SOLID PARTICLES CONTAINING SOLID PRIMARY PARTICLES THAT CONSIST ESSENTIALLY OF NATIVE CELLULOSE

Abstract

The invention relates to solid particles containing solid primary particles that consist essentially of native cellulose and optionally a binder, to the production and use thereof.

Claims

1. Solid particles having an average particle size from 15 μm to 2000 μm, comprising: solid primary particles, wherein the solid primary particles have an average particle size from 3 μm to 20 μm with at least 95% by weight of native cellulose obtained from plant fibres; and at least one binder.

2. The particles according to claim 1, which are spray-dried particles, granulated particles, or compacted particles.

3. The particles according to claim 1, which are spray-dried particles having an average particle size from 15 μm to 250 μm.

4. The particles according to claim 1, which are granulated particles having an average particle size from 200 μm to 450 μm.

5. The particles according to claim 1, which are compacted particles having an average particle size from 200 μm to 2000 μm.

6. The particles according to claim 1, wherein the solid primary particles contained therein have a maximum solubility in water at pH 7.0, 20° C. and 1 bar from 0 g/L to 0.5 g/L.

7. The particles according to claim 1, which have a bulk density of 100-300 g/L.

8. The particles according to claim 1, wherein the native cellulose obtained from plant fibres has a crystallinity factor from 40 to 90%.

9. The particles according to claim 1, wherein the native cellulose obtained from plant fibres has an average degree of polymerization of 1 to 50 000.

10. The particles according to claim 1, wherein the native cellulose obtained from plant fibres has a type 1 cellulose content in the crystalline fraction of greater than 95% by weight based on the total crystallinity.

11. The particles according to claim 1, wherein the particles are spray-dried particles having an average particle size from 120 μm to 180 μm, and wherein the primary particles contained therein have an average particle size from 3 μm to 15 μm.

12. The particles according to claim 1, wherein the binder is at least one selected from the group consisting of guar, alginic acid, alginate, dextrin, carbomer, maltodextrin, methyl cellulose, ethyl cellulose, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, cottonseed oil, povidone, ceratonia, dextrose, polydextrose, starch, gelatin, pregelatinized starch, hydrogenated vegetable oil, maltodextrin, microcrystalline cellulose, polyethylene oxide, polymethacrylates, and cellulose fibres.

13. A method for producing solid particles having an average particle size from 15 μm to 2000 μm, comprising: adding a liquid and a binder to solid primary particles having an average particle size from 3 μm to 20 μm that comprise at least 95% by weight of native cellulose obtained from plant fibres; and agglomerating the primary particles by granulating, compacting, or spray drying.

14. The method according to claim 13, wherein the solid particles have an average particle size from 200 μm to 450 μm, and wherein the agglomeration is carried out by granulation.

15. The method according to claim 13, wherein the binder dissolved in the liquid is added dropwise to the primary particles or is fed in via a nozzle.

16. The method according to claim 14, further comprising: drying the particles in a temperature range from 60° C. to 140° C.

17. The method according to claim 13, wherein the solid particles have an average particle size from 200 μm to 2000 μm, and wherein the agglomeration is carried out by compaction.

18. The method according to claim 17, wherein the compaction is carried out using a roller compactor.

19. Particles obtained by the method according to claim 13.

20. A method of absorption in an aqueous medium, comprising: contacting the particle according to claim 1, with at least one substance selected from the group consisting of flavourings, cosmetics, and pharmaceutical active substances.

Description

[0092] The following figures form part of the examples:

[0093] FIG. 1: Spray-dried particles comprising solid primary particles having an average particle size of 9 μm (inventive)

[0094] FIG. 2: Spray-dried particles comprising solid primary particles having an average particle size of 2 μm (non-inventive)

EXAMPLES

Example 1: Oil Absorption and Flowability

[0095] Spray-dried particles were produced as described below from commercially available native cellulose obtained from plant fibres:

Spray Drying:

[0096] The suspension of the cellulose primary particles in water (5-25% by weight of cellulose) was prepared using a disperser and optionally mixed with a binder solution for 30 minutes using an overhead stirrer. Three different spray-drying processes were used:

[0097] a) This dispersion was then conveyed to the spray dryer (Niro Minor from GEA®-evaporation capacity: 6 kg.sub.H2O/h) by means of a peristaltic pump (2.5 kg/h) and atomized using a two-component nozzle (atomizing gas: nitrogen—0.5 bar). Hot nitrogen (50 Nm.sup.3/h, T.sub.in=240° C., cocurrent) was used as the drying gas. The particles were separated and collected in a cyclone.

[0098] b) This dispersion was then conveyed to the spray dryer (evaporation capacity: 120 kg.sub.H2O/h) by means of an eccentric screw pump (25 kg/h) and atomized using a rotary atomizer (speed of rotation: 33 Hz). Hot nitrogen (400 Nm.sup.3/h, T.sub.in=200° C., cocurrent) was used as the drying gas. The particles were separated and collected in a cyclone.

[0099] c) This dispersion was then conveyed to the spray dryer (evaporation capacity: 1200 kg.sub.H2O/h) by means of a high-pressure pump (2000 kg/h) and atomized through a plurality of pressure nozzles (2.29 mm/40 bar). Hot nitrogen (air inflow speed: 8 m/s, T.sub.in=200° C., cocurrent) was used as the drying gas. The particles were dried further with hot air in a fluidized bed (T.sub.in=60° C.).

[0100] If binder (methyl cellulose (MC) or gum arabic (GA)) was used, an aqueous composition thereof was first prepared: Powdered binder was added at a temperature of 80° C., with stirring, to the same amount of water as is present in the cellulose dispersion to be incorporated. After 20 minutes, as soon as the binder had become finely dispersed, the same amount of water, which had a temperature of 20° C., was again added and the composition was cooled to 0-5° C. with stirring. Stirring was continued for a further 40 minutes until the binder had dissolved completely.

[0101] In the size range of the primary particles according to the invention, Tego® Feel Green and Diacel 10 and Diacel 90 were used; below the range according to the invention, finely milled Tego® Feel Green was used as the primary particles and above the claimed range Tego® C10 was used. In products 2 and 5 (Table 2), methyl cellulose was added as an additional binder. In products 6 and 7 (Table 2), gum arabic was added as an additional binder.

Determination of Oil Absorption

[0102] Predrying the carrier material: Weigh 1.5 g of the carrier substance (cellulose) into a 100 ml screw-cap laboratory bottle and dry uncapped overnight in a vacuum drying cabinet (45° C., 20 mbar). If necessary, close the mouth with a paper towel and a rubber band to prevent loss of material when switching on the vacuum.

[0103] Loading the carrier material: After this, load the dried samples with the 3 g of oil (limonene) and mix well with a spatula. Ensure as far as possible that too much mixture does not stick to the spatula. Screw the cap on the bottle and allow to stand for approx. 3 hours.

[0104] Centrifugation: Fold 5 round filters (Ø5.5 cm) into a funnel shape and insert into a 50 ml Falcon tube. Weigh 3 g of the cellulose-oil mixture into the Falcon tube, making sure that the mixture is unable to bypass the filter by running down the side and that it does not stick to the side of the Falcon tube. Centrifuge the filled Falcon tube (Hettich Rotina 380R centrifuge, rotor radius: 14.8 cm/4300 rpm/duration: 6 min).

[0105] Weighing the filter cake: Determine the empty weight of a suitable glass dish (as small as possible, since oversized dishes result in inaccurate weight measurements on the analytical balance). Place the entire filter cake in the glass bowl, break it up a little with the spatula and weigh it.

[0106] Drying the filter cake: After this, dry the filled glass dish in the vacuum drying cabinet for at least 12 hours (45° C., 20 mbar) and then reweigh (again covering the glass dish with a paper towel and a rubber band). From the difference in weight before and after drying, determine the loading of the carrier with oil prior to drying.

Determination of Angle of Repose

[0107] The angle of repose was measured in accordance with ISO 4324.

Determination of Flowability

[0108] The flowability of the carrier substances was determined with the aid of a series of glass funnels having different outlet openings. For the test, the funnels are held in place with a holder above a collecting vessel. To cover the funnel opening, a playing card is clamped between the funnel and the vessel. The funnel is filled with the carrier substance to a height two cm below the upper edge of the funnel. The card is then removed and the powder runout is assessed on the basis of the following scale.

TABLE-US-00001 TABLE 1 Properties of cellulose primary particles. Runout from funnel Rating of d [mm]* Flowability 1 2.5 very good 2 5.0 3 8.0 4 12.0 5 18.0 6 24.0 poor 7 — no runout from 6 Stability of d50 of the Flowability Oil absorption the primary primary of the capacity particles; Bulk particles primary g oil/g primary fines fraction/ density Primary particles in μm particles particles abrasion in % in g/L 1: Tego ® Feel 8.75 7 1.2 93 183 Green 2: Diacel 10 9.0 7 1.1 — 200 3: Diacel 90 38 7 — — 224 4: Milled Tego ® 3 / / / / Feel Green (aqueous (aqueous (aqueous (aqueous suspension) suspension) suspension) suspension) 5: Tego ® C10 44 7 1.2 — 252 6: Microcrystalline 150 7 0.4 49 345 cellulose (MCC) *Sample runs out smoothly with a single tap; if this occurs only after 2-4 taps, a rating of +0.5 is given. “—” not determined; “/” measurement not possible

[0109] The primary particles 1-5 (Tab. 1) consist of at least 95% by weight of native cellulose obtained from plant fibres.

TABLE-US-00002 TABLE 2a Results for the production of cellulose particles. d50 of Flowability of Oil-absorption Bulk Angle of Spray-drying particles spray-dried capacity density repose Spray-dried product process in μm products g oil/g particles in g/L in ° 1: Diacel 10 a) 50 1.31 242 40 2*: Diacel 10 with 10% a) 66 1.2 253 30 by weight MC 3: Milled Tego ® Feel a) 18 0.7 596 — Green 4: Tego ® C10 no particles formed 5*: Tego ® Feel Green a) 62 4 1.37 235 — with 10% by weight MC 6*: Diacel 10/Diacel 90 b) 187 1 1.0 280 30 (90:10% by weight) + 10% by weight GA 7*: Diacel 10 + 10% b) 182 1 1.0 300 30 by weight GA “—” not determined; “/” measurement not possible; “*” inventive

TABLE-US-00003 TABLE 2b Results for the production of cellulose particles. Flowability Oil absorption d50 of of capacity Bulk Angle of Spray-dried Spray-drying particles spray-dried g oil/g density repose product process in μm products particles in g/L in ° 8: Emcocel — 216 2 0.8 200-370 No flow LP200 (MCC) 9: Emcocell 90M — 112 5 0.9 250-370 37 (MCC) 10: Vivapur 200 — 218 5 0.7 310-370 34 (MCC) 11: Vivapur 12 — 140 5 0.8 300-360 37 (MCC) 12:Vitacel CS — 308 2 0.5 370 — 250G (cellulose) 13: Sanacel — 59 7 1.1 — 53 pharma 150 (cellulose) “—” not determined; “/” measurement not poossible; “*” inventive

[0110] It is immediately evident from the results listed in Table 2 that the spray drying of primary particles in the size range according to the invention results in particles having increased oil absorption capacity. If the primary particles are too small, the oil absorption capacity is low; if they are too large, no flowable particles are obtained.

[0111] The inclusion of binders such as methyl cellulose or gum arabic increases the mechanical stability of the particles, characterized by reduced fines formation.

Example 2: Absorption and Desorption of Pharmaceutical Active Substances

[0112] 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-pyrazol-1-yl]benzenesulfonamide (celecoxib, Aarti Drugs Ltd., Mumbai, India) was loaded on various cellulose preparations.

[0113] The active substance celecoxib was incorporated in a mixture of different components consisting of Miglyol® 812, Tween® 80, Gelucire® 44/14 and D-α-tocopherol polyethylene glycol 1000 succinate (d-TPGS).

[0114] The cellulose, MCC and silica preparations are loaded with the latter oily formulation, which contains celecoxib.

[0115] Desorption was investigated with 25 mg or an equivalent amount of celecoxib in a USP Apparatus II (Pharma Test PWTS 1210) in 500 ml of 0.1 N HCl at 100 rpm and 37±0.5° C. (HPLC (Agilent 1260 Infinity), HPLC pump (G1311B), autosampler (G1329B), column oven (G1316A) and UV detector (G1314C), from Agilent Technologies (USA), Knauer Nucleosil 100-7 C18 (125×4.6 mm, 7 μm) column, 40° C., mobile phase acetonitrile:water:trimethylamine mixture (300:300:0.9 v/v), adjusted to pH 3.00 with phosphoric acid, flow rate 1.8 ml/min, injected volume 5 μl, celecoxib measured at 254 nm, limit of quantitation 0.05 μg/ml, run time 7 min).

[0116] The products 1, 2, 3 and 4 (Table 3) were produced by spray-drying process a), and products 9 and 10 (Table 3) by spray-drying process c), of example 1. Product 5 (Table 3) was produced using the process of the invention, by process step C) granulation in an intensive mixer (Eirich model ELS Eco). This was done by charging the mixer bowl with Tego® 010 cellulose fibres and adding the starch adhesive solution via a nozzle. Mixing was then continued for a certain period. The granules were dried overnight in an air-circulation oven at 100° C. and finally graded through sieves. The target fraction was initially set at 200-410 μm. The starch adhesive solution was prepared by adding 125 g of cornstarch to 500 ml of hot water (90-95° C.) with vigorous stirring. The temperature was maintained for 15 min to achieve gelatinization of the starch.

TABLE-US-00004 TABLE 3a Results for the production of cellulose particles. Release in Spray- d50 of Loading Release Release Release g.sub.formulation/ drying particles g.sub.formulation/ in % after in % after in % after g.sub.carrier process in μm g.sub.carrier 5 min 10 min 15 min after 5 min 1: Diacel 10 a) 14 1.15 82 91 95 0.94 2*: Diacel 10 + a) 16 1.23 80 88 95 0.98 9% by weight MC 3*: Diacel 10 + a) 18 1.26 88 98 100 1.11 17% by weight MC 4*: Diacel 10 + a) 19 1.26 80 93 96 1.01 23% by weight MC 5*: Tego ® Feel Granulation 300 1.29 83 89 90 1.07 Green + 6% by weight starch adhesive 6: Avicel PH- — 50 0.90 83 86 89 0.75 101 (MCC) 7: Aeroperl ® — 30 1.40 23 30 32 0.32 300 Pharma (silica) “*” inventive

TABLE-US-00005 TABLE 3b Results for the production of cellulose particles. Release in Spray- d50 of Loading Release Release Release g.sub.formulation/ drying particles g.sub.formulation/ in % after in % after in % after g.sub.carrier process in μm g.sub.carrier 5 min 10 min 15 min after 5 min 8: Syloid ® — 50 1.44 17 21 22 0.24 XDP 3050 (silica) 9* Diacel 10/ c) 187 1.15 93 99 99 1.07 Diacel 90 (90:10% by weight) + 10% by weight GA 10* Diacel c) 182 1.14 92 98 98 1.05 10 + 10% by weight GA 11: Emcocel — 216 0.83 85 93 95 0.71 LP200 (MCC) 12: Emcocell — 112 0.72 85 95 96 0.61 90M (MCC) 13: Vivapur — 218 0.66 84 92 92 0.55 200 (MCC) 14: Vivapur 12 — 140 0.81 85 92 94 0.69 (MCC) 15: Vitacel CS — 308 0.39 86 93 94 0.34 250G (cellulose) 16: Sanacel — 59 0.98 85 94 95 0.83 pharma 150 (cellulose) “*” inventive

[0117] It is immediately evident from the results listed in the table that the particles according to the invention achieve very high loading rates and that these very high loading rates in turn result in more rapid release of pharmaceutical active substances than is the case for conventional particles (g of formulation per g of carrier released after 5 min). Compared with silicon dioxide-based absorbents (see Table 3), the particles according to the invention likewise release the active substance more rapidly and to a greater degree.

[0118] In addition, the particles according to the invention have better flowability than the conventional microcrystalline cellulose (Avicel PH-101), show flowability comparable to that of silicon dioxide-based absorbents and are also suitable for the production of tablets and capsule fillings.

Example 3: Tableting

[0119] The particles according to the invention were further processed into tablets on their own and in combination with other components. This process step was carried out using the EP-1 tablet press (eccentric press) from Erweka GmbH (Heusenstamm, Germany). The thickness, diameter and hardness of the various tablets was determined using the TBH 125 tablet hardness tester, likewise from Erweka GmbH (Heusenstamm, Germany). For the determination of the tablet parameters mentioned, 2 tablets (n=2) were in each case analysed for each different composition.

[0120] For the examples in Table 4, a tablet formulation was produced from the following constituents: lactose monohydrate (46.2%), talc (3.00%), silica (colloidal) (0.5%), various particle types (30.0%), maize starch (5.0%), magnesium stearate (0.3%) and celecoxib (15.0%).

TABLE-US-00006 TABLE 4 Results for the tableting of cellulose particles. Spray-drying Thickness** Diameter** Hardness** process [mm] [mm] [N] 1*: Diacel a) 4.82 ± 0.115 10.070 ± 0.010  46.0 ± 1.0    10 + 10% by weight MC 2*: Diacel 10/Diacel 90 c) 3.63 ± 0.007 10.02 ± 2.828 40 ± 0.014 (90:10% by weight) + 10% by weight GA 3*: Diacel c)  3.5 ± 0.148 9.99 ± 0   48 ± 0    10 + 10% by weight GA 4: Emcocel — 3.44 ± 0.007 9.975 ± 2.121 44.5 ± 0.007.sup.  LP200 (MCC) 5: Vivapur — 3.44 ± 0.078 9.98 ± 4.95 38.5 ± 0     200 (MCC) 6: Sanacel — 3.55 ± 0.007 10.01 ± 1.414 56 ± 0.028 Pharma 150 **n = 2 ± SD “*” inventive

[0121] The particles according to the invention can be further processed into tablets using the mentioned eccentric press. For comparability of the materials with one other, tablets having a thickness in the range of approx. 4.3-5.0 mm and a diameter of approx. 10.0-10.1 mm were produced.

[0122] The hardness of the tablets obtained (see Table 4) is for the listed materials in the range of approx. 40-50 N. This hardness thus determined means that the tablets based on the particles according to the invention are likewise suitable for further processing (for example coating). The hardness of the products according to the invention is comparable to the MCC products.