DE102006057188A1 - Cellulose ethers for solid formulations - Google Patents

Abstract

The present invention relates to a novel process for the preparation of cellulose ethers, which are distinguished by a particularly low proportion of fine dust and a particularly advantageous for tablet pressing compressibility.

Description

The The present invention relates to a novel process for the preparation of cellulose ethers, characterized by a particularly low content at fine dust and a for the tablet pressing particularly advantageous compressibility.

The controlled release of active ingredients from tablet formulations has been known in principle for a long time and includes different ones Release profiles. These include an immediate, a delayed or a controlled release of the respective active substance Matrix formulations and / or admixtures.

To prevent a release of the drug in the stomach and to effect a targeted release in the intestine, for example, enteric coatings are used. For this example, hydroxypropylmethylcellulose can be used in admixture with ethylcellulose ( US 2,887,440 ).

A time-shared release is referred to as "sustained release" or "controlled release". To provide such release characteristics from tablet formulations, various approaches based on cellulose ethers have been pursued in the past:
So was already in 1962 in US 3,065,143 the use of carboxymethylcellulose or hydroxypropylmethylcellulose (HPMC) has been proposed. These formulations, upon contact with water, form a gel barrier which prevents spontaneous release of the active ingredient and causes release of the active ingredient over a period of at least 4 hours.

Out US 3,870,790 For example, HPMC may be known in blends with ethylcellulose, with the HPMC moistened in thin layers over a period of greater than 24 hours before use under controlled conditions. The release is influenced both by the level of moistening and by the pressing pressure in the tabletting step.

US 4,226,849 describes sustained-release formulations based on HPMC, which was previously subjected to a hydrolysis and oxidation step.

In US 4,369,172 discloses the use of low-viscosity HPMC having a hydroxypropoxyl content of 9 to 12% and a molecular weight of less than 50,000 g / mol in order to achieve a sustained-release characteristic.

Out EP-A 0 223 590 the use of finely divided hydroxypropyl cellulose and its optional blending with HPMC in sustained-release tablet formulations is known. The fineness of the HPMC is described herein as not critical to release. The finely divided HPC is obtained, for example, by grinding coarser HPC in a ball mill.

For the purpose mentioned in US 2005/0260267 discloses the use of HPMC with bimodal or multimodal molecular weight distribution.

The aforementioned cellulose ether based approaches to providing However, sustained-release tablet formulations are with disadvantages. So it comes in the context of tablet production relatively significant quality fluctuations the cellulose ether, which i.a. in not equally satisfactory Sustained-release behavior impact.

Furthermore show the known finely divided cellulose ether Methocel types the DOW and Metolose types of ShinEtsu with satisfactory compressibility relative high levels of dust, which in turn for reasons of pollution and Work safety undesirable are.

By manufacturing process as in EP-A 1 127 910 . US 6,509,461 . US 6,872,820 For example, methylhydroxyethylcelluloses (MHEC) with low dust levels are available. However, these have a low compressibility and are therefore unsuitable as a matrix material for sustained-release tablets.

For grinding and drying of moist cellulose ethers is in EP-A 0 370 447 a method is described which is based on simultaneous impact and friction comminution and has the aim of preventing a reduction in viscosity during comminution as far as possible. EP-A 0 835 882 describes a further development of this method with the aim of further reducing the proportion of oversize grain. This is due to changed air achieved in the mill. How far can be produced so fine cellulose ethers with low dust levels and good compressibility, as they are desirable for the preparation of tablet-shaped sustained-release formulations is not apparent from the publications.

In the GB 2 262 527 describes a process for grinding drying of cellulose ethers after gelation, unfortunately, the cellulose ethers described there do not provide the desirable high compressibility. The in the GB 2 262 527 Although described comparative products without gelling before the mill drying provide a high compressibility, but have a non-practical low bulk density.

task the present invention was now to provide cellulose ether particles, which are used for industrial production of sustained-release formulations are suitable and the aforementioned disadvantages of the prior art such as high dust content and / or lack of compressibility not have and bulk densities of at least 280 g / l.

These Task was now by the method described below and the thereafter available Dissolved cellulose ether.

object The present invention is a process for the preparation of Celluloseetherpartikeln, in which a water and / or alcohol damp Cellulose ethers having a moisture content of 20 to 50 wt .-% in one Mill crushed and dried, this mill being a concentrically arranged, equipped with several blow bars racquet and a concentric to the racquet arranged strainer basket and further includes the peripheral speed of the racquet wheel 90 to 140 m / s and the peripheral speed of the screen basket 30th up to 60 m / s.

The Relative speed beater wheel to Siebkorb amounts thus at least 120 m / s.

One Another subject is the cellulose ethers themselves.

Such a device for comminution and drying of cellulose ethers is already in principle EP-A 0 370 447 or EP-A 0 835 882 described above. In the context of the present invention, however, it has been shown that precisely the ratio of impact to friction comminution, which can be achieved by a high peripheral speed of the beater wheel and high relative speed of racket wheel to screen basket, critical for achieving high compressibilities at the same time satisfactorily high bulk densities Product is. It is particularly advantageous if, at the same time as the circumferential speeds, the cross-sectional area of the perforations of the friction plates is also particularly high, ie an opening of at least 2 mm and a gap width of at least 2 mm in the longitudinal direction.

In Such a used according to the invention Device are racquet and Siebkorb typically in a housing with a side entrance opening to coaxia len input of the ground material and the transport gas and a discharge for the ground and dried good and the transport gas. To the introduction another gas flow, which is the space between strainer and casing flows through can be another opening tangential to the housing to be appropriate.

Furthermore is in the case an entrance opening for the input of the feed material and for the introduction of the transport gas axially to the shaft of the racquet wheel in the interior of the screen basket available (not separately in the Figures drawn).

The screen basket has saw teeth segments in sections one behind the other at the circumference ( 5 ) and apertured friction plates ( 4 ) on. The beater wheel and the screen basket are driven in opposite directions by waves.

Prefers is the moisture based on water and / or alcohol of the process according to the invention cellulose ether used as feedstock 35 to 48 wt .-%.

wet of the feed material of less than 20% by weight, based on the total weight is in the process of the invention however undesirable, because then too high temperatures in the mill and undesirably low Residual moisture in the ground and dried final product obtained become.

The cellulose ethers used in the process according to the invention are preferably methylcellulose (MC) having a methoxyl content of 15 to 40% and also their mixed derivatives such as hydroxyethylmethylcellulose (HEMC) and Hy hydroxypropylmethylcellulose (HPMC).

The determination of the chemical etherification of the cellulose ethers is carried out according to USP 29 ( United States Pharmacopeia 29, The United States Pharmacopeial Convention, meeting at Washington, DC March 9-13, 2005 ).

The HPMC has a substitution corresponding to a methoxyl content from 15 to 40%, preferably 17% to 30%, more preferably 19 % to 24% and a hydroxypropoxyl content 4 to 12%. Preferred is in the HPMC the hydroxypropoxyl content 6 to 9%, particularly preferably 6.5 to 8.5%, most preferably 7.0 to 8.0%.

The viscosity this cellulose ether can be widely varied and is typically 1 to 500,000 cps as 2 wt .-% solution in water measured with an Ubbelohde viscometer at 20 ° C.

Such Cellulose ethers are by prior art methods of the prior art available in the art, wherein a crude cellulose alkalized, etherified and then washed will and finally is subjected to grinding drying. The viscosity of such Types is typically 1,000 to 150,000 cps at 20 ° C. For example by acid hydrolysis Degradation by means of HCl are viscosities of 400 and less cps possible.

in the Following the etherification reaction, the crude product is mixed with hot water optionally washed several times and by means of a separation unit according to the prior art separated from the washing solution. As separation units come, for example, continuously working Band filter or rotary pressure filter in question.

One has such obtained in the form of a filter cake cellulose ether usually a residual moisture based on water and / or alcohol of ≥ 50 Wt .-% on. For moisture separation, this is then, for example by means of a mechanical press or a gas stream on a Residual moisture <50% by weight dewatered. The gas stream may be, for example, compressed air or water vapor act. This aftertreatment can be done both on the filtration unit downstream units as well as on the filtration unit even done become.

One so usually as a filter cake available moist cellulose ether preferably has a humidity of 35 to 50 wt .-%, more preferably 40 to 48 wt .-% and can directly into the process according to the invention for producing the finely divided cellulose ether with a low dust content and high compressibility be used.

Lies the moisture of the filter cake undesirably low, so this can for generating the feed material by adding water to the desired Value to be set. To avoid unwanted gelation, this can be hot Water, preferably in the temperature range 60 to 90 ° C are used.

to Adjustment of the moisture content of the cellulose ether as a feedstock can this over it Be mixed with a lower cellulose ether, the ratio to choose both cellulose ethers so is that the resulting feed then preferably a 3 to 12 wt .-%, particularly preferably 4 to 9 wt .-% lower humidity having.

to The above-mentioned reduction of the moisture can be already ground-dried Cellulose ethers are used, both coarse and finely divided can be. As a coarse fraction is preferably in a the Mahltrocknungsschritt downstream Siebschritt cellulose ethers obtained. The particle size of the coarse fraction is about 150 to 500 microns

When Mixing units come continuous or discontinuous Mixer with horizontal or vertical shaft in question. As mixing tools are preferably those of the ploughshare or Beckerschaufel type used, also screw mixers or ribbon mixers can be used.

During the Laundry, Filtration, drainage and the discontinuous or continuous generation of the Charge is a gag by excessive shearing or cooling or Shear and cooling absolutely to avoid. The mixing devices connected to the laundry should therefore be heated or insulated.

A Predrying and / or pre-shredding before the grinding drying step is possible and can by means of aggregates according to the state carried out the technique become. For example, the entry is the mill by means of a transport gas, which is preheated. Depending on the distance Entry of feed into the gas stream to mill entry can be so for example a current drying can be realized. For pre-shredding come for example cross beater mills or hammer mills in question.

Furthermore can be an extra Drying inside the mill by entry of an additional preheated Gas stream, to the mill no regrind transported, realized.

As well is a tempering of the mill - both Heating, as well as cooling conceivable.

The Transport gas promotes the milled material into a separator such as e.g. Filter or Cyclone separator or a combination of both.

The Peripheral speed of the whipper wheel is preferably 90 to 130 m / s, more preferably 95 to 120 m / s.

The Peripheral speed of the screen basket is preferably 33 to 55 m / s, particularly preferably 35 to 50 m / s.

The screen basket is a drum-shaped device whose circumference is arranged by successively arranged sawtooth segments ( 5 ) and apertured friction plates ( 4 ) is formed ( 1 ). These friction plates preferably have oblique punching, whereby unilaterally (outwardly or inwardly) tooth projections ( 6 ) arise ( 2 ). The punctures result in isosceles trapezoidal to semi-elliptic (rounded isosceles trapezoid) openings. The longitudinal direction corresponds to the height of the trapezoid, the gap width of the base of the trapezoid. The punched holes preferably have an opening of 2 to 8 mm in the longitudinal direction and a gap width of 2 to 8 mm. Particularly preferably, the Austanzungen have an opening of 2.5 to 6 mm in the longitudinal direction and a gap width of 2.5 to 6 mm.

Prefers forms the same number of sawtooth segments and friction plates, more preferably 4 sawtooth segments and 4 friction plates or 6 sawtooth segments and 6 friction plates the circumference of the screen basket.

A mixed equipment with friction plates, which have different sizes of the punched-out, is possible. With 4 friction plates in this case 2 of the friction plates have Austanzungen with an opening of 3 to 6 mm in the longitudinal direction and a gap width of 3 to 6 mm. At 6 Reibblechen have in this Case 2 or 3 of the friction plates punched out with an opening of 3 to 6 mm in the longitudinal direction and a gap width of 3 to 6 mm. The distribution then takes place symmetrical over the circumference of the screen basket, wherein on each friction plate a sawtooth segment follows.

The Saw teeth the sawtooth have a height from 1 to 10 mm, preferably 2 to 5 mm.

Of the Distance between club wheel (Top edge of the blow bar) and strainer basket (tooth top edge of friction plate or Tooth of the sawtooth segment) is 1 to 12 mm, preferably 1.5 to 8 mm, most preferably 2.0 to 6 mm.

Of the Strainer basket generally has a diameter of 800 to 1600 mm in widths of 100 to 700 mm.

Prefers This is the process according to the invention obtained, ground-dried, powdered product subsequently sieved to reduce the proportions of particles of> 140 μm, preferably> 180 μm (coarse fraction) to reduce. The coarse fractions separated in this way can go to the mill and / or filter cake be returned to the production of the output. For separation Sieves used have mesh sizes of 140 to 400 microns, preferably 160 to 250 μm, more preferably 180 to 220 microns.

The possess obtained by this method cellulose ether immediately after production, even without downstream classification steps a particularly low proportion of fine dust and one for tablet pressing particularly advantageous compressibility and have at the same time Practical bulk density on.

to Characterization of the cellulose ether particles becomes a laser diffraction method (Equipment HELOS with powder dispersion RODOS from Sympatec). From the intensity distribution the scattered light becomes the particle size distribution of the collective of the cellulose ether particles. The evaluation takes place according to the Fraunhofer theory under the assumption of a form factor from 1. As result one receives a particle diameter of the laser diffraction. There are mean volume diameter measured and the resulting particle size distribution is a distribution in volume percent (vol.%).

One Another object of the invention are the so available Cellulose ether particles which have a proportion of particles smaller than 180 μm of at least 80% and a dust content of particles <15.5 microns of a maximum of 4% each determined by laser diffraction and a compressibility of the cellulose ether particles according to Test F according to ASTM D6393-99 "Carr Compressibility" of at least 29 % exhibit.

Prefers the particles have a compressibility of 30 to 50%, especially preferably from 31 to 43% and most preferably from 32 to 39%.

The compressibility For example, with the "Powder Tester "of the company Hosokawa Micron Ltd, Runcorn, Cheshire, UK.

Prefers have the obtainable by the process according to the invention Cellulose ether particles have the aforementioned fineness, where at the same time determined by laser diffraction share of Particles smaller than 90 μm of at least 50%. Particularly preferred is additionally the Proportion of particles of <45 μm at least 25%.

Prefers is in addition to the above-mentioned dust content of particles <15.5 microns, the proportion at particles <5.5 microns maximum 2%, more preferably at most 1%.

The bulk weight of the products at least 280 g / l, preferably 280 to 600 g / l, more preferably 290 to 500 g / l, most preferably 300 to 450 g / l.

The Product moisture based on water and / or alcohol content amount typically 1 to 10 wt%, preferably 2 to 7 wt%, especially preferably 2.5 to 5 wt .-%.

The cellulose ethers according to the invention are ideal as an additive or binder in solid formulations. Especially in solid formulations of the pharmaceutical industry, food supplements and food industry as well as feed or agrochemical Industry.

Prefers become the cellulose ethers according to the invention used in solid formulations, which then by mechanical processes or thermal and mechanical processes be brought into a defined shape. In particular, such Solid formulations brought by compression in tablet form.

The Solid formulations are pressed directly or optionally compacted before the actual pressing process for the production of the tablet, e.g. by rolling or granulating, e.g. with the addition of solvents dissolved polymeric granulation aids such as HPMC, hydroxypropylcellulose or polyvinylpyrrolidone.

Prefers become the cellulose ethers according to the invention used to determine the release behavior of substances such as pharmaceutical agents, pesticides, fragrances and flavorings, Vitamins, minerals, trace elements to change. Especially should cause a temporally distributed release of these substances become.

Examples

Unless stated otherwise, the viscosities of the products below correspond to the product labeling in accordance with United States Pharmacopeia 29, The United States Pharmacopeial Convention, meeting at Washington, DC March 9-13, 2005 (USP 29).

The viscosities The cellulose ethers used were based on 2 wt .-% - solutions in Water measured with an Ubbelohde viscometer at 20 ° C.

The Particle fractions were laser diffracted using a HELOS device determined by the company Sympatec. The dispersion was carried out by means of the dispersing section RODOS from Sympatec. The evaluation of the Diffraction pattern is done according to the Fraunhofer theory. As a result receives a particle diameter of the laser diffraction. It will be medium Volume diameter measured and the resulting distribution is one Volume distribution.

The compressibility The cellulose ether particle was determined according to Test F according to ASTM D6393-99 "Carr Compressibility" the "taps" was 180 each.

The HPMC used in the experiments was prepared by prior art processes by etherification of cellulose. For the etherification of cellulose, for example, in the EP-A 1 180 526 . EP-A 1 279 680 and EP-A 1 589 035 and the literature cited therein.

The subsequent Laundry the obtained by etherification of cellulose HPMC was also in accordance with the prior art carried out the technique.

In the experiments, a substitution type HPMC 2910 was used as a water-moist filter cake. To adjust the moisture essential to the invention, this was mixed either with HPMC of lower humidity (such as the coarse fractions separated during product sieving) or with water. The grind-drying device was operated with the following parameters:
Peripheral speed of the club wheel: 94 m / s
Number of blow bars on the perimeter of the club wheel: 90
Peripheral speed sieve basket: 33.5 m / s
Friction plates: 2 × 4.0 mm and 2 × 5.0 mm
Sawtooth: 4 × 2.5 mm
Distance between club wheel and strainer basket: 2.0 mm

The product was sieved through a 220 μm sieve.

Example 11

To the A comparison was made with an HPMC with a methoxy content of 22.3% and a hydroxypropoxy content of 9.2% and a viscosity of 4000 cps with a feed moisture of 60 wt .-% and 55 wt .-% after the same procedure. The products showed with 27.2 and 28.6 insufficient compressibilities.

Example 12

For comparison, an HPMC having a methoxy content of 22.7%, a hydroxypropoxy content of 6.0% and a viscosity of 4000 cps with a feed moisture content of 45% by weight was similarly dried by the same method, but the peripheral speeds of the beater wheel and the screen basket changed:
Peripheral speed beater wheel: 83 m / s
Peripheral speed sieve basket: 31 m / s

It were friction plates with openings a gap width of 2.5 mm used.

When Product was a watty HPMC with a non-practical bulk weight of only 220 g / l with a compressibility of 36.2%.

Example 13

The same HPMC as in Example 11 was prepared from a filter cake having a moisture content of 48% by weight on a sieve-free mill of the type UltraRotor according to the method of GB 2 262 527 but without gelling the ground material. The product obtained was a wadded HPMC with a non-practical bulk density of only 210 g / l with a compressibility of 41.0%.

Example 14

In a further comparative experiment, the same HPMC was used according to the method of GB 2 262 527 and ground on a sieve-free UltraRotor mill.

The Product had a practical bulk density of 395 g / l, however, showed a compressibility of only 23.1%.

The following list shows that commercially available cellulose ethers have a comparatively high proportion of very fine dust with particle sizes <5.5 μm or <15.5 μm. trade name substitution type Viscosity cps Proportion <5.5 μm Proportion <15.5 μm Proportion <45 μm Proportion <90 μm Compressibility [%] Methocel ^® K4M CR 2208 4000 1.8 4.1 22.9 51.8 Not determined Metolose ^® 90 SH 4.000 2208 4000 3.1 6.9 33.7 66.6 39.0 Metolose ^® 90 SH 4.000 2208 4000 2.1 4.2 26.0 56.4 Not determined Metolose ^® 90 SH 100,000 2208 100000 2.6 5.4 32.6 65.4 Not determined Metolose ^® 60 SH 4000 2910 4000 2.9 6.8 32.4 68.5 Not determined Methocel ^® E4M CR 2910 4000 2.2 5.5 32.4 71.1 35.9 Methocel ^® E4M CR 2910 4000 0.9 6.0 34.6 72.8 37.0 Methocel ^® E4M CR 2910 4000 1.1 5.3 24.6 61.6 30.1 Methocel ^® E4M CR 2910 4000 1.5 4.7 18.6 50.7 26.3

In the commercial products Methocel ^® and Metolose ^® is trademark of the Dow Chemical Company and the Shin Etsu Chemical Company.

However, the following Walocel® show ^® commercial products (Wolff Cellulosics GmbH & Co. KG, Walsrode, DE) a remarkably low fine dust and acceptable bulk densities, however, the compressibility is not satisfactory. trade name bulk weight Proportion <5.5 μm Proportion <15.5 μm Proportion <45 μm Proportion <90 μm Proportion <180 μm compressibility MKX 40,000 PF (MHEC) 390 g / l 0.1 1.3 21.6 65.9 96.8 25.9 M 5255 (MHEC) 450 g / l 0.6 3.7 26.6 64.9 93.2 23.9

To evaluate the tabletting, powder mixtures were pressed on a rotary tablet press using the direct tabletting method in a round format 12 mm diameter (strongly curved) at a press force of 25 kN. Composition powder mixture in parts by weight: Modeling agent (salicylic acid) 12.5 Lactose monohydrate 97% <0.063 mm 56.3 HPMC 30.0 magnesium stearate 0.4 Highly disperse silica 0.8

• *Bei den handelsüblichen Celluloseethern zeigte sich bei der Einnwaage, Abmischung und Tablettierung eine erhöhte Belastung der Umgebungsluft und somit der Mitarbeiter und eine verstärkte Belegung der Maschinen durch HPMC-Feinststaub.

The HPMCs were of the type 2208 with a viscosity of 4000 cps, differing in different compressibilities, grading curves, particulate matter and bulk densities: Ex. Compressibility [%] Proportion <180 μm Proportion <15.5 μm Waste weight [g / l] Tablet hardness, N Review tableting and tablet hardness 15 23.8 51.3 0.2 439 48 Tablet hardness insufficient 16 20.9 99.7 1.2 482 - Tablet hardness not determinable, tableting does not give stable tablets 17 35.3 87.0 1.3 330 137 Very good tablet hardness 18 34.8 91.9 2.2 350 138 Very good tablet hardness 19 29.8 89.8 1.4 390 107 Tablet hardness sufficient 20 39.0 92.0 6.9 334 153 Very good tablet hardness * 21 41.0 83.9 2.5 210 - Flowability of the powder mixture for tableting insufficient, tablet hardness and tablet weights uneven

• * In the case of commercially available cellulose ethers, there was an increased load on the ambient air and thus on the employees and an increased occupancy of the machines by HPMC fine dust during the weighing, mixing and tableting.

1

casing

2

beater

3

blow bars

4

friction plates

5

Sägezahnsegment

6

Dental supernatants

7

wave beater

8th

wave strainer

9

discharge

Claims (13)

Process for the preparation of cellulose ether particles, in which a water and / or alcohol-moist cellulose ether with a moisture content of 20 to 50 wt .-% as a feed in one Mill crushed and dried, this mill being a concentrically arranged, equipped with several blow bars racquet and a concentric to the racquet arranged strainer basket and further includes the peripheral speed of the racquet wheel 90 to 140 m / s and the peripheral speed of the screen basket 30th up to 60 m / s. Method according to claim 1, characterized in that the moisture based on water and / or Alcohol of the cellulose ether used as feedstock 40 bis 48 wt .-% is. Method according to claim 1 or 2, characterized in that as cellulose ether methylcellulose (MC), Hydroxyethylmethylcellulose (HEMC), and / or hydroxypropylmethylcellulose (HPMC). Method according to one the claims 1 to 3, characterized in that the cellulose ether in the form a water and / or alcohol wet filter cake used becomes. Method according to one the claims 1 to 4, characterized in that as a feedstock a mixture from at least two cellulose ethers of different moisture used is, with these mixed in a quantitative ratio be that the moisture of the feed material is 4 to 9 wt .-% lower, as the moisture of the cellulose ether with the highest water and / or alcohol content, which was used to prepare the feed. Method according to one of claims 1 to 5, characterized in that the Umfangsgeschwin The speed of the racket wheel is 95 to 120 m / s and the peripheral speed of the screen basket 35 to 50 m / s. Method according to one the claims 1 to 6, characterized in that the circumference of the screen basket by the same number of Sägezahnsegmenten and friction plates is formed. Method according to claim 7, characterized in that the screen basket by 4 saw tooth segments and 4 friction plates or 6 sawtooth segments and 6 friction plates is formed. Method according to one the claims 1 to 8, characterized in that the friction plates oblique Austanzungen with isosceles trapezoidal to semi-elliptic (rounded isosceles trapezoid) openings have, in the longitudinal direction an opening from 2 to 8 mm and a gap width of 2 to 8 mm. Method according to one the claims 1 to 9, characterized in that the distance between the beater wheel (beater bar upper edge) and sieve basket (tooth top edge of the friction plate or tooth of the sawtooth segment) 1 to 12 mm. Cellulose ether particles containing a proportion of particles smaller 180 μm of at least 80% and a dust content of particles <15.5 μm of maximum 4% each determined by means of laser diffraction, a compressibility of the cellulose ether according to Test F according to ASTM D6393-99 "Carr Compressibility" of at least 29 % and a bulk density of at least 280 g / l. Cellulose ether particles according to claim 11, characterized in that that they have a compressibility of 31 to 39%. Use of the cellulose ethers according to claim 11 or 12 in medicines, nutritional supplements or plant protection products.