Component surface-active properties of the compositions analogous preparations for substitution of the surfactant therapy for lung diseases


The invention relates to the field of medicine and for the application of hydrogenated soy phosphatidylcholine (Phospholipon-N) as an active ingredient, providing a surface-active properties of drugs for substitution of the surfactant therapy. The invention provides a need for surfactant therapy surface-active properties of drugs at low cost. table 2.

The invention relates to medicine, namely to technologies for medicinal products for substitution of the surfactant therapy for respiratory distress syndrome (RDS), resulting in premature infants due to the underdevelopment of its own system of pulmonary surfactant in adults as a result of some heavy shock and diseases.

The urgency of the problem due to the extremely high cost available for the treatment of these diseases medicines, in particular allowed in Russia (1994) drug "Ektomorf" (Exosurf Neonatal, manufacturing firms "Wellcome Foundation, UK) - cost single dose is more than $ 500, due to the complexity of the synthesis of the main active component (dialektologie artificial surfactant preparation "ALEC" (U.S. production) and also causes an almost equally high cost of the latter. In the world there are a number of other surfactant preparations, obtained on the basis of extracts from the lungs of pigs or cattle (Survanta", "Curosurf", the new Russian drug "Surfactant-BL"). Their cost is also high (200-400 dollars), and in addition, in connection with the recent increase in animal diseases (foot and mouth disease, spongiform encephalitis) their use is associated with risk of infection and associated additional control measures.

However, the need for such drugs is quite high, as RDS develops in 20% of premature infants and is a major cause of perinatal morbidity and mortality [1]. In a country such as the United States noted in approximately 40 000 cases of RDS per year [2], which when extrapolated to the population of Russia may indirectly indicate a high prevalence of this disease in our country. In addition, 27% of newborns with low birth weight even in the absence of RDS observed "respiratory failure" requiring additional supply of oxygen or of detention in the conditions of constant high pressure. This condition, as well as RDS, stopped by the introduction of exogenous surfactant preparation.

In addition, radiation, or chemical lung or overdose of some drugs (heroin or barbiturates).

All these cases are caused by the absence or insufficiency (newborns) or damage (in adults) private surfactant - thin, mainly phospholipid films on the surface of the alveoli, preventing them from sticking together when you exhale. Inhaled introduction of artificial surfactant restores the ability to breath until the regeneration of the native, endogenous surfactant, which in the case of RDS infants sometimes 1-2 single doses of the drug. But, of course, such a high cost does not allow you to use it in all appropriate cases, which often leads to death.

The main component of the native surfactant and all evidence to date its analogues is the phospholipid DPPC, which includes two palmitic acid acid (C16:0), which ensures its high surface-active properties: the ability to rasplachivatsa" and "shrink" on the interface water - air" (appearing on the surface of lung alveoli during breathing). In addition to the above Ecosurf DPPC is the current top used in the world of such drugs, including those based on raw materials from bovine lung the body donor also quite expensive. There are reports of a mixture of saturated and unsaturated phospholipids together with triglycerides and/or steroids as part substitution for surfactant therapy [4].

Closest to the proposed is "composition for pulmonary surfactant"[1, 5] , based on which the manufactured drug "Ektomorf", each vial contains 108 mg of DPPC, 12 mg of cetyl alcohol (hexadecanol), and 8 mg of tyloxapol, to ensure the density of the saline solution is added also 46,75 mg NaCl. Immediately before use the contents of the ampoule is dissolved in 8 ml of sterile water (final concentration of DPPC, hexadecanol and tyloxapol is 13.5, 1.5, and 1 mg/ml) [1].

The aim of the present invention is to research the possibility of replacing synthetic DPPC at a more affordable component with a close chemical composition and having a close surface-active properties.

It should be noted that there are reports of use in pulmonology soybean phosphatidylcholine, representing mainly talinolol-phosphatidylcholine (DLPH) containing unlike DPPC two balance linoleic (dimensional) fatty acids (C18:2). However, formirovanie surfactant of the fetus (i.e., prevent RDS), as well as for the treatment of acute and chronic pneumonia [6]. To ensure the same RDS this phospholipid in principle not necessary, as it is due to the presence of two unsaturated hydrocarbon chains (instead of two rich in DPPC) is unable to provide the required level of surface activity of the monolayer.

Known for a relatively cheap drug (268 Euro per 1 kg) - modified soy phosphatidylcholine under the trade name "Phospholipon-N" (produced by Rhone-Poulenk, Nattermann Phospholipid Gmbh, Germany - France). He is a hydrogenated soybean phosphatidylcholine, which as a result of the process of hydrogenation of linoleic acid (C18:2) replaced by stearic (C18:0). The result of the presence of soybean phosphatidylcholine small amount of mixed molecular species containing in a single molecule of linoleic and palmitic fatty acids, is the presence in Phospholipase-N" and palmitic acid (the same as in DPPC), but in much smaller quantities - 14%. The main its fatty acid (86%) is stearic part of distearoylphosphatidylcholine.

Phospholipon-N finds application in pharmacology as the basis of liposomal drugs for intravenous use as a component of oral drugs to reduce its irritating effect on the gastrointestinal tract; so, chloroquin in the liposomes of Phospholipon-N effective against the pathogen of malaria [7]. It is also known the use of Phospholipon-N (synonym - hydrogenated soy lecithin, Soyalecithin NC 95H, Phospholipon100H) in the outer and cosmetic products [8, 9], as well as in scientific research related to the application of liposomes [10].

About using it as a component of inhaled drugs for substitution of the surfactant therapy message is not available. Our studies and examples indicate the proximity of the surface-active properties of DPPC (and prepared on the basis of the surfactant preparations and compositions similar to existing drugs) to those for Phospholipon-N. This suggests the possibility of commercial use of this drug as a medicinal component of the surfactant preparations instead of DPPC. Presents a comparison of the surface-active properties of the films at the interface water - air" simulating the surface of lung alveoli. Films were formed as pure phospholipid is DPPC and Phospholipon 90-N, and prepared on the basis of the surfactant drugs - dosage forms "Ecosurf the rod, but with the replacement of DPPC on Phospholipon-N.

The results show that the parameters of the surface tension and surface adsorption at the interface water - air" Phospholipon-N may be adequate (at a much lower cost) substitute for DPPC in the composition of phospholipid preparations for substitution of the surfactant therapy, in particular drug "Ektomorf".

Example 1.

In the digital container tensiometer TO 10ST Kruss GMBX (Germany - France) with a surface area of 15 cm2put a 9.5 ml of 0.9% NaCl solution and measured the surface tension of the water surface (at the interface with air) using a platinum plate (registering retention force of the plate on the surface). When the surface tension was 70 mn(millinewton)/m, which corresponds to a known value for the water surface [8]. Surface activity of phospholipids was determined by their ability to reduce this initial value.

To determine the surface activity of the sample compared phospholipid is DPPC (Sigma, USA) and Phospholipon-N (firm Rhone-Poulenk", France) was dissolved in a mixture of chloroform-ethanol, 9: 1, to a concentration of 2.3 mg/ml; 2-5 μl of the solution was carefully layered on poverhnostei phospholipids in water and their amphiphilic structure). Were determined using the same platinum plate surface tension of the formed film.

Similar measurements were also carried out with the finished product Ecosurf (firm Wellcome, UK), and with the same composition, but with the use of Phospholipon-N instead of DPPC. For this 108 mg of Phospholipon-N and 12 mg of cetyl alcohol (hexadecanol), was dissolved in 1.5 ml of ethanol and was rapidly injected by syringe 8 ml of NaCl solution containing 8 mg of tyloxapol (Triton WR-1339). The resulting solution was subjected to homogenization by repeated sudden prodavlivanii through a needle of the syringe to obtain a homogeneous opaque solution.

To account for the possible impact of the procedure of the preparation of the drug, which, of course, from that in the industrial preparation of Ecosurf, we have prepared a composition with the composition of Ecosurf in our laboratory conditions. They took the same number of components (108 mg DPPC, 12 mg hexadecanol and 8 mg of tyloxapol in 8 ml of 0.9% NaCl), but connecting them by the above-described laboratory procedures for obtaining Fosfolipidzawisimah composition. The results of determination of the surface tension are given in table 1.

As you can see, DPPC and Phospholipon-N them the Urfa slightly higher what is its main component, DPPC due to the presence of other components necessary to solubilize and alveolar surface distribution of phospholipid - hexadecanol and tyloxapol.

Prepared in laboratory conditions, the composition of the same composition (i.e., using the same ratios of DPPC, hexadecanol and tyloxapol) was close to the value of the surface tension to prepared in the same conditions, a similar composition, but containing instead of the DPPC Phospholipon-N.

This indicates the similarity of the used phosphatidylcholine (actually DPPC and distearoylphosphatidylcholine, DSFH) in terms of their ability to reduce surface tension, which, in turn, determines the similarity of this parameter composition comprising Phospholipon-N, properties Ecosurf.

Example 2.

In this example, measured another parameter characterizing surface-active properties - surface adsorption, which determines when the medicinal use of the ability of phospholipid molecules left in the aqueous phase of the alveoli during expiration, again be returned to the surface during the expansion of the alveoli in the next breath. Under the surface adsorbtsiya in volume of the aqueous phase. For this purpose the container digital tensiometer TO 10ST Kruss GMBX containing 9.5 ml NaCl (with a surface of 15 square cm) was rapidly injected 0.5 ml (the concentration of phosphatidylcholine of 0.54 mg/ml) tested phospholipid emulsion - commercial Ecosurf, full analogue, prepared in the laboratory or prepared under the same conditions with the same drug, but Phospholipon-N instead of DPPC.

The contents of the container is stirred by a stirrer for 10 seconds, and then recorded the process of reducing the surface tension due to the gradual adsorption of molecules of phosphatidylcholine from the aqueous phase at the interface water-air". After reaching the minimum surface tension curves were on the plateau (corresponding to the maximum possible surface concentration of phospholipid molecules). While the magnitude of the surface adsorption were as follows (table. 2).

Differences of surface adsorption of Ecosurf and prepared composition of the same composition unreliable, which indicates that there is virtually no influence of technology on this parameter is defined, as you can see, it is a composition.

The composition with the composition of Ecosurf, but in which DPPC replaced by Phospholipon-N, the surface tension, demonstrated in example 1. Almost the same values of surface adsorption possess themselves of the source components - DPPC and phospholipon.

Thus, as the surface tension, and surface adsorption of the proposed composition with the composition of Ecosurf, but with substitution of DPPC on Phospholipon-N, are close to those for the original composition of Ecosurf. This indicates the similarity of these compositions against surface-active properties of the underlying substitution surfactant therapy for lung diseases and, consequently, on the use of Phospholipon 90-N as a substitute for expensive DPPC in the future of the surfactant preparations.

Sources of information 1. Grebennikov C. A., Milenin O. B., Rumin And. And. Respiratory distress syndrome in newborns. M., 1995.

2. Fujiwara T., Robertson C. in "Pulmonary surfactant", ed. B. Robertson et al., Elsevier, Amsterdam, 1992, 561-92.

3. Morley, S., in "Pulmonary surfactant", ed. B. Robertson et al., Elsevier, Amsterdam, 1992, p.605-633.

4. U.S. patent, 5134129, CL 514/78, 514/547, 514/925, 1993.

5. U.S. patent 5110806, CL 514/78, 128/203.12, 128/207.14, 1992.

6. Gundermann, K.-J. , in "The "essential" Phospholipids as a membrane therapeutic", Szczecin, 1993, 193-194.

7. Peeters, P. A. M., de Leest K., W. Eling et al. Chloroquine blood levels after administration of the Liposime-Encapsulated Drug. Pharm. Res. 1989, 6(9), 787-93.

8. Gestztes A., Mezei M. Topical d Gel dosage forms. Springer Verlag, Berlin, 1987.

10. Nishihata T. , Kotera, K., Nakano Y. Yamazaki M. Rat percutaneous Transport of diclofenac and influence of hydrogenated soya phospholipids. Chem.Pharm. Bull. 1987, 3509, 38007-38012.

11. Sun Century Experimental studies of neonatal surfactant disfunction and surfactant therapy in meconium aspiration syndrome. Karolinska Institute, Stockholm, Sweden, 1993, 6-67.


The use of Phospholipon-N as an active ingredient, providing a surface-active properties of drugs for substitution of the surfactant therapy.


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