Dispersible dosage form

Abstract

The present invention provides for method of improving flowability and loose bulk density of functionalized natural- and/or synthetic calcium carbonate comprising material, to the use of such improved material in ready to use granules and thereof produced dispersible dosage forms.

Claims

1. A method for producing a dispersible dosage form, comprising the steps of: a) providing a functionalized calcium carbonate-comprising material, which is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more acids in an aqueous medium, wherein the carbon dioxide is formed in situ by the acid treatment and/or is supplied from an external source; b) providing at least one disintegrant; c) optionally providing at least one further formulating aid; d) mixing the functionalised calcium carbonate-comprising material of step a), the at least one disintegrant of step b) and the optionally at least one further formulating aid of step c); e) compacting the mixture obtained in step d) by means of a roller compactor at a compaction pressure in the range from 200 to 2000 kPa (2 to 20 bar) into a ribbon; f) milling the ribbon of step e) into granules; and g) sieving the granules of step f) by at least one mesh size; wherein the functionalised calcium carbonate-comprising material provided in step a) has an intra-particle intruded specific pore volume within the range of 0.15 to 1.35 cm.sup.3/g, calculated according to the mercury intrusion porosimetry measurement.

2. The method of claim 1, further comprising a step b1) of providing at least one active ingredient or inactive precursor or both between step b), and step c) or step d).

3. The method of claim 1, further comprising a step d1) of providing at least one lubricant after step d) and mixing the mixture of step d) with the at least one lubricant of step d1) in a mixing step d2) prior to the compacting step e).

4. The method of claim 2, further comprising a step d1) of providing at least one lubricant after step d) and mixing the mixture of step d) with the at least one lubricant of step d1) in a mixing step d2) prior to the compacting step e).

5. The method of claim 1, further comprising a step h) of providing at least one active ingredient and/or inactive precursor and optionally a step i) of providing further additives, and mixing the granules of step f) with the at least one active ingredient and/or inactive precursor of step g) and the optionally provided further additives of step h).

6. The method of claim 1, further comprising a final step j) of tableting the material obtained in the last step.

7. The method according to claim 1, wherein the natural ground calcium carbonate is selected from calcium carbonate comprising minerals selected from the group consisting of marble, chalk, limestone, dolomite and any mixture thereof; and the precipitated calcium carbonate is selected from the group of precipitated calcium carbonate having aragonitic, vateritic, or calcitic mineralogical crystal forms, and any mixture thereof.

8. The method of claim 1, wherein the functionalized calcium carbonate-comprising material is a reaction product of natural ground calcium carbonate with carbon dioxide and phosphoric acid in an aqueous medium, wherein the carbon dioxide is formed in situ by the acid treatment and/or is supplied from an external source.

9. The method according to claim 1, wherein the functionalised calcium carbonate-comprising material has a BET specific surface area of from 20 m.sup.2/g to 450 m.sup.2/g, measured using the nitrogen and BET method according to ISO 9277.

10. The method according to claim 1, wherein the functionalised calcium carbonate-comprising material has a BET specific surface area of from 20 m.sup.2/g to 140 m.sup.2/g, measured using the nitrogen and BET method according to ISO 9277.

11. The method according to claim 1, wherein the functionalised calcium carbonate-comprising material comprises particles having a volume median grain diameter d.sub.50 of from 2 m to 50 m.

12. The method according to claim 1, wherein the functionalised calcium carbonate-comprising material comprises particles having a volume median grain diameter d.sub.50 of from 1 m to 35 m.

13. The method according to claim 1, wherein the functionalised calcium carbonate-comprising material has an intra-particle intruded specific pore volume within the range of 0.30 to 1.30 cm.sup.3/g, calculated according to the mercury intrusion porosimetry measurement.

14. The method according to claim 1, wherein the functionalised calcium carbonate-comprising material has an intra-particle intruded specific pore volume within the range of 0.40 to 1.25 cm.sup.3/g, calculated according to the mercury intrusion porosimetry, measurement.

15. The method according to claim 1, wherein the granules have a flowability from 1.36 g/s to 5.75 g/s when compacted at 1000 kPa (10 bar) and sieved with mesh sizes of 180 m, 250 m, 355 m, 500 m, and 710 m, and the granules with size less than 180 m and more than 710 m were excluded, when measured according to European Pharmacopeia, 7.sup.th Ed Strassbourg (France): Council of Europe 2011, at an opening diameter from 5 min to 9 mm.

16. The method according to claim 1, wherein the granules have a loose bulk density of 0.65 g/cm.sup.3 when compacted at 1000 kPa (10 bar) and sieved with mesh sizes of 180 m, 250 m, 355 m, 500 m, and 710 m, and the granules with size less than 180 m and more than 710 m were excluded.

17. The method according to claim 1, wherein the at least one disintegrant is selected form the group consisting of modified cellulose gums, insoluble cross-linked polyvinylpyrrolidones, starch glycolates, micro crystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, homopolymers of N-vinyl-2-pyrrolidone, alkyl-, hydroxyalkyl-, carboxyalkyl-cellulose esters, alginates, microcrystalline cellulose and its polymorphic forms, ion exchange resins, gums, chitin, chitosan, clays, gellan gum, crosslinked polacrillin copolymers, agar, gelatine, dextrines, acrylic acid polymers, carboxymethylcellulose sodium/calcium, hydroxypropyl methyl cellulose phthalate, shellac, and any mixture thereof.

18. The method according to claim 1, wherein the at least one disintegrant is a modified cellulose gum.

19. The method according to claim 1, wherein the at least formulating aid is at least one inner-phase lubricant and/or outer-phase lubricant; and is provided in a total amount from 0.1 wt.-% to 10.0 wt.-%, based on the total weight of the functionalized calcium carbonate-comprising material of step a).

20. The method according to claim 1, wherein the at least formulating aid is at least one inner-phase lubricant and/or outer-phase lubricant; and is provided in a total amount from 0.3 wt.-% to 5.0 wt.-%, based on the total weight of the functionalized calcium carbonate-comprising material of step a).

Description

(1) FIG. 1: Particle size distribution of granules after compaction and sieving

(2) FIG. 2: shows a mercury porosimetry plot of the pore size distribution of FCC powder and roller compacted FCC granules. During the roller compaction process, FCC particles slipped closer together until the surfaces of different particles were in contact. This process of rearrangement and bonding during roller compaction is reflected in the porosimetry plot. Due to this densification of the powder bed, the high peak of FCC powder at a diameter of 1-10 m was reduced dramatically and at the same time shifted to a smaller pore diameter. Nevertheless, the mercury porosimetry plot showed as well that the intraparticle structure of FCC can withstand the pressure during roller compaction and remains intact.

(3) FIG. 3: SEM pictures of FCC. Figures a) and b) show the surface of the granules, whereas Figure c) and d) show a cross-section through a FCC granule.

EXAMPLES

(4) Materials and Methods

(5) Functionalized calcium carbonate (FCC), Omya International AG, Switzerland) was used as a filler. Modified cellulose gum (Ac-Di-Sol, FMC, USA) was used as a disintegrant. Magnesium stearate (Novartis, Switzerland) was used as a lubricant for tableting.

(6) Methods

(7) Roller Compaction and Milling

(8) Before roller compaction, FCC was blended with 3% (w/w) of disintegrant. Therefore, FCC and the disintegrant were mixed for 10 min in a tumbling mixer (Turbula T2C, Willy A. Bachofen AG, Switzerland) at 32 rpm. Roller compaction was performed with a Fitzpatrick Chilsonator IR220 roller compactor (The Fitzpatrick Company, USA) at a pressure of 10 bar. The feed rate and the roll speed were adjusted to obtain a ribbon thickness of 0.6 mm. The obtained ribbons were milled into granules with a FitzMill L1A (The Fitzpatrick Company, USA) at 300 rpm.

(9) Granule Analysis

(10) A vibrating sieve tower was used to analyze the particle size distribution. 100 g of granules were put on steel wire screens (Vibro Retsch, Germany) with mesh sizes of 180 m, 250 m, 355 m, 500 m, and 710 m and the sieving tower was shaken for 10 minutes at a shaking displacement of 1.5 mm. The amount of powder remaining on each sieve was weighted, whereas granules with a size of less than 180 m or more than 710 m were excluded for further processing.

(11) The particle size distribution of FCC granules with 3% (w/w) of disintegrant thus obtained showed that the mixture mainly contained coarse granules as shown in FIG. 1.

(12) Flowability of selected granular fraction (from 180 m to 710 m) was measured according to European Pharmacopeia, 7.sup.th Ed Strassbourg (France): Council of Europe 2011. A Mettler PM460 balance (Mettler Toledo, Switzerland) and a funnel with three different openings (5 mm, 7 mm, and 9 mm) were used to measure the flowability.

(13) Loose Bulk Density

(14) 120 g of the granules of selected granular fraction (from 180 m to 710 m) were sieved through a 0.5 mm screen by means of a brush. 1000.5 g of this sample were carefully filled through a powder funnel into the 250 mL measuring cylinder and the volume was read off to the nearest 1 mL. The loose bulk density was the calculated according the formula:
Loose bulk density [g/mL]=bulk volume [mL]/weighed sample [g]

(15) and the result was recorded to the nearest 0.01 g/mL.

(16) BET Specific Surface Area of a Material

(17) The BET specific surface area was measured via the BET process according to ISO 9277 using nitrogen, following conditioning of the sample by heating at 250 C. for a period of 30 minutes. Prior to such measurements, the sample was filtered, rinsed and dried at 110 C. in an oven for at least 12 hours.

(18) Pore size distribution was measured with a Micromeritics Autopore V 9620 mercury porosimeter. This porosimeter has a maximum applied pressure of mercury 414 MPa (60,000 psia) which is equivalent to a pore diameter of 0.004 m (4 nm). Equilibration time used at each pressure was 20 seconds. This instrument can measure pore diameters over the 0.004 m-1100 m range.

(19) Mercury porosimetry is based on the physical principle that a non-reactive, non-wetting liquid will not penetrate pores until sufficient pressure is applied to force its entrance. The relationship between the applied pressure and the pore size into which mercury will intrude is given by the Young-Laplace equation:

(20) $D=\frac{-4\cos }{P}$

(21) where P is the applied pressure, D is the diameter, is the surface tension of mercury (480 dyne cm.sup.1 (0.48 Nm.sup.1)) and is the contact angle between mercury and the pore wall, usually taken to be 140. The required pressure is inversely proportional to the size of the pores, only slight pressure being required to intrude mercury into large macropores, whereas much greater pressures are required to force mercury into micropores.

(22) All results were corrected using the software Pore-Comp for mercury and penetrometer effects and also for sample skeletal compression (Gane, P. A. C., Kettle, J. P., Matthews, G. P. and Ridgway C. J. (1996): Void space structure of compressible polymer spheres and consolidated calcium carbonate paper-coating formulations, Industrial & Engineering Chemistry Research Journal 35 (5), 1753-1764.)

(23) Tablet Preparation

(24) All granules with a size between 180 m and 710 m were used for tableting. Prior to the compaction, the granules were mixed in a tumbling mixer (Turbula T2C, Willy A. Bachofen AG, Switzerland) for 10 minutes at 32 rpm. The granules were compressed with a 11.28 mm round, flat tooling, using a Styl'One 105 mL tablet press (Medel'Pharm, France). The tablet press was instrumented with the Analis software version 2.01 (Medel'Pharm, France). A tablet with a weight of 500 mg and a hardness of 100 N was compacted out of the selected granule fraction. The resulting setting for the punch gap was kept constant over the whole compressive pressure range, ranging from 52 MPa to 116 MPa. Punches and die were manually lubricated with magnesium stearate.

(25) Tablet Analysis (Weight, Diameter, Height, Crushing Force, Tensile Strength, and Disintegration)

(26) Tablet weight, diameter, height, and crushing force were measured directly after tablet compression. Weight was determined with a Delta Range AX204 balance (Mettler Toledo, Switzerland). Diameter and height were measured with a micrometer screw of type CD-15CPX (Mitutoyo, Japan). Crushing forces were measured with a tablet hardness tester (8M, Dr. Schleuniger Pharmatron, Switzerland).

(27) Tensile strength was calculated with equation (1):

(28) $\begin{array}{cc}{}_t=\frac{2*F}{n*d*h}& \left(1\right)\end{array}$
where .sub.t is the radial tensile strength (MPa), F is the crushing force (N), d is the tablet diameter (mm), and h is the tablet thickness (mm).

(29) The disintegration and dispersion kinetics of the tablets were measured with a tensiometer (Krss Processor Tensiometer K100MK2, Germany) according to the method described by Stimimann T, Maiuta N D, Gerard D E, Alles R, Huwyler J, Puchkov M. Functionalized Calcium Carbonate as a Novel Pharmaceutical Excipient for the Preparation of Orally Dispersible Tablets. Pharm Res. 1 Jul. 2013; 30(7):1915-25, or this study we used distilled water at room temperature as a dispersion media.