Pharmaceutical composition containing a mixture of proenzymes and enzymes

Abstract

Pharmaceutical composition containing a mixture of proenzymes and enzymes, containing proenzymes trypsinogen and chymotrypsinogen and enzymes ct-amylase and lipase as active substances, and one or more pharmaceutically acceptable excipients, for simultaneous, separate and subsequent administration of the composition in parenteral or transmucosal way, the composition has anti-proliferative and anti-metastatic effects to cancer tumours and is intended for therapeutic, prophylactic and anti-metastatic use in mammals.

1 . Anti-proliferative and anti-metastatic pharmaceutical composition containing a mixture of proenzymes and enzymes, wherein the composition consists of following active substances: proenzyanes trypsinogen and chyrmotrypsinogen, and enzymes α-amylase and lipase, wherein the ratio of enzymatic active substances, namely activities of trypsinogen (T), chymotrypsinogen A (CH), α-amylase B.s (A) and lipase T.a. (L) for T:CHI:A:L ratio expressed in m.u. is in the range from 150:150:40:1 to 400:1200:200:1, and further comprises one or more pharmaceutically acceptable excipients, for simultaneous, separate and subsequent administration of the composition in parenteral or transmucosal way, while the composition is for therapeutic, prophylactic and anti-metastatic use in mammals. 
     
     
         2 . Pharmaceutical composition according to  claim 1 , wherein the trypsinogen is of type I, chymotrypsinogen is of type A, α-amylase is produced by  Bacillus  sp. and lipase is from  Triticum aestivum.    
     
     
         3 . Pharmaceutical composition according to  claim 1 , wherein the minimum enzymatic activity of active substances is as follows: trypsinogen 40 m.u./mg, chymotrypsinogen 60 m.u./mg, α-amylase 20 m.u./mg and lipase I m.u./mg. 
     
     
         4 . Pharmaceutical composition according to  claim 1 , wherein at least one of the active substances is replaced with biologically similar active substance obtained by extraction from higher plants, animals or by cultivation procedures using mould cells, yeast cells, or bacteria, the primary structure of the biologically similar substance with the active substance which it has replaced in the composition being at least 70% identical and the position of active places essential for the effect is at least 95% identical. 
     
     
         5 . Pharmaceutical composition according to  claim 1 , wherein the composition is for systemic sublingual, rectal, inhalation or parenteral administration. 
     
     
         6 . Pharmaceutical composition according to  claim 1 , wherein it contains as the pharmaceutically acceptable excipients: one or more hydrophilic polyhydric alcohols;
 hydrophilic low molecular alcohols;   saccharides;   polysorbates; poloxamers;   one or more lipophilic excipients;   esters of higher fatty acids with glycerol or propylene glycol;   esters of lower monovalent alcohols;   esters of higher fatty acids with medium and higher fatty alcohols;   higher fatty alcohols and analogously higher fatty acids   vegetable oils;   phospholipids;   sterols;   biocompatible and biodegradable polymers   or any combination thereof.   
     
     
         7 . Pharmaceutical composition according to  claim 1  designed for sublingual administration, wherein it is in the form of nanofibres, while it contains
 at least one of polyvinyl polymers like polyvinylpyrrolidone with molecular weight approx. 30,000 to 50,000 and polyvinyl alcohols with molecular weight from 20,000 to 200,000, of cellulose derivatives like methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and/or polysaccharides of starch type like hydroxyethyl starch, carboxymethyl starch sodium salt and/or dextrins with molecular weight from 4,000 to 80,000, 
 and/or of biotechnological polysaccharides of dextran type with molecular weight from 10,000 to 80,000, 
 and/or glucuronate type substances like xanthan mucilage, and/or further polyuronides or their salts, particularly sodium, potassium, like hyaluronans, alginans, pectinans, arabinans and/or polymers based on acrylic, methacrylic acids and/or their copolymers like carboxyvinyl polymers (carbomers) cross-linked with s polyalkenyl ethers of sugars or poly alcohols (like diallyl sucrose a diallyl penta erythritol, biodegradable polyesters of α-hydroxy acids like (PDLLA), (PGA), (PLGA), polycaprolactones with molecule weight from 10,000 to 100,000, further polymeric excipients of copolymer type like polyvinyl caprolactam-polyvinyl acetate polyethylene glycol. 
 
     
     
         8 . Pharmaceutical composition or its part according to  claim 1  designed for inhalation administration, wherein it contains at least one or more saccharides, including trehalose, mannitol, glucose and/or various forms of lactose. 
     
     
         9 . Pharmaceutical composition according to  claim 1 , wherein it is in the form of nanofibre stabilized preparation for direct administration of active substances or as stabilized storage of active substances in an intermediate product or in the final preparation. 
     
     
         10 . The pharmaceutical composition according to  claim 6 , wherein the hydrophilic polyhydric alcohol includes polyethylene glycol with a molecular weight of between 100 to 8,000. 
     
     
         11 . The pharmaceutical composition according to  claim 6 , wherein the hydrophilic low molecular alcohol is selected from glycerol, propylene glycol, n-propanol, or any combination thereof. 
     
     
         12 . The pharmaceutical composition according to  claim 6 , wherein the saccharide is selected from trehalose, mannitol, lactose, sorbitol, myoinositol, or any combination thereof. 
     
     
         13 . The pharmaceutical composition according to  claim 6 , wherein the polysorbate is selected from polysorbate 20, polysorbate 60, polysorbate 80, or any combination thereof. 
     
     
         14 . The pharmaceutical composition according to  claim 6 , wherein the poloxamer is selected from poloxamer 182, poloxamer 417, poloxamer 908, or any combination thereof. 
     
     
         15 . The pharmaceutical composition according to  claim 6 , wherein the lipophilic excipient includes hydrogenated triglycerides selected from hydrogenated glycerol trioleate, hydrogenated glycerol cocoate, or any combination thereof. 
     
     
         16 . The pharmaceutical composition according to  claim 6 , wherein the esters of higher fatty acids with glycerol or propylene glycol are selected from glycerol tripalmitate, glycerol trioleate, glycerol tristearate, glycerol distearate, glycerol dioleate, glycerol monolaurate, propylene glycol myristate, glycerol dipalmitostearate, or any combination thereof. 
     
     
         17 . The pharmaceutical composition according to  claim 6 , wherein the esters of lower monovalent alcohol is selected from diisopropyl adipate, isopropyl laurate, isopropyl linoleate, isopropyl palmitate, or any combinations thereof. 
     
     
         18 . The pharmaceutical composition according to  claim 6 , wherein the esters of higher fatty acids with medium and higher fatty alcohols include myristyl stearate, capryl stearate, cetyl palmitate, caprin behenate, lauroyl oleate, or any combination thereof. 
     
     
         19 . The pharmaceutical composition according to  claim 6 , wherein the higher fatty alcohol is selected from lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, behenyl alcohol and the analogous higher fatty acids is selected from lauric, myristic, palmitic, stearic, lignoceric, arachidonic, behenic acids and their ethoxylated derivatives, selected from polyethylene glycol 10 oleyl alcohol, polyethylene glycol 25 stearyl alcohol, polyethylene glycol 40 stearyl alcohol, stearoyl polyethylene glycol 32 glycerol, polyethylene glycol 15 hydroxy stearate, or any combination thereof. 
     
     
         20 . The pharmaceutical composition according to  claim 6 , wherein the vegetable oil is selected from cottonseed oil, sunflower oil, groundnut oil, soya oil, castor oil, and their ethoxylated derivatives selected from polyoxyl 35 ricinoleate, or any combination thereof. 
     
     
         21 . The pharmaceutical composition according to  claim 6 , wherein the phospholipids are selected from egg lecithin, soya lecithin, dioleoylphosphatidylcholine, dipalmitoylphosposphatidylserine, or any combination thereof. 
     
     
         22 . The pharmaceutical composition according to  claim 6 , wherein the sterols are selected from cholesterol and its derivatives selected from cholesteryl linoleate, cholesteryl acetate, or any combination thereof. 
     
     
         23 . The pharmaceutical composition according to  claim 6 , wherein the biocompatible and biodegradable polymers are selected from polyesters selected from poly-DL-lactic acid (PDLLA), polyglycolic acid (PGA), poly-DL-lactic glycolic acid (PLGA), or any combination thereof.