerated by feeding the powder into a twin screw feeder (K-Tron), sieving in an oscillating sieve (0.5 mm mesh size), spheronizing in a rotating pan with a peripheral speed of 0.5 m/s for 4 minutes and then sieving again using the same sieve, then spheronizing once more for 6 minutes before final sieving (mesh size 1.0 mm) to give a powder of a bulk density of 0.35 g/ml.
• K-Tron twin screw feeder
• sieving in an oscillating sieve 0.5 mm mesh size
• spheronizing in a rotating pan with a peripheral speed of 0.5 m/s for 4 minutes and then sieving again using the same sieve, then spheronizing once more for 6 minutes before final sieving (mesh size 1.0 mm) to give a powder of a bulk density of 0.35 g/ml.
• micronized budesonide 200 parts by weight was mixed with 800 parts of lactose monohydrate.
• the blend was micronized using a high pressure air jet mill and then con- ditioned using the process of US 5,709,884.
• the mixture was then spheronized using the process of EP-A-721 331 and filled into the storage compartment of Turbuhaler®.
• a glucocorticosteroid was used for treatment of mild COPD in a large group of patients during a period of three years.
• the patients were chosen to fulfill the criteria of mild COPD and they were all smokers.
• Mild COPD patients are defined as patients having a forced expiratory volume in 1 second (FEVi.o) values > 65 % of predicted FEVi . o , and they are distinguished from asthma by having ⁇ 10% reversibility in bronchodilator test.
• the patients (1277 patients finished the trial) suitable for the treatment started their medication or alternatively were given placebo (half of the group) on their third visit. They were closely followed 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 by using a Turbuhaler ® breath-actuated dry-powder inhaler (budesonide, 400 ⁇ g twice a day). An equivalent placebo was used.
• Figure 2 shows the clear effect on patients having a smoking exposure of less than 26 pack-years, where the disease has not progressed as much as for the more heavy smokers (Figure 3 for less than 36 years and Figure 4 for more than 36 years).
• Figure 5 shows the patients with ⁇ 26 pack-years having a smaller decline in FEVi . o compared to the individuals with a higher and/or longer cigarette exposure.

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• 1998
  • 1998-04-20 SE SE9801368A patent/SE9801368D0/xx unknown
• 1999
  • 1999-03-18 AU AU30625/99A patent/AU3062599A/en not_active Abandoned
  • 1999-03-18 WO PCT/SE1999/000426 patent/WO1999053926A1/en not_active Application Discontinuation
  • 1999-03-18 CA CA002329008A patent/CA2329008A1/en not_active Abandoned
  • 1999-03-18 CN CN99807636A patent/CN1306429A/zh active Pending
  • 1999-03-18 BR BR9909786-9A patent/BR9909786A/pt not_active IP Right Cessation
  • 1999-03-18 JP JP2000544330A patent/JP2002512193A/ja active Pending
  • 1999-03-18 EP EP99912204A patent/EP1073441A1/en not_active Withdrawn
  • 1999-04-20 AR ARP990101816A patent/AR018191A1/es unknown
• 2002
  • 2002-01-17 HK HK02100375.3A patent/HK1038703A1/zh unknown

Non-Patent Citations (1)

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