MEDICAMENTS CONTAINING RIBOFLAVIN EXHIBITING IMPROVED FLOWABILITY

Abstract

Antihypertensive agents which are crystalline having a general plate shape may be difficult to formulate as they often do not exhibit good flowability properties. Addition of spray-dried riboflavin surprisingly improves flowability of these agents.

Claims

1. A composition comprising: a) an active ingredient which comprises at least 50% plate shaped crystals when observed under a microscope, and the active ingredient comprises at least 50% spheres and irregular spheres by volume as measured by a particle size and shape analyzing instrument; and b) spray-dried riboflavin.

2. A composition according to claim 1 wherein the weight ratio between the active ingredient and the spray-dried riboflavin is 10:1 to 1:10.

3. A composition according to claim 1 wherein the active ingredient is an antihypertensive agent.

4. A composition according to claim 1 wherein the antihypertensive agent is a calcium channel blocker.

5. A composition according to claim 4 wherein the calcium channel blocker is selected from the group consisting of: amlodipine, diltiazem, felodipine, iradipine, nicardipine, nifedipine, nisoldipine, lercanidipine, nitrendipine, azelnidipine, verapamil and a pharmaceutically acceptable salt thereof the aforementioned calcium channel blockers.

6. A composition according to claim 4 which is amlodipine or amlodipine besylate.

7. An oral formulation comprising the composition of claim 1 which is a tablet, capsule, or powdered form.

8. A method of improving flowability of an active ingredient comprising the steps of: a) mixing the active ingredient with spray-dried riboflavin to obtain a composition comprising active ingredient and spray-dried riboflavin; b) determining the flow rate of the composition of step a); and c) comparing the flow rate of the composition of step a) to the flow rate of the active ingredient in the absence of riboflavin to determine if there is an improved flowability.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0048] FIG. 1 is an electron micrograph of amlodipine besylate crystals, a calcium channel blocker (magnification of 200×).

[0049] FIG. 2 is an electron micrograph of spray-dried riboflavin magnification 200×.

[0050] FIG. 3 has electron micrographs of two calcium channel blocker crystals. FIG. 3a is diltiazem, FIG. 3B is felodipine. Both are magnification 200×

[0051] FIG. 4 has electron micrographs of two calcium channel blocker crystals. FIG. 4a is nifedipine; FIG. 4b is lercanidipine. Magnification 200×.

[0052] FIG. 5 has electron micrographs of crystals. FIG. 5a is indapamide, (a diuretic), and FIG. 5 b is nitrendipine, a calcium channel blocker. Magnification is 200×

[0053] FIG. 6 a has an electron micrograph of verapamil hydrochloride, a calcium channel blocker. Magnification is 200×.

[0054] FIG. 7 has an electron micrograph of a beta blocker atenolol.

[0055] The antihypertensive agent such as amlodipine or a pharmaceutically acceptable salt and spray-dried riboflavin composition of this invention may be formulated into any type of oral formulation; preferred formulations include tablets, capsules, and the like using known methods and known formulation additives.

[0056] The composition comprising the crystalline antihypertensive agent may be produced by simply mixing the crystalline antihypertensive agent and the spray-dried riboflavin. In some embodiments, amlodipine having a plate shaped crystalline habit is mixed with spray-dried riboflavin.

[0057] The following non-limiting Examples are presented to better illustrate the invention.

EXAMPLES

Example 1

[0058] Methods

[0059] Scanning Electron Microscopy (SEM)

[0060] The morphology of tested materials was analyzed using Scanning Electron Microscope (TM 3030, Hitachi, Tokyo, Japan) with the magnification of 200.

[0061] Flowability

[0062] The powder flowability was determined with a Pharmatest PTG-S4 automated powder characterization instrument (Pharma Test Apparatebau AG, Hamburg, Germany). This system measures the flow behavior of granules and powders in compliance with the current EP <2.9.36/17> and USP <1174> pharmacopoeia, as well as, with the international ISO 4324 standards.

[0063] Mass flow rate (g/min) was determined via the method of flow through an orifice. Flow rate is interpreted as the time needed for a specified amount of powder (10 g) to flow through an orifice with different diameters. A free-flowing powder should be able to flow through the whole set of diameters 5, 7, 9 and 10 mm. The plot of flow rate vs. orifice diameter is referred as flow curve. Three parallel measurements were performed to determine the flow rate. Results are presented in Table 1

TABLE-US-00001 TABLE 1 Product Weight (g) mm mm 7 mm 5 mm [/1] Riboflavin 10.0 Time 13.6 12.0 24.1 * Universal [sec] (UQ70910171) Rotation 0 0 0 0 [rpm] Flowrate  44 g/min  50 g/min 25 g/min  0 g/min [/2] 1:1 Mix of 10.0 Time 5.5 5.8 13.6 * Ribo.Univ./ [sec] Amlodipine Rotation 0 0 0 0 Besylate [rpm] Flowrate 109 g/min 103 g/min 44 g/min  0 g/min [/3] Amlodipine 10.0 Time * * * * Besylate [sec] Rotation 0 0 0 0 [rpm] Flowrate  0 g/min  0 g/min  0 g/min  0 g/min [/4] 1:4 Mix of 10.0 Time 3.0 4.4 6.7 16.8 Ribo.Univ./ [sec] Amlodipine Rotation 0 0 0 0 Besylate [rpm] Flowrate 198 g/min 135 g/min 90 g/min 36 g/min * Powder does not flow

Example 2

[0064] Following the same methods as outlined in Example 1, the flowability of hydrochlorothiazide, a diuretic was measured with and without spray-dried riboflavin. Results are presented in Table 2, below.

TABLE-US-00002 TABLE 2 Product Weight (g) 10 mm 9 mm 7 mm 5 mm [/1] Hydrochlorothiazide 10.0 Time [sec] * * * * (2597487) Rotation 0 0 0 0 (rpm) Flowrate  0 g/min  0 g/min 0 g/min 0 g/min [/2] 1:1 Mix of 10.0 Time [sec] 4.3 5.2 * * Hydrochlorothiazide Rotation 0 0 0 0 (2597487)/ (rpm) B2 Universal Flowrate 138 g/min 115 g/min 0 g/min 0 g/min (UQ70910171) * Powder does not flow

Example 3

[0065] Following the same methods as outlined in Example 1, the flowability of enalapril, an ACE inhibitor was measured with and without spray-dried riboflavin. Results are presented in Table 3, below.

TABLE-US-00003 TABLE 3 Product Weight (g) 10 mm 9 mm 7 mm 5 mm [/1] Enalapril (maleate) 10.0 Time [sec] * * * * (0497851-2) Rotation 0 0 0 0 (rpm) Flowrate  0 g/min  0 g/min  0 g/min  0 g/min [/2] 1:1 Mix of B2 10.0 Time [sec] 6.3 6.7 11.8 57.8 Universal/Enalapril Rotation 0 0 0 0 (rpm) Flowrate 96 g/min 90 g/min 51 g/min 10 g/min [/3] 1:3 Mix of B2 10.0 Time [sec] 6.2 9.9 15.5 * Universal/Enalapril Rotation 0 0 0 0 (rpm) Flowrate 97 g/min 61 g/min 39 g/min  0 g/min * Powder does not flow

Example 4

[0066] Following the same methods as outlined in Example 1, the flowability of atenolol, a beta blocker was measured with and without spray-dried riboflavin. Results are presented in Table 4, below.

TABLE-US-00004 TABLE 4 Product Weight (g) 10 mm 9 mm 7 mm 5 mm [/1] Atenolol 10.0 Time [sec] * * * * (0514195-9) Rotation 0 0 0 0 (rpm) Flowrate  0 g/min  0 g/min  0 g/min 0 g/min [/2] 1:1 Mix of B2 10.0 Time [sec] 5.3 4.6 19.4 * Universal/Atenolol Rotation 0 0 0 0 (rpm) Flowrate 114 g/min 130 g/min 31 g/min 0 g/min [/3] 1:2 Mix of B2 10.0 Time [sec] 3.3 5.3 16.7 * Universal/Atenolol Rotation 0 0 0 0 (rpm) Flowrate 184 g/min 113 g/min 36 g/min 0 g/min * Powder does not flow

Example 5

Comparative Examples

[0067] Using methods as described above in Examples 1, 2, 3 and 4 crystals of various antihypertensive drugs were mixed with riboflavin. Results are presented below:

TABLE-US-00005 TABLE 5 Morphology vs flowability improvement Plate-shaped crystal Improved Flowability Compound morphology with Riboflavin Calcium Channel Inhibitors Amlodipine Besylate Yes YES Nifedipine Yes No Felodipine Yes YES Nitrendipine Yes No Angiotensin Receptor Blockers (ARB) Candesartan Cilexetil no no Olmesartan no no Valsartan no no Diuretics Hydrochlortiazide Yes YES Indapaminde yes No ACE inhibitors Enalapril Yes YES Beta-blockers Metoprolol Tartate No no Carvediol Yes no Atenolol Yes YES

Example 6

[0068] Compounds from Example 5 which showed improved flowability were further examined for particle size using the Malvern Morpho G3 instrument. “Vol.M.M” reflect the size of those particles which constitute the bulk of the sample volume. Particle sizes were measured and results are shown below. d(0.1) presents the diameter of 10% of all particles, d(0.5) is the diameter of 50% of all particles and d(0.9) presents the diameter of 90% of the particles in the sample.

Amlodipine besylate: [0069] d(0.1)=25 μm [0070] d(0.5)=72 μm [0071] d(0.9)=163 μm [0072] Vol.M.M d(4,3): 87 μm

Felodipine

[0073] d(0.1)=147 μm [0074] d(0.5)=320 μm [0075] d(0.9)=478 μm [0076] Vol.M.M d(4,3): 325 μm

Hydrochlortiazide

[0077] d(0.1)=123 μm [0078] d(0.5)=319 μm [0079] d(0.9)=551 μm [0080] Vol. M.M. d(4.3): 337 μm

Enalapril

[0081] d(0.1)=32 μm [0082] d(0.5)=129 μm [0083] d(0.9)=304 μm [0084] Vol.M.M. d(4,3): 157 μm

Atenolol

[0085] d(0.1)=36 μm [0086] d(0.5)=100 μm [0087] d(0.9)=218 μm [0088] Vol.M.M d(4,3): 117 μm

Riboflavin Universal

[0089] d(0.1)=44 μm [0090] d(0.5)=93 μm [0091] d(0.9)=172 μm [0092] Vol.M.M d(4,3): 106 μm

[0093] Results: all of the compounds where the percentage of the sum of the sphered/irregular sphered is at least 50% showed improved flowability. Amlodipine was 60%, felodipine was 65%, hydrochlorothiazide was 74%, enalapril was 78% and atenolol 53%. Riboflavin universal was 95%. On the other hand, if the percentage of the sum of the spheres/irregular spheres was less than 50%, then riboflavin did not improve flowability. This was observed for diltiazem 32%, nitrendipine 31%, Indapaminde 13% and Valsartan 39%.