Method for producing a composition having lipase activity and a composition suitable for pharmaceutical use with improved safety characteristics

Abstract

The present invention relates to a method for producing a composition having lipase activity and a composition suitable for pharmaceutical use, which has improved safety characteristics. The present invention describes a method for producing a solid or semi-solid composition, particularly a solid oral composition for pharmaceutical use, the method comprising treating an enzyme or enzyme mixture having lipase activity and a surfactant component under defined process parameters. The method is suitable for reducing undesired biological contamination, such as viral contamination, of the enzyme or enzyme mixture while maintaining its desired biological activity, such as enzyme activity. The method is suitable for industrial use. Also described is a solid or semi-solid composition comprising an enzyme or enzyme mixture having lipase activity, a surfactant component and a polymer additive, optionally comprising other adjuvants. The composition can preferably be obtained by the method as described herein. The present invention also describes a pharmaceutical composition comprising the solid or semi-solid composition as described herein.

Description

[0001] This application is a divisional application of a Chinese national phase patent application with the application number 201580055596.8 after the PCT application with the international application number PCT / EP2015 / 075787, the international filing date of November 05, 2015, and the invention title of "Process for producing a composition having lipase activity with improved safety characteristics and a composition suitable for pharmaceutical use" entered the Chinese national phase on April 13, 2017.

[0002] In a first aspect, the present application relates to a process or method for producing a composition having lipase activity with improved safety characteristics, said process or method comprising subjecting certain mixtures to a process variant selected from melt granulation, melt pelletization, and melt extrusion at a defined temperature and for a defined time period, said certain mixtures comprising at least (a) a biological material of human or mammalian origin having lipase activity, and (b) a surfactant component comprising at least one surfactant. Due to the surfactants and processing parameters further detailed herein, the process or method can substantially reduce the concentration of harmful biological contaminants (especially certain viruses) that may be present in the biological starting material while retaining the desired biological activity of the biological material, especially its desired lipase activity in the form of its desired enzyme activity. The biological material of human or mammalian origin may be, in particular, an enzyme or enzyme mixture having lipase activity, such as pancreatin and / or a digestive enzyme mixture containing pancreatin, especially porcine pancreatin.

[0003] In a second aspect, the present invention relates to a solid or semi-solid composition comprising: (a) an enzyme or enzyme mixture having lipase activity, preferably pancreatin and / or a digestive enzyme mixture containing pancreatin; (b) a surfactant component comprising a surfactant, a co-surfactant, and preferably a lipophilic phase; (d) a polymer additive; and (c) optionally other auxiliaries. The composition is suitable for pharmaceutical use. The solid or semi-solid composition can preferably be prepared by the processes and methods disclosed herein.

[0004] A pharmaceutical composition comprising the composition having lipase activity is further described herein. The pharmaceutical composition as described herein can preferably be administered to humans, in particular, by oral administration.

[0005] 1. Background

[0006] The risk of biological contamination, especially viral contamination, is a common feature of products of human or animal, especially mammalian origin (such as trypsin of porcine origin). Although other biological contaminants such as bacteria or protozoa may be present in the starting materials, these biological contaminants are usually inactivated during the established manufacturing processes for products designated for human use. There is still a need for better and more effective methods to inactivate more resistant biological contaminants (such as moderately to highly resistant viruses, especially highly resistant viruses such as non-enveloped viruses) in products for human use, merely as a preventive safety measure.

[0007] Known methods for virus inactivation include, for example, pasteurization, dry heat, vapor heat, solvent / detergent treatment, and low pH. The choice of method for virus inactivation depends on the target biological properties of the product to be processed and the contamination, the purification methods used, and the nature of the virus of concern. For example, solvent or detergent treatment can disrupt the lipid membrane of enveloped viruses and has thus been used for their inactivation. However, many non-enveloped viruses are generally not inactivated by solvent or detergent treatment. Heat, especially dry heat, is a known physical inactivation treatment for even highly resistant non-enveloped viruses in biological materials where the desired biological properties are to be preserved, but only few of the said methods are known to be usable on an industrial scale, in which large-scale processing at high efficiency within a relatively short time period and preservation of the desired biological activity are required. Known methods for using dry heat on an industrial scale to reduce the concentration of more resistant viruses in products for therapeutic use such as enzymes usually require an extended time period of several hours and monitoring of the moisture content to avoid impairing the desired biological activity of the target product, such as the desired enzyme activity present in porcine trypsin (see, for example, WO 2007 / 014896 A1 and EP 2 255 086 A1).

[0008] In WO 2005 / 092370 A1, a pharmaceutical composition comprising an enzyme mixture having lipase activity is described, and the composition can be prepared by mixing the enzyme with a surfactant, whereby the mixture can be processed by melt extrusion, melt granulation, or melt pelletization at a temperature of about 50°C. Although the described processing conditions retain good lipolytic activity, it has been found by virus-spiking experiments (not disclosed in WO 2005 / 092370) that the processing conditions described therein are not sufficient to inactivate more resistant viruses such as moderately resistant viruses, moderately to highly resistant viruses, or highly resistant viruses. In particular, if the contaminated composition is subjected to the conditions described in WO 2005 / 092370 A1, significant inactivation of viruses such as highly resistant porcine parvovirus ("PPV") can be expected.

[0009] EP 864 326 A2 relates to a process for the processing of pancreatin, in particular, in a matrix which does not contain a self-emulsifying system.

[0010] Pancreatin (pancreatic lipase) according to the EU (US) Pharmacopoeia is a pancreatic extract containing several digestive enzymes, the properties of which are defined by standard monographs such as those in the European (Ph.Eur., see monograph 350 “Pancreatic powder”) or US (USP) Pharmacopoeia. Pancreatin is derived from the pancreas of mammals and particularly includes the excreted pancreatic enzymes lipase, α-amylase and the proteases trypsin and chymotrypsin, as well as other enzymes. Pancreatin for pharmaceutical use usually has a bovine or porcine origin, with porcine pancreatin being preferred. Pancreatin from porcine pancreas for therapeutic use is manufactured only from pigs declared fit for human consumption under veterinary supervision according to a strictly controlled process.

[0011] Pharmaceutical compositions containing pancreatin (pancreatic lipase) such as are used to supplement digestive enzymes in the treatment and / or prevention of dyspepsia in mammals, particularly humans, and in particular dyspepsia caused by chronic exocrine pancreatic insufficiency in patients such as those suffering from cystic fibrosis, chronic pancreatitis or who have undergone upper gastrointestinal surgery.

[0012] 2. General overview

[0013] In a first aspect, the present invention provides a process for the preparation of a solid or semi-solid composition, preferably for pharmaceutical use, which composition comprises a biomaterial of human or mammalian origin, in particular pancreatin or a mixture of digestive enzymes containing pancreatin, derived from mammals, and a defined surfactant component. The process is suitable for substantially reducing harmful biological contaminants, such as may have been present or may have been present prior to the process in the biomaterial, to levels acceptable to the health authorities for pharmaceuticals. Harmful biological contaminants which can be reduced by the process as described herein particularly include viruses, including both enveloped and non-enveloped viruses with different degrees of resistance, such as moderately resistant viruses, moderately-highly resistant viruses and highly resistant viruses. At the same time, the process is suitable for maximally retaining the desired activity of the biomaterial used, in particular the desired and therapeutically valuable enzyme activities (such as lipolytic, amylolytic and / or proteolytic activities) of pancreatin or a mixture of digestive enzymes containing pancreatin. For example, the process as described herein is suitable for producing pharmaceutical compositions containing pancreatin or a pancreatin-containing mixture having improved in vivo lipolytic efficiency and acid stability as described in, for example, WO 2005 / 092370 A1, which pharmaceutical compositions have the additional benefit of strong biosafety characteristics.

[0014] Furthermore, due to their high efficiency, the methods as described herein are suitable for industrial use as they allow the production, on an industrial scale, of compositions such as pancreatin or pancreatin-containing digestive enzyme mixtures for pharmaceutical use, while exposing the compositions to high temperatures only for a time period significantly shorter than the time periods known from the prior art processes and methods (see, for example, WO 2007 / 014896 A1 or EP 2 255 086 A1).

[0015] Since the methods as described herein generally do not involve the use of water or other solvents, they are generally used for processing any moisture-sensitive biomaterials derived from tissues of human or mammalian animal sources, including, for example, porcine pancreatin.

[0016] In one embodiment, the present invention thus provides a method for preparing a composition, in particular a lipase-containing composition, whereby a mixture comprising the following is processed at a temperature of not less than 70 °C for a time period of not less than 30 seconds:

[0017] (a) a biomaterial derived from tissues of human or mammalian sources, in particular pancreatin and / or a pancreatin-containing digestive enzyme mixture derived from a mammal, and

[0018] (b) a surfactant component, which comprises

[0019] (i) at least one surfactant, and

[0020] (c) optionally one or more pharmaceutically acceptable adjuvants.

[0021] In a preferred alternative of the method, a solid or semi-solid composition is prepared. In a further preferred alternative, melt granulation, melt pelletization or melt extrusion is used to process the mixture for preparing the solid or semi-solid composition. In a preferred alternative, the mixture is treated at a temperature of 90 °C - 130 °C for a time period of not less than 30 seconds and not more than 45 minutes (“min.”).

[0022] In a preferred alternative of the method, the surfactant component (b) further comprises (ii) at least one co-surfactant. In other preferred alternatives of all embodiments, the surfactant component (b) further comprises (iii) a lipophilic phase. In a further preferred alternative of all embodiments, the surfactant component (b) is a self-emulsifying mixture comprising the following:

[0023] (i) at least one surfactant,

[0024] (ii) at least one co-surfactant, and

[0025] (iii) preferably a lipophilic phase.

[0026] In a further preferred alternative of the method, the mixture comprising components (a), (b) and (c) further comprises at least one polymer additive as component (d) as further specified below.

[0027] In a preferred method, the mixture for processing to prepare a solid or semi-solid composition as described herein may thus comprise:

[0028] (a) A biomaterial derived from human or mammalian tissue, said biomaterial preferably being an enzyme or enzyme mixture having at least lipase activity, in particular pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammals;

[0029] (b) A surfactant component, which comprises:

[0030] (i) At least one surfactant,

[0031] (ii) Optionally at least one co-surfactant, and

[0032] (iii) Optionally a lipophilic phase,

[0033] (c) Optionally one or more pharmaceutically acceptable adjuvants, and

[0034] (d) Optionally at least one polymer additive.

[0035] In a second aspect, there is also provided herein a solid or semi-solid composition comprising: (a) a biomaterial derived from human or mammalian source, such as an enzyme or enzyme mixture having lipase activity, in particular pancreatin or pancreatin-containing digestive enzyme mixture derived from mammals, (b) a defined surfactant component and (d) a polymer additive. The composition is optimized with respect to its processability in the method as described herein, has the effect of improved biosafety characteristics, while preserving a high level of enzyme activity, and also exhibits excellent mechanical properties even at high temperatures such as those occurring in warmer climate zones. Furthermore, with respect to increased lipolytic efficiency and stability in the acidic pH range after administration to a patient, the solid or semi-solid composition exhibits similar advantageous properties to the compositions disclosed in WO 2005 / 092370 A1. In a preferred alternative, the solid or semi-solid composition is a pharmaceutical composition, preferably a pharmaceutical composition for oral use.

[0036] In an embodiment, the present invention thus also provides a solid or semi-solid composition comprising:

[0037] (a) An enzyme or enzyme mixture having lipase activity, in particular pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammals;

[0038] (b) a surfactant component having

[0039] (i) at least one surfactant

[0040] (ii) at least one co - surfactant, and

[0041] (iii) a lipophilic phase, preferably; and

[0042] (c) optionally one or more pharmaceutically acceptable adjuvants, and

[0043] (d) a polymer additive selected from hydrophilic polymers having a melting point or glass transition temperature of 50 °C - 160 °C, more particularly 50 °C - 70 °C or 50 °C - 65 °C;

[0044] wherein the weight - to - weight ratio (“w / w”) of additive (d) to the surfactant component (b) is from 0.4 (2:5) to 1.5 (3:2), preferably from 1 (1:1) to 1.33 (2:1.5), and most preferably 1 (1:1).

[0045] The solid or semi - solid composition as described herein can be produced by the methods as described herein and their preferred variants.

[0046] In addition, the present invention provides a pharmaceutical composition comprising the composition according to the above, optionally comprising one or more pharmaceutically acceptable excipients.

[0047] The following terms and abbreviations used herein shall have the meanings as explained hereinafter:

[0048] As used herein, “API” stands for “active pharmaceutical ingredient”. The preferred API as disclosed herein is pancreatin, particularly porcine pancreatin commonly used for therapeutic purposes, i.e., pancreatin according to the requirements of standard pharmacopoeias such as Ph.Eur. and / or USP, and is suitable for oral administration in the treatment and / or prevention of dyspepsia in mammals (particularly humans), and particularly dyspepsia caused by chronic exocrine pancreatic insufficiency in patients such as those suffering from cystic fibrosis, chronic pancreatitis or patients who have undergone upper gastrointestinal surgery. In each case, relative to the total weight of porcine pancreatin, as measured by the method of Ph.Eur., porcine pancreatin for therapeutic use generally has no more than 5% by weight, preferably no more than 3.5% by weight of residual moisture content (loss on drying). Due to the nature of the methods as described herein, it is suitable for porcine pancreatin having a moisture content even lower than 3.5% (w / w) (loss on drying).

[0049] As used herein, the term "biological material of animal origin" includes mammals and non-mammals (such as birds and insects), however mammalian origin, particularly porcine or bovine origin, is preferred, and porcine origin is most preferred.

[0050] As used herein, the term "comprises" or "comprising" is intended to include the meaning of "consisting of".

[0051] The terms "enzyme" and "enzyme mixture" as used herein particularly refer to mammalian pancreatic enzymes, pancreatic enzymes or pancreatic lipases of mammalian origin, particularly bovine or porcine origin. Key enzymes for oral therapeutic use of mammalian pancreatic enzymes include lipases, proteases and amylases known in the art.

[0052] As used herein, the term "extrudate" refers to a composition that has been processed and shaped by melt extrusion. Typically, the extrudate exits the extruder at the die side. The extrudate generally has the same composition as the molten composition.

[0053] The term "molten composition" as used herein refers to a mixture that has been thermally softened and contains a biological material (particularly pancreatic enzyme) (a), a surfactant component (b), optionally one or more auxiliaries (c), and optionally one or more polymer additives (d). The molten composition generally has the same composition as the extrudate.

[0054] The term "molten mass" as used herein refers to the surfactant component (b) that has been thermally softened and optionally contains one or more auxiliaries (c) and optionally contains one or more polymer additives (d).

[0055] As used herein, the term "minimum residence time" refers to the minimum amount of time that the molten composition (including the API) in an extruder (particularly a twin-screw extruder) takes from the extruder inlet of the API to the orifice (die) to determine the minimum time period required to achieve robust inactivation of certain virus types while minimizing any loss of the desired biological activity. It will be understood that the minimum residence time varies and can be adjusted in a known manner depending on, for example, the size of the extruder, the applied screw speed, the screw configuration and the feed rate. Compared with the mean residence time or average residence time, the minimum residence time is determined when a tracer substance (e.g., curcumin or The time period when the red (substance) first appears on the die side. This time period can be determined in a known manner, for example, visually, that is, by determining the time period from when the API with the marker substance is fed into the extruder until the marker substance first appears on the die side of the extruder (i.e., measuring the time period required for the API to be transported from the inlet to the die side in the extruder). This period can also be determined by determining the start of the curve of the known (calculated) residence time distribution known in the art and described herein.

[0056] As used herein, the terms "pancreatic enzyme", "pancreatin", and "pancreatic lipase" refer to an enzyme mixture derived from the mammalian pancreas that contains digestive enzymes such as lipase, protease, and amylase as the main components. In particular, the terms "pancreatin", "pancreatin", and "pancreatic lipase" may be used synonymously herein and refer to pancreatic extracts suitable for therapeutic use according to standard pharmacopoeias, which contain several digestive enzymes whose properties are defined by the standard monographs as explained above. Due to standard manufacturing methods, "pancreatic enzyme", "pancreatin", and "pancreatic lipase" are usually provided in powder form as "pancreatin powder", sometimes also called "pancreatic powder". Pancreatic enzyme, pancreatin, and pancreatic lipase can also and preferably be APIs. Depending on their source, pancreatin is a natural product from animals, especially mammalian sources. It is known that when used, for example, in industrial processes such as those described herein, natural products can undergo certain changes in their exact properties. For example, due to certain differences in the manufacturing process, these changes can occur between different batches from the same supplier (depending on the source from which the pancreas is obtained), or can occur between batches from different suppliers. Although pancreatin products for therapeutic use are obtained with a highly reproducible and standardized quality, certain changes in processing properties may occur between different pancreatin batches. Such changes can lead to, for example, changes in the processes and compositions as described herein to obtain, for example, optimal performance and processability with approximately + / - 5 wt% pancreatin. Pancreatin suitable for the processes, methods, and compositions described herein can be obtained, for example, from Nordmark Arzneimittel GmbH & Co. (KG, Uetersen, Germany); Scientific Protein Laboratories (SPL) (Waunakee, Wisconsin, USA); Abbott Laboratories GmbH (Neustadt, Germany); or can be prepared according to known methods (see, for example, EP 115 023) or methods similar to these methods.

[0057] As used herein, the term "pharmaceutical composition" means a composition comprising a product obtained by the methods described herein and optionally one or more pharmaceutically acceptable excipients.

[0058] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic response, and other problem complications, commensurate with a reasonable benefit / risk ratio.

[0059] As used herein, the term "processing at a temperature" means that the molten composition itself is processed at the temperature due to the total energy applied. For the melt granulation process, the total energy applied is typically the thermal energy provided, for example, by an oil bath. For the melt extrusion process, the total energy applied is typically a combination of (i) the thermal energy provided by the barrel of the extruder and (ii) the mechanical energy according to, for example, screw speed, throughput, net torque, and shear force. Generally, the molten composition (extrudate) can thus be assumed to have the temperature at which the mixture for preparing the solid composition is to be processed. The suitable temperature or temperature range for the melt extrusion process variants provided herein is typically measured as the temperature of the product (extrudate, molten composition) at the exit of the extruder (die side), which exit is typically located directly behind the die through which the extrudate exits the extruder. As described in the "Product temperature" section, the temperature is typically measured with an infrared thermometer.

[0060] For the melt extrusion process variants, the terms "product temperature" and "extrudate temperature" are used herein to mean the temperature of the homogenized and extruded material in the barrel of the homogenized extruder measured at the die exit using a suitable thermometer, for example, a calibrated infrared thermometer (Testo 845). Generally, the temperature of an extrudate or an extrudate strand is measured several times (e.g., 3 to 5 times), with the highest temperature shown being used in each case. Then, the average value of the highest temperatures from several measurements is recorded as the relevant temperature. The composition of the product and the extrudate corresponds to the composition of the mixture for preparing the solid composition as described herein. For the melt granulation method and the melt pelletization method, the product temperature and / or the temperature of the molten composition can be measured directly using an inserted thermometer, for example, a digital inserted thermometer (Testo 720).

[0061] The terms "solid (oral) composition", "solid composition", or "solid or semi - solid composition" as used herein are intended to cover compositions having a defined external shape suitable for (full) oral administration, i.e., also intended to cover soft and / or semi - solid compositions, including, for example, lozenges.

[0062] As used herein, the time period applied for processing a mixture for preparing a solid or semi-solid composition refers to the time period during which the mixture is to be exposed to a specified processing temperature (product or extrudate temperature) in order to achieve the desired effects as described herein (maximizing the reduction of biocontaminants and maximizing the desired biological activity of the retention of biomaterials). For discontinuous process variants (e.g., discontinuous melt granulation, discontinuous melt pelletization), the suitable time period for processing the mixture is typically the time period measured as the holding time at the desired product temperature once the desired product temperature is reached. For semi-continuous (e.g., batch melt extrusion) or continuous (e.g., continuous melt extrusion) process variants, the suitable time period for processing the mixture is preferably the time period measured as the minimum residence time as described herein.

[0063] As used herein, numerical indications provided in the format of a range or interval (e.g., temperature of "50 °C - 160 °C" or weight percentage of "2 wt.% - 90 wt.%") are intended to specify (in addition to, for example, the explicitly measured values provided in the Examples section) any value (integer, fraction) included within the given range or interval including the range boundaries, which range boundaries include the boundaries according to the usual rounding rules. For example, the temperature range of "50 °C - 160 °C" will in particular include any one of 49.5 °C, 50 °C, 52.2 °C, 55.5 °C, and 160.4 °C. In this document, the term "weight % (% by weight)" may be abbreviated as "weight % (wt.-%)".

[0064] The energy for achieving the defined process temperature for any embodiment of the process disclosed herein can be applied as thermal energy (heating) or as mechanical energy (e.g., stirring, kneading) or by a combination of thermal and mechanical energy. In a preferred embodiment, the mixture for preparing the solid composition is homogenized before and / or during processing. The homogenization can be carried out by any suitable method, such as by shaking, stirring, or kneading. Homogenization by using a homogenizing extruder is preferred. The homogenization method can be used simultaneously to provide the energy for achieving the defined process temperature. Preferred embodiments of the methods disclosed herein use melt granulation, melt pelletization, or melt extrusion techniques. Melt extrusion techniques are more preferred.

[0065] As provided herein, the lower limits of the processing time and processing temperature are selected such that, when compared to the viral load of the same composition (product) before the process, in biomaterials derived from human or animal tissues, preferably in the trypsin and / or trypsin-containing digestive enzyme mixture of the final composition, the viral load of moderately resistant viruses, moderately - highly resistant viruses, and - in a preferred embodiment - even highly resistant viruses can be significantly reduced. Any upper limits of the processing time and processing temperature provided herein are selected such that, when compared to the key biological activity of the same product before the process, in biomaterials derived from human or animal tissues of the final composition, the required key biological activity is preserved at an acceptable level. When the biomaterial derived from human or animal tissues is an enzyme or enzyme mixture having at least lipase activity (such as trypsin), the key biological activity is lipolytic activity, amylolytic activity, and / or proteolytic activity. Based on general knowledge and the information provided in this specification, a person skilled in the art can determine the minimum and maximum processing times (residence times) to achieve an appropriate reduction in viral load on the one hand and maintain the enzyme activity of the key enzyme within the required range on the other hand, and thus appropriately adjust the process parameters. 3. Description of the Drawings

[0067] Figure 1 is a general setup of a (single) screw suitable for the process as described herein.

[0068] Figure 2 is a preferred screw configuration of a co - rotating twin screw (“X4.1” configuration) on a micro - scale (the two co - rotating screws shown).

[0069] 4. Detailed Description

[0070] In a first aspect, the present invention thus provides a method for preparing a solid or semi - solid composition preferably for pharmaceutical use, the method comprising processing a mixture by a method selected from melt granulation, melt pelletization, and melt extrusion, in each case at a product temperature of 90 °C - 130 °C for a time period of not less than 30 seconds and not more than 45 minutes, the mixture comprising:

[0071] (a) 40 wt% - 75 wt% of trypsin and / or trypsin - containing digestive enzyme mixture derived from mammals;

[0072] (b) 10 wt% - 50 wt% of a surfactant component, which comprises

[0073] (i) At least one surfactant selected from polyethylene glycol-fatty acid monoesters; polyethylene glycol-fatty acid diesters; polyethylene glycol glycerol fatty acid esters; ethylene glycol alkyl ethers; polyethylene glycol glycerol fatty acid esters; polyethylene glycol alkyl ethers; oligoethylene glycol alkyl ethers; polyethylene glycol sterol ethers; polyethylene glycol sorbitan fatty acid esters; sugar esters; D-α-tocopherol polyethylene glycol 1000 succinate; fatty acid amidoalkyl betaines having C2-C 22 fatty acids; lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine, and mixtures of any of the foregoing,

[0074] (ii) Optionally, at least one co-surfactant selected from partial esters of glycerol, propylene glycol, and / or polyglycerol with aliphatic carboxylic acids; esters of ethyl diglycol with aliphatic carboxylic acids; partial ethers of glycerol, propylene glycol, and / or polyglycerol with fatty alcohols; ethers of ethyl diglycol with aliphatic alcohols, and mixtures of any of the foregoing, and

[0075] (iii) Optionally, a lipophilic phase selected from diglycerides of aliphatic carboxylic acids, triglycerides of aliphatic carboxylic acids, and mixtures of any of the foregoing;

[0076] (c) 0 wt%-25 wt% of one or more pharmaceutically acceptable adjuvants, and

[0077] (d) 0 wt%-35 wt% of a polymer additive selected from hydrophilic polymers having a melting point or glass transition temperature of 50°C-160°C;

[0078] And wherein the weight percentages of components (a), (b), (c), and (d) are w / w of the mixture for preparing the solid composition and in each case add up to 100 weight percent of the mixture.

[0079] Preferred variants of the process for preparing a solid or semi-solid composition include the following process steps:

[0080] aa) Prepare a mixture for processing by mixing components (a), (b), (c), and (d) in the amounts and ratios required to obtain the desired target composition. The mixing of the components can be carried out in different ways, for example, as described in more detail herein for the process variants melt granulation, melt pelletization, and melt extrusion.

[0081] bb) Introduce energy into the mixture. By introducing energy into the mixture, the temperature of the mixture increases. The increase in temperature generally leads to the plasticization of the mixture. As described in more detail herein for the process variants melt granulation, melt pelletization, and melt extrusion, the introduction of energy into the mixture can be carried out in different ways, for example by heating and / or applying mechanical energy.

[0082] cc) Shape the plasticized mixture. For example, as described in more detail herein for the process variants melt granulation, melt pelletization, and melt extrusion, shaping the plasticized mixture, such as the plasticized mixture obtained in process step bb), can be carried out in different ways. The plasticized mixture can be shaped into a form suitable for the production of pharmaceutical dosage forms, such as an extrudate strand, or can be directly shaped into a pharmaceutical dosage form, such as a pill, granule, or powder. The form suitable for the production of pharmaceutical dosage forms can be further processed into a pharmaceutical dosage form, for example, by crushing the extrudate into pills (actively or passively) and / or by rounding rough pills into spheres, pills, or pellets having a spherical or nearly spherical shape.

[0083] dd) Reduce the energy introduced into the mixture. By reducing the energy introduced into the mixture (including stopping the introduction of energy), the mixture will generally solidify while maintaining its shape, such as the shape produced by process step cc). Thus, reducing the energy introduced into the mixture can produce a solid or semi-solid composition as described herein.

[0084] ee) Optionally collect the solid or semi-solid composition obtained from the method, and / or optionally further process the solid or semi-solid composition into a pharmaceutical dosage form as described in more detail herein.

[0085] In a preferred variant of the process, process steps aa)-ee) are carried out in the order given above.

[0086] In a preferred process variant, the mixture for preparing the solid or semi-solid composition is homogenized before and / or during processing.

[0087] In a further preferred process variant, the composition or extrudate formed during or as a result of the process is subsequently processed into granules, pellets, pills, spheres, tablets, and / or powders.

[0088] Component (a) is preferably present in an amount of 40% to 75% by weight of the mixture, more preferably in an amount of 40% to 70%, 45% to 68% or 47% to 68% by weight. In other preferred embodiments, component (a) is present in an amount of 50% to 70% by weight of the mixture, more preferably in an amount of 58% to 70% (64% + / - 6%) by weight, and even more preferably in an amount of 60% to 68% by weight.

[0089] The surfactant component (b) is preferably present in an amount of 10% to 50% by weight, preferably 15% to 45% by weight, more preferably 15% to 30% by weight or 15% to 25% by weight of the mixture.

[0090] The component (c), a pharmaceutically acceptable adjuvant, may be present in an amount of 0% to 25% by weight, preferably 0% to 20% by weight, more preferably 0% to 15% by weight, and even more preferably 0% to 10% by weight of the mixture. In one embodiment, the component (c) is present in an amount of 20% to 25% by weight. In a preferred embodiment, the component (c) is present in an amount of 0% to 5% by weight.

[0091] The component (d), a polymer additive, may be present in an amount of 0% to 35% by weight, preferably 5% to 35% by weight, more preferably 10% to 30% by weight, and even more preferably 10% to 25% by weight of the mixture.

[0092] Preferably, the w / w ratio between the polymer additive component (d) and the surfactant component (b) is between 0.4 (2:5) and 1.5 (3:2), more preferably between 0.75 and 1.3. Most preferably, their w / w ratio is 1:1.

[0093] In a preferred embodiment of the process as described herein, the component (a) is porcine pancreatin in an amount of 64% ± 6% by weight of the mixture, and the components (b), (d) and further optionally the adjuvant (c) together are present in an amount of 36% ± 6% by weight of the mixture.

[0094] In other preferred embodiments of the process as described herein, the components (b) and (d) account for 30% to 42% (36% ± 6%) of the mixture or composition and consist of the following in a 1:1 w / w ratio: (b) a semi-synthetic lauroyl polyglycol-32 glyceride based on hydrogenated palm kernel oil, having a melting point of about 42.5°C to 47.5°C (e.g., 44 / 14); and (d) polyethylene glycol 4000, and further contains (c) 100 ppm to 150 ppm, preferably 150 ppm of butylated hydroxyanisole (a known mixture of 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole, abbreviated hereinafter as "BHA") relative to the combined total weight of the components (b) and (d).

[0095] The solid or semi-solid composition and / or the mixture for preparing the solid or semi-solid composition as described herein preferably contains less than 1% by weight of solvent (including water) relative to the total weight of the solid composition or mixture and may be solvent-free.

[0096] Component (a), pancreatic enzymes derived from mammals and / or a mixture of pancreatic enzyme-containing digestive enzymes is preferably porcine pancreatic enzymes as commonly used for therapeutic purposes as more specifically explained herein.

[0097] Surfactant component (b) comprises (i) at least one surfactant. As used herein, a surfactant is a chemical compound comprising at least two moieties, a first moiety that is hydrophilic and / or polar or ionic and has a high affinity for water, and a second moiety that contains a fatty chain of greater or lesser length and is hydrophobic (lipophilic); i.e., surfactants are generally amphiphilic. Surfactants with lower HLB ("hydrophile-lipophile balance") values are more hydrophobic (lipophilic), while surfactants with higher HLB values are more hydrophilic (lipophobic). Surfactants suitable for use in the methods as described herein have HLB values above 6 and below 18, preferably above 8 and below 16 (according to the definition and method of Griffin). Surfactants can be any surfactant suitable for pharmaceutical compositions and can be anionic, cationic, zwitterionic, or non-ionic. Surfactants can be classified according to their chemical structure. Generally, the chemical classes polyethylene glycol-fatty acid monoesters; polyethylene glycol-fatty acid diesters; polyethylene glycol glycerol fatty acid esters; ethylene glycol alkyl ethers; polyethylene glycol glycerol fatty acid esters; polyethylene glycol alkyl ethers; oligomeric ethylene glycol alkyl ethers; polyethylene glycol sterol ethers; polyethylene glycol sorbitan fatty acid esters; sugar esters, in particular monoesters, diesters, and / or triesters of sucrose with food fatty acids, such as sucrose stearate, sucrose palmitate, sucrose laurate, and / or sucrose oleate of suitable quality; d-α-tocopheryl polyethylene glycol 1000 succinate ("vitamin E TPGS"); and amphoteric compounds such as fatty acid amidoalkyl betaines having C2-C 22 and mixtures thereof are suitable. The oligomeric ethylene glycols and their derivatives as described herein mean having a degree of polymerization (or average degree of polymerization, if applicable) of the ethylene glycol moiety of 2-8 and particularly include di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), and hexa(ethylene glycol). Representative but non-limiting disclosures of preferred surfactants for use in the processes as described herein can be found on page 7, line 13 to page 10, line 31 of WO 2005 / 092370 A1, specifically including the disclosure on page 15, lines 4-32.

[0098] More preferred surfactants that can be used in the processes disclosed herein can be selected from: (I) nonionic surfactants, which include polyethylene glycol fatty acid monoesters and / or diesters having aliphatic C6-C 22 carboxylic acids; polyethylene glycol glycerol fatty acid esters having aliphatic C6-C 22 carboxylic acids; polyethylene glycol alkyl monoesters and / or diesters having aliphatic C 12 -C 18 alcohols; oligomeric ethylene glycol ethers having aliphatic C2-C 18 alcohols; and mixtures of any of the above; and (II) ionic surfactants, which include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine; and mixtures of any of the above, and mixtures of any of the above surfactants from (I) and (II).

[0099] Nonionic surfactants are preferred. Among the ionic surfactants, lecithin is preferred.

[0100] The aliphatic carboxylic acids as described herein may also be referred to as "fatty acids" and may include saturated, unsaturated, and polyunsaturated carboxylic acids having a chain length that can be from 4 to 22 carbon atoms, preferably from 6-22 carbon atoms.

[0101] The fatty alcohols as described herein may include saturated, unsaturated, and polyunsaturated alcohols (where applicable) having a chain length that can be from 2 to 22 carbon atoms, such as from 2-18 carbon atoms, from 12-18 carbon atoms, or from 12-22 carbon atoms.

[0102] In a preferred embodiment, the surfactant component (b) further comprises (ii) at least one co-surfactant. As used herein, a co-surfactant or co-emulsifier is a chemical compound having hydrophobic (lipophilic) and hydrophilic moieties but with the hydrophobic (lipophilic) nature predominating. It is intended to render the aqueous and oil phases in the microemulsion mutually soluble. The HLB value of the co-surfactant suitable for use with the process as described herein is less than 10, preferably less than 8, and even more preferably less than 6. The co-surfactant can be a partial ester of a polyhydric / polyvalent alcohol such as glycerol, propylene glycol and / or polyglycerol (such as diglycerol, triglycerol, tetraglycerol) with an aliphatic carboxylic acid ("fatty acid"); an ester of ethyl diglycol with an aliphatic carboxylic acid; a partial ether of glycerol, propylene glycol and / or polyglycerol with an aliphatic alcohol ("fatty alcohol"); an ether of ethyl diglycol with an aliphatic alcohol and mixtures of any of the foregoing. The co-surfactants can be classified according to their chemical structure. Generally, chemical classes such as monoglycerides, polyglycerolated fatty acids and propylene glycol fatty acid esters are suitable. Representative but non-limiting disclosures of preferred co-surfactants for use in the process as described herein can be found in WO2005 / 092370 A1, from line 33 on page 10 to line 6 on page 12, expressly including the disclosure from line 4 to line 32 on page 15.

[0103] More preferred co-surfactants can be selected from monoacylglycerols of aliphatic C6-C 22 carboxylic acids, monoethers of glycerol with aliphatic C 12 -C 22 alcohols, partial esters of propylene glycol with aliphatic C6-C 22 carboxylic acids, partial esters of polyglycerol with aliphatic C6-C 22 carboxylic acids, oligoethylene glycol monoesters of aliphatic C6-C 22 carboxylic acids, oligoethylene glycol diesters of aliphatic C6-C 22 carboxylic acids and mixtures of any of the foregoing.

[0104] In a preferred embodiment, the surfactant component (b) further comprises (iii) a lipophilic phase. As used herein, the lipophilic phase (also referred to as the lipid phase) is a water-immiscible substance, such as a water-immiscible liquid. As used herein, the lipophilic phase is preferably a diglyceride, a triglyceride, and / or a mixture of triglycerides and diglycerides. Suitable lipophilic phases are preferably diglycerides and triglycerides of aliphatic carboxylic acids (fatty acids) having 4 to 22 carbon atoms, particularly 6 to 22 carbon atoms, and mixtures thereof. Representative but non-limiting disclosures of preferred lipophilic phases for use in the processes described herein can be found on page 12, line 8 to page 13, line 24 of WO 2005 / 092370 A1, specifically including the disclosure on page 15, lines 4 - 32.

[0105] More preferably, the lipophilic phase can be selected from the diacylglycerol esters and triacylglycerol esters of aliphatic C6-C 22 carboxylic acids or mixtures thereof.

[0106] Several commercially available surfactant and / or co-surfactant compositions can contain small to moderate amounts of diglycerides and triglycerides, typically as a result of incomplete reaction of triglyceride starting materials in, for example, transesterification reactions. Examples of such compositions are disclosed, for example, on page 13, line 26 to page 15, line 32 of WO 2005 / 092370 A1 and, in addition to surfactant (i) and / or co-surfactant (ii), can be suitable for providing part of the mixture (b), all or part of the lipophilic component / phase (iii).

[0107] Preferred commercially available compositions comprising surfactants, co-surfactants, and / or lipophilic phases include, for example, all from Gattefossé (Lyon, France) such as can be obtained as propylene glycol octanoate (CASRN: 85883 - 73 - 4, 85883 - 73 - 4), and, for example, can be obtained as glycerol monolinoleate (CASRN: 68424 - 61 - 3).

[0108] A more preferred variant of the surfactant component (b) for all embodiments of the processes and compositions described herein can be a mixture comprising the following components:

[0109] (i) at least one in an amount of preferably 2 wt% to 90 wt% of the surfactant component Surfactant selected from the group consisting of: polyethylene glycol monoesters of aliphatic C6-C 22 carboxylic acids; polyethylene glycol diesters of aliphatic C6-C 22 carboxylic acids; polyethylene glycol monoesters of aliphatic C6-C 22Polyethylene glycol glycerol esters of carboxylic acids; having aliphatic C 12 -C 18 Polyethylene glycol alkyl monoethers of alcohols; having aliphatic C 12 -C 18 Polyethylene glycol alkyl diethers of alcohols, having aliphatic C2-C 18 Oligoethylene glycol ethers of alcohols; lecithin; lysolecithin; phosphatidylcholine; phosphatidylethanolamine; phosphatidylglycerol; phosphatidylserine; lysophosphatidylcholine; lysophosphatidylethanolamine; lysophosphatidylglycerol; lysophosphatidylinositol; lysophosphatidic acid; lysophosphatidylserine or mixtures of any of the foregoing;

[0110] (ii) At least one in an amount preferably from 5% to 60% by weight of the surfactant component, Co-surfactant Agent selected from the group consisting of: monoacylglycerols of carboxylic acids having aliphatic C6-C 22 monoethers of glycerol with aliphatic C 12 -C 22 monoethers of propylene glycol with aliphatic C6-C 22 partial esters of polyglycerol with aliphatic C6-C 22 partial esters of carboxylic acids, oligomeric ethylene glycol monoesters of carboxylic acids having aliphatic C6-C 22 oligomeric ethylene glycol diesters of carboxylic acids having aliphatic C6-C 22 or mixtures of any of the foregoing; and

[0111] (iii) In an amount preferably from 0% to 70% by weight of the surfactant component, Lipophilic phase selected from the group consisting of: diacylglycerols of carboxylic acids having aliphatic C6-C 22 triacylglycerols of carboxylic acids having aliphatic C6-C 22 or mixtures of any of the foregoing.

[0112] Preferred variants of the surfactant component (b) for all embodiments of the processes and compositions described herein may comprise 2% - 90% by weight, more particularly 40% - 90% by weight, and even more particularly 60% - 85% by weight surfactant (i); 5% - 60% by weight, more particularly 5% - 40% by weight, and even more particularly 15% - 30% by weight co-surfactant (ii); and 0% - 70% by weight, more particularly 5% - 40% by weight, even more particularly 15% - 30% by weight lipophilic phase (iii), all weight % being relative to the total weight of the surfactant component (b) and in each case adding up to 100%.

[0113] Preferably, the surfactant component (b) is a mixture of surfactants and / or co-surfactants, which may be produced, for example, due to an incomplete (transesterification) reaction of the starting materials used for its manufacture - also containing a certain amount of diglycerides and triglycerides (i.e., the lipophilic phase as used herein), and thus can represent a complete system composed of a surfactant, a co-surfactant, and a lipophilic phase. Such complete systems that can represent the surfactant component (b) are, for example, surfactant components (b) called self-microemulsifying drug delivery systems and are disclosed, for example, in WO 95 / 08983 (equivalent to US 6312704) or WO99 / 44589 (equivalent to US 2003 / 021844). Preferred surfactant components (b) of this type are, for example, all from Gattefossé (Lyon, France) and can be obtained commercially as oleoyl polyglyceryl-6 glycerol ester EP (CAS RN: 97488-91-0, 9004-96-0, 69071-70-1, 68424-61-3), which can be obtained commercially as M1944CS; lauroyl polyglyceryl-6 glycerol ester (CAS RN: 93334-20-4, 9004-81-3, 57107-95-6, 27638-00-2), which can be obtained commercially as M2130 CS; lineoyl polyglyceryl-6 glycerol ester EP (CAS RN: 85536-08-9, 9004-96-0, 85536-08-9, 61789-25-1), which can be obtained commercially as M2125CS; or capryloyl / caproyl polyglyceryl glycerol ester (CAS RN: 85536-07-8, 84963-88-2, 223129-75-7, 85409-09-2, 73398-61-5, 61791-29-5), which can be obtained commercially.

[0114] Particularly preferred complete systems that can represent the surfactant component (b) are: all from Gattefossé (Lyon, France) and can be obtained commercially as 44 / 14 (CAS RN: 93334-20-4, 9004-81-3), a commercially available semi-synthetic lauroyl polyglycol-32 glyceride based on hydrogenated palm kernel oil, having a melting point of about 42.5°C - 47.5°C, and containing about 72 wt% of mono- and diesters of polyethylene glycol ("PEG") 1500, 20 wt% of glycerol monoesters, glycerol diesters and glycerol triesters of fatty acids, and about 8 wt% of free PEG 1500 (distribution of the fatty acids: C8 < 15 wt%, C10 < 12 wt%, C12 < 30 wt% - 50 wt%, C14 5 wt% - 25 wt%, C16 4 wt% - 25 wt%, C18 5 wt% - 35 wt%), < 3 wt% of free glycerol; and may be used as 50 / 13 (CAS RN: 91744-66-0, 9004-99-3), a commercially available semi-synthetic stearoyl polyglycol-32 glyceride, having a melting point of about 46°C - 51°C, and containing about 72 wt% of mono- and diesters of PEG 1500, 20 wt% of glycerol monoesters, glycerol diesters and glycerol triesters of PEG 1500, and about 8 wt% of free PEG 1500 (distribution of the fatty acids: C8 < 3 wt%, C10 < 3 wt%, C12 < 5 wt%, C14 < 5 wt%, C16 40 wt% - 50 wt%, C18 48 wt% - 58 wt%), < 3 wt% of free glycerol. 44 / 14 is most preferred.

[0115] In an embodiment, the mixture for preparing a solid or semi-solid composition may further comprise (c) one or more pharmaceutically acceptable adjuvants. Suitable pharmaceutically acceptable adjuvants may be selected from carriers (sometimes also referred to as "diluents" or "fillers"), binders (sometimes also referred to as "adhesives"), disintegrants, lubricants, glidants, stabilizers, surfactants, film–formers, emollients, wetting agents, sweeteners, pigments / colorants, antioxidants and preservatives.

[0116] Suitable carriers include, without limitation, polyols such as mannitol, sorbitol, xylitol; disaccharides such as lactose, sucrose, dextran and maltose; polysaccharides such as maltodextrin and dextran; starches such as corn starch; celluloses such as microcrystalline cellulose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or mixtures thereof; cyclodextrine and inorganic agents such as dicalcium phosphate, calcium hydrogen phosphate; hydroxyapatite, tricalcium phosphate, talc and silica. Microcrystalline cellulose, sucrose and / or lactose are preferably used as carriers.

[0117] Suitable antioxidants include, without limitation, ascorbic acid, α-tocopherol, resveratrol, carotenoids, propyl gallate, octyl gallate, lauryl gallate, tert-butylhydroquinone, BHA, and butylated hydroxytoluene. BHA is preferably used as the antioxidant.

[0118] Suitable binders include, without limitation, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), pregelatinized starch, and combinations thereof, preferably HPMC.

[0119] Suitable disintegrants include, without limitation, calcium carboxymethyl cellulose (CMC-Ca), sodium carboxymethyl cellulose (CMC-Na), cross-linked PVP (such as crospovidone, or XL), alginic acid, sodium alginate, guar gum, cross-linked CMC (sodium cross-linked carboxymethyl cellulose, such as ), sodium carboxymethyl starch (sodium carboxyethyl starch) (such as or ), preferably cross-linked PVP and / or sodium cross-linked carboxymethyl cellulose.

[0120] Suitable lubricants include, without limitation, magnesium stearate, aluminum silicate or calcium silicate, stearic acid, hydrogenated castor oil, talc, glyceryl behenate, sodium stearyl fumarate, and combinations thereof, preferably magnesium stearate.

[0121] Suitable glidants include, without limitation, colloidal SiO2 (such as, 200), magnesium trisilicate, powdered cellulose, talc, and combinations thereof, preferably colloidal SiO2.

[0122] Preferred as component (c) as used herein is a carrier, preferably microcrystalline cellulose, sucrose, and / or lactose; an antioxidant, preferably BHA, and a disintegrant, preferably cross-linked PVP. The antioxidant, especially BHA, is preferably present in a concentration of 50 ppm to 200 ppm, more preferably 100 ppm to 150 ppm, especially 150 ppm, relative to the total weight of the molten mass.

[0123] In a preferred embodiment of the process as described herein, the mixture for preparing the solid or semi-solid composition comprises a polymeric additive (d). A mixture comprising one or more polymeric additives. Preferably, the polymeric additive is selected from hydrophilic polymers having a melting point or glass transition temperature of 50°C - 160°C, more preferably 50°C - 70°C or 50°C - 65°C. In other preferred embodiments, the polymeric additive is selected from hydrophilic polymers having a melting point or glass transition temperature of 50°C - 110°C. In one embodiment, the hydrophilic polymer having a melting point or glass transition temperature of 50°C - 110°C is selected from polymers having at least hydrophilic chains at the ends of the chains.

[0124] Suitable hydrophilic polymers may preferably be selected from polyoxyalkenes, poloxamers, polyvinylpyrrolidone (“PVP”) and / or polyvinylpyrrolidone-vinyl acetate copolymers.

[0125] In a preferred embodiment, the polymeric additive is a hydrophilic polymer selected from polyethylene glycol and poloxamer or a mixture of such hydrophilic polymers. Preferably, PEG and / or poloxamer having an average molecular weight of 3000 g / mol - 30000 g / mol, more preferably 3250 g / mol - 25000 g / mol, such as PEG 4000, PEG 8000, PEG20000 and / or poloxamer 188 (the poloxamer 188 may be commercially obtained as 188 from BASF SE (Ludwigshafen, Germany)). Also preferred are hydrophilic polymers having an average molecular weight of 3250 g / mol - 15000 g / mol and more preferably 3500 g / mol - 9000 g / mol. In the most preferred embodiment, the polymeric additive is PEG4000. PEGs having different average molecular weights are commercially available from various suppliers (e.g., from Merck Chemicals GmbH (Darmstadt, Germany)).

[0126] Suitable hydrophilic polymers may also be polyvinylpyrrolidone (“PVP”), especially PVP grades having a rated K value (measured in 1 wt / vol% or 5 wt / vol% aqueous solution) of not less than 16, such as 17PF, 30 or 90F; and / or polyvinylpyrrolidone-vinyl acetate copolymers, especially copovidone, such as VA64, all of the above products are commercially available from BASF SE.

[0127] In a preferred embodiment of the process as described herein, the mixture for preparing the solid or semi-solid composition comprises:

[0128] (a) 40% to 75% by weight, preferably 40% to 70% by weight, of mammalian-derived pancreatin and / or pancreatin-containing digestive enzyme mixture;

[0129] (b) 10% to 50% by weight, preferably 15% to 45% by weight, of surfactant component,

[0130] (c) 0% to 10% by weight of one or more pharmaceutically acceptable adjuvants, and

[0131] (d) 5% to 35% by weight, preferably 10% to 30% by weight, of polymer additive,

[0132] wherein the weight percentages of components (a), (b), (c) and (d) are w / w of the mixture for preparing the solid or semi-solid composition, and in each case add up to 100% by weight of the mixture.

[0133] In a more preferred embodiment of the process for preparing the solid composition as described herein, the mixture for preparing the solid composition is particularly suitable for melt extrusion or twin-screw melt granulation and comprises:

[0134] (a) 50% to 75% by weight, preferably 50% to 70% by weight, of porcine pancreatin;

[0135] (b) 15% to 30% by weight of surfactant component, which comprises:

[0136] (i) 2% to 90% by weight, relative to the surfactant component, of at least one surfactant,

[0137] (ii) 5% to 60% by weight, relative to the surfactant component, of at least one co-surfactant, and

[0138] (iii) 0% to 70% by weight, relative to the surfactant component, of lipophilic phase,

[0139] wherein in each case, the percentages (i), (ii) and (iii) add up to 100% by weight of the surfactant component,

[0140] (c) 0% to 5% by weight of one or more pharmaceutically acceptable adjuvants selected from carriers and / or antioxidants, and

[0141] (d) 10% to 25% by weight of at least one hydrophilic polymer having a melting point or glass transition temperature of 50°C to 160°C,

[0142] The weight percentages of components (a), (b), (c) and (d) are w / w of the mixture for preparing the solid composition and in each case add up to 100% by weight of the mixture.

[0143] In another more preferred embodiment, the mixture for preparing the solid composition is particularly suitable for melt extrusion, twin-screw melt extrusion or twin-screw melt granulation and comprises:

[0144] (a) 50% to 75% by weight, preferably 50% to 70% by weight of porcine pancreatin;

[0145] (b) 15% to 30% by weight of a surfactant component, which comprises:

[0146] (i) 2% to 90% by weight, relative to the surfactant component, of at least one surfactant selected from polyethylene glycol monoesters of aliphatic C6-C 22 carboxylic acids; polyethylene glycol diesters of aliphatic C6-C 22 carboxylic acids; polyethylene glycol glycerol esters of aliphatic C6-C 22 carboxylic acids; polyethylene glycol alkyl monoesters of aliphatic C 12 -C 18 alcohols; polyethylene glycol alkyl diesters of aliphatic C 12 -C 18 alcohols; oligomeric ethylene glycol ethers of aliphatic C2-C 18 alcohols; lecithin and mixtures of any of the foregoing,

[0147] (ii) 5% to 60% by weight, relative to the surfactant component, of at least one co-surfactant selected from monoacylglycerols of aliphatic C6-C 22 carboxylic acids; monoethers of glycerol with aliphatic C 12 -C 22 alcohols; partial esters of propylene glycol with aliphatic C6-C 22 carboxylic acids and / or partial esters of polyglycerol with aliphatic C6-C 22 carboxylic acids; oligomeric ethylene glycol monoesters of aliphatic C6-C 22 carboxylic acids, and / or oligomeric ethylene glycol diesters of aliphatic C6-C 22 carboxylic acids and mixtures of any of the foregoing, and

[0148] (iii) 0% to 70% by weight, relative to the surfactant component, of a lipophilic phase selected from diacylglycerols of aliphatic C6-C 22 carboxylic acids; triacylglycerols of aliphatic C6-C 22 carboxylic acids and mixtures of any of the foregoing,

[0149] wherein in each case, the percentages (i), (ii), and (iii) add up to 100% by weight of the surfactant component,

[0150] (c) 0% - 5% of one or more pharmaceutically acceptable adjuvants selected from carriers, disintegrants, and / or antioxidants,

[0151] (d) 10% - 25% of at least one polymer additive which is a hydrophilic polymer having a melting point or glass transition temperature of 50°C - 110°C,

[0152] wherein the weight percentages of components (a), (b), (c), and (d) are w / w of the mixture for preparing the solid composition and in each case add up to 100% by weight of the mixture.

[0153] The mixture for preparing the solid composition as described herein, particularly the preferred mixture as defined herein, is generally thermoplastic and can be shaped into a suitable form at elevated temperature. The mixture can contain components having a melting point or glass transition temperature higher than the actual processing temperature applied but which can nevertheless be processed smoothly at a specified temperature in melt granulation, melt pelletization, and / or melt extrusion process variants. For example, certain PVP grades having a glass transition temperature higher than 130°C can be contained in the mixture as described herein as the polymer additive (c). Nevertheless, such a mixture can be processed at a temperature below the glass transition temperature of the PVP polymer additive (e.g., at a temperature of 90°C - 130°C) provided the mixture as a whole softens or melts sufficiently to be processed as described herein.

[0154] In the method as described herein, the mixture for preparing the solid or semi-solid composition is processed by a method selected from melt granulation, melt pelletization, and melt extrusion. Melt granulation and melt extrusion are preferred. Melt extrusion is most preferred.

[0155] In certain variants of the process as described herein, the mixture for preparing the solid or semi-solid composition is processed by melt pelletization to produce a multi-particle form such as granules, pellets, pills, spheres, and / or powders. In the melt pelletization process, one or more fusible components of the mixture for preparing the solid or semi-solid composition, such as component (b) 44 / 14 and / or (c) such as polyethylene glycol 4000 is mixed with mammalian-derived trypsin and / or a trypsin-containing digestive enzyme mixture, and the resulting mixture is then processed by suitable process variants such as centrifugation and / or heating to a temperature above the melting point (or glass transition temperature) of the fusible component (as a whole). The treated mixture is then allowed to cool, thereby forming a multi-particulate solid or semi-solid composition. The multi-particulate form resulting from this process variant can be further processed into other oral administration forms, such as tablets, in a known manner. For example, the melt granulation method for direct granulation processes from WO 02 / 40045 is well known.

[0156] In a preferred variant of the process as described herein, the mixture for preparing the solid or semi-solid composition is processed by melt granulation. The term "melt granulation" is used herein to describe a process for obtaining multi-particulate forms such as granules, pellets, pills, spheres, and / or powders by adding a molten binder or adhesive or a solid binder or adhesive that melts during the process. This process is also referred to as "melt agglomeration" or "thermoplastic granulation". This process can be used to formulate active pharmaceutical ingredients for the production of pharmaceutical compositions commonly used for oral use (see, for example, Halle P.D. et al., Journal of Pharmacy and Phytotherapeutics 1(3)(2013)6 - 10). The multi-particulate form resulting from this process variant can be further processed into other oral administration forms, such as tablets, in a known manner.

[0157] In a variant of the melt granulation process as described herein, the mixture for preparing the solid or semi-solid composition is preferably processed for a time period of not less than 180 seconds (3 minutes) and not more than 30 minutes (1800 seconds) at a temperature (product temperature) of not less than 90 °C and not more than 125 °C. In a more preferred variant of the melt granulation process, the mixture for preparing the solid or semi-solid composition is processed for a time period of not less than 300 seconds (5 minutes) and not more than 30 minutes (1800 seconds) at a temperature of not less than 90 °C and not more than 125 °C. As explained in more detail herein, the term "processed at a certain temperature" means that the mixture for preparing the solid or semi-solid composition (the molten composition) itself is processed at that temperature due to the total energy applied.

[0158] In the general scheme of a variant of the melt granulation process as described herein, the components of the mixture for preparing the solid or semi-solid composition as defined above are mixed in a suitable reaction vessel, such as a beaker, in the required amounts and proportions. The fusible component, for example component (b) such as 44 / 14, and / or (c) such as polyethylene glycol 4000, can first be melted or softened at an elevated temperature (e.g., at a temperature of 40°C - 60°C, more particularly 45°C - 55°C, such as at 50°C). If desired, a suitable pharmaceutically acceptable adjuvant such as an antioxidant e.g. BHA can be added, and the resulting premix or melt mass can be homogenized for a time period of 1 - 15 minutes, preferably 3 - 10 minutes, such as 5 minutes, in a known manner (e.g., by stirring). Stirring can be carried out by any suitable device such as a palette knife, a known laboratory mixer or a known high-shear mixer. Component (a), e.g., porcine pancreatin in the form of pancreatic powder for therapeutic use, can then be added at an elevated temperature (e.g., at the elevated temperature described above, such as at about 50°C), and the resulting mixture can then be further homogenized, e.g., by stirring. Under continuous stirring, the mixture can then be heated, e.g., by using an oil bath, to the target temperature (product temperature) of the process variant as described above, such as to 70°C - 120°C or 90°C - 130°C, preferably to 90°C - 125°C such as to 90°C. The target temperature can be maintained for the required time period such as 30 - 1800 seconds, such as 300 seconds.

[0159] In other embodiments of the melt granulation process for preparing solid or semi-solid compositions as described herein, a mixture comprising the following is processed at a temperature not lower than 70°C for a time period not less than 300 seconds:

[0160] (a) an enzyme or enzyme mixture having at least lipase activity, and

[0161] (b) a surfactant component, which comprises:

[0162] (i) at least one surfactant,

[0163] (ii) at least one co-surfactant, and

[0164] (iii) an optional lipophilic phase,

[0165] (c) an optional one or more additional pharmaceutically acceptable adjuvants, and

[0166] (d) an optional at least one polymer additive,

[0167] wherein the mixture is homogenized before and / or during processing, and wherein melt granulation is used to process the mixture.

[0168] In an alternative to this and other embodiments of the melt granulation process, the mixture is processed for a time period of not less than 300 seconds and not more than 45 minutes at a temperature of not less than 70 °C and not more than 130 °C. In another alternative of this embodiment, the mixture is processed for a time period of not less than 300 seconds and not more than 30 minutes at a temperature of not less than 80 °C and not more than 130 °C.

[0169] In a particularly preferred variant of the process as described herein, the mixture for preparing the solid or semi-solid composition is processed by melt extrusion. The terms "melt extrusion" or "melt extruded" ("ME") are used herein to describe the process of heating and / or compressing a blend composition to a molten or softened state and then forcing it through an orifice, in which the extruded product (extrudate) forms a shape that can solidify upon cooling. The blend composition is typically conveyed through one or more heating zones by a screw mechanism. The one or more screws can be rotated within a barrel, which is typically cylindrical in shape, with only a small clearance existing between the outer diameter of the screw and the inner diameter of the barrel. Due to the nature of the mixtures used in the processes for preparing solid compositions described herein, the process variant using a twin-screw extruder can also be referred to as "twin-screw granulation" or "twin-screw melt granulation". For example, the melt extrusion technique and its application in the pharmaceutical industry from Breitenbach, European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107 - 117 are known per se.

[0170] The melt extrusion process as disclosed herein can be conveniently carried out using an extruder, preferably a homogenizing extruder such as a single-screw extruder, a twin-screw extruder, a triple-screw extruder or a planetary extruder. A twin-screw extruder, particularly a co-rotating twin-screw extruder, is preferred.

[0171] In a preferred alternative of the melt extrusion process variant, the mixture for preparing the solid or semi-solid composition is processed at a product temperature of not less than 95 °C and not more than 125 °C (95 °C - 125 °C), more preferably at a product temperature of 90 °C - 120 °C, and even more preferably at a product temperature of 100 °C - 110 °C. In a preferred alternative, when processed, the temperature of the product (extrudate) at the die side does not exceed 108 °C + / - 5 °C.

[0172] In a preferred alternative of the melt extrusion process, the mixture for preparing the solid or semi-solid composition is processed at the product temperature for a time period of not less than 30 seconds and not more than 30 minutes, preferably not less than 40 seconds and not more than 20 minutes, more preferably not less than 50 seconds and not more than 10 minutes, and even more preferably not less than 60 seconds and not more than 5 minutes (60 - 300 seconds). In a further preferred embodiment, the mixture is processed at the product temperature for a time period of 60 - 100 seconds, more preferably 80 + / - 15 seconds, even more preferably 83 + / - 5 seconds and still more preferably 83 + / - 3 seconds, all of the above temperatures being at the preferred temperatures as described in the previous paragraph.

[0173] In a particularly preferred alternative of the melt extrusion process variant, the mixture for preparing the solid or semi-solid composition is processed at a product temperature of not less than 90 °C and not more than 130 °C (90 °C - 130 °C) for a time period of not less than 30 seconds and not more than 30 minutes. In a preferred alternative, the mixture is processed at a product temperature of not less than 95 °C and not more than 125 °C (95 °C - 125 °C) for a time period of not less than 50 seconds and not more than 10 minutes. In another particularly preferred alternative, the mixture is processed at a product temperature of not less than 100 °C and not more than 120 °C (100 °C - 120 °C), especially 105 °C - 115 °C, for a time period of not less than 60 seconds and not more than 5 minutes.

[0174] The suitable time period for the melt extrusion process variant (e.g., the specific embodiments, alternatives and variants as described below) can preferably be measured as the "minimum residence time" as described herein.

[0175] In one embodiment of the melt extrusion process variant as described herein, component (a) is first mixed with one or more fusible components (surfactant component (b) and / or component (d)) to form a premix, then the premix thus obtained is heated to produce a melt, and finally the molten premix is placed in an extruder ("premix feed" variant) for processing. In the extruder, the premix can be mixed with the other components of the composition or can be processed without further mixing with additional components. The premix feed variant is used to operate the process discontinuously (batchwise).

[0176] In another embodiment of the melt extrusion process variant as described herein, component (a) is fed directly into the extruder as a powder, powder mixture, compacted or granulated powder or powder mixture, and is mixed in the extruder with a mixture of surfactant component (b) and optionally polymer additives (component (d)), wherein the mixture is in a molten or sufficiently softened state ("direct feed" variant). The mixture in the molten or sufficiently softened state may also contain an antioxidant in a concentration sufficient to preserve the mixture from oxidation. The direct feed variant is generally preferred because it allows for continuous processing.

[0177] Examples of preferred melt extrusion equipment suitable for the melt extrusion process variant as described herein are provided below:

[0178] In a preferred embodiment, the melt extrusion equipment can generally be a known co-rotating twin screw extruder, which contains a mixing / conveying zone, a heating / melting zone, and a pumping zone that continuously lead to the orifice (die). In the mixing / conveying zone, the powder blend is mixed, and the aggregates are reduced to primary particles by the shear force between the screw elements and the barrel. In the heating / melting zone, the temperature is at or above the melting point, glass transition temperature, or softening temperature / softening temperature range of the molten mass or molten composition to sufficiently melt or soften the molten mass or molten composition for smooth extrusion. In an embodiment, the process as described herein can be a twin screw melt granulation process, in which the powdered API is mixed with other components as described by the action of the twin screw to produce a molten mass, and then the molten mass is extruded through a screen die plate.

[0179] Once in a sufficiently molten or softened state, after the powder feed, the homogenized blend (molten mass) can be pumped onto the screw by an inlet pump. At the orifice (die), the molten mass can form strands, cylinders, or films. The exiting extrudate is then typically solidified by a cooling process. Once solidified, the extrudate can then be further processed to form pellets, spherical granules, fine powders, tablets, etc.

[0180] The diameter range of a typical pilot plant extruder is 18 - 30 mm, while extruders for industrial scale production are generally larger, for example with a diameter of not less than 50 mm. In the pharmaceutical field, the melt extrusion equipment generally includes an extruder, downstream auxiliary equipment for extrusion, and other monitoring tools for performance and product quality assessment.

[0181] Individual components known per se within the extruder and which can generally be used together with the preferred process embodiments as described herein are for example:

[0182] - A feed hopper, which is used to feed materials into the feed zone of the barrel;

[0183] - A temperature control barrel that houses the extruder screw. The barrel section can be heated, for example, by an electric heater or a liquid. Barrel cooling helps maintain the temperature of the product (molten composition) required within the processing section at the temperature setpoint. The extruder barrel is typically cooled by a liquid and sometimes by air. The most efficient heat transfer design uses axial cooling holes inside the barrel body and is close to the process melt flow;

[0184] - A rotating screw: The extruder used in the process as described herein preferably includes two co-rotating screws within a fixed cylindrical barrel ("co-rotating twin-screw extruder"). For example, for an extruder with a modular design to facilitate variable screw configurations, the extrusion screw is characterized by the "length-to-diameter ratio" or "L / D" that represents the length of the screw divided by the diameter. The screw length in an extrusion process is typically given as the L / D ratio (screw length divided by screw diameter). The L / D of the preferred screw used in the process as described herein is at least 15:1, such as 25:1 or 32:1. Conventional screws known in the art can generally be used. Suitable screw lengths and screw configurations applicable to the process as described herein can be easily adapted by measures known in the art and the additional disclosures provided herein. In a preferred embodiment, generally provided (per screw) includes at least one kneading block, preferably 2 - 8 kneading blocks, more preferably 4 - 6 kneading blocks, in each case exceeding 4 - 6 L / D, whereby co-rotating screws are preferred;

[0185] - A screw drive unit;

[0186] - A die: In the process as described herein, the die used in the process / extruder setup can preferably be a punching die with a hole diameter of 0.5 to 2.0 mm, preferably 0.7 to 1.5 mm, and more preferably 0.8 mm.

[0187] The molten extrusion process variant as described herein can preferably be carried out in a co-rotating twin-screw extruder that preferably additionally has kneading elements on the twin screws. Thus, the setup for a typical extrusion process can include the following elements known per se:

[0188] - One or more feed hoppers for weight analysis or volume analysis feeding of powder or molten / liquid components; In a preferred embodiment of the process as described herein, the API is fed as a powder, while the components of mixture b) are preferably fed through a liquid feeder;

[0189] - A temperature control barrel that houses the helical rod;

[0190] - A conveying and kneading system (preferably) or conveying and kneading elements (preferably) for material transportation and mixing respectively. Screws for changing the residence time and optimizing the homogenization of the molten mass and / or molten composition can be assembled from modules. The general arrangement showing the specific modules / parts of the screw (initial part to avoid backflow / solid feed / molten liquid feed / kneading element / conveying element) is shown in Figure 1 Herein. The optimized combination of such screw elements can be identified, for example, by performing a DoE (Design of Experiments) study based on statistical procedures known in the art, such as using software like "Design " of the latest version of Stat-Ease Inc.

[0191] - A die system for forming an extrudate (preferably a screen die), and

[0192] - Downstream auxiliary equipment (e.g., for cooling, granulating, rounding, collecting), also coordinated for continuous processing.

[0193] Preferred embodiments of the melt extrusion process variants as described herein include the following features:

[0194] - The end of the conveying element at the die side (e.g., the screw end) preferably provides a flat (i.e., about 90°) rather than a cubic or circular end;

[0195] - The die preferably does not exhibit die channels in which the molten composition has to pass a certain distance without being actively pushed or transported. Thus, a flat die design such as a screen die plate is preferred. The gap generated between the die position end and the die position (die plate) should be minimized (<1 mm) to minimize or avoid any dead volume at the die position that can lead to "stratification" of the mixture or segregation of its components. In a preferred embodiment, the distance between the end of the conveying element (e.g., the screw end) and the die side (e.g., the screen die plate or perforated disk) should not be more than 1 millimeter ("mm"), preferably not more than 0.5 mm, more preferably not more than 0.4 mm, and still more preferably not more than 0.3 mm.

[0196] On a microscale or laboratory scale, for example, a Three Tec twin-screw extruder 9 mm (ZE9) can be used in combination with a balance feeder (weight loss feeder), a Three Tec (ZD5) 5 mm powder feeder, an HNP pump (feeder for liquids), and an infrared (IR) temperature measurement device (e.g., Testo 845), which provides rapid temperature measurement where the minimum and maximum temperature values are updated at 100 ms time intervals.

[0197] For pilot-scale processes, as required, for example, a Gabler DE-40 twin-screw extruder (40 mm diameter) for higher processing temperatures can be used in combination with a gravimetric feeder (loss-in-weight feeder) K-Tron, an HNP pump 024 (feeder for liquids), and an IR measuring device (temperature measurement) Testo 845.

[0198] For industrial-scale processes, for example, a Gabler DE-100 (100 mm diameter) extruder or a Gabler DE-120 (120 mm diameter) extruder can be suitable, each equipped as required for higher processing temperatures, optionally in combination with a Gabler Spheronizer R-400 or R-600.

[0199] The equipment as described above is available from Three Tec GmbH (Seon CH); Gabler GmbH & Co KG (Ettlingen DE), HNP Microsysteme GmbH (Schwerin DE); Coperion K-Tron Sewell (USA) and Testo AG (Lenzkirch, DE).

[0200] Preferred melt extrusion process variables applicable to the processes as described herein are described below:

[0201] The "throughput" of an extruder is characterized by the mass of the molten composition passing through the extruder in a given time interval. As will be understood, the throughput will depend in particular on the size / diameter of the extruder. In an embodiment of the process as described herein, for a 9 mm extruder, a suitable throughput is, for example, about 2 - 3 g / min, and for a 40 mm extruder, about 133 g / min + / - 5%. On a larger scale, especially industrial scale, for a 100 mm extruder, the throughput can be, for example, 8 to 60 kg / h (133 g / min + / - 5% up to 3600 g / min + / - 5%).

[0202] The "screw speed" is used to control the residence time. It should be understood that a suitable screw speed will need to be adapted to the scale of the extrusion process. In a preferred embodiment, especially when using a Gabler D40 extruder, the screw speed is adjusted to 50 to 120 rpm, preferably to 75 + / - 15 rpm, and most preferably to 70 - 80 rpm.

[0203] As used herein, the term "residence time" refers to the time that the molten composition spends in an extruder (especially a twin-screw extruder) from the extruder inlet of the API to the orifice (die). The residence time depends in particular on the specific properties of the material being processed (such as composition, fluidity and viscosity), and can be determined according to methods known in the art according to the process or process settings, such as by Altomare et al., Biotechnology Progress, 2(3)(1986)157-163; Gao et al., Polymer Engineering and Science, 40(1)(2000)227-237, Poulesquen et al., Polymer Engineering and Science 43(2)(2003)1849-1862 and / or Dhenge et al., Powder Technology 229(2012)126-136 or the references cited in any of the above documents. In the literature, "average residence time" or "mean residence time" is usually indicated. These can be calculated in a known manner from the "residence time distribution" determined experimentally (see, for example, Dhenge et al.). For the processes described herein, the tracer used to determine the residence time can be a dye, such as curcumin or sudan red. It is generally not necessary to permanently determine or monitor the residence time ("minimum residence time", "average residence time" or "mean residence time") during production runs. Instead, for a particular extruder, screw configuration, molten composition and parameter settings, once the residence time has been determined, it is usually sufficient to run the process without further monitoring and / or addition of tracer. Re-calibration of the process should be necessary, and the minimum residence time under any new or changed configuration can be easily determined again by the methods explained above.

[0204] When the biomaterial derived from tissues of human or mammalian origin is an enzyme or enzyme mixture having lipase activity, especially pancreatin or pancreatin-containing mixtures derived from mammals, the residence time tolerance is a function of the remaining enzyme (especially lipase and amylase) activity acceptable after the applied temperature and extrusion process. When compared to the enzyme activity before the extrusion process, there should be no more than about 30%, preferably no more than 25%, 20%, 15% or 10% loss of the key enzyme activity after the extrusion process. On an industrial scale, the residence time should be such that the loss of key enzyme activity after the extrusion process preferably does not exceed 10%-15%. In a more preferred embodiment, the loss of key enzyme activity does not exceed 10%.

[0205] It will be understood that the product temperature measured at the die side is a function of the temperature of the barrel of the extruder and the mechanical energy provided by the screw of the extruder. To achieve and maintain the desired product temperature (usually measured by an IR thermometer as the temperature of the extrudate leaving the extruder at the die side), the application of thermal energy by heating the barrel needs to be balanced with the application of mechanical energy by the applied screw and screw setting / configuration. In the processes described herein, the desired temperature of the product (molten composition and / or extrudate) is typically achieved when the barrel temperature is generally maintained in the range of 60 °C - 130 °C. In a preferred embodiment, the extrusion is carried out at a barrel temperature of 80 °C - 130 °C, preferably at a barrel temperature of 80 °C - 120 °C, in order to ensure that the product temperature at the die is in the range of 90 °C - 130 °C or the preferred temperature values provided herein (see above). It is known in the art to adjust the desired product temperature by coordinating relevant parameters such as barrel temperature, screw configuration, and / or screw speed.

[0206] In a preferred alternative of the molten extrusion process variant, the following parameters are applied or adjusted in a screw extruder, preferably a co-rotating twin-screw extruder:

[0207] - Feeding of the API onto the screw is carried out by a conveying element providing a pitch of 1.5 L / D at a distance of 2.25 L / D.

[0208] - Metering of the molten mass into the extruder is carried out by a conveying element providing a pitch of 1 L / D at a distance of 3 L / D after the API metering port.

[0209] - The distance between the API and the molten mass metering port is 3.2 L / D.

[0210] - The first kneading zone is characterized by one kneading element having a length of 1 L / D, the one kneading element providing five ridges, whereby each ridge is arranged at an angle of 45° to the next ridge. Also provided is a reversely kneading element with a 45° offset placed on the screw after another conveying section.

[0211] - Conveying zones with pitches of 0.75 L / D and then 0.5 L / D are plugged onto the screw between two kneading zones.

[0212] - In front of the die position, the screw arrangement provides conveying zones with two different pitches of 0.75 L / D and then 0.5 L / D over a length of 3.25 L / D.

[0213] - The effective extrusion length provides a total length of 15 L / D or more.

[0214] - D o / D i The ratio is 1.8;

[0215] -D o / The shaft center distance is 0.8;

[0216] -D i / The shaft center distance is 1.5;

[0217] - The position of the feed inlet for API feed is at 0 - 2.25L / D;

[0218] - The position of the feed inlet for the feed of the molten mass is at 4 - 6L / D;

[0219] - The ratio of the blank surface (total surface of the die holes) of the design of the sieve - like die plate to the total surface of the product contact area is 0.19 (in the small - scale, the number of holes in the die plate is 32, and in the pilot - scale is 387; the diameter of the die holes in both scales is 1.0 mm; the thickness of the die plate is 1.0 mm).

[0220] “D o ” designates the outer diameter of the screw / screw element of the (twin) screw extruder. “D i ” designates the inner diameter of the screw / screw element of the (twin) screw extruder. “D o / D i ratio” refers to the outer - to - inner screw element diameter ratio of the (twin) screw extruder. At low D o / D i ratios, very little free volume can be obtained in the extruder, and at higher D o / D i ratios, a higher extruder free volume can be obtained, thus allowing more material to be processed.

[0221] Exemplary screw arrangements indicating different zones of the screw are shown in Figure 1 .

[0222] The preferred screw configuration is called “X4.1”. The details of this configuration are shown in Table 1 below. In addition, a sketch of the screw configuration X4.1 is shown in Figure 2 .

[0223] Compositions or extrudates formed by the processes described herein can subsequently be further processed into granules, pellets, pills, spheres, capsules, tablets, or powders by methods known in the art. The extrudates can be broken into small pieces (actively or passively), which can then be rounded in a conventional rounding device or spheronizer to provide pills, granules, or spheres of the desired size. Preferably, the extrudates can be transferred to a conventional rounding device and rounded into spheres having a diameter of 0.5 - 2 mm and a regular shape as described, for example, in WO 2007 / 020259 A2 and WO 2007 / 020260 A2. Spheres having the desired size and shape are sometimes also referred to as "microspheres" or "mini - microspheres".

[0224] Preferred embodiments of the processes described herein include rounding the extrudates or extrudate fragments into pills or spheres. Pills or spheres of a suitable size, preferably having a diameter of 0.5 - 2 mm and a regular shape, can then be obtained, for example, by rounding in a known manner. Extrudates obtained by the processes described herein generally do not need to be cut into smaller fragments before rounding, as they typically break into smaller fragments, for example, having an approximately cylindrical shape when extruded from the die. Before rounding, the extrudates can be cooled down, for example, by aging them at room temperature or using a conveyor belt to cool them by ambient air or by using active cooling before collecting them. Active cooling can be carried out by using a suitable belt equipped with a cooling mechanism that can be air and / or cooling by a water pipe. The rounding or spheronizing of the extrudates or extrudate fragments is preferably carried out after pre - heating the spheronizer at a temperature between, for example, 35 °C and 56 °C, such as between 45 °C and 50 °C. The rounded extrudate fragments can then be cooled before collection by aging them at room temperature or using a conveyor belt to cool them by ambient air or by using active cooling. In a particularly preferred embodiment, the cord - like extrudates can be converted into spheres (pills) of a regular shape in a subsequent rounding step, for example, in a double - jacketed spheronizer such as the Gabler Spheronizer R - 250, Gabler Spheronizer R - 400, or Gabler Spheronizer R - 600 (all from Gabler, Ettlingen, Germany), according to batch. Pills or spheres having a diameter or any dimension length not exceeding 5 mm are generally referred to as "mini - microspheres" or "pellets". Mini - microspheres or pellets containing porcine pancreatin and manufactured by the processes described herein are a particularly preferred pharmaceutical form.

[0225] In a preferred embodiment, the rounded extrudates obtained after rounding can be graded, for example, by using known Kressner sieves having a screening size of approximately 0.7 mm and 1.6 mm, with a grading yield > / = 75%. As used herein, "> / =" means "greater than or equal to".

[0226] In other embodiments, the process as described herein may include the step that the obtained composition or extrudate may subsequently be processed into other oral dosage forms such as granules, tablets, coated tablets or powders.

[0227] In additional embodiments, the granules, pellets, spheres, tablets, coated tablets or powders thus obtained may also be coated, if desired, with a functional coating such as an enteric coating or a non-functional coating such as an aesthetic coating. In a preferred embodiment, the granules, pellets, spheres, tablets, coated tablets or powders thus obtained are not coated with an enteric coating.

[0228] Table 1 : Preferred screw settings (also referred to hereinafter as "X4.1")

[0229]

[0230] Symbols and abbreviations used in all tables herein:

[0231] Ex.: Example; n.a.: Not applicable; n.av.: Not available; n.d.: Not determined; *: Due to the variability of the method, the measured value is different from the expected theoretical value

[0232] The solid pharmaceutical preparation or dosage form for oral administration obtained by the process as described herein is preferably in the form of pellets or spheres, more preferably in the form of micropellets or microspheres. All of the above forms may further be incorporated into capsules such as gelatin capsules, all of which are suitable for pharmaceutical use; blisters, sachets or bottles such as PVC bottles.

[0233] Therefore, according to the above, the subsequent process steps of the process as described herein may include one or more of the following steps listed below:

[0234] - Cooling the extrudate obtained by the melt extrusion process as described herein

[0235] - Optionally grinding the extrudate and optionally sieving the ground extrudate

[0236] - Cutting / crushing the obtained extrudate into cylindrical pellets

[0237] - Spheronizing the extrudate into spheres / microspheres, pellets / micropellets or granules

[0238] - Drying

[0239] - Optional (film) coating of the pellets, granules or particles

[0240] - Optionally blending the ground extrudate with one or more pharmaceutically acceptable excipients

[0241] - Optionally, blend the pills, spheres or granules with one or more pharmaceutically acceptable excipients

[0242] - Formulate the resulting blend into a solid oral dosage form such as a hard gelatin capsule or a tablet, or fill it into a suitable container such as a bottle, for example, a PVC bottle.

[0243] In a preferred embodiment, the process as described herein includes one or more of the above steps as a continuous process.

[0244] All the processes as described above can be scaled up as needed. For the melt extrusion process variants as described herein, it is known in the art that the basic geometry of the extruder should be as close as possible to the above, while the ratio of the outer diameter (D o ) to the inner diameter (D i ) of the screw is a key parameter. In addition, the screw profile and / or the helical rod configuration should also be similar. However, it is well known that quality and heat transfer limitations may occur, and it is necessary to adjust the settings and have longer process sections and / or alternative screw designs to ensure dispersion and uniformity (see, for example, Swanborough, A., “Benefits of Continuous Granulation for Pharmaceutical Research, Development and Manufacture”, Application Note LR-63, Thermo Fisher Scientific, 2008 or Markarian, J., “Scale-up Challenges in Hot Melt Extrusion”, Pharmaceutical Technology, 20(4)(2012)88-92).

[0245] In yet another aspect, there is provided a pharmaceutical composition comprising a solid or semi-solid composition obtained by the process as described herein, the pharmaceutical composition further optionally comprising one or more conventional pharmaceutically acceptable excipients. The pharmaceutical composition provided by the process as described herein can be used to supplement digestive enzymes in the treatment and / or prevention of dyspepsia in mammals, particularly dyspepsia caused by chronic exocrine pancreatic insufficiency in patients such as those suffering from cystic fibrosis, chronic pancreatitis or those who have undergone upper gastrointestinal surgery. The pharmaceutical composition or dosage form as described herein can preferably be an oral dosage form particularly suitable for administration to humans.

[0246] The solid or semi-solid compositions and / or dosage forms as described herein can be further formulated into pharmaceutical compositions using one or more conventional pharmaceutically acceptable excipients commonly used in formulation techniques, such as those mentioned in, for example, "Lexikon der Hilfstoffe" by Fiedler, 5th Edition, Editio Cantor Verlag Aulendorf 2002, and "The Handbook of Pharmaceutical Excipients", 4th Edition, American Pharmaceutical Association, 2003, and can be selected from carriers, diluents or fillers, binders, disintegrants, lubricants, glidants, stabilizers, surfactants, film formers, emollients, wetting agents, sweeteners, pigments / colorants, antioxidants, preservatives, etc. Suitable carriers, binders, disintegrants, lubricants and glidants can be, for example, those described in more detail above as pharmaceutically acceptable auxiliaries.

[0247] In addition, the pharmaceutical compositions and / or dosage forms as described herein can be film-coated or modified-release coated using known coating methods and commercially available coating materials such as mixtures of film-forming polymers, opacifiers, colorants and plasticizers. Preferably, and due to their beneficial properties such as excellent acid stability, the pharmaceutical compositions and / or dosage forms provided herein are preferably not coated with enteric coatings.

[0248] The dosage forms as described herein can be formulated according to known methods, such as those described in, for example, "Pharmazeutische Technologie", 11th Edition, Deutscher Apotheker Verlag 2010 or "Pharmazeutische Technologie", 9th Edition, Wissenschaftliche Verlagsgesellschaft Stuttgart, 2012.

[0249] Lists of other suitable excipients can also be found in textbooks such as Remington's Pharmaceutical Sciences, 18th Edition (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy, 19th Edition (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd Edition (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); the Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th Edition (Walter Lund, ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference.

[0250] In a preferred embodiment, spherical particles (microspheres or pellets) with a diameter of 0.5 - 2 mm can be produced as described above, and then the spherical particles are filled into hard gelatin capsules or bottles without any other excipients or additives.

[0251] In a second aspect, the present invention also provides a solid or semi-solid composition preferably for pharmaceutical use, comprising:

[0252] (a) 40 wt% - 75 wt% of a mammalian-derived pancreatic enzyme and / or a pancreatic enzyme-containing digestive enzyme mixture of the composition;

[0253] (b) 10 wt% - 50 wt% of a surfactant component of the composition, which has

[0254] (i) 2 wt% - 90 wt% of at least one surfactant relative to the surfactant component, which is selected from: (aa) non-ionic surfactants, which include those having an aliphatic C6 - C 22Polyethylene glycol fatty acid monoesters and / or diesters of carboxylic acids; having aliphatic C6-C 22 Polyethylene glycol glycerol fatty acid esters of carboxylic acids; having aliphatic C 12 -C 18 Polyethylene glycol alkyl monoethers and / or diesters of alcohols, having aliphatic C2-C 18 Oligomeric ethylene glycol ethers of alcohols; and mixtures of any of the foregoing; and (bb) ionic surfactants, which include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine; and mixtures of any of the foregoing, and mixtures of any of the foregoing surfactants from (aa) and (bb);

[0255] (ii) 5 wt%-60 wt% of at least one co-surfactant, relative to the surfactant component, selected from monoacylglycerols of carboxylic acids having aliphatic C6-C 22 Glycerol and aliphatic C 12 -C 22 Monoethers of alcohols, propylene glycol and aliphatic C6-C 22 Partial esters of carboxylic acids, polyglycerol and aliphatic C6-C 22 Partial esters of carboxylic acids, having aliphatic C6-C 22 Oligomeric ethylene glycol monoesters of carboxylic acids, having aliphatic C6-C 22 Oligomeric ethylene glycol diesters of carboxylic acids and mixtures of any of the foregoing, and

[0256] (iii) 0 wt%-70 wt% of a lipophilic phase, relative to the surfactant component, selected from diacylglycerols and triacylglycerols of carboxylic acids having aliphatic C6-C 22 And / or mixtures of any of the foregoing;

[0257] wherein in each case, the percentages (i), (ii) and (iii) add up to 100 wt% of the surfactant component;

[0258] (c) 0 wt%-25 wt% of one or more pharmaceutically acceptable adjuvants of the composition, and

[0259] (d) 5 wt%-50 wt% of a polymer additive selected from hydrophilic polymers having a melting point or glass transition temperature of 50°C-160°C;

[0260] The ratio between the polymer additive (d) and the surfactant component (b) is thus from 0.4 (2:5) to 1.5 (3:2), preferably 1 (1:1), and all weight percentages of the components (a), (b), (c) and (d) in the composition thus add up to 100% by weight.

[0261] The pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammals (a) may preferably be present in an amount of 40% to 70% by weight, 45% to 68% by weight, 47% to 68% by weight or 68% by weight of the solid or semi-solid composition. In other particularly preferred embodiments, component (a) is present in an amount of 50% to 70% by weight, more preferably in an amount of 58% to 70% (64% + / - 6% by weight), and still more preferably in an amount of 60% to 68% by weight.

[0262] The surfactant component (b) may preferably be present in an amount of 15% to 40% by weight, 15% to 30% by weight, 15% to 25% by weight, 17.5% to 25% by weight or 20% by weight of the solid or semi-solid composition. The surfactant (i), co-surfactant (ii) and lipophilic phase (iii) may preferably be present in the solid or semi-solid composition in the same amounts and ratios as described above for the process of the first aspect of the invention.

[0263] One or more pharmaceutically acceptable adjuvants (c) may preferably be present in an amount of 0% to 20% by weight, more preferably 0% to 10% by weight, and still more preferably 0% to 5% by weight of the solid or semi-solid composition.

[0264] The polymer additive (d) may preferably be present in an amount of 5% to 35% by weight, 10% to 30% by weight, 10% to 25% by weight or 15% to 25% by weight of the solid or semi-solid composition.

[0265] Preferably, the w / w ratio between the polymer additive component (d) and the surfactant component (b) in the solid or semi-solid composition is between 0.4 (2:5) and 1.5 (3:2), more preferably between 0.75 and 1.3. Most preferably, their w / w ratio is 1:1.

[0266] Component (a), the pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammals in the solid or semi-solid composition is preferably pancreatin, and more preferably porcine pancreatin as commonly used for therapeutic purposes as more detailedly explained herein.

[0267] Component (b), the surfactant component in the solid or semi-solid composition as described above can be the same as or substantially the same as the preferred surfactant component of the process of the first aspect of the present invention. The surfactant mixture (b) of the above solid or semi-solid composition can be particularly and preferably selected from 44 / 14 and / or 50 / 13, both as described in detail above. Comprising 44 / 14 as the surfactant mixture (b) of the solid or semi-solid composition is most preferred.

[0268] Component (c), one or more pharmaceutically acceptable adjuvants in the solid or semi-solid composition as described above can be the same as or substantially the same as the suitable pharmaceutically acceptable adjuvants of the process of the first aspect of the present invention. Preferably, component (c) can be selected from carriers, preferably microcrystalline cellulose, sucrose and / or lactose; antioxidants, preferably BHA, and disintegrants, preferably cross-linked PVP. The antioxidant, especially BHA, is preferably present in a concentration of 50 ppm to 200 ppm, more preferably 100 ppm to 150 ppm, especially 150 ppm, relative to the total weight of the solid or semi-solid composition.

[0269] Component (d), the polymer additive in the solid or semi-solid composition as described above can be the same as or substantially the same as the suitable polymer additive of the process of the first aspect of the present invention. Preferably, the polymer additive is selected from hydrophilic polymers with a melting point or glass transition temperature of 50°C - 70°C or 50°C - 65°C. In other preferred embodiments, the polymer additive is selected from hydrophilic polymers with a melting point or glass transition temperature of 50°C - 110°C. In one embodiment, the hydrophilic polymer with a melting point or glass transition temperature of 50°C - 110°C is selected from polymers with at least hydrophilic chains at the ends of the chains. In a more preferred embodiment, the polymer additive in the solid or semi-solid composition can be selected from PEG and / or poloxamer with an average molecular weight of 3000 - 30000 g / mol, more preferably 3250 - 25000 g / mol. In particular, the polymer additive in the solid or semi-solid composition can be PEG4000, PEG 8000, PEG 20000 and / or poloxamer 188.

[0270] In addition, a solid or semi-solid composition preferably containing PEG 20000 as the hydrophilic polymer additive (d) in a (d):(b) ratio of 1:1, and a composition containing PEG 4000 as the polymer additive (d), and the polymer additive (d) is used in a (d):(b) ratio of 1:1 to 2:1.5.

[0271] Other preferred solid or semi-solid compositions comprise:

[0272] (a) Porcine pancreatin, in an amount of 58% to 70% by weight, preferably 60% to 68% by weight, of the composition,

[0273] (b) 44 / 14, in an amount of 15% to 20% by weight of the composition, and

[0274] (d) PEG 4000, in an amount of 15% to 25% by weight of the composition,

[0275] wherein the total amount by weight of components (a), (b) and (d) is 100% w / w,

[0276] In some aspects, the present invention also provides a solid or semi-solid composition comprising:

[0277] (a) An enzyme or enzyme mixture having lipase activity;

[0278] (b) A surfactant mixture, which comprises:

[0279] (i) At least one surfactant

[0280] (ii) At least one co-surfactant, and

[0281] (iii) A lipophilic phase;

[0282] (c) Optionally one or more pharmaceutically acceptable adjuvants, and

[0283] (d) A hydrophilic polymer additive having a melting point or glass transition temperature of 50°C to 65°C;

[0284] whereby the ratio of additive (d) to mixture (b) is from 0.4 (2:5) to 1.5 (3:2).

[0285] In a second aspect of the present invention, the solid or semi-solid composition as described herein can preferably be prepared by melt extrusion using a twin-screw extruder, preferably a co-rotating twin-screw extruder. In certain embodiments, the composition can generally also be prepared at a lower temperature, for example at a barrel temperature of the extruder of about 50°C to 60°C or at a product temperature of about 45°C to 70°C.

[0286] In yet another embodiment, the present invention also provides a pharmaceutical composition comprising the solid or semi-solid composition according to the present invention and optionally further comprising one or more conventional pharmaceutically acceptable excipients. The conventional pharmaceutically acceptable excipients can be the same as or substantially the same as the suitable conventional pharmaceutically acceptable adjuvants in the process of the first aspect of the present invention, or alternatively can be the pharmaceutically acceptable adjuvants as described above for the process of the first aspect of the present invention.

[0287] Exemplary formulations and processes for preparing a molten composition according to the processes described herein are detailed in the following examples. Accordingly, the following examples are intended to illustrate the invention without limiting its scope. Examples

[0288] Unless otherwise stated, the pancreatin (porcine pancreatin powder, therapeutic grade) used in the following examples was supplied by Abbott (Neustadt, Germany).

[0289] 1. Melt granulation

[0290] For the manufacture of solid or semi-solid compositions by a process variant of melt granulation, the surfactant component (b) and / or the polymer additive (c) (as required for the target composition) are mixed in a glass beaker in the required weight ratio and heated (oil bath) until molten (usually at about 50 °C). If required, one or more pharmaceutically acceptable adjuvants (c) are added to the received melt thus obtained (for example, 150 ppm BHA can be added to samples not foreseen for virus doping, relative to the total weight of the received melt), and the combined components are mixed with a palette knife for about 5 minutes to achieve homogenization. Then, at about 50 °C, the porcine pancreatin powder of therapeutic grade (virus-doped or non-virus-doped, if applicable) is added to the received melt in the required amount (weight ratio), and mixing is continued. The mixture is carefully heated with stirring until the specified target (product) temperature of the mixture (70 °C - 130 °C), for example 120 °C, is reached. The temperature is measured with a digital insertion thermometer (Testo 720). After a defined holding time at the target temperature (for example 5 minutes), about 2 g of sample is taken from the glass beaker, at least one each from the top, middle and bottom of the glass beaker, and sieved (800 microns). Samples (about 1 g) from non-virus-doped porcine pancreatin are used to determine the residual enzyme activity. Similarly, samples (about 1 g) from virus-doped pancreatin powder (without antioxidant / BHA) are used to determine the residual virus load. The solid or semi-solid compositions manufactured according to this protocol are shown in Tables 2a and 2b below.

[0291] The virus reduction factor (as the log reduction factor, LRV, explained below) and the recovery of lipase activity after the process run (measured as the lipase activity found after the process run divided by the lipase activity found before the process run, in %) are determined as explained in the method section.

[0292] Examples 38 - 57 were produced by the melt granulation process according to the present invention. Examples 38 - 43 and 47 - 57 were produced by the preferred melt granulation process according to the present invention. Example C1 is a comparative example with a composition not according to the present invention. Examples 36 - 54 and 56 - 57 represent the solid or semi - solid compositions of the present invention.

[0293] Table 2a : A composition manufactured by the melt granulation process as described herein

[0294]

[0295] As can be seen from the examples manufactured by variations of the melt granulation process as described herein (see Tables 2c - 2e), when a process (target) temperature of not less than 90 °C and not more than 130 °C (90 °C - 130 °C), 95 °C - 125 °C or 105 °C - 130 °C is applied for a time period of not less than 30 seconds and not more than 45 minutes, such as not less than 180 seconds and not more than 30 minutes or such as not less than 300 seconds and not more than 30 minutes (processing time at the target temperature; holding time), a high to extremely high activity of the target enzyme in porcine pancreatin can be preserved.

[0296] Table 2b : A composition manufactured by the melt granulation process as described herein (continued)

[0297]

[0298] It can also be seen from the examples manufactured by variations of the melt granulation process as described herein (see Tables 2a - 2c) that when the mixture is processed for a time period of 300 seconds at a temperature of 70 °C, the concentration of moderately resistant viruses (using PsRV as a model for moderately resistant virus types) in the resulting solid or semi - solid composition can be very significantly reduced (LRV ≥ 6.8). When the mixture is processed for a time period of 300 seconds at a temperature of 90 °C, the concentration of moderately to highly resistant viruses (using, for example, FCV as a model for moderately - highly resistant virus types) in the resulting solid composition can be very significantly reduced (LRV ≥ 6.4). When the mixture is processed at a temperature of 110 °C for 1800 seconds (30 minutes) or alternatively at a temperature of 120 °C for a time period of 180 seconds, the concentration of highly resistant viruses (using, for example, PPV as a model for highly resistant virus types) in the resulting solid composition can be significantly reduced (LRV is about 3). At a temperature of 120 °C for a time period of 300 seconds, an even more significant virus inactivation (LRV ≥ / = 3.6) can be observed.

[0299] Table 2c : A composition manufactured by the melt granulation process as described herein (continued)

[0300]

[0301] Table 2d : Compositions produced by the melt granulation process as described herein (continued)

[0302]

[0303] For comparison purposes, Table 2a - 2c (last row) also shows the LRV of the pancreatin preparation only that has been treated in the same manner (virus type, addition, target temperature, holding time at target temperature) as the corresponding examples shown in the same row of the respective table. The data show that virus inactivation by heating in the pancreatin - only samples is significantly lower than virus inactivation in the samples treated by the melt granulation process variants according to the invention and / or in the samples representing the solid or semi - solid compositions according to the invention.

[0304] Table 2e : Compositions produced by the melt granulation process as described herein (continued)

[0305]

[0306] 2. Melt extrusion

[0307] To optimize the mixture or composition for processes selected from melt pelletization, melt granulation, and melt extrusion as described herein, particularly for melt extrusion, and to optimize the content of the API pancreatin, preparations with different compositions and API contents were prepared and evaluated with respect to processability in view of extrusion, spheronization, and maintenance of the required biological activity (lipase activity). The results from these experiments are summarized in Tables 3a - 3d below. The lipase activity shown was determined as described in the following method section.

[0308] The compositions shown in Tables 3a - 3d were prepared by a melt extrusion process using a Gabler DE - 40 - T D15 twin - screw extruder (pilot scale, screw diameter 40 mm, screw length 600 mm) with a die plate (wall thickness 1.0 mm and 387 holes with a diameter of 1.0 mm, the die plate being fixed with a support plate to have a 0.2 mm - 0.3 mm gap from the extruder screw), and subsequent spheronization was carried out using a Gabler R 250 double - jacketed spheronizer equipped with a tempering device. The extruder screw has the features explained in the Figure 1 description. Thereafter, the reference numerals and terms corresponding to those shown in Figure 1 are used to indicate the parts of the extruder.

[0309] The pancreatic enzyme powder or the premix having pancreatic enzyme is fed into the extruder immediately after the initial section 1 and onto the solid material feed section 2 by means of a weight loss feeder.

[0310] The molten mass (components (b) and (d) of the preferred composition shown above) is provided in a stirred container heated to about 20 °C above its freezing point immediately after the solid material feed section 2 by means of a pump (usually a peristaltic dosing pump Verderflex (Verder, Haan, Germany)) and fed into the extruder onto the medium pitch section (molten feed section) 3. The feed pipe of the pump is provided with an external heating pipe having a medium tempered at about 75 °C (+ / - 5 °C) and isolating heat loss. The dose of the melt is adjusted by setting the pump speed based on the mass-velocity-calibration of the respective melt. The doses of the melt and the pancreatic enzyme are set according to the compositions shown in Tables 3a - 3c below.

[0311] In front of the die plate, compression is generated due to the pressure of the material conveyed by the extruder screw and the resistance of the die plate, so that a uniform extrudate with a homogeneous composition and consistency can be produced during the process cycle. To establish such a uniform extrudate, first a stable melt flow with a regulated melt dose is established from the heating container down through the die plate. Then the weight loss feeder is operated according to the specified pancreatic enzyme or pancreatic enzyme-containing premix concentration in the extrudate to feed the corresponding solid powder pancreatic enzyme onto a part of the solid material feed section 2 of the extruder screw, said part being adjacent to the interface between the initial section 1 and the solid material feed section 2. This processing sequence can avoid harmful mechanical loads. From the time when the stable extrudate composition is produced in the extruder and present at the die plate until the time when the melt in the heating container or the pancreatic enzyme powder in the weight loss feeder becomes short, a period of about 1 hour is used to collect the extrudate using a bowl made of stainless steel. During this period, 8 kg of extrudate is produced in Example "4" (see Table 3a), while 10 kg of extrudate is usually produced in all other examples and comparative examples. After said period, the feeding of the pancreatic enzyme powder is stopped first, and thereafter the feeding of the melt is stopped.

[0312] During all operations of the extruder, the barrel temperature of the extruder is set to about 50 °C - 60 °C (usually equivalent to a product temperature of about 45 °C - 70 °C). The first kneading element section 4 and the second kneading element section 6 are used to mix the materials for producing the extrudate. The experiments in this section were run at a barrel temperature below 90 °C (product temperature not measured), but were found to be applicable to suitable mixtures and / or compositions preselected for processing at higher temperatures (see below).

[0313] The rounding of the extrudate to the shape of spherical pellets preferably requires establishing an internal extrudate temperature below the melting temperature of the extruded material, particularly low enough to avoid agglomeration and high enough to avoid embrittlement that is harmful to shaping, particularly rounding.

[0314] To establish a suitable internal extrudate temperature, the collected extrudate was left at room temperature for 2 hours and then loaded into a rounding machine. The rounding machine was then placed and operated in a heating cabinet at 50 °C to achieve a temperature of the material inside the rounding machine close to 42 °C.

[0315] It was found that the rounding machine could be operated to produce uniform pellets at an average yield of 90% within the following operating parameters for each batch: loading 250 g - 400 g; rounding period 4 - 7 minutes, and rotational speed 600 - 1200 rpm.

[0316] The spherical pellets were classified using Kressner sieves with a screening size of approximately 0.7 mm and a screening size of approximately 1.6 mm, and the classification yield was 75% - 80% of the theoretical yield.

[0317] Table 3a : A composition manufactured by a melt extrusion process (pilot scale) as described herein at a barrel temperature of 50 °C - 60 °C.

[0318]

[0319] Symbols used in Tables 3a - 3c for evaluating extrusion (characterizing quality):

[0320] (1): Extrusion has no problems and processability is good; (2): Processing is possible, but the oversize fraction > 1.6 mm; (3): Processing is possible but not optimal, high viscosity; (4): Too wet for processing; (5): Very dry, high dust content;

[0321] Symbols used in Tables 3a - 3c for evaluating rounding (characterizing quality):

[0322] (01): Rounding is good - excellent, low loss; (02) Processing is not optimal, accumulation; (03) Processing is not optimal, low yield; (04): Processing is possible but not optimal.

[0323] Examples 2 - 4, 8 - 14, H, and a - b represent the solid or semi - solid compositions of the present invention. Examples 2, 3, 4, 8, 9, 10, 11, 12, 13, 14, and H represent the preferred solid or semi - solid compositions of the present invention. The examples shown in Tables 3a - 3c were produced by a melt extrusion process similar to the melt extrusion process according to the present invention.

[0324] Table 3b: Composition manufactured by a melt extrusion process (pilot scale) at a barrel temperature of 50°C - 60°C as described herein (continued)

[0325]

[0326] It can be estimated from the experiments shown in Tables 3a - 3c that when the components and their amounts and ratios are selected according to the present disclosure, mixtures for preparing solid or semi - solid compositions with a pancreatin content of about 40 wt% - 75 wt% can be processed smoothly in the melt extrusion process as described herein, and the solid or semi - solid compositions produced by said process have preserved the desired enzyme activity to the highest degree. When the process variants and compositions characterized as preferred or more preferred herein are selected, more preferred processes and solid or semi - solid compositions can be obtained.

[0327] Table 3c : Composition manufactured by a melt extrusion process (pilot scale) at a barrel temperature of 50°C - 60°C as described herein (continued)

[0328]

[0329] Thus, in a preferred embodiment of the present invention, solid or semi - solid compositions are preferred, said solid or semi - solid compositions comprising PEG 20000 as polymer additive (d) and a composition with a (d):(b) ratio of 1:1 and comprising PEG4000 as polymer additive (d), and said polymer additive (d) is used at a (d):(b) ratio of 1:1 to 2:1.5.

[0330] In other experiments, solid or semi - solid compositions were prepared on different scales by a twin - screw melt extrusion process. The general scheme of such a process is provided below. On the one hand, the extruders mentioned are used to illustrate certain aspects of the present invention without limiting the scope of the present invention, and on the other hand, they represent preferred embodiments for implementing the twin - screw melt extrusion process as described herein, according to the first aspect of the present invention:

[0331] Table 3d : Composition manufactured by a melt extrusion process (pilot scale) at a barrel temperature of 50°C - 60°C as described herein (continued)

[0332]

[0333] Before the extrusion process, by mixing and heating the surfactant component (b) at the w / w ratio required to obtain the desired composition (for example, at a ratio of 1:1 w / w) (e.g., Prepare a molten mass using API (trypsin powder) (e.g., 44 / 14) and / or a polymeric additive (d) (e.g., PEG4000). Before the start of heating and mixing, add one or more pharmaceutically acceptable auxiliaries (c) in the desired amount / ratio (e.g., 150 ppm BHA, relative to the total weight of the molten mass). Then transfer the molten mass to a glass beaker equipped with a magnetic stirrer and heat it to a suitable temperature (e.g., about 75 + / - 5 °C) under continuous stirring for the duration of the entire manufacturing process to avoid solidification of the molten mass during the process. The tubing system (heated to about 80 °C) transports the molten mass to the extruder through a suitable pump, preferably a heated pump (e.g., a heated HNP pump). Before feeding the API (trypsin powder) into the extruder, transfer the molten mass onto the screw of the extruder through a pouring hole (thus, the dosing of the molten mass is carried out through the heated pump system and the heated tubing). Control the composition of the corresponding formulation by a weigh-in process and by adjusting the feed rate of the trypsin powder (solid feed system) and the feed rate of the molten mass monitored by the pump unit. In the pre-setting stage, adjust the process settings and composition of the formulation for the corresponding excipients.

[0334] Before the start of the extrusion process for the two feed devices, calibrate the solid feeder (for API powder, e.g., a ZD 5 gravimetric solid feeder) and the melt feeder (for the molten mass) by compiling a characteristic dosing control curve. Similarly, calibrate the liquid feed unit (HNP pump). Finally, perform a weight check of the output rate and adjust the output rate to obtain the desired trypsin:molten mass ratio. Once the set points of the feed rates of the two components (API and molten mass) are confirmed to conform to the formulation of the composition, start the extrusion run.

[0335] Add the API (trypsin) as a solid powder onto the screw of the extruder using a feed system (e.g., a K-Tron feeder for pilot scale; a Three Tec 5mm feeder for micro scale), thereby controlling the feed rate gravimetrically through the feed system.

[0336] Before starting the extrusion and dosing of the components (including optional excipients), heat the barrel of the extruder to the target temperature (suitable for achieving the desired product temperature). At the end of the extruder, pass the molten composition through a die plate (die hole diameter of about 1.0 mm) to produce several "spaghetti"-shaped extrudate strands. During the extrusion process, control the throughput by weighing the extrudate and the consumption of the molten mass over a certain time period (about 10 minutes). For a process run time of about 40 minutes (per batch), the batch size for micro scale results in about 100 g, and for pilot scale it is about 5.3 kg (batch size relative to the effective output / yield).

[0337] After cooling to room temperature, a suitable portion of the extrudate so received is transferred to a conventional spheronizer (e.g., Gabler Spheronizer R-250) preheated to a suitable temperature, e.g., about 49 °C. The extrudate is then spheronized to obtain approximately spherical pellets with a diameter of about 2 mm. After cooling to room temperature, in a representative process run, the pancreatin pellets are sized using a 0.7 mm Kressner screen (oversize particles), and then a 1.6 mm Kressner screen (undersize particles) to yield pancreatin pellets at a theoretical yield of about 90%. The completed pancreatin pellets can then be filled into suitable containers (e.g., PVC bottles) for storage.

[0338] The minimum residence time of the extrusion run is determined by visual inspection using a suitable tracer or marker substance (e.g., curcumin from Merck Darmstadt, Germany). After the processing conditions have stabilized, a single dose of the marker substance (curcumin) is added on time to the pancreatin powder (about 50 mg curcumin for a throughput of 2.5 g / min on the microscale, about 500 mg curcumin for a throughput of 8 kg / h on the pilot scale), and the so-marked pancreatin is fed directly into the inlet of the extruder. The time period until the marked pancreatin first appears at the die end of the extruder is then recorded as the minimum residence time by visual inspection.

[0339] In an alternative process, the minimum residence time can also be determined spectroscopically. As described above, the pancreatin powder marked with curcumin is fed directly into the inlet of the extruder. Samples are taken at 5-second intervals (about 0.2 g each for the microscale, about 2 g each for the pilot scale) starting from the beginning of the extrusion process, after about 55 seconds, and over a time period of about 150 seconds. The samples (about 7.3 g each) are then dissolved in acetone (about 66 ml each), and the concentration of curcumin in the samples is determined photometrically at a wavelength of λ = 421 nm (Shimadzu UV-1602). The concentration values are plotted against the time scale to obtain a concentration-versus-time curve. In this method, it is not necessary to determine the absolute concentration or amount of the tracer (e.g., curcumin), as only a relative comparison between samples taken at different times is required. To find the minimum residence time, it is sufficient to determine the start of the residence time distribution curve representing the initial appearance of the tracer at the die side.

[0340] A comparison of the minimum residence times found by the visual inspection method and the spectroscopic method for the selected process runs is given in Table 4, showing excellent correlation of the results obtained from the two methods for a given process run.

[0341] Preferred compositions (molten or solid compositions) suitable for use with the processes described herein, particularly for melt extrusion process variants, are shown in Table 5 below.

[0342] Table 4 : Process parameters for an exemplary extrusion process for the processes described herein (different scales, twin-screw extrusion)

[0343]

[0344] Table 5 : Preferred solid or semi-solid compositions for use in the processes described herein

[0345]

[0346] In Table 6, exemplary formulations and process parameters for a melt extrusion process variant of the processes described herein using a twin-screw extrusion (Three Tec extruder ZE9) on a micro scale and certain screw configurations are outlined.

[0347] Table 6a : Exemplary formulations and process parameters for the melt extrusion process described herein (screw setting "X4.1" or modifications thereof)

[0348]

[0349] Examples 19 - 24 represent solid or semi-solid compositions according to the invention and are produced by a melt extrusion process according to the invention. The process run for Example 23 was defective as the target product temperature of 130 °C was exceeded due to overheating and congestion at the pancreatic enzyme powder inlet. Examples C2 - C4 are comparative examples that do not represent solid or semi-solid compositions according to the invention, but Examples C3 and C4 are produced by a melt extrusion process according to the invention. Although Examples C3 - C4 can be processed, the resulting extrudates / strands are not optimal for further processing into a stable pharmaceutical product as the consistency of the strands obtained is too soft and viscous. The comparison of the processability / results of Examples 5 and 6 with C3 and C4 shows that the solid or semi-solid compositions according to the invention exhibit excellent processability under the conditions of the processes according to the invention (including treatment at higher temperatures), particularly in melt extrusion process variants.

[0350] Table 6b : Exemplary formulations and process parameters for the melt extrusion process described herein (screw setting "X4.1" or modifications thereof), continued

[0351]

[0352] Footnote explanations used in Tables 6a and 6b: 1: Visual inspection; 2 : Output weight

[0353] 3 : Minimum residence time, undetermined but estimated from other process runs with similar parameters

[0354] In Table 7, exemplary formulations and process parameters of melt extrusion process variants of the process as described herein using laboratory-scale twin-screw extrusion and certain screw configurations are outlined.

[0355] Table 7 : Exemplary formulations and process parameters of the melt extrusion process as described herein

[0356]

[0357] The footnotes used in Table 7 are explained as follows: mod.: modified; #B2: screw rod setting similar to X4.1 but applying more mechanical stress

[0358] In Table 8, exemplary formulations and process parameters of melt extrusion process variants of the process as described herein using pilot-scale twin-screw extrusion (Gabler DE 40 extruder) and certain screw configurations are outlined. The pancreatin in Examples 58 - 60 was supplied by SPL.

[0359] Table 8 : Exemplary formulations and process parameters of the melt extrusion process as described herein (screw rod setting "X4.1")

[0360]

[0361] Symbols used in Table 8 for evaluating extrusion (characterizing quality): (1): Good processability. Symbols used in Table 8 for evaluating spheronization (characterizing quality): (01): Good spheronization, low loss; (02) Spheronization possible, but lower yield of round pellets.

[0362] It can also be seen from the experimental examples provided herein that the processing time at the product temperature for effectively reducing the bioburden, particularly the viral load, in biomaterials derived from human or mammalian tissues, especially pancreatin, can be further reduced to a time period of, for example, less than 10 minutes, such as less than 5 minutes, using a homogenizing extruder in a preferred process variant.

[0363] 3. Comparative test

[0364] Effect of extrusion on virus inactivation

[0365] The potential of a conventional extrusion process with a subsequent drying step to reduce the infectious viral load in pancreatin samples was investigated.

[0366] The pancreatic enzyme intermediate (therapeutic grade) from the production process was admixed with a similar high-titer FCV virus suspension as described in the method section, with the following deviation for the high-titer FCV virus suspension: the stock solution was used "as is", and the liquid was filtered out from the admixed sample to receive a material equivalent to the wet process intermediate before drying. Drying was carried out in laboratory-scale equipment to obtain the admixed pancreatic enzyme. The pancreatic enzyme was gently ground with a pestle and re-wetted with pure isopropanol (50% w / w relative to the pancreatic enzyme used). As described in the method section, a pre-treated sample was taken to determine the total virus load. The wetted pancreatic enzyme was fed into a conventional single-screw extruder (type: Wyss & Probst Pharmes 35T) equipped with holes (diameter 1.0 mm) in a plate (thickness 0.8 mm), and extruded twice at a screw speed of 45 rpm. After extrusion (for a total of approximately 90 minutes), a post-treated sample was taken and analyzed for virus content. Subsequently, the extruded pancreatic enzyme was aliquoted into glass bottles (approximately 2.5 g each) and sealed. Immediately before placing the vials in a pre-heated drying oven (45 °C, temperature monitored), the seals were removed. Samples were taken from the dryer after 90 minutes, 12 hours, 20 hours, and 60 hours and analyzed for virus content in each case similar to that described in the method section.

[0367] Data from this experiment (see Table 9) showed that extrusion and / or heating to 45 °C had no effect on virus inactivation in wet pancreatic enzyme.

[0368] Table 9 : Effect of the conventional extrusion process on virus reduction in wet pancreatic enzyme samples

[0369] Sample (trypsin) <![CDATA[Log 10 Total viral load]]> LRV After wetting with isopropanol (loading) 8.41 --- After the second extrusion 8.11 <![CDATA[0.30* 1 > After drying at 45 °C for 90 minutes 7.39 <![CDATA[0.72* 2 > After drying at 45 °C for 12 h 8.88 <![CDATA[-0.77* 2 > After drying at 45 °C for 20 h 8.35 <![CDATA[-0.24* 2 > After drying at 45 °C for 60 h 8.40 -0.29*2

[0370] 1 : refers to the loaded sample after wetting; 2 : refers to the sample after the second extrusion.

[0371] Effect of surfactant components on virus inactivation

[0372] It is known from the prior art that the use of detergents can help inactivate enveloped viruses in biological materials (see, for example, Sofer, "Biopharm Int. (2002), 15(9), 28–42), while non-enveloped viruses are generally not inactivated by detergents (see, for example, WHO Technical Report, Series No. 924, 2004, Annex 4, p. 168). In its own experiments, it could be confirmed that at 37 °C alone 44 / 14 and 55 / 13 showed only moderate inactivation of enveloped viruses (LRV 2-3; bovine diarrhea virus, PsRV), while no inactivation of non-enveloped viruses (Rotavirus A, FCV, PPV) was observed under these conditions.

[0373] Method

[0374] 1. General method for evaluating virus clearance with an additive formulation

[0375] For determining virus reduction as a result of the applied process variant, samples of component (a) (API, trypsin) are spiked with a suitable model virus of defined concentration before the process and the remaining virus concentration after the process run is analyzed as described in more detail below. Similarly, but in different samples not spiked with virus, the lead enzyme activity of the API (trypsin) is determined before the process and after the process run as described in more detail below.

[0376] Method for determining virus load reduction - VCS (Virus Clearance Study)

[0377] Proof of the virus inactivation or removal capacity of a biopharmaceutical manufacturing process is carried out by the intentional spiking of scaled-down versions of specific manufacturing process steps with high-titer preparations of model viruses such as Pseudorabies virus ("PsRV"), an enveloped DNA virus, low resistance, feline Calicivirus ("FCV"), a non-enveloped RNA virus (medium - high resistance), Reovirus Type 3 (Reo3), a non-enveloped RNA virus (medium to high resistance), and porcine parvovirus PPV, a non-enveloped DNA virus (very high resistance), and subsequently comparing the infectious virus titers of pre-treatment and post-treatment samples in cell culture-based virus-specific infectivity assays. Parvoviruses represent the viruses of greatest interest in preparations intended for human and / or other animals, as they are widespread in pigs and, considering the sensitivity of the active pharmaceutical ingredient, represent and simulate the most difficult-to-inactivate target contaminants. Thus, proof that the target parvovirus has been inactivated is generally accepted as evidence that the disclosed method will also inactivate other similarly or less resistant viruses such as non-enveloped viruses and larger enveloped viruses.

[0378] The embodiments described herein are carried out according to the recommendations of "Note for guidance on virus validation studies: The design, contribution and interpretation of studies validating the inactivation and removal of viruses (CPMP / BWP / 268 / 95, February 1996)".

[0379] The starting material for each method is trypticase powder (API) spiked with a target model virus (e.g., PPV). A high-titer virus stock suspension is harvested from cell culture, lyophilized in a freeze-dryer, and the virus titer (infectivity) is examined in sub-fractions of the lyophilizate. Shortly before the virus clearance experiment, the virus lyophilizate is homogeneously mixed with the drug substance by a milling process to achieve a virus spiking / API ratio of approximately 5% - 10% (w / w). The spiked API is then used in a melt extrusion or melt granulation process (if applicable).

[0380] As is recognized in the art and as used herein, the reduction in virus titer when comparing two samples is typically reported as the "log reduction value" ("LRV"), sometimes also referred to as the "log reduction factor". Log reduction indicates the reduction in virus concentration in logarithmic units to the base 10. For example, a log titer reduction of 1 indicates a 90% reduction in virus concentration (i.e., the number of viruses found after the process is 10 times smaller than before the process was applied); a log titer reduction of 2 indicates a 99% reduction in virus concentration (i.e., the number of viruses found after the process is 100 times smaller than before the process was applied); a log titer reduction of 3 indicates a 99.9% reduction in virus concentration (i.e., the number of viruses found after the process is 1000 times smaller than before the process was applied), and a log titer reduction of 4 indicates a 99.99% reduction in virus concentration (i.e., the number of viruses found after the process is 10000 times smaller than before the process was applied).

[0381] During the virus clearance experiment, process samples are taken directly before treatment and immediately after virus inactivation treatment (extrusion process or melt granulation process, if applicable) and quantitatively analyzed by standard end-point titration, and additionally the post-treatment samples are quantitatively analyzed by large volume plating.

[0382] Generally, for each model virus, the corresponding system of a permissive cell line and a virus strain is used to determine the infectivity before and after treatment. The virus stock solution is prepared from a master virus stock solution, characterized, for example, by sequence analysis, growth kinetics, phenotypic analysis, and / or by immunostaining with the corresponding antibody (e.g., anti-PPV). An intermediate virus stock solution is prepared from the master virus stock solution, and a virus working batch derived therefrom is prepared, which is used as a virus spiking preparation after lyophilization. The cell cultures used in the virus clearance experiments are derived from a master cell bank characterized, for example, by identity, purity, and mycoplasma absence. The master cell bank is used to prepare a working cell bank. For this purpose, the cells are passaged in cell culture flasks at a cell line-specific density and harvested, centrifuged, counted after reaching confluence or high cell density, and seeded at a cell-specific density for pre-treatment and post-treatment sample titration in fresh cell culture flasks and / or microtiter plates. The matching systems of model virus strains and permissive cell lines are as follows: PsRV strain AK MK 35 in Vero 76 cells, African green monkey kidney cell line; FCV strain F9 (ATCC VR-782) in KE-R CCLV-RIE 138, feline embryo cell line; PPV strain NADL-2 (ATCC VR-742) in SK6 CCLV-RIE 262, porcine kidney cell line; Reo3 strain RVB-011 in HEK 293, human embryonic kidney cell line. The cell lines "Vero 76", "KE-R CCLV-RIE 138", "SK6 CCLV-RIE 262" and the virus strains "PsRV AK MK35" and "Reo-3 RVB-011" are available from the cell bank of the – Federal Research Institute for Animal Health, Südufer 10, 17493 Greifswald, Insel Riems, Germany, see also the website of the FLI: https: / / www.fli.bund.de / de / startseite / service. The cell line "HEK 293" (CRL-1573) and the virus strains "FCV F9" (VR-782) and "PPV NADL-2" (VR-742) are available from the "American Type Culture Collection" (ATCC) at LGC Standards GmbH, Mercatorstr. 51, 46485 Wesel, see also the website of the ATCC: http: / / www.lgcstandards-atcc.org / products / all.

[0383] Furthermore, before the actual virus clearance experiments, the starting materials (unspiked API, representing the pre-treated samples) of the non-interfering and non-cytotoxic sample dilutions and the formulated API (melt extrudate or melt granulate (if applicable), representing the post-treated samples) were determined by cytotoxicity and interference pre-tests.

[0384] Virus titers were determined by end-point titration and large volume plating. For end-point titration, serial three-fold dilutions of the samples at non-interfering and non-cytotoxic concentrations were prepared in cell culture medium and incubated for a specified incubation period on the respective permissive cell line. Readout was performed by microscopic examination of virus-induced cell morphological changes (cytopathic effect, CPE) and additionally by immunostaining for PPV. For large volume plating, a larger volume of the resuspended test article at non-interfering and non-cytotoxic concentrations was added to a defined number of wells containing the respective permissive cell line in cell culture medium. Readout was performed similar to the end-point titration method.

[0385] For the calculation of the median tissue culture infective dose value (TCID 50 value), its standard deviation and the calculation of the 95% confidence limits, the Spearman-Kaerber algorithm as given by Loewer was applied (see, Bundesanzeiger Nr. 84, S. 3-8, 1994). In cases where no virus could be detected in all parallel samples at the lowest sample dilution or in large volume plating, the titer was calculated by the Poisson formula and given as log 10 TCID50 / ml, with a probability of 95%. The reduction factor was determined as the difference in the log 10 TCID50 values of the pre-treated sample (pre-extrusion load sample) and the post-treated sample (i.e., after extrusion).

[0386] Melt extrusion

[0387] Reproduce the relevant melt extrusion process parameters using a micro melt extruder (Three Tec extruder ZE 9). Prepare the melt mass of the excipient as described for the formulation experiments. Homogeneously incorporate the API with the lyophilized model virus formulation to obtain, for example, a 5%-10% incorporation (w / w). Achieve the dosing of the melt mass and the feeding of the incorporated API as described for the formulation experiments. Once the set point for the feeding rate controlling the formulation composition has been confirmed, start the extrusion run. Just before filling the incorporated API into the solid feed unit, take samples for analysis of the virus titer and immediately dilute for titration on the corresponding susceptible cells. Release the processed material as an extrudate from the micro extruder through a dye plate and collect in a glass beaker. After the extrusion process has reached a steady state (about 15 minutes), collect the extrudate for the post-treatment process samples. After about 10 g have been collected, cool the collected extrudate to ambient temperature. Then process the extrudate through a sieve (800 microns), and weigh out two 0.5 g powders, resuspend in cell culture medium to a predetermined non-cytotoxic and non-interfering concentration, and immediately titrate on the corresponding susceptible cells.

[0388] The process parameters applied to four manufacturing samples by twin-screw melt extrusion on a micro scale are shown in Tables 10 and 11 below. Examples 32-35 contain the weight % API as shown in Table 11. Each composition 32-35 also contains 44 / 14 and PEG 1:1 (w / w) to make up to 100 wt% and 150 ppm BHA. The API (porcine pancreatin) from the same batch was used to prepare all four example compositions. The results of the virus analysis from the twin-screw melt extrusion samples are shown in Table 11 below.

[0389] Table 10 : Process parameters for manufacturing samples (extrudates) for virus analysis by twin-screw melt extrusion

[0390]

[0391] Table 11 : Overview of the results of samples (extrudates) for virus analysis manufactured by twin-screw melt extrusion on a micro scale and the virus inactivation ability of the melt extrusion process

[0392]

[0393] #Below the DL (detection limit)

[0394] The results demonstrate significant inactivation of the full range of selected model viruses. Provide up to 3 log according to the process / process conditions of the process as described herein 10Significant inactivation of highly resistant virus (PPV) with an LRV of 3 and very effective inactivation of moderately to highly resistant viruses (FCV and Reo3). Both the enveloped virus (PsRV) and the non-enveloped viruses Reo3 and FCV were inactivated below the detection limit (DL).

[0395] Melt granulation

[0396] Samples for determining the residual virus load after application of the melt granulation process were prepared as described above. The samples were analyzed as described above for the melt-extruded samples, but using the samples taken from the reaction vessel for the melt granulation process instead of the extrudates.

[0397] For each virus inactivation experiment, in Examples (36 - 49), 6 g of API (porcine pancreatin powder, therapeutic grade) was homogenized with 1 g of the lyophilized virus preparation with the corresponding virus type. The admixed API was mixed with the receiving melt made of 2 g 44 / 14 and 2 g of PEG 4000 as described above.

[0398] The results of the virus analysis from the melt granulation samples are shown in Tables 2a - 2c.

[0399] 2. General method for determining the recovered enzyme activity

[0400] The enzyme activity in the samples after processing (melt granulation or melt extrusion, if applicable) has been determined according to the following procedure. The results are provided above (see, for example, Tables 6 and 7 and the "Melt granulation" section)

[0401] Samples for determining enzyme activity (lipolysis, proteolysis or amylolysis, if applicable) are usually taken directly from the manufacturing process and used after cooling to room temperature without further treatment, i.e., the samples are the extrudates in the case of extrusion or from the reaction vessel in the case of melt granulation (see above). In some cases, the extrudates are further processed into test samples by rounding before determining the enzyme activity. It can be shown that rounding has no or no relevant effect on the enzyme activity.

[0402] All tests for enzyme activity were carried out according to the relevant method for "Pancreatin powder" of Ph.Eur. All enzyme activities measured are given in "U / g". The enzyme activity of the test samples containing pancreatin was determined as follows:

[0403] The enzyme activity of the pancreatin powder (therapeutic grade) used to produce the test sample is determined according to Ph.Eur. relative to the relevant reference standards (described in detail below) and is taken as the initial enzyme (lipolytic, proteolytic, amylolytic, as applicable) activity. Then, the test sample as disclosed herein (usually in the form of granules or extrudates) is produced using pancreatin from the same batch as that used for the determination of the initial enzyme activity. Then, the resulting enzyme activity of the test sample is calculated based on the relative (weight / weight %) content of pancreatin in the test sample, which also contains additional components as disclosed herein, such as surfactants, co-surfactants, lipophilic phases, polymer additives, and / or other pharmaceutically acceptable agents (adjuvants).

[0404] For example, to calculate the lipase (lipolytic) activity of pancreatin and the test sample, the initial lipase activity in the pancreatin powder (therapeutic grade) is determined relative to a lipase reference standard (see Ph.Eur.) and is found to be, for example, 70000 U / g. Then, the pancreatin powder from the same batch is used to produce a test sample, for example, in the form of an extrudate. The composition of the extrudate is, for example, 60% w / w pancreatin and 40% w / w other components (as disclosed herein). This method is further explained in the following exemplary calculation method:

[0405] - Initial lipase activity in the pancreatin as determined: 70000 U / g;

[0406] - Expected lipase activity in the test sample after processing: 42000 U / g (60% of 70000 U / g);

[0407] - Lipase activity found in the test sample after processing: 40000 U / g;

[0408] - Remaining lipase activity in the test sample after processing: 95% (100 * 40000 U / g / 42000 U / g).

[0409] The methods applied to determine the enzyme activity are standard in the art and show a generally acceptable variance of approximately 5% for all enzyme activities tested, thus potentially producing measured values of enzyme activity higher than 100%. This variation may be attributed to the dual effect of method variability in the Ph.Eur. determination (determination of the enzyme, such as lipase activity, in the drug substance and determination of the enzyme, such as lipase activity, in the drug product).

[0410] Determination of lipase activity: An aliquot (about 2 - 5 g) of the test sample containing pancreatin as described above is taken and used for subsequent analysis. The required amount of the test sample for lipase activity determination (depending on the expected activity) is comminuted (e.g., crushed or ground, depending on the state / consistency of the test sample) and directly extracted from the test sample with a buffer solution as described in Ph.Eur. Using this standard analytical method, the hydrolytic activity of lipase in the sample to be studied is determined using an olive oil emulsion as the substrate. The free fatty acids cleaved from the triglycerides of olive oil are titrated with sodium hydroxide solution at a constant pH of 9.0. The lipase activity of the sample is determined by comparing the rate of hydrolysis of the olive oil emulsion substrate by the suspension of the pancreatin-containing sample with the rate of hydrolysis of the same substrate by the suspension of a standard pancreatic reference powder (reference standard of Ph.Eur. as described in the monograph "Pancreatic Powder (Lipase) BRP") under the same conditions.

[0411] Determination of amylase activity: An aliquot (about 2 - 5 g) of the test sample containing pancreatin as described above is taken and used for subsequent analysis as described above for lipase activity. In each case, the amylolytic activity is determined by comparing the rate of hydrolysis of the starch solution substrate by the suspension containing amylase with the rate of hydrolysis of the same substrate by the suspension of a reference standard under the same conditions. The determination of amylase is based on the hydrolysis of starch. Starch is hydrolyzed by amylase at pH 6.8 and at a constant temperature (25.0 + / - 0.1 °C) in the presence of sodium chloride. The reducing groups produced by hydrolysis react with iodine in an alkaline solution, and the excess is titrated with thiosulfate.

[0412] Determination of protease activity: An aliquot (about 2 - 5 g) of the test sample containing pancreatin as described above is taken and used for subsequent analysis as described above for lipase activity. The proteolytic activity is determined by comparing the amount of peptide released per minute from the casein solution substrate (as defined in the monograph on pancreatic powder in Ph.Eur., not precipitable by 50 g / L trichloroacetic acid solution) with the amount of such peptide released from the same substrate by the reference standard of pancreatic powder ("Protease BRP") under the same conditions. Casein is hydrolyzed by protease for a defined time (15 minutes) at pH 7.5 and at a temperature of 35 °C + / - 0.5 °C.

Claims

1. A method for preparing a solid or semi-solid composition, which comprises processing a mixture by a method selected from melt granulation, melt pelletization, and melt extrusion, in each case at a product temperature of 90°C - 125°C for a time period of not less than 30 seconds and not more than 45 minutes, the mixture comprising: (a) 40% to 75% by weight of a mammalian-derived pancreatin and / or a pancreatin-containing digestive enzyme mixture, wherein the pancreatin is porcine pancreatin; (b) 10% to 50% by weight of a surfactant component, which comprises (i) at least one surfactant selected from polyethylene glycol - fatty acid monoesters; polyethylene glycol - fatty acid diesters; polyethylene glycol glycerol fatty acid esters; ethylene glycol alkyl ethers; polyethylene glycol glycerol fatty acid esters; polyethylene glycol alkyl ethers; oligoethylene glycol alkyl ethers; polyethylene glycol sterol ethers; polyethylene glycol sorbitan fatty acid esters; sugar esters; D-α-tocopherol polyethylene glycol 1000 succinate; fatty acid acylaminoalkyl betaines having C2 - C 22 fatty acids; lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine, and mixtures of any of the foregoing, (ii) optionally at least one co-surfactant selected from glycerol, propylene glycol, and / or partial esters of polyglycerol with aliphatic carboxylic acids; esters of ethyl diglycol with aliphatic carboxylic acids; partial ethers of glycerol, propylene glycol, and / or polyglycerol with fatty alcohols; ethers of ethyl diglycol with aliphatic alcohols, mono- or diesters of oligoethylene glycol with aliphatic carboxylic acids (fatty acids), and mixtures of any of the foregoing, and (iii) optionally a lipophilic phase selected from diglycerides of aliphatic carboxylic acids, triglycerides of aliphatic carboxylic acids, and mixtures of any of the foregoing; (c) 0% to 25% by weight of one or more pharmaceutically acceptable adjuvants, the one or more pharmaceutically acceptable adjuvants being one or more antioxidants, wherein the one or more antioxidants are present at a concentration of 50 ppm to 200 ppm relative to the total weight of the solid or semi-solid composition, and (d) 5% to 50% by weight of a polymer additive selected from hydrophilic polymers having a melting point or glass transition temperature of 50°C - 70°C; and wherein the weight percentages of components (a), (b), (c), and (d) add up to 100% by weight of the mixture, and the weight ratio between the polymer additive (d) and the surfactant component (b) is between 0.4 (2:5) and 1.5 (3:2).

2. The method according to claim 1, wherein the surfactant component (b) in the mixture for preparing the solid composition comprises: (i) At least one surfactant in an amount of 2% to 90% by weight, relative to the surfactant component, selected from: (aa) nonionic surfactants including polyethylene glycol fatty acid monoesters and / or diesters of aliphatic C6-C 22 carboxylic acids; polyethylene glycol glycerol fatty acid esters of aliphatic C6-C 22 carboxylic acids; polyethylene glycol alkyl monoethers and / or diesters of aliphatic C 12 -C 18 alcohols; oligomeric ethylene glycol ethers of aliphatic C2-C 18 alcohols; and mixtures of any of the foregoing; and (bb) ionic surfactants including lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine; and mixtures of any of the foregoing, and mixtures of any of the foregoing surfactants from (aa) and (bb); (ii) At least one co-surfactant in an amount of 5% to 60% by weight, relative to the surfactant component, selected from monoacylglycerols of aliphatic C6-C 22 carboxylic acids, monoesters of glycerol with aliphatic C 12 -C 22 alcohols, partial esters of propylene glycol with aliphatic C6-C 22 carboxylic acids, partial esters of polyglycerol with aliphatic C6-C 22 carboxylic acids, partial esters of oligoethylene glycol with aliphatic C6-C 22 carboxylic acids, di-esters of oligoethylene glycol with aliphatic C6-C 22 carboxylic acids, and mixtures of any of the foregoing, and (iii) 0 wt% - 70 wt% of a lipophilic phase, relative to the surfactant component, selected from diacylglycerols and triacylglycerols of aliphatic C6-C 22 carboxylic acids or mixtures of any of the foregoing, In each case, the percentages (i), (ii) and (iii) add up to 100% by weight of the surfactant component.

3. The method according to any one of claims 1 or 2, wherein the mixture for preparing the solid composition comprises: (a) 40% to 75% by weight of the mammalian-derived trypsin and / or trypsin-containing digestive enzyme mixture; (b) 10% to 50% by weight of the surfactant component, (c) 0% to 15% by weight of the one or more pharmaceutically acceptable adjuvants, and (d) 5% to 35% by weight of the polymer additive; and wherein the weight percentages of components (a), (b), (c) and (d) add up to 100% by weight of the mixture.

4. The method according to any one of claims 1 or 2, wherein the mixture for preparing the solid composition comprises: (a) 40% to 70% by weight of the mammalian-derived trypsin and / or trypsin-containing digestive enzyme mixture; (b) 15% to 45% by weight of the surfactant component, (c) 0% to 10% by weight of the one or more pharmaceutically acceptable adjuvants, and (d) 10% to 30% by weight of the polymer additive; and wherein the weight percentages of components (a), (b), (c) and (d) add up to 100% by weight of the mixture.

5. The method according to any one of claims 1 or 2, wherein the mixture for preparing the solid composition is homogenized before and / or during processing.

6. The method according to any one of claims 1 or 2, wherein the polymer additive (d) is selected from hydrophilic polymers having a melting point or glass transition temperature of 50°C to 65°C.

7. The method according to any one of claims 1 or 2, wherein component (a) is porcine trypsin in an amount of 64% ± 6% by weight of the mixture, and components (b), (d) and further optionally the adjuvant (c) are present together in an amount of 36% ± 6% by weight of the mixture.

8. The method according to any one of claims 1 or 2, wherein components (b) and (d) account for 30% to 42% by weight of the mixture and are composed of the following substances in a 1:1 weight ratio: (b) Semi-synthetic lauroyl polyglyceryl-32 esters based on hydrogenated palm kernel oil, having a melting point of about 42.5 °C - 47.5 °C; and (d) polyethylene glycol 4000, and further comprising (c) 100 ppm - 150 ppm BHA relative to the combined total weight of components (b) and (d).

9. The method according to any one of claims 1 or 2, wherein components (b) and (d) account for 30% to 42% by weight of the mixture and are composed of the following substances in a 1:1 weight ratio: (b) Semi-synthetic lauroyl polyglyceryl-32 esters based on hydrogenated palm kernel oil, having a melting point of about 42.5 °C - 47.5 °C; and (d) polyethylene glycol 4000, and further comprising (c) 150 ppm BHA relative to the combined total weight of components (b) and (d).

10. The method according to any one of claims 1 or 2, wherein the processing method is melt extrusion and an extruder selected from the following is used: single-screw extruder, twin-screw extruder, triple-screw extruder, and planetary extruder.

11. The method according to claim 10, wherein a twin-screw extruder is used.

12. The method according to claim 10, wherein a co-rotating twin-screw extruder is used.

13. The method according to claim 10, wherein the mixture for preparing the solid composition is processed for a time period of not less than 50 seconds and not more than 10 minutes at a product temperature of not less than 95 °C and not more than 125 °C.

14. The method according to any one of claims 1 or 2, wherein melt granulation is used as a processing method for a time period of not less than 180 seconds and not more than 30 minutes at a product temperature of not less than 90 °C and not more than 125 °C.

15. The method according to any one of claims 1 or 2, wherein the formed composition or extrudate is subsequently processed into granule agents, pills, tablets, and / or powders.

16. The method according to any one of claims 1 or 2, wherein the formed composition or extrudate is subsequently processed into granular agents and / or spheres.

17. A pharmaceutical composition, which comprises a composition obtained by the method according to any one of claims 1 to 16, and optionally further comprises one or more pharmaceutically acceptable excipients.

18. A solid or semi-solid composition, which comprises: (a) 40% to 75% by weight of the composition of mammalian-derived pancreatin and / or pancreatin-containing digestive enzyme mixture, wherein the pancreatin is porcine pancreatin; (b) 10% to 50% by weight of the composition of a surfactant component, which has (i) relative to the surfactant component, 2% to 90% by weight of at least one surfactant selected from: (aa) non-ionic surfactants, which include those having aliphatic C6-C 22Polyethylene glycol fatty acid monoesters and / or diesters of carboxylic acids; having aliphatic C6-C 22 Polyethylene glycol glycerol fatty acid esters of carboxylic acids; having aliphatic C 12 -C 18 Polyethylene glycol alkyl monoesters and / or diesters of alcohols, having aliphatic C2-C 18 Oligomeric ethylene glycol ethers of alcohols; and mixtures of any of the foregoing; and (bb) ionic surfactants, which include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine; and mixtures of any of the foregoing, and mixtures of any of the foregoing surfactants from (aa) and (bb); (ii) 5 wt%-60 wt% of at least one co-surfactant, relative to the surfactant component, selected from monoacylglycerols of carboxylic acids, glycerol with aliphatic C 22 -C 12 -C 22 monoethers of alcohols, propylene glycol with aliphatic C6-C 22 partial esters of carboxylic acids, polyglycerol with aliphatic C6-C 22 partial esters of carboxylic acids, having aliphatic C6-C 22 oligomeric ethylene glycol monoesters of carboxylic acids, having aliphatic C6-C 22 oligomeric ethylene glycol diesters of carboxylic acids and mixtures of any of the foregoing, and (iii) 0 wt%-70 wt% of a lipophilic phase, relative to the surfactant component, selected from diacylglycerols and triacylglycerols of carboxylic acids and / or mixtures of any of the foregoing; 22 wherein in each case, the percentages (i), (ii) and (iii) add up to 100 wt% of the surfactant component; (c) 0 wt%-25 wt% of one or more pharmaceutically acceptable adjuvants of the composition, the one or more pharmaceutically acceptable adjuvants being one or more antioxidants, wherein the one or more antioxidants are present at a concentration of 50 ppm to 200 ppm relative to the total weight of the solid or semi-solid composition, and (d) 5 wt%-50 wt% polymer additive selected from hydrophilic polymers having a melting point or glass transition temperature of 50°C - 70°C; ​Thus, the ratio between said polymer additive (d) and said surfactant component (b) is from 0.4 (2:5) to 1.5 (3:2), and thus all weight percentages of components (a), (b), (c) and (d) in said composition add up to 100% by weight; and wherein said solid or semi-solid composition is subjected to a method selected from melt granulation, melt pelletization and melt extrusion at a temperature of 90 °C - 125 °C and for a time period between 30 seconds and 45 minutes.

19. The solid or semi-solid composition according to claim 18, wherein the ratio between said polymer additive (d) and said surfactant component (b) is 1 (1:1).

20. The solid or semi-solid composition according to claim 18, wherein said pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammal (a) is porcine pancreatin.

21. The solid or semi-solid composition according to any one of claims 18 to 20, wherein said polymer additive (d) is selected from hydrophilic polymers having a melting point or glass transition temperature of 50 °C - 65 °C.

22. The solid or semi-solid composition according to any one of claims 18 to 20, wherein said polymer additive is selected from PEG 20000, PEG 4000 and poloxamer 188.

23. The solid or semi-solid composition according to any one of claims 18 to 20, wherein said pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammal (a) is present in an amount of 40% - 70% by weight of said composition.

24. The solid or semi-solid composition according to any one of claims 18 to 20, wherein said pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammal (a) is present in an amount of 50% - 70% by weight of said composition.

25. The solid or semi-solid composition according to any one of claims 18 to 20, wherein said pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammal (a) is present in an amount of 45% - 68% by weight of said composition.

26. The solid or semi-solid composition according to any one of claims 18 to 20, wherein said pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammal (a) is present in an amount of 47% - 68% by weight of said composition.

27. The solid or semi-solid composition according to any one of claims 18 to 20, wherein said pancreatin and / or pancreatin-containing digestive enzyme mixture derived from mammal (a) is present in an amount of 68% by weight of said composition.

28. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the surfactant component (b) is present in an amount of 15% to 40% by weight of the composition.

29. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the surfactant component (b) is present in an amount of 15% to 30% by weight of the composition.

30. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the surfactant component (b) is present in an amount of 15% to 25% by weight of the composition.

31. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the surfactant component (b) is present in an amount of 17.5% to 25% by weight of the composition.

32. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the surfactant component (b) is present in an amount of 20% by weight of the composition.

33. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the one or more pharmaceutically acceptable adjuvants (c) are present in an amount of 0% to 20% by weight of the composition.

34. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the one or more pharmaceutically acceptable adjuvants (c) are present in an amount of 0% to 10% by weight of the composition.

35. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the one or more pharmaceutically acceptable adjuvants (c) are present in an amount of 0% to 5% by weight of the composition.

36. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the polymer additive (d) is present in an amount of 5% to 35% by weight of the composition.

37. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the polymer additive (d) is present in an amount of 10% to 30% by weight of the composition.

38. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the polymer additive (d) is present in an amount of 15% to 25% by weight of the composition.

39. The solid or semi-solid composition according to any one of claims 18 to 20, wherein the surfactant component (b) is selected from: semi-synthetic lauroyl polyglycol-32 glycerides based on hydrogenated palm kernel oil, having a melting point of about 42.5 °C - 47.5 °C, and containing about 72% by weight of mono- and diesters of polyethylene glycol 1500, 20% by weight of glycerol monoesters, glycerol diesters and glycerol triesters of fatty acids, and about 8% by weight of free polyethylene glycol 1500 (the distribution of the fatty acids: C8 < 15% by weight, C10 < 12% by weight, C12 < 30% - 50% by weight, C14 5% - 25% by weight, C16 4% - 25% by weight, C18 5% - 35% by weight), < 3% by weight of free glycerol; and semi-synthetic stearoyl polyglycol-32 glycerides, having a melting point of about 46 °C - 51 °C, and containing about 72% by weight of mono- and diesters of polyethylene glycol 1500, 20% by weight of glycerol monoesters, glycerol diesters and glycerol triesters of polyethylene glycol 1500, and about 8% by weight of free polyethylene glycol 1500 (the distribution of the fatty acids: C8 < 3% by weight, C10 < 3% by weight, C12 < 5% by weight, C14 < 5% by weight, C16 40% - 50% by weight, C18 48% - 58% by weight), < 3% by weight of free glycerol.

40. The solid or semi-solid composition according to any one of claims 18 to 20, which comprises (a) porcine pancreatin, in an amount of 58% - 70% by weight, (b) 44 / 14, in an amount of 15% w / w - 20% w / w, and (d) PEG 4000, in an amount of 15% w / w - 25% w / w, wherein the total amount of components (a), (b) and (d) is 100% w / w.

41. The solid or semi-solid composition according to claim 40, wherein the amount of porcine pancreatin is 60% w / w - 68% w / w.

42. A pharmaceutical composition comprising the solid or semi-solid composition according to any one of claims 18 to 41 and optionally a conventional pharmaceutically acceptable excipient.

43. Use of the solid or semi-solid composition according to any one of claims 18 - 41 or the pharmaceutical composition according to any one of claims 17 and 42 in the preparation of a medicament for the prevention or treatment of exocrine pancreatic insufficiency.

44. The use according to claim 43, wherein the exocrine pancreatic insufficiency is exocrine pancreatic insufficiency in patients suffering from a digestive disorder, pancreatitis, cystic fibrosis, type I diabetes and / or type II diabetes.

45. The solid or semi-solid composition according to any one of claims 18 - 20 or the pharmaceutical composition according to any one of claims 17 and 42, wherein the solid or semi-solid composition or the pharmaceutical composition is used for preventing or treating exocrine pancreatic insufficiency.

46. The solid or semi-solid composition or pharmaceutical composition according to claim 45, wherein the exocrine pancreatic insufficiency is exocrine pancreatic insufficiency in a patient suffering from a digestive disorder, pancreatitis, cystic fibrosis, type I diabetes and / or type II diabetes.

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