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, wherein the solid fat or mixture of different solid fats comprises at least 80 wt % triglycerides, a hydroxyl value of 1 to 15 and less than 1 wt % of unsaturated fatty acids; and at least one anti-oxidation agent that is compatible therewith, 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 small distance between melting and freezing point, wherein the melting point is between 33.5° C. and 35.5° C. and the freezing point is 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

BRIEF DESCRIPTION OF THE DRAWINGS

(1) 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

(2) Examination of the Clinical Efficacy and Acceptance of the Suppositories by Patients

(3) 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.

(4) 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.

(5) 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.

(6) 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 the corre- (81.0%) sponding part of a disease activity index (modified UC-DAI/Ulcerative Colitis-Disease Activity Index) N/N (%)

(7) 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”.

(8) The results of the patient survey are summarized in table 11 below.

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

(10) 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.

(11) 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.