PHARMACEUTICAL FORMULATION FOR THE TREATMENT OF INFLAMMATORY CHANGES TO THE RECTUM

Abstract

Disclosed is 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, based on the total weight of the formulation, as well as at least one anti-oxidation agent that is compatible therewith.

Claims

1. A pharmaceutical formulation for rectal administration, containing budesonide or pharmaceutically compatible salt or derivative thereof; at least 80 wt % of a solid fat or a mixture of different solid fats, based on the total weight of the formulation, at least one anti-oxidation agent, wherein the budesonide is present in a micronized form, wherein 100% of the particles are smaller than 10 μm per particle.

2. The formulation of claim 1, wherein the formulation has a melting point between 33.5° C. and 35.5° C. and a freezing point between 32.5° C. and 34.5° C.

3. The formulation of claim 1, wherein the formulation comprises at least 85% of the solid fat or mixture of different solid fats.

4. The formulation of claim 1, wherein the formulation comprises at least 90% of the solid fat or mixture of different solid fats.

5. The formulation of claim 1, wherein the formulation comprises at least 95% of the solid fat or mixture of different solid fats.

6. The formulation of claim 1, wherein the formulation comprises at least 99% of the solid fat or mixture of different solid fats.

7. The formulation of claim 1, wherein the formulation is a suppository for anal administration.

8. The formulation of claim 7, wherein the suppository has a weight of about 0.8 g to about 1.2 g.

9. The formulation of claim 1, wherein the formulation comprises 1.8 to 4.2 mg of budesonide.

10. The formulation of claim 9, wherein the formulation comprises 1.8 to 2.2 mg of budesonide.

11. The formulation of claim 9, wherein the formulation comprises 3.8 and 4.2 mg of budesonide.

12. The formulation of claim 1, wherein the at least one anti-oxidation agent comprises ascorbyl palmitate.

13. The formulation of claim 12, wherein the ascorbyl palmitate is present in a concentration of 50 ppm to 200 ppm.

14. The formulation of claim 1, wherein the formulation is prepared under exclusion of oxygen.

15. The formulation of claim 1, wherein the formulation is packaged in the form of suppositories in a gas-tight cast film.

16. A pharmaceutical formulation according to claim 1 for the treatment of inflammatory diseases of the rectum.

17. A pharmaceutical formulation according to claim 1 for the treatment of acute ulcerative proctitis.

18. The formulation of claim 1, wherein the formulation is storage stable at environmental conditions of 25° C./60% relative humidity for at least 24 months.

Description

[0071] Preferred embodiments of the present invention are illustrated by the following examples.

EXAMPLE 1: INFLUENCE OF THE SOLID FAT TO THE DEGRADATION OF BUDESONIDE IN SOLID FAT OF DIFFERENT QUALITIES WITHOUT STABILIZATION

[0072]

TABLE-US-00001 TABLE 1 Content [%] 3 months 3 months 25° C./ 30° C./ 60% rel. 65% rel. Batch Composition Initially humidity humidity V1860 Budesonide 2 mg 96.2 86.6 75.3 Witepsol ® H15 1798 mg Total: 1800 mg V1866 Budesonide 2 mg 94.4 77.5 70.2 Witepsol ® W45 1798 mg Total: 1800 mg

[0073] Without any further stabilizing measures budesonide 2 mg suppositories of the solid fat type are instable, wherein also the nature of the solid fat used has influence on the stability. Already after a storage period of 3 months a reduction in content of 10% and more is shown at 25° C./60% relative humidity. Here, the stability of budesonide with the solid fat type Witepsol® W45 is clearly less favorable than with the quality Witepsol® H15. Due to the small proportion of mono- and diglycerides Witepsol® H15 has a low hydroxyl value, while Witepsol® W45 has a higher proportion of mono- and diglycerides. Thus, for Witepsol® H15 there is reduced the possibility of an interaction between the free hydroxyl groups of the solid fat and the functional groups of the active ingredient molecule.

EXAMPLE 2: SATURATION SOLUBILITY OF BUDESONIDE IN THE SOLID FAT TYPE WITEPSOL® H15

[0074] The solubility of budesonide was determined in the molten Witepsol® H15 at 40° C. Here, increasing amounts of budesonide were suspended in the solid fat basis. After separation of the undissolved proportion and freezing of the suppository mass the dissolved or undissolved proportion, respectively, was determined with HPLC/UV as follows:

TABLE-US-00002 TABLE 2 Potency of the Proportion of Budesonide suppositories/dosage dissolved in Witepsol ® H15 1 mg Budesonide in 1 g 0.97 mg/g corresponding to 100% Witepsol ® H15 2 mg Budesonide in 1 g 1.47 mg/g corresponding to 75% Witepsol ® H15 3 mg Budesonide in 1 g 1.64 mg/g corresponding to 55% Witepsol ® H15 4 mg Budesonide in 1 g 1.65 mg/g corresponding to 42% Witepsol ® H15

[0075] Accordingly, the saturation concentration of budesonide in Witepsol® H15 determined at 40° C. is ca. 1.5 mg/g. In a 1 g suppository with a dosage of 2 mg budesonide 75% of the active ingredient are molecularly disperse dissolved in the solid fat basis, with a dosage of 4 mg these are 55%. Thus, the budesonide suppositories according to the invention are a blend of a solution and a suspension preparation. Only the dissolved proportion of budesonide has to be stabilized by the addition of antioxidants.

[0076] To determine the saturation concentration of budesonide in Witepsol® H15 a 1 g suppository was prepared with different budesonide dosages and left for a period of 24 hours at 40° C. Subsequently, there was performed a centrifugation (10 minutes at 4000 rpm) to sediment undissolved budesonide. Finally, the suppositories were hardened for 2 hours in a refrigerator (2-8° C.). To determine the budesonide concentration the suppositories were divided in two different ratios (lower part with suppository tip and upper part). The two parts were individually processed for HPLC assay and then analyzed. From the individual weighed portions as well as the obtained content values the budesonide concentration was calculated in mg/g. The dissolved proportion of budesonide distributes homogenously in the suppository basis, while the undissolved proportion accumulates in the suppository tip. Thus, the results of the budesonide assay in the upper part of the suppositories represent the dissolved proportion of budesonide. These values are found in the table.

EXAMPLE 3: CHOICE OF A SUITABLE ANTIOXIDANT FOR THE STABILIZATION OF DISSOLVED BUDESONIDE IN THE SOLID FAT TYPE WITEPSOL® H15

[0077] For the selection attempts different antioxidants described in the prior art were tested. Here, budesonide 2 mg suppositories with a mass of 1.8 g were used that contain the active ingredient completely dissolved in the solid fat basis. The antioxidants were added in a concentration of 100 ppm of the preparation. The control batch was free from antioxidant. As the casting molds laminated films consisting of polyvinylchloride films (PVC) coated with low density polyethylene (LDPE) were used that did not contain an additional barrier layer of polyvinylidene chloride (PVdC). The suppositories were stored at 30° C./65% relative humidity for a period of 30 days. After preparation and storage the contamination profile of the budesonide suppositories was determined with HPLC/UV. The following two tables summarize the tested formulations as well as the results.

TABLE-US-00003 TABLE 3 Batch: Composition: V1912 V1915 V1916 V1917 Budesonide, 2 mg 2 mg 2 mg 2 mg micronized.sup.1 Ascorbyl Palmitate 0.180 mg — — — (100 ppm) DL-α-Tocopherol — 0.180 mg — — (100 ppm) Butylated — — 0.180 mg — Hydroxyanisole (100 ppm) Witepsol ® H15 1797.820 mg 1797.820 mg 1797.820 mg 1798.000 mg Suppository Mass 1800.000 mg 1800.000 mg 1800.000 mg 1800.000 mg .sup.1Particle size distribution: 100% < 10 μm, ≥95% < 5 μm, ≥80% < 3 μm

TABLE-US-00004 TABLE 4 V1912 V1916 (100 ppm V1915 (100 ppm V1917 ascorbyl (100 ppm DL- butylated Batch: (control) palmitate) α-tocopherol hydroxyanisole Storage period 0 30 0 30 0 30 0 30 at 30° C./65% rel. humidity in days Sum of 1.34 6.03 0.73 0.65 2.13 14.10 1.89 15.52 degradation products (%) Increase during 4.69 — 11.97 13.63 storage (%)

[0078] Without the addition of an antioxidant (control batch, batch V1917) a budesonide degradation of ca. 5% can be observed within 30 days at 30° C./65% relative humidity (see also example 1). The addition of 100 ppm DL-a-tocopherol and butylated hydroxyanisole does not lead to a stabilization of the suppositories (see batches V1915 and V1916). Surprisingly, the degradation of the active ingredient in the presence of these antioxidants even increases significantly. Thus, DL-a-tocopherol and butylated hydroxyanisole do not represent options for the stabilization of the budesonide suppositories. In contrast, ascorbyl palmitate shows a significant anti-oxidative effect. During the storage period no degradation of budesonide can be observed. The experiment is performed under conditions that are unfavorable for the budesonide stability such as complete solubility of the active ingredient in the solid fat as well as the use of cast films without any further oxygen barrier to be able to show the anti-oxidative effect of ascorbyl palmitate.

EXAMPLE 4: OPTIMUM CONCENTRATION OF ASCORBYL PALMITATE AS AN ANTIOXIDANT FOR THE STABILIZATION OF DISSOLVED BUDESONIDE IN THE SOLID FAT TYPE WITEPSOL® H15

[0079] The effect of ascorbyl palmitate as an antioxidant for the stabilization of budesonide was tested with the following recipes of budesonide 2 mg suppositories:

TABLE-US-00005 TABLE 5 Batch: Composition: V2035 V2034 V2036 Budesonide, 2 mg 2 mg 2 mg micronized.sup.1 Ascorbyl Palmitate 0.075 mg 0.100 mg 0.125 mg (75 ppm) (100 ppm) (125 ppm) Witepsol ® H15 997.925 mg 997.900 mg 997.875 mg Suppository Mass 1000.000 mg 1000.000 mg 1000.000 mg .sup.1Particle size distribution: 100% < 10 μm, ≥95% < 5 μm, ≥80% < 3 μm

[0080] Thus, for all suppositories the proportion of budesonide dissolved in the solid fat basis and to be stabilized is 75%. As the casting molds laminated films of LDPE/PVC/PVdC were used. After manufacture and storage of 24 months at 25° C./60% relative humidity the contamination profile of the budesonide suppositories was determined with HPLC/UV. The results obtained were as follows:

TABLE-US-00006 TABLE 6 V2035 V2034 V2036 (75 ppm ascorbyl (100 ppm ascorbyl (125 ppm ascorbyl Batch: palmitate) palmitate) palmitate) Storage Period in 0 24 0 24 0 24 Months Sum of 0.19 2.93 0.16 2.17 0.19 1.70 Degradation Products (%) Increase during 2.74 2.01 1.51 Storage (%)

[0081] Ascorbyl palmitate stabilizes the budesonide molecularly disperse dissolved in the solid fat basis depending on the concentration. 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

[0082]

TABLE-US-00007 TABLE 7 Composition Budesonide, micronized.sup.1 2 mg 4 mg Ascorbyl Palmitate 0.10-0.15 mg 0.10-0.15 mg (100-150 ppm) (100-150 ppm) Witepsol ® H15 997.85-997.900 mg 995.85-995.90 mg Suppository Mass 1000.00 mg 1000.00 mg Casting Mold cast film of cast film of LDPE/PVC/PVdC LDPE/PVC/PVdC .sup.1Particle size distribution: 100% < 10 μm, ≥95% < 5 μm, ≥80% < 3 μm

EXAMPLE 6: SHELF LIFE TESTS OF THE PREFERRED EMBODIMENTS OF BUDESONIDE 2 MG AND 4 MG SUPPOSITORIES

[0083] Budesonide 2 mg and 4 mg suppositories were prepared in the preferred embodiment with 100 ppm ascorbyl palmitate and stored at 25° C./60% relative humidity for shelf life tests. After manufacture and in regular intervals during the storage the content and the purity of the suppositories were determined with HPLC/UV. The two following tables summarize the results for budesonide 2 mg suppositories and budesonide 4 mg suppositories.

TABLE-US-00008 TABLE 8 Budesonide 2 mg Suppositories with 100 ppm Ascorbyl Palmitate, Batch V2042 Storage Period (Months) at 25° C./60% rel. Humidity 0 3 6 9 12 18 24 Content of 99.5 97.3 96.2 96.5 96.0 95.0 96.6 Budesonide (%) Sum of 0.16 0.09 0.16 0.27 0.36 0.72 0.86 Degradation Products (%)

TABLE-US-00009 TABLE 9 Budesonide 4 mg Suppositories with 100 ppm Ascorbyl Palmitate, Batch V2043 Storage Period (Months) at 25° C./60% rel. Humidity 0 3 6 9 12 18 24 Content of 99.4 99.0 99.6 99.6 98.0 98.0 97.6 Budesonide (%) Sum of 0.10 0.10 0.10 0.16 0.24 0.38 0.38 Degradation Products (%)

[0084] The budesonide content and the sum of degradation products change only slightly during storage. With the surprisingly found combination of physical and chemical stabilization the shelf life of the budesonide 2 mg and 4 mg suppositories is ensures for a period of at least 24 months at 25° C./60% relative humidity.

EXAMPLE 7: IN VITRO RELEASING TESTS OF BUDESONIDE 2 MG SUPPOSITORIES

[0085] The budesonide suppositories composited and prepared according to the invention release the active ingredient over a period of 2 hours. Within this period, both the proportion of the active ingredient that is suspended and present in a micronized form and the proportion that is molecularly disperse dissolved in the solid fat basis is released. This ensures that the active ingredient is available over a sufficiently long period of time on the rectal mucosa and can exert its therapeutic effect. FIG. 1 shows the releasing profile of budesonide 2 mg suppositories of batch V2042 after manufacture (T0) and after storage of 24 months at 25° C./60% relative humidity (T24). The determination takes place at 37° C., preferably with the flow cell described in the European Pharmacopoeia (apparatus 4), that is operated with a flow rate of 16 ml/min as a closed system. Citric acid phosphate buffer pH 6.8 with an addition of 0.5% of sodium dodecyl sulphate is used as the medium. In order to be able to describe the releasing kinetics sampling is performed after 15, 30, 45, 60, 90, and 120 minutes. The budesonide dissolved in the release medium is determined with HPLC/UV.

BRIEF DESCRIPTION OF THE DRAWINGS

[0086] FIG. 1 shows the releasing profile of budesonide 2 mg suppositories of batch V2042 after manufacture (T0) and after storage of 24 months at 25° C./60% relative humidity (T24).

EXAMPLE 8: EXAMINATION OF THE CLINICAL EFFICACY AND ACCEPTANCE OF THE SUPPOSITORIES BY PATIENTS

[0087] During a double blind study budesonide suppositories were tested on patients suffering from proctitis. 79 patients in total were treated, wherein different suppositories with different active ingredients were tested without the patients knowing exactly which suppository they received.

[0088] During these tests it was found after which period of time a clinical remission, defined as “first day”, with ≤3 defaecations/day, wherein all had to be without blood in the feces, was observed. With the suppositories according to the invention this period was 8 days in median terms.

[0089] As a further parameter there was determined the percentage of patients that showed a mucosal healing, wherein this was determined via endoscopy of the affected section of the intestine and was measured as the corresponding part of a disease activity index (modified UC-DAI/Ulcerative Colitis-Disease Activity Index). Said value was 81%. The results obtained with budesonide suppositories according to the invention with 4 mg of active ingredient (1 g total weight) are summarized in table 10 below.

TABLE-US-00010 TABLE 10 Efficacy Parameter Clinical Remission, defined as 8 days first day with ≤3 defaecations/day and all without blood in the feces Required Time of Treatment Mucosal Healing 64/79 Endoscopy of the affected section of the intestine, measured as (81.0%) the corresponding part of a disease activity index (modified UC- DAI/Ulcerative Colitis-Disease Activity Index) N/N (%)

[0090] As a further essential aspect that just with suppositories plays an important role there was examined the acceptance of the suppositories according to the invention in patients. Here, data were collected via a corresponding questionnaire, wherein application of the suppositories in the morning and impairment were queried. To the first question, “How do you assess the use of suppositories in the morning?” patients could answer with “easy/not too arduous/difficult”. To the second question, “How much did using suppositories in the morning impair your daily routine?” the patients could answer with “considerable/not too much/nearly not at all”.

[0091] The results of the patient survey are summarized in table 11 below.

TABLE-US-00011 TABLE 11 Patient Acceptance Application of the easy not too difficult no Suppositories in the arduous statement Morning N/N (%) 62/79 (78.5) 12/79 (15.2) 2/79 (2.5) 3/79 (3.8) Impairment of the nearly not not too consid- no everyday life by the at all much erable statement Application of the Suppositories in the Morning N/N (%) 46/79 (58.2) 26/79 (32.9) 4/79 (5.1) 3/79 (3.8)

[0092] In summary, it can be concluded that a majority of the patients (78.5%) judged the application in the morning as easy and simple. Moreover, the majority of the patients (58.2%) found almost no impairment of the everyday life by the application of the suppositories in the morning.

[0093] These data show that the suppositories according to the invention are not only storage-stable, but also have a very good clinical efficacy with simultaneous high acceptance by the patients.