WO2011160145A1

WO2011160145A1 - Use of cellulose in tablets

Info

Publication number: WO2011160145A1
Application number: PCT/AT2011/000268
Authority: WO
Inventors: Josef Innerlohinger; Johann Manner; Ksenija Varga
Original assignee: Lenzing Ag
Priority date: 2010-06-23
Filing date: 2011-06-16
Publication date: 2011-12-29
Also published as: AT509515A1; AT509515B1

Abstract

The invention relates to the use of particles made of cellulose II to produce tablets and to the tablets produced in such a way themselves.

Description

Use of cellulose in tablets

The present invention relates to the use of particles of cellulose-II for the production of tablets as well as to the tablets thus produced themselves.

State of the art

The use of cellulosic materials for the production of tablets is known, especially in the pharmaceutical industry, but also in other fields, where mechanically stable tablets with good disintegration properties in water are required (.Haushaltszwecke, animal feed, fertilizers,

Nutritional supplements, cleansing formulations, etc.). In addition to a large number of cellulose derivatives also find a large amount of powders of pure cellulose use. In particular, these materials fulfill the function of the tabletting agent, i. the substance that forms the main component of the tablet.

As a tabletting agent, on the one hand, the so-called powder cellulose is used, which is produced by the comminution of purified pulp. Due to its method of preparation, it always has the fibrous structure of native cellulose, resulting in poor flowability and thus in general

leads to poor processing properties. Such celluloses tend to produce less firm compress during tableting. Therefore, mostly microcrystalline cellulose (MCC) is used for tableting. In the production of the MCC from pulp, in addition to the mechanical comminution, a treatment with acid, whereby the amorphous portions of the cellulose are degraded and a material with a high crystalline content is formed. Depending on the process, the individual crystallites can be brought into different forms. So here are also aggregates / agglomerates of spherical shape possible. These are very free-flowing and can therefore be well dosed / process. The tablets produced therefrom have a very high strength. Another quantitatively important tablet ingredient are the so-called.

Disintegrating agents which bring about the disintegration of the tablet necessary for the intended effect of the respective tablet and thus to ensure a uniform release of active substance. These are usually around

Substances which swell strongly on contact with liquids and which by their increase in volume effectively "burst" the tablets Depending on their chemical composition and proportion, it is possible to control whether the decomposition takes place slowly or quickly.There are countless examples in the literature; the following: Ishikawa T. et al., Chem Pharm. Bull 47 (1999), 1451-1454, Rawas-Qalaji MM et al., AAPS Pharm Tech Tech 7 (2006), article 41, EP 218056 A1 and US 2010/015221 A1.

With MCC or conventional cellulose powder, the possibilities to incorporate or apply additional materials into the particles are limited. An application of additives is only possible as a coating or as storage in aggregates or agglomerates.

Recently, so-called coprocessed celluloses are used, to which a further substance, which introduces additional property, is already added during production. Some exemplary examples of co-processed celluloses can be found in Freitag F. et. al., Pharm. Dev. Technol. 10 (2005), 353-362; Levis S.R. and Deasy P.B., International Journal of Pharmaceutics 230 (2001), 25-33 or in WO 2008/057267 A2.

Common to all cellulose powders described so far is that it is always native cellulose, ie cellulose, which is made from

natural, vegetable sources such as wood or cotton. Native cellulose always has the same microstructure, that is to say an arrangement of the cellulose molecules which is referred to in the specialist literature as a structure type. Although cellulosic I type cellulose powders can absorb a certain amount of water, this amount of water is usually insufficient for a tablet blasting action. Therefore, for such an effect, cellulose I must always be derivatized. The resulting Cellulose derivatives are usually highly hygroscopic and swell accordingly in the presence of water.

Thus, according to the known state of the art, tablets are made using a tabletting agent, which is usually the main constituent of the tablet, and a tablet disintegrating agent, which is another

Structure and other properties than the tabletting agent prepared. In addition to cellulose-I, there is another common structural type known as cellulose-II. The two structural types can be

simply differentiate radiographically. Cellulose can be converted into cellulose II by dissolving in suitable solvents and subsequent regeneration. This process takes place in the industrially used processes for the conversion of cellulose, including the viscose and the lyocell process.

Both methods have long been known and are mainly for

Production of textile staple fibers, continuous filaments and films used. In addition to variable shaping, the process of dissolving and regenerating the cellulose offers another advantage. There are several ways in this process to incorporate or apply additional materials to the particles. These possibilities are known to the person skilled in the literature.

Recently, WO 2009/036480 A1 also discloses the production of spherical cellulose I I particles. Due to the possibility of variable shaping, these particles can be adapted to the requirement profile of the planned application. In the case of cellulose II particles, due to the complete dissolution of the cellulose during the process according to WO 2009/036480 A1, it is also possible to incorporate various substances into the particles. It is also possible to coat these cellulose II particles with various substances. The use of underivatized cellulosic materials with cellulose II structure in tablets is not known.

task

Given the state of the art, the task was the,

Make composition of tablets easier and cheaper and still achieve good decay behavior.

This task could be solved by using

Cellulose particles with cellulose II structure in the production of tablets.

The tablets may be both pharmaceutical-grade preparations and other tablets, for example for household purposes, animal feeds, fertilizers or food supplements.

The cellulose particles according to the present invention always consist of underivatized cellulose.

Surprisingly, it was possible to achieve a stronger explosive effect in the tablet than with conventional MCC or ground pulp. Since cellulose II particles have the functions of both

Combine tabletting agents as well as disintegrants, the formulation of a tablet can be simplified because a substance can be saved in the recipe.

Preferably, the proportion of cellulose particles having cellulose-II structure in the inventive use is at least 10 wt.% Of

Total mass of a tablet. Particularly preferably, for example in the case that the particles with cellulose II structure are used both as tableting agent and because of their explosive effect, the proportion of cellulose particles having cellulose II structure is at least 50% by weight. Because of the processing properties, usually spherical particles will be preferred during tableting, but also elongated or plate-like forms are conceivable. To describe the present invention, the term "spherical" is to be understood as follows: The particles have an axial ratio (1: d) between 1 and 2.5 and show no fibrous fissures or fibrils under the microscope.

For the purposes of the present invention, particles having a particle size in the range from 1 pm to 400 pm and a mean particle size are preferred

Particle size x ₅ o between 4pm and 250pm, having an approximately spherical particle shape with irregular surface, a crystallinity in the range of 15% to 45 _% _ according to the ¹³ C_NMR method and a bulk density between 250g / l and 750g / l , Particularly suitable here are z. B. cellulose II particles, which are prepared from a solution of underivatized cellulose in a mixture of an organic substance and water, based on the Lyocell technology, wherein the solution free-flowing under their

Solidification temperature is cooled, the solidified cellulose solution is crushed, the solvent is washed out and the crushed, washed out particles are dried. Such a method is known, for example, from WO 2009/036480 A1. As organic

Substances in these solvent systems are, in particular, N-methylmorpholine N-oxide (NMMO) and the substances known as "lonic liquids".

Further suitable particles with cellulose II structure are those which are prepared according to WO 2009/036479 A1. Also suitable in principle are particles which are produced by comminuting commercially available textile cellulosic synthetic fibers having an average diameter of between 5 and 20 μm and a length of between 5 and 200 mm, preferably between 20 and 60 mm, by means of a precision cutting mill. Such fibrous powders are particularly suitable for the present purpose if they have a mean diameter between 5 and 20 μηι and a number-weighted average length between 200 and 800 pm.

For the production of cellulose II particles, which are suitable for the present invention, viscose, the cupro as well as working with caustic soda method are also suitable. An example of sodium hydroxide solution is the BioCellSolv process.

From the lower crystallinity of cellulose-II also follows a better accessibility and absorption capacity of the particles. Thus are suitable

Cellulose II powder also as a carrier for active ingredients and

Active substances. As stated in the prior art, they already allow additional substances to be introduced into cellulose II particles during their production. With regard to tableting applications, these are more likely to be further tabletting excipients, which thus need not be added separately in the final step of tablet production. The actual active ingredients are preferred only during tableting

added, but here are the well-known good carrier properties of cellulose-Il depending on the substance class of advantage.

However, it is quite an advantage of the present invention that the cellulose-II particles can already be provided with additives during or after their preparation. For example, the incorporation of additives such as

For example, additional swelling agent possible, which in particular the blasting effect can be influenced. The additives are preferably already introduced into the cellulose solution and remain after regeneration in the cellulose particles. However, it is also possible to apply additives to the cellulose particles after the formation of the cellulose particles, but in particular before their first drying, that is to say in the never-dried state.

The present invention also relates to the in the

use according to the invention produced tablets themselves Tablets are characterized as containing cellulose particles having a cellulose II structure. Preferably, the proportion of cellulose particles with cellulose II structure at least 10 wt.% Of

Total mass of a tablet. Particularly preferably, for example in the case that the particles with cellulose II structure are used both as tableting agent and because of their explosive effect, the proportion of cellulose particles having cellulose II structure is at least 50% by weight.

The invention will now be explained by way of examples. These are to be understood as possible embodiments of the invention. By no means is the invention limited to the scope of these examples,

Examples:

Three cellulose powders were characterized for swelling of relevant values:

• Avicel PH 101 from FMC Biopolymers (microcrystalline cellulose)

• Arbocel BWW 40 from JRS (ground pulp)

· TENCEL CP 50 from Lenzing AG (spherical cellulose powder,

manufactured according to the lyocell method)

The crystalline content of cellulose was determined by NMR, the

Water retention capacity (WRV) and the water vapor sorption isotherms.

To determine the WRV a defined amount of powder was placed in special centrifuge tubes (with drain for the water) and with

enough water is added. Thereafter, spin-off was carried out for 15 minutes at 3000 rpm and the moist powder was weighed immediately afterwards. The wet powders were dried at 105 ° C for 4 hours and the dry weight was determined. The calculation of the WRV took place according to the following formula:

WRV [%] = (m _f -mt) / m _t * 100 (m _f = mass wet, m _t = mass dry) The crystallinity of the samples was determined by ¹³ C solid-state NMR; the exact method for this is described in Zuckerstätter G. et.al., Lenzinger Berichte 87 (2009), 38-46. It should be noted that the crystallinities determined by means of NMR can not be compared directly with the values obtained from other methods (WAXS, Raman spectroscopy, etc.).

The water vapor sorption was after the volumetric

Adsorption method with the device BELSORP-max (BEL Inc., Japan) measured. Both adsorption and desorption were determined at 23 ° C in the pressure range p / ρθ from about 0.1 to 0.9.

Table 1 summarizes the values obtained for crystallinity and WRV. Figure 1 shows the isotherms. It turns out that the

The ability to absorb water and its retention capacity correlate with the K r isa lity of cellulose.

Table 1

Example 2

The swelling of the two cellulose powders Avicel PH 101 and TENCEL CP 50 already described in Example 1 on contact with liquid water was determined as follows. A small amount of powder was applied to a slide so that the particles were as isolated as possible. The powders were covered with a coverslip and a drop of water was carefully applied to the edge of the coverslip. Due to the capillary effect, the water was sucked in the direction of the particles, which absorbed the water and thus swelled up. The swelling was observed under a microscope (Olympus BX 51) equipped with a digital camera that is directly connected to a PC. There were series images with one image per second made and the size of the particles using software analySIS 5.0 (from Soft Imaging). measured. Fig. 2 shows left Avicel PH 101 particles in the dry state (unswollen) and right after complete swelling in water. The complete swelling was reached after approx. 3 sec.

Fig. 3 shows left TENCEL CP 50 particles in the dry state

(unswollen) and right after complete swelling in water. The complete swelling was reached after approx. 10 sec.

The low water absorption and thus low swelling occurred in Avicel PH 101 within the first few seconds after contact with water; at

TENCEL CP 50 was swollen evenly over a period of about 8 seconds. Based on the measured diameter increases, the volume increase was calculated based on a spherical geometry with 13% for Avicel and 131% for TENCEL. The determined swelling behavior correlates with the data from Example 1.

Example 3

Using a hydraulic press, in each case 0.1 g of Avicel PH 101 and TENCEL CP 50 with a cylindrical shape (diameter 7 mm) were pressed at a pressure of 2.5 bar platelets. The sheet of Avicel PH 101 had a thickness of 1 mm, that of TENCEL CP 50 was slightly thicker (~ 1, 15mm). The two platelets were placed in water and the decay behavior observed. After only two minutes in unstirred water at room temperature, a clear difference was found. 4 shows on the left a plate of Avicel PH 101 and on the right a plate of TENCEL CP 50.

Claims

claims:

1. Use of cellulose particles for the production of tablets, characterized in that the particles have a cellulose II structure.

2. Use according to claim 1, characterized in that the cellulose particles have a spherical shape.

3. Use according to claim 1, characterized in that the cellulose particles were prepared by the lyocell method.

4. tablets, characterized in that they cellulose particles

contained, which have a cellulose II structure.

5. Tablets according to claim 4, characterized in that the proportion of cellulose particles with cellulose II structure is at least 10% by weight.

6. Tablets according to claim 5, characterized in that the proportion of cellulose particles with cellulose II structure is at least 50 wt.%.