Oral suspension of liposome-encapsulated insulin lyophilized preparation and preparation process thereof

Abstract

The invention relates to an oral suspension of a liposome-encapsulated insulin lyophilized preparation, named as O-SCULI. The O-SCULI contains lecithin, cholesterol, polyglycol aliphatic acid ester, vitamin E, insulin, water, sodium chloride and phosphate buffer. The invention also provides a two-step process of the O-SCULI, comprising (1) a dewatering / moistening control process: preparing a liposome-encapsulated insulin lyophilized preparation and SCLI so that the encapsulation rate of the insulin is increased to 80 percent by liposome amalgamation; and (2) a respective constant volume / stepped liquefaction process: preparing the SCLI into an O-SCULI oral suspension, preventing the SCLI liposome from leaking and keeping the constant encapsulation rate of the insulin. After a patient acutely takes the O-SCULI, the liposome insulin effectively enters the intestine-hepatic portal vein, the liver and the blood circulation to reduce blood sugar, blood fatty acids and blood ketone with highutilization degree. After a patient continuously orallly takes the oral suspension, the saccharification of hematoglobin, triglyceride and, aminotransferase and the oxidative stress are reduced, the structural damage of liver cells is recovered, and the comprehensive curative effects of diabetes treatment by using various liver functions are improved. The invention also opens up a new path for non-injection administration of active polypeptide protein, such as cytochrome C, albumin, interferon, and the like.

Description

(1) Field of invention [0001] The patent invention belongs to the field of medicine, and in particular relates to a new oral insulin liposome dosage form, in particular to the oral suspension of liposome-encapsulated insulin freeze-dried preparation, its preparation process and pharmaceutical application. At the same time, the patented process design and preparation technology of the present invention provides preparation technology methods for the oral administration or other administration methods of other protein and polypeptide bioengineering drugs, so as to develop new dosage forms and open up new routes for drug administration. (2) Technical background: [0002] Diabetes is the third largest disease in the world with the highest disability rate and death rate after cardiovascular disease and cancer. The International Diabetes Federation Conference estimates that there are about 180 million diabetics in the world, with an annual growth rate of 2-3%. All countries are vi...

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Problems solved by technology

[0006] The 3rd, but, up to now, " oral liposomal insulin " and other " oral insulin " new formulations have not yet come out successfully [Adel Pinhasi Mila Gomeberg, Patent application title: SolidComposition for Intra-Oral Delivery Insulin, Patent No: 20090274756 , USPC, Class: 424484; Martin Werle, et al., Sci Pharm. (2008) 76: 751-760, doi: 10.3797 / scipharm.0806-04; T. et al., International Journal of Pharmaceuticals 277 (2004) 91-97; El-Sayed Khafagy, et al., Advanced Drug Delivery Reviews 59 (2007) 1521-1546; Takahiro Goto, et al., Pharmaceutical Research, Volume 23, 2, p384 , February(2006), DOI: 10.1007 / s11095-005-9175-7; Fude Cui et al., Journal of Controlled Release 114(2006) 242-250; Zang Hongmei et al., Research Progress of Insulin Liposome Preparations in the Treatment of Diabetes , Anhui Medical and Pharmaceutical Journal (2004) Apr, 8(2), p81-82; Zelihagql Degim; et al., LifeSciences 75(2004) 2819-2827; Gerardo P.Carino, et al., Oral Insulin delivery, Advanced Drug Delivery Reviews 35(1999) 249-257]

[0007] For oral liposomal insulin, the main problems are: (1) technical problems such as multiple preparation processes and various large, medium and small single-chamber or multi-lamellar liposomes encapsulating water-soluble protein polypeptides have not been stabilized; Solve, the encapsulation rate of insulin is all lower (20-40%); (2) liposome small unilamellar liposome is easy to fuse mutually in suspension, and large lobe liposome structure is very unstable, thereby industrialized product dosage form all (3) Although the lyophilized preparation of liposomes can keep the structure of the preparation relatively stable, it is most likely to cause the rupture of the lyophilized liposome membrane structure and cause a large amount of insulin in the process of hydration and reconstruction. Leakage, the leakage rate often reaches more than 30-50%; (4) liposome freeze-dried preparations are made into various oral freeze-dried liposome dosage forms of non-suspension, then its oral insulin measurement is difficult to determine, and it has not solved the problem of oral insulin. Stability in the intestines, and how to enter the intestinal cells and liver and re-enter the blood circulation; (5) the most important issue, the relative bioavailability of the currently known oral liposomal insulin dosage forms and related oral insulin dosage forms is very high. Low (within 1-5%), high production cost, difficult to meet the 10% development requirement

[0010] The invention of this patent overcomes the ubiquitous problems of low encapsulation rate and bioavailability of liposomes, poor production stability of dosage forms, etc., and provides a brand-new oral suspension of lyophilized preparations of insulin encapsulated in phospholipid liposomes. That is O-SCULI; its liposome insulin has high encapsulation rate, high bioavailability, good structural stability, simple and novel process, which not only solves the problem of storage and transportation of "liposome-encapsulated insulin freeze-dried preparation", but also solves the problem of O-SCULI The large unilamellar liposome membrane of SCULI dosage form is easy to rupture and the problem of insulin leakage and its oral accurate quantification. Therefore, O-SCULI oral suspension has the advantages of reducing peripheral blood sugar (bioavailability up to 22.2%) and other comprehensive treatment of diabetes. The innovative function of the index; the new dosage form of O-SCULI is a new development of oral liposomal insulin dosage form, and its preparation procedure and process method also open up a new way for the preparation of other polypeptide and protein bioengineering drugs for non-injection administration

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