PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR THE SUSTAINED RELEASE OF SOMATOSTATIN ANALOGS

Abstract

Process for the preparation of an injectable pharmaceutical composition for the sustained release of somatostatin analogues. Composition prepared according to such a process.

Claims

1. A process for preparing an injectable sustained release pharmaceutical composition, the process comprising the steps of: lyophilizing a mixture comprising a somatostatin analog salt and an aqueous acid solution; and hydrating the resulting lyophilizate; wherein: the lyophilization is performed only once; and the final pH of the composition is from 5 to 7.

2. The process of claim 1, wherein the somatostatin analog is lanreotide.

3. The process of claim 1, wherein the acid is acetic acid.

4. The process of claim 1, wherein the final pH of the composition is from 5.8 to 6.4.

5. The process of claim 1, wherein the aqueous acid solution contains acetic acid at a concentration suitable for providing the requisite final pH.

6. The process of claim 1, wherein the lyophilizate is hydrated with a solution containing acetic acid at a concentration suitable to provide a composition having an anhydrous acetate content of 9.1 to 10.5% by weight.

7. The process of claim 1, wherein a 23 to 27 g/l lanreotide composition and a 13 to 17% by weight acetic acid composition are combined to form the mixture.

8. (canceled)

9. The process of claim 7, wherein the lyophilization occurs over a period of at least 40 hours.

10. The process of claim 7, wherein the temperature of the mixture is: reduced over a period of up to 30 minutes and then retained constant for 2 to 4 hours; further reduced over a period of up to 15 minutes and then retained constant for 2.5 to 4.5 hours; increased over a period of 15 to 25 hours and then retained constant for at least 40 hours; and further increased over a period of 0.5 to 1.5 hours and then retained constant for at least 16 hours.

11. The process of claim 10, wherein, after the temperature of the mixture is reduced, the atmospheric pressure is reduced to 15 to 25 bar and remains constant as the temperature of the mixture increases.

12. The process of claim 1, wherein the lyophilizate is hydrated by dissolving it in an amount of water that is less than 50% of the amount needed to completely dissolve the lanreotide salt.

13. A sustained release pharmaceutical composition prepared according to the process of claim 1.

14. The composition of claim 13, the composition being capable of releasing the lanreotide in vivo over a period of at least 15 days.

15. The composition of claim 13, wherein the composition comprises from 15 to 35% by weight lanreotide base.

16. The composition of claim 13, wherein the composition is suitable for use after storage for more than 12 months at a temperature of between 2 and 8 C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0085] FIG. 1 is a plot of syringe injection force (SIF) (in Newtons) versus pH for compositions prepared by a process according to the invention including a single lyophilization (represented by filled circles) and compositions prepared by a process including two lyophilizations (represented by filled squares).

[0086] FIG. 2 is a plot of flow rate (micro-liters per minute) versus pH for compositions prepared by a process according to the invention including a single lyophilization (represented by filled circles) and compositions prepared by a process including two lyophilizations (represented by filled squares).

[0087] FIG. 3 is a plot showing the percentage of lanreotide acetate released after 2.75 hours versus pH during an in vitro test of compositions prepared by a process according to the invention including a single lyophilization (represented by filled circles) and compositions prepared by a process including two lyophilizations (represented by filled squares).

[0088] FIG. 4 is a plot showing the percentage of lanreotide acetate released after 9.25 hours versus pH during an in vitro test of compositions prepared by a process according to the invention including a single lyophilization (represented by filled circles) and compositions prepared by a process including two lyophilizations (represented by filled squares).

[0089] FIG. 5 is a plot showing the percentage of lanreotide acetate released after 24.25 hours versus pH during an in vitro test of compositions prepared by a process according to the invention including a single lyophilization (represented by filled circles) and compositions prepared by a process including two lyophilizations (represented by filled squares).

[0090] FIG. 6 is a plot showing the relation between the acetate content (AcOH level) and the pH of the composition. Data of pH are plotted in function of the acetate content in % (w/w) of the active substance.

COMBINING LANREOTIDE ACETATE AND AQUEOUS ACETIC ACID, FOLLOWED BY FIRST LYOPHILISATION

[0091] A pre-lyophilization pool was prepared by adjusting the concentration of pure Lanreotide [BIM 23014] to 252 g/l in an aqueous solution of 15% acetic acid solution. The pool was loaded into a metal tray and placed in a lyophiliser whose shelves were cooled from room temperature to 2 C. over 10 minutes and then held at this temperature for 3 hours. The cooled mixture was then frozen to 40 C. over 10 minutes and then held at this temperature for 2.75 hours.

[0092] To effect the lyophilisation, a vacuum to 20 bar was applied and maintained while the lyophiliser shelves were heated from 40 C. to 25 C. over 20 hours, held at this temperature for a further 63.3 hours and further heated to 35 C. for 23 hours.

[0093] Optional Acidification

[0094] Water for injection was acidified with glacial acetic acid.

[0095] Hydration of the Lyophilizate

[0096] The lanreotide acetate lyophilizate powder was combined with acidified water for injection to a specified concentration of pure lanreotide using the following steps. The lanreotide acetate and water were weighed and placed into two separate cylinders, fitted with pistons and linked together via a three-way valve. Prior to hydration, a vacuum of between 100 and 600 bar was applied to the cylinder containing the lanreotide acetate powder via the three-way valve. The water was then introduced into the cylinder containing the lanreotide acetate, again via the three-way valve. The lanreotide acetate then underwent static hydration for at least two hours. The dispersion was then homogenised by passing the contents back and forth between the two cylinders via the three-way-valve, using the pistons. The process yielded a lanreotide acetate supersaturated gel.

Summary of Examples 1 to 9

[0097] A summary of the specific conditions of each example appears in Table 1, below.

TABLE-US-00001 TABLE 1 Example AcOH (% w/w) Lanreotide No. Batch API Added Total (% w/w) pH 1 04K TS 9.9 0.0 9.9 24.83 6.01 2202 2 DS 9.5 0.0 9.5 24.82 6.25 361/022 3 04K TS 9.2 0.0 9.2 24.75 6.41 2205 4 04K TS 8.2 0.0 8.2 24.70 6.86 2204 5 04K TS 8.2 0.5 8.7 24.73 6.61 2204 6 04K TS 8.2 2.5 10.7 24.60 5.78 2204 7 FFD 04K 7.5 1.2 8.7 24.88 6.51 TS 2205 8 N006.21 9.7 1.3 11.0 24.88 5.73 00006 9 FFD 04K 7.5 0.0 7.5 24.87 6.95 TS 2205

[0098] Three columns are presented under the AcOH heading, each of which relates to weight percentage of acetic acid. The API column identifies the amount of acetic acid in the lyophilizate (also termed the active principal ingredient), before hydration. The Added column identifies the amount of acetic acid, if any, added to the water used in the hydration process. A zero in the API column indicates that the optional acidification step was not employed. The Total column provides the total amount of acetic acid present in the composition, made up of the sum of the API and added columns.

[0099] The Lanreotide column provides the weight percentage of lanreotide peptide in the finished composition. The pH column provides the pH value of the finished composition.

[0100] The examples 1-6 correspond to compositions prepared by a process according to the present invention and including a single lyophilization; the examples 7-9 correspond to compositions prepared by a process including two lyophilizations according to the process as described in the PCT application WO 99/48517.

Characteristics of the Compositions Prepared in Examples 1 to 9

[0101] Properties of the compositions prepared according to Examples 1 to 9 are tabulated in Table 2, below, and graphed in FIGS. 1 to 6.

TABLE-US-00002 TABLE 2 SIF Flow Example Mean Mean Routine IVT Mean (% released) No. (N) (l/min) Q(2.75 h) Q(9.25 h) Q(24.25 h) 1 18.9 96.8 18.7 53.3 92.5 2 21.4 83.0 17.5 51.2 91.6 3 21.8 83.5 17.3 48.8 89.4 4 30.3 9.9 15.8 46.0 87.1 5 25.4 34.0 18.4 52.1 92.0 6 17.2 144.8 19.5 54.7 94.7 7 24.4 56.1 17.0 48.2 88.3 8 17.3 136.9 20.7 57.6 95.2 9 26.7 1.0 15.7 45.5 84.5

[0102] Injectability of the compositions was measured both in terms of the strength required to discharge the syringe (syringe injection force or SIF) and the viscosity of the compositions, measured in terms of flow rate.

[0103] The flow rate method was developed based upon the principles of the reference NF EN ISO 1133: Determination of the melt mass flow rate (MFR) and the melt volume flow rate (MVR) of thermoplastics. In this technique, the viscosity of the solution is determined indirectly, under temperature-controlled conditions, by measuring the flow throughout a standarised stainless-steel test syringe while a constant pressure is applied. The flow of the supersaturated gel through the syringe (which is proportional to the viscosity) is measured and expressed as a flow-rate (l/min).

[0104] Syringe injection force (SIF) test was developed to assess the maximum force needed to discharge, at a constant displacement rate (200 mm/min), the formulation contained in the finished drug product syringe maintained in vertical position.

[0105] Release of the active ingredient was measured using an in vitro test (NT), in which the percentage of the active component released (Q) was measured after 2.75 h, 9.25 h and 24.25 h. The in vitro released test was object of an specific development bearing in mind the special characteristics of the formulation for which none of the conventional in vitro dissolution apparatus was applicable. As a result, a small drug product holding device was developed to retain the formulation in a dialysis membrane. The in vitro dissolution profile is obtained in saline solution by using the pharmacopoeial dissolution (basket) apparatus, as described in the USP test <711> Dissolution, apparatus 1 and in the Eur.Pharm. 2.9.3 monograph.

[0106] In FIG. 1, syringe injection force (SIF) is plotted against pH. The graph demonstrates that as the pH increases, the SIF also increases, and the extent of the ST increase is not dependent on whether the single lyophilization process or double lyophilization process was employed.

[0107] In FIG. 2, flow rate is plotted against pH. The flow rate is inversely proportional to pH in that as pH increases, the flow rate decreases. As with acetic acid concentration and SIF, the flow rate parameter is not influenced by whether the single lyophilization process or double lyophilization process was employed.

[0108] In FIGS. 3, 4 and 5, the proportion of the active ingredient released is plotted against pH during an in vitro test of the compositions, measured after 2.75 hours, 9.25 hours and 24.25 hours, respectively. The graphs demonstrate that the release rate decreases with increasing pH when the concentration is kept constant.

Example 10: Preferred Procedure for the Preparation of Compositions According to the Invention

[0109] A pre-lyophilization pool was prepared by dissolving 25 g/l pure lanreotide [BIM-23014] in an aqueous solution of 15% acetic acid solution. The pool was loaded into a hollow metal tray and cooled from room temperature to 2 C. over 10 minutes and then held at this temperature for 3 hours. The cooled mixture was then frozen to 40 C. over 10 minutes and then held at this temperature for 2.75 hours. A vacuum to 20 bar was applied and maintained while the mixture was heated from 40 C. to 25 C. over 20 hours and further heated to 35 C. for 16.75 hours.

[0110] Water for injection was acidified with glacial acetic acid sufficient to provide a final anhydrous acetate content of 9.6% to 10%. The acidified water and lanreotide acetate were then combined to a concentration of 24.6% pure lanreotide and 9.6% to 10% anhydrous acetate as follows: the lanreotide acetate and water were weighed and placed into two separate cylinders, fitted with pistons and linked together via a three-way valve. Prior to hydration, a vacuum of between 100 and 600 bar was applied to the cylinder containing the lanreotide acetate powder via the three-way valve. The water was then introduced into the cylinder containing the lanreotide acetate, again via the three-way valve. The lanreotide acetate then underwent static hydration for at least two hours. The dispersion was then homogenised by passing the contents back and forth between the two cylinders, using the pistons. The process yielded a lanreotide acetate supersaturated gel of pH 6.2.

[0111] While the present invention has been described with reference to one specific embodiment, it will be appreciated that various modifications and changes could be made without departing from the scope of the invention.