MXPA97002303A - Compositions containing at least one glucocorticoid in combination with a pulmonary surgical agent for the treatment of child respiratory suffering syndrome and respiratory suffering syndrome ag - Google Patents

Abstract

The present invention relates to novel compositions for the treatment of IRDS and ARDS, which contain at least one glucocorticosteroid and a pulmonary surfactant. The duration of treatment and the mortality associated with these syndromes can be significantly reduced with the novel compositions proposed.

Description

COMPOSITIONS CONTAINING AT LEAST ONE GLUCOCORTICOID IN COMBINATION WITH AN AGENT PULMONARY SURGICAL FOR THE TREATMENT OF SYNDROMES OF CHILDHOOD RESPIRATORY SUFFERING AND ACUTE RESPIRATORY SUFFERING SYNDROME Technical Field The invention relates to novel compositions for the treatment of Children's Respiratory Suffering Syndrome and Acute Expiratory P Syndrome.

Prior art it is well known that a treatment of pregnant women who tend to prematurely deliver birth with glucocorticosteroids (GCS) can mitigate the consequences of the Infant Respiratory Suffering Syndrome (= IRDS) for their babies (eg, H. R. Gamsu, BM Mullinger, P. Donai and CH Dash: Antenatal administration of Betamethasone to prevent respiratory distress syndrome in preterm infants: report of a UK multicentre trial, Brit. J. Obi.t. Gyn. 1989, 46: 410-10; Review: A. N. Papageorgiou and L. Stern: J. Perinat.Med. 1986, 14: 75-86). For this reason, pregnant women are treated with GCS. Then, we try to delay the birth for at least 24 hours in order to obtain the effect of maturation of the GCS on the lung. For several years, preterm infants have been treated with pulmonary lensioactive agents (LSF) by intertracheal or interbronchial instillation in order to avoid and / or treat IRDS (A. Jobe and M. Ikegami: Surfactant for the treatment of respiratory distress syndrome. Am. Rev. Respir Dis. 1987, 136: 1256-75; MS Reynolds and KA Wallander, Use of surfactant in the prevention and therapy of neonatal respiratory distress syndrome, Cli. Pharm. 1989, 8: 559-76). For some time now there have been more and more pivotal studies where LSF was successfully used for the treatment of Acute Respiratory Distress Syndrome (ARDS) of different formation. (Overview eg BB Lachmann, D. Gommers and EP Eijking: Exogenous surfactant therapy in adults, Atenw.-Lungenkrkh., 1993, 19: 581-91; TJ Gregory et al .: Survanta supplementation in patients with acute respiratory distress syndrome (ARDS) , Am. J. Respir. Crit. Care Med. 1994, 149; A567). Corticosteroids are applied for ARDS? Vith only little success (G.R. Bernard et al .: High-dose corticosteroids in patients with adult respiratory distress syndrom, N. Engl. J. Med. 1987, 317: 1565-70).

Description of the Invention It has now been surprisingly found that, by applying a combination of glucocorticosteroids and pulmonary surfactants, a synergistic effect can be obtained in the treatment of IRDS and ARDS.

The invention therefore relates to a composition for the treatment of IRDS and ARDS that contains at least one glucocorticosteroid and a pulmonary surfactant. Additional embodiments of the invention may be taken from the patent claims. As glucocorticosteroids, those that are suitable for application in the lung are of interest. By way of example, betamethasone, methylprednisolone, dexamethasone and ciclesonide are mentioned. In accordance with this invention, under the numerous known compositions of lung surfactants, those which show the function of the natural surfactant agent will be understood. With these compositions, phospholipids are preferred, which among others may additionally contain lung surfactant proteins. One of the commercial products mentioned "Curosurf" ® (Serono, Pharma GmbH, 85716 Unterschleißheim), which is a highly purified natural surfactant from homogenized pork lungs, Survanta < 5 (Abbott GmbH, Wiesbaden) and Alveofact ® (Dr. Karl Thomae GmbH Biberach), which are both extracts of lamb lungs and, Exosurf ® (Deutsche Wellcome GmbH, Burgwedel), a synthetic phospholipid containing auxiliaries. Considered to be considered are considered to be the lung surfactants of both proteins from natural sources such as for example lung lavage or extraction of amniotic fluid as well as proteins produced by genetic engineering. In connection with this invention, the lung surfactant proteins designated SP-B and SP-C and their modified derivatives are of interest. The amino acid sequences of these lung surfactant proteins are known, its isolation or production by genetic engineering (WO-86/03408, EP-A-0251449, WO-89/04326, WO-87/06943, WO-88/03170, EP-A-0368823 and EP-A-0348967 ). EP-B-0100910, EP-A-01 10498, EP-B-01 19656, EP-B-0145005 and EP-B-028601 1 describe the compositions of phospholipids with and without proteins of pulmonary surfactant, which by way of example they are of interest as components of the compositions in accordance with this invention. The compositions according to this invention are provided either as powder for inhalation application or in fluid form for intertracheal or interbronchial application. A powder is obtained by lyophilization and micronization of the preparation of pulmonary surfactant fluid before or after the addition of glucocorticosteroids. The compositions according to this invention contain from 1 to 30% by weight of glucocorticosteroid (depending on the efficacy of the GCS: a table can be taken with the relative values of the glucocorticosteroid efficiencies of Goodman / Gillman, Pharmacological Basis of Therapeutics , Pergamon Press, page 1447, 8a.De) and 15 to 95% by weight of pulmonary surfactant of the dry mass (for example betamethasone 7% and LSF 92% or methylprednisolone 37% and LSF 63%). The compositions according to this invention are applied 3 to 4 times daily for 2 to 4 days. As an example, preparations containing 4 mg of betamethasone and 50 mg of phospholipids; they are applied 6 times every 6 hours by inhalation or intratracheally or intrabronchially.

Pharmacology Adult Sprague Dawley rats were artificially synthesized with pure oxygen and positive final expiratory pressure to guarantee (= PEEP to ensure oxygenation of the rats) and then two of them were washed until their own LSF was washed (B. Lachmann, B. Robertson and J. Vogel: In vivo lung-lavagei as an experimental model of the respiratory distress syndrome, Acta Anesth, Scand., 1980, 24: 231-6, D. Háfner, U. Killian and R Beume: Comparison of four lung surfactant preparations in animal model of adult respiratory distress syndrome (ARDS) Am. Rev. Respi. Dis. 1993, 147: A719; D. Háfner, P.-G. Germann, D. Hauschke , Pulmonary Pharmacology (1994) 7, 319-332). This was manifested by the fact that the initial values of the animals of the arterial oxygen partial pressure (Pa02) of 500-550 mm Hg (ventilation with pure oxygen and PEEP) decreased to values of 50-1 10 mm Hg. Animals in the control group, which are not treated with LSF, continue to exhibit those low Pa02 values during the examination period. Five minutes after Pa02 descended to these values, LSF or LSF together with a glucocorticosteroid, intratracheal instillation was performed. Blood gases were determined 5, 30, 60, 90 and 120 minutes after instillation. Then the PEEP was reduced from 8 to 6 cm H20 (first reduction of PEEP). After another 15 minutes PEEP was reduced to 3 cm H20 (second reduction of PEEP). Blood gases were determined at 5 minutes after both reductions in PEEP. The following table 1 row A shows the mean values (± standard deviation) of Pa02 in mm Hg during the period from 5 to 120 minutes (constant PEEP of 8 cm H20) after inter-tracheal instillation. Row B shows the mean values (± standard deviation) of Pa02 after the first PEEP reduction after intertracheal instillation. From row C the mean values (± standard deviation) of Pa02 can be taken during the second PEEP reduction. The table shows that the single application of the glucocorticosteroid (in this case budesonide) does not influence Pa02. This follows from the comparison with untreated control animals. The application of LSF (25 or 100 mg / kg) causes an increase in Pa02. The addition of 600 μg of budesonide to each dose of LSF significantly improves the Pa02 values compared to the respective doses of LSF. From this it follows that the combined application of glucocorticosteroids and LSF leads to an unexpected synergistic effect. Therefore it is possible to either save a portion of the very expensive LSF or obtain an improved effect of each of the components. Table 1 The histopathological examination of the lungs of these animals after the end of the experiment shows a severe formation of the so-called hyaline membranes (HM) and a strong infiltration of inflammatory cells [for example polymorphonuclear neotroph leukocytes (= PMNL)] since the Symptom of the development of a syndrome of acute respiratory distress. Examination of the preparations according to the invention which contain dexamethasone or ciclesonide and a mixture of phospholipids showed that oxygenation and histological chan(inhibition of the formation of MH and inhibition of PMNL infiltration) compared to the application of LSF or GCS were improved s inergistically. From this it is observed that due to this unexpected synergistic effect the treatment of I RDS and ARDS can be shortened and the high mortality in relation to these syndromes can be reduced.

Claims (7)

1. CLAIMS 1. Compositions for the treatment of IRDS and ARDS containing at least one glucocorticosteroid and a pulmonary surfactant. The compositions according to claim 1, characterized in that betamethasone, methylprednisolone, dexamethasone and / or ciclesonide are contained as glucocorticosteroids. 3. The compositions according to claim 1, characterized in that mixtures of phospholipids are contained as pulmonary surfactant. 4. The compositions according to claim 3, characterized in that the phospholipids present are contained in natural pulmonary tepsioactive agents. 5. The compositions according to claim 3, characterized in that the lung surfactant proteins are additionally contained. 6. The compositions according to claim 5, characterized in that SP-B and / or SP-C and / or its modified derivatives are contained. 7. The compositions according to claim 4, characterized in that the pulmonary surfactants obtained by pulmonary lavage are contained.