MXPA01008776A - Medicament for treating diabetes - Google Patents

Abstract

The invention relates to the use of physiologically acceptable enzyme mixtures with lipolytic, proteolytic and amylolytic activity, of microbial or animal origin, but especially to the use of digestive enzyme mixtures such as pancreatin or digestive enzyme mixtures containing pancreatin, for treating diabetes. The invention also relates to the production of medicaments suitable for this treatment. One variant of the invention relates to the use of this enzyme mixture with lipolytic, proteolytic and amylolytic activity, especially digestive enzyme mixtures such as pancreatin or digestive enzyme mixtures containing pancreatin, for the adjuvant treatment of Type I and Type II Diabetes mellitus.

Description

MEDICATION FOR THE TREATMENT OF DIABETES DESCRIPTION OF THE INVENTION The present invention relates to the use of mixtures of physiologically acceptable enzymes with lipolytic, proteolytic and amylolytic activity, but especially to mixtures of digestive enzymes such as, for example, pancreatin for the treatment of diabetes and for the production of appropriate medications for this treatment.

In particular, the invention relates in this case to the use of these mixtures of enzymes with lipolytic, proteolytic and amylolytic activity, but in particular of pancreatin or mixtures of digestive enzymes containing pancreatin for the auxiliary treatment of primary diabetes, both of type I as well as type II. Diabetes is usually understood as diabetes mellitus, known as "sugar disease". This is differentiated - among other things, for example, secondary forms of diabetes that can present as sequelae of disease of other primary diseases - substantially two major groups of disorders of carbohydrate metabolism, specifically type I diabetes due to deficiency of insulin and type II diabetes due to a reduction in the activity of insulin, being that the development of the disease depends among other things of the respective type. In addition, diabetes is a chronic disease with various symptomatic pathological conditions and is accompanied, for example, by disorders of fatty metabolism, circulation and also the metabolism of glucose. Among the typical symptoms of this disease are an increase in blood sugar (hyperglycemia), expulsion of sugar with urine (glucosuria), tendency to infections and itching. Diabetes tends to progress and in many cases it is accompanied by various complications. Complications are known, for example, diseases of the nerves and blood vessels. Therefore, it is necessary to adapt the therapy to each individual case in each phase of the disease and select the appropriate drugs for the individual case. Furthermore, it may be desirable within the framework of this therapy to resort to other medicines in addition to the one chosen as primary within the framework of an auxiliary treatment, which may exert a supportive effect on the therapy or a positive influence on the subsequent development of the disease. . The object of the invention is therefore to provide new pharmaceutical preparations for the treatment of diabetes mellitus. In particular, the object of the invention is to provide new pharmaceutical preparations for the auxiliary treatment in the therapy of diabetes that exert an additional effect in support of the therapy or a positive influence on the subsequent course of the diabetic disease, for example by reducing the sequelae. In accordance with the invention, mixtures of enzymes with lipolytic, proteolytic and amylolytic activity are used for the preparation of pharmaceutical preparations for the treatment of diabetes mellitus in large mammals and humans, such as, for example, mixtures of corresponding enzymes of microbial origin and / or in particular mixtures of digestive enzymes of animal origin, preferably mixtures of pancreatin digestive enzymes or pancreatin-like enzymes. Within the framework of the. present invention can be used in mixtures of physiologically acceptable enzymes with lipolytic, proteolytic and amylolytic activity which are of animal or microbiological origin at will. Accordingly, mixtures of enzymes with lipolytic, proteolytic and amylolytic activity that are created within the framework of the invention can be either of purely microbial origin, of purely animal origin or also a mixture of enzymes of animal and microbial origin. Therefore, in a variant of the invention, the mixture of enzymes used is of purely microbial origin. As microbial enzymes, in particular enzymes from bacteria such as, for example, of Bacillus or Pseudomonas strains, or fungal cultures such as fungi with mycelium (mold), for example of the strain Rhizopus or Aspergillus. Examples of these microbial enzymes and / or physiologically acceptable mycelium fungi are already described in the state of the art, for example, in connection with their preparation and use for the treatment of digestive problems. The lipases can come from, for example, Bacillus or Pseudomonas strains, the amylases and also the fungal lipases with mycelium, for example from the Rhizopus strain, and the proteases, for example, also from Aspergillus. However, in a preferred variant within the framework of the invention, it will be in particular those mixtures of digestive enzymes with lipolytic, proteolytic and amylolytic activity whose characteristics are similar to those of pancreatin. Accordingly, mixtures of digestive enzymes containing pancreatin, and in particular pancreatin itself, are preferred within the scope of the present invention, although pancreatin or mixtures of digestive enzymes containing pancreatin can still be added if desired. one or more microbial enzymes, that is, obtained from microorganisms of the group of lipases, proteases and amylases.

Pancreatin is a known enzyme mixture with lipolytic, proteolytic and amylolytic activity that can be obtained commercially, for example, under the brand name Kreon® in the form of granules, agglomerates or capsules with micro agglomerates resistant to gastric juices , and which is applied medicinally for the replacement of enzymes, for example in the case of pancreatic insufficiency, digestive insufficiency after operations of the stomach, diseases of the liver and bile, mucoviscoidosis and chronic pancreatitis. Pancreatin is usually obtained as a mixture of natural enzymes by extracting the pancreas from pigs, for example, according to the methods described in German patent applications DE 25 12 746 and DE 42 03 315, to subsequently become their own. known to the galenic form. The enzymes of the pancreas are usually administered orally as solid preparations. In a variant of the invention, the pharmaceutical preparations prepared according to the invention preferably contain pancreatin or mixtures of digestive enzymes containing pancreatin. In these pharmaceutical preparations prepared according to the invention, pancreatin or mixtures of digestive enzymes containing pancreatin may contain, if desired, in addition to pancreatin, additionally still one or more physiologically acceptable enzymes from the group of lipases, proteases and amylases, such and how they can be obtained from microorganisms. Suitable microbial enzymes are, for example, Bacillus or Pseudomonas strains or fungal cultures such as fungi with mycelium, for example Rhizopus or Aspergillus strains, which are already mentioned in particular for this particular addition. The lipases which are added to pancreatin or mixtures of enzymes containing pancreatin can come from this, for example, from Bacillus or Pseudomonas strains, the amylases and also the lypses added from fungi with mycelium, for example from the Rhizopus strain, and the proteases added for example also from Aspergillus. It was now discovered that the mixtures of enzymes with physiologically acceptable lipolytic, proteolytic and amylolytic activity described within the framework of this invention, which may come from sources of microbial and / or animal origin, can not only be applied for the treatment of conditions of deficiency of digestive enzymes as they can be caused by pathological changes of the pancreas due to chronic pancreatitis, digestive insufficiency after stomach operations, by diseases of the liver or bile, but surprisingly they are also suitable for the treatment of primary diabetes mellitus in mammals older and human. But in particular, mixtures of preceding enzymes with physiologically acceptable lipolytic, proteolytic and amylolytic activity, but preferably, for example, the pancreatma itself or the mixtures of digestive enzymes containing pancreatin, the enzymes suitable for the auxiliary treatment in diabetes therapy, are suitable. which also contain additions of microbial enzymes, for example, one or more microbial lipases, proteases and / or amylases, being that they provide an additional effect that supports the therapy of diabetes or exert a positive influence on the subsequent development of the disease diabetic, that is, in particular to minimize the sequelae of diabetic disease. In this case, the use of the physiologically acceptable enzyme mixtures applied according to the invention, preferably, for example, pancreatma or mixtures of digestive enzymes containing pancreatma, optionally with microbial enzymatic additives, also has advantages in those patients in which, in addition to primary diabetes mellitus there are complications with respect to an exocna pancreatic insufficiency also present. In addition to mixtures of microbial enzymes and / or mixtures of digestive enzymes of animal origin that were described, as in particular pancreatin or mixtures of digestive enzymes containing pancreatin, the pharmaceutical preparations according to the invention may contain pharmaceutical adjuvants and / or additives and optionally stabilizers. Thus it is possible that the enzyme mixtures are contained in an active amount (in each case determined on the basis of the active units of the lipolytic, proteolytic and amylolytic components) in combination with adjuvants and / or pharmaceutical vehicles in solid or liquid pharmaceutical preparations. The lipolytic activity can generally be found in the range of from 5000 to 45,000 units of Ph lipase per dosage unit. Eur., The proteolytic activity usually in the range of 200 to 3000 units of Ph. Eur. Protease and the amylolitic activity usually in the range of 3500 to 45,000 units of Ph amylase. Eur. (Ph. Eur. = European Pharmacopoeia). As examples for typical dosage units, mixtures of enzymes may be mentioned exemplarily with the following activities: a) about 10000 Ph. Eur. Of lipase / about 8000 Ph. Eur. Amylase / approximately 600 Ph. Eur. Of protease; b) approximately 25000 Ph. Eur. De lipasa / approximately 18000 Ph. Eur. Amylase / about 1000 Ph. Eur. Of protease; or c) about 40000 Ph. Eur. of lipase / about 40000 Ph. Eur. of amylase / about 2600 Ph. Eur. of protease. As examples of solid preparations, orally applicable preparations such as tablets, dragees, capsules, powders, granules or agglomerates are mentioned. These solid preparations may contain the usual organic and / or inorganic pharmaceutical carriers, such as, for example, lactose, talc or starch in combination with conventional pharmaceutical adjuvants, for example lubricants or agents for coating tablets. Liquid preparations such as solutions, suspensions or emulsions of the active substances may contain the customary diluents such as water, oils and / or suspending agents such as polyethylene glycols or the like. Additionally it is possible to add other adjuvants, such as preservatives, flavor correctors, stabilizers (for example, complex lipids) and the like. The mixtures of enzymes can be mixed and formulated with the adjuvants and / or pharmaceutical vehicles in a manner known per se. For the preparation of solid medicinal forms it is possible to mix the enzyme mixtures in a conventional manner, for example with the adjuvants and / or vehicles and granulate or agglomerate them wet or dry. The granulates, agglomerates or powders can be filled directly into capsules or bags and compressed in the usual way to tablet cores. These, if desired, can be coated in a known manner. Liquid preparations can be obtained in the form of solutions or suspensions by dissolving or dispersing the components and optionally other adjuvants in a suitable liquid vehicle. The antidiabetic effects as well as the positive influence on the development of diabetic disease, in particular within the framework of an auxiliary treatment in a diabetes therapy can be verified for the mixtures of enzymes with physiologically acceptable lipolytic, proteolytic and amylolytic activity employed according to to the invention, such as, for example, the mixtures of microbial enzymes previously described and in particular pancreatin or mixtures of digestive enzymes containing pancreatin, by determining the activity on pharmacological parameters such as those that are usually used to rule about diabetic diseases. These parameters can be, for example, improvement, ie the reduction of glycogen hemoglobin (HbA? C), the reduction of blood glucose level, the decrease of hypoglycemic attacks, as well as the decrease of hyperglycemia.

To test the positive effects of the described enzyme mixtures on the glycemic control, a double-simulated, placebo-controlled, multicentre group study with pancreatin in the form of Mini-microspheres® Kreon® 10000 (mini-agglomerates in capsules) in insulin-dependent diabetic patients (IDDM = type I) with additional exocrine pancreatic insufficiency. The group of patients (male / female) was of arbitrary distribution with an amount of approximately 74 patients per group respectively. The treatment was carried out over a period of 4 months with an oral dosage of 16 to 18 Kreon capsules per day. In each case, 4 capsules were administered in the main meals (3 per day) and in each case two capsules between meals (2 to 3 per day). One capsule with Mini-spheres® Kreon® 10000 contained 150 mg pancreatin with an enzyme content indication of 10000 Ph units. Eur. De lipasa, 8000 units Ph. Amilase Eur. And 600 units Ph. Eur. Of protease. The placebo group was given the corresponding placebo minimicroespheric capsules without enzymatic activities. The effectiveness of the enzyme mixture applied with respect to the glycemic control was determined by measuring the level of glycolyzed hemoglobin (HbAlc). In this a positive influence on the level of HbAic is desirable as a relevant clinical improvement of diabetes mellitus. Additional diabetic parameters were the blood glucose levels (insulin / glucagon), the evaluation of hypoglycemic attacks, the state of fat-soluble vitamins (A, D and E), the daily insulin dose, the body weight and hyperglycemic periods. After a pre-study evaluation to select the patient collection, the patients went through an 8-week preparation phase (without enzyme mix / placebo administration) to adjust patients to individual insulin dosages. Before the beginning of the research period of 4 months of parallel groups of double simulation itself a baseline assessment was then carried out. The insulin dose should be kept as stable as possible during the study (± 10%), with the exception of the first month of treatment in which an adjustment of the insulin dosage was still permissible. An adjustment of insulin necessary after the randomization had been carried out resulted in the exclusion of the patient from the study, but nevertheless short-term adaptations were allowed as a consequence of, for example, acute illness. The patients underwent several intermediate evaluations during the course of the study and to conclude, an additional evaluation was carried out. Gastroenterological parameters such as fat in defecation, characteristic of defecation, coefficient of absorption of fat (CFA by its acronym in English (Coefficient of Fat Absorption)) and clinical symptoms were also measured separately from the diabetic parameters. Through the previously outlined research, a positive influence on the parameters of diabetes is observed with the administration of pancreatin, both in terms of a positive influence of glycemic hemoglobin (HbA? C), as well as in regard to better glycemic control: such as, for example, the stabilization of blood sugar developments (leveling) and, for example, the reduction of hypoglycemic attacks as well as hyperglycemia. The results of the study therefore demonstrate that by means of the administration according to the invention mixtures of enzymes with physiologically acceptable lipolytic, proteolytic and amylolytic activity, a better adjustment of diabetes mellitus can be obtained. It could be shown separately that in the collection of diabetic patients accompanied by exocrine pancreatic insufficiency, gastroenterological parameters are also positively influenced., for example, fat to defecation, characteristic of defecation, CFA and clinical symptoms, and that the feeding status of these patients is improved in its entirety. Accordingly, mixtures of enzymes with physiologically acceptable lipolytic, proteolytic and amylolytic activity, in particular pancreatin or mixtures of enzymes containing pancreatin, also with the described microbial enzyme additives are suitable for the preparation of pharmaceutical preparations for the treatment of diabetes mellitus. , in particular for the auxiliary treatment of diabetes mellitus; in this, diabetes mellitus can also be accompanied by an exocrine pancreatic insufficiency. The pharmacologically favorable effects of the mixture of enzymes applied on the diabetic parameters and the improvement of the diabetes mellitus state will be further explained by the clinical study described below and the results obtained therewith. Clinical study To evaluate the effectiveness of Mini-microspheres® Kreon® 10000 compared with placebo on the glycemic control of diabetic insulin-dependent patients (IDDM for its acronym in English (insulin dependent diabetes mellitus)) with pancreatic insufficiency exotrina was carried out a parallel group study doubly simulated multicentre controlled with placebo. I. Concept of the study The clinical research report that follows is an intermediate evaluation of a study regarding the effectiveness of Mini-microspheres® Kreon® 10000 in the treatment of insulin-dependent patients (IDDM) through glycemic control. Therefore, the report provides a synoptic table of the study and the results obtained in an intermediate way after including approximately half of the necessary patients. Purpose of the study The main purpose of the study was to evaluate the effect of Mini-spheres® Kreon® 10000 on the glycemic control of diabetic insulin-dependent patients with exocrine pancreatic insufficiency. There are several variables to evaluate glycemic control. The most important parameter is HbAic, which should be lower in the treated group than in the placebo group. This parameter was chosen as the main parameter. Additional parameters were investigated the number of hyperglycemic attacks and hyperglycemic events, the fasting and post-meal blood sugar values, the daily insulin dose, the body weight and the level in the plasma of vitamins (A / D and E) soluble in fat. The parameters of pancreatic exocrine function disorder were also evaluated, among them the frequency and consistency of defecation, abdominal pain, bloating, flatulence and the general clinical impression of the disease from the point of view of the patient and the researcher. Tolerance and safety were assessed using standard tests. Patient population For this study, patients with insulin-dependent diabetes mellitus were used. This population of patients was chosen as a model test group for patients with diabetes mellitus because this group is the best defined. It had been planned to include 74 patients per treatment group to reach a test group size of 148 patients in total. In patients, the disease should have started before the age of 30, and they should have started with insulin therapy within a year of diagnosis. Patients whose diabetes mellitus was not proven to be insulin dependent were excluded. To ensure that randomly distributed patients had a certain degree of exocrine pancreatic insufficiency, fecal values of 1-elastase were assessed. This parameter is a measure to determine an exocrine malfunction of the pancreas. To participate in the study, the value of 1-elastase should be less than or equal to 100 μg / g of feces. Patients with values higher than this were excluded from the study. Patients with exocrine pancreatic insufficiency due to other reasons that insulin-dependent diabetes mellitus (eg, chronic pancreatitis, cystic fibrosis) were excluded from the study. Other inclusion criteria were: male and female and at least 18 years of age. Other exclusion criteria were any other serious illness that would have limited participation in or completion of the study (with the exception of diagnoses that cause the aforementioned disease of the study), known allergy to pancreatin and / or pig insulin, any malignant type in relation to the digestive tract during the past 5 years, any type of gastrointestinal operation and short bowel syndrome, hemachromatosis, any previous history of drug addiction, including alcohol, Positive urine pregnancy test or pregnancy or existing breastfeeding period (in the case of women), severe allergy or any previous history of strong abnormal reactions to medications, suspect non-compliance or lack of cooperation, ingestion of any experimental active substance in the last 4 weeks before beginning the study and any other reason that in the opinion of the investigator would prohibit the participation of the patient in the study. Design After signing the information / acceptance form, all patients underwent a previous screening of the 1-elastase in the feces. As soon as the 1-elastase values were less than / equal to 100 μg / g of feces and the patients met the inclusion criteria and were not affected by the exclusion criteria they were included in the initial phase of at least 8 weeks. During the initial phase, the patient had to reach a stable insulin dosage, which includes no change in the number of insulin injections and the type of insulin, no change from standard treatment to intensive treatment or pump injections. The level of HbA? C should be in the range between 0.07 and 0.10 (in metric units). Body weight should be kept stable with deviations not exceeding 5 kg between evaluations. At the end of the initial phase, the appropriate patients were randomized, either to Mini-microspheres® Kreon® 10000 or to placebo. The treatment period was set at 16 weeks, with several intermediate evaluations after 1, 2, 4 and 10 weeks and a final evaluation after 16 weeks. During the first 4 weeks, adaptations of insulin were allowed. After 4, 10 and 16 weeks, extensive investigations were carried out regarding glycemic control (see the purpose of the study). Treatment and dosing Patients were randomly assigned to either the Mini-microspheres® Kreon® 10000 or placebo. Patients should receive according to scheme 16 to 18 capsules / day. The number of capsules per food was determined. In the three main meals patients had to take 4 capsules and in the (2 to 3) intervals between meals 2 capsules. This corresponds to 40000 Ph units. Eur of lipase per main meal and 20000 Ph. Eur units per interval between meals. A total dose of 160000 to 180000 Ph. Eur units of lipase was administered. This reflects the dose that was used in clinical investigations with patients with chronic pancreatitis and therefore should be sufficient for the treatment of patients with exocrine pancreatic insufficiency.

Statistics The analysis of the primary parameters was a covariation analysis using a linear model with the covariant as the baseline, the main effects of treatment and center, of the measurements observed over time and of the interaction of the treatment through from the center. The alpha level when tested was 5%. The analysis was carried out in the test group envisaged for the treatment consisting of all randomized patients who, after 4 weeks of treatment with a stable insulin dose, had at least one HbA? C measurement. Since only the intermediate analysis obtained is reported below, no model group of the protocol pair was defined. The size of the test groups was calculated as 74 patients per group using an alpha level of 5%, a standard deviation for HbA? C sigma = 0.015 and an amount of 80% to determine a difference of 0.007. An intermediate analysis is expected as soon as half of the patients have finished the study (37 patients per group). II. Results of the study Patient group: Due to low recruitment, the interim analysis was carried out with 71 patients, who were randomized to either Mini-microspheres® Kreon® 10000 or placebo. The 71 patients are included in the safety test group and have received at least one dose of study medication. Based on the criteria for the test group scheduled for treatment (ITT), it was possible to gather 65 patients for the HbAic analysis (Table 1).

Table 1: G Patient test groups ITT = intent-to-treat Demographics: The following table 2 offers a synoptic table about the most important demographic data Table 2: Demographic data SD = Standard deviation for its acronym in English BMI = body mass index for its acronym in English As can be seen from the table, the demographic data of both treatment groups are comparable, although due to the random distribution some men were assigned to the Kreon group, which in the sequel led to slightly higher values for the size, weight and body weight index in the Kreon group. However, these deviations can be considered as not important for the interpretation of the results of effectiveness. The same is applicable for the age at which the diabetes occurred, the duration of the illness or the duration of the insulin treatment. In all cases there were only small differences in the mean or median values between the two treatment groups. Therefore, it is possible to consider the severity of the disease as similar in both treatment branches. Neither 1-elastase values were significantly different between the two groups during the previous screening (57.3 ± 26.5 for Kreon versus 62.0 ± 29.8 for placebo). Parameters of effectiveness The results for the most important parameters of HbA? C are compiled in table 3. The table contains the data of the ITT test group.

Table 3: HbA test group? C - ITT SEM = Standard error of the mean by its acronym in English Table 3 shows that Kreon leads after 4 to 10 weeks to statistically significantly lower levels of HbAic and to a clear trend even after 16 weeks. This demonstrates that Kreon has the potential to improve glycemic control in patients with insulin-dependent diabetes mellitus.

This is underlined by table 4, which indicates the number of patients with improvement, without improvement or worsening in relation to the HbA? C values of the baseline.

Table 4 Number of patients with improvement, without improvement or worsening in relation to HbAic values of the baseline.

In the placebo treatment there were many more patients who showed a worsening of their HbA? C levels during the temporal comparison with Kreon. The tendency to worsen is relatively low with Kreon, whereas in contrast with placebo the majority of patients suffered a worsening. Again a clear sign that Kreon is indeed in a position to improve glycemic control of insulin-dependent diabetes mellitus. The reason why many patients get worse is in the design of the study that requires an almost optimal treatment before the random distribution, which, in a normal condition like the one seen in the placebo group, leads to a rapid decline of the glycemic control. Kreon is able to reduce this deterioration. Similar diagnoses were observed regarding the number of mitigated to moderate hyperglycemic attacks that occurred (Table 5).

Table 5 Change in the number of hyperglycemic attacks < o = fewer attacks compared to the baseline = o = equal number of attacks compared to the baseline > o = greater number of attacks compared to the baseline Table 5 shows that approximately 50% of patients who received Kreon had less mitigated to moderate hyperglycemic attacks compared to the placebo group, in which only 39% of the patients had this diagnosis. With regard to the amount of higher glucose levels per week - an indicator of hyperglycemic periods - a comparable but less strong effect was found. The fasting and breakfast blood glucose levels were not significantly different, nor was the insulin dose required by the patients. The number of negative events was not different in both treatment groups. In the case of treatment with Kreon, some more negative events were observed in the digestive system and in the placebo treatment more negative events of metabolic / nutritional disorder as well as the group of negative events of the respiratory system. The number of patients who withdrew due to negative events was the same in both groups. III. Conclusion In summary, there are strong indications that Kreon has a favorable effect on the treatment of diabetic patients dependent on insulin with exocrine pancreatic insufficiency and that it leads to better glycemic control. This means that Kreon should be added in the treatment of these patients to improve the most important factor in their treatment. Since diabetic patients dependent on insulin were used as a model, it can be assumed that the same favorable effects should also be observed in diabetic patients not dependent on insulin, particularly when they also have exocrine pancreatic insufficiency. The following example should explain in more detail the preparation of a pharmaceutical preparation containing pancreatin for the treatment of diabetes, in particular for the auxiliary treatment of diabetes, without however limiting the scope of the invention. Example 120 kg of pancreatin was mixed in a commercial mixer with 30 kg of polyethylene glycol 4000 and wetted with about 20 kg of propan-2-ol. The mixture was pressurized through an extruder equipped with a matrix of holes with perforations of 0.8 mm internal diameter and a subsequent cutting device. With this, pieces of rope with a rope length of up to 20 mm were obtained.

The pieces of rope were broken in a rounder (Caleva type) in portions of in each case approximately 15 kg and were rounded to form spherical agglomeratesIn addition, 300 g of very fluid paraffin were added to each portion and, depending on the residence time in the rounding apparatus (3 to 6 min.), still approximately 300 to 400 g of propan-2-ol. After drying in a commercial grid sheet dryer, approximately 90% of pancreatin microaglomerate cores with a diameter of 0.7 to 1.4 mm were obtained, classified with a 0.7 mm sieve (sieving of small grains <; 0.7 mm) and a 1.4 mm sieve (sieving of large grains> 1.4 mm) with a pancreatin content of approximately 78%. The gravimetric density was 0.7 g / ml. Next the microagglomerate cores are coated resistant to gastric juices in a manner known to them in a conventional film application apparatus with a solution of hydroxypropylmethylcellulose phthalate (type HP55), dibutyl phthalate, very fluid paraffin and silicone oil (Dimethicone 1000) in acetone. As a yield, approximately 90% of pancreatin microaglomerates resistant to gastric juices are obtained with a diameter in the range of 0.7 to 1.6 mm classified with a sieve of 0.7 mm (sieving of small grains <0.7 mm) and a sieve of 1.6 mm. (sieving of large grains> 1.6 mm) with a pancreatin content of approximately 60% in relation to film-coated microagglomerates and a gravimetric density of 0.8 g / ml. The microagglomerates are then filled into hard gelatine capsules or bags customary in commerce.

Claims (8)

1. CLAIMS 1. Use of mixtures of enzymes with physiologically acceptable lipolytic, proteolytic and amylolytic activity for the preparation of pharmaceutical preparations for the treatment of type I primary diabetes mellitus in older mammals and humans.
2. 2. Use according to claim 1, characterized in that a mixture of lipases, proteases and amylases of microbial origin is used as a mixture of enzymes.
3. Use according to claim 1, characterized in that pancreatin and / or a mixture of digestive enzymes similar to pancreatin is used as a mixture of enzymes.
4. 4. Use according to claim 3, characterized in that a mixture of digestive enzymes containing pancreatin is used as a digestive enzyme mixture similar to pancreatin.
5. 5. Use according to claim 3 or 4, characterized in that pancreatin or a mixture of digestive enzymes containing pancreatin is used, being that pancreatin or the mixture of digestive enzymes containing pancreatin is also added one or more microbial enzymes of the group of lipases, proteases and amylases.
6. 6. Use one of claims 1 to 5, characterized in that pharmaceutical preparations are prepared for the auxiliary treatment of diabetes mellitus.
7. 7. Use one of claims 1 to 6, characterized in that pharmaceutical preparations are prepared for the treatment of diabetes mellitus accompanied by exocrine pancreatic insufficiency.
8. 8. Method for the preparation of pharmaceutical preparations for the treatment of type I primary diabetes mellitus, characterized in that a physiologically acceptable mixture of enzymes with lipolytic, proteolytic and amylolytic activity in an amount effective to improve clinical diabetic parameters and / or reduce the sequelae of diabetes, preferably pancreatin and / or a mixture of digestive enzymes similar to pancreatin are transformed with the usual pharmaceutical adjuvants into a suitable medicament form.