DIRECT COMPRESSION EXCIPIENT BASED ON LACTOSE, CELLULOSE AND STARCH

Abstract

The present invention relates to compositions comprising at least one lactose component, at least one cellulose component and at least one starch component, its preparation and its use, particularly as a direct tabletting excipient.

Claims

1. Agglomerate comprising at least one lactose component, at least one cellulose component and at least one starch component.

2. Agglomerate according to claim 1, wherein the lactose component is selected from anhydrous lactose and lactose monohydrate.

3. Agglomerate according to claim 1, wherein the cellulose component is selected from cellulose, microcrystalline cellulose (MCC) and powder cellulose; and cellulose derivatives, hypromellose (hydroxypropylmethylcellulose (HPMC)), hydroxypropylcellulose (HPC), hydroxyethyl cellulose (HEC), carboxymethylcellulose (CMC), carboxyethylcellulose (CEC), ethylcellulose (EC), hypromellosephthalate and salts thereof.

4. Agglomerate according to claim 1, wherein the starch component is selected from starch, native starch, and pregelatinized starch; and starch derivatives, particularly native starch.

5. Agglomerate according to claim 1, wherein the agglomerate consists of at least one lactose component, at least one cellulose component and at least one starch component.

6. Agglomerate according to claim 1, wherein the agglomerate is substantially free of a lubricant.

7. Agglomerate according to claim 1, having a total amount of water of less than 9% by weight, based on a total amount of the agglomerate.

8. Agglomerate according to claim 1, wherein the agglomerate is in the form of granules, having a mean particle size d.sub.50 of 5-500 μm.

9. Agglomerate according to claim 8, in the form of a homogeneous mixture of all components.

10. Agglomerate according to claim 1 further comprising at least one pharmaceutically active component and optionally further excipients, such as glidants, fillers, binders, antistatic agents, surfactants, humectants and lubricants.

11. Method for manufacturing an agglomerate according to claim 1 comprising the steps of (i) providing a solution or suspension comprising at least one lactose component, at least one cellulose component and at least one starch component in a liquid medium, and (ii) spraying the solution or suspension obtained in step (i) in an environment at an increased temperature, optionally at reduced pressure, thereby removing the liquid medium at least partially.

12. Method according to claim 11, wherein the liquid medium is selected from water, an organic solvent, and mixtures thereof.

13. Method according to claim 11, which is conducted in a spray dryer.

14. Use of an agglomerate according to claim 1 as an excipient in making oral dosage forms, as a tabletting excipient, or as a direct tabletting excipient.

15. Oral dosage form comprising an agglomerate according to claim 1, at least one pharmaceutically active component, and optionally further excipients.

16. Agglomerate according to claim 7, having a total amount of water of 0.001-5.5% by weight, based on the total amount of the agglomerate.

17. Agglomerate according to claim 8, wherein the agglomerate is in the form of granules having a mean particle size d.sub.50 of 50-250 μm.

18. Method according to claim 11, wherein the liquid medium is an organic solvent comprising ethanol, acetic acid, acetone, or a mixture thereof.

19. Use of an agglomerate according to claim 16 as an excipient in making oral dosage forms, as a tabletting excipient, or as a direct tabletting excipient.

20. Oral dosage form comprising an agglomerate according to claim 16, at least one pharmaceutically active component, and optionally further excipients.

Description

FIGURES

[0045] FIG. 1: Tablet hardness vs. compaction pressure: composition of the invention, MicroceLac and StarLac

[0046] FIG. 2: Disintegration time vs. tablet hardness: composition of the invention, MicroceLac and StarLac

[0047] FIG. 3: Disintegration time vs. compaction pressure: composition of the invention and physical mixtures

[0048] FIG. 4: Hardness vs. compaction pressure in paracetamol-containing tablet: composition of the invention, MicroceLac and StarLac

[0049] FIG. 5: Friability vs. compaction pressure in paracetamol-containing tablet: composition of the invention, MicroceLac and StarLac

[0050] FIG. 6: Disintegration time vs. tablet hardness in paracetamol-containing tablet: composition of the invention, MicroceLac and StarLac

[0051] FIG. 7: Paracetamol release vs. time: composition of the invention, MicroceLac and StarLac

[0052] FIG. 8: SEM-image of agglomerates of the invention

[0053] FIG. 9A + B: SEM-image of agglomerates according to Example 5

[0054] FIG. 9C: SEM-image of a physical mixture according to Example 5

[0055] FIG. 10: Tensile strength vs. compaction pressure at different mixing times

[0056] FIG. 11: Hardness vs. compaction force for composition 9 and PM9

EXAMPLES

[0057] Methods

[0058] Release times are determined using apparatus II (Erweka, Germany DT 808 LH). The tests take place in 1000 ml 0.01 HCl, 0.05 M phosphate buffer (pH 6.8) [produced according to the United States Pharmacopeial Convention (USP)] or acetate buffer (pH 4.5) [USP] at a rotation speed of 50 rpm. The quantitative measurement of the released active substance is carried out by means of UV spectroscopy.

[0059] Tablets were pressed on a Korsch apparatus EK 0 using punches having 7 mm (round), 8 mm (round) and 11 mm (round), providing tablets having a tablet weight of 150 mg, 240 mg or 500 mg, respectively.

[0060] Friability was tested according to Ph. Eur method on a Erweka friability tester.

[0061] Tablet hardness was tested with a Erweka TBH 425 tablet hardness tester.

Example 1

Tablets of the Invention

[0062] Composition 1 according to the invention was manufactured by spray-drying an aqueous suspension/solution (solid content: 40 wt.-%) containing lactose monohydrate, microcrystalline cellulose and native maize starch (see Table

[0063] 1) in a spray-drying apparatus under the following conditions: water evaporation 1500 kg/h, inlet air temperature 165° C. and 40 bar dispersion pressure with one component nozzles. The obtained aggregates of the invention were mixed with magnesium stearate and tablets (8 mm, round, 240 mg) were pressed on a Korsch EK 0 apparatus. The composition of the tablets is indicated in Table 1.

[0064] For comparison, tablets were prepared from MicroceLac® and StarLac® using magnesium stearate as additional lubricant in the same manner as described above.

[0065] The tablet hardness was determined in relation to the respective compaction pressure used during tablet preparation. From FIG. 1, it can clearly be observed that the tablet hardness of the composition of the invention is comparable to the tablet hardness of MicroceLac®. MicroceLac® is known to provide excellent compactability and hardness. On the other hand, the tablets were subjected to a disintegration test. FIG. 2 shows the results of the disintegration time versus tablet hardness. It can be seen that despite the high tablet hardness of the tablets of the invention (>175N), the disintegration time is still below 200 seconds and thus comparable to the StarLac tablets. StarLac® is known as an excipient for short tablet disintegration times. From the results above, it can be seen that the tablets of the present invention synergistically combine the desirous characteristics of StarLac® and MicroceLac®, resulting in tablets having ideal hardness at excellent short disintegration times.

TABLE-US-00001 TABLE 1 Composition of tablets according to Example 1 Compo- tablet sition 1 MicroceLac 1 StarLac 1 Composition of 99.5 — — invention [wt-%]: 70% lactose monohydrate, 20% microcrystalline cellulose, 10% native maize starch MicroceLac ® 100 [wt-%]: — 99.5 — 75% α-lactose monohydrate 25% microcrystalline cellulose StarLac ® [wt-%]: — — 99.5 85% α-lactose monohydrate 15% native maize starch magnesium stearate  0.5  0.5 0.5

[0066] Further compositions (compositions 2-4) were made under the conditions as described above. Tablets were pressed in the same manner as described above. The compositions and test results of the tablets are shown in Table 2.

TABLE-US-00002 TABLE 2 Compositions 2-3 Compo- Compo- sition 2 sition 3 80% lactose monohydrate 99.5 — 12.5% microcrystalline cellulose 7.5% native maize starch [wt-%] 60% lactose monohydrate — 99.5 25.5% microcrystalline cellulose 12.5% native maize starch [wt-%] magnesium stearate [wt.-%] 0.5 0.5 Tablet hardness [N] at 6 kN 70 170 compaction force 9 kN 93 249 13 kN  122 311 disintegration time (s) at 6 kN 26 48 compaction force 9 kN 22 178 13 kN  15 315

[0067] All tablets shown in Table 2 have good hardness at acceptable disintegration times.

[0068] FIG. 8 shows a representative SEM-image of an agglomerate of the compositions according to the invention. Also from the SEM image of complete and broken agglomerates it can be derived that the agglomerates represent a homogeneous mixture.

EXAMPLE 2

Physical Mixtures

[0069] In order to compare the tablets according to the invention with tablets produced from physical mixtures, tablets (7 mm, round, 150 mg) were pressed on a Korsch EKO apparatus. The physical mixtures were homogeneously mixed on a turbula blender, Willy A. Bachofen Maschinenfabrik, Muttenz, Swiss before tabletting. The composition of the tablets is shown in Table 3.

TABLE-US-00003 TABLE 3 Comparison of composition of the invention and physical mixtures Compo- Compo- sition 5 sition 6 PM 5 PM 6 composition of the invention: 99.5 96.5 — — 70% lactose monohydrate 20% microcrystalline cellulose 10% native maize starch [wt-%] lactose monohydrate [wt-%] — — 69.65 67.55 microcrystalline cellulose [wt-%] — — 19.9 19.3 native maize starch [wt-%] — — 9.95 9.65 magnesium stearate [wt-%]  0.5 0.5 0.5 0.5 sodium croscarmellose [wt-%] — 3 — 3

[0070] The disintegration times in water at 37° C. of the obtained tablets were determined. The data are illustrated in FIG. 3. FIG. 3 shows that the tablets of the present invention (compositions 5 and 6) in each case have significantly reduced disintegration time as compared to the tablets prepared from the physical mixture (PM).

EXAMPLE 3

Drug-containing Tablets

[0071] Paracetamol-containing tablets (11 mm, round, 500 mg) were prepared on a Korsch EK 0. The composition of the tablets is indicated in Table 4.

TABLE-US-00004 TABLE 4 Composition of drug-containing tablets Compo- sition 7 MicroceLac 7 StarLac 7 composition of the invention: 88 — — 70% lactose monohydrate 20% microcrystalline cellulose 10% native maize starch [wt-%] StarLac ® [wt-%] — — 88 MicroceLac ® [wt-%] — 88 — magensium stearate [wt-%] 1 1 1 Aerosil [wt-%] 1 1 1 paracetamol [wt-%] 10 10 10

[0072] The results in Example 1 also apply to the tablets of the invention containing an active ingredient such as paracetamol. As can be seen from FIGS. 4-7, the tablet hardness and friability of the tablets according to the invention are comparable to those of the MicroceLac tablet (which is known to have excellent hardness and friability characteristics) (FIGS. 4 and 5). On the other hand, however, the disintegration time of the tablets according to the invention is comparable to the disintegration rate of the StarLac tablet (which is known to have excellent disintegration characteristics) (FIG. 6). The release of paracetamol over time is indicated in FIG. 7. The graph shows the fastest release time for the tablets of the invention (composition 7) as compared to the reference tablets (MicroceLac 7 and StarLac 7). This release profile makes the compositions of the invention ideally suitable for immediate release applications.

EXAMPLE 4

Tablets with Higher Amounts of Active Agent

[0073] Tablets (11 mm, round, 500 mg) containing paracetamol (30%) as a pharmaceutically active component were prepared on a Korsch EKO apparatus. The composition of the tablets is indicated in Table 5.

TABLE-US-00005 TABLE 5 Tablets containing 30% of paracetamol Compo- sition 8 MicroceLac 8 StarLac 8 composition of the invention: 68.5 — — 70% lactose monohydrate 20% microcrystalline cellulose 10% native maize starch [wt-%] StarLac ® [wt-%] — — 68.5 MicroceLac ® [wt-%] — 68.5 — magnesium stearate 1 1 1 Aerosil [wt-%] 0.5 0.5 0.5 paracetamol [wt-%] 30 30 30 tablet hardness (N) at  7 kN 52 51 — compaction force [kN] 13 kN 90 104 — 19 kN 115 133 — Friability (%) at  7 kN 2.5 1.8 — compaction force [kN] 13 kN 0.5 0.2 — 19 kN 5.4 2.4 — disintegration  7 kN 0:44  2:04 — time [min] at 13 kN 0:44 25:32 — compaction force [kN] 19 kN 1:25 >60 —

[0074] While the StarLac 8 tablets have high and thus unacceptable friability at any compaction force, the results in Table 5 clearly show that the tablets according to the invention have an acceptable hardness (>90 N), acceptable friability (<1%) and acceptable short disintegration times (<1 min) at a compaction force of 13 kN. The tablets containing MicroceLac (MicroceLac 8) have an acceptable hardness (104 N). However, these tablets provide long and unacceptable disintegration times (>25 min).

EXAMPLE 5

Morphological Observations

[0075] In order to investigate the morphological properties, agglomerates according to the invention were made of 70% lactose monohydrate, 20% microcrystalline cellulose and 10% native maize starch. The agglomerate according to the invention was manufactured by spray-drying an aqueous suspension/solution (solid content 40 wt.-%) in a spray-drying apparatus under the following conditions: water evaporation 1,500 kg/h, inlet air temperature 165° C. and 40 bar dispersion pressure with one component nozzles (composition 9). For comparison, a physical mixture made of 70% spray-dried lactose monohydrate, 20% microcrystalline cellulose and 10% native maize starch was compounded in a turbula blender, Willy A. Bachofen Maschinenfabrik, Muttenz, Switzerland (PM9). The SEM-micrographs of the agglomerate according to the invention (FIG. 9A and B) and the physical mixture (FIG. 9C) are illustrated in the Figures. In the agglomerate according to the invention, all compounds together form homogeneous sphericals and cannot be separated by physical processes. Therefore, the predetermined concentration of the components in the composition can be ensured at any time during delivery. In the physical mixture, the components lactose, cellulose and starch are separated from each other (FIG. 9C). Due to the different sizes and characteristics of the compounds, at least a partial segregation of the components might occur, which makes it impossible to deliver several portions having the same composition.

EXAMPLE 6

[0076] In a further step, 0.5 wt.-% magnesium stearate were added to composition 9 and the physical mixture PM9 prepared in Example 5. Composition 9 and PM9, respectively, were mixed with magnesium stearate at different mixing times (0.5, 2.0 and 5.0 minutes). From the magnesium stearate containing compound 9 and the magnesium stearate containing physical mixture PM9, tablets were pressed on a Korsch EKO apparatus (8 mm, round, 240 mg). The tablets were compacted at different compaction pressures. In FIG. 10, the tensile strength is shown over the compaction pressure. The data show that the agglomerates according to the invention (composition 9) are far less sensitive to the mixing procedure than the physical mixture.

[0077] In FIG. 11, the tablet hardness is shown over the compaction force. The results evidence that the compressibility of tablets containing composition 9 is improved over tablets containing a physical mixture.

[0078] The following items further describe the present invention: [0079] 1. Composition comprising at least one lactose component, at least one cellulose component and at least one starch component. [0080] 2. Composition according to item 1, wherein the lactose component is selected from anhydrous lactose and lactose monohydrate. [0081] 3. Composition according to item 1 or 2, wherein the cellulose component is selected from cellulose, such as microcrystalline cellulose (MCC), and powder cellulose; and cellulose derivatives, such as hypromellose (hydroxypropylmethylcellulose (HPMC)), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), carboxy-ethylcellulose (CEC), ethylcellulose (EC), hypromellosephthalate, and salts thereof. [0082] 4. Composition according to any of items 1-3, wherein the starch component is selected from starch, such as native starch, pregelatinized starch and starch derivatives, particularly native starch. [0083] 5. Composition according to any of items 1-4, wherein the lactose component is present in an amount of 55-90% by weight, more preferably 60-90% by weight, more preferably 65-85% by weight, more preferably 65-75% by weight and even more preferably 68-72% by weight or 72-75% by weight, based on the total mass of the composition. [0084] 6. Composition according to any of items 1-5, wherein the cellulose component is present in an amount of 5-30% by weight, preferably 10-30% by weight, more preferably 15-25% by weight and even more preferably 19-22% by weight or 15-19% by weight, based on the total mass of the composition. [0085] 7. Composition according to any of items 1-6, wherein the starch component is present in an amount of 5-25% by weight, preferably 5-20% by weight, more preferably 8-13% by weight, and even more preferably 8-12% by weight or 11-13% by weight, based on the total mass of the composition. [0086] 8. Composition according to any of items 1-7, wherein the composition consists of at least one lactose component, at least one cellulose component and at least one starch component. [0087] 9. Composition according to any of items 1-8, wherein the composition consists of lactose monohydrate, microcrystalline cellulose and native starch. [0088] 10. Composition according to any of items 1-9, wherein the composition is substantially free of a lubricant. [0089] 11. Composition according to any of items 1-10 having a total amount of water of less than 9% by weight, preferably 0.001-8% by weight, more preferably 0.001-7% by weight, more preferably 0.001-6.5% by weight and even more preferably 0.001-5.5% by weight, based on the total amount of the composition. [0090] 12. Composition according to any of items 1-11 having a total amount of free water of less than 8% by weight, preferably 0.001-5% by weight, more preferably 0.001-3% by weight, based on the total amount of the composition. [0091] 13. Composition according to any of items 1-12, wherein the composition is in the form of agglomerates, such as granules, particularly having a mean particle size d.sub.50 of 5-500 μm, preferably 50-250 μm. [0092] 14. Composition according to item 13, wherein the agglomerate represents an homogeneous mixture of the components of the composition. [0093] 15. Composition according to any of items 13 or 14, wherein the agglomerate has a spherical morphology or a spheroidal morphology. [0094] 16. Composition according to any of items 1-15 further comprising at least one pharmaceutically active component and optionally further excipients. [0095] 17. Composition according to item 16, wherein the excipients are selected from the group consisting of glidants, fillers, binders, antistatic agents, surfactants, humectants and lubricants. [0096] 18. Method for manufacturing a composition according to any of items 1-17 comprising the steps of [0097] (i) providing a solution or suspension comprising at least one lactose component, at least one cellulose component and/or at least one starch component in a liquid medium, and [0098] (ii) spraying the solution or suspension obtained in step (i) in an environment at an increased temperature, optionally at reduced pressure, thereby removing the liquid medium at least partially. [0099] 19. Method according to item 18, wherein the liquid medium is selected from water, organic solvents such as ethanol, acetic acid and acetone, and mixtures thereof. [0100] 20. Method according to any of items 18 or 19, wherein the total amount of lactose component, cellulose component and/or starch component is in the range of between 5 and 60% by weight, preferably 30-50% by weight, based on the total amount of the solution or suspension. [0101] 21. Method according to any of items 18-20, wherein the temperature in step (ii) is in the range of 30-300° C., preferably about 50-250° C. [0102] 22. Method according to any of items 18-21, wherein spraying in step (ii) is performed through nozzles, particularly one-substance or two-substance nozzles. [0103] 23. Method according to any of items 18-22, wherein the pressure in step (ii) is in the range of 0 to 1.0 bar, preferably 0 to 0.5 bar, more preferably 0.003 to 0.4 bar. [0104] 24. Method according to any of items 18-23 which is conducted in a spray dryer. [0105] 25. Method according to any of items 18-24, wherein step (ii) is conducted in the presence of particles of at least one of the cellulose component, the starch component or the lactose component. [0106] 26. Method according to item 25 which is conducted in a fluid bed granulator. [0107] 27. Use of a composition according to any of claims 1-17 as an excipient in making oral dosage forms, particularly as a tabletting excipient, more particularly as a direct tabletting excipient. [0108] 28. Use of the composition according to any of claims 1-17 in cosmetics, cleaning applications or engineering. [0109] 29. Oral dosage form comprising a composition according to any of claims 1-17, at least one pharmaceutically active component, and optionally further excipients. [0110] 30. Oral dosage form according to claim 29 for immediate release. [0111] 31. Oral dosage form according to any of claim 29 or 30, which is a tablet, a capsule, a sachet or a granulate.