MXPA06010854A

MXPA06010854A - Oral pharmaceutical compositions of lipase-containing products, in particular of pancreatin, containing surfactants

Info

Publication number: MXPA06010854A
Application number: MXPA/A/2006/010854A
Authority: MX
Inventors: Thumbeck Bernd; Boedecker Bernd; Shlieout George; Schaefer Siegfried; Gregory Petercolin
Original assignee: Solvay Pharmaceuticals Gmbh*
Priority date: 2004-03-22
Filing date: 2006-09-22
Publication date: 2007-04-20

Abstract

The invention relates to novel pharmaceutical compositions of lipase-containing products for oral administration, in particular pancreatin and pancreatin-containing prod-ucts, or of enzyme products which contain at least one lipase of non-animal, especially microbial origin. These pharmaceutical compositions improve the lipolytic activity and in particular result in stabilisation of the lipase in the acidic pH range. These novel oral pharmaceutical compositions are characterized in that they contain a system which comprises at least one surfactant and one co-surfactant and optionally a lipophilic phase, and that they are self-emulsifiable on contact with a hydrophilic and a lipophilic phase. These novel pharmaceutical compositions are well suited for the treatment and/or prophylaxis of maldigestion, in particular maldigestion based on chronic exocrine pancreatic insufficiency, in mammals and humans.

Description

pancreatin as a mixture of natural enzymes by extraction of porcine pancreas, and is then converted in a known manner into the desired pharmaceutical form. Pancreatic enzymes are usually administered orally in the form of solid preparations. Pancreatin is thus commercially available, for example, under the tradename Kreon® in the form of granules, globules or capsules with enteric coated microbeads. In order that, when taken orally, the mixtures of enzymes administered are not irreversibly denatured in the stomach by gastric acid and proteolytic enzymes, such as pepsin present there, it is necessary to provide the enzyme mixtures with an enteric coating. Such a coating allows mixtures of intact enzymes to pass through the stomach to its point of action, the duodenum, where, due to the neutral to slightly alkaline conditions prevailing there, the protective layer is broken down and the enzymes are released. Like the endogenous pancreatic enzymes of healthy humans, enzymes supplied orally can exert their enzymatic action there, in particular amylolitic, lipolytic and proteolytic activity. Such solid pancreatin formulations which can be coated with an enteric film are described, for example, in EP 0 021 129 Al. EP 0 583 726 A1 discloses pancreatin microgrid cores that can be coated with an enteric film having a pancreatin content of 65-85, in particular 75-80% by weight, having a bulk density of 0.6 g / ml to 0.85 g / ml, consisting substantially of pancreatin, polyethylene glycol 4000 and low paraffin viscosity, containing per 100 parts by weight of pancreatin: 15-50, in particular 20-30, parts by weight of polyethylene glycol 4000; and 1.5-5, in particular 2-3, parts by weight of low viscosity paraffin, and having a spherical to ellipsoidal shape, the sphere diameter of the minor axis being in the range of 0.7-1, 4 mm, in particular 0.8-1.2 mm, and having a particle size distribution in which at least 80% of the pancreatin microbead nuclei have a minor axis to major axis ratio in the range from 1.1 to 1.2. In addition, EP 0 826 375 A1 discloses the use of lecithin as a stabilizing agent added to water-soluble pharmaceutical preparations of digestive enzyme mixtures containing protease / lipase mixtures, in particular pancreatin, and which are suitable for the preparation of solutions aqueous for continuous introduction into the gastrointestinal tract by means of probes. Lecithin is added to stabilize digestive enzyme mixtures against a decrease in lipolytic activity under the influence of moisture.

In the case of drug formulations not coated with enteric films, it is known that at the point of action of the enzymes, in the duodenum, often only a very small proportion of the lipase contained in the pharmaceutical preparation and taken with it is active . Thus, in DE 36 42 853 Al, such deactivation of the enzyme is attributed to insufficient neutralization of the gastric acid in the duodenum. While in a healthy human being the post-prandial intraduodenal pH value is approximately 6, patients with pancreatic insufficiency have only a pH value of 4. With this pH value, the lipase contained in the pharmaceutical preparation has only one fifth of the activity that would otherwise have a pH value of 6. It is therefore an object of the invention to enable pharmaceutical compositions containing enzymes or mixtures of enzymes with at least lipolytic activity and have improved lipolytic activity, and particularly show a stabilization of lipase activity in the acid pH range. According to the invention, pharmaceutical compositions intended for oral administration are provided which comprise enzymes or mixtures of enzymes with at least lipolytic activity and a system comprising at least one surfactant and at least one co-surfactant, and are characterized in that they can emulsify themselves in contact with a hydrophilic phase and a lipophilic phase. Preferably, the hydrophilic phase used to form the final emulsion after ingestion of the pharmaceutical composition is supplied by the physiological fluid of the digestive medium. In a further embodiment of the present invention, the lipophilic phase used to form the final emulsion in the digestive tract after ingestion of the pharmaceutical composition is at least partially supplied by the lipids present in the ingested food. In particular, to achieve this object the invention provides pharmaceutical compositions containing systems comprising at least one surfactant, a co-surfactant and a lipophilic phase. Surprisingly, a lipase-containing pharmaceutical composition, containing such a system, has improved lipolytic activity and a lipolytic activity that is stabilized in the acid pH range. The use of such a system in pharmaceutical compositions of enzymes or mixtures of enzymes with at least lipolytic activity also has the advantage that pharmaceutical compositions containing such enzymes or mixtures of enzymes can also be used without enteric coatings, as described for example in US Pat. EP 0 583 726 A1. In the pharmaceutical compositions according to the invention, the reduction of the lipolytic activity during the passage through the stomach is very much less than with pharmaceutical compositions prepared without the aforesaid system. By means of the system consisting of surfactant, co-surfactant and optionally a lipophilic phase, the lipolytic activity of the pharmaceutical compositions according to the invention is stabilized in the acidic pH range of the stomach compared to conventional formulations. The fact that the use of such enteric-coated polymer films and softeners which are otherwise necessary to film-coat various forms of medicaments (granules, pellets, mini-pellets, pills, etc.) in the preparation of the medicaments can be dispensed with. Lipase-containing compositions according to the invention produce additional advantages. Thus, the safety profile of the pharmaceutical composition is improved by omitting the enteric polymer films and softeners, because their unnecessary absorption is avoided. In addition, the proportions of the amount of film coating material in the medicament forms provided with an enteric film are about 20-30% of the total weight of the medicament form. Dispense with these additives makes the amount of medication form smaller, which produces better acceptance by patients. The possibility of dispensing with enteric coating enzymes or mixtures of enzymes also has the advantage that complete mixing of the pharmaceutical preparation with the chyme can take place as soon as in the stomach. Consequently, it forms an emulsion or microemulsion with an increased surface area, in which the lipase contained in the pharmaceutical composition is distributed in such a way that optimal attack possibilities are given to decompose the triglycerides found in the chyme. The formation of emulsion and microemulsion is further enhanced by the lipolytic decomposition of triglycerides to form di and mono-glycerides and free fatty acids. Thus, the improved possibilities of attack for lipase produce intensified decomposition of triglycerides. The higher concentration of free fatty acids resulting from the food that is provided thus produces better absorption of fat in the duodenum. In vitro, an increase in lipolytic activity of about 10% was determined for the pharmaceutical composition according to the invention compared to conventional lipase-containing pharmaceutical preparations. The pharmaceutical compositions according to the invention thus exhibit stabilization of the lipolytic activity in the stomach, as well as in the duodenum; additionally, due to the intensified formation of a (micro) emulsion, the lipolytic activity increases. The (micro) emulsion already produced independently in the stomach produces better activation of the lipase contained in the pharmaceutical composition. Self-emulsifying pharmaceutical compositions in general are already known from the prior art. Thus, for example, EP 0 670 715 describes a composition administered per-orally which is suitable for forming a microemulsion in situ with the biological fluid of the organism and is thus said to improve the biological availability of an active substance. Such pharmaceutical compositions are known by the term SMEDDS® (Self Microemulsifying Drug Delivery System) and consist in principle of a mixture of one or more active substances with a defined lipophilic phase, a defined surfactant and a defined co-surfactant, whose properties are specified such that the final product is capable of forming a microemulsion in contact with a given volume of physiological liquid. In addition, EP 1 058 540 Bl discloses what is termed a SMEDDS® formulation in a particular dosage form, referred to as a "globule". These globules are composed of an active substance, in particular indomethacin, a binding agent which is suitable for improving the biological availability of the active substance, for example Gelucire® 44/14, and a diluent, for example lactose, in micronized form. The object of the systems known up to now of the prior art that automatically form a microemulsion was, however, always to increase the bioavailability of mostly lipophilic active substances because the formulation of SMEDDS®, due to the formation of micelles, allows a better absorption of the substance active through the duodenal wall 10 in the blood circulation. In contrast, the purpose of the present invention is to provide a pharmaceutical composition that does not contain any lipophilic active substance to be absorbed into the bloodstream, but provides as an active agent enzymes or mixtures of enzymes with at least lipolytic activity that develop their action in the tract gastrointestinal. The self-emulsifiable pharmaceutical compositions according to the invention produce a surprising increase in the lipolytic activity contained therein and an improved stability of the lipase in the acid pH range. Such pharmaceutical compositions of lipase-containing enzyme products, which are self-emulsifiable in contact with a hydrophilic phase and which comprise a system consisting of a surfactant, a co-surfactant and optionally a lipophilic phase, have not hitherto been described in the prior art. . Subramanian and Wasan describe an assay in which they demonstrate that the substance Gelucire® 44/14 in vitro has an inhibitory effect on the activity of pancreatic lipase [Subramanian R. & Wasan K.M. (2003) "Effect of lipid excipients on in vitro pancreatic lipase activity" Drug. Dev. Ind. Pharm. 29 (8): 885-90]. In this experiment, a test buffer containing a particular lipid is mixed with separate solutions of Gelicire® 44/14, pancreatic lipase and co-lipase, and the influence of Gelucire® 44/14 on the lipase activity is measured. Since it decreases the activity of. lipasa, the 11 authors conclude that Gelucire® and similar lipid additions to pharmaceutical formulations may have an adverse effect on the in vitro activity of pancreatic lipase. In contrast, the present invention shows that self-emulsifiable pharmaceutical compositions consisting of mixtures of lipase-containing enzymes and a system such as for example Gelucire® 44/14 produce an increase in the lipolytic activity contained in the pharmaceutical formulation. Some expressions as used in the context of the present invention are explained in more detail below. The value of the "hydrophilic-lipophilic balance" (= HLB) is an empirical parameter commonly used to characterize the relative hydrophilicity and lipophilicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance (the "HLB" value). Surfactants or co-surfactants with lower HLB values are more lipophilic, and have higher solubility in oils, while surfactants or co-surfactants with higher HLB values are more hydrophilic, and have higher solubility in aqueous solutions. It must be taken into account that for anionic, cationic or positive and negative charged compounds the HLB scale is not generally applicable. Generally, the HLB value of a surfactant or co-surfactants is a practical guide used to allow the formulation of industrial, pharmaceutical and cosmetic emulsions. However, for many important surfactants, 12 including various polyethoxylated surfactants, it has been reported that the HLB values can differ as much as about 8 units of HLB, depending on the empirical method chosen to determine the value of the HLB [Schott, J. Pharm. Sciences, 79 (1), 87-88 (1990)]. Likewise, for certain block copolymers containing poly (propylene oxide) (poloxamers), the HLB values may not accurately reflect the true physicochemical nature of the compounds. Finally, commercial surfactants and / or co-surfactants are not generally pure compounds, but are often complex mixtures of compounds, and the value of the HLB indicated for a particular compound may be more precisely characteristic of the commercial product of which the compound is a main component. Different commercial products having the same surfactant component and / or main co-surfactant may have, and typically have, different HLB values. In addition, a certain amount of variability from batch to batch is expected even for a simple commercial surfactant and / or co-surfactant product. A surfactant in the context of the present invention is a chemical compound comprising two groups, the first being hydrophilic and / or polar or ionic and having a high affinity for water, and the second containing an aliphatic chain of greater or lesser length and which is hydrophobic (lipophilic); that is, a surfactant compound must be amphiphilic It is intended that these chemical compounds cause the formation and stabilization of oil-in-water emulsions. Surfactants with lower HLB values are more lipophilic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Suitable surfactants in the context of the present invention have a HLB value above 6 and below 18, preferably above 8 and below 16. The surfactants can be any suitable surfactant for use in pharmaceutical compositions. Suitable surfactants can be anionic, cationic with positive and negative charge, or non-ionic. Such surfactants can be grouped into some general chemical classes as explained below. It should be noted that the invention is not limited to the surfactants indicated herein, which show representative, but not exclusive, lists of available surfactants. PEG fatty acid monoester surfactants: Although polyethylene glycol (PEG) itself does not function as a surfactant, a variety of fatty acid esters-PEG has useful surfactant properties. These are particularly preferred PEG-fatty acid monoesters with C6-C22 aliphatic carboxylic acids, whereby the polyethylene glycol comprises f6 to 60 ethylene oxide units per molecule. They are 14 examples of commercially available polyethoxylated fatty acid monoester surfactants: PEG-4 laurate, PEG-4 oleate, PEG-4 stearate, PEG-5 stearate, PEG-5 oleate, PEG-6 oleate, PEG oleate -7, laurate of PEG-6, laurate of PEG-7, stearate of PEG-6, laurate of PEG-8, oleate of PEG-8, stearate of PEG-8, oleate of PEG-9, stearate of PEG-9 , PEG-10 laurate, PEG-10 oleate, PEG-10 stearate, PEG-12 laurate, PEG-12 oleate, PEG-12 ricinoleate, PEG-12 stearate, PEG-15 stearate, Oleate of PEG-15, PEG-20 laurate, PEG-20 oleate, PEG-20 stearate, PEG-25 stearate, PEG-32 laurate, PEG-32 oleate, PEG-32 stearate, PEG stearate -30, PEG 4-100 monolaurate, PEG monooleate 4-100 and PEG monostearate 4-100. Fatty Acid Diester-PEG Surfactants: Polyethylene glycol (PEG) fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention. Particularly preferred are fatty acid diesters-PEG with C6-C22 aliphatic carboxylic acids, whereby the polyethylene glycol comprises from 6 to 60 ethylene oxide units per molecule. Representative commercially available fatty acid-PEG diesters are: PEG-4 dilaurate, PEG-4 dioleate, PEG-6 dilaurate, PEG-6 dioleate, PEG-6 distearate, PEG-8 dilaurate, PEG dioleate -8, PEG-8 distearate, PEG-10 dipalmitate, PEG-12 dilaurate, PEG-15 distearate 12, PEG-12 dioleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32 dioleate and PEG-32 distearate. PEG-fatty acid mono- and diester mixtures: In general, mixtures of surfactants, including mixtures of two or more commercial surfactant products, are also useful in the present invention. Particularly preferred are mixtures of PEG-fatty acid mono- and diesters with C6-C22 aliphatic carboxylic acids, whereby the polyethylene glycol comprises from 6 to 60 ethylene oxide units per molecule. Several PEG-fatty acid esters are commercially available as mixtures of mono and diesters. Representative commercially available surfactant mixtures are: mono, dilaurafo of PEG 4-150, mono, dioleate of PEG 4-150 and mono, distearate of PEG 4-150. Esters of polyethylene glycol (PEG) glycerol fatty acids: In addition, PEG glycerol fatty acid esters are suitable surfactants in the context of the present invention, such as PEG-20 glyceryl laurate, PEG-15 glyceryl laurate, PEG-15-laurate 40 glyceryl, PEG-20 glyceryl stearate, PEG-2Q glyceryl oleate and PEG-30 glyceryl oleate. Particularly preferred are fatty acid esters of PEG glycerol with C6-C22 aliphatic carboxylic acids, whereby the polyethylene glycol comprises from 6 to 60 ethylene oxide units. 16 Polyethylene glycol (PEG) alkyl ethers (mono and / or polyethylene glycol monoethers): Suitable surfactants for use in the present invention are polyethylene glycol ethers and alkyl alcohols. Particularly preferred are mono- and / or fatty acid-PEG diethers with C 2 -CI 8 aliphatic alcohols, whereby the polyethylene glycol comprises from 6 to 60 ethylene oxide units per molecule. Some examples of these commercially available surfactants are: PEG-2 oleyl ether (olet-2), PEG-3 oleyl ether (olet-3), PEG-5 oleyl ether (olet-5), PEG-10 oleyl ether (oleyl-) 10), PEG-20 oleyl ether (olet-20), PEG-4 lauryl ether (laureth-4), PEG-9 lauryl ether, PEG-23 lauryl ether (laureth-23), PEG-2 cetyl ether, PEG- 10 cetyl ether, PEG-20 cetyl ether, PEG-2 stearyl ether, PEG-10 stearyl ether and PEG-20 stearyl ether. Polyethylene glycol sterol ethers: Surfactants suitable for use in the present invention are PEG derivatives of sterols. Examples of surfactants of this class are: PEG-24 cholesterol ether, PEG-30 cholestanol, PEG-25 phytosterol, PEG-5 soy sterol, PEG-10 soy sterol, PEG-20 soy sterol and PEG-30 soy sterol. Polyethylene glycol sorbitan fatty acid esters: A variety of fatty acid esters of PEG-sorbitan are available and are suitable for use as surfactants in the present invention. Examples of these surfactants are: PEG-10 sorbitan laurate, PEG-17 monolaurate sorbitan, PEG-4 sorbitan monolaurate, PEG-80 sorbitan monolaurate, PEG-6 sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, PEG-4 sorbitan monostearate, PEG-8 monostearate sorbitan, PEG-6 sorbitan monostearate, PEG-20 sorbitan tristearate, PEG-60 sorbitan tetrastearate, PEG-5 sorbitan monooleate, PEG-6 sorbitan monooleate, PEG-20 sorbitan monooleate, PEG-40 sorbitan oleate , PEG-20 sorbitan trioleate, PEG-6 sorbitan tetraoleate, PEG-30 sorbitan tetraoleate, PEG-40 sorbitan tetraoleate, PEG-20 sorbitan monoisostearate and PEG sorbitol hexaoleate. Sugar esters: Sugar esters, in particular monoesters, are suitable surfactants for use in the present invention. Examples of such surfactants are: distearate / sucrose monostearate, sucrose dipalmitate, sucrose monostearate, sucrose monopalmitate, sucrose monolaurate and sucrose monolaurate. Polyoxyethylene-polyoxypropylene block copolymers: POE-POP block copolymers are a unique class of polymeric surfactants. The unique structure of the surfactants, with hydrophilic POE moieties and lipophilic POPs, in well defined relationships and positions, provides a wide variety of surfactants suitable for use in the present invention. The generic term for these polymers is "poloxamer" (CAS 9003-11-6). These polymers have - the 18 formula: HO (C2H0) a (C3H60) b (C2H40) aH, where "a" and "b" denote the number of polyoxyethylene and polyoxypropylene units, respectively. In addition, amphoteric compounds such as fatty acid amidoalkyl betaines with C2-C22 fatty acids are suitable surfactants. The surfactant can also be, or include as component, an ionic surfactant, including cationic, anionic and positively and negatively charged surfactants. Preferred anionic surfactants include salts of fatty acids and bile salts. Preferred cationic surfactants include carnitines. Specifically, preferred ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate; lauroyl carnitine; palmitoyl carnitine; Myristoyl carnitine, alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkyl sulfates; docusate sodium; carnitines; and mixtures thereof. More specifically, preferred ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, stearoyl 2 lactylate, stearoyl lactylate, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycokenedeoxycholate, taurokenedeoxycholate, ursodeoxycholate, tauroursodeoxycholate, glycoseodeoxycholate, colilsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecil sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines and salts and mixtures thereof. A co-surfactant, which is also sometimes referred to as a "co-emulsifier", in the context of the present invention is likewise a chemical compound having hydrophobic (lipophilic) and hydrophilic portions, but predominantly hydrophobic (lipophilic) nature. ). It is intended to make the aqueous and oily phases in a mutually soluble microemulsion. Suitable co-surfactants in the context of the present invention have a HLB value of less than 10, preferably below 8 and even more preferably less than 6. The co-surfactants can be any partial esters and / or partial alcohol ethers polyhydric (polyvalent), such as glycerol, 20 propylene glycol (1,2-propanediol; 1,2-dihydroxypropane), ethyl diglycol or even polyglycerols (such as diglycerol, triglycerol, tetraglycerol, etc.) with aliphatic carboxylic acids (fatty acids) or aliphatic alcohols (fatty alcohols). Additional co-surfactants are given below, which can be grouped into some general chemical classes. It should be noted that the invention is not limited to the co-surfactants indicated herein, which show representative, but not exclusive, lists of co-surfactants available. Monoglycerides: A particularly important class of co-surfactants is the class of monoglycerides, which are generally lipophilic. Mixtures of monoglycerides with C6-C22 aliphatic carboxylic acids are particularly preferred. Examples of this class of co-surfactants are: monopalmitolein (C16: 1), monoelaidine (C18: 1), monocaproin (C6), monocaprylin, monocaprin, monolaurin, glyceryl monomiristate (C14), glyceryl monooleate (C18: 1), glyceryl monooleate, glyceryl monolinoleate, ricinoleate glyceryl, glyceryl monolaurate, glyceryl monopalmitate, glyceryl monostearate, glyceryl monopalmate, glycerol monostearate, glyceryl caprylate and glyceryl caprate, as well as mixtures thereof. Polyglycerated fatty acids: They are also co- 21 suitable surfactants for the present invention polyglycerol esters of fatty acids, in particular polyglycerol monoesters. Mixtures of polyglycerol esters with C6-C22 aliphatic carboxylic acids are particularly preferred. They are examples of esters of. commercially available polyglyceryl suitable: polyglyceryl-2-stearate, polyglyceryl-2-oleate, polyglyceryl-2-isostearate, polyglyceryl-3-oleate, polyglyceryl-4-oleate, polyglyceryl-4-stearate, polyglyceryl-6 oleate, polyglyceryl dioleate -2 and polyglyceryl dioleate-6. Propylene glycol fatty acid esters: Co-surfactants suitable for use in the present invention are partial propylene glycol and fatty acid esters, in particular monoesters. Mixtures of propylene glycol esters with C6-C22 aliphatic carboxylic acids are particularly preferred. Examples of co-surfactants of this class: monocaprylate, propylene glycol monolaurate, propylene glycol oleate, propylene glycol myristate, propylene glycol monostearate, propylene glycol hydroxystearate, propylene glycol ricinoleate, propylene glycol isostearate, propylene glycol monooleate, propylene glycol, dicaprylate / dicaprate propylene glycol, propylene glycol dioctanoate, caprylate / propylene glycol caprate, propylene glycol dilaurate, propylene glycol distearate, propylene glycol dicaprylate and propylene glycol dicaprate. 22 A lipophilic phase in the context of the present invention is understood to mean, a liquid immiscible with water. Reference can also be made to the lipophilic phase as being a lipid phase. For compositions of the present invention in which the system also includes a lipophilic component, the lipophilic component is preferably a triglyceride or a mixture of a triglyceride and a diglyceride. Suitable lipophilic phases are preferably di and triacylglycerides of aliphatic carboxylic acids (fatty acids) with 4 to 22 carbon atoms, in particular with 6 to 22 carbon atoms, and also mixtures thereof. Preferred diglycerides in the context of the present invention are mixtures of diglycerides with C6-C22 aliphatic carboxylic acids. Examples are glyceryl dioleate, glyceryl dipalmitate, glyceryl dilaurate, glyceryl dilinoleate, glyceryl dicaprylate, glyceryl dicaprate, glyceryl caprylate / glyceryl distearate, glyceryl stearate / palmitate, glyceryl oleate / linoleate and dimyristate. of glyceryl. Preferred triglycerides are those which solidify at room temperature, with or without the addition of appropriate additives, or those which, in combination with surfactants and / or co-surfactants and / or particular active ingredients, solidify at room temperature. Examples of triglycerides suitable for use in the present invention are: olive oil, almond oil, arachis oil, babassu oil, beeswax, currant seed oil, borage oil, buffalo oil, candela nut oil, canola oil, castor oil, oil Chinese vegetable oil, cocoa butter, coconut oil, coffee seed oil, corn oil, cottonseed oil, crambe oil, cufea oil, primrose oil, grape seed oil , ground nut oil, hemp seed oil, illipe fat, capoc seed oil, linseed oil, menhaden oil, mo rah butter, mustard seed oil, ocytic oil, olive oil, oil palm oil, palm kernel oil, peanut oil, poppy seed oil, rapeseed oil, rice bran oil, safflower oil, salt fat (Shorea robusta), sesame oil, shark liver oil , shea nut oil, soybean oil, oil of this type lingia, sunflower oil, tall oil, tea seed oil, tobacco seed oil, tung oil (China wood oil), ucuhuba, vernonia oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, hydrogenated vegetable oil, hydrogenated cottonseed and castor oil, partially hydrogenated soybean oil, soybean oil and partially cottonseed hydrogenated, mono, 24 glyceryl di and tribehenate, glycerol tributyrate, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprate, glyceryl trincanoate, glyceryl trilaurate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl tristearate, glyceryl triaryquinate, glyceryl trimyristoleate, glyceryl tripalmitoleate, glyceryl trioleate, glyceryl trilinoleate, glyceryl trilinolenate, glyceryl tricaprylate / caprate, tricaprylate / caprate / glyceryl laurate, tricaprylate / caprate / glyceryl linoleate, tricaprylate / caprate / glyceryl stearate, tricaprylate / laurate / glyceryl stearate, glyceryl 1, 2-caprylate-3-linoleate, glyceryl 1, 2-caprate-3-stearate, glyceryl 1,2-laurate-3-myristate, 1,2-myristate-3-laurate glyceryl, glyceryl 1,3-palmitate-2-butyrate, glyceryl-1,3-stearate-2-caprate, glyceryl-1, 2-linoleate-3-caprylate. Fractionated triglycerides, modified triglycerides, synthetic triglycerides and triglyceride mixtures are also within the scope of the invention. Preferred triglycerides include vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, medium and long chain triglycerides and structured triglycerides. In addition, the following compounds may be suitable as lipophilic phase: aliphatic hydrocarbons of low viscosity and high viscosity, and also in particular oleyl ester of oleic acid, isooctyl stearate, hexyl ester of lauric acid, di-n-butyl adipate, isopropyl myristate, palmitate isopropyl and isopropyl stearate, oleyl alcohol, ethereal oils, isopropyl caprylate, isopropyl caprinate and isopropyl laurate.

Complete systems composed of surfactant, co-surfactant and lipophilic phase Various commercial surfactant and / or co-surfactant compositions contain small to moderate amounts of di and triglycerides, typically as a result of incomplete reaction of a triglyceride starting material in, for example, a transesterification reaction. Such commercial surfactant and / or co-surfactant compositions, although nominally referred to as "surfactants" and / or "co-surfactant", may be suitable to provide, in addition to the surfactant portion and / or co-surfactant of the system, all or part of the lipophilic component, ie, the di and triglyceride component, for the compositions of the present invention. Other commercially available surfactant and / or co-surfactant compositions having a significant amount of water content are known to those skilled in the art. diglycerides- and triglycerides. It should be appreciated that such compositions, which contain di and triglycerides as well as surfactants and / or co-surfactants, may be suitable to provide the complete system composed of surfactant, co-surfactant and lipophilic phase, of the compositions of the present invention. Typical examples of such systems are the so-called macrogolglycerides (or polyoxyethylated glycerides) with different kinds of fatty acids. The macrogolglycerides are mixtures of monoesters, diesters and triesters of glycerol and monoester and diester of PEG (= polyethylene glycol, macrogol, polyoxyethylene, poly (ethylene oxide), polyglycol) with fatty acids, so that the molecular mass of PEG can be defined in this way as the nature of fatty acids. The macrogolglycerides can be obtained by a partial hydrolysis / esterification reaction of triglycerides using the respective macrogol. Alternatively, macrogolglycerides can be obtained by esterification of glycerol and the macrogol and the corresponding free fatty acids. As triglycerides, a variety of natural and / or hydrogenated oils can be used. More commonly, the oils used are castor oil or hydrogenated castor oil or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil or almond oil, or the corresponding hydrogenated vegetable oil. 27 Typically, such trans-esterification products of oils and polyethylene glycol (or other poly-alcohols) are named for their adducts: PEG-20 castor oil, PEG-23 castor oil, PEG-30 castor oil, PEG-35 oil castor oil, PEG-38 castor oil, PEG-40 castor oil, PEG-50 castor oil, PEG-56 castor oil, PEG-7 hydrogenated castor oil, PEG-10 hydrogenated castor oil, PEG-20 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-30 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-45 hydrogenated castor oil, PEG-50 hydrogenated castor oil, PEG-60 oil hydrogenated castor oil, PEG-80 hydrogenated castor oil, PEG-8 corn oil, PEG-20 corn oil, PEG-20 almond oil, PEG-25 trioleate, PEG-40 palm kernel oil, PEG-60 corn oil, PEG-60 almond oil, PEG-8 caprylic / capric glycerides, lauroyl macrogol-32 glyceride (= PEG-32 palm kernel oil h oxygenated, for example, Gelucire® 44/14), stearoyl macrogol glyceride (for example, Gelucire® 50/13). Examples of commercial co-surfactant compositions of monoglycerides, which additionally contain di and triglycerides, include some members of the co-surfactant families Maisines® (Gattefosse) and Imwitors® (Hüls). These commercial compositions can be used to provide the co-surfactant and the lipophilic phase in a composition. They are 28 specific examples of these compositions: Maisine® 35-1 (linoleic glycerides) and Imiteor® 742 (caprylic / capric glycerides). Carboxylic acids aliphatic with 6 to 22 carbon atoms: In the context of the present invention, aliphatic carboxylic acids with 6 to 22 carbon atoms are understood as C6-C22 aliphatic carboxylic acids. Thus, carboxylic acids selected from the group containing caproic acid (C6), caprylic acid (C8), capric acid (CIO), lauric acid (C12), myristic acid (C14), palmitic acid (C16), stearic acid are preferably used. (C18), arachidic acid (C20) and behenic acid (C22), as well as the corresponding unsaturated carboxylic acids, such as palmitoleic acid (C16), oleic acid (C18), linoleic acid (C18), linolenic acid (C18), Eicosenoic acid (C20), individually or as a mixture. In a particularly preferred manner, the saturated carboxylic acids are selected. Aliphatic alcohols with 12 to 18 carbon atoms: In the context of the present invention, aliphatic alcohols having 12 to 18 carbon atoms are understood as C? 2-C ?β aliphatic alcohols. Thus, alcohols selected from the group containing lauryl alcohol (C12), myristyl alcohol (C14), cetyl alcohol (C16), stearyl alcohol (C18), oleyl alcohol (C18), linolelic alcohol (C18) and linolenilic alcohol ( C18), individually or as a 29 mixture. In a particularly preferred manner, the saturated alcohols are selected. Aliphatic alcohols with 12 to 22 carbon atoms: In the context of the present invention, aliphatic alcohols with 12 to 22 carbon atoms are understood as aliphatic alcohols Ca2-C22. Thus, alcohols selected from the group containing lauryl alcohol (C12), myristyl alcohol (C14), cetyl alcohol (C16), stearyl alcohol (C18), arachidyl alcohol (C20), behenyl alcohol (C22), oleyl alcohol ( C18), linolelic alcohol (C18) and linolenyl alcohol (C18), individually or as a mixture. In a particularly preferred manner, the saturated alcohols are selected. The hydrophilic phase in the context of the present invention is understood in particular to mean an aqueous phase which is preferably supplied by the physiological liquid of the digestion medium and / or by an aqueous liquid ingested in parallel with the food and / or the pharmaceutical preparation. . Enzymes or mixtures of enzymes with at least lipoiitic activity: In the context of the present invention it is understood that means mixtures of physiologically acceptable enzymes containing at least one lipase. In addition, enzymes or mixtures of enzymes may also have proteolytic activity in addition to lipolytic activity, i.e. they contain at least one protease, and / or amylolitic activity, that is, they contain at least one amylase. Enzymes or mixtures of enzymes having purely lipolytic activity (i) can be used; or (ii) lipolytic and proteolytic; or (iii) lipolytic and amylolytic; or (iv) lipolytic, proteolytic and amylolytic. Enzymes or mixtures of suitable enzymes can be of any animal or microbiological origin. The mixtures of enzymes with at least lipolytic, and optionally also proteolytic and / or amylolytic activity used in the context of the invention may therefore be of purely microbial origin or of purely animal origin, or alternately represent a mixture of enzymes of animal origin and microbial. In the case of enzyme products containing lipase of non-animal origin as well as preparations thereof, these are mixtures of enzymes comprising at least one lipase and optionally also at least one protease and / or amylase. These enzymes can be derived from plants or from fungal or bacterial origin. These lipases, proteases and / or amylases can be obtained, for example, by fermentation of optionally recombinant bacteria or fungi. Enzyme products containing lipase may be composed of enzyme preparations derived purely from microbes (ie, enzymes obtained from fungi or bacteria) or enzyme preparations obtained from plants, but also from synthetic mixtures of enzyme preparations of plants, bacteria and / or fungi, optionally produced recombinantly in a microbial system. In addition, the recombinantly produced enzyme may be an enzyme variant or a mutated enzyme that is functionally equivalent or has structural aspects similar to an enzyme of natural origin. By "recombinantly produced microbial enzyme", in particular "recombinantly produced lipase, amylase or protease", is meant an enzyme produced by recombinant DNA technology, the enzyme being of microbial origin, that is, obtained from fungi or bacteria. In the context of this invention, suitable lipases are recombinantly produced microbial lipases possessing lipolytic activity, preferably at a relatively low pH. In the context of this invention, suitable proteases are recombinantly produced microbial proteases possessing proteolytic activity, preferably at a relatively low pH. In the context of this invention, suitable amylases are recombinantly produced microbial amylases which possess amylolitic activity, preferably at a relatively low pH. The recombinantly produced microbial enzyme, ie the lipase, amylase or protease, can be an enzyme variant or a mutated enzyme that is functionally equivalent or that has structural aspects similar to an enzyme of natural origin. 32 Preferred recombinantly produced microbial lipases are lipases derived from fungi, for example from Humicola, Rhizomucor, Rhizopus, Geotrichum or Candida species, in particular Humicola lanuginosa (Thermomyces lanuginosa), Rhizomucor miehei, Rhizopus javanicus, Rhizopus arrhizus, Rhizopus oryzae, Rhizopus delamar , Candida cylindracea, Candida rugosa or Geotrichum - candidum; or they can be derived from bacteria, for example, from Pseudomonas, Burkholderia or Bacillus species, in particular Burkholderia cepacia. Most preferred are lipases derived from a strain of Humicola lanuginosa (Thermomyces lanuginosa) or Rhizomucor miehei. Lipases of microbial origin that can be used in the context of the present invention and their production by, for example, recombinant technology, are described in, for example, EP-Publications No. 0600868, 0238023, 0305216, 0828509, 0550450, 1261368 , 0973878 and 0592478, whose publications are included here for reference. Preferred recombinantly produced microbial amylases are amylases derived from fungi, for example, from Aspergillus or Rhizopus species, in particular Aspergillus niger or Aspergillus oryzae; or they can be derived from bacteria, for example, Bacillus species, in particular Bacillus subtilis. More preferred are amylases derived from a strain of Aspergillus oryzae. Amylases of microbial origin that can be used in the 33 • context of the present invention and its production by recombinant technology are described in, for example, < Publication of EP N ° 0828509, whose publication is included here as a reference. Preferred recombinantly produced microbial proteases are proteases derived from fungi, for example, from Aspergillus or Rhizopus species, in particular Aspergillus melleus, Aspergillus oryzae, Aspergillus niger or Rhizópus oryzae; or they can be derived from bacteria, for example, Bacillus species, in particular Bacillus subtilis. Proteases derived from a strain of Aspergillus melleus are more preferred. Proteases of microbial origin are described which can be used in the context of the present invention in, for example, EP 1 186 658 and Pariza & Johnson [Pariza MW & Johnson EA: "Evaluating the safety of microbial enzyme preparations used in food processing: update for a new century". Regul Toxicol Pharmacol. April 2001; 33 (2): 173-86. Review], whose publications are included here for reference. The recombinantly produced microbial enzyme, i.e., lipase, amylase or protease, preferably the recombinantly produced lipase, can be obtained by fermenting a fungal cell, for example, belonging to the genus Aspergillus, such as A. niger, A. oryzae or A nidulans; a 34 yeast cell, for example, belonging to a strain of Saccharomyces, such as S. cerevisiae, or a methylotrophic yeast of the Hansenula genera, such as H. polymorpha, or Pichia, such as P. pastoris; or a bacterial cell, for example, belonging to a strain of Bacillus, such as B. subtilis or B. lentus; transforming the cell with the gene that codes for the microbial lipase. The most preferred host organisms are members of Aspergillus oryzae. A variant enzyme or mutated enzyme is obtainable by altering the DNA sequence of the parent gene or its derivatives. The enzyme or mutated enzyme variant can be expressed and produced when the nucleotide sequence of DNA encoding the respective enzyme is inserted into a suitable vector in a suitable host organism. The host organism does not necessarily have to be identical to the organism from which the parent gene originates. Methods for introducing mutations into genes are well known in the art, see for example Patent Application EP 0 407 225. The preferred mutated lipase or lipase variants are obtainable from mother microbial lipases. In a preferred embodiment,. the mother lipase is derived from a fungus, for example, a strain of Humicola or Rhizomucor, preferably a strain of Humicola lanuginosa or a strain of Rhizomocur miehei. In another preferred embodiment, the mother lipase is derived from yeast, by example, derived from a strain of Candida. In a further preferred embodiment, the mother lipase is derived from a bacterium, for example, derived from a strain of Pseudomonas. The most preferred variants of lipase or mutated lipases are lipase variants of mother lipases comprising a trypsin-like catalytic triad including an active serine residue located in an elongated, primarily hydrophobic, binding pocket of the lipase molecule in the lipase molecule. that the electrostatic charge and / or hydrophobicity of a lipid contact zone comprising residues located in the vicinity of the lipase structure containing the active serine residue, whose residues can participate in the interaction with the substrate at or during hydrolysis , has been changed by deleting or substituting one or more negatively charged amino acid residues for neutral (s) or positively charged (s) amino acid residue (s), and / or substituting one or more neutral amino acid residues per residue ( s) of amino acid (s) positively charged, and / or by deleting or substituting one or more hydrophobic amino acid residues per amino acid residue (s). hydrophobic do (s). Preferably, pharmaceutically compatible auxiliaries, vehicles and / or excipients are selected in the context of the present invention from the group consisting of free polyethylene glycols having an average molecular weight of from about 200 to about 6,000, glycerol, alcohols 36 lower, in particular straight chain or branched C? ~ C4 alcohols such as 2-propanol, sugars, such as lactose, sucrose or dextrose; polysaccharides, such as maltodextrin or dextrates; starches; cellulosic products, such as microcrystalline cellulose or microcrystalline cellulose / sodium carboxymethyl cellulose; inorganic products, such as dicalcium phosphate, hydroxyapatite, tricalcium phosphate, talc or titanium dioxide; and polyols, such as mannitol, xylitol, sorbitol or cyclodextrin; and mixtures of the above substances. The present invention describes pharmaceutical compositions for oral administration, which are self-emulsifiable in contact with a hydrophilic phase and a lipophilic phase, said composition comprising: (i) enzymes or mixtures of enzymes with at least lipolytic activity, and (ii) a system comprising • at least one surfactant, • at least one co-surfactant, and • optionally a lipophilic phase. Preferably, the pharmaceutical composition according to the invention comprises enzymes or mixtures of enzymes with at least lipolytic activity and a system comprising • as surfactant, at least one agent having a HLB value greater than 6 and less than 18, 37 • as a co-surfactant, at least one agent having a HLB value of less than 10, and • as a lipophilic phase, a lipid phase, whereby the system comprising surfactant, co-surfactant and lipophilic phase has a value of HLB from about 4 to 16, and a melting point greater than or equal to 20 ° C, preferably greater than or equal to 25 ° C. The surfactant of the system is preferably chosen from the group consisting of fatty acid esters of polyethylene glycol; esters of polyethylene glycol glycerol fatty acids; polyethylene glycol alkyl ethers, polyethylene glycol sterol ethers, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, ionic surfactants and mixtures thereof. Even more preferred, the surfactant is selected from the group consisting of mono and / or diesters of polyethylene glycol fatty acids (PEG) with C6-C22 aliphatic carboxylic acids; fatty acid esters of polyethylene glycol (PEG) glycerol with C6-C22 aliphatic carboxylic acids; mono and / or polyethylene glycol (PEG) diereters alkyl with C ?2-Ci8 aliphatic alcohols, and mixtures thereof. In particular, the surfactant used is represented by a mixture of polyethylene glycol mono- and diesters (PEG) with Ce-C22 aliphatic carboxylic acids and / or polyethylene glycol mono- and di-ethers (PEG) with C ?2-C18 aliphatic alcohols, for example. that polyethylene glycol (PEG) comprises from 6 to 60 ethylene oxide units per molecule (PEG-6 to PEG-60, also referred to as PEG 300 to PEG 3000), preferably by a mixture of polyethylene glycol mono- and diesters with aliphatic carboxylic acids Ce -C22, whereby polyethylene glycol comprises from 6 to 40 ethylene oxide units per molecule. The co-surfactant of the system is preferably selected from the group consisting of mono acyl glycerides, glycerol monoethers, propylene glycol partial esters, polyglycerol partial esters, ethyldiglycol partial esters and mixtures thereof. Even more preferred, the co-surfactant is chosen. of the group consisting of mono acyl glycerides with aliphatic carboxylic acids Ce-C22, monoethers of glycerol ethers with aliphatic C? 2-C? a alcohols, partial esters of propylene glycol with C6-C22 aliphatic carboxylic acids, partial esters of polyglycerol with C6-C22 aliphatic carboxylic acids , and mixtures thereof. Particularly preferred co-surfactants are mono-acyl glycerides of C6-C22 aliphatic carboxylic acids and / or glycerol monoethers with C1-C22 aliphatic alcohols, especially mono-acyl glycerides of C6-C22 aliphatic carboxylic acids. The lipophilic phase is preferably represented by di and / or triacylglycerides, preferably di and / or triacylglycerides with C6-C22 aliphatic carboxylic acids. Therefore, in a preferred embodiment, the system that 39 part "of the pharmaceutical composition comprises • as surfactant, a mixture of polyethylene glycol mono- and diesters (PEG) with C6_C22 aliphatic carboxylic acids and / or polyethylene glycol mono- and di-ethers (PEG) with C 2 -C 8 aliphatic alcohols, whereby polyethylene glycol (PEG) comprises from 6 to 60 units ethylene oxide per molecule, preferably a mixture of polyethylene glycol mono- and diesters with C6-C22 aliphatic carboxylic acids, whereby the polyethylene glycol comprises from 6 to 40 ethylene oxide units per molecule: • as co-surfactant, mono-acyl glycerides of C6-C22 aliphatic carboxylic acids and / or glycerol monoethers with C12-C22 aliphatic alcohols, preferably mono-acyl glycerides of C6-C22 aliphatic carboxylic acids, and • as a lipophilic phase, di and triacylglycerides of aliphatic carboxylic acids Ce -C22 The pharmaceutical composition according to the invention is preferably characterized in that the system comprises from 2 to 90% by weight of surfactants as defined above, from 5 to 60% by weight of co-surfactants as defined above, and 0 to 70% by weight of the lipophilic phase as defined above, whereby the components surfactant, co-surfactant and Lipophilic phase form up to 100% by weight of the system and the system consisting of surfactant, co-surfactant and the lipophilic phase form 10% to 95% by weight of the pharmaceutical composition. Preferably, the pharmaceutical composition is characterized in that the system consisting of surfactant, co-surfactant and lipophilic phase forms from 10 to 70% by weight, preferably from 20 to 50% by weight, more preferably from 25 to 40% by weight, the pharmaceutical composition. In a further embodiment, the pharmaceutical composition according to the invention is characterized in that the system comprises • from 40 to 90% by weight, preferably from 60 to 85% by weight, of surfactants, • from 5 to 40% by weight, preferably 15- 30% by weight of co-surfactants, and • from 0 to 40% by weight, preferably 15-30% by weight, of the lipophilic phase, whereby the total of co-surfactants and the lipophilic phase together is at least 10% by weight, preferably between 15 and 40% by weight of the system. In the context of the present invention, the pharmaceutical compositions may additionally contain pharmaceutically conventional compatible auxiliaries, carriers and / or excipients as defined below. 41 In particular, the pharmaceutically compatible auxiliaries, vehicles and / or excipients are selected from the group consisting of free polyethylene glycols having an average molecular weight of from about 200 to about 6,000, glycerol, lower alcohols, in particular C 1 -C 4 chain alcohols. straight or branched such as 2-propanol, sugars, such as lactose, sucrose or dextrose; cellulose products, such as microcrystalline cellulose or microcrystalline cellulose / sodium carboxymethylcellulose, and mixtures of the above-mentioned substances. In a preferred embodiment, the proportion of the pharmaceutically compatible auxiliary products and / or excipients contained therein is at most 20% by weight of the pharmaceutical composition. In a further preferred embodiment, the pharmaceutical composition according to the invention comprises a mixture of macrogolglycerides representing the system consisting of surfactant, co-surfactant and lipophilic phase, whereby the macrogolglycerides are a mixture of mono, di and triacylglycerides and mono and diesters of polyethylene glycol (PEG) of C6-C22 aliphatic carboxylic acids, and also possibly small proportions of glycerol and free polyethylene glycol. The polyethylene glycol (PEG) contained in the mixtures of macrogolglycerides is preferably PEG having an average of 6 at most 40 ethylene oxide units per molecule or 42. a molecular weight between 200 and 2,000. A further aspect of the invention provides that the pharmaceutical composition comprises a system consisting of surfactant, co-surfactant and lipophilic phase, the system having a HLB value greater than or equal to 10 and a melting point greater than or equal to 30 °. C. In a preferred embodiment, the system has a HLB value of 10 to 16, preferably 12 to 15, and has a melting point between 30 and 60 ° C, preferably between 40 and 50 ° C. In particular, the system characterized by the HLB value and the melting point is a mixture of mono, di and triacylglycerides and mono and diesters of polyethylene glycol (PEG) with aliphatic carboxylic acids with 8 to 20 carbon atoms, whereby the polyethylene glycol preferably has from about 6 to about 32 ethylene oxide units per molecule, and the system optionally contains free glycerin and / or free polyethylene glycol. The HLB value of such a system is preferably regulated by the chain length of the PEG. The melting point of such a system is regulated by the chain length of the fatty acids, the chain length of the PEG and the degree of saturation of the fatty acid chains, and therefore the starting oil for the preparation of the mixture of macrogolglycerides. "Aliphatic carboxylic acids Cs-Cis" designates mixtures in which caprylic (C8) acid, acid 43 is present. capricum (CIO), lauric acid (C12), myristic acid (C14), palmitic acid (C16) and stearic acid (C18) in a significant and variable proportion, if these acids are saturated, and the corresponding Cs-Cis unsaturated carboxylic acids . The proportion of these fatty acids can vary according to the starting oils. Such a mixture of mono, di and triacylglycerides and mono and diesters of polyethylene glycol (PEG) with aliphatic carboxylic acids having 8 to 18 carbon atoms can be obtained, for example, by a reaction between a polyethylene glycol with a molecular weight between 200 and 1,500 and a starting oil, the starting oil consisting of a mixture of triglycerides with fatty acids which are selected from the group containing caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid and linolenic acid, individually or as a mixture. Optionally, the product of such reaction may also contain small proportions of glycerin and free polyethylene glycol. Such a mixture is commercially available for example under the trade name Gelucire®. An advantageous embodiment of the invention stipulates that, of the products known under the trade name Gelucire®, in particular "Gelucire® 50/13" and / or "Gelucire® 44/14" represent mixtures suitable for use in pharmaceutical preparations according to the invention. the invention. 44 Gelucire® 50/13 is a mixture of mono, di and triacylglycerides and mono and diesters of polyethylene glycol, forming palmitic acid (C16) and stearic acid (C18) of 40% to 50% and 48% to 58%, respectively, higher proportion of bound fatty acids. The proportion of caprylic acid (C8) and capric acid (CIO) is less than 3% in each case, and the proportion of lauric acid (C12) and myristic acid (C14) is less than 5% in each case. A preferred embodiment of the present invention provides a pharmaceutical composition comprising a mixture containing a mixture of mono, di and triacylglycerides and polyethylene glycol mono and diesters of C8-Ci8 aliphatic carboxylic acids and also possibly small proportions of glycerin and free polyethylene glycol, the system having a melting point between 46 ° C and 51 ° C and a HLB value of around 13. Gelucire® 44/14 is a mixture with mono, di and triacylglycerides and mono and diesters of polyethylene glycol, the respective proportions being from palmitic acid (C16) 4 to 25%, stearic acid (C18) 5 to 35%, caprylic acid (C8) less than 15%, capric acid (CIO) less than 12%, lauric acid (C12) from 30 to 50% and myristic acid (C14) from 5 to 25%.

Gelucire® 44/14 can be prepared, for example, by an alcoholysis / esterification reaction using palm kernel oil and polyethylene glycol 1500. A preferred embodiment of the present invention provides a pharmaceutical composition comprising a system containing a mixture of mono, di and triacylglycerides and polyethylene glycol mono and diesters of C 8 -C 8 aliphatic carboxylic acids and also possibly small proportions of glycerin and free polyethylene glycol, the system having a melting point between 42 ° C and 48 ° C and a HLB value of about 14. In an alternative embodiment, the pharmaceutical composition of the invention is characterized in that an ionic surfactant is used as the surfactant. Preferably, the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine and mixtures thereof, and is preferably lysophosphatidylcholine. In particular, a pharmaceutical composition of the invention comprises a system containing • as a surfactant, lysophosphatidylcholine, • as co-surfactant, a mixture of mono acyl glycerides with saturated and / or unsaturated C 6 -C 20 aliphatic carboxylic acids, preferably with oleic acid and / or linoleic, and • a lipophilic phase of di and / or triacylglycerides with acids, aliphatic carboxylic acids Ci6-C20, preferably 46 with oleic and / or linoleic acid. As a mixture of mono, di and triacylglycerides with saturated and / or unsaturated C? 6-C20 aliphatic carboxylic acids commercially available, Maisine® (Gattefosse) can be used. Preferably, said pharmaceutical composition is characterized in that the system comprises from 2 to 10%, preferably 5%, by weight of lysophosphatidylcholine, from 28 to 51% by weight of mono acyl glycerides, preferably of oleic acid and linoleic acid, and of 36 to 54% by weight of diacylglycerides and from 4 to 20% by weight of triacylglycerides, preferably of oleic acid and linoleic acid, whereby the system consisting of surfactant, co-surfactant and the lipophilic phase together forms from 10% to 30% , preferably 20%, by weight of the pharmaceutical composition. For the pharmaceutical preparations according to the invention, preferably solid orally administered dosage forms can be selected, for example, powders, pellets, granules, pellets or microspheres, with which, if desired, capsules or sachets can be filled or compressed to form pellets. The granules are preferably produced by melt granulation. The pellets are usually manufactured from powder or granules of melt. The globules can be produced by exploiting the thermoplastic properties of the auxiliary products in a high performance mixer (melting globulization) 47 or by traditional methods, for example, extrusion (e.g., melt extrusion or wet extrusion) and spheronization. If individual types of enzymes are present and are obtained separately, such as a lipase, a protease or an amylase of microbial origin, these can be present in this case together or spatially separated from each other, if the individual enzymes are not spatially separated from each other , dry working and / or storage is preferred. The pharmaceutical compositions according to the invention, which are self-emulsifiable by contact with a hydrophilic phase and optionally a lipophilic phase, contain enzymes or mixtures of enzymes with at least lipolytic activity as active substance. In a preferred variant of the present invention, enzymes or mixtures of enzymes can also have, in addition to the lipolytic activity, proteolytic activity, that is, contain at least one protease, and / or amylolitic activity, that is, contain the minus one amylase. In a preferred variant of the present invention, the lipolytic activity of enzymes or mixtures of enzymes is provided by a microbial lipase. In another embodiment, the pharmaceutical composition contains enzymes or mixtures of enzymes that are pancreatin and / or pancreatin type, preferably pancreatin-containing mixtures of digestive enzymes. Preferably, the mixtures 48 of pancreatin and / or pancreatin-type digestive enzymes form 65-85%, in particular 75-80% by weight, of the pharmaceutical composition. Alternatively, the enzyme mixture used is a mixture of at least one microbial lipase and one or more microbial enzymes from the group of proteases and amylases is used as a mixture of enzymes. In a variant of the invention, the mixture of enzymes used is purely of microbial origin. Examples of such physiologically acceptable bacterial and / or fungal enzymes have already been described in the prior art, together with methods for obtaining these enzymes and their use for the treatment of maldigestion. For example, such synthetic mixtures of lipase, protease and amylase, each of which is obtained microbially, and also pharmaceutical preparations containing these mixtures are described in the international patent application WO 02/060474 and the patent application EP 0 828 509. Preferably, the pharmaceutical composition contains microbial enzymes that form 5-80%, in particular 20-60% by weight, of the pharmaceutical composition. In the context of the invention, mixtures of digestive enzymes with lipolytic, proteolytic and amytic activity, whose properties are close to those of pancreatin, are more preferred. The mixtures of digestive enzymes that 49 contain pancreatin and also in particular pancreatin itself are therefore preferred in the context of the present invention as described above. However, it is possible to add one or more microbial enzymes, ie, lipases, proteases and / or amylases, obtained from microbial sources, if desired, to pancreatin or mixtures of digestive enzymes containing pancreatin. They are in particular microbial enzymes suitable for the sole use as a mixture of enzymes or even as an addition to pancreatin or mixtures of digestive enzymes containing pancreatin bacterial or fungal enzymes, such as Bacillus or Pseudomonas species, or fungal cultures, such as of the species Aspergillus, -Humicola or Rhizomucor. Preferably, the microbial enzymes, in particular the microbial lipase, are produced recombinantly. In a further preferred variant of the present invention, the microbial lipase is a variant of lipase or a mutated lipase. The present invention also relates to the use of a system comprising • at least one surfactant, • at least one co-surfactant, and • optionally a lipophilic phase to stabilize the lipolytic activity in the acid pH range and / or improve .lipolytic activity 50 of solid pharmaceutical preparations containing enzymes or mixtures of enzymes with at least lipolytic activity, preferably pancreatin or pancreatin-type digestive enzyme mixtures. The additional possible configurations of the system to be used, consisting of surfactant, co-surfactant and lipophilic phase, correspond to the modalities already mentioned for the self-emulsifying pharmaceutical preparation according to the invention, which comprises such system. The invention also relates to a process for the preparation of solid pharmaceutical preparations containing enzymes or mixtures of enzymes with at least lipolytic and optionally also proteolytic and / or amytic activity, preferably pancreatin and / or mixtures of digestive enzymes of the pancreatin type. According to the invention, enzymes or mixtures of enzymes are then converted into a suitable medicament form with a system comprising a surfactant selected from the group consisting of fatty acid esters of polyethylene glycol; esters of polyethylene glycol glycerol fatty acids; polyethylene glycol alkyl ethers, polyethylene glycol sterol ethers, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, ionic surfactants and mixtures thereof; • a co-surfactant chosen from the group constituted 51 by mono acyl glycerides, glycerol monoethers, propylene glycol partial esters, polyglycerol partial esters, ethyldiglycol partial esters and mixtures thereof, and a lipophilic phase, which is represented by di and / or triacylglycerides. And also optionally conventional pharmaceutically compatible auxiliary products, vehicles and / or excipients. The additional possible configurations of the system consisting of surfactant, co-surfactant and lipophilic phase, and to be used in the preparation process, correspond to the modalities already mentioned for the self-emulsifiable pharmaceutical preparations according to the invention, comprising such system. It is intended that the following examples further explain the invention, but without limiting its scope: Example 1: Preparation of compositions containing pancreatin according to the invention and comparison of the lipolytic activity of a conventional pancreatin formulation and a pancreatin formulation according to the invention comprising a system consisting of a surfactant, a co-surfactant and a lipophilic phase. • a) Usual preparation (globules) not according to 52 invention: The usual formulation was prepared according to the process described in the patent specification EP 0 583 726. 120 g of pancreatin and 30 g of PEG 4000 were initially dry mixed and then wetted with 20 g of isopropanol. The wet mixture was extruded and then rounded in a suitable round finder with the aid of paraffin oil. The produced globules were then dried. b) Preparation according to the invention (globules) (Example IA) 350 g of Gelucire® 50/13 were melted in a wide-mouthed glass in a water bath at a temperature of 52 ° C. The melt was mixed with 650 g of pancreatin in a double jacket mixer for 10 min. The homogeneous mixture was placed in a melt extruder for extrusion. The extrudate was then rounded in a suitable rounder or spheronizer. The obtained globules had a diameter of 1.0-1.6 mm. c) Preparation according to the invention (granules) (Example IB) 300 g of Gelucire® 44/14 were melted in a beaker in a water bath at a temperature of 48 ° C. The melt was mixed with 700 g of pancreatin in a double jacket mixer for approximately 15 min. and then cooled, (melt granulation). The determination of lipase activity in 53 Function of the pH value and also the change of the time-dependent lipase activity was carried out according to the method of the "Federation Internationale Pharmaceutique / European Pharmacopeia" (hereinafter abbreviated as FIP / Ph.Eur.): With this standard analysis method , the hydrolytic activity of the lipase is determined in the sample to be investigated with the olive oil substrate. The fatty acids separated from the triglycerides of the olive oil are titrated with sodium hydroxide solution at a constant pH of 9.0. The lipase activity of the sample is determined by comparing the proportion in which the sample hydrolyzes an emulsion of olive oil with the ratio in which a suspension of a standard pancreas reference powder hydrolyzes the same substrate under the same conditions . The absolute and relative lipolytic activity of the usual preparation and the preparation according to the invention (globules) determined in each case according to FIP / Ph.Eur. they are summarized in Table 1. The absolute and relative lipolytic activity of the usual preparation and the preparation according to the invention (granules) determined in each case according to FIP / Ph.Eur. they are summarized in Table 2: Table 1: Absolute and relative lipolytic activity of the standard preparation and the preparation according to the invention (globules with Gelucire® 50/13) 54 Table 2: Absolute and relative lipolytic activity of the standard preparation and the preparation according to the invention (granules with Gelucire® 44/14) It is clear from the data that the addition of systems comprising at least one surfactant, at least one co-surfactant and a lipophilic phase to pharmaceutical preparations of enzymes and mixtures of enzymes with at least lipolytic activity, preferably pancreatin and / or mixtures of type pancreatin digestive enzymes, contributes to the activity 55 improved lipolytic compared to customary pancreatin formulations known in the current state of the art. The absolute lipolytic activity of the respective pharmaceutical preparation, determined according to FIP / Ph.Eur., Is expressed with reference to the total lipolytic activity present theoretically in the sample in the form of a relative activity, in order to take into account the different concentrations of pancreatin in the formulations. The comparison of the relative lipase activities determined shows that the relative lipase activity of the preparations according to the invention is approximately 10% higher than those of the usual formulations. Accordingly, the pharmaceutical preparations according to the invention have increased lipolytic activity compared to customary pancreatin formulations. Furthermore, with reference to the value of the relative lipase activity of the preparation according to the invention of more than 100%, it is clear that there is an activation effect of the lipase by the system consisting of surfactant, co-surfactant and optionally added lipophilic phase. to the preparations according to the invention.

Example 2 Comparison of the stability of the lipolytic activity of a usual pancreatin formulation and a 56 pancreatin formulation according to the invention comprising a system consisting of surfactant, co-surfactant and lipophilic phase at different pH values In order to compare the stability of the lipolytic activity of a usual pancreatin formulation and a pharmaceutical formulation according to the invention that comprising a mixture of enzymes with at least lipolytic activity and a system consisting of at least one surfactant, at least one co-surfactant and a lipophilic phase, the activity of such a customary pancreatin formulation was compared to the activity of a Gelucire® mixture. and pancreatin incubated for up to 2 hours at different pH values (pH 6, pH 5 and pH 4). a) Standard preparation (globules): The usual formulation was prepared according to the procedure described in EP 0 583 726. 120 g of pancreatin and 30 g of PEG 4000 were initially dry mixed and then wetted with 20 g. g of isopropanol. The wet mixture was extruded and then rounded in a suitable round finder with the aid of paraffin oil. The produced globules were then dried. b) Preparation according to the invention (globules) - Example 2 300 g of Gelucire® 44/14 were melted in a beaker in a water bath at a temperature of 48 ° C. The melt was mixed with 700 g of pancreatin in a mixer 57 double deck and high speed (melting globulization). The determination of the activity of the lipase as a function of the pH value and also the change in the time-dependent lipase activity take place according to the method of the FIP / Ph.Eur. as described above. To determine the release behavior of the lipase at different pH values in the usual preparation and the preparation according to the invention, the samples were incubated in a decomposition apparatus for 2 hours at 37 ° C in phosphate buffer solution (pH 6, pH 5, pH 4). At intervals of 15 minutes, samples were taken and the lipolytic activity of the samples was determined according to the FIP / Ph.Eur method. described before-. 600 ml of buffer (67 mM phosphate, 34 mM NaCl, pH 6.0, pH 5.0, pH 4.0) were heated to a constant temperature of 37 ° C in a 1 1 wide-mouthed glass in a Decomposition meter Once the constant temperature was reached, 2 g of sample was added to the wide-mouthed vessel and the decomposition meter was set in motion. The pH value of the phosphate buffer was kept constant during the test time. At intervals of 15 minutes in each case, samples were taken and the lipolytic activity of the samples was determined according to FIP / Ph.Eur. The relative lipolytic activity determined after 15, 30, 45, 60, 75, 90, 105 and 120 minutes of preparation 58 usual and the preparation according to the invention according to FIP / Ph.Eur. they are summarized in the following Table 3; details are given in% of the activity of the respective sample as compared to a standard pancreas reference powder according to FIP / Ph.Eur.

Table 3: pH dependence of the relative lipolytic activity of a usual pancreatin formulation and a pancreatin preparation according to the invention It can be seen from these data that the addition of systems comprising at least one surfactant, at least one co-surfactant and a lipophilic phase to pharmaceutical preparations of enzymes and mixtures of enzymes with at least lipolytic activity, preferably pancreatin and / or mixtures of type Pancreatin digestive enzymes, helps to stabilize the lipolytic activity in the acidic pH range. With a pH value of 6, the comparison of the lipolytic activity of a usual pancreatic preparation and a preparation of Pancreatin according to the invention for a time of 120 minutes shows that the lipolytic activity in both forms of preparation over time only decreases relatively slightly, again being observed within the first hour the lipolytic activity of the preparation according to the invention increased by approximately 10% compared to the usual way. However, it is known that a pH value of 6 does not have a great influence on lipolytic activity. On the other hand, with a pH value of 5, the lipolytic activity of the usual preparation is reduced much more rapidly compared to the preparation according to the invention. While the preparation according to the invention has lost less than 10% of the lipolytic activity after 90 minutes, the usual preparation has only a remaining lipolytic activity of less than 70% compared to a pancreas reference powder according to FIP / Ph.Eur . In particular, with a pH value of 4, the preparation according to the invention has a lipolytic (residual) activity markedly higher than the usual preparation. Accordingly, the pharmaceutical preparations according to the invention have a substantially increased lipolytic activity in the acidic pH medium.

Example 3 Dependence of the dosage of a pancreatin formulation according to the invention comprising a system 60 consisting of a surfactant, co-surfactant and lipophilic phase on the digestibility of a high-fat diet in the small pig insufficient exocrine pancreatic. The effectiveness of a globulized pharmaceutical formulation according to the invention comprising a mixture of enzymes with at least lipolytic activity and a system consisting of at least one surfactant, at least one of these, was analyzed in these pigs fed a high-fat diet (32%). 'co-surfactant and a lipophilic phase to improve the digestion and absorption of fat in small pigs, in which the pancreatic duct has been ligated to induce a complete pancreatic exocrine insufficiency. a) Preparation according to the invention (globules) 250 g of Gelucire® 44/14 (Gattefossé) were melted in a beaker in a water bath at a temperature of 48 ° C. The melt was mixed with 750 g of pancreatin in a double-deck, high speed mixer (melt-flow globulization). The globule size of this formulation was similar to that of the commercialized pancreatin product. Determination of lipase activity Studies were performed on 6 small pigs (Ellegaard, female Gdttingen small pigs) with induced exocrine pancreatic insufficiency, weighing 20-30 kg in surgery. The pigs were prepared, as previously described [Tabelin R, Gregory P, Kamphues J. 1989: Studies on 61 nutrient digestibilities (pre-caecal and total) in pancreatic duct-ligated pigs and the effects of enzymé substitution. J. Anim. Physiol. to. Ani. Nutr. 82, 251-263] under halothane anesthesia; following a laparotomy through the midline; the pancreatic duct was ligated, after which the pigs were chronically provided with an ileo-cecal re-entrant fistula that was externalized on the right side. The success of the pancreatic duct ligation was confirmed (fecal chymotrypsin assay) before starting the digestibility studies, which began at least 4 weeks after the pigs recovered from the surgery. The pigs were fed two meals of 250 g / day (08.00 and 20.00 h) of a high-fat diet (containing: 180 g of Altromin 9021 double ground [modified], 70 g of soybean oil [Roth] ]; the total contents are 99% of dry matter, 4% of crude ash, 32% of crude fat, 16% of crude protein, 28% of starch, 3% of crude fiber) plus 0.625 g of Cr203 per meal, mixed with 1 liter of water. The meals plus the enzymes were mixed together carefully immediately before giving to the pigs. The meals were generally consumed in 5 minutes. During the study, the pigs received 0, 28,000 or 336,000 units of FIP lipase per meal as a formulation according to the invention for 14 days, with a complete accumulation of feces during the last 5 days. The stool (and the 62 Feeding) were frozen at -20 ° C, lyophilized and analyzed by Weender [Naumann C, Bassier R. 1993: Die Chemische Untersuchung von Futtermittein. 3. Aufl. VDLUFA-Verlag, Darmstadt] to determine the dry matter content (drying at 103 ° C for 8 h) and crude fat (determined gravimetrically after boiling for 30 min with concentrated HCl, followed by a 6 h extraction with ether of petroleum), while Cr203 was oxidized to chromate and the chromium content was calculated by extinction- at 365 nm [Petry H, Rapp W. 1970: Zur Problematik der Chromoxidbestimmung in Verdauungsversuchen. Z. Tierphysiol. Tierernáhrung und Futtermitelikunde 27, 181-189]. The content of fat and chromium determined by 100 g of fed dry matter and faeces (see above) allowed the calculation of fat digestibility (CFA) according to the formula: [% Cr203 in food] [% fat in faeces]% fat digestibility = 100- (x xlOO) [% Cr203 in faeces] [% fat in food] For the preparation according to the invention, the efficacy is given to improve the digestion and absorption of fat in small pigs, in which the pancreatic duct has been ligated to induce exocrine insufficiency complete pancreatic, measured in%. of fat digestibility, for 63 different amounts of added lipase activity (given in FIP / Ph.Eur units).

Table 4:% fat digestibility in small pigs receiving a pancreatin preparation according to the invention *, ** The results are mean ± D.T. The formulation according to the invention caused a very strong and dose-dependent improvement of the fat digestibility, already showing a highly effective improvement with the lowest dose tested.

Example 4 Comparison of the stability of the lipolytic activity of a conventional pancreatin powder and a pancreatin formulation according to the invention comprising a system consisting of a surfactant, a co-surfactant and a lipophilic phase at different pH values. They prepared. Additional preparations according to 64 invention and analyzed with respect to its lipolytic activity compared to pancreatin powder at different acidic pH values (pH 6, pH 5 and pH 4). (a) Preparation for comparison not according to the invention: Pancreatin powder. (b) Preparation according to the invention - Example 4A 700 g of pancreatin powder 200 'g of Gelucire® 44/14 (Gattefosse) 100 g of Labrasol® (Gattefosse) Gelucire® 44/14 and Labrasol® were mixed and melted in a wide-mouthed glass in a water bath at a temperature of 48 ° C. The melt was mixed with 700 g of pancreatin in a double-deck, high speed mixer (melt granulation). (c) Preparation according to the invention - Example 4B 800 g of pancreatin powder 190 g of Maisine® (Gattefosse) 10 g of LPC (lysophosphatidylcholine) Maisine® and lysophosphatidylcholine were mixed and melted in a wide-mouthed glass in a bath of water at a temperature of 48 ° C. The melt was mixed with 800 g of pancreatin in a double-deck, high speed mixer (melt granulation). The determination of the activity of lipase in 65 Function of the pH value and also the time-dependent change of the lipase activity were performed as described in Example 2. The release behavior of the lipase at different pH values in the pancreatin powder and the preparation according to the The invention was carried out as described above for Example 2. The relative lipolytic activity determined after 15, 30, 45, 60, 75, 90, 105 and 120 minutes of the pancreatin powder and the preparations "Example 4A" and. " Example 4B "according to the invention according to FIP / Ph.Eur. they are summarized in the following Tables 5A and 5B; details are given in% of the activity of the respective sample as compared to a standard pancreas reference powder according to FIP / Ph.Eur.

Table 5A: pH dependence of the relative lipolytic activity of a standard pancreatin powder and pancreatin preparation "4A" according to the invention 66 Table 5B: pH dependence of the relative lipolytic activity of a standard pancreatin powder and pancreatin preparation "4B" according to the invention It can be concluded from these data that the addition of systems comprising at least one surfactant, at least one co-surfactant and a lipophilic phase a. Pharmaceutical preparations of enzymes and mixtures of enzymes with at least lipolytic activity, preferably pancreatin and / or pancreatin-like mixtures of digestive enzymes, contribute to stabilizing the lipolytic activity in the acid pH range.

Example 5 Determination of the lipolytic activity of a formulation according to the invention comprising a lipase of microbial origin and a system consisting of a surfactant, a co-surfactant and a lipophilic phase, and determination of the stability at different pH values 67 In order to determine the lipolytic activity and show the improved stability at acid pH of a pharmaceutical formulation according to the invention comprising a mixture of enzymes with at least lipolytic activity, whereby the lipolytic activity is provided by a microbial lipase, produced optionally recombinantly, and a system consisting of at least one surfactant, at least one co-surfactant and a lipophilic phase, is determined at different pH values (pH, pH 5, pH 4 and 3) the activity of a pharmaceutical formulation consisting of a mixture of Gelucire® and a microbial lipase, and compared to an unstabilized lipase preparation. a) Preparation according to the invention (granulate) 562.5 g of Gelucire® 44/14 were melted in a beaker in a water bath at a temperature of 48 ° C. 937.5 g of a microbial lipase preparation was provided (representing the active lipase protein approximately 50 to 60% (w / w) of the dry matter of the preparation) in a double-bed blender at 46 ° C, the molten Gelucire was then added and the compounds were mixed in a first stage at low speed for 3 min. , then for about min. at high speed and finally cooled (melt granulation). b) Preparation for comparison (not according to the invention) 68 A microbial lipase preparation was prepared using common atomization technique. The determination of lipase activity was carried out according to the "Federation Internationale Pharmaceutique" (hereinafter FIP) method for microbial lipases, except that the concentration of bile salts is mM. With this standard analysis method, the hydrolytic activity of the lipase in the sample to be determined is determined using olive oil as substrate. The released fatty acids are titrated with sodium hydroxide solution at a constant pH of 7.0. The lipase activity of the sample is determined by comparing the proportion in which the sample hydrolyzes an olive oil emulsion with the proportion in which a suspension of a reference powder of microbial lipase hydrolyzes the same substrate under the same conditions . To determine the pH stability of the lipase at different pH values in an unstabilized preparation and in the preparation according to the invention, the samples were incubated in a decomposition apparatus for 2 hours at 37 ° C in buffer solution (pH 5 , pH 4 and pH 3). At 15 minute intervals, samples were taken and the lipolytic activity was determined in the samples according to the FIP method. 100 mg of lipase were incubated in 100 ml of buffer 69 (0.1 M malonic acid buffer, 1 mM calcium chloride pH 3, 4 and 5) at 37 ° C. Samples were withdrawn every 15 min. for a total duration of 2 hours and the lipolytic activity of the samples was determined as follows: a suspension was prepared in olive oil by mixing 175 olive oil with 630 ml of a solution of 700 g of gum arabic and 94.4 g of calcium chloride dihydrate in 5,900 ml of water for 15 minutes in a food mixer at maximum speed. The emulsion was cooled to 37 ° C and adjusted mel pH to pH 6, 8 with sodium hydroxide solution. Three reference solutions were prepared by extracting an appropriate amount of standard FIP microbial lipase with an ice-cooled solution of 1% (m / v) sodium chloride, such that reference solutions were obtained with 50 FlP-U / ml, 65 FlP-U / ml and 80 FlP-U / ml. Sample solutions were prepared by extracting a sample amount corresponding to approximately 6,500 activity units for 15 minutes with a total of 100 ml of an ice cold sodium chloride solution of 1% (m / v). The samples were further diluted in ice-cold sodium chloride solution of 1% (m / v), such that the titration ratio was within the range of the titration ratios obtained with the reference solutions. The titration ratios of the reference and sample solutions were determined by combining in a 70 Thermostated container 19 ml suspension in olive oil with 10 ml of a solution of 492 mg of lipase activating mixture (FIP) in 500 ml of water. The combined solutions were thermostatted at 37 ° C and the pH was adjusted to pH 7.0. One ml of reference solution or sample solution was added and the fatty acids released under conditions of stable pH were titrated with a 0.1 M sodium hydroxide solution for a duration of 5 minutes. The titration ratio was calculated by linear regression from at least 9 measurement points between the 60th and 300th degrees of titration. From the titration proportions of the reference solutions, a calibration function was calculated by linear regression. The calibration function has the form y = mx + b, where y: titration ratio; m: slope; x: FIP units of the reference solution; and b: ordered at the origin. Using the values determined thus for m and b, the lipolytic activity x was calculated for each sample solution using the formula x = (y-b) / m. The relative lipolytic activity is determined after 0, 15, 30, 45, 60, 75, 90, .105 and 120 minutes of an unstabilized microbial lipase preparation and the preparation according to the invention in accordance with FIP. A comparison of the results obtained can show the improved lipolytic activity and the increased stability within the acid pH range of the formulation according to the invention. comprising a preparation of microbial lipase on the preparation of unstabilized lipase.

Claims

72
CLAIMS 1. Pharmaceutical composition for oral administration, which is self-emulsifiable in contact with a hydrophilic phase and a lipophilic phase, characterized in that it comprises: (i) enzymes or mixtures of enzymes with at least lipolytic activity, and (ii) a system comprising: at least one surfactant, which is an agent having a hydrophilic-lipophilic balance value greater than 6 and less than 18; and at least one co-surfactant, which is an agent having a hydrophilic-lipophilic balance value of less than 10. 2. Pharmaceutical composition according to claim 1, characterized in that the hydrophilic phase used to form the final emulsion after of ingestion is supplied by the physiological fluid of the digestive medium.
3. Pharmaceutical composition according to claim 1 or 2, characterized in that the lipophilic phase used to form the final emulsion in the digestive tract after ingestion is at least partially supplied by the lipids present in the ingested food.
4. Pharmaceutical composition according to one of claims 1 to 3, characterized in that the system also comprises a lipophilic phase.
5. Pharmaceutical composition according to claim 4, characterized in that the system comprises a lipophilic phase as a lipophilic phase, so that the system that comprising surfactant, co-surfactant and lipophilic phase has a hydrophilic-lipophilic balance value of about 4 to 16, and a melting point greater than or equal to 20 ° C, preferably greater than or equal to 25 ° C.
6. Pharmaceutical composition according to claims 4 or 5, characterized in that the system comprises a surfactant selected from the group consisting of fatty acid esters of polyethylene glycol; esters of polyethylene glycol glycerol fatty acids; polyethylene glycol alkyl ethers, polyethylene glycol sterol ethers, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, ionic surfactants and mixtures thereof; a co-surfactant selected from the group consisting of mono acyl glycerides, glycerol monoethers, propylene glycol partial esters, polyglycerol partial esters, ethyldiglycol partial esters and mixtures thereof, and a lipophilic phase represented by di and / or triacylglycerides.
7. Pharmaceutical composition according to claim 6, characterized in that the system comprises a surfactant selected from the group consisting of polyethylene glycol fatty acid diesters and / or diesters with C6-C22 aliphatic carboxylic acids; fatty acid esters of polyethylene glycol glycerol with C6-C22 aliphatic carboxylic acids; mono and / or polyethylene glycol alkyl diéteres with 74 C 2 -C 2 aliphatic alcohols and mixtures thereof; a co-surfactant selected from the group consisting of monoacylglycerides with C6-C22 aliphatic carboxylic acids, monoethers of glycerol ethers with C2-C2 aliphatic alcohols, partial esters of propylene glycol with C6-C22 aliphatic carboxylic acids, partial esters of polyglycerol with acids C6-C22 aliphatic carboxylic acids and mixtures thereof, and a lipophilic phase represented by di and / or triacylglycerides with C6-C22 aliphatic carboxylic acids.
8. Pharmaceutical composition according to claim 7, characterized in that the system comprises, as a surfactant, a mixture of polyethylene glycol mono- and diesters with C6-C22 aliphatic carboxylic acids and / or polyethylene glycol mono- and di-ethers with C2-C aliphatic alcohols. ? s, whereby the polyethylene glycol comprises from 6 to 60 ethylene oxide units per molecule, as a co-surfactant, mono-acyl glycerides of C6-C22 aliphatic carboxylic acids and / or glycerol monoethers with C? 2-C22 aliphatic alcohols, and lipophilic phase, di and triacylglycerides of C6-C22 aliphatic carboxylic acids.
9. Pharmaceutical composition according to claim 8, characterized in that a mixture of polyethylene glycol mono- and diesters with Cd-C22 aliphatic carboxylic acids is used as the surfactant, whereby the polyethylene glycol comprises from 6 to 40 ethylene oxide units per molecule, and 75 monacylglycerides of aliphatic carboxylic acids Ce-C22 are used as co-surfactants.
10. Pharmaceutical composition according to one of claims 4 to 9, characterized in that the system comprises from 2 to 90% by weight of surfactants; from 5 to 60% by weight of co-surfactants and from 0 to 70% by weight of the lipophilic phase; whereby the surfactant, co-surfactant and lipophilic phase components together form up to 100% by weight of the system and the system forms 10% to 95% by weight of the pharmaceutical composition.
11. Pharmaceutical composition according to claim 10, characterized in that the system consisting of surfactant, co-surfactant and lipophilic phase forms from 10 to 70% by weight, preferably from 20 to 50% by weight, more preferably from 25 to 40% by weight, of the pharmaceutical composition.
12. Pharmaceutical composition according to one of claims 10 or 11, characterized in that the system comprises from 40 to 90% by weight, preferably from 60 to 85% by weight, of surfactants; from 5 to 40% by weight, preferably 15-30% by weight, of co-surfactants and from 0 to 40% by weight, preferably 15-30% by weight, of the lipophilic phase, together being the total -surfactants and the lipophilic phase at least 10% by weight, preferably between 15 and 40% by weight, of the system. 76
13. Pharmaceutical composition according to one of claims 4 to 12, characterized in that the composition contains additional pharmaceutically compatible auxiliaries, vehicles and / or excipients.
14. Pharmaceutical composition according to claim 13, characterized in that the additional pharmaceutically compatible auxiliaries, vehicles and / or excipients are selected from the group consisting of polyethylene glycol, glycerol, C? -C4 alcohols, sugars, cellulose products and mixtures of the substances above.
15. Pharmaceutical composition according to claim 13 or 14, characterized in that the additional pharmaceutically compatible auxiliaries, vehicles and / or excipients form a maximum of 20% by weight of the pharmaceutical composition.
16. Pharmaceutical composition according to one of claims 4 to 15, characterized in that macrogolglycerides represent the system comprising surfactant, co-surfactant and lipophilic phase and also possibly small proportions of glycerin and free polyethylene glycol, whereby macrogolglycerides are a mixture of mono, di and triacylglycerides and polyethylene glycol mono and diesters of Cg-C22 aliphatic carboxylic acids, the polyethylene glycol comprising from about 6 to 77 approximately 32 ethylene oxide units per molecule.
17. Pharmaceutical composition according to claim 16, characterized in that the system comprising surfactant, co-surfactant and lipophilic phase has a hydrophilic-lipophilic balance value greater than or equal to 10, and a melting point greater than or equal to 30 ° C.
18. Pharmaceutical composition according to claim 17, characterized in that the system has a hydrophilic-lipophilic ratio of 10 to 16, preferably 12 to 15, and a melting point between 30 and 60 ° C, preferably between 40 and 50 ° C.
19. Pharmaceutical composition according to claim 18, characterized in that the system contains a mixture of mono, di and triacylglycerides and polyethylene glycol mono and diesters of aliphatic carboxylic acids Cs-Cis, and optionally small proportions of glycerol and / or free polyethylene glycol, and has a melting point between 42 ° C and 48 ° C and a HLB value of about 14.
20. Pharmaceutical composition according to claim 18, characterized in that the system contains a mixture of mono, di and triacylglycerides and mono and polyethylene glycol diesters of aliphatic carboxylic acids Ca-Cig, and optionally small proportions of glycerol and free polyethylene glycol, the system having a melting point between 46 ° C and 51 ° C and a HLB value of about 13. 78
21. Pharmaceutical composition according to claim 16, characterized in that the system contains a mixture of mono, di and triacylglycerides and mono and diesters of polyethylene glycol PEG-32 mainly of aliphatic carboxylic acids Cs-Ci8, a mixture of mono, di and triacylglycerides and mono and polyethylene glycol PEG-8 diesters mainly of C6-C? aliphatic carboxylic acids, and optionally small proportions of glycerol and free polyethylene glycol.
22. Pharmaceutical composition according to claim 6, characterized in that an ionic surfactant is used as the surfactant.
23. Pharmaceutical composition according to claim 22, characterized in that the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine and mixtures thereof. themselves, and is preferably lysophosphatidylcholine.
24. Pharmaceutical composition according to claim 23, characterized in that the system comprises, as a surfactant, lysophosphatidylcholine; as a co-surfactant, a mixture of monoacylglycerides with saturated and / or unsaturated C! 6-C20 al aliphatic carboxylic acids, preferably. 79 with oleic and / or linoleic acid, and a lipophilic phase represented by di and / or triacylglycerides with C6-C20 aliphatic carboxylic acids, preferably with oleic and / or linoleic acid.
25. Pharmaceutical composition according to claim 24, characterized in that the system comprises from 2 to 10%, preferably 5%, by weight of lysophosphatidylcholine; from 28 to 51% by weight of mono acyl glycerides mainly of oleic and linoleic acid; from 36 to 54% by weight of diacylglycerides and from 4 to 20% by weight of triacylglycerides mainly of oleic acid and linoleic acid, so that the system consisting of surfactant, co-surfactant and the lipophilic phase together form 10% to 30%, preferably 20%, by weight of the pharmaceutical composition.
26. Pharmaceutical composition according to one of claims 1 to 25, characterized in that it is a solid pharmaceutical preparation in the form of a powder, granules, pellets, globules or the like.
27. Pharmaceutical composition according to one of claims 1 to 26, characterized in that the lipolytic activity of the enzymes or mixtures of enzymes is provided by a microbial, in particular bacterial or fungal lipase.
28. Pharmaceutical composition in accordance with one- 80 of claims 1 to 26, characterized in that enzymes or mixtures of enzymes also have proteolytic and / or amylolytic activity.
29. Pharmaceutical composition according to claim 28, characterized in that the enzymes or mixtures of enzymes are pancreatin and / or pancreatin type, preferably pancreatin-containing mixtures of digestive enzymes.
30. Pharmaceutical composition according to claim 29, characterized in that pancreatin and / or pancreatin-type mixtures of digestive enzymes form 65-85%, in particular 75-80% by weight, of the pharmaceutical composition.
31. Pharmaceutical composition according to claim 28, characterized in that a mixture of at least one microbial lipase and one or more microbial enzymes from the group of proteases and amylases is used as a mixture of enzymes.
32. Pharmaceutical composition according to claim 31, characterized in that the microbial enzymes form 5-80%, in particular 20-60% by weight, of the pharmaceutical composition.
33. Pharmaceutical composition according to claim 28, characterized in that the enzymes or mixture of enzymes are pancreatin or a pancreatin-containing mixture of digestive enzymes, which additionally contain one or more microbial enzymes selected from the group of lipases., proteases and amylases.
34. Pharmaceutical composition according to one of claims 27a, 31a or 33a, characterized in that the microbial lipase is of fungal or bacterial origin and is produced recombinantly.
35. Pharmaceutical composition according to claim 34, characterized in that said lipase is a variant of lipase or a mutated lipase.
36. Use of a system comprising at least one surfactant, which is an agent having a hydrophilic-lipophilic balance value greater than 6 and less than 18, and at least one co-surfactant, which is an agent having a value of the hydrophilic-lipophilic balance less than 10, and optionally a lipophilic phase, to stabilize the lipolytic activity in the acid pH range and / or to improve the lipolytic activity of solid pharmaceutical preparations containing enzymes or enzyme mixtures with at least lipolytic activity , preferably pancreatin or pancreatin-like mixtures of digestive enzymes.
37. A process for preparing solid pharmaceutical preparations containing enzymes or mixtures of enzymes with at least lipolytic activity, characterized in that the enzymes or enzyme mixtures are converted into a suitable drug form with a system comprising 82 surfactant chosen from the group consisting of fatty acid esters of polyethylene glycol; esters of polyethylene glycol glycerol fatty acids; polyethylene glycol alkyl ethers, polyethylene glycol sterol ethers, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, ionic surfactants and mixtures thereof; a co-surfactant selected from the group consisting of mono acyl glycerides, glycerol monoethers, propylene glycol partial esters, partial polyglycerol esters, ethyldiglycol partial esters and mixtures thereof, and a lipophilic phase represented by di and / or triacylglycerides also optionally auxiliaries , conventional pharmaceutically compatible vehicles and / or excipients.
38. Process for preparing solid pharmaceutical preparations according to claim 37, characterized in that the system of surfactant, co-surfactant and lipophilic phase is a system as defined in one of claims 5 to 12 and 16 to 25.