PHARMACEUTICAL FORMULATION FOR THE TREATMENT OF INFLAMMATORY CHANGES OF THE RECTAL

Abstract

The invention relates to a storage-stable pharmaceutical formulation for rectal administration, containing budesonide or a pharmaceutically-compatible salt or derivative thereof, and at least 80 wt.% of a solid fat or a mixture of different solid fats in relation to the total weight of the formulation, as well as at least one anti-oxidation agent that is compatible therewith.

Description

Pharmaceutical formulation for the treatment of inflammatory conditions of the rectum Crohn's disease and ulcerative colitis are chronic inflammatory diseases of the gastrointestinal tract. The etiology of these diseases is unknown, although an autoimmune component is widely assumed. Crohn's disease can present with a variety of clinical manifestations and can be localized in various parts of the small intestine as well as the large intestine. Ulcerative colitis is an inflammatory bowel disease that is essentially limited to the large intestine. The disease is characterized by recurrent inflammation, primarily affecting the mucosal layer and occasionally the submucosa of the colon. Acute inflammation is characterized by chronic diarrhea or constipation, intestinal bleeding, cramps, and abdominal pain. This is sometimes distinguished from ulcerative proctitis, which is considered a milder form of ulcerative colitis. Specially formulated oral medications can be used to treat these conditions. However, due to the diarrhea that often accompanies the disease, oral administration can be disadvantageous. Rectally administered pharmaceutical formulations are also known in the prior art. Gross et al., Aliment.Pharmacol.Ther. 2006, 23, 303-312, compared budesonide foams with budesonide enemas in the treatment of active ulcerative proctitis or proctosigmoiditis. Belluzzi et al. (Gastroenterology, Vol. 104 (4, Suppl.) 1993) introduced suppositories containing 5-aminosalicylic acid or budesonide. The budesonide suppositories used in their study contained 0.5 mg budesonide and were administered three times daily. Alternatively, suppositories containing 500 mg 5-aminosalicylic acid were administered three times daily. US 5,449,520 discloses pharmaceutical compositions for rectal administration containing a topical drug acting on the colon. The rectal foams disclosed therein contain mesalazine or budesonide as the active pharmaceutical ingredient. WO 2015 / 073846 describes a method for treating ulcerative colitis using a rectal foam. This foam is an emulsion containing budesonide, propylene glycol, cetyl alcohol, water, and suitable additives. German utility model DE 297 17 252 discloses a drug kit consisting of a budesonide-containing and a ursodeoxycholic acid-containing drug for the treatment of cholestatic liver diseases. One formulation example relates to budesonide-containing suppositories, where budesonide is suspended in hard fat. German patent DE 198 49 737 discloses suppositories containing a combination of active ingredients consisting of 5-ASA and budesonide suspended in hard fat. Due to the high proportion of 5-ASA, these suppositories have a relatively high weight and therefore a correspondingly large size. One disadvantage of the known pharmaceutical formulations is that some patients dislike using enemas or rectal foams. Another requirement is the need for a pharmaceutical formulation that provides the active ingredient budesonide in a storage-stable form. It is an object of the present invention to provide a pharmaceutical formulation of budesonide for rectal application which is stable in storage and which enables painless insertion as well as targeted, local application of the active ingredient limited to the rectum, due to optimal shape, consistency and suitable size. These criteria are met according to the invention by the dosage form of suppositories. Suppositories contain a single dose of the active pharmaceutical ingredient budesonide, which may be dissolved (solution preparation), emulsified (emulsion preparation) and suspended (suspension preparation) in a lipid-containing or water-soluble preparation. The pharmaceutical formulations according to the invention are highly stable over time. A problem with the production of suppositories is that when such preparations are stored at room temperature or slightly elevated temperatures (20-3°C), which frequently occur during the summer months or in warmer regions, the pharmacologically active ingredient budesonide degrades to biologically inactive or less active degradation products. The pharmaceutical formulations according to the invention address this issue. Formulations remain stable for extended periods (12-24 months) even at elevated temperatures (20-30°C). This means that after storage for 24 months at 25°C, at least 90%, preferably at least 95%, and preferably at least 97% of the originally used active ingredient (budesonide) is still present in pharmacologically active form. The present invention relates to a preparation for rectal administration, in particular a suppository, comprising budesonide or a pharmaceutically compatible salt or derivative thereof as a therapeutically active ingredient, and used after insertion for the treatment of inflammatory diseases of the rectum (rectal inflammation). High demands must be placed on the selection of a suitable base. This base must be both chemically stable and inert, thus exhibiting high compatibility with the active pharmaceutical ingredient, and also be compatible with the mucous membranes and thus free from mucosal irritation during application. Furthermore, after application, it must reliably release the incorporated active pharmaceutical ingredient at the site of application by melting or dissolving. The present invention therefore relates to a storage-stable pharmaceutical formulation for rectal administration, which contains budesonide or a pharmaceutically acceptable salt or derivative thereof and at least 80% by weight of a hard fat or a mixture of different hard fats based on the total weight of the formulation, as well as at least one compatible antioxidant. In a preferred embodiment of the present invention, a hard fat composition is selected that has a small difference between its melting and solidification points. The melting point is the temperature at which the suppository melts. This melting point is preferably between approximately 33.5°C and approximately 35.5°C, more preferably between 34.0°C and 35.0°C. The solidification point is the temperature at which the suppository solidifies after manufacture, i.e., the point at which the suppository becomes solid after manufacture. According to the invention, this solidification point is preferably between approximately 32.5°C and 34.5°C, particularly preferably between 33.0°C and 34.0°C. In a preferred embodiment, the hard grease used according to the invention has a high proportion of triglycerides, which is preferably above 80 wt.%, particularly preferably above 90 wt.% and most preferably above 95 wt.%. The characteristic value of these hard fats is known as the hydroxyl value. According to the invention, the hard fats used have a low hydroxyl value, which is in the range of 1 to 15, preferably 5 to 15 and particularly preferably 5 to 10. Another characteristic of the preferred hard fats is that the proportion of unsaturated fatty acids is less than 1 wt.%, particularly preferably less than 0.5 wt.%. The suppositories according to the invention are designed for anal administration. Therefore, their shape is chosen for ease of application and tolerability by the majority of patients, as they cause neither pain nor discomfort during administration. In a preferred embodiment, the suppositories have a so-called "torpedo shape." The size of the suppositories, determined by their overall weight, is also important. Preferably, the weight is between 0.8 g and 1.2 g, and particularly preferably between 0.95 g and 1.05 g. In a preferred embodiment, the suppository according to the invention comprises as The active ingredient budesonide in an amount between 1.8 mg and 2.2 mg per suppository, preferably between 1.9 mg and 2.1 mg budesonide per suppository and most preferably between 1.95 mg and 2.05 mg budesonide per suppository. In another preferred embodiment, the suppository according to the invention contains budesonide as the active ingredient in an amount between 3.8 mg and 4.2 mg per suppository, preferably between 3.9 mg and 4.1 mg budesonide per suppository and most preferably between 3.95 mg and 4.05 mg budesonide per suppository. According to the invention, it is preferred that the suppository contains only budesonide as the pharmacologically active ingredient and no other pharmacologically active component. In particular, the suppositories according to the invention most preferably do not contain 5-ASA (5-aminosalicylic acid). Since 5-ASA itself is sensitive to oxidation, the addition of 5-ASA could lead to an undesirable browning of the suppository. In a preferred embodiment, the suppositories according to the invention contain ascorbyl palmitate as an antioxidant. The concentration of the ascorbyl palmitate is preferably 50 ppm to 200 ppm, particularly preferably 125 to 175 ppm, and most preferably 150 ppm. Another preferred aspect of the present invention is that the budesonide is in micronized form. Micronized form means that the particle size of the active ingredient is very small, with 100% of the particles being smaller than 10 pm per particle. A key aspect of the present invention is the storage stability of the suppositories according to the invention. This storage stability can be further increased by various process steps during manufacturing. Firstly, the suppositories are manufactured in the absence of oxygen. This can be achieved by nitrogen purging during manufacturing or by working under an oxygen atmosphere. On the other hand, in the manufacture of the suppositories, the molten mass is preferably poured into a blister film where it hardens. In a preferred embodiment, the suppositories according to the invention are in a gas-impermeable Wrapped in foil. It is well known that opioid-containing or water-soluble preparations are used as a base for suppositories. Triglycerides are the preferred lipids. Hard fat is a semi-synthetic mixture of mono-, di-, and triglycerides of saturated fatty acids. Starting with palm kernel and coconut fats, defined hard fats with specific melting properties and hydroxyl values ​​can be obtained by saponifying and re-esterifying glycerol with suitable saturated fatty acids. This is achieved through the ratio of mono-, di-, and triglycerides. The properties of hard fat can thus be modified by selecting the fatty acids and the degree of esterification, influencing characteristics such as melting point, water absorption capacity, and brittleness. Due to the absence of unsaturated fatty acids, hard fats have better stability properties than cocoa butter, which therefore plays only a minor role as a suppository base. The selection of suitable hard greases plays a crucial role in achieving the required bearing stability. Therefore, the hard greases described here are preferred, with achieving the desired bearing stability being a decisive factor. The ratio of budesonide (active ingredient) to hard grease is particularly important for achieving bearing stability. The hard fats preferably used according to the invention are based on glycerides of saturated C12-C18 fatty acids. They consist largely of triglycerides with a diglyceride content of at most 15% and a monoglyceride content of no more than 1%. In the production of the hard fats according to the invention, vegetable fats are first purified into fatty acids and glycerol and then decomposed with water at high temperature. The fatty acid mixture is hydrogenated, fractionated, and vacuum-distilled, primarily to remove short-chain fatty acids. The preferably used C12-C18 fatty acids are adjusted to a suitable mixture and esterified with purified glycerol. This reaction mixture is then further purified, in particular by washing, vacuum drying, treatment to remove dyes, and steam distillation. In the preferably used hard waxes, the proportion of C12-C18 fatty acid chains is at least 85%, preferably at least 90%.It is also important that the hydroxyl value of the hard fats is preferably less than approximately 10. The hydroxyl value is primarily determined by monoglycerides, as these provide two hydroxyl groups from the glycerol residue, and by diglycerides, which possess one free hydroxyl group. The hydroxyl value can be measured by determining the amount of KOH required to neutralize the amount of acetic acid consumed during the acetylation of the hard fat. The hydroxyl value thus indicates the number of free hydroxyl groups in the hard fat base. Since the hard fats used according to the invention are typically purified of glycerol, the hydroxyl value is an indicator of the presence of mono- and / or diglycerides in the hard fat mixture. If further additives are present in the hard fat mixture that contribute free hydroxyl groups, these also influence the hydroxyl value. Another important characteristic of the hard fats used according to the invention is the iodine value. The iodine value indicates the number of grams of halogen (iodine) consumed by 100 g of the hard fat mixture. The consumption of the halogen primarily occurs in unsaturated compounds, i.e., unsaturated fatty acids. Since this proportion is very small according to the invention, the iodine value of the grades used is below 3, preferably below 2. An essential parameter of the suppository base is also the peroxide value. This value reflects the amount of peroxide, in milliequivalents of active oxygen, present in 1000 g of the suppository base. In the suppository bases used according to the invention, the peroxide value, expressed in meq O / kg, is a maximum of 5, preferably a maximum of 3, and particularly preferably a maximum of 1. In addition to lipid-containing suppository bases, water-soluble, acrogol-based masses are also used, which dissolve in rectally present fluids. Macrogol 6000 or mixtures of high and low molecular weights are preferred. The proportions of macrogol-based additives range from 0 to 20%, preferably from 0 to 5%, and most preferably from 0.1% to 3% by weight of the finished formulation. If such components are used, care must be taken to ensure a low peroxide value of no more than 5 meq O₂ / kg. Budesonide is a glucocorticoid with high local anti-inflammatory efficacy. The substance is practically insoluble in water (0.014 mg / ml, Merck Index), but due to its lipophilic properties, significant amounts dissolve in organic solvents such as ethanol, methanol, and chloroform. Depending on the medium used, the dissolved substance is more or less unstable. This instability is partly a consequence of the oxidative degradation of budesonide. Therefore, without further measures, the commonly used application of lipid-containing or water-soluble bases is not an option for the preparation of stable and well-tolerated budesonide suppositories, as the active pharmaceutical ingredient dissolved in these vehicles is rapidly degraded. As described in Example 1, simple budesonide suppositories made from hard fat of varying quality (Witepsol® H15, Witepsol® W45) show a reduction in content of approximately 10% after storage of 3 months at 25°C / 60% relative humidity. Mixtures of budesonide with macrogols are inherently incompatible due to the peroxides naturally present or formed in trace amounts within this matrix and, because of the local mucosal irritation these suppositories cause after use, do not represent an alternative for the treatment of inflammatory diseases of the rectum. In contrast, the budesonide suppositories according to the invention do not exhibit the disadvantages inherent in the prior art. The present invention is made possible only by a combination of measures, i.e., at least two, preferably at least three, of the measures listed below, none of which alone is sufficient to achieve the desired goal. The present invention therefore relates to stable and well-tolerated budesonide suppositories, which can be obtained by the following measures: (a) the use of budesonide as a pharmaceutically active ingredient in a suitable particle size distribution, (b) the selection of a suitable hard grease quality, (c) the addition of ascorbyl palmitate as an antioxidant to the hard fat base in an optimized concentration, (d) the adjustment of an optimal ratio of budesonide dissolved and suspended in the hard fat base, (e) the use of a suppository shape or size that is optimal for the application described and (f) the use of a cast film with lower permeability to oxygen as packaging material. Preferably, two or more of these measures (i.e., 3, 4, 5 or 6) are combined. The budesonide suppositories composed and manufactured according to the invention have sufficient stability to allow storage and use of the suppositories at ambient conditions of 25°C / 60% relative humidity for at least 24 months. At the same time, the invention ensures that the application of the suppositories for the treatment of the indication according to the invention is painless due to their size and shape, and that after insertion of the suppositories, the portion of the suspended active pharmaceutical ingredient rapidly sediments from the molten base onto the affected mucosal areas, while the dissolved portion spreads out of the base. This ensures both patient compliance and the This allows budesonide to remain effective for a sufficiently long period of time. Lipophilic hard fat bases are particularly suitable for the production of stable budesonide suppositories. Hard fat types with a high triglyceride content (at least approximately 85%) and thus a low hydroxyl number (5-15) have proven especially advantageous. Hard fats generally consist of a mixture of various mono-, di-, and triglycerides. Depending on the composition of the hard fat, this results in a varying number of free OH groups, leading to different properties. A key characteristic of hard fats is therefore the hydroxyl number. Hard fat types with hydroxyl numbers < 15 are of greatest importance. Due to the low number of free OH groups, these suppository bases rarely exhibit incompatibilities with hydrolysis-sensitive substances or substances containing free acid groups. In general, hard fats with a high hydroxyl number, on the other hand, exhibit good emulsifying properties and minimal cracking upon solidification.A tendency towards post-hardening can be observed, and incompatibilities with the active ingredients are possible. However, hard fats with a low hydroxyl number of < 15 have lower emulsifying properties, are more prone to cracking upon solidification, and show little tendency towards post-hardening. According to the invention, hard fat types are preferably used that contain as few or no unsaturated fatty acids as possible, because unsaturated compounds are frequently subject to oxidation reactions and can become rancid. The degree of unsaturated bonds in a lipid can be determined by the iodine value (Ph. Eur. 2.5.4). Hard fat consists of a mixture of mono-, di-, and triglycerides. Variations in the composition and the esterified fatty acids can alter the melting point of the hard fat. A preferred commercially available type is Witepsol® H 15. This particularly preferred grade contains predominantly saturated fatty acids (iodine value < 3), is characterized by a small difference between its melting point (33.5–35.5°C) and solidification point (32.5–34.5°C), and exhibits only a slight tendency to post-harden after pouring. Using this base ensures that the budesonide suppositories melt at body temperature and release the active ingredient. Surprisingly, it has been found that only a combination of the active ingredient, both molecularly dispersed and suspended in this particularly preferred hard fat grade, enables the production of shelf-stable budesonide suppositories. This optimized combination of solution and suspension preparation in a suppository allows further stabilization measures to be limited to the dissolved portion of the active ingredient.As described in Example 2, the solubility of budesonide in the particularly preferred hard fat grade Witepsoi® H 15 is 1.5 mg / g. This saturation concentration allows the calculation of the dose solubility of the active ingredient in the base and thus a targeted selection of the amount of antioxidant required for stabilization. With a budesonide dose of 2 mg or 4 mg and a suppository mass of 1.8 g, 100% of the dose is molecularly dispersed in the 2 mg form (pure solution suppository), while for the 4 mg form the dissolved fraction is 67.5% (combined variant of solution and suspension suppository). Therefore, the weight ratio of budesonide to total suppository mass is preferably between 1-10 to 1000 and particularly preferably between 1-5 to 1000. Only the targeted reduction of the suppository mass from 1.8 g to 1 g, as preferred according to the invention, makes it possible to realize the combined suppository variant for the desired dose range of 2 mg to 4 mg. In the case of the budesonide 2 mg suppositories, 75% of the dose is then present in dissolved form and 25% in suspended form. For the budesonide 4 mg suppositories, the ratio is 37.5% (dissolved fraction) and 62.5% (suspended fraction). This ensures that an optimal concentration of antioxidant can be added, which exerts its stabilizing effect exclusively on the dissolved active ingredient fraction of 37.5% to 75.0%. Only this surprisingly discovered complex interaction of physical and chemical stabilization of the preparation enables the long-term stability of budesonide suppositories at ambient conditions and thus eliminates the need for refrigeration. By reducing the mass from 1.8 g to approximately 1 g, the budesonide suppository simultaneously acquires a size and shape particularly advantageous for application, thus ensuring painless insertion. The suppositories according to the invention have a weight of approximately 0.8 to 1.2 g, preferably 0.9 to 1.1 g, and most preferably 0.95 to 1.05 g. As described in Example 1, the active ingredient fraction dissolved in molecularly dispersed form in the hard fat base must be stabilized by the addition of an antioxidant excipient. Antioxidants are a group of excipients that act as radical scavengers or as substances that are themselves easily oxidizable and can thus protect the active ingredient from oxidation. Surprisingly, it has now been found that of the antioxidants commonly used in non-aqueous, lipophilic systems, such as ascorbyl palmitate, DL-α-tocopherol, and butylhydroxyanisole, only ascorbyl palmitate proves suitable for stabilization. Example 3 shows the results of the selection tests. It is striking that, contrary to the desired antioxidant effect, the excipients DL-α-tocopherol and butylhydroxyanisole actually further accelerate the degradation of budesonide in the hard fat base. The use of ascorbyl palmitate in a concentration range of 50 ppm to 250 ppm has proven particularly suitable. Example 4 shows the concentration-dependent effect of ascorbyl palmitate on the impurity profile of budesonide 2 mg suppositories during a storage period of 24 months at 25°C / 60% relative humidity. Compared to the unstabilized budesonide suppositories from Example 1, only this measure enables long-term stabilization of the active ingredient dissolved in the hard fat, with a concentration range of 100 ppm to 200 ppm ascorbyl palmitate proving particularly effective. With the described reduction of the suppository mass to 1 g and the optimized addition of 100 ppm ascorbyl palmitate, budesonide suppositories can be produced that are stable for at least 24 months at 25°C / 60% relative humidity and do not require refrigeration. Example 5 describes the composition of preferred embodiments of budesonide 2 mg and 4 mg suppositories. The molten suppository mass is poured into plastic molds, where it then solidifies rapidly. Each suppository is dispensed volumetrically. The composite films used to hold the melt preferably consist of 100 pm-thick polyvinyl chloride films (LDPE / PVC / PVdC) coated with polyvinylidene chloride (40 g / m²) and low-density polyethylene (40 pm). This mold provides a enhanced barrier against oxygen and represents an additional protective mechanism for the formulation. The barrier protection can be further enhanced by using aluminum foil molds for the budesonide suppositories. In a preferred embodiment, the suppositories according to the invention are produced entirely under a nitrogen atmosphere. This means that after the individual components of the finished pharmaceutical formulation are combined, the air is evacuated and the mixture is then purged with nitrogen or an inert gas to prevent oxidative reactions. The molten suppository mass containing the active ingredient is then transferred directly into the prepared gas-tight composite films, where curing takes place. The composite films are designed to define the finished suppository shape and, after filling, can be sealed in such a way as to largely prevent oxygen contact with the suppository mass. The measures according to the invention make it possible to produce budesonide suppositories that are stable at room temperature. The results of the shelf-life studies of Example 6 impressively demonstrate that the selected combination of stabilization measures and protective mechanisms enables the provision of stable budesonide suppositories. The particle size of the active ingredient budesonide should be as small as possible. To achieve this, the budesonide is micronized in a suitable mill (e.g., a jet mill). According to the invention, the micronization is carried out such that 100% of the particles are smaller than 10 μm. The micronized budesonide is incorporated into the molten hard fat via the powder feed station of an inline homogenizer. This breaks down particle aggregates and results in a uniform distribution of the undissolved portion of the active ingredient in the base. Reducing the particle size is also a suitable means of preventing active ingredient sedimentation during the preparation process. It is also important that the particles do not clump together. The risk of particle agglomeration is generally greater the smaller the particles are, since the surface area of ​​the individual particles increases with decreasing particle size, and thus their surface energy rises.The addition of a small amount of surfactant (usually less than 0.5% by weight of the micronized budesonide preparation) can prevent the risk of particle growth. Adding a surfactant can also improve the spreading and wetting of the active ingredient in the rectal fluid. However, it is important to choose a surfactant that does not cause any undesirable side effects when the suppository is administered. For therapeutic use, the active pharmaceutical ingredient budesonide is used in dosages of 2 mg to 4 mg. The active ingredient is used in micronized form, with 100% of the particles being smaller than 10 μm, at least 95% smaller than 5 pm, and at least 80% smaller than 3 pm. The particle size distribution of budesonide is determined by laser diffraction analysis (laser diffractometry). Budesonide is wet-dispersed in an aqueous medium. After irradiation of the particles with monochromatic laser light, the diffraction pattern is determined, from which the particle size distribution can then be calculated. The use of micronized budesonide prevents sedimentation of suspended budesonide in the molten suppository mass during manufacturing, thus ensuring uniform distribution of the active ingredient in the poured and solidified molds.Simultaneously, micronization increases the dissolution rate of the budesonide in the rectal fluid after insertion and melting of the suppository onto the mucosa. Example 7 shows the results of in vitro release tests of budesonide 2 mg suppositories over a period of 2 hours. Within this period, both the suspended portion and the portion dissolved in the hard fat base are released. The formulation according to the invention thus ensures that the entire dose of budesonide is released from the formulation and remains available on the rectal mucosa for a sufficiently long period, thereby achieving a therapeutic effect. The suppositories according to the invention are preferably used for the treatment of inflammatory diseases of the rectum. These are preferably acute diseases where rapid relief of symptoms is desirable. The suppositories according to the invention are preferably used for the treatment of patients with active ulcerative proctitis. In a preferred embodiment, a suppository containing 2 mg budesonide or a suppository containing 4 mg budesonide is administered once in the morning and once in the evening. The budesonide suppositories according to the invention are therefore particularly suitable for the treatment of active ulcerative proctitis. In a clinical study in patients with acute ulcerative proctitis, in which embodiments of the present invention were investigated either alone or as combination therapy with conventional mesalazine suppositories compared to conventional mesalazine suppositories, it was shown that the use of the budesonide suppositories according to the invention led to a significant reduction in the time to resolution of clinical symptoms. This endpoint was defined in the clinical study as the first day of three consecutive days with a score of 0 for rectal bleeding and stool frequency. The rate of patients achieving clinical and endoscopic remission or an improvement in their symptoms was higher in the group treated with budesonide suppositories. Clinical and endoscopic remission was defined as a modified DAI-UC (Disease Activity Index - Ulcerative Colitis) score of < 1, with a score of 0 in both rectal bleeding and stool frequency, and a reduction of at least 1 point in the subcategory "mucosal appearance." An improvement in symptoms required a reduction of at least 3 points in the total score. The handling of the budesonide suppositories according to the invention with reduced suppository mass also achieved higher acceptance among patients compared to the mesalazine suppositories that were tested as a comparator. In a particular embodiment of the present invention, the budesonide suppositories according to the invention are used as part of a combination therapy with mesalazine suppositories. Such a combination therapy preferably consists of administering one budesonide suppository in the morning and one mesalazine suppository in the evening, or one mesalazine suppository in the morning and one budesonide suppository in the evening. The modified UC-DAI assessment standard, as published by Kamm et al. (2007, Gastroenterology, 132, pp. 66-75), is used to evaluate the efficacy of the suppositories. Reference is expressly made to Table 1 and the associated parameter definitions disclosed therein. Preferred embodiments of the present invention are illustrated by the following examples. Example 1: Influence of hard grease on the degradation of budesonide in hard grease of different qualities without stabilization Table 1 Without further stabilization measures, budesonide 2 mg suppositories of the hard fat type are unstable, and the nature of the hard fat used also influences stability. Even after a storage period of 3 months at 25°C / 80% relative humidity, a content decrease of 10% or more is observed. The stability of budesonide with the hard fat type Witepsoi® W45 is significantly less favorable than with the grade Witepsoi® H15. Due to its low mono- and diglyceride content, Witepsoi® H15 has a low hydroxyl number, while Witepsoi® W45 has a higher mono- and diglyceride content. This reduces the potential for interaction between the free hydroxyl groups of the hard fat and the functional groups of the active ingredient molecule in Witepsoi® H15. Example 2: Saturation solubility of budesonide in the Hartfeit type WitepsoP H15 The solubility of budesonide was determined in molten Witepsol® H15 at 40°C. Increasing amounts of budesonide were suspended in the hard fat base. After separation of the undissolved fraction and solidification of the suppository mass, the dissolved and undissolved fractions were determined by HPLC / UV as follows: Table 2 The saturation concentration of budesonide in Witepsol® H15, determined at 40 °C, is therefore approximately 1.5 mg / g. In a 1 g suppository with a dosage of 2 mg budesonide, 75% of the active ingredient is molecularly dispersed in the hard fat base; with a dosage of 4 mg, this figure is 55%. Thus, the budesonide suppositories according to the invention represent a mixture of solution and suspension preparation. Only the dissolved fraction of Budesonide must be stabilized by the addition of antioxidants. To determine the saturation concentration of budesonide in Witepsol® H15, 1 g suppositories with different budesonide dosages were prepared and left to stand for 24 hours at 40 °C. They were then centrifuged (10 minutes at 4000 rpm) to sediment any undissolved budesonide. Finally, the suppositories were solidified in a refrigerator (2–8 °C) for 2 hours. To determine the budesonide concentration, the suppositories were divided into two parts (lower part with the suppository tip and upper part) in different ratios. The two parts were processed individually for HPLC assay and then analyzed. The budesonide concentration in mg / g was calculated from the individual samples and the obtained assay values. The dissolved portion of budesonide is distributed homogeneously in the suppository base, while the undissolved portion accumulates in the suppository tip.Therefore, the results of the budesonide content determination in the upper part of the suppositories reflect the dissolved fraction of budesonide. These values ​​can be found in the table. Example 3: Selection of a suitable antioxidant for stabilizing dissolved budesonide in the hard fat type WitepsoP H15 For the selection trials, various antioxidants described in the prior art were tested. Budesonide 2 mg suppositories with a mass of 1.8 g were used, containing the active ingredient completely dissolved in the hard fat base. The antioxidants were added to the preparation at a concentration of 100 ppm. The control formulation was free of antioxidants. Composite films consisting of polyvinyl chloride (PVC) films coated with low-density polyethylene (LOPE) were used as molds; these films did not contain an additional barrier layer of polyvinylidene chloride (PVdC). The suppositories were stored at 30°C / 65% relative humidity for 30 days. After manufacturing and storage, the impurity profile of the budesonide suppositories was determined by HPLC / UV. The following two tables summarize the tested formulations and the results. 1 Particle size distribution: 100% < 10 μιη, > 95% < 5 pm, > 80% < 3 pm Table 3 Batch: 1917 1312 1915 1916 (Control) (100 ppm (100 ppm DL-oc- (1§0 ppm Ascorbyl palmita tocopherol butylhydroxy t) antsol Storage period at 30°C / 65% relative humidity: 0 30 0 30 0 30 0 30 in days Total of Mining product 1.34 6.03 0.73 0.65 2.13 14.10 1.89 15.52 ten (%) increase during the 4.69 — 1 1 ,97 13.63 Laoerung (%) Table 4 Without the addition of an antioxidant (control batch, lot V1917), budesonide degradation of approximately 5% is observed within 30 days at 30°C / 85% relative humidity (see also Example 1). The addition of 100 ppm DL-α-tocopherol and butylhydroxyanisole does not stabilize the suppositories (see lots V1915 and V1916). Surprisingly, the degradation of the active ingredient even increases significantly in the presence of these antioxidants. Thus, DL-α-tocopherol and butylhydroxyanisole are not options for stabilizing the budesonide suppositories. Ascorbyl palmitate, on the other hand, shows a significant antioxidant effect. No degradation of budesonide is observed during storage. The experiment was carried out under conditions that were unfavorable for budesonide stability, such as complete solubility of the active ingredient in hard fat and the use of cast films without any further oxygen barrier, in order to demonstrate the antioxidant effect of ascorbyl palmitate. Example 4: Optimal concentration of ascorbyl palmitate as an antioxidant for stabilizing dissolved budesonide in the hard fat type WitepsoF H15 The effect of ascorbyl palmitate as an antioxidant for stabilizing budesonide was tested with the following formulations of budesonide 2 mg suppositories: Batch: V2035 ¥2034 ¥2036 Composition: Budesonide, 2 mg 2 mg 2 mg micronized1 Ascorbyipalmitate 0.075 mg (75 ppm) 0.100 mg (100 0, 125 mg (125 PPm) ppm) Witepsol® H 15 997.925 mg 997.900 mg 997.875 mg Supposttorial mass 1000,000 mg 1000,000 mg 1000,000 mg 1 Particle size distribution: 100% < 10 pm, > 95% < 5 μιη, > 80% < 3 pm Table 5 For all suppositories, the proportion of budesonide dissolved in the hard fat base and requiring stabilization is 75%. Composite films made of LDPE / PVC / PVdC were used as molds. After production and storage for 24 months at 25°C / 60% relative humidity, the impurity profile of the budesonide suppositories was determined by HPLC / UV. The following results were obtained: Table 6 Ascorbyl palmitate stabilizes the budesonide, which is molecularly dispersed in the hard fat base, in a concentration-dependent manner. The preferred embodiment of budesonide 2 mg and 4 mg suppositories contains ascorbyl palmitate in a concentration range of 100 ppm to 150 ppm. Example 5: Qualitative and quantitative composition of the preferred embodiments of budesonide 2 mg and 4 mg suppositories 1 Particle size distribution: 00% < 10 μm, > 95% < 5 μm, > 80% < 3 μm Table 7 Example 6: Durability tests of the preferred embodiments of budesonide 2 mg and 4 mg suppositories Budesonide 2 mg and 4 mg suppositories were prepared in the preferred formulation containing 00 ppm ascorbyl palmitate and stored at 25°C / 60% relative humidity for stability testing. After preparation and at regular intervals during storage, the content and purity of the suppositories were determined by HPLC / UV. The following two tables summarize the results for budesonide 2 mg and budesonide 4 mg suppositories. Table 8 Budesonide 4 mg suppositories with 100 ppm ascorbyl palmitate, lot V2043 Storage time (months) at 25°C / 60% relative humidity 0 3 6 9 12 24 Budesonide content (%) 99.4 99.0 99.6 99.6 98.0 98.0 97.6 Total of Degradation products 0.10 0.10 0.10 0.16 0.24 0.38 0.38 (%) Table 9 The budesonide content and the total amount of degradation products change only minimally during storage. Thanks to the surprisingly successful combination of physical and chemical stabilization, the shelf life of the budesonide 2 mg and 4 mg suppositories is guaranteed for at least 24 months at 25°C / 60% relative humidity. Example 7; In vitro release experiments of budesonide 2 mg suppositories The budesonide suppositories, formulated and manufactured according to the invention, release the active ingredient over a period of 2 hours. Within this period, both the suspended and micronized portion of the active ingredient, as well as the molecularly dispersed portion in the hard fat base, are released. This ensures that the active ingredient is available on the rectal mucosa for a sufficiently long period and can exert its therapeutic effect. Figure 1 shows the release profile of budesonide 2 mg suppositories of batch V2042 after manufacturing (TO) and after storage for 24 months at 25°C / 60% relative humidity (T24). The determination is preferably carried out at 37°C using the flow cell (apparatus 4) described in the European Pharmacopoeia, which is operated as a closed system at a flow rate of 16 ml / min.A citric acid-phosphate buffer at pH 6.8 with the addition of 0.5% sodium dodecyl sulfate is used as the medium. To describe the release kinetics, samples are taken after 15, 30, 45, 60, 90, and 120 minutes. The budesonide dissolved in the release medium is determined by HPLC / UV. Example 3: Verification of the clinical efficacy and patient acceptance of the suppositories. In a double-blind study, budesonide suppositories were administered to patients with Proctitis was tested. A total of 79 patients were treated, with various suppositories containing different active ingredients being tested, without the patients knowing exactly which soft suppository they received. These trials determined the timeframe after which clinical remission, defined as "first day," with fewer than 3 bowel movements per day, all of which had to be free of blood in the stool, was observed. For the suppositories according to the invention, this timeframe was a median of 8 days. As a further parameter, the percentage of patients showing mucosal healing was determined, as observed via endoscopy of the affected intestinal segment and measured as the corresponding proportion of a disease activity index (modified UC-DAI / UIcerative Colitis-Disease Activity Index). This value was 81%. The results obtained with budesonide suppositories according to the invention containing 4 mg of active ingredient (1 g total weight) are summarized in Table 10 below. Table 10 Another essential aspect, particularly important for suppositories, was the patient acceptance of the suppositories according to the invention. Data was collected using a questionnaire that inquired about the use of the suppositories in the morning and the degree of discomfort experienced. To the first question, "How would you rate the use of the suppositories in the morning?", patients could answer "slightly / not too bothersome / discomfortable". To the second question, "How much did the use of the suppositories in the morning affect your daily routine?", patients could answer "considerably / not too much / hardly at all". The results of the patient survey are summarized in Table 1 below. Table 11 In summary, it can be stated that the vast majority of patients (78.5%) rated the morning application as easy and simple. Furthermore, the vast majority of patients (58.2%) reported almost no disruption to their daily lives from using the suppository in the morning. These data demonstrate that the suppositories according to the invention are not only stable in storage, but also exhibit very good clinical efficacy with high patient acceptance.

Claims

Patent claims 1. Pharmaceutical formulation for rectal administration, containing budesonide or a pharmaceutically acceptable salt or derivative thereof and at least 80% by weight of a hard fat or a mixture of different hard fats based on the total weight of the formulation, and at least one compatible antioxidant.

2. Formulation according to claim 1, characterized in that it has a small distance between the melting and solidification points, wherein the melting point is between 33.5°C and 35.5°C and the solidification point is between 32.5°C and 34.5°C.

3. Formulation according to one of claims 1 or 2, characterized in that the hard fat has a high proportion of triglycerides, namely > 80 wt.%, a hydroxyl number of 1 to 15 and contains less than 1 wt.% unsaturated fatty acids.

4. Formulation according to one of claims 1 to 3, characterized in that it is a suppository for anal administration.

5. Formulation according to claim 4, characterized in that it contains 1.8 to 4.2 mg budesonide per suppository.

6. Formulation according to claim 5, characterized in that it contains 1.8 to 2.2 mg budesonide per suppository.

7. Formulation according to claim 5, characterized in that the weight per suppository is between 3.8 and 4.2 mg budesonide.

8. Formulation according to one of the preceding claims, characterized in that the weight per suppository is between 0.8 and 1.2 g.

9. Formulation according to any one of claims 1 to 8, characterized in that the antioxidant is Ascorbylpa imitation.

10. Formulation according to claim 8, characterized in that the ascorbyl palmitate is present in a concentration of 50 ppm to 200 ppm.

1. Formulation according to one of claims 1 to 10, characterized in that the budesonide is in micronized form, wherein 100% of the particles are smaller than 10 μπι per particle.

12. Formulation according to one of claims 1 to 1 1 , characterized in that the storage-stable pharmaceutical formulation was produced under exclusion of oxygen.

13. Formulation according to one of claims 1 to 12, characterized in that the pharmaceutical formulation is packaged in suppository form in a gas-impermeable casting film.

14. Pharmaceutical formulation according to any one of claims 1 to 13 for use in the treatment of inflammatory diseases of the rectum.

15. Pharmaceutical formulation according to any one of claims 1 to 13 for use in the treatment of acute ulcerative proctitis.

16. Pharmaceutical formulation for use according to one of claims 14 or 15 in combination with mesalazine suppositories.