WO2012119997A1

WO2012119997A1 - Pharmaceutical formulation for producing rapidly disintegrating tablets

Info

Publication number: WO2012119997A1
Application number: PCT/EP2012/053771
Authority: WO
Inventors: Karl Kolter; Silke Gebert; Sandra Kruse; Michael SCHÖNHERR
Original assignee: Basf Se
Priority date: 2011-03-09
Filing date: 2012-03-06
Publication date: 2012-09-13
Also published as: EP2683365A1; JP2014507454A; BR112013022017A2; CN103415284B; CN103415284A

Abstract

Pharmaceutical formulation in the form of granules comprising a) 60% - 96% by weight of non-film-forming sugars or sugar alcohols, b) 1% - 10% by weight of film-forming sugars or sugar alcohols, c) 3% - 25% by weight of disintegrants, d) 0% - 10% by weight of water-insoluble, film-forming polymers, e) 0% - 15% by weight of further, customary pharmaceutical excipients, the sum of components a) to e) being 100% by weight.

Description

Pharmaceutical formulation for the preparation of rapidly disintegrating tablets Description

The present invention relates to pharmaceutical formulations in the form of granules for the preparation of rapidly disintegrating tablets containing non-film-forming sugars or sugar alcohols, film-forming sugars or sugar alcohols, cross-linked polyvinylpyrrolidone and water-insoluble polymers.

Rapidly disintegrating in the mouth and / or rapidly dissolving tablets are becoming increasingly important for the oral administration of drugs. Such tablets must taste pleasant within a short time, preferably within 30 seconds in the oral cavity, and must not leave a sandy feeling. Furthermore, they should be easy to prepare, the direct tabletting offers considerable advantages over the wet granulation, and have a high mechanical strength, so they survive packaging procedures, transport and also the squeezing out of packaging unscathed.

The products and methods described so far do not meet these requirements or only very poorly.

Fast disintegrating tablets often consist of sugars and sugar alcohols, effervescent systems, microcrystalline cellulose and other non-water-soluble fillers such as calcium hydrogen phosphate, cellulose derivatives, corn starch, or polypeptides. Furthermore, water-soluble polymers, conventional disintegrants (crosslinked PVP, Na and Ca salt of crosslinked carboxymethylcellulose, sodium salt of carboxymethyl starch, low-substituted hydroxypropylcellulose L-HPC) and essentially inorganic water-insoluble components (silicas, silicates, inorganic pigments) Commitment. Furthermore, the tablets may also contain surfactants.

WO 2003/051338 describes a direct tabletting and readily compressible excipient formulation which contains mannitol and sorbitol. First, an auxiliary premix is prepared by dissolving mannitol and sorbitol in water followed by spray drying (ordinary spray drying and SBD). Mannitol can additionally be added to this coprocessed mixture. Tablets which additionally contain disintegrants, release agents, pigment and an active ingredient should disintegrate within 60 seconds in the oral cavity.

In US 2002/0071864 A1 a tablet is described which disintegrates within 60 seconds in the oral cavity and is mainly formulated from a physical mixture of spray-dried mannitol and a coarse cross-linked polyvinylpyrrolidone as well as a limited selection of active ingredients. These tablets have a breaking strength of about 40N and produce an unpleasant, sandy mouthfeel. According to US Pat. No. 6,696,085 B2, a type C methacrylic acid copolymer is to be used as disintegrant. The methacrylic acid copolymer type C is a gastric juice-resistant polymer, which is not soluble in the acidic pH range, in the pH range of 7, as it is in the oral cavity, but is water-soluble. In addition to a low breaking strength (<20N), the tablets have a high friability (> 7%) and contain a high proportion in the range of

15% by weight of a coarse-grained disintegrant. Consequently, they have a low mechanical strength and produce an unpleasant, sandy mouthfeel due to the high proportion of coarse disintegrant. EP 0839526 A2 describes a pharmaceutical dosage form consisting of an active ingredient, erythritol, crystalline cellulose and a disintegrant. Furthermore, mannitol is incorporated and crosslinked as disintegrants polyvinylpyrrolidone used, so that a physical mixture is formed. The tablets should disintegrate within 60 seconds in the oral cavity.

In the application JP 2004-265216 a disintegrating in the mouth within 60 seconds tablet consisting of an active ingredient, a water-soluble polyvinyl alcohol-polyethylene glycol copolymer, sugar / sugar alcohol (mannitol) and disintegrants is described. WO 2007071581 describes preparations which consist of a sugar or sugar alcohol and cross-linked polyvinylpyrrolidone which are agglomerated with an aqueous dispersion of a water-insoluble polymer. A disadvantage of these preparations is that tablets produced therefrom undergo considerable prolongations of the disintegration time when stored at elevated temperature and elevated humidity. In addition, the preparations require relatively high amounts of lubricant in the tableting and they tend to stick to the punches.

The object of the present invention was to find quickly disintegrating tablets in the mouth, which leave a pleasant mouthfeel, are mechanically very stable, experience no disintegration prolongations when stored at elevated humidity and temperature and show no tendency to stick in the tableting.

Accordingly, a pharmaceutical preparation has been found which consists of granules containing

a) 60-96% by weight of non-film-forming sugars or sugar alcohols,

b) 1 - 10 wt .-% film-forming sugars or sugar alcohols

c) 3 - 25 wt .-% disintegrant,

d) 0-10% by weight of water-insoluble, film-forming polymers

e) 0 - 15 wt .-% further pharmaceutically customary auxiliaries, consists, wherein the sum of the components a) to e) is 100 wt .-%. Furthermore, a process for the preparation of such preparations in the form of granules was found. The granules are particularly suitable for the production of rapidly disintegrating tablets in the mouth.

Furthermore, rapidly disintegrating tablets containing such preparations were found in the mouth. The tablets disintegrate in the mouth or in an aqueous medium within 40 seconds, preferably within 30 seconds, more preferably within 20 seconds.

As a film-forming in the context of the invention, a sugar or sugar alcohol is then called when an aqueous solution gives a film-like, smooth coating when dried at 45 ° C. Non-film-forming sugars or sugar alcohols show a powdery or crystalline structure after drying.

The pharmaceutical preparations contain as component a) 60-96 wt .-% of at least one non-film forming sugar or sugar alcohol, more preferably 80 to 90 wt .-% non-film-forming sugars, sugar alcohols or mixtures thereof. As non-film-forming sugars or sugar alcohols are mannitol, erythritol, or xylitol. The sugar or sugar alcohol components are preferably finely divided, with mean particle sizes of from 5 to 100 μm. preferably 10 to 80μιη. If desired, the particle sizes can be adjusted by grinding.

Mannitol, xylitol, erythritol or mixtures thereof are preferably used. Very particularly preferred is mannitol.

Component b) used is 1 to 10% by weight of film-forming sugars or sugar alcohols, particularly preferably 2 to 6% by weight of film-forming sugars or sugar alcohols or mixtures thereof. The film-forming sugars or sugar alcohols include: sucrose, glucose, for example in the form of glucose syrup, fructose, lactose, trehalose, sorbitol, maltitol, lactitol, palatinit® (isomalt) and glucose syrup.

To determine the film-forming property, 30.0 g of a 15% strength by weight solution of the sugar or sugar alcohol in water are initially added at 23 ° C. This solution is poured onto glass plates with a depression (dimensions: 20 cm x 6.5 cm, recess 0.3 cm) and dried at 45 ° C for 4 hours and then visually assessed. The measurement takes place in ambient air. The ambient air has a relative humidity of 40% at 23 ° C. The drying can be done for example on the heating plate of a film-drawing device. A film-drawing device, for example, is a commercial device such as the Coatmaster 509 MC. The term "film-forming" refers to the products that are present as a clear film or coating after the drying process.When crystals are visible or the mass appears powdery, the substances are classified as "non-film-forming". Accordingly, for example, a clear film / coating: sorbitol, lactitol maltitol, palatinite, lactose, sucrose, trehalose or glucose. Crystals or a powdery structure form, for example, mannitol, xylitol or erythritol.

As component c) disintegrants in amounts of 3 to 25 wt .-%, preferably, 4 to 20 wt .-%, particularly preferably 5 to 15 wt .-%, are used. Suitable disintegrants are cross-linked polyvinylpyrrolidones, sodium croscarmellose, cross-linked Na-carboxymethyl starch or L-hydroxypropylcellulose (L-HPC). L-HPC is a low substituted hydroxypropyl cellulose with a degree of substitution of 5 to 16% (after drying for 1 h at 105 ° C). It is also possible to use mixtures of these disintegrating agents.

Preferred disintegrants are cross-linked polyvinylpyrrolidones. Such crosslinked polyvinylpyrrolidones are water-insoluble (less than 1 part in 10,000 parts solvent), but not film-forming. The crosslinked polyvinylpyrrolidone may have an average particle size (volume average) of from 2 to 60 μm, preferably from 2 to less than 50 μm, particularly preferably from 2 to less than 30 μm. Very particular preference is given to cross-linked polyvinylpyrrolidones having a hydration capacity of greater than 6.5 g / g. The hydration capacity is determined by the following method:

2 g of polymer are weighed into a centrifuge tube and allowed to swell with 40 ml of water for 15 minutes. The mixture is then centrifuged for 15 minutes at 2000 rpm and the supernatant liquid is poured off as completely as possible. The measurement takes place at 20 ° C.

Hydration Capacity = Weighing Tare

Weighing The high hydration capacity of the cross-linked polyvinylpyrrolidone leads to a very rapid disintegration in the formulation and gives a particularly soft mouthfeel.

Optionally, water-insoluble film-forming polymers in amounts of 0 to 10% by weight, preferably 0 to 6% by weight, particularly preferably 1 to 5% by weight, can be used as component d). Preference is given to polymers which are insoluble in the pH range from 1 to 14, ie have a pH-independent water insolubility at each pH. But also suitable are polymers which are insoluble in water at any pH in the pH range of 6 to 14. The polymers should be film-forming polymers. In this context, film-forming means that the polymers in aqueous dispersion have a minimum film-forming temperature of -20 to + 150 ° C., preferably 0 to 100 ° C. Suitable polymers are polyvinyl acetate, ethyl cellulose, methyl methacrylate-ethyl acrylate copolymers, Ethylaci lat-methyl methacrylate-trimethylammoniumethyl methacrylate terpolymers, or Butylmethaci lat-methyl methacrylate-dimethylaminoethyl methacrylate terpolymers

The acrylate-methacrylate copolymers are described in detail in the European Pharmacopoeia as Polyacrylate Dispersion 30%, in the USP as Ammonio Methacrylate Copolymer and in JPE as Aminoalkyl-Methacrylate Copolymer E.

The preferred component d) is ethylcellulose. Suitable ethylcelluloses usually have an ethoxyl content of 45 to 50%. Such ethylcelluloses and also the determination of the ethoxyl content are described in various pharmacopoeias such as e.g. the USP 34 (201 1) described. The viscosity of the ethyl cellulose, measured as a 5% strength by weight solution in toluene / ethanol 8: 2, is 3 to 400 mPas, preferably 4 to 200 and particularly preferably 5 to 100 mPas. The measurement is carried out at 25 ° C in a Ubbelohde viscometer.

If desired, the taste and appearance of the tablets obtained from the formulations can be further improved by addition of pharmaceutically customary auxiliaries (components e) in amounts of from 0 to 15% by weight, for example as acidifiers, buffer substances, sweeteners, flavors, flavor enhancers and colorants , The following substances are particularly suitable here: citric acid, tartaric acid, ascorbic acid, sodium dihydrogen phosphate, cyclamate, saccharin sodium, aspartame, menthol, peppermint flavor, fruit flavors, vanilla flavor, glutamate, riboflavin, beta carotene, water-soluble dyes, finely divided lakes.

By adding water-soluble polymers, the mouthfeel can be further improved by increasing the softness and the sense of volume. Suitable substances are, for example, polyvinylpyrrolidones, vinylpyrrolidone-vinyl acetate copolymers, polyvinyl alcohols, polyvinyl alcohol-polyethylene glycol graft copolymers, polyethylene glycols, ethylene glycol-propylene glycol block copolymers, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carragenans, pectins, xanthans, alginates. Furthermore, surfactants can also be added as components e). Suitable surfactants are, for example, sodium lauryl sulfate, dioctylsulfosuccinate, alkoxylated sorbitan esters such as polysorbate 80, polyalkoxylated derivatives of castor oil or hydrogenated castor oil, for example Cremophor® RH 40, alkoxylated fatty acids, alkoxylated hydroxyfatty acids, alkoxylated fatty alcohols, alkali metal salts of fatty acids and lecithins.

Furthermore, finely divided pigments can be added to further improve the disintegration because they increase the internal interfaces and thus water can penetrate faster in the tablet. Of course, these pigments such as iron oxides, titanium dioxide, colloidal or precipitated silica, calcium carbonates, calcium phosphates must be very finely divided, otherwise a grainy taste is produced. The formulations according to the invention in the form of granules can be prepared by built-up agglomeration in mixers, fluidized bed apparatus, paddle dryers or spray towers. In this case, solid starting materials and granulation are first brought together and dried the moist material simultaneously or subsequently. According to the present invention, the granulating liquid used is an aqueous solution of component b), the film-forming sugar or sugar alcohol.

Upon agglomeration into granules in the fluidized bed, an aqueous solution of the powdered film-forming sugar or sugar alcohol, which is a fluidized mixture of non-film forming sugar or sugar alcohol and crosslinked PVP, and optionally further polymers or adjuvants, is sprayed, thereby agglomerating the fine particles ,

According to a further embodiment of the invention, a disintegrant, preferably crosslinked PVP, is suspended in the aqueous granulating liquid containing the film-forming sugars or sugar alcohols.

According to a further embodiment of the invention, insoluble film-forming polymer is suspended in the aqueous granulating liquid containing the film-forming sugars or sugar alcohols.

According to a further embodiment of the invention, in the aqueous granulating liquid containing the film-forming sugars or sugar alcohols, a disintegrating agent, preferably crosslinked PVP, and insoluble film-forming polymer are suspended.

In the production in spray towers, the so-called FSD or SBD (fluidized spray drying) technology is preferably used. In this case, a solution of the non-film-forming sugar or sugar alcohol in water is first spray-dried, in the lower part of the spray dryer or in a connected fluidized bed is the addition of crosslinked PVP and the injection of an aqueous solution of the film-forming sugar or sugar alcohol as a spray solution, whereby the particles agglomerate , Fine particles can also be blown again in front of the spray nozzle of the sugar or sugar alcohol solution and additionally agglomerated. It is also possible in the spray tower, FSD or SBD process control starting from the crystalline form of non-film-forming sugar or non-film-forming sugar alcohol. In this case, the crystalline sugar or sugar alcohol is added at the top of the spray tower or in the fine material recycling stream. By spraying an aqueous solution of the film-forming sugar or sugar alcohol, the crystalline solid of the non-film-forming sugar (alcohol) is agglomerated in the tower to give granules.

The spray-drying of the non-film-forming sugar (alcohol) s usually takes place from aqueous solutions with a concentration of 10 to 50 wt .-%. The film-forming sugar alcohol is usually used in the form of aqueous solutions with a concentration of 1 to 40 wt .-%. The concentration of the film-forming sugar alcohol in the aqueous spray solution can also be varied in two or more process steps.

It is crucial for all described embodiments of the granulation process that the process conditions are selected such that a relative exhaust air humidity of greater than 85%, preferably greater than 90% and particularly preferably greater than 95% with an upper limit of 99.5%. results. A relative exhaust air humidity of more than 85% is set by adjusting the spray rate, the supply air temperature, the supply air volume and the humidity of the supply air. The two main parameters are the spray rate and the supply air temperature. An increase in the spray rate and a reduction in the supply air temperature lead to an increase in the exhaust air humidity.

The spray rate can be selected in the range of 3 g to 35 g per minute per kg of powder, preferably 5 g to 30 g per minute per kg of powder.

The supply air temperatures are 20 to 80 ° C, preferably 30 to 60 ° C.

The exhaust air temperatures are 10 to 60 ° C, preferably 10 to 40 ° C and particularly preferably 15 to 30 ° C.

The granulation is preferably carried out at a spray rate of 5 g to 30 g per minute per kg Pulvervor- läge in combination with a supply air temperature of 30 to 60 ° C and an exhaust air temperature of 10 to 40 ° C.

Particularly preferably, the granulation is carried out at a spray rate of 6 g to 18 g per minute per kg powder template in combination with a supply air temperature of 35 to 50 ° C and an exhaust air temperature of 15 to 25 ° C.

The supply air humidity can be up to 99.5% r.F. be.

For the granulation process, it may be beneficial to run a multi-stage spraying process. In this case, the concentration of the aqueous spray solution of the film-forming sugar or sugar alcohol is varied in several steps. Initially, the concentration is kept very low - it may even be 0% by weight (spraying water) - to humidify the submitted materials and to set a high exhaust air humidity. This does not involve agglomeration into granules. Thereafter, the concentration of the aqueous spray solution of the film-forming sugar or sugar alcohol is increased, whereby the submitted materials agglomerate into granules. In the individual stages, the process conditions can be varied within the given limits. Preference is given to a two-stage process in which the spray rate in the first stage is 1.5 to 3 to 3 times the spray rate of the second stage. Particularly preferred is a two-stage process as described above, in which pure water is used as the spray solution in the first stage. The mass ratio of the spray solutions of the first and second stages may be varied from 1 to 5 to 5 to 1, preferably 1 to 2 to 2 to 1.

The granule size can be controlled by the amount of film-forming sugar or sugar alcohol in the product. The more of this substance is introduced, the larger the granules.

As a further adjustment parameter for the granule size, the fineness of the spray droplet of the binder solution (adjustable via the atomizing gas pressure), the nozzle geometry and the distance of the nozzle from the product bed can be considered. The finer and more uniformly sprayed, the finer and more uniform the granules result. The farther the nozzle is away from the product bed, the worse is the agglomeration behavior. The atomization gas pressure is usually in the range from 0.5 to 5 bar, preferably from 1.0 to 3.0 bar. As nozzles usually two-fluid nozzles are used. The nozzle diameters are usually in the range of 0.5 to 4.0 mm, preferably 0.8 to 3.0 mm. The distance of the nozzles from the product bed depends on the size of the atomizer. Which distances are suitable in the individual case can be determined by the person skilled in the art by means of a few customary tests.

After completion of the spraying process, the moist material is dried. In this process, the intake air temperature is increased in order to accelerate the drying process. Typical temperatures are 30-100 ° C. During the drying phase, it may be advantageous to reduce the amount of supply air and thus prevent abrasion of the granules by a high mechanical load.

When produced in a paddle dryer, the materials submitted are sprayed with a solution of the film-forming sugar or sugar alcohol in water and dried simultaneously or subsequently.

Furthermore, the granules can also be prepared in a mixer by means of a continuously guided mixture aggregation. One such continuous type of mixed aggregation is the so-called "Schugi granulation." Solid starting materials and the granulating liquid containing the film-forming sugar or sugar alcohol are intensively mixed in a continuously operating, vertically arranged high-speed mixer (see also M. Bohnet, "Mechanical Process Engineering"). , Wiley VCH Verlag, Weinheim 2004, p. 198 ff.)

The granules thus obtained have an average particle size (volume average) of 100-600 μιη, preferably 120-500 μιη and particularly preferably 140-400 μιη on. The film-forming sugar or sugar alcohol serves as an agglomerating agent to agglomerate the fine non-film-forming sugars or sugar alcohol crystals and the particles of crosslinked PVP. The granules according to the invention can be tabletted with small amounts of lubricant, which results in no significant influence on the disintegration time. Furthermore, the granules according to the invention do not stick to the punches, whereby higher tabletting speeds and shorter tableting processes are achieved. The formulations according to the invention are preferably suitable for the preparation of tablets rapidly disintegrating in the mouth.

The formulations according to the invention can advantageously also be used for the production of tablets which are allowed to disintegrate in a glass of water before use. The production of tablets, which are swallowed intact, is of course possible.

For the production of tablets, the usual methods can be used, wherein the direct tabletting and roll compaction offer particular advantages. Due to the special properties of the formulations according to the invention, generally only the active ingredient, the formulation according to the invention and a lubricant are required. The tablet formulation is thus very simple, very reproducible and easy to validate the procedure.

Surprisingly, it has been found that a film-forming sugar or sugar alcohol can function as a very effective binder with appropriate process control, which also significantly accelerates the disintegration of tablets. In this way, the production of granules is possible which contain neither a water-soluble polymer nor a water-insoluble polymer as a binder. In fact, the use of water-soluble polymers leads to significantly longer disintegration times of tablets, and the use of water-insoluble polymers gives rise to quickly disintegrating tablets, which, however, exhibit considerable disintegration prolongations when stored at elevated temperature and / or elevated humidity.

The disintegration time of the preparations according to the invention is not influenced by increased temperature and humidity.

Furthermore, the preparations according to the invention have exceptionally good flowability and compressibility, which lead to very stable tablets. The breaking strength of the tablets produced with the aid of the pharmaceutical formulations according to the invention is> 50 N. Frequently, the breaking strengths are above 80 N, even when using difficult to press active ingredients. The friability is <0.2%. Damage to the usual tablet handling thus does not occur. Due to the fine cross-linked polyvinylpyrrolidone, the tablets show almost no changes in the tablet surface upon moist storage. In contrast to coarse cross-linked polyvinylpyrrolidone, there is no pilling due to highly swollen particles. The formulations according to the invention are thus very stable on storage and retain their attractive appearance.

The production of the granules takes place, as mentioned, with exhaust air moisture content of at least 85% RH. Such exhaust air moistures are completely unusual, since conventional formulations with such exhaust air humidities completely clump together and can no longer be swirled and processed. Surprisingly, it was found that below 85% RH no satisfactory granulation takes place, but above 85% very uniform granules are formed and the process can be run without any problems.

Examples

Examination on film formation:

To determine the film-forming property, initially at 23 ° C., 30.0 g of a 15% by weight solution of the sugar or sugar alcohol in water were prepared. This solution was poured onto glass plates having a pit (dimensions: 20 cm x 6.5 cm, recess 0.3 cm) and dried at 45 ° C for 4 hours and then visually evaluated. The ambient air had a relative humidity of 40% at 23 ° C. The drying took place on a heating plate of the film applicator Coatmaster 509 MC (Erichsen).

The particle size determinations listed below were carried out by means of a Malvern Mastersizer. Examples A-H show the agglomerating effect of film-forming sugars or sugar alcohols.

Non-film-forming sugar / sugar alcohol and cross-linked PVP and other auxiliaries were introduced in a fluidized bed and with a 3 wt .-% aqueous solution of film-forming sugar or sugar alcohol, in the fluidized bed granulator (Glatt, GPCG 3.1) by top spray method were sprayed, agglomerated.

The following manufacturing conditions were used:

Batch size:

Concentration of the binder solution / dispersion

supply air temperature:

Exhaust air temperature:

spray rate

In all cases, a relative humidity of the exhaust air of greater than 90% was achieved.

Table 1: Formulation composition of granules A to H in% by weight AB c DEFGHI

Xylitol 85 - - - - - - - 82

mannitol

(Pearlitol® 50 C) - 87 87 87 - 83 85 85 - average particle size 50 μιη

erythritol

(Eridex® 16952) ground - - - - 84 - - - - Mean Particle Size 40 μιη

cross-linked PVP

(Kollidon® CL-SF) 12 10 10 10 12 12 10 10 10 average particle size 17 μιτι

Sorbitol 3.0 3.0 - - - 5.0 3.0 3.0 -

Maltitol - - 3.0 - 4.0 - - - 3.0

Lactitol - - - 3.0 - - - - -

Polyvinyl alcohol / polyethylene glycol Block copolymer - - - - - - 2 - - (Kollicoat® IR)

Methacrylic acid / ethyl acrylate copolymer 5.0

(Kollicoat® MAE 100 P)

ethylcellulose

- - - - - - - 2.0 -

Kollicoat® MAE 100 P: powder, 97% by weight of methacrylic acid-ethyl acrylate copolymer (1: 1), 2.3% by weight of polysorbate 80, 0.7% by weight of sodium lauryl sulfate

Ethyl cellulose: 7 mPas, ethoxyl content 48.0 - 49.5%

Kollicoat® IR: Graft copolymer of 25% by weight of PEG6000 and 75% by weight of polyvinyl alcohol side chains, MW 45,000 D.

The granules produced had the following properties: Mean particles

Slope angle [°]

size [μιη]

A 269 31

B 241 31

C 254 31

D 235 31

E 284 30

F 340 29

G 301 30

H 248 31

I 267 31

The particle size was determined by light diffraction and used as average particle size (volume average) of the D (4,3) value.

The granules thus prepared were mixed with 2.0% by weight of lubricant (sodium stearyl fumarate) in a Turbula mixer for 5 minutes. Subsequently, these mixtures were tabletted on a fully instrumented rotary tablet press (Korsch XL 100/8) at a speed of 40 rpm. The rotary tablet press was equipped with 8 punches (10 mm, biplan, faceted). The tablet weight was adjusted to 300 mg. The pressing force was adjusted so that the breaking strength of the tablets was 50 N.

The tablets were tested for breaking strength (tablet tester HT-TMB-CI-12 F, Messrs. Kraemer), friability (Roche Friabilator, Erweka) and disintegration time in phosphate buffer pH 7.2 (disintegration tester ZT 74, Erweka).

Table 2: Tablet properties Formulations A to I

Comparative Examples

Example J (comparative example to B)

Agglomeration of mannitol with a non-film-forming sugar

The preparation was carried out analogously to Example B, but instead of a sorbitol solution, a xylitol solution was used.

There was almost no agglomeration. The mean particle size was 97μιτι and the angle of slope at 44 °. Tableting was not possible due to poor flowability.

Example K (comparative example to B)

Agglomeration at a relative humidity of 70% (less than 85%)

The preparation was carried out analogously to Example B, but the spray rate was adjusted so that a relative exhaust air humidity of 70% resulted.

There was almost no agglomeration. The mean particle size was 89μιη and the slope angle at 43 °. Tableting was not possible due to poor flowability.

Example L (Comparative Example to Example H of WO 2007/071581)

Agglomeration of mannitol with a non-water-soluble film-forming polymer)

The preparation was carried out analogously to Example H of the above cited Offenlegungsschrift.

The disintegration time of the tablets directly after preparation was 30 s. The tablets were then stored at 40 ° C./75% RH and at 60 ° C. for 4 weeks. The disintegration time increased to 180s or 204s. Examples M - P

Examples M to P show the suitability of a fast disintegrating excipient in a drug formulation. The rapidly disintegrating excipient is prepared by agglomeration in the fluidized bed analogously to Example C. The direct tabletting agent thus prepared was mixed with active ingredient and 0.5 to 1.0% by weight of lubricant (Mg stearate) and then pressed on a rotary tablet press (Korsch PH 100/6) into tablets having a breaking strength of 50 N. Table 3: Active ingredient, amount of active ingredient, tablet weight and diameter of the active ingredient formulations M - P

Table 4: Tablet properties Formulations J to M

Examples Q to S

Non-film-forming sugar / sugar alcohol and crosslinked PVP and other auxiliaries were introduced in a fluidized bed and first with demineralized water and then with a 6 wt .-% aqueous solution of the film-forming sugar or sugar alcohol in the fluidized bed granulator (Glatt, GPCG 3.1) sprayed by topspray method, agglomerated. The following manufacturing conditions were used:

Batch size: 2.5 kg

Concentration of binder solution / dispersion: 6% by weight

Supply air temperature: 45 ° C

Exhaust air temperature: 16 - 23 ° C

Spray rate of water 150 g / min

Spray rate Binder solution 60 g / min

Water quantity 1, 25 kg

Amount of binder solution 1, 25 kg

Table 1: Formulation composition of the granules Q to S in% by weight

Q R S

mannitol

(Pearlitol® 50 C) 83 85.0 88.5 average particle size 50 μιη

cross-linked PVP

(Kollidon® CL-F) 12 10 8 average particle size 30 μιη

Sorbitol 3.0 - -

Maltitol - 3,5 -

Lactitol - - 2.5

Ethylcellulose, fine powder, 7

mPas, 48% by weight of ethoxyl groups 2.0 1, 5 1, 0 The granules produced had the following properties:

The particle size was determined by means of light diffraction and used as average particle size (volume average) of the D (4,3) value.

Claims

claims

1 . Pharmaceutical formulation in the form of granules containing

a) 60-96% by weight of non-film-forming sugars or sugar alcohols,

b) 1 - 10 wt .-% film-forming sugars or sugar alcohols

c) 3 - 25 wt .-% disintegrant,

d) 0-10% by weight of water-insoluble, film-forming polymers

e) 0 - 15 wt .-% further pharmaceutically customary excipients

wherein the sum of components a) to e) is 100% by weight.

2. A formulation according to claim 1, characterized in that the average particle size of the granules is 100 μιη to 600 μιη.

3. Formulation according to claim 1 or 2, containing as non-film-forming sugar alcohol mannitol, erythritol or xylitol or mixtures thereof.

4. Formulation according to claim 1 or 2, containing as a film-forming sugar alcohol sorbitol, lactitol, isomalt or maltitol or mixtures thereof.

5. A formulation according to any one of claims 1 to 3, comprising as disintegrants a cross-linked polyvinylpyrrolidone having an average particle size less than 50 μιη.

6. A formulation according to any one of claims 1 to 5, comprising as disintegrants a cross-linked polyvinylpyrrolidone having a hydration capacity greater than 6.5 g / g.

7. A formulation according to any one of claims 1 to 6, wherein acidifiers, sweeteners, flavors, flavor enhancers, dyes, binders, thickeners, surfactants and finely divided pigments are used as further pharmaceutically conventional substances.

8. A formulation according to any one of claims 1 to 7, comprising granules of a) 70-93 wt .-% non-film-forming sugars or sugar alcohols,

b) 2-8% by weight of film-forming sugars or sugar alcohols

c) 4-20% by weight disintegrants,

d) 0-6 wt .-% water-insoluble, film-forming polymers

e) 0 - 15 wt .-% further pharmaceutically customary excipients.

9. A formulation according to any one of claims 1 to 8, containing agglomerates

80-90% by weight of non-film-forming sugars or sugar alcohols, 2-6% by weight of film-forming sugars or sugar alcohols

Gd / Ya 08.02.201 1 0 Fig / 0 Seq c) 5-15% by weight cross-linked polyvinylpyrrolidone,

d) 1 - 5 wt .-% water-insoluble, film-forming polymers

e) 0 - 15 wt .-% further pharmaceutically customary excipients.

10. tablets, obtained using a pharmaceutical formulation according to any one of claims 1 to 9, wherein the tablets have in aqueous medium disintegration times of less than 30 seconds.

1 1. Tablets according to claim 10, wherein the tablets have a breaking strength greater than 50 N.

12. Tablets according to claim 10 or 1 1, containing 20 to 99 wt .-%, based on the total tablet weight, of a pharmaceutical formulation according to any one of claims 1 to 9.

13. Tablets according to one of claims 10 to 12, containing further auxiliaries.

14. A process for the preparation of a pharmaceutical formulation according to any one of claims 1 to 9, characterized in that non-film-forming sugar or sugar alcohol particles and crosslinked polyvinylpyrrolidone are agglomerated with an aqueous solution of the film-forming sugar or sugar alcohol.

A process according to claim 16, characterized in that non-film-forming sugar or sugar alcohol particles are agglomerated with an aqueous solution of the film-forming sugar or sugar alcohol which contains the additionally cross-linked polyvinylpyrrolidone suspended.

A process according to claim 15, characterized in that non-film-forming sugar or sugar alcohol particles are agglomerated with an aqueous solution of the film-forming sugar or sugar alcohol which additionally contains water-insoluble polymer and crosslinked polyvinylpyrrolidone suspended.

17. The method according to any one of claims 14 to 16, characterized in that the agglomeration takes place in a fluidized bed granulator, a mixer, a paddle dryer or a spray tower.

18. The method according to any one of claims 14 to 17, characterized in that the agglomeration is carried out at a relative exhaust air humidity of greater than 85%.

19. The method according to any one of claims 14 to 18, characterized in that the agglomeration is carried out at a relative exhaust air humidity of greater than 90%.

20. The method according to any one of claims 14 to 19, characterized in that the agglomeration is carried out at a relative exhaust air humidity of greater than 95%.

21. Method according to one of claims 14 to 20, characterized in that the granulation is carried out in two stages and in the first stage water is sprayed as granulating liquid onto the powder master.

22. The method according to any one of claims 14 to 21, characterized in that the granulation at a spray rate of 5 g to 30 g per minute per kg powder template in combination with a supply air temperature of 30 to 60 ° C and an exhaust air temperature of 10 to 40 ° C is performed.

23. The method according to any one of claims 14 to 21, characterized in that the granulation at a spray rate of 6 g to 18 g per minute per kg powder template in combination with a supply air temperature of 35 to 50 ° C and an exhaust air temperature of 15 to 25 ° C is performed.