Dosage form

Abstract

The present invention relates to a dosage form comprising at least one functionalized calcium carbonate-comprising material (FCC) and at least one hot melt extruded polymer resin, a method for producing same, a pharmaceutical, nutraceutical, cosmetic, home and personal care product comprising the dosage form and the uses thereof.

Claims

1. A carrier for a pharmaceutical, nutraceutical, cosmetic, home and personal care product dosage form consisting of a hot melt extruded composition of: a) at least one functionalized calcium carbonate-comprising material which is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H.sub.3O.sup.+ ion donors, wherein the carbon dioxide is formed in situ by the one or more H.sub.3O.sup.+ ion donors treatment and/or is supplied from an external source, and b) at least one polymer resin selected from the group comprising polyethylene, polystyrene, polyvinylchloride, polyamide 66 (nylon), polycaprolactame, polycaprolactone, acrylic polymers, acrylonitrile butadiene styrene, polybenzimidazole, polycarbonate, polyphenylene oxide/sulfide, polypopylene, teflon, polylactic acid, polylactic acid-based polymer, and aliphatic polyester, wherein the at least one functionalized calcium carbonate-comprising material is dispersed in the composition and the weight ratio of functionalized calcium carbonate-comprising material to polymer resin ranges from 95:5 to 5:95; wherein the carrier is a powder, tablets, mini-tablets, granules, pellets, capsules or tablet-in-cup and c) an optional active ingredient, wherein the active agent is i) loaded onto or mixed with the composition, ii) dispersed in the composition, iii) is in form of a core, which is at least partially covered by the composition, or iv) in form of a layer which at least partially covers a core, made from the composition, or e) in form of a layered structure of at least two layers, wherein at least one layer is made from the composition.

2. The carrier of claim 1, wherein the natural ground calcium carbonate is selected from calcium carbonate containing minerals selected from the group comprising marble, chalk, dolomite, limestone and mixtures thereof, or the precipitated calcium carbonate is selected from the group comprising precipitated calcium carbonates having aragonitic, vateritic or calcitic mineralogical crystal forms and mixtures thereof.

3. The carrier according to claim 1, wherein the at least one functionalized calcium carbonate-comprising material: a) has a BET specific surface area of from 20 m.sup.2/g to 450 m.sup.2/g measured using nitrogen and BET method according to ISO 9277; and/or b) comprises particles having a volume median grain diameter d.sub.50 (vol) of from 1 μm to 50 μm; and/or has an intra-particle intruded specific pore volume within a range of 0.15 to 1.35 cm.sup.3/g, calculated from a mercury intrusion porosimetry measurement.

4. A carrier for a pharmaceutical, nutraceutical, cosmetic, home and personal care product dosage form consisting of a hot melt extruded composition of: a) at least one functionalized calcium carbonate-comprising material which is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H.sub.3O.sup.+ ion donors, wherein the carbon dioxide is formed in situ by the one or more H.sub.3O.sup.+ ion donors treatment and/or is supplied from an external source, b) at least one polymer resin selected from the group comprising polyethylene, polystyrene, polyvinylchloride, polyamide 66 (nylon), polycaprolactame, polycaprolactone, acrylic polymers, acrylonitrile butadiene styrene, polybenzimidazole, polycarbonate, polyphenylene oxide/sulfide, polypopylene, teflon, polylactic acid, polylactic acid-based polymer, and aliphatic polyester, and c) an active agent and/or a prodrug thereof; wherein the at least one functionalized calcium carbonate-comprising material is dispersed in the composition and a weight ratio of functionalized calcium carbonate-comprising material to hot melt extruded polymer resin ranges from 95:5 to 5:95; wherein the carrier is in form of powder, tablets, mini-tablets, granules, pellets, capsules or tablet-in-cup.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 refers to the schematic representation of the TIC compaction.

(2) FIG. 2 refers to a scanning electron microscope picture of a granule.

(3) FIG. 3 refers to the Heckel plot of the FCC-PCL.

(4) FIG. 4 refers to the modified Heckel plot of the FCC-PCL

(5) FIG. 5 refers to the Leuenberger plot of the FCC-PCL.

(6) FIG. 6 refers to a scanning electron microscope picture of the tablet-in-cup (TIC).

EXAMPLES

(7) 1. Materials

(8) The core tablet consisted of 96% (m/m) metformin HCl (Harman Finochem Limited), 2% (m/m) polyvinylalcohol (PVA) and 2% (m/m) Carbopol 980 NF (Lubrizol, Advanced Materials, Belgium).

(9) Formulation for the cup consists of a 1:1 (m/m) mix of functionalized calcium carbonate (FCC) (Omya International AG, Switzerland, BET specific surface area of 62.8 m.sup.2/g, d.sub.50 of 11.7 μm, d.sub.98 of 26.7 μm) and polycaprolacton (Capa 6506, Perstorp UK Limited). Magnesium stearate (Sandoz, Switzerland) was used for lubrication.

(10) Kombiglyze® XR 5 mg/500 mg (Astra Zeneca, US) was taken as a reference.

(11) 2. Methods

(12) Scanning Electron Microscopy (SEM)

(13) Scanning electron microscopy (SEM) pictures were made with FEI Nova Nano SEM 230. The samples were sputtered with a 20-40 nm gold layer by a LEICA EM ACE600 Double Sputter coater.

(14) Preparation of the Core Tablet

(15) All excipients were sieved (<500 μm) and blended using the Turbula blender (T2C, W. A. Bachofer, Switzerland) with the speed 32 rpm for 10 min. This core formulation was compacted on Styl'One compaction simulator (Medel'pharm, France) with a 10 mm flat punch. Compaction cycle was defined with the following speed sections: Filling 2 sec, upper punch approach 1.5 sec, compaction 70 msec, relaxation 1.0 sec, ejection 5 sec and tablet selection 70 msec. Compaction force was set at 17 kN.

(16) Preparation of the Cup Formulation

(17) For the cup formulation hot melt granulation was carried out on a twin screw hot-melt extruder with perforated die (Three-Tec, ZE9 20602, Switzerland). The 5 heat cells were adjusted to following temperatures: Cell 1: 10° C., cell 2: 50° C. and cell 3, 4, 5 to 80° C. Feed rate was set between 3.1 g/in and 4.5 g/min. Twin screws were set at 100 rpm. The extruded product was cryo-milled with an IKA A11 (IKA, Germany) single-speed hand-mill with cut-tooling. The milled product was sieved through a 500 μm sieve. To analyze the cup formulation, a deformation profile was performed with 11.28 mm flat Euro D punch using compaction pressures from 50 MPa to 300 MPa.

(18) Preparation of the Tablet-in-Cup (TIC)

(19) The compaction of the TIC was carried out with a 13 mm beveled punch. Cycle was defined with following speed sections: Filling 2 sec, upper punch approach 10 sec, compaction 70 msec, relaxation 0.14 sec, ejection 70 msec and tablet selection 70 msec. Compaction force was set at 20 kN. Filling height was set at 9.2 mm, the core was placed centered on the lower punch and cup formulation (<500 μm) was filled in the die manually; see FIG. 1.

(20) Hardness Test

(21) The empty cups for hardness testing were produced the same way as the TIC-device but instead of a core tablet, a metal tablet was used as a template. After compaction the metal tablet was removed. Hardness testing (TIC n=6; core n=6, cup without core n=3) was carried out with Dr. Schleuniger Tablet Tester 8M (Switzerland).

(22) Compressability, Compactability, Dissolution and Friability

(23) Compressibility of the FCC-PCL composite was investigated using the Heckel equation (eq. 1) [R. Heckel, “Density-pressure relationships in powder compaction,” Trans. Metall. Soc. AIME, vol. 221, pp. 671-675, 1961]:

(24) $\begin{array}{cc}\ln \left(\frac{1}{1-\rho }\right)=k.Math.\sigma +A,& \left(\mathrm{eq}\mathrm{.1}\right)\end{array}$

(25) Where k is the Heckel parameter (MPa.sup.−1), σ is the compressive pressure (MPa), ρ is the density of the tablet (g/cm.sup.3) and A is a constant. Compressive stress was varied between 45 MPa and 295 MPa. Density of the tablet was calculated according to equation 2 [J. Ilkka and P. Paronen, “Prediction of the compression behaviour of powder mixtures by the Heckel equation,” Int. J. Pharm., vol. 94, no. 1-3, pp. 181-187, June 1993]:

(26) $\begin{array}{cc}\rho =\frac{\left(\frac{m}{\pi .Math.r^{2}h}\right)}{{\rho }_{\mathrm{true}}},& \left(\mathrm{eq}\mathrm{.2}\right)\end{array}$

(27) Where m is the mass of the tablet (g), r is the radius of the tablet (cm), h is the tablet height and ρ.sub.true is the true density of the material (g/cm.sup.3). The yield pressure was calculated by taking the reciprocal of the Heckel slope (eq. 3) [J. Ilkka and P. Paronen, “Prediction of the compression behaviour of powder mixtures by the Heckel equation,” Int. J. Pharm., vol. 94, no. 1-3, pp. 181-187, June 1993]

(28) $\begin{array}{cc}\left({\sigma }_y=\frac{1}{k}\right)& \left(\mathrm{eq}\mathrm{.3}\right)\end{array}$

(29) In order to investigate compaction susceptibility of the material, modified Heckel equation (eq. 4) was used [M. Kuentz and H. Leuenberger, “Pressure susceptibility of polymer tablets as a critical property: A modified heckel equation,” J. Pharm. Sci., vol. 88, no. 2, pp. 174-179, February 1999]:

(30) $\begin{array}{cc}\sigma =\frac{1}{C}\left[{\rho }_{\mathrm{ro}}-\rho -\left(1-{\rho }_{\mathrm{ro}}\right).Math.\ln \left(\frac{1-\rho }{1-{\rho }_{\mathrm{ro}}}\right)\right],& \left(\mathrm{eq}\mathrm{.4}\right)\end{array}$

(31) Where σ is the compressive pressure (MPa), C is a constant (MPa.sup.−1), ρ.sub.rc is the critical density (g/cm.sup.3) and ρ is the relative tablet density (g/cm.sup.3).

(32) Powder compactibility was investigated by plotting tensile strength as a function of compressive pressures [H. Leuenberger and B. D. Rohera, “Fundamentals of Powder Compression. I. The Compactibility and Compressibility of Pharmaceutical Powders,” Pharm. Res., vol. 3, no. 1, pp. 12-22, February 1986]. Tensile strengths were calculated according to equation 5 for round tablets and according to equation 6 for shaped tablets [“The United States Pharmacopoeia.,” [Online]. Available: http://www.drugfuture.com/pharmacopoeia/usp32/pub/data/v32270/usp32nf27s0_c1217.html]:

(33) $\begin{array}{cc}{\sigma }_t=\frac{2.Math.F}{\pi .Math.d.Math.h},& \left(\mathrm{eq}\mathrm{.5}\right)\\ {\sigma }_t=\frac{10.Math.F}{\pi D^2.Math.\left(2.04\frac{t}{D}-0.126\frac{t}{W}+3.15\frac{W}{D}+0.01\right)},& \left(\mathrm{eq}\mathrm{.6}\right)\end{array}$

(34) Where σ.sub.t is the tensile strength (MPa), F is the crushing force (N), d is the diameter (mm) of the round tablets and h the height of the round tablet (mm). For shaped tablet D is the tablet width, t is the tablet height and W is the shaft height (mm). Information about the deformation of the material under stress and the bonding properties of the material was assessed by calculating the factors compactibility and compression susceptibility using Leuenberger equation 7 [H. Leuenberger and B. D. Rohera, “Fundamentals of Powder Compression. I. The Compactibility and Compressibility of Pharmaceutical Powders,” Pharm. Res., vol. 3, no. 1, pp. 12-22, February 1986]:
σ.sub.t=σ.sub.t max.Math.(1−e.sup.(−γ.Math.σ.Math.ρ)).  (eq.7)

(35) Where σ.sub.t is the tensile strength, σ.sub.t max is the tensile strength when compressive pressure (σ).fwdarw.∞ and relative density (ρ).fwdarw.1, γ is the compression susceptibility and σ is the applied compressive pressure. Data from 50 MPa to 300 MPa were included in the calculation.

(36) Dissolution testing (TIC: n=6; Kombiglyze®XR: n=3, cores n=6) was carried out on SOTAX AT7 Smart (Sotax, Switzerland) connected to a UV-spectrometer (Amersham Biosciences, Ultraspec 3100pro, UK) with a Sotax CY 7-50 pump (Sotax, Switzerland). Dissolution profile was measured in water (37° C.), USP apparatus 2, 50 rpm over 24 hours for TIC and Kombiglyze®XR and 3 hours for the cores respectively. The spectrometer was set to 250 nm, concentration were calculated according the following equation 8:
y=0.0015x+0.0102, R.sup.2=0.9998  (eq.8)

(37) Friability (n=10) was tested by using Erweka TA200 (Erweka, Germany).

(38) F2 criterion was calculated according to the FDA [U.S. Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research (CDER), “Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage Forms.” August-1997] as set out in equation 9:

(39) $\begin{array}{cc}{f}_2=50.Math.\log \left\{{\left[1+\frac{1}{n}{\Sigma \left(R_t-T_t\right)}^2\right]}^{-0.2}.Math.100\right\},& \left(\mathrm{eq}\mathrm{.9}\right)\end{array}$

(40) where Rt is the drug release in % (m/m) at time t of the reference sample and Tt is the drug release in % (m/m) at time t of the test sample, n=146.

(41) Tensile Strength

(42) Tensile strength was calculated with equation 10:

(43) $\begin{array}{cc}{\sigma }_t=\frac{S\times F}{\pi \times d\times h}& \left(\mathrm{eq}\mathrm{.10}\right)\end{array}$

(44) where σ.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). Crushing forces were measured with a tablet hardness tester (8M, Dr. Schleuniger Pharmatron, Switzerland).

(45) 3. Results

(46) To produce the cup formulation, e.g. a FCC-PCL composite, first FCC and PCL were mixed and then hot melt granulation was carried out. During hot melt granulation, torque remained constant at 3.21±0.04 Nm. Temperatures of cell 3, cell 4 and cell 5 were 80.12±0.66° C., 80.02±2.31° C. and 80.20±3.01° C., respectively. Only the temperatures of cell 3 to 5 were taken into consideration as polymer melting is happening in these cells only. The production of the FCC-PCL composite used to form the cup did not pose problems.

(47) After granulation, the product was frozen, milled and sieved. FIG. 2 shows a SEM picture of the granules with the lamellar structure of FCC embedded in PCL. Only the granules with the size <500 μm were further used. The results of Heckel, modified Heckel and Leuenberger analysis are shown in Table 1. FIGS. 3, 4 and 5 show the Heckel plot, modified Heckel plot and Leuenberger plot.

(48) TABLE-US-00001 TABLE 1 Results for the FCC-PCL composite Values for FCC-PCL Parameters composite Heckel analysis k (10.sup.−3MPa.sup.−1) ± SD  2.65 ± 0.22 A ± SD  2.09 ± 0.04 σ.sub.y (MPa) 377.36 adj.R.sup.2  0.873 Modified Heckel analysis C (10.sup.−3MPa.sup.−1)  0.20 ± 0.14 ρ.sub.rc ± SD 0.847 ± 0.04 adj. R.sup.2  0.940 Leuenberger analysis σ.sub.max (MPa) ± SD  3.44 ± 0.07 γ (10.sup.−3MPa.sup.−1) 19.43 ± 1.11 adj.R.sup.2   0.870

(49) From Heckel analysis the value for σ.sub.y is 377.36 MPa. This value is comparable with the results in a previous study, where the FCC alone had a yield pressure of σ.sub.y=294 MPa [T. Stirnimann, S. Atria, J. Schoelkopf, P. A. C. Gane, R. Alles, J. Huwyler, and M. Puchkov, “Compaction of functionalized calcium carbonate, a porous and crystalline microparticulate material with a lamellar surface,” Int. J. Pharm., vol. 466, no. 1-2, pp. 266-275, May 2014]. The values are higher than reported in other studies, where plastically deforming material showed a yield pressure of 40-135 MPa [S. Jain, “Mechanical properties of powders for compaction and tableting: an overview,” Pharm. Sci. Technol. Today, vol. 2, no. 1, pp. 20-31, January 1999]. It is shown that FCC-PCL, at a relative density of ρ=0.843, forms a stable compact.

(50) From Leuenberger analysis the value for σ.sub.tmax yielded 3.44 MPa, which shows plastic behavior of the material. For γ a value of 19.43 10.sup.−3 MPa.sup.−1 was found. This value is high compared to the FCC investigated in the previous study and is significantly greater than the value for MCC (7.56*10.sup.−3 MPa.sup.−1) [T. Stimimann, S. Atria, J. Schoelkopf, P. A. C. Gane, R. Alles, J. Huwyler, and M. Puchkov, “Compaction of functionalized calcium carbonate, a porous and crystalline microparticulate material with a lamellar surface,” Int. J. Pharm., vol. 466, no. 1-2, pp. 266-275, May 2014]. Such value indicates additional bonding action of PCL polymer on FCC lamellae. High values of γ indicate plastic behavior and that at already low compressive pressures the maximal tensile strength can be reached. Both values, γ and σ.sub.tmax, show the good bonding properties of the material.

(51) The core tablets and cup material were compacted to form the TIC device. The parameters of the core tablets, which were subsequently compacted to the TIC device, are shown in Table 2. Resulting parameters of the TIC device (i.e., core compacted in the cup), are also shown in Table 2 along with measured parameters of a reference product (Kombiglyze® XR). During hardness testing of the TIC, core and cup were not falling apart. Separately, the hardness of the cup was assessed without core tablet and yielded 90.50±4.68 N.

(52) TABLE-US-00002 TABLE 2 Parameters of the core, TIC and reference Average Core TIC Reference Weight [mg] 517.46 ± 2.32 994.53 ± 5.67 1197.90 ± 9.87 Diameter [mm]  10.03 ± 0.00  13.06 ± 0.00   9.78 ± 0.02* |  19.60 ± 0.02.sup.# Height [mm]  5.36 ± 0.03  5.70 ± 0.03   7.20 ± 0.02 Hardness [N] 127.00 ± 8.63 261.33 ± 15.19  297.33 ± 45.83 Tensile  1.50 ± 0.11  2.24 ± 0.12   3.33 ± 0.05 strength [MPa] Volume [mm.sup.3] 423.49 ± 2.16 755.05 ± 4.01 985.7 Friability [%] —  0.00** — Drug load [%] 96.63 50.27  41.73 *width of oblong tablet, .sup.#length of oblong tablet, **no mass change was detected

(53) The flow of the cup material under compaction was excellent for both, slow (10 sec) and fast (70 msec) compaction cycles. In both cases the cup material distribution was homogeneous i.e. forming equally-sized cup walls, without cracks, ruptures or gaps. An example of a compacted cup is shown in FIG. 6.

(54) The release profiles of the reference (Kombiglyze®XR 5 mg/500 mg) and the TIC show that the release profile of the TIC is slightly slower than the profile of the reference. Showing a linear section between 200 min and 800 min. Standard deviation was not more than 1.33% (m/m) in the case of the reference and not more than 2.58% in the case of the TIC. The f2 test yielded a value of 78.60, hence the dissolution profiles can be considered as being identical.

(55) The parameters of the tablets show that the TIC is 203 mg lighter than the reference. Hence, drug load is 8.5% higher in the TIC compared to the reference. The TIC device is less voluminous (754.27±3.82 mm.sup.3) compared to the reference (985.7 mm.sup.3), which makes it easier to swallow. The amount of excipient to control the release was 20 mg; this is 2% (m/m) of the total mass of the TIC.

(56) During friability test no mass change was detected. The TIC devices are stable and showed no breakage or deformation, hence a coating is not required. The cup without core tablet was stable with a hardness of 90.50 N which is not surprising due to the values γ and σ.sub.tmax indicating good bonding at low compressive stresses. As shown in FIG. 6 the connection between core and cup is tight and hence no dose dumping can be expected. Friability was undetectable. This shows high stability of the cup and its ability to stabilize the core.

(57) Furthermore, it is to be noted that the FCC-PCL composite material is suitable for human consumption and biodegradable.