Compositions for the treatment of respiratory distress syndrome in newborns and acute respiratory distress syndrome, containing at least one glucocorticosteroid combined with pulmonary surface-active substance

 

(57) Abstract:

The invention relates to pharmaceutical industry and relates to a composition for the treatment of respiratory distress syndrome. The invention lies in the fact that the proposed composition for the treatment of respiratory distress syndrome of newborns (RDTS) and acute respiratory distress syndrome (ARDS) contains at least one glucocorticosteroid and one pulmonary surfactant. The invention significantly reduces the duration of treatment and to reduce due to these syndromes mortality. 7 C.p. f-crystals, 1 table.

The invention relates to a new composition for the treatment of respiratory distress syndrome of newborns (RDTS) and acute respiratory distress syndrome (ARDS).

It is known that treatment with glucocorticosteroids (GCS) mothers who are prone to premature birth, can mitigate the effects of respiratory distress syndrome in their newborns (see, for example, Gamsu H. R., B. M. Mullinger, P. Donai and C. H. Dash, Antenatal administration of Betamethasone to prevent respiratory distress syndrome in preterm infants: report of a UK multicentretrial, Brit. J. Obst. Gyn., 1989, 96: 410-10; Review: A. N. Papageorgiou, and L. Stern, J. Perinat. Med. 1986, 14: 75-86). The mother receive corticosteroids. Then the attempt is made for the lungs. Also for many years premature children is administered by intratracheal or intrabronchial instillation of pulmonary surfactant (pulmonary surfactant) for the prevention and/or treatment of RDTS (A. Jobe and M. Ikegami, Surfactant for the treatment of respiratory distress syndrome. Am. Rev. Respir. Dis. 1987, 136: 1256-75; M. S. Reynolds, and K. A. Wallender, Use of surfactant in the prevention and treatment of neonatal respiratory distress syndrome, Clin. Pharm. 1989, 8: 559-76). Recently, a growing number of fundamental studies in which pulmonary surfactant is successfully used for treatment of acute respiratory distress syndrome other origin, for example, B. Lachmann, D. Gommers, and E. P. Eijking, Exogenous surfactant therapy in adults, Atemw.-Lungenkrkh. 1993, 19: 581-91; T. J. Gregory, and others, Survanta supplementation in patients with acute respiratory distress syndrome [ARDS], Am. J. Respir. Crit. Care Med. 1994, 149: A567). When ARDS corticosteroids are used less successfully (G. R. Bernard, and others, High-dose corticosteroids in patients with the adult respiratory distress syndrome, N. Engl. J. Med. 1987, 317: 1565-70).

It has been unexpectedly found that the introduction of a combination of corticosteroids and pulmonary surfactants can be achieved by a synergistic effect in the treatment of RDTS and ARDS.

The object of the present invention is in accordance with this composition for the treatment of RDTS and ARDS, containing at least one glucocorticosteroid and one e of corticosteroids may be considered those which are suitable for introduction into the lung. For example, you can name betamethasone, budesonide, methylprednisolone, dexamethasone, ciclesonide.

Under pulmonary surfactants are understood according to the invention, numerous famous composition having a function of natural lung surfactant. When it comes to the songs, especially phospholipids, which may contain, in particular, more and proteins pulmonary surfactant. Commercial products should be called Curosurf(Serona, Pharma GmbH, 85716 Unterschleissheim), highly refined natural surfactants from homogenized porcine lung, Survanta(Abbott GmbH, Wiesbaden) and Alveofact(Dr. Karl Thomae GmbH, Biberach), both are extracts from the lungs of cattle, as well as Exosurf(Deutsche Wellcome GmbH, Burgwedel), a synthetic phospholipid with auxiliary substances. As proteins pulmonary surfactants suitable as proteins obtained from natural sources, for example by pulmonary lavage or extraction from amniotic fluid and proteins obtained by genetic engineering methods. Of interest according to the invention, in particular, proteins of pulmonary surfactant, denoted as SP-B and SP-C, and their modified derivatives. Amino acid, posleratni (WO-88/03408, EP-A-0251449, WO-89/04326, WO-87/06943, WO-88/03170, EP-A-0368823 and EP-A-0348967). In EP-B-0100910, EP-A-0110498, EP-B-0119056, EP-B-0145005 and EP-B-0286011 described phospholipid composition of proteins pulmonary surfactant and without any, which may be considered, for example, as components of the preparations according to the invention.

Compositions according to the invention are prepared either in the form of a powder for inhalation use, or in liquid form for intratracheal or intrabronchial administration. Compositions in the form of a powder obtained by freeze-drying liquid preparations of pulmonary surfactant, for example before or after adding the glucocorticosteroid, followed by micronization. Compositions according to the invention contain from 1 to 30 wt.% the glucocorticosteroid (depending on the activity of glucocorticosteroid; table with relative activities of glucocorticoids given in Goodman/Gillman, the Pharmacological Basis of Therapeutics, Pergamon Press, page 1447, 8th ed.) and from 15 to 95 wt.% pulmonary surfactant in terms of dry weight (for example, 7% of betamethasone and 92% of pulmonary surfactant or 37% of methylprednisolone and 63% of lung surfactant).

The preparations according to the invention is administered to the patient 3-4 times a day for 2-4 days. For example, preparations containing 4 mg of betamethasone and 50 mg of phospholipids, enter 6 times and the R> Adult rats Sprague Dawley subjected to mechanical ventilation with pure oxygen with positive pressure at the end of the expiratory (peep; to ensure oxygen saturation rats) and washed until such time as their own pulmonary surfactant will not be washed (B. Lachmann, B. Robertson, and J. Vogel, In vivo lung-lavage as an experimental model of the respiratory distress syndrome, Acta Anesth. Scand. 1980, 24: 231-6; D. Hafner, U. Kilian and R. Beume: Comparison of four lung surfactant preparations in an animal model of adult respiratory distress syndrome, Am. Rev. Respir. Dis. 1993, 147: A719; D. Hafner, P.-G. Germann, D. Hauschke, Pulmonary Pharmacology (1994) 7, 319-332). This is manifested in the fact that animals arterial partial pressure of oxygen (PaO2crashed with initial values 500-550 mm RT.article (when ventilation with pure oxygen and positive pressure at the end of exhalation) to values 50-110 mm RT.article Animals of the control group, which does not give the pulmonary surfactant, P-valueaO2during the whole observation time saves these low values. After 5 min after P-valueaO2fell to these values, the animals buried vnutritrahealno pulmonary surfactant, respectively pulmonary surfactant together with a glucocorticosteroid. Determine blood gases after 5, 30, 60, 90 and 120 min after instillation. Then peep reduced from 8 to 6 cm of water.article (the first reduction P is after each of these two reductions peep.

In table 1 in the row And show the mean values ( standard deviation) values of PaO2in mm RT.article during the period of time from 5 to 120 min (constant peep 8 cm water.CT.) after intratracheal instillation. In line B shows the mean values ( standard deviation) values of PaO2after the first reduction peep after intratracheal instillation. In the line shows the average values of PaO2( standard deviation) during the second reduction peep after backfilling. The table shows that the introduction of only one glucocorticosteroid (in this case, the budesonide) has no effect at PaO2. It is clear from comparison with untreated control animals. Introduction pulmonary surfactant (25 or 100 mg/kg) leads to increased PaO2. Add 600 mcg of budesonide to the appropriate dosage pulmonary surfactant significantly improves the performance of PaO2in comparison with these dosages pulmonary surfactant. It follows that when the joint introduction of corticosteroids and pulmonary surfactant is achieved unexpected effect than the sum of the effect of individual components. So you can either save some very dragoste eposredstvenno for the experiment, histological examination of the lungs of these animals showed the formation of a large number of so-called vitreous membranes (CM) and a strong influx of inflammatory cells (for example, polymorphonuclear neutrophilic leukocytes (PMNL) as expressed by the development of acute syndrome of dyspnea.

In the study on this model, the preparations according to the invention containing dexamethasone or ciclesonide and a mixture of phospholipids with proteins, surfactants, or without such, it was found that oxygen saturation and histological changes (inhibition of education SEE and suppresses inflow PMNL) synergistically improves in comparison with the introduction of only one lung surfactant or glucocorticosteroid. Hence, due to this unexpected synergistic effect during the treatment of respiratory distress syndrome of newborns and acute respiratory distress syndrome may be reduced, and due to these syndromes high mortality reduced.

1. Composition for the treatment of respiratory distress syndrome in newborns and acute respiratory distress syndrome, containing at least one glucocorticosteroid and one pulmonary surfactant.

2. The composition according to p. 1, characterized in that it contains from 15 to 95 wt.% pulmonary surfactant and from 1 to 30 wt.% glucorticosteroids.

3. The composition according to p. 1, characterized in that as glucocorticosteroids it contains becuase fact, as pulmonary surfactant contains a mixture of phospholipids.

5. The composition according to p. 4, characterized in that it contains phospholipids found in natural pulmonary surfactant.

6. The composition according to p. 4, characterized in that it further contains proteins pulmonary surfactant.

7. The composition according to p. 6, characterized in that it contains proteins SP-B and/or SP-C, and/or their modified derivatives.

8. The composition according to p. 5, characterized in that it contains pulmonary surfactant obtained by lung lavage.

 

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