SPHERICAL BEADS FOR USE IN PRODUCING PHARMACEUTICALLY ACTIVE PELLETS

Abstract

Improved spherical beads that may be used in producing pharmaceutically active pellets by depositing a pharmaceutically active agent on the surface of said spherical beads. The spherical beads includes a pharmaceutically acceptable carrier material, including: a) at least 60 wt. % of phosphoric acid calcium salt and b) up to 40 wt. % of organic material.

Greater than or equal to 90 wt % of the spherical beads have a particle size in the range of from 90 μm to 1200 μm. The spherical beads have: a bulk density of at least or more than 1000 g/l, a specific surface area of at most or less than 10 m.sup.2/g, and a hardness of at least or more than 600 g/mm.sup.2. Also included is a method for producing such spherical beads and to pharmaceutically active pellets being prepared by depositing a pharmaceutically active agent on the surface of the spherical beads.

Claims

1. Spherical beads for use in producing pharmaceutically active pellets being prepared by depositing a pharmaceutically active agent on the surface of said spherical beads, wherein the spherical beads consist of a pharmaceutically acceptable carrier material, said carrier material consisting of: a) at least 60 wt. % of phosphoric acid calcium salt and b) up to 40 wt. % of organic material, wherein ≥90 wt. % of the spherical beads have a particle size in the range of from 90 μm to 1200 μm and wherein the spherical beads have: a bulk density of at least 1000 g/l, a specific surface area of at most 10 m.sup.2/g, and a hardness of at least 600 g/mm.sup.2.

2. The spherical beads according to claim 1, wherein the phosphoric acid calcium salt is selected from the group consisting of monobasic calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate and mixtures thereof.

3. The spherical beads according to claim 2, wherein the phosphoric acid calcium salt is anhydrous or contains water of hydration.

4. The spherical beads according to claim 1, wherein the organic material is selected from the group consisting of microcrystalline cellulose, lactose, gelatin, cellulose and its derivatives, starch and its derivatives, saccharides and polysaccharides, synthetic polymers and mixtures thereof.

5. The spherical beads according to claim 4, wherein the organic material is anhydrous or contains water of hydration.

6. The spherical beads according to claim 1, wherein the spherical beads have a sphericity of at least 0.8.

7. The spherical beads according to claim 1, wherein the spherical beads have a surface roughness of at least 0.9.

8. The spherical beads according to claim 1, wherein the spherical beads do not disintegrate when being placed in water at a temperature of 25±1° C. for 24 h.

9. The spherical beads according to claim 1, wherein the circle equivalent diameter of the beads reduces by less than 1% when placing the beads in water at a temperature of 25±1° C. for 24 h and stirring with a speed of 50 rpm.

10. A method for producing spherical beads for use in producing pharmaceutically active pellets being prepared by depositing a pharmaceutically active agent on the surface of said spherical beads, wherein the spherical beads consist of a pharmaceutically acceptable carrier material, wherein the carrier material consists of: a) at least 60 wt. % of phosphoric acid calcium salt and b) up to 40 wt. % of organic material, and wherein the spherical beads are obtained by mixing the carrier material and water in a mixing device for at least 1 minute and up to 10 minutes, thereby producing a mixture, wherein the temperature of said mixture is increased by 4 to 6° C. per minute by the mechanical mixing energy applied by the mixing device to the mixture, only.

11. The method for producing spherical beads according to claim 10, wherein ≥90 wt. % of the spherical beads obtained by said method have a particle size in the range of from 90 μm to 1200 μm, and wherein the spherical beads obtained by said method have: a bulk density of at least 1000 g/l, a specific surface area of at most 10 m.sup.2/g, and a hardness of at least 600 g/mm.sup.2.

12. Pharmaceutically active pellets being prepared by depositing a pharmaceutically active agent on the surface of the spherical beads according to claim 1.

13. The pharmaceutically active pellets according to claim 12, wherein the pharmaceutically active agent is deposited on the surface of the spherical beads by depositing a solution, a suspension or a powder of said pharmaceutically active agent on the surface of the spherical beads.

14. The pharmaceutically active pellets according to claim 13, wherein the solution, the suspension or the powder of the pharmaceutically active agent forms a layer on the surface of the spherical beads.

Description

[0061] In the examples mentioned below it is referred to FIGS. 1 and 2, wherein

[0062] FIG. 1 shows a microscopic photograph of inventive spherical beads containing 80% of dibasic calcium phosphate anhydrous (Example 1) before (left) and after (right) 24 hours mixing with water,

[0063] FIG. 2 shows a microscopic photograph of inventive spherical beads containing 60% of dibasic calcium phosphate anhydrous (Example 2) before (left) and after (right) 24 hours mixing with water, and wherein

[0064] FIG. 3 shows SEM micrographs of a spherical bead prepared according to Example 1 as well as a close-up of the bead surface.

EXAMPLES

Examples 1-4

Preparation of Calcium Phosphate-Based Spherical Beads

[0065] Calcium salt of orthophosphoric acid was placed in a mixing pan of a high-energy mixing device (Eirich, Intensive mixer type RV01) together with an organic component. The grade of each component and the ratio between the two components is presented in the Table 1.

[0066] After addition of water the powder mass was blended for 1 minute. The mixing pan was rotated clockwise with the speed of 45 rpm. The mixing tool was rotated counterclockwise with the speed of 27 m/s. The amount of water used depends on the ration between components and is given in Table 1 expressed as percentage in relation to the mass of dry components. The wet material obtained from the high-energy mixing process was then transferred to a spheronizer and spheronized for 10 minutes with a speed of 800 rpm. The obtained spherical beads were dried in a fluid-bed drier at a temperature of 80° C. for around 30 minutes—until value of LoD determined at a moisture analyzer balance at 105° C. was below 1-2%. The dry spherical beads were then classified between sieves of 100 μm and 1000 μm and analyzed further. Table 2 shows the physical characteristics of the obtained beads.

TABLE-US-00001 TABLE 1 Median particle size* Exam- Exam- Exam- Exam- [μm] ple 1 ple 2 ple 3 ple 4 Dibasic calcium 25 80% — 80% 60% phosphate anhydrous Dibasic calcium 60 — 80% — — phosphate anhydrous Microcrystalline 65 20% 20% — 40% cellulose type 101 Microcrystalline 15 — — 20% — cellulose type 105 Water 35% 35% 35% 35% 45% *starting material

TABLE-US-00002 TABLE 2 Parameter Example 1 Example 2 Example 3 Example 4 Bulk density >1100 g/l >1100 g/l >1100 g/l >1000 g/l Degree of sphericity ≥0.9 ≥0.9 ≥0.9 ≥0.9 LoD <1% <1% <1% <2% Friability <1% <1% <1% <1% Hardness >600 g/mm.sup.2 >600 g/mm.sup.2 >600 g/mm.sup.2 >600 g/mm.sup.2 Angle of repose <30° <30° <30° <30°

[0067] FIG. 3 shows SEM micrographs of a spherical bead prepared according to Example 1 as well as a close-up of the bead surface. The micrographs reveal very dense and porous-free surface of these beads which indicate very small specific surface area. Moreover, one can distinguish the lighter spots of calcium phosphate and darker of microcrystalline cellulose uniformly distributed in the bead.

Example 5

Physical Stability of Beads in Contact with Water

[0068] Beads prepared according to Example 1 and 4 containing 80% w/w and 60% w/w respectively were placed in water at a temperature of 25±1° C. for 24 h. During this time the liquid was stirred with a speed of 50 rpm. Before and after experiment they were tested in terms of bulk density, particle size and surface roughness. The results are given in the Table 3 and represented by FIGS. 1 and 2.

[0069] The results show essentially no changes in bead properties after 24 hours mixing with water. One can notice an insignificant decrease in bead size caused by the partial dissolution of the substance from the surface and erosion during such a long mixing time. Nevertheless this phenomenon did not impact significantly on the particles surface or shape.

TABLE-US-00003 TABLE 3 Beads containing 80% of dibasic Beads containing 60% of dibasic calcium phosphate anhydrous calcium phosphate anhydrous mixed with mixed with Parameter initial water for 24 h initial water for 24 h Bulk density >1100 g/l >1100 g/l >1000 g/l >1000 g/l Circle Equivalent 752 ± 63 μm 749 ± 59 μm 923 ± 138 μm 917 ± 104 μm diameter Maximum diameter 786 ± 78 μm 784 ± 75 μm 984 ± 204 μm 969 ± 118 μm Minimum diameter 724 ± 57 μm 716 ± 48 μm 878 ± 119 μm 876 ± 95 μm Surface roughness 0.996 ± 0.005 0.995 ± 0.007 0.982 ± 0.033 0.980 ± 0.021

Example 6

Effect of Spheronization

[0070] The physical properties of beads produced with or without additional spheronization step have been analyzed. Particularly, beads prepared according to Example 1 have been used in this respect, and the results of this experiment are indicated in the below table 4.

[0071] The data show that spheronization is not required in order to obtain the physical characteristics of the inventive spherical beads. Accordingly, the inventive spherical beads having the physical characteristics as claimed are obtainable without any spheronization step.

TABLE-US-00004 TABLE 4 beads before beads after Parameter spheronization spheronization Bulk density 1000-1100 g/l 1100-1200 g/l Degree of sphericity 0.87 ± 0.03 0.93 ± 0.01 Surface roughness 0.97 ± 0.02 0.99 ± 0.01