| Title of Invention | "PHARMACEUTICAL COMPOSITION AND PROCESS FOR THEIR PREPARATION" |
|---|---|
| Abstract | The present invention relates to a pharmaceutical composition for oral administration, which is self-emulsifiable on contact with a hydrophilic phase and a lipophilic phase, said composition comprising: (i) enzymes or enzyme mixtures with at least lipolytic activity, and (ii) a system comprising • at least one surfactant in an amount of 2 to 90% by weight, • at least one co-surfactant in an amount of 5 to 60% by weight • in an amount of 0 to 70% by weight, a lipophilic phase represented by di- and/or triacylglycerides with aliphatic C6-C22 carboxylic acids, whereby the components surfactant, co-surfactant and the lipophilic phase together make up to 100% by weight of the system, and the system makes up 10% to 95% by weight of the pharmaceutical composition. The present invention also relates to the process for the preparation of solid pharmaceutical preparations. |
| Full Text | The present invention relates to pharmaceutical compositions and process for their preparation. The invention relates to novel pharmaceutical compositions of lipase-contalning products for oral administration, in particular pancreattn and pancreatin-containing products, or of enzyme products containing at least one lipase of non-animal, especially microbial origin, in which the pharmaceutical compositions provide improved lipolytic activity, in particular a stabilisation of the lipase in the acidic pH range. These novel pharmaceutical compositions are characterised in that they contain a system which comprises at least one surfactant and one co-surfactant, 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. .Maldigestion in mammals and humans is usually based on a deficiency of digestive enzymes, in particular on a deficiency of endogenous lipase, but also of protease and/or amylase. The cause of such a deficiency of digestive enzymes is frequently a hypofunction of the pancreas Substitution with similarly acting exogenous digestive enzymes or mixtures of di-gestive enzymes has proved effective treatment for a deficiency in endogenous digestive enzymes. Most frequently, pharmaceutical preparations {= preparations) which contain porcine pancreatin (= pancreatin) are nowadays used for this purpose. Such mlxtures of digestive enzymes obtained from the pig pancreas comprise lipases, amy-lases and proteases, and can be used effectively for enzyme substitution therapy in humans owing to the great similarity of the enzymes and accompanying substances contained therein to the contents of human pancreatic juices. For example, processes are described in German patent applications DE 25 12 746 and DE 42 03 315 by which pancreatin is obtained as a natural enzyme mixture by extraction from porcine pancreas and subsequently is converted in a known manner into the desired pharmaceuti-cal form. The pancreatic enzymes are usually administered orally in the form of solid preparations. Thus pancreatin is commercially available for example under the trade name Kreon® in the form of granules, pellets or capsules with enteric-coated mlcropel-lets. In order that, when taken orally, the administered enzyme mixtures are not irre-versibly 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 enables the intact enzyme mixtures to pass through the stomach as far as their point of action, the duodenum, where, owing to the neutral to slightly afkaline conditions prevailing there, the proiective layer is broken down and the enzymes are released. Like the endogenous pancreatic enzymes of healthy humans, the orally supplied enzymes can exert their enzymatic action, in particular amylolytic, lipolytic and proteolytic activity, there. Such solid pancreatin formulations which can be coated with an enteric film are described e.g. in EP O 021 129 A1. EP O 583 726 A1 describes pancreatin micropellet cores coatable with an enteric film having a pancreatin content of 65-85, in particular 75-80% by weight, which have a bulk density of 0.6 g/ml to 0.85 g/ml, consisting substantially of pancreatin, polyethyl-ene glycol 4000 and low-viscosity paraffin, containing per 100 parts by weight pancreatin: 15-50, in particular 20-30, parts by weight polyethylene glycol 4000; and 1.5-5, in particular 2-3, parts by weight low-viscosity paraffin, and having a spherical to ellip-soid form, the sphere diameter or 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 micropellet cores have a ratio of minor axis to major axis in the range of 1:1 to 1:2. Furthermore, EP O 826 375 A1 describes the use of leclthln as a stabilising agent added to water-soluble pharmaceutical preparations of mixtures of digestive enzymes which contain protease/lipase mixtures, in particular pancreatin, and which are suitable for the preparation of aqueous solutions for continuous introduction into the gastroin-testinal tract by means of probes. The lecithin is added to stabilise the mixtures of digestive enzymes against a decrease in the lipolytic activity under the influence of mois-ture. In the case of medicament 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 therewith is active. Thus in DE 36 42 853 A1 such enzyme deactivation is ascribed to insufficient neutralisation of the gastric acid in the duodenum. Whereas in a healthy human the postprandial intraduodenal pH value is about 6, patients with pancreatic insufficiency only have a pH value of 4. At this pH value, the lipase contained in the pharmaceutical preparation has only one fifth of the activity that it would otherwise have at a pH value of 6. It is therefore an object of the invention to make pharmaceutical compositions available which cqntain enzymes or enzyme mixtures with at least lipolytic activity and have improved lipolytic activity and in particular show a stabilisation of the activity of the lipase in the acidic pH range. According to the invention, pharmaceutical compositions intended for oral ad-ministration are provided which comprise enzymes or enzyme mixtures with at least lipolytic activity and a system comprising at least one surfactant and at least one co-surfactant, and are characterized in that tney can themselves be emulsified on contact with a hydrophilic phase and a lipophilic phase. Preferably the hydrophilic phase used to form the final ernulsion after ingestion of the pharmaceutical composition is supplied by the physiological fluid of the digestive milieu. 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 iipids present in the food ingested. In particular, to achieve this object the invention provides pharmaceutical compositions which contain systems which comprise at least one surfactant, one co-surfactant and a lipophilic phase. Surprisingly, a lipase-containing pharmaceutical composition containing such a system has improved lipolytic activHy and a lipolytic activity which is stabilised in the acidic pH range. The use of such a system in pharmaceutical compositions of enzymes or enzyme mixtures with at least lipolytic activity furthermore has the advantage that pharmaceutical compositions containing such enzymes or enzyme mixtures can also be used without enteric coatings, such as are described for example in EP O 583 726 Al In the pharmaceutical compositions according to the invention the reduction in the lipolytic activity during passage through the stomach is very much less than with pharmaceutical compositions prepared without the aforementioned 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 stabilised in the acidic pH range of the stomach compared with convenţional formulations. The fact that the use of such enteric-coated polymer films and softeners which are otherwise necessary for film-coating various medicament forms (granules, pellets, mini-tablets, tablets etc.) can be dispensed with in the preparation of the lipase-containing compositions according to the invention yieids further advantages. Thus the safety profite of the pharmaceutical composition is improved by omitting the enteric polymer films and softeners, since unnecessary taking thereof is avoided. Furţhermore, the proportions of the amount of film-coating material in the medicament forms pro-vided with an enteric film is approx. 20-30% of the entire weight of the medicament form. Dispensing with these additives makes the amount of medicament form to be taken smaller, which results in better acceptance by the patients. The possibility of dispensing with enteric coating of the enzymes or enzyme mixtures furthermore has the advantage that thorough mixing of the pharmaceutical preparation with the chyme can take place as earty as in the stomach. Thereupon, there forms an emulsion or micro-emulsion with enlarged surface, on which the lipase con-tained In the pharmaceutical composition is distributed such that it îs given optimum possibilities for attack for breaking down the triglycerides found in the chyme. The for-mation of emulsion and microemulsion is further intensified by the lipolytic breakdown of the triglycerides to form di- and monoglycerides and free fatty acids. Thus the improved possibilities of attack for the lipase result in intensified breakdown of the triglycerides. The hlgher concentration of free fatty acids resulting from the food which is thus provlded results In better făt absorption in the duodenum. In vitro, an increase in the lipolytic activity by about 10% compared with convenţional lipase-containing pharmaceutical preparations was determined for the pharmaceutical composition according to the invention. The pharmaceutical compositions according to the invention thus exhibit stabilisation of the lipolytic activity in the stomach as well as in the duodenum; addi-tionally, owing to the intensifled formation of a (micro)emulsion, the lipolytic activity is increased. The (micro)emulsion already produced independentiy in the stomach results in 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 O 670 715 describes a perorally administered composition which is suitable for forming a microemulsion in situ with the biologica! liquid of the organism and thus is said to improve the biologica! availability of an active substance. Such pharmaceutical compositions are known under the term SMEDDS® (Seif Microemulsifying Drug Delivery System) and consist in principie of a mixture of one or more active substances with a defined lipophilic phase, a defined surfactant and a de-fined co-surfactant, the properties of which are specified such that the end product is capable of forming a microemulsion on contact with a given volume of physiological liquid. Furthermore, EP 1 058 540 B1 describes what is called a SMEDDS® formulation in a particular pharmaceutical form, which is referred to as "pellef. These pellets are composed of an active substance, in particular indomethacin, a binding agent which is suitable for improving the biologica! availability of the active substance, for example Gelucire* 44/14, and a diluent, for example lactose, in micronised form. The object of the systems known hitherto from the prior art which automatically form a microemulsion was however always to increase the bioavailability of mostly lipophilic active substances in that the SMEDDS® formulation, owing to the micelle formation, permits better absorption of the active substance through the duodenal wall into the blood circulation. In contrast, the aim of the present invention is to provide a pharmaceutical composition which does not contain any lipophilic active substances to be absorbed înto the bloodstream, but provides as active agent enzymes or enzyme mixtures with at least lipolytic activity which develop their action in the gastrointestinal tract. The self-emulsifiable pharmaceutical compositions according to the invention result In a surprislng increase of the llpolytlc activity contalned thereln and In an im-proved stability of the lipase in the acidic pH ranga. Such pharmaceutical compositions of lipase-containing enzyme products which are self-emulsifiable on contact with a hy-drophillc phase and which comprise a system consisting of a surfactant, a co-surfactant and optionally a lipophllic phase have not been described hitherto In the prior art. Subramanian and Wasan describe an assay in which they demonstrate that the substance Geluclre® 44/14 in vitro has an inhibiting effect on the pancreatic lipase activity [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 particular lipid-containing assay buffer with separate solutions of Gelucire9 44/14, pancreatic lipase and co-lipase is mixed, and the influence of Gelucire® on the lipase activity is measured. Since the lipase activity decreases, the authors conclude that Gelucire® and similar lipidic additions to pharmaceutical formulations can have an adverse effect on the in vitro activity of the pancreatic lipase. In contrast, the present invention shows that self-emulsifiable pharmaceutical compositions consisting of lipase-containing enzyme mixtures and a system such as for example Gelucire0 44/14 result in 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 "hvdroDhilic-lipophilic balance" (= HLB) value is an empirica! parameter commonly used to characterize the relative hydrophilicity and lipophilicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (the "HLB" value). Surfac-tants or co-surfactants with lower HLB values are more lipophilic, and have greater solubility in oils, whereas surfactants or co-surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. It should be kept in mind, that for anionic, cationic, or zwitterionic compounds the HLB scale is not gener-ally applicable. Generally, the HLB value of a surfactant or co-surfactants is a practicai guide used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. How-ever, for many important surfactants, including severa! polyethoxylated surfactants, it has been reported that HLB values can differ by as much as about 8 HLB units, de- pending upon the empirical method chosen to determine the HLB value [Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)]. Likewise, for certain polypropylene oxide con-taining block copolymers (poloxamers), the HLB values may not accurately reflect the true physlcal chemical nature of the compounds. Finally, commercial surfactant and/or co-surfactant products are generally not pure compounds, but are often complex mix-tures of compounds, and the HLB value reported for a particular compound may more accurately be characteristic of the commercial product of which the compound is a major component. Different commercial products having the same primary surfactant and/or co-surfactant component can, and typically do, have different HLB values. In addition, a certain amount of lot-to-lot variability is expected even for a single commercial surfactant and/or co-surfactant product. A surfactant in the context of the present invention is a chemical compound com-prising 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 being hydrophobic (lipophilic); i.e., a surfactant compound must be amphi-philic. These chemical compounds are intended to căuşe the formation and stabilisa-tion of oil-in-water emulsions. Surfactants with lower HLB values are more lipophilic, and have greater solubility in oils, whereas 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 an HLB value above 6 and below 18, pref-erably above 8 and below 16. Surfactants can be any surfactant suitable for use in pharmaceutical compositions. Suitable surfactants can be anionic, cationic, zwitterionic or non-ionic. Such surfactants can be grouped into some general chemical classes as explained below. It shouid be emphasized thatthe invention is not limited to the surfactants indicated herein, which show representative, but not exclusive, lists of available surfactants. PEG-FattvAcid Monoester Surfactants: Although polyethylene glycol (PEG) itself does not function as a surfactant, a variety of PEG-fatty acid esters have usefui surfactant properties. Particulary preferred are PEG-fatty acid monoesters with aliphatic Ce-Cs2 carboxylic acids, whereby the polyethylene glycol comprises 6 to 60 ethylene oxide units per molecule. Examples of polyethoxylated fatty acid monoester surfactants commercially available are: PEG-4 laurate, PEG-4 oleate, PEG-4 stearate, PEG-5 stearate, PEG-5 oleate, PEG-6 oleate, PEG-7 oleate, PEG-6 laurate, PEG-7 laurate, PEG-6 stearate, PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-9 stearate, PEG-10 laurate, PEG-10 oleate, PEG-10 stearate, PEG-12 laurate, PEG-12 oleate, PEG-12 ricinoleate, PEG-12 stearate, PEG-15 stearate, PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, PEG-20 stearate, PEG-25 stearate, PEG-32 laurate, PEG-32 oleate, PEG-32 stearate, PEG-30 stearate, PEG 4-100 monolaurate, PEG 4-100 monooleate, and PEG 4-100 monostearate. PEG-Fattv Acid Dlester Surfactants: Polyethylene glycol (PEG) fatty acid diesters are also suitable for use as surfactants in the compositions of the presant invention. Particulariy preferred are PEG-fatty acid diesters with aliphatic Ce-Qs carboxylic acids, whereby the polyethyiene glycol comprises 6 to 60 ethylene oxide units per molecule. Representative PEG-fatty acid diesters commercially available are: PEG-4 dilaurate, PEG-4 dioleate, PEG-6 dilaurate, PEG-6 dioleate, PEG-6 distearate, PEG-8 dilaurate, PEG-8 dioleate, PEG-8 distearate, PEG-10 dipalmitate, PEG-12 dilaurate, PEG-12 distearate, PEG-12 dioleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-2O distearate, PEG-32 dilaurate, PEG-32 dioleate, and PEG-32 distearate. PEG-Fattv Acid Mono- and Di-ester Mixtures: In general, mixtures of surfactants are also useful in the present invention, including mixtures of two or more commercial surfactant producte. Particulariy preferred are mixtures of PEG-fatty acid mono- and diesters with aliphatic C6-Cz2 carboxylic acids, whereby the polyethyiene glycol comprises 6 to 60 ethylene oxide units per molecule. Several PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters. Representative surfactant mixtures commercially available are: PEG 4-150 mono, dilaurate; PEG 4-150 mono, dioleate; and PEG 4-150 mono, distearate. Polvethvlene Glvcol (PEG) Glvcerol Fattv Acid Esters: In addition, PEG glycerol fatty acid esters are suitable surfactants in the context of the present invention, such as PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-15 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. Particulariy preferred are PEG glycerol fatty acid esters with aliphatic C6-GZJ carboxylic acids, whereby the polyethyiene glycol comprises 6 to 60 ethylene oxide units per molecule. Polvethvlene Glvcol (PEG) Alkvl Ethers (mono- and/or dlethers of polvethvlene glvcoO: Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in the present invention. Particularly preferred are PEG-fatty acid mono- and/or dieth-ers with aliphatic C1z-d8 alcohols, whereby the polyethylene glycol comprises 6 to 60 ethylene oxide units per molecule. Some commercially available examples of these surfactants are: PEG-2 oleyl ether (oleth-2), PEG-3 oleyl ether (oleth-3), PEG-5 oleyl ether (oleth«5), PEG-10 oleyl ether (oleth-10), PEG-20 oleyl ether (oleth-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. Polvethvlene Glvcol Sterol Ethers: PEG-derivatives of sterols are suitable surfactants for use in the present invention. Examples of surfactants of this class are: PEEG-24 cholesterol ether, PEG-30 cholestanol, PEG-25 phytosterol, PEG-5 soya sterol, PEG-10 soya sterol, PEG-20 soya sterol, and PEG-30 soya sterol. Polvethvlene Glvcol Sorbitan Fattv Acid Esters: A variety of PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in the present invention. Examples of these surfactants are: PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, 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 sorbitan monostearate, 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: Esters of sugars, in particular mono-esters are suitable surfactants for use in the present invention. Examples of such surfactants are: Sucrose distearate/monostearate, Sucrose dipalmitate, Sucrose monostearate, Sucrose monopalmitate, Sucrose monolaurate, and Saccharose monolaurate. Polvoxvethvlene-PolvoxvDroDvIene Block Copolvmers: The POE-POP block co-polymers are a unique class of polymeric surfactants. The unique structura of the sur- factants, with hydrophillc POE and lipophilic POP moletles in well-deflned ratios and positions, provides a wide variety of surfactants suitable for use in the present inven-tion. The generic term for these polymers is "poloxamer" (CAS 9003-11-6). These polymers have the formula: HOţC^^OyCaHeO^CaHUOJaH, where "a" and "b" denote the number of polyoxyethylene and polyoxypropylene unrts, respectively. Furthermore, amphoteric compounds such as fatty acid-amidoalkyl betaines with C2-C22 fatty acids are suitable surfactants. The surfactant can also be, or include as a component, an Ionic surfactant. in-cluding cationic, anionlc and zwitterionic surfactants. Preferred anionic surfactants include fatty acid salts 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; pro-pylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkylsulfates; sodium docusate; carnitines; and mixtures thereof. More specifically, preferred ionic surfactants are lecithin, lysolecithin, phosphati-dylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phos-phatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphati-dylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, stearoyl-2-lactylate, stearoyl lactylate, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycho-late, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenode-oxycholate, ursodeoxycholate, tauroursodeoxycholate, glycoursodeoxycholate, cholyl-sarcosine, N-methyi taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof. A co-surfactant. sometimes also referred to as a "co-emulsifier", in the context of the present invention is equally a Chemical compound which has both hydrophobic (lipophilic) and hydrophilic portions, but with the hydrophobic (lipophilic) nature pre- dominating. It is intended to make the aqueous and olly phases In a mlcroemulsion mutually soluble. Suitable co-suriactants in the context of the present invention have an HLB value below 10, preferably below 8 and even more preferred below 6. Co-surfactants can be any parţial esters and/or parţial ethers of polyhydric (polyvalent) alcohols, such as glycerol, propylenglycol (1,2-propanediol; 1,2-dihdroxypropane), ethyl-diglycol or even polyglycerols (such as diglycerol, triglycerol, tetraglycerol etc.) with aliphatic carboxylic acids (fatty acids) or aliphatic alcohols (fatty alcohols). Further co-surlactants, which can be grouped into some general chemical classes, are given below. It should be emphasized that the invention is not limited to the co-surfactants indicated herein, which show representative, but not exclusive, lists of available co-surfactants. Mono-glycerides: A particularly important class of co-surfactants is the class of mono-glycerides, which are generally iipophilic. Particulary preferred are mixtures of monoglycerides with aliphatic C6-C22 carboxylic acids. Examples of this class of co-surfactants are: Monopalmitolein (C16:1), Monoelaidin (C18:1), Monocaproin (C6), Monocaprylin, Monocaprin, Monolaurin, Glyceryl monomyristate (C14), Glyceryl monooleate (C18:1), Glyceryl monooleate, Glyceryl monolinoleate, Glyceryl ricinoleate, Glyceryl monolaurate, Glyceryl monopalmitate, Glyceryl monostearate, Glyceryl mo-nopalmate, Glycerol monostearate, Glyceryl caprylate, and Glyceryl caprate as well as mixtures thereof. Polyglycerized Fattv Acids: Polyglycerol esters of fatty acids, in particular Poly-glycerol mono-esters, are also suitable co-surfactants for the present invention. Particulary preferred are mixtures of polyglycerol esters with aliphatic Ce-Cz? carboxylic acids. Examples of suitable polyglyceryl esters commercially available are: Polyglyc-eryl-2 stearate, Polyglyceryl-2 oleate, Polyglyceryl-2 isostearate, Polyglyceryl-3 oleate, Polyglyceryl-4 oleate, Polyglyceryl-4 stearate, Polyglyceryl-6 oleate, Polyglyceryl-2 dioleate and Polyglyceryl-6 dioleate. Propvlene Glvcol Fattv Acid Esters: Parţial esters of propylene glycol and fatty acids, in particular mono-esters, are suitable co-surfactants for use in the present invention. Particularly preferred are mixtures of propylene glycol esters with aliphatic C6-carboxylic acids. Examples of co-surfactants of this class are: Propylene glycol monocaprylate, Prapylene glycol monolaurate, Propylene glycol oleate, Propylene gly-col myristate, Propylene glycol monostearate, Propylene glycol hydroxy stearate, Propylene glycol ricinoleate, Propylene glycol isostearate, Propylene glycol monooleate, .Propylene glycol dicaprylate/dicaprate, Propylene glycol dioctanoate, Propylene glycol caprylate/caprate, Propylene glycol dilaurate, Propylene glycol distearate, Propylene glycol dicaprylate, and Propylene glycol dicaprate. A lipophilic phase in the context of the present invention is understood to mean a water-immiscible liquid. The lipophilic phase may also be referred to as being a lipidic phase. For compositions of the present invention wherein 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 tria-cylglycerides 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 di-glvcerides in the context of the present invention are mixtures of di-giycerides with aliphatic Ce-Cza carboxylic acids. Examples are: Glyceryl dioleate, Glyceryl dipalmitate, Glyceryl dilaurate, Glyceryl dilinoieate, Glyceryl dicaprylate, Glyceryl dicaprate, Glyceryl caprylate/caprate, Glyceryl distearate, Glyceryl stearate/ palmi-tate, Glyceryl oleate/linoleate and Glyceryl dimyristate., Preferred triglvcerides are those which solidify at ambient room temperature, with or without addition of appropriate additives, or those which in combination with particular surfactants and/or co-surfactants and/or active ingredients solidify at room temperature. Examples of triglycerides suitable for use in the present invention are: Aceituno oii, Almond oii, Araehis oii, Babassu oii, Beeswax, Blackcurrant seed oii, Borage oii, Buffalo ground oii, Candlenut oii, Canola oil.Castor oii, Chinese vegetable tallow oii, Cocoa butter, Coconut oii, Coffee seed oii, Corn oii, Cottonseed Oii, Crambe oii, Cup-hea species oii, Evening primrose oii, Grapeseed oii, Groundnut oii, Hemp seed oii, lllipe butter, Kapok seed oii, Linseed oii, Menhaden oii, Mowrah butter, Mustard seed oii, Oiticica oii, Olive oii, Palm oii, Palm kernel oii, Peanut oii, Poppy seed oii, Rape-seed oii, Rice bran oii, Safflower Oii, Sal făt, Sesame oii, Shark liver Oii, Shea nut oii, Soybean Oii, Stillingia oii, Sunflower oii, Tall oii, Tea seed oii, Tobacco seed oii, Tung oii (China wood oii), Ucuhuba, Vernonia oii, Wheat germ Oii, Hydrogenated castor oii, Hydrogenated coconut oii, Hydrogenated cottonseed oii, Hydrogenated palm oii, Hy- drogenated soybean oii, Hydrogenated vegetable oii, Hydrogenated cottonsead and castor oii, Partially hydrogenated soybean oii, Partially hydrogenated soy and cotton-seed oii, Glyceryl mono-, di-, tri-behenate, Glycerol tributyrate, Glyceryl tricaproate, Glyceryl trlcaprylate, Glyceryl tricaprate, Glyceryl triundecanoate, Glyceryl trilaurate, Glyceryl trimyristate, Glyceryl tripalmitate, Glyceryl tristearate, Glyceryl triarchidate, Glyceryl trimyristoleate, Glyceryl tripalmitoleate, Glyceryl trioleate, Glyceryl trilinoleate, Glyceryl trilinolenate, Glyceryl tricaprylate/caprate, Glyceryl tricaprylate/caprate/laurate, Glyceryl tricaprylate/caprate/linoleate, Glyceryl tricaprylate/caprate/ stearate, Glyceryl tricaprylate/laurate/stearate, Glyceryl 1,2-caprylate-3-linoleate, Glyceryl 1,2-caprate-3-stearate, Glyceryl 1,2-laurate-3-myristate, Glyceryl 1,2-myristate-3-laurate, Glyceryl 1,3-palmitate-2-butyrate, Glyceryl 1,3-stearate-2-caprate, Glyceryl 1,2-linoleate-3-caprylate. Fractionated triglycerides, modified triglycerides, synthetic triglycerides, am d mix-tures of triglycerides 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 stnjctured triglycerides. Furthermore, the following compounds may be suitable as lipophilic phase: low-viscosity and high-viscosity aliphatic hydrocarbons, and also in particular oleic acid oleyl ester, isooctyl stearate, lauric acid hexyl ester, di-n-butyl adipate, isopropyl myristate, isopropyl palmitate and isopropyl stearate, oleyl alcohol, ethereal oils, isopropyl caprylate, isopropyl caprinate and isopropyl laurate. Complete Systems composed of surfactant. co-surfactant and lipophilic phase Several 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, while nominally referred to as "surfactants" and/or "co-surfactant", may be suitable to provide - in addition to the surfactant and/or co-surfactant part of the system - all or part of the lipophilic component, i.e. the di- and triglyceride component, for the compositions of the present invention. Still other commercial surfactant and/or co-surfactant composltlons having signifl-cant di- and triglyceride content are known to those skilled in the art. It should be ap-preciated that such compositions, which contain di- and triglycerides as well as surfac-tants 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 for such kind of systems are so-called macrogolglycerides (or polyoxyethylated glycerides) with different kinds of fatty acids. Macrogolglycerides are mixtures of mono-esters, di-esters and tri-esters of glycerol and mono-ester and di-ester of PEG (=Polyethylene glycol, Macrogol, Polyoxyethlene, Poly Ethylene Oxide, Polyglycoi) with fatty acids, whereby the molecular mass of the PEG can be defined as well as the nature of the fatty acids. Macrogolglycerides can be obtained by a parţial hydrolysis/esterification reaction of triglycerides using the respective macrogol. Alterna-tively, 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. Most commonly, the oils used are castor oii or hydrogenated castor oii or an edible vegetable oii such as corn oii, olive oii, peanut oii, palm kernel oii, apricot kernel oii, or almond oii, or the corresponding hydrogenated vegetable oii. Typically, such transesterification products of oils and polyethylenglycol (or other polyalcohols) are named by there educts: PEG-20 castor oii, PEG-23 castor oii, PEG-30 castor oii, PEG-35 castor oii, PEG-38 castor oii, PEG-40 castor oii, PEG-50 castor oii, PEG-56 castor oii, PEG-7 hydrogenated castor oii, PEG-10 hydrogenated castor oii, PEG-20 hydrogenated castor oii, PEG-25 hydrogenated castor oii, PEG-30 hydrogenated castor oii, PEG-40 hydrogenated castor oii, PEG-45 hydrogenated castor oii, PEG-50 hydrogenated castor oii, PEG-60 hydrogenated castor oii, PEG-80 hydrogenated castor oii, PEG-8 corn oii, PEG-20 corn oii, PEG-20 almond oii, PEG-25 trioleate, PEG-40 palm kernel oii, PEG-60 corn oii, PEG-60 almond oii, PEG-8 caprylic/capric glycerides, Lauroyl macrogol-32 glyceride (= PEG-32 hydrogenated palm kemel oii, e.g. Gelucire®44/14), Stearoyl macrogol glyceride (e.g. Gelucire® 50/13) Examples of commercial co-surfactant compositions of mono-glycerides, in addi-tion containing di- and triglycerides include some members of the co-surfactant families Maisines® (Gattefosse) and Imwitors® (Huls). These commercial compositions may be used for providing the co-surfactant and the lipophilic phase in one composition. Spe- clflc examples of these composltlons are: Maisine® 35-I (llnoleic glycerides) and Imwi-tor® 742 (caprylic/capric glycerides). Aliphatic carboxvlic acids 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 aliphatic C6-C22 carboxylic acids. Thus preferably carboxylic acids selected from the group containing caproic acid (C6), caprylic acid (C8), capric acid (C10), lauric acid (C12), myristlc acid (C14), pa l mitic acid (C16), stearic acid (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 (C 18), linolenic acid (C 18), eicosenoic acid (C20), individually or as a mixture, are used. Particularly preferably, the saturated carboxylic acids are selected. Aliphatic alcohols with 12 to 18 carbon atoms: In the context of the present invention, aliphatic alcohols with 12 to 18 carbon atoms are understood as aliphatic C12-Ci8 alcohols. Thus preferably alcohols selected from the group containing lauryl alcohol (C 12), myristyl alcohol (C14), cetyl alcohol (C16), stearyl alcohol (C 18), oleyl alcohol (C18), linoleyl alcohol (C18) and linoleny! alcohol (C18), individually or as a mixture, are used. Particularly preferably, 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 dz-Czz alcohols. Thus preferably alcohols selected from the group containing lauryl alcohol (C12), myristyl alcohol (CU), cetyl alcohol (C16), stearyl alcohol (C 18), arachidyl alcohol (C20), behenyl alcohol (C22), oleyl alcohol (C 18), linoleyl alcohol (C18) and lino-lenyl alcohol (C 18), individually or as a mixture, are used. Particularly preferably, 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 paradei with the food and/or the pharmaceutical preparation. Enzymes or enzyme mixtures with at least lipolvtic activitv in the context of the present invention are understood to mean physiologically acceptable enzyme mixtures which contaln at least one lipase. Furthermore, the enzymes or enzyme mlxtures may however also have proteolytic activity in additlon to the lipolytic activity, i.e. contain at least one protease, and/or amylolytic activity, i.e. contain at least one amylase. Enzymes or enzyme mlxtures may be use which exhibit (i) purely lipolytic; or (ii) lipolytic and proteolytic; or (iii) lipolytic and amylolytic; or (iv) lipolytic, proteolytic and amylolytic activity. Suitable enzymes or enzyme mixtures may be of any animal or microbiologica) origin. The enzyme mixtures 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 alternatively represent a mixtura of enzymes of animal and microbial origin. In the case of lipase-containing enzyme products of non-animal origin as well as preparations thereof, these are enzyme mixtures comprising at least one lipase and optionally also at least one protease and/or amylase. These enzymes may be plant-derived or of fungal or bacteria! origin. These lipases, proteases and/or amylases may for example be obtained by fermentation of optionally recombinant bacteria or fungi. The lipase-containing enzyme products may be composed of purely microbial derived enzyme preparations (i.e. enzymes obtained from lungi or bacteria) or enzyme preparations obtained from plants, but also of synthetic mixtures of enzyme preparations from plants, bacteria and/or fungi, optionally produced recombinantly in a microbial system. Furthermore, the recombinantly produced enzyme may be an enzyme variant or a mutated enzyme being functionally equivalent or having structural features similar to a naturally occurring enzyme. By "recombinantly produced microbial enzyme", in particular "recombinantly produced lipase, amylase or protease", is meant an enzyme produced by way of recombinant DNA-technology, the enzyme being of microbial origin, i.e. obtained from fungi or bacteria. In the context of this invention suitable lipases are recombinantly produced microbial lipases triat possess lipolytic activity, preferably at relatively low pH. In the context of this invention suitable proteases are recombinantly produced microbial proteases that possess proteolytic activity, preferably at relatively low pH. In the context of this invention suitable amylases are recombinantly produced microbial amylases that possess amylolytic activity, preferably at relatively low pH. The recombinantly produced microblal enzyme, i.e. the llpase, amylase or prote-ase, may be an enzyme variant or a mutated enzyme being functionally equivalent or having structural features similar to a naturally occurring enzyme. Preferred recombinantly produced microbial lipases are llpases derived from fungi, e.g. 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 may be derived from bacteria, e.g. from Pseudomonas, Burkholderia or Bacillus species, in particular Burkholderia cepacia. Most preferred are lipases derived from a străin of Humicola lanuginosa (Thermomyces lanuginosa) or Rhizomucor miehei. Lipases of microbial origin which can be used in the context of the present inven-tion and their production by e.g. recombinării technology are described in e.g. EP Pub-lication Nos. 0600868, 0238023, 0305216, 0828509, 0550450,1261368, 0973878 and 0592478, which publications are hereby included by reference. Preferred recombinantly produced microbial amylases are amyiases derived fromfungi, e.g. from Aspergillus or Rhizopus species, in particular Aspergilius niger or Aspergillus oryzae; or may be derived from bacteria, e.g. from Bacillus species, in particular Bacillus subtilis. Most preferred are amylases derived from a străin of Aspergillus oryzae. Amylases of microbial origin which can be used in the context of the present in-vention and their production by recombinării technology are described in e.g. EP Publi-cation No. 0828509, which publicatlon is hereby included by reference. Preferred recombinantly produced microbial proteases are proleases derived from fungi, e.g. from Aspergillus or Rhizopus species, in particular Aspergillus melleus, Aspergillus oryzae, Aspergillus niger, or Rhizopus oryzae; or may be derived from bacteria, e.g. from Bacillus species, in particular Bacillus subtilis. Most preferred are proteases derived from a străin of Aspergillus melleus. Proteases of mlcroblal origin which can be used In the context of the present In-vention are described in e.g. Publication 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. 2001 Apr; 33(2): 173-86. Re vie w], which publications are hereby included by reference. The recombinantly produced microbial enzyme, i.e. lipase, amylase or protease, preferably the recombinantly produced lipase, may be obtained by fermentation of a fungal cell, e.g. belonging to the genus Aspergillus, such as A. niger, A. oryzae, or A. nidulans; a yeast cell, e.g. belonging to a străin of Saccharomyces, such as S. cere-visiae, or a methylotrophic yeast from the genera Hansenula, such as H. polymorpha, or Phichia, such as P. pastoris; or a bacteria! cell, e.g. belonging to a străin of Bacillus, such as B. subtilis, or B. lentus; the cell being transformed with the gene encoding the microbial lipase. Most preferred host organisme are members of Aspergillus oryzae. An enzyme variant or mutated enzyme is obtainable by alteration of the DNA se-quence of the parent gene or rts derivatives. The enzyme variant or mutated enzyme may be expressed and produced when the DNA nudeotide sequence 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 originated. The methods for introducing mutations into genes are well known in the art, vide e.g. Patent Application EP O 407 225. Preferred lipase varia nts or mutated lipases are obtainable from parent microbial lipases. In a preferred embodiment the parent lipase is derived from a fungus, e.g. a străin of Humicola or Rhizomucor, preferably a străin of Humicola lanuginosa or a străin of Rhizomucor mieriei. In another preferred embodiment the parent lipase is derived from yeast, e.g. derived from a străin of Candida. In a further preferred embodiment the parent lipase is derived from a bacterium, e.g. derived from a străin of Pseu-domonas. More preferred lipase variants or mutated lipases are lipase variants of parent lipases comprising a trypsin-like catalytic triad including an active serine residue located in a predominantly hydrophobic, elongated binding pocket of the lipase molecule, wherein 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, which residues may participate in the interaction with the substrate at or during hydrolysis, has been changed by deletlng or substltutlng one or more negatively charged amino acid residues by neutral or positively charged amino acid residue(s), and/or by substituting one or more neutral amino acid residues by positively charged amino acid residue(s), and/or by deletlng or substituting one or more hydrophobic amino acid residues by hydrophobic amino acid residue(s). Pharmaceutically compatible auxiliaries, carriers and/or excipients in the context of the present inventlon are preferably selected from the group consistlng of free poly-ethylene glycols having an average molecular weight of about 200 to about 6000, glyc-erol, lower alcohols, in particular straight-chain or branched CrC4-alcohols such as 2-propanol, sugars, such as lactose, sucrose or dextrose; polysaccharides, such as mal-todextrin or dextrates; starches; cellulosics, such as microcrystalline cellulose or micro-crystalline cellulose/sodium carboxymethyl cellulose; inorganics, such as dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc, or titania; and polyols, such as mannitol, xylitol, sorbitol or cyclodextrin; and mixtures of the aforementioned sub-stances. The present invention discloses pharmaceutical compositions for oral administra-tion, which are self-emulsifiable on contact with a hydrophilic phase and a lipophilic phase, saidcomposition comprising: (i) enzymes or enzyme mixtures 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 enzyme mixtures with at least lipolytic activity and a system comprising • as surfactant at least one agent having an HLB value above 6 and below 18, • as co-surfactant at least one agent having an HLB-value below 10, and • as lipophilic phase a lipidic phase, whereby the system comprising surfactant, co-surfactant and lipophilic phase has an HLB 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. The surfactant of the system Is preferably chosen from the group conslsting of polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyethylene glycol alkyl ethers, polyethylene glycol sterol ethers, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block co-polymers, ionic surfactants and mixtures thereof. Even more preferred, the surfactant is chosen from the group consisting of polyethylene glycol (PEG) fatty acid mono- and/or di-esters with aliphatic Ce-Caz carboxylic acids; polyethylene glycol (PEG) glycerol fatty acid esters with aliphatic Ce-Cz» carboxylic acids; polyethylene glycol (PEG) alkyl mono- and/or di-ethers with aliphatic Cia-Cis alcohols, and mixtures thereof. In particular, the surfactant used is represented by a mixture of polyethylene glycol (PEG) mono-and di-esters with aliphatic Ce-Qa carboxylic acids and/or polyethylene glycol (PEG) mono- and di-ethers with aliphatic Ci2-Ci8 alcohols, whereby the polyethylene glycol (PEG) comprises 6 to 60 ethylene oxide unite per molecule (PEG-6 to PEG-60, also named as PEG 300 to PEG 3000), preferably by a mixture of polyethylene glycol mono- and di-esters with aliphatic Ce-Czz carboxylic acids, whereby the polyethylene glycol comprises 6 to 40 ethylene oxide units per molecule. The co-surfactant of the system is preferably chosen from the group consisting of mono-acylglycerides, mono-ethers of glycerol, parţial esters of propylenglycol, parţial esters of polyglycerol, parţial esters of ethyl diglycol and mixtures thereof. Even more preferred, the co-surfactant chosen from the group consisting of mono-acylglycerides with aliphatic Ce-C^z carboxylic acids, mono-ethers of glycerol ethers with aliphatic C12-C16 alcohols, parţial esters of propylenglycol with aliphatic Cg-C^ carboxylic acids, parţial esters of polyglycerol with aliphatic Ce-Czj carboxylic acids, and mixtures thereof. Particularly preferred co-surfactants are monoacylglycerides of aliphatic Ce-Qg carboxylic acids and/or monoethers of glycerol with aliphatic Ci2-C22 alcohols, especially monoacylglycerides of aliphatic Ce-Cjs carboxylic acids. The lipophilic phase is preferably represented by di- and/or triacylglycerides, preferably di- and/or triacylglycerides with aliphatic Ce-C^ carboxylic acids. Therefore, in a preferred embodiment, the system being part of the pharmaceuti-cal composition comprises • as surfactant a mixture of polyethylene glycol (PEG) mono- and di-esters with aliphatic Ce-Ccarboxylic acids and/or polyethylene glycol (PEG) mono- and di-ethers wlth allphatic C12-C18 alcohols, whereby the polyethylene glycol (PEG) comprises 6 to 60 ethylene oxide units per molecule, preferably a mix-ture of polyethylene glycol mono- and di-esters with aliphatic Ce-Caa carbox-ylic acids, whereby the polyethylene glycol comprises 6 to 40 ethylene oxide units per molecule; • as co-surfactant monoacylglycerides of aliphatic Ce-C carboxylic acids and/or monoethers of glycerol with aliphatic C12-C22 alcohols, preferably monoacylglycerides of aliphatic Ce-Czz carboxylic acids, and • as lipophilic phase di- and triacylglycerides of allphatic Ce-C carboxylic ac ids. The pharmaceutical composition according to the invention is preferably charac-terlsed in that the system comprises • 2 to 90% by weight surfactants as defined above, • 5 to 60% by weight co-surfactants as defined above, and • O to 70% by weight of the lipophilic phase as defined above, whereby the components surfactant, co-surfactant and the lipophilic phase to- gether make up to 100% by weight of the system and the system consisting of surfactant, co-surfactant and the lipophilic phase makes up 10% to 95% by weight of the pharmaceutical composition. Preferably, the pharmaceutical composition is characterised in that the system consistlng of surfactant, co-surfactant and fipophilic phase makes up 10 to 70% by weight, preferably 20 to 50% by weight, more preferably 25 to 40% by weight, of the pharmaceutical composition. In a further embodiment, the pharmaceutical composition according to the invention is characterised in that the system comprises • 40 to 90% by weight, preferably 60 to 85% by weight, surfactants, • 5 to 40% by weight, preferably 15-30% by weight, co-surfactants, and • o 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 pharmaceutlcal composîtlons may furthermore contain pharmaceutically convenţional compatible auxiliaries, carriers and/or excipients as defined hereinafter. In particular, the pharmaceutically compatible auxiliaries, carriers and/or excipients are selected from the group consisting of free polyethylene glycols having an av-erage molecular weight of about 200 to about 6000, glycerol, lower alcohols, in particular straight-chaln or branched Ci-C4-alcohols such as 2-propanol, sugars, such as lao tose, sucrose or dextrose; cellulosics, such as microcrystalline cellulose or microcrys-talline cellulose/sodium carboxymethyl cellulose, and mixtures of the aforementioned substances. In a preferred embodiment, the proportion of the pharmaceutically compatible auxiliaries and/or excipients furthermore 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 macrogolglyceride mixtura representing the system consisting of surfactant, co-surfactant and lipophific phase, whereby the macrogolglycerides are a mixtura of mono-, di- and tri-acylglycerides and polyethylene glycol (PEG) mono-and di-esters of aliphatic Ce-C^ carboxylic acids, and also possibly small proportions of glycerol and free polyethylene glycol. The polyethylene glycol (PEG) contained in the macrogolglyceride mixtures is preferably PEG which has on average 6 to at most 40 ethylene oxide units per molecule or a molecular weight of between 200 and 2000. One further aspect of the invention provides for the pharmaceutical composition to comprise a system consisting of surfactant, co-surfactant and lipophilic phase, the system having an HLB value greater than or equal to 10 and a melting point greater than or equal to 3O°C. In a preferred embodiment, the system has an HLB value of 10 to 16, preferably of 12 to 15, and has a melting point of between 30 and 60°C, preferably between 40 and 50°C. In particular, the system characterlsed by HLB value and meltlng point is a mix-ture of mono-, di- and triacylgylcerldes and mono- and dlesters of polyethylene glycol (PEG) with aliphatic carboxylic acids with 8 to 20 carbon atoms, whereby the polyethylene glycol preferably has 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 hence the starting oii for the preparation of the macrogolglyceride mixture. "Aliphatic C8-Ci8 carboxylic acids" designates mixtures in which caprylic acid (C8), capric acid (C10), lauric acid (C12), myristic acid (C 14), pal mitic acid (C16) and stearic acid (C18) are contained in a significant and variable proportion, if these acids are saturated, and the corresponding unsaturated C8-Ci8 carboxylic acids. The propor-tions of these fatty acids may vary according to the starting oils. Such a mixture of mono-, di- and triacylgylcerides and mono- and diesters of polyethylene glycol (PEG) with aliphatic carboxylic acids with 8 to 18 carbon atoms can for example be obtained by a reaction between a polyethylene glycol with a molecular weight of between 200 and 1500 and a starting oii, the starting oii consisting of a triglyceride mixture 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 iinolenic acid, individually or as a mixture. Optionally, the product of such a 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®. One advantageous embodiment of the invention provides that, of the producte known under the trade name Gelucire * in particular "Gelucire ® 50/13" and/or 'Gelucire® 44/14" represent suitable mixtures for use in the pharmaceutical preparations according to the invention. Gelucire® 50/13 is a mixture with mono-, di- and triacylglycerides and mono- and diesters of polyethylene glycol, with palmitic acid (C16) and stearic acid (C18) at 40 %to 50 %and 48 % to 58 %, respectively making up the major proportion of bound fatty acids. The proportion of caprylic acid (C8) and capric acid (C10) is less than 3% in each case, and the pnoportlon of lauric acid (C12) and myrlstlc acid (C14) In each case is less than 5%. A preferred embodiment of the present invention provides for a pharmaceutical composition which comprises a system containing a mixture of mono-, di- and triacyl-glycerides and polyethylene glycol mono- and diesters of aliphatic C8-Ci8 carboxylic acids and also possibly small proportions of glycerin and free polyethylene glycol, the system having a melting point belween 46°C and 51 °C and an HLB value of around 13. Gelucire® 44/14 is a mixture with mono-, di- and triacylgylcerides and mono- and diesters of polyethylene glycol, the respective proportions of palmitic acid (C16) being 4 to 25%, stearic acid (C18) 5 to 35%, caprylic acid (C8) less than 15%, capric acid (C10) less than 12%, lauric acid (C12) 30 to 50% and myristic acid (C14) 5 to 25%. Gelucire® 44/14 can for example be prepared by an alcoholysis/esterification reaction using palm kernel oii and polyethylene glycol 1500. One preferred embodiment of the present invention provides for a pharmaceutical composition which comprises a system containing a mixture of mono-, di- and triacyl-glycerides and polyethylene glycol mono- and diesters of aliphatic C8-Ci8 carboxylic acids and also possibly small proportions of glycerin and free .polyethylene glycol, the system having a melting point belween 42°C and 48°C and an HLB value of around 14. In an alternative embodiment, the pharmaceutical composition of the invention is characterised in that an ionic surfactant is used as surfactant. Preferably, the ionic sur-factant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcho-line, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophos-phatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophos-phatidylinositol, lysophosphatidic acid, lysophosphatidylserine, and mixtures thereof; and is preferably lysophosphatidylcholine. In particular, a pharmaceutical composition of the inventions comprises a system containing • as surfactant lysophosphatidylcholine, • as co-surfactant a mixture of mono-acylglycerides with aliphatic saturated and/or unsaturated C16-C2o carboxylic acids, preferably with oleic and/or li- noleic acid, and • a lipophilic phase of di- and/or triacylglycerides with aliphatic Cie-Cao carbox ylic acids, preferably with oleic and/or linoleic acid. As a commercially available mixture of mono-, di- and triacylglycerides with aliphatic saturated and/or unsaturated C19-C20 carboxylic acids Maisine® (Gattefosse) can be used. Preferably, said pharmaceutical composition is characterised in that the system comprises 2 to 10%, preferably 5%, by weight lysophosphatidylchollne, 28 to 51% by weight mono-acylglycerides mainly of oleic acid and linoleic acid, and 36 to 54% by weight di-acylglycerides and 4 to 20% by weight tri-acylglycerides mainly of oleic acid and linoleic acid, whereby the system consisting of suriactant, co-surfactant and the lipophilic phase together makes up 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 may be selected, for example powders, pellets, granules, tablets, or microspheres, which if desired may be filled into capsules or sa-chets or may be compressed to form tablets. Granules are preferably produced by melt granulation. Tablets are usually made from the powder or the melt granules. Pellets can be produced either by exploiting the thermoplastic properties of the auxiliaries in a heavy-duty mixer (melt pelletisation) or by tradiţional methods e.g. extrusion (e.g. melt extrusion or wet extrusion) and spheronisation. If individual enzyme types are present and are obtained separately, such as a lipase, a protease or an amylase from microbial origin, these may in this case be present together or spatially separated from each other. If the individual enzymes are not spatially separated from each other, dry proc-essing and/or storage is preferred. The pharmaceutical compositions according to the invention, which are self-emulsifiable on contact with a hydrophilic phase and optionally a lipophilic phase, con-tain enzymes or enzyme mixtures with at least lipolytic activity as active substance. In a preferred variant of the present invention, the enzymes or enzyme mixtures may how- ever, in addition to the llpolytic activity, also have proteolytlc activlty, i.e. contain at least one protease, and/or amylolytic activity, i.e. contain at least one amylase. In one preferred variant of the present invention, the lipolytic activity of the enzymes or enzyme mixtures is provided by a microbial lipase. In another embodiment, the pharmaceutical composition contains enzymes or enzyme mixtures whlch are pancreatin and/or pancreatin-like, preferably pancreatin-containing mixtures of digestive enzymes. Preferably, the pancreatin and/or pancreatin-like mixtures of digestive enzymes make up 65 — 85%, in particular 75 - 80% by weight, of the pharmaceutical composition. Alternatively, the enzyme mixtura 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 enzyme mixture. In one variant of the invention, the enzyme mixture used is purely of microbial origin. Examples of such physiologically acceptable bacteria! and/or fungal enzymes have already been described in the prior art, together with procedures how to obtain these enzymes and with their use for the treatment of maldigestjpn. For example such synthetic mixtures of lipase, protease and amylase, each of which are microbially ob-tained, and also pharmaceutical preparations containing these mixtures are described in internaţional patent application WO 02/060474 and patent application EP O 828 509. Preferably, the pharmaceutical composition contains microbial enzymes making up 5 - 80%, in particular 20 - 60% by weight, of the pharmaceutical composition. In the context of the invention, most preferred are those mixtures of digestive enzymes with lipolytic, proteolytic and amylolytic activity, the properties of which are close to those of pancreatin. Pancreatin-containing mixtures of digestive enzymes and also in particular pancreatin itself are therefore preferred in the context of the present invention as disclosed above. However it is possible to add to the pancreatin or the pancreatin-containing mixtures of digestive enzymes if desired one or more microbial enzymes, i.e. lipases, proteases and/or amylases obtained from microbial sources. Suitable microbial enzymes for the sole use as enzyme mixtura or even as addition to pancreatin or the pancreatin-containing mixtures of digestive enzymes are in particular bacteria! or fungal enzymes, such as from the species Bacillus or Pseudomonas, or from fungal cultures, such as from the species Aspergillus, Humicola or Rhizomucor. Preferably, the microbial enzymes, in particular the microbial lipase, are recombinantly produced. In a further preferred variant of the present invention the microbial lipase is a lipase variant or a mutated lipase. The present invention furthermore relates to the use of a system comprising • at least one surfactant, • at least one co-surfactant, and • optionally a lipophilic phase for stabilising the lipolytic activity in the acidic pH range and/or for improving 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. The possible further configurations of the system to be used, consisting of surfactant, co-surfactant and lipophilic phase, correspond to the embodiments aiready men-tioned for the self-emulsifiable pharmaceutical preparation according to the invention, which comprises such a system. The invention also relates to a process for the preparation of solid pharmaceutical preparations containing enzymes or enzyme mixtures with at least lipolytic and optionally also proteolytic and/or amylolytic activity, preferably pancreatin and/or pancreatin-like mixtures of digestive enzymes. According to the invention, the enzymes or enzyme mixtures are then converted into a suitable medicament form with a system comprising • a surfactant chosen from the group consisting of polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; 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 consisting of mono-acylglycerides, mono- ethers of glycerol, parţial esters of propylenglycol, parţial esters of polyglycerol, parţial esters of ethyl diglycol and mixtures thereof, and • a lipophilic phase, which is represented by di- and/or trlacylglycerides. and also optionally convenţional, pharmaceutically compatible auxiliaries, canriers and/or excipients. The further possible configurations of the system consisting of surfactant, co-surfactant and lipophilic phase and to be used in the preparation process conrespond to the embodiments already mentioned for the self-emulsifiable pharmaceutical preparation according to the invention, which comprises such a system. The following examples are intended to explain the invention further, but without limiting its scope: Example 1: Preparation of pancreatin-containing compositions according to the invention and com-parison of the lipoiytic activity of a usual pancreatin formulation and a pancreatin formu-lation according to the invention comprising a system consisting of a surfactant, co-surfactant and lipophilic phase a) Usual preparation (pellets) not according to the invention: The usual formulation was prepgred according to the process disclosed in patent speci-fication EP O 583 726. 120 g pancreatin and 30 g PEG 4000 were initially dry-mixed and then moistened with 20 g isopropanol. The moist mixture was extruded and then rounded in a suitable rounder with the aid of paraffin oii. The pellets produced were then dried. b) Preparation according to the invention (pellets) (Example 1 A) 350 g Gelucire® 50/13 was melted in a beaker in a water bath at a temperature of 52°C. The molton mass was mixed with 650 g pancreatin in a dual-jacket mixer for 10 min. The homogenous mixture was placed in a melt extruder for extrusion. Then the extrudate was rounded in a suitable rounder or spheroniser. The pellets obtained hâd a diameter of 1.0-1.6 mm. c) Preparation accordlno to the invention (granules) (Exemple 300 g Gelucire* 44/14 was melted in a beaker in a water bath at a temperatura of 48°C. The molten mass was mixed with 700 g pancreatin in a dual-jacket mixer for approx. 15 min. and then cooled (melt granulation). The determination of the activity of the lipase as a function of the pH value and also the time-dependent change in lipase activity was performeri in accordance with the method of the "Federation Internationale Phatmaceutique/European Pharma-copeia" (abbreviated hereafter to FIP/Ph.Eur.). With this standard analysis method, the hydrolytic activity of the lipase in the sample to be investigated is determined with the substrate olive oii. The free fatty acids cleaved off from the triglycerides of the olive oii are titrated with sodium hydroxide solution at a constant pH of 9.0. The lipase activity of the sample is determined by the comparison of the rate at which the sample hydrolyses an olive oi) ernulsion with the rate at which a suspension of a standard pancreas refer-ence powder hydrolyses the same substrate under the same conditions. The absolute and relative lipolytic activity of the usual preparation and the preparation according to the invention (pellets) determined in each case in accordance with FIP/Ph.Eur. are summarised 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 in accordance with FIP/Ph.Eur. are summarised in Table 2: Table 1: Absolute and relative lipolytic activity of the standard preparation and the preparation according to the invention (pellets with Gelucire" 50/13) (Table Removed) Table 2: Absolute and relative llpolytic activity of the standard preparation and the preparation according to the irwention (granules with Gelucire*44/14) (Table Removed) It becomes 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 enzyme mixtures with at least lipolytic activity, preferably pancreatin and/or pancreatin-like mixtures of digestive enzymes, contributes to im-proved lipolytic activity compared with usual formulations of pancreatin known in the state of the ari The absolute lipolytic activity of the respective pharmaceutical preparation deter-mined in accordance with FIP/Ph.Eur. is expressed with reference to the total lipolytic activity theoretically present in the sample in the form of a relative activity, in order to take account of the different concentrations of pancreatin in the formulations. Compari-son 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 with usual formulations of pancreatin. Furthermore, with reference to the value of the relative lipase activity of the preparation according to the invention of more than 100%, it becomes clear that there is an activation effect of the lipase by the system consisting of surfactant, co-surfactant and optionally lipophilic phase added to the preparations according to the invention. Example 2 Comparison of the stability of lipolytic activity of a usual pancreatin formulation and a pancreatin formulation according to the invention comprising a system consisting of a surfactant, co-surfactant and lipophilic phase at different pH values In order to compare the stablllty of llpolytlc activity of a usual pancreatin formula-tion and a pharmaceutical formulation according to the Invention comprising an enzyme mixture 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 usual pancreatin formulation was compared with the activity of a mixture of Gelucire® and pancreatin incubated for up to 2 hours at different pH values (pH 6, pH 5 and pH 4). a) Standard preparation foellets): The usual formulation was prepared according to the process disclosed in patent speci-fication EP O 583 726. 120 g pancreatin and 30 g PEG 4000 were initially dry-mixed and then moistened with 20 g isopropanol. The moist mixture was extruded and then rounded in a suitable rounder and with the aid of paraffin oii. The pellets produced were then dried. b) Preparation according to the invention (pellets) - Exemple 2 300 g Gelucire® 44/14 was melted in a beaker in a water bath at a temperatura of 48°C. The molten mass was mixed with 700 g pancreatin in a dual-casing high-speed mixer (melt pelletisation). The determination of the activity of the lipase as a function of the pH value and also the time-dependent change in lipase activity takes place in accordance with the method of the FIP/Ph.Eur. as described above. To determine the release behaviour 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 solu-tion (pH 6, pH 5, pH 4). At intervals of 15 minutes, samples were taken and the lipolytic activity in the samples was determined in accordance with the FIP/Ph.Eur. method described above. 600 ml buffer (67 mM phosphate, 34 mM NaCI, pH 6.0, pH 5.0, pH 4.0) was heated to a constant temperature of 37°C in a 1 l beaker in the decomposition tester. Once the constant temperature hâd been reached, 2 g of sample was added to the beaker and the decomposition tester was set moving. The pH value of the phosphate buffer was kept constant during the testing time. At intervals of 15 minutes in each case, samples were taken and the lipolytic activity In the samples was determined in accordance with FIP/Ph.Eur. The relative lipolytic activity determined after 15, 30,45, 60, 75, 90,105 and 120 minutes of the usual preparation and the preparation according to the invention in accordance with FIP/Ph.Eur. are summarised in Table 3 below; details are cjiven in % of the activity of the respective sample compared with a standard pancress reference powder in accordance with FIP/Ph.Eur. Table 3: pH-dependency of the relative lipolytic activity of a usual pancreatin formulation and a pancreatin preparation according to the invention (Table Removed) It can be seen from these data that the addition of systems compri-sing at least one surfactant, at least one co-surfactant, and a lipophilic phase to phsrmaceutical preparations of enzymes and enzyme mixtures with at least lipolytic activity, preferably pancreatin and/or pancreatin-like mixtures of digestive enzymes, contributes to stabilis-ing the lipolytic activity in the acidic pH range. At a pH vaiue of 6, comparison of the lipolytic activity of a usual pancreatin preparation and a pancreatin preparation according to the invention over a tlme of 120 minutes shows that the lipolytic acstivity in both preparation forms over time decreases only relatively slightly, with the lipolytic activity of the preparation according to the invention increased by approximatehy 10% compared with the usual formulation again being observed within the first hour. However, a pH value of 6 is known not to have any great influence on the lipolytic activity. On the other hand, at a pH value of 5 the lipolytic activity of the usual preparatio n is reduced very much more quickly compared with the preparation according to the invention. Whereas the preparation according to the invention has (ost less than 10% of the lipolytic activity after 90 minutes, the usual preparation has only a lipolytic activity of less than 70% remalning compared with a pancreas reference powder in accordance with FIP/Ph.Eur. In particular at a pH value of 4, the preparation according to the inven-tion has a markedly greater lipolytic (residual) activity than the usual preparation. Ao cordingly, the pharmaceutical preparations according to the invention have a substan-tially increased lipolytic activity in the acidîc pH medium. Example 3 Dosage dependence of a pancreatin formulation according to the invention comprising a system consisting of a surfactant, co-surfactant and lipophilic phase on digestibility of a high lat diet in the Pancreatic exocrine insufficient mlnipig The efficacy of a pelleted pharmaceutical formulation according to the invention comprising an enzyme mixture with at least lipolytic activity and a system consisting of at least one surfactant, at least one co-surfactant, and a lipophilic phase to improve digestion and absorption of făt in minipigs, in which the pancreatic duet has been ligated to induce a complete pancreatic exocrine insufficiency, was analysed in these pigs fed a high (32%) făt diet. a) Preparation accordinq to the invention (pellets) 250 g Gelucire® 44/14 (Gattefosse) was melted in a beaker in a water bath at a temperatura of 48°C. The molten mass was mixed with 750 g pancreatin in a dual-casing high-speed mixer (melt pelletisation). The pellet size of this formulation was similar to thatofthe marketed pancreatin product. Determination of the activitv of lipase Studies were performed in 6 minipigs (Ellegaard, female Gottingen minipigs) with induced pancreatic exocrine insufficiency, weighing 20-30 kg at surgery. The pigs were prepared as previously described (Tabeling R, Gregory P, Kamphues J. 1999: Studies on nutrient digestibilities (pre-caecal and total) in pancreatic duct-ligated pigs and the effects of enzyme substitution. J. Anim. Physiol. a. Anim. Nutr. 82, 251-263] under halothane anaesthesia; following a mid-line laparotomy; the pancreatic duet was ligated after which the pigs were chronically fitted with an ileo-caecal re-entrant fistula which was exteriorized on the right flank. The success of the pancreatic duet ligatlon was conflrmed (faecal chymotrypsin test) before starting the digestibility studies, which began at least 4 weeks after the pigs hâd recovered from the surgery. The pigs were fed two 250 g meals/day (08.00 and 20.00h) of a high făt diet (containing: 180g double-milled Altromin 9021 [modified], 70 g soya oii [Roth]; overall contents are 99% dry matter, 4% crude ash, 32% crude făt, 16% crude protein, 28% starch, 3 % crude fibre) plus 0.625 g Cr2O3 per meal, mixed with 1 litre water. The meals plus enzymes were carefully mixed together immedlately before offering to the pigs. The meals were generally consumed within 5 minutes. During the study the pigs received 0, 28.000 or 336.000 FIP ţipase units per meal as a formulation according to the invention for 14 days, with a complete collection of faeces for the last 5 days. The faeces (and the feed) were frozen at -20°C, freeze dried, and a Weender analysis was performed [Naumann C, Bassler R. 1993: Die chemische Untersuchung von Futtermitteln. 3. Aufl. VDLUFA-Verlag, Darmstadt] to determine content of dry matter (drying at 103°C for 8h), and crude făt (determined gravimetrically after boiling for 30 min with conc. HCI, foilowed by a 6h extraction with petrol ether), while Cr203 was oxidized to chromate and chromium content was calcu-lated via extinction at 365 nm [Petry H, Rapp W. 1970: Zur Problematik der Chro-moxidbestimmung in Verdauungsversuchen. Z. Tierphysiol. Tieremâhrung und Futter-mitellkunde 27, 181-189]. The content of făt and chromium determined per 100 g dry matter feed and faeces (see above) allowed calculation of the digestibility of făt (CFA) according to the formula: The efficacy to improve digestion and absorption of făt in minipigs, in which the pancreatic duet has been ligated to induce a complete pancreatic exocrine insuffi-ciency, measured in the % făt digestibility is given for the preparation according to the invention for different amounts of lipase activity added (given in FIP/Ph.Eur. units). Table 4: % făt digestlbillty in minipigs receiving a pancreatin preparation accord-ing to the invention (Table Removed) Results are mean ± S.D. The formulation according to the invention caused a very strong and dose-dependent improvement in făt digestibility, already showing a highly efficient improve-ment at the lower dose tested. Example 4 Comparison of the stability of lipolytic activity of a usual pancreatin powder and a pancreatin formulation according to the invention comprising a system consisting of a sur-factant, co-surfactant and lipophilic phase at different pH values Further preparations according to the invention were prepared and analysed with regard to their lipolytic activity in comparison to pancreatin powder at different acidic pH values (pH 6, pH 5 and pH 4). a) Preparation for comparison not accordino to the invention: Pancreatin powder b) Preparation accordino to the invention - Example 4A 700 g Pancreatin powder 200 g Gelucire™ 44/14 (Gattefosse) 100 g Labrasol™ (Gattefosse) The Gelucire® 44/14 and the Labrasol9 were mixed and melted in a beaker in a water bath at a temperature of 48°C. The molten mass was mixed with 700 g pancreatin in a dual-casing high-speed mixer (melt granulation). c) Preparation acoordlng to the Inventlon — Example 4B 800 g Pancreatin powder 190 g Maisine® (Gattefosse) 10 g LPC (Lysophosphatidylcholine) The Maisine® and the Lysophosphatidylcholine were mixed and melted in a beaker in a water bath at a temperature of 48°C. The molten mass was mixed with 800 g pan-creatin in a dual-caslng high-speed mixer (melt granulation). The determination of the activity of the lipase as a function of the pH value and also the time-dependent change in lipase activity was performed as described in Example 2. The release behaviour of the lipase at different pH values in the pancreatin powder and the preparation according to the invention was performed 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 in accordance with FIP/Ph.Eur. are summarised in Ta-bles 5A and 5B below; details are given in % of the activity of the respective sample compared with a standard pancreas reference powder in accordance with FIP/Ph.Eur. Table SA: pH-dependency of the relative lipolytic activity of a standard pancreatin powder and the pancreatin preparation "4A" according to the invention (Table Removed) Table 5B: pH-dependency of the relative lipolytic activity of a standard pancreatln powder and the pancreatin preparation "4B" according to the invention (Table Removed) From these data it can be concluded that the addition of systems comprising at least one surfactant, at least one co-surfactant, and a lipophilic phase to pharmaceuti-cal preparations of enzymes and enzyme mixtures with at least lipolytic activity, pref-erably pancreatin and/or pancreatin-like mixtures of digestive enzymes, contributes to stabilising the lipolytic activity in the acidic pH range. Example 5 Determinatlon of the lipolytic activity of a formulation according to the invention comprising a lipase of microblal origin and a system consisting of a surfactant, co-surfactant and lipophilic phase and determination of stability at different pH values In order to determine the lipolytic activity and to show the improved stability at acidic pH of a pharmaceutical formulation according to the invention comprising an enzyme mixtura with at least lipolytic activity, whereby the lipolytic activity is provided by a microbial, optionally recombinantly produced lipase, and a system consisting of at least one surfactant, at least one co-surfactant, and a lipophilic phase, the activity of a pharmaceutical formulation consisting of a mixture of Gelucire™ and a microbial lipase is determined at different pH values (pH 6, pH 5, pH 4 and 3) and compared to a not stabilized lipase preparation. a) Preparation according to the invention (granulate) 562.5 g Gelucire® 44/14 was melted in a beaker in a water bath at a temperatura of 48°C. 937.5 g of a microbial lipase preparation (the active lipase protein representing about 50 to 60% (w/w) of the dry matter of the preparation) were provided in a dual- jacket mixer at 46°C, then the molton Gelucfre was added and the compounds were mixed in a first step at low speed for 3 min, then for approx. 15 min. at high speed and finally cooled (melt granulation). b) Preparation for comoarison (not according to the Invention) A microbial lipase preparation was prepared by using common spray dry technique. Determination of the activity of the lipase was performed in accordance with the method of the "Federation Internationale Pharmaceutique" (abbreviated hereafter to FIP) for microbial lipases, except that the concentration of bile salts is 10 mM.. With this standard analysis method, the hydrolytic activity of the lipase in the sample to be investigated is determined using olive oii as substrate. Released free fatty acids are titrated with sodium hydroxide solution at a constant pH of 7.0. The lipase activity of the sample is determined by comparison of the rate at which the sample hy-drolyses an olive oii emulsion with the rate at which a suspension of a microbial lipase reference powder hydrolyses the same substrate under the same conditions. To determine the pH-stability of the lipase at different pH values in an unstabi-lized 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 intervals of 15 minutes, samples were taken and the lipolytic activity in the samples was determined in accordance with the FIP method. 100 mg of lipase were incubated in 100 ml buffer (0.1 M malonic acid buffer, 1 mM calcium chioride pH 3,4 and 5) at 37°C. Samples were drawn every 15 min for a total duration of 2 hours and the lipolytic activity of the samples was determined as follows: An olive oii suspension was prepared by mixîng 175 g olive oii with 630 ml of a solution of 700 g of gum arabic and 94.4 g calcium chioride di-hydrate in 5,900 ml wa-ter for 15 minutes in a food mixer at maximal speed. The emulsion was cooled to 37°C and the pH adjusted to pH 6.8 with sodium hydroxide solution. Three reference solu-tions were prepared by extracting an appropriate amount of FIP microbial lipase standard with an ice-cold 1% (m/v) solution of sodium chioride such that reference solutions with 50 FlP-U/ml, 65 FlP-U/ml and 80 FlP-U/ml were obtained. Sample solutions were prepared by extracting an amount of sample corresponding to app. 6,500 units activity for 15 minutes with a total of 100 ml Ice-cold 1% (m/v) solutlon of sodium chioride. The samples were further diluted in ice-cold 1% (m/v) solution of sodium chioride such that the titration rate was within the range of the titration rates obtained with the reference solutions. The titration rates of the reference and sample solutions were determined by combining in a thermostated vessel 19 ml of olive oii suspension with 10 ml of a solution of 492 mg llpase activating mixtura (PIP) in 500 ml of water. The combined solutions were thermostated to 37°C and the pH adjusted to pH 7.0. One ml of reference solution or sample solution were added and the released fatty acids titrated under pH stable conditions with 0.1 M sodium hydroxide solution for a duration of 5 minutes. The titration rate was calculated by linear regression from at least d measurement points between the 60th and the SOOth second of titration. From the titration rates of the reference solutions a calibration function was calculated by linear regression. The calibration function takes the form y = mx + b where y: titration rate; m: slope; x: FlP-units of the reference solution; and b: axis intercept. Us-ing the values thus determined 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 determined after O, 15, 30, 45, 60, 75, 90, 105 and 120 minutes of an unstabilized microbial lipase preparation and the preparation accord-ing to the invention in accordance with FIP are determined. A comparison of the results obtained can show the improved lipolytic activity and the increased stability within the acidic pH range of the formulation according to the invention comprising a microbial lipase preparation over the unstabilized lipase preparation. WE CLAIM: 1. A pharmaceutical composition for oral administration, which is self-emulsifiable on contact with a hydrophilic phase and a lipophilic phase, said composition comprising: (i) enzymes or enzyme mixtures with at least lipolytic activity, and (ii) a system comprising • at least one surfactant in an amount of 2 to 90% by weight, chosen from the group consisting of polyethylene glycol fatty acid mono- and/or di-esters with aliphatic C6-C22 carboxylic acids; polyethylene glycol glycerol fatty acid esters with aliphatic C6-C22 carboxylic acids; polyethylene glycol alkyl mono- and/or di-ethers with aliphatic C12-C18 alcohols, and mixtures thereof; or an ionic surfactant selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophospha-tidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophos-phatidylinositol, lysophosphatidic acid, lysophosphatidylserine, and mixtures thereof, • at least one co-surfactant in an amount of 5 to 60% by weight, chosen from the group consisting of mono-acylglycerides with aliphatic C6-C22 carboxylic acids, mono-ethers of glycerol ethers with aliphatic C12-C18 alcohols, partial esters of propylenglycol with aliphatic C6-C22 carboxylic acids, partial esters of polyglyc-erol with aliphatic C6-C22 carboxylic acids, and mixtures thereof, and • in an amount of 0 to 70% by weight, a lipophilic phase represented by di- and/or triacylglycerides with aliphatic C6-C22 carboxylic acids, whereby the components surfactant, co-surfactant and the lipophilic phase together make up to 100% by weight of the system, and the system makes up 10% to 95% by weight of the pharmaceutical composition. 2. A pharmaceutical composition as claimed in claim 1, wherein the hydrophilic phase used to form the final emulsion after ingestion is supplied by the physiological fluid of the digestive milieu. 3. A pharmaceutical composition as claimed in claim 1 or 2, wherein 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 food ingested. 4. A pharmaceutical composition as claimed in one of claims 1 to 3, wherein the system comprises a lipophilic phase. 5. A pharmaceutical composition as claimed in claim 4, wherein the system comprises • as surfactant at least one agent having a hydrophilic-lipophilic balance value above 6 and below 18, • as co-surfactant at least one agent having a hydrophilic-lipophilic balance value below 10, and • as lipophilic phase a lipidic phase, whereby the system 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. A pharmaceutical composition as claimed in claim 1, wherein the system comprises • as surfactant a mixture of polyethylene glycol mono- and di-esters with aliphatic C6-C22 carboxylic acids and/or polyethylene glycol mono- and di-ethers with aliphatic C12-C18 alcohols, whereby the polyethylene glycol comprises 6 to 60 ethylene oxide units per molecule, • as co-surfactant monoacylglycerides of aliphatic C6-C22 carboxylic acids and/or monoethers of glycerol with aliphatic C12-C22 alcohols, and • as lipophilic phase di- and triacylglycerides of aliphatic C6-C22 carboxylic acids. 7. A pharmaceutical composition as claimed in claim 6, wherein a mixture of polyethylene glycol mono- and di-esters with aliphatic C6-C22 carboxylic acids, whereby the polyethylene glycol comprises 6 to 40 ethylene oxide units per molecule, are used as surfactant, and monoacylglycerides of aliphatic C6-C22 carboxylic acids are used as co-surfactant. 8. A pharmaceutical composition as claimed in claim 1, wherein the system consisting of surfactant, co-surfactant and lipophilic phase makes up 10 to 70% by weight, preferably 20 to 50% by weight, more preferably 25 to 40% by weight, of the pharmaceutical composition. 9. A pharmaceutical composition as claimed in one of the claims 1 or 8, wherein the system comprises • 40 to 90% by weight, preferably 60 to 85% by weight, surfactants, • 5 to 40% by weight, preferably 15-30% by weight, co-surfactants, and • 0 to 40% by weight, preferably 15-30% by weight, of the lipophilic phase, the total of co-surfactants and the lipophilic phase together being at least 10% by weight, preferably between 15 and 40% by weight of the system. 10. A pharmaceutical composition as claimed in one of claims 4 to 9, wherein the composition in addition contains pharmaceutically compatible auxiliaries, carriers and/or ex-cipients. 11. A pharmaceutical composition as claimed in claim 10, wherein the pharmaceutically compatible auxiliaries, carriers and/or excipients are selected from the group consisting of polyethylene glycol, glycerol, C1-C4-alcohols, sugars, cellulosics and mixtures of the aforementioned substances. 12. A pharmaceutical composition as claimed in claim 10 or 11, wherein the pharmaceutically compatible auxiliaries, carriers and/or excipients make up a maximum 20% by weight of the pharmaceutical composition. 13. A pharmaceutical composition as claimed in one of the claims 4 to 12, wherein ma-crogolglycerides represent the system comprising surfactant, co-surfactant and lipophilic phase and also possibly small proportions of glycerin and free polyethylene glycol, whereby the macrogolglycerides are a mixture of mono-, di- and triacylglycerides and polyethylene glycol mono- and diesters of aliphatic C6-C22 carboxylic acids, with the polyethylene glycol comprising about 6 to about 32 ethylene oxide units per molecule. 14. A pharmaceutical composition as claimed in claim 13, wherein the system comprising surfactant, co-surfactant and lipophilic phase has a hydrophilic-lipophilic balance value of greater or equal than 10, and a melting point greater than or equal to 30°C. 15. A pharmaceutical composition as claimed in claim 14, wherein the system has a hydrophilic-lipophilic ratio of 10 to 16, preferably of 12 to 15, and a melting point of between 30 and 60°C, preferably between 40 and 50°C. 16. A pharmaceutical composition as claimed in claim 15, wherein the system contains a mixture of mono-, di- and triacylglycerides and polyethylene glycol mono- and diesters of aliphatic C8-C18 carboxylic acids, and optionally small proportions of glycerol and/or free polyethylene glycol, and has a melting point between 42°C and 48°C and an HLB value of around 14. 17. A pharmaceutical composition as claimed in claim 15, wherein the system contains a mixture of mono-, di- and triacylglycerides and polyethylene glycol mono- and diesters of aliphatic C8-C18 carboxylic acids and optionally small proportions of glycerol and free polyethylene glycol, the system having a melting point between 46°C and 51°C and an HLB value of around 13. 18. A pharmaceutical composition as claimed in claim 13, wherein the system contains a mixture of mono-, di- and triacylglycerides and polyethylene glycol PEG-32 mono- and diesters mainly of aliphatic C8-C16 carboxylic acids, a mixture of mono-, di- and triacylglycerides and polyethylene glycol PEG-8 mono- and diesters mainly of aliphatic C6-C10 carboxylic acids and optionally small proportions of glycerol and free polyethylene glycol. 19. A pharmaceutical composition as claimed in claim 1, wherein the system comprises • as surfactant lysophosphatidylcholine, • as co-surfactant a mixture of mono-acylglycerides with aliphatic saturated and/or unsaturated C16-C20 carboxylic acids, preferably with oleic and/or linoleic acid, and • a lipophilic phase represented by di- and/or triacylglycerides with aliphatic C16-C20 carboxylic acids, preferably with oleic and/or linoleic acid. 20. A pharmaceutical composition as claimed in claim 19, wherein the system com prises • 2 to 10%, preferably 5%, by weight lysophosphatidylcholine, • 28 to 51% by weight mono-acylglycerides mainly of oleic acid and linoleic acid, and • 36 to 54% by weight di-acylglycerides and 4 to 20% by weight triacylglycerides mainly of oleic acid and linoleic acid, whereby the system consisting of surfactant, co-surfactant and the lipophilic phase together makes up 10% to 30%, preferably 20%, by weight of the pharmaceutical composition. 21. A pharmaceutical composition as claimed in one of claims 1 to 20, wherein it is a solid pharmaceutical preparation in the form of a powder, granules, tablets, pellets or the like. 22. A pharmaceutical composition as claimed in one of claims 1 to 21, wherein the lipolytic activity of the enzymes or enzyme mixtures is provided by a microbial, in particular bacterial or fungal, lipase. 23. A pharmaceutical composition as claimed in one of claims 1 to 21, wherein the enzymes or enzyme mixtures furthermore also have proteolytic and/or amylolytic activity. 24. A pharmaceutical composition as claimed in claim 23, wherein the enzymes or enzyme mixtures are pancreatin and/or pancreatin-like, preferably pancreatin-containing mixtures of digestive enzymes. 25. A pharmaceutical composition as claimed in claim 24, wherein the pancreatin and/or pancreatin-like mixtures of digestive enzymes make up 65 - 85%, in particular 75 - 80% by weight, of the pharmaceutical composition. 26. A pharmaceutical composition as claimed in claim 23, wherein a mixture of at least one microbial lipase and one or more microbial enzymes from the group of proteases and amylases is used as enzyme mixture. 27. A pharmaceutical composition as claimed in claim 26, wherein the microbial enzymes make up 5 - 80%, in particular 20 - 60% by weight, of the pharmaceutical composition. 28. A pharmaceutical composition as claimed in claim 23, wherein the enzymes or enzyme mixture are pancreatin or a pancreatin-containing mixture of digestive enzymes, additionally containing one or more microbial enzymes selected from the group of lipases, proteases and amylases. 29. A pharmaceutical composition as claimed in one of the claims 22, 26 or 28, wherein the microbial lipase is of fungal or bacterial origin and is recombinantly produced. 30. A pharmaceutical composition as claimed in claim 29, wherein said lipase is a lipase variant or a mutated lipase. 31. A process for the preparation of solid pharmaceutical preparations for oral administration containing enzymes or enzyme mixtures with at least lipolytic activity, characterised in that the enzymes or enzyme mixtures are converted into a suitable medicament form with a system comprising • a surfactant chosen from the group consisting of polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; 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 consisting of mono-acylglycerides, mono-ethers of glycerol, partial esters of propylenglycol, partial esters of polyglycerol, partial esters of ethyl diglycol and mixtures thereof, and • a lipophilic phase represented by di- and/or triacylglycerides. and also optionally conventional, pharmaceutically compatible auxiliaries, carriers and/or excipients, characterised in that the system of surfactant, co-surfactant and lipophilic phase is a system as defined within one of the claims 5 to 9 and 13 to 20. |
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| Patent Number | 251863 | ||||||||||||||||||
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| Indian Patent Application Number | 5334/DELNP/2006 | ||||||||||||||||||
| PG Journal Number | 16/2012 | ||||||||||||||||||
| Publication Date | 20-Apr-2012 | ||||||||||||||||||
| Grant Date | 12-Apr-2012 | ||||||||||||||||||
| Date of Filing | 14-Sep-2006 | ||||||||||||||||||
| Name of Patentee | SOLVAY PHARMACEUTICALS GMBH. | ||||||||||||||||||
| Applicant Address | HANS-BOECK-LER-ALLEE 20, 30173 HANNOVER, GERMANY. | ||||||||||||||||||
Inventors:
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| PCT International Classification Number | A61K 38/48 | ||||||||||||||||||
| PCT International Application Number | PCT/EP2005/051295 | ||||||||||||||||||
| PCT International Filing date | 2005-03-21 | ||||||||||||||||||
PCT Conventions:
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