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Claims for Patent: 4,397,839

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Claims for Patent: 4,397,839

Title: Surface active material and process for preparing same
Abstract:A surface active material having the capacity of reducing the surface tension in pulmonary alveoli significantly is provided. This material comprises, based on the dry weight of the material, 68.6-90.7% of phospholipid, 0.3-13.0% of neutral fat, 0.0-8.0% of total cholesterol, 1.0-27.7% of free fatty acids, 0.1-2.0% of carbohydrate, and 0.0-3.5% of protein. The material is produced by subjecting mammalian lung tissue to a series of procedures including acetic acid ester treatment, organic solvent mixture treatment, differential centrifugation, density gradient centrifugation and dialysis, and optionally adding a phosphatidylcholine, a neutral fat, and/or a free fatty acid to the resulting product. A pharmaceutical composition comprising the surface active material is usable for the clinical treatment of respiratory distress syndrome.
Inventor(s): Tanaka; Yuji (Toda, JP)
Assignee: Tokyo Tanabe Company, Limited (JP)
Application Number:06/354,628
Patent Claims: 1. A surface active material comprising (1) phospholipid, neutral fat, total cholesterol, free fatty acids, carbohydrate, protein and water, all of which are obtained from the lung tissue of a mammal, and (2) optionally at least one additional component selected from the group consisting of a phosphatidylcholine, a neutral fat and a free fatty acid, characterized in that the overall phospholipid content is 68.6-90.7%, the overall neutral fat content is 0.3-13.0%, the total cholesterol content is 0.0-8.0%, the overall free fatty acid content is 1.0-27.7%, the carbohydrate content is 0.1-2.0%, the protein content is 0.0-3.5%, and the water content is 2.1-5.2%, all based on the dry weight of the material, the surface tension of the material as measured at 15.degree.-25.degree. C. by Wilhelmy's method in which the material is added dropwise to the surface of physiological saline in an amount of 0.3-0.8 .mu.g per square centimeter of the surface area thereof being 30.1-47.5 dynes/cm when the surface area is 54.0 cm.sup.2.

2. A surface active material as claimed in claim 1 wherein the overall phospholipid content is estimated by multiplying its phosphorus content by 25; the overall neutral fat content is estimated by expressing its constituents in terms of mono-, di- and trioleoylglycerols and then calculating the sum total thereof; the total cholesterol content was estimated by expressing its constituents in terms of free cholesterol and cholesterol palmitate and then calculating the sum total thereof; and the overall free fatty acid content, the carbohydrate content and the protein content are expressed in terms of palmitic acid, glucose and bovine serum albumin, respectively.

3. A surface active material as claimed in claim 1 wherein the phospholipid consists essentially of, on a weight basis, 58.4-85.0% of phosphatidylcholine, 0.1-12.0% of phosphatidylglycerol, 3.5-12.6% of phosphatidylethanolamine, and 3.2-12.1% of sphingomyelin.

4. A surface active material as claimed in claim 3 wherein the content of phosphatidylcholine having two saturated fatty acid residues based on the total weight of phosphatidylcholine is 61.3-87.5%.

5. A surface active material as claimed in claim 1, 2, 3 or 4 wherein the phosphatidylcholine optionally used as an additional component is dipalmitoylphosphatidylcholine.

6. A surface active material as claimed in claim 1, 2, 3 or 4 wherein the neutral fat optionally used as an additional component is a member selected from the group consisting of tripalmitoylglycerol, tristearoylglycerol, trioleoylglycerol and mixtures thereof.

7. A surface active material as claimed in claim 1, 2, 3 or 4 wherein the fatty acid optionally used as an additional component is a member selected from the group consisting of palmitic acid, stearic acid, oleic acid and mixtures thereof.

8. A surface active material as claimed in claim 1, 2, 3 or 4 wherein the mammal is selected from the group consisting of cattle, horses, sheep and pigs.

9. A pharmaceutical composition useable for the treatment of respiratory distress syndrome comprising an effective amount of a surface active material as set forth in claim 1 and a pharmaceutically acceptable carrier thereof.

10. A pharmaceutical composition as claimed in claim 9 wherein the effective amount for adult patients is between 500 and 3,000 mg per treatment.

11. A pharmaceutical composition as claimed in claim 9 wherein the effective amount for premature infants is between 50 and 400 mg per treatment.

12. A pharmaceutical composition as claimed in claim 9, 10 or 11 wherein the carrier is selected from the group consisting of water and an electrolyte solution.

13. A pharmaceutical composition as claimed in claim 12 wherein the electrolyte solution is physiological saline.

14. A pharmaceutical composition as claimed in claim 9, 10 or 11 wherein the effective amount is administered directly into the airway of patients with respiratory distress syndrome.

15. A pharmaceutical composition as claimed in claim 14 wherein the effective amount is administered in the form of a suspension.

16. A method of producing a surface active material comprising (1) phospholipid, neutral fat, total cholesterol, free fatty acids, carbohydrate, protein and water, all of which are obtained from the lung tissue of a mammal, and (2) optionally at least one additional component selected from the group consisting of a phosphatidylcholine, a neutral fat and a free fatty acid, characterized in that the overall phospholipid content is 68.6-90.7%, the overall neutral fat content is 0.3-13.0%, the total cholesterol content is 0.0-8.0%, the overall free fatty acid content is 1.0-27.7%, the carbohydrate content is 0.1-2.0%, the protein content is 0.0-3.5%, and the water content is 2.1-5.2%, all based on the dry weight of the material, the surface tension of the material as measured at 15.degree.-25.degree. C. by Wilhelmy's method in which the material is added dropwise to the surface of physiological saline in an amount of 0.3-0.8 .mu.g per square centimeter of the surface area thereof being 30.1-47.5 dynes/cm when the surface area is 54.0 cm.sup.2, the method comprising the steps of:

(a) bringing the minced lung tissue of a mammal into contact with an electrolyte solution to obtain an extract;

(b) centrifuging the extract to collect a crude sediment;

(c) adjusting the specific gravity of an aqueous suspension of the crude sediment by the addition of sodium chloride and centrifuging the adjusted suspension to isolate a top layer comprising an emulsified scum layer;

(d) dialyzing an aqueous suspension of the top layer and lyophilizing the dialyzed suspension to obtain a crude dry product;

(e) bringing the crude dry product into contact with an acetic acid ester to collect a material insoluble in the acetic acid ester and then bringing the insoluble material into contact with an organic solvent mixture to obtain a purified filtrate; and

(f) concentrating the purified filtrate to obtain a solid residue, optionally adding to the solid residue at least one additional component selected from the group consisting of a phosphatidylcholine, a neutral fat and a free fatty acid, so as to provide an overall phospholipid content of 68.6-90.7%, an overall neutral fat content of 0.3-13.0%, and an overall free fatty acid content of 1.0-27.7%, all based on the dry weight of the final product, at well as an overall phosphatidylcholine content of 58.4-85.0% based on the total weight of phospholipid, and then lyophilizing the resulting mixture.

17. A method as claimed in claim 16 wherein the lung tissue minced with a meat grinder is used in step (a).

18. A method as claimed in claim 16 wherein the electrolyte solution used in step (a) is physiological saline.

19. A method as claimed in claim 16 wherein, in step (c), the specific gravity of the aqueous suspension of the crude sediment is adjusted to 1.10-1.20.

20. A method as claimed in claim 16 wherein, in step (d), the aqueous suspension of the top layer is dialyzed through a cellophane membrane.

21. A method as claimed in claim 16 wherein, in step (e), 1 part of the crude dry material is suspended in 20-200 parts of the acetic acid ester at a temperature of -10.degree. to 10.degree. C.

22. A method as claimed in claim 21 wherein the acetic acid ester is selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate and butyl acetate.

23. A method as claimed in claim 16 wherein, in step (e), 1 part of the material insoluble in the acetic acid ester is suspended in 20-200 parts of the mixed organic solvent.

24. A method as claimed in claim 23 wherein the organic solvent mixture is selected from the group consisting of chloroform-methanol with a volume ratio of 2:1, chloroform-ethanol with a volume ratio of 2:1, chloroform-isopropanol with a volume ratio of 2:1, and ether-ethanol with a volume ratio of 1:3.

25. A method as claimed in claim 16 wherein, in step (f), the phosphatidylcholine optionally added to the solid residue is dipalmitoylphosphatidylcholine.

26. A method as claimed in claim 16 wherein, in step (f), the neutral fat optionally added to the solid residue is a member selected from the group consisting of tripalmitoylglycerol, tristearoylglycerol, trioleoylglycerol and mixtures thereof.

27. A method as claimed in claim 16 wherein, in step (f), the free fatty acid optionally added to the solid residue is a member selected from the group consisting of palmitic acid, stearic acid, oleic acid and mixtures thereof.

28. A method as claimed in claim 16 wherein the centrifugation of step (b) is carried out at 8,000-20,000 r.p.m. and the centrifugation of step (c) is carried out at 5,000-13,000 r.p.m.

29. A method as claimed in claim 16 wherein the mammal used in step (a) is selected from the group consisting of cattle, horses, sheep and pigs.

30. A method as claimed in claim 29 wherein 0- to 4-months-old calves are used.

31. A method as claimed in claim 29 wherein 3-months-old young pigs are used.
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