ORAL COMPOSITIONS AT LOW DOSAGE OF CYTOTOXIC PROTEINS

Abstract: Pharmaceutical compositions for the oral and sublingual administration containing proteins extractable from mammalian liver. Such proteins include the proteins marked with UK101 and UK114 and described in WO 92/10197 and WO 96/02567 as well as ubiquitin, contained in the UK101 extract.

Description: ORAL COMPOSITIONS AT LOW DOSAGE OF CYTOTOXIC PROTEINS The present invention relates to pharmaceutical compositions for oral and sublingual administration containing proteins extractable from mammalian liver. Such proteins include the proteins referred to as UKl O l and UK1 14 and described in WO 92/10197 and WO 96/02567 as well as ubiquitin, contained in the UKl O l extract. It has been observed that the subcutaneous administration of UKlOl and UK1 14 induces a clear cytotoxicity in serum of both healthy subjects and in tumor carriers subjects. The main responsible for this effect is the 14Kd protein (UK1 14) contained in the protein extract UK101. The UK1 14 amino acidic sequence has been described in FEBS Let. 393, 147-150, 1996. At present, clinical experimentations to verify the UKl O l and UK114 therapeutic efficacy are in progress. To this order, patients suffering from colon and breast carcinoma are treated with UKlOl and UK1 14 subcutaneous injections, at dosages ranging from 1 to 10 mg/week. The protein nature of the active principle obviously forces the parenteral route In fact, at present it is not known the possibility to administer proteins orally, due to their high metabolic instability. To avert this inconvenience, it has been suggested several answers such as the use of suitable carriers or the encapsulation in liposomes, but until now the results have been unfavourable. Now it has been found that it is possible to administer UK1 14 and UKl Ol or ubiquitin orally at low dosages, preferably for sublingual 2 administration, thus inducting a seric cytotoxicity comparable to or higher than that obtainable for subcutaneous administration. The oral/sublingual route also shows clear advantages in practicality and safety terms. The invention therefore provides pharmaceutical compositions for UKl O l and UK1 14 oral and/or sublingual administration. Suitable administration forms include, for example, aqueous suspensions to administer in drops, granules or sublingual tablets by a quickly disintegration, effervescent or chewable tablets or its equivalent forms. The compositions of the invention can be prepared using conventional techniques and excipients, widely known in the pharmaceutical field. The UKl O l and UK1 14 unitary dosages can range from 10 x 10 "4 to 10 x 10- 15 g. In the case of solutions to administrate in drops, the concentration of the active principle can range from 10 "5 to 10 "10 M. The administration of 10-15 drops a day proved to be sufficient to induce cytotoxicity in the patient serum, which can be evidenced on carcinoma cells Jurkat and Kato III according to standard protocols. EXAMPLE 17 patients suffering from tumors in advanced phase (8 sarcoma, 4 breast carcinoma, 2 pancreas carcinoma and 3 colon carcinoma) have been treated with 5-20 drops/day of an 1 % hydroalcoholic solution of ethanol in a UKl Ol concentration of 10 " ° M. The treatment continued for 30 consecutive days, involved in 70% of the cases an improvement in the subjective conditions of the patients, particularly a decrease in the painful symptomatology, a decrease in the tumor mass in 20% of the cases, joined to a cytotoxicity visible in the 3 patients serum on cell lines Jurkat and Kato III.

Claims: 4 CLAIMS 1 Oral pharmaceutical compositions containing as active principle a protein selected from ubiquitin, UKl 14 and UKl Ol . 2 Composition according to claim 1 , suitable for the sublingual administration. 3 Compositions according to claim 2, in the form of drops , granules or sublingual tablets. 4 Compositions according to any one of the previous claims, containing from 10 "4 to 10 "15 g of UKl Ol , UKl 14 and ubiquitin for unitary.

Inventors: BARTORELLI ALBERTO, SANTI CESARE, BARTORELLI, ALBERTO, SANTI, CESARE
Applicants: BARTORELLI ALBERTO, SANTI CESARE, ZETESIS SPA, BARTORELLI, ALBERTO, SANTI, CESARE, ZETESIS S.P.A.
Application year: 1999
Main classification: A61K38
IPC codes: A61K9, A61K38, A61P35