JP2014507454A - Pharmaceutical formulation for manufacturing fast-disintegrating tablets - Google Patents

Abstract

a) 60-96% by weight non-film-forming sugar or sugar alcohol, b) 1-10% by weight film-forming sugar or sugar alcohol, c) 3-25% by weight disintegrant, d) 0- Granular pharmaceutical formulation comprising 10% by weight of a water-insoluble film-forming polymer, e) 0-15% by weight of further conventional pharmaceutical additives, the sum of components a) -e) being 100% by weight .
[Selection figure] None

Description

  The present invention relates to a granular pharmaceutical preparation for producing a fast-disintegrating tablet comprising a non-film-forming sugar or sugar alcohol, a film-forming sugar or sugar alcohol, a crosslinked polyvinylpyrrolidone, and a water-insoluble polymer.

  Tablets that disintegrate rapidly and / or dissolve rapidly in the mouth are becoming increasingly important for oral administration of drugs. The tablets should disintegrate in the mouth within a short time, at most within 30 seconds, have a pleasant taste and should not leave a rough feel. In addition, the tablets are easy to produce due to direct compression, which offers significant advantages over wet granulation processes, and are high enough to withstand packaging procedures, transportation and squeeze out of the packaging. Should have mechanical strength.

  The products and methods described thus far are only inadequate, even if these requirements are met.

  Fast-disintegrating tablets should consist of sugars and sugar alcohols, effervescent systems, microcrystalline cellulose, and other water-insoluble excipients such as calcium hydrogen phosphate, cellulose derivatives, corn starch, or polypeptides There are many. In addition, water-soluble polymers, conventional disintegrants (cross-linked PVP, cross-linked carboxymethyl cellulose Na and Ca salts, sodium carboxymethyl starch, L-HPC which is low substituted hydroxypropyl cellulose), and essentially inorganic Use water-insoluble components (silicon dioxide, silicates, inorganic pigments). In addition, the tablets can contain a surfactant.

  WO2003 / 051338 describes an auxiliary formulation containing mannitol and sorbitol that can be directly compressed and easily compressed. First, an auxiliary premix is prepared by dissolving mannitol and sorbitol in water followed by spray drying (conventional spray drying and SBD methods). Mannitol can be further added to the co-processing mixture. Tablets further include disintegrants, sustained release agents, pigments, and active ingredients that reportedly disintegrate in the oral cavity within 60 seconds.

  US2002 / 0071864A1 states that tablets that disintegrate in the oral cavity within 60 seconds are mainly formulated from a physical mixture of spray-dried mannitol and coarse granular cross-linked polyvinylpyrrolidone, and from a limited selection of active ingredients. It is described that it is formulated. These tablets have a breaking strength of about 40 N and produce an unpleasant and rough feel in the mouth.

  According to US 6,696,085 B2, methacrylic acid copolymer type C appears to be used as a disintegrant. Methacrylic acid copolymer type C is an enteric polymer and is insoluble in the acidic pH range, but is soluble in the pH range 7 as seen in the oral cavity. In addition to the low breaking strength (<20N), the tablets are highly friable (> 7%) and contain a coarse granular disintegrant in a high fraction in the region of about 15% by weight. As a result, the tablets have a low mechanical strength and produce an unpleasant and rough feel in the mouth due to the high fraction of coarse granular disintegrant.

  EP0839526A2 describes a pharmaceutical dosage form consisting of an active ingredient, erythritol, crystalline cellulose, and a disintegrant. In addition, since the disintegrant used, including mannitol, is cross-linked polyvinyl pyrrolidone, a physical mixture is obtained. Tablets are said to disintegrate in the oral cavity within 60 seconds.

  Application JP2004-265216 describes a tablet that disintegrates in the mouth within 60 seconds and comprises an active ingredient, a water-soluble polyvinyl alcohol-polyethylene glycol copolymer, a sugar / sugar alcohol (mannitol), and a disintegrant.

  WO2007071581 describes a formulation consisting of sugar or sugar alcohol and cross-linked polyvinyl pyrrolidone that is aggregated with an aqueous dispersion of a water-insoluble polymer. It is a disadvantage of these formulations that the tablets produced therefrom have a significantly prolonged disintegration time when stored at elevated temperatures and humidity. Furthermore, the formulation requires a relatively large amount of lubricant during tableting and tends to stick to the punch.

WO2003 / 051338 US2002 / 0071864A1 US6,696,085B2 EP0839526A2 Patent application 2004-265216 WO2007071581

  The purpose of the present invention is to leave a pleasant feeling in the mouth, mechanically very stable, does not prolong disintegration time when stored at elevated temperature and humidity, and does not tend to stick during tableting. It was to find a fast-disintegrating tablet.

Therefore,
a) 60-96% by weight of non-film-forming sugar or sugar alcohol
b) 1-10% by weight of a film-forming sugar or sugar alcohol
c) 3-25% by weight of disintegrant
d) 0 to 10% by weight of a water-insoluble film-forming polymer
e) consists of granules containing 0-15% by weight of further auxiliaries customary for medicines,
The sum of components a) to e) is 100% by weight,
A pharmaceutical formulation has been found.

  Furthermore, a method for producing the granular preparation has also been found.

  Granules are particularly suitable for producing oral fast disintegrating tablets.

  Furthermore, an orally rapidly disintegrating tablet containing the above preparation was also found. The tablet disintegrates in the mouth or in an aqueous environment within 40 seconds, preferably within 30 seconds, particularly preferably within 20 seconds.

  Within the context of the present invention, film-forming is used to refer to a sugar or sugar alcohol where a smooth film-like coating is produced when the aqueous solution is dried at 45 ° C. Non-film-forming sugars or sugar alcohols exhibit a powder structure or a crystal structure after drying.

  The pharmaceutical preparation comprises as component a) 60-96% by weight of at least one non-film-forming sugar or sugar alcohol, particularly preferably 80-90% by weight of non-film-forming sugar, sugar alcohol, or A mixture of Suitable non-film-forming sugars or sugar alcohols are mannitol, erythritol, or xylitol. The sugar or sugar alcohol component is preferably finely divided to have an average particle size of 5 to 100 μm, and preferably an average particle size of 10 to 80 μm. If necessary, the particle size can be adjusted by grinding.

  Preference is given to using mannitol, xylitol, erythritol or mixtures thereof. Mannitol is very particularly preferred.

  As component b) 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 are used. Film-forming sugars or sugar alcohols include sucrose, glucose in the form of glucose syrup, fructose, lactose, trehalose, sorbitol, maltitol, lactitol, Palatinit® (isomalt), and glucose syrup .

  In order to measure the film-forming property, first, 30.0 g of an aqueous solution of 15% by weight sugar or sugar alcohol is prepared at 23 ° C. The solution is poured into a glass plate with indentations (dimensions: 20 cm × 6.5 cm, indentation 0.3 cm), dried at 45 ° C. for 4 hours and then visually evaluated. The measurement is performed in ambient air. The ambient air here is 23 ° C. and has a relatively high humidity of 40%. Drying can be performed, for example, on a heating plate of a film-drawing instrument. A suitable film stretching device is, for example, the commercial equipment Coatmaster 509 MC.

  The product present as a transparent film or coating after the drying operation is called “film-forming”. A substance is classified as “non-film-forming” if the crystals are visible and most appear powdery.

  Thus, for example, the following form a transparent film / coating: sorbitol, lactitol, maltitol, palatinit, lactose, sucrose, trehalose, or glucose. The crystal or powder structure is formed, for example, by mannitol, xylitol, or erythritol.

  As component c) a disintegrant is used in an amount of 3 to 25% by weight, preferably 4 to 20% by weight, particularly preferably 5 to 15% by weight. Suitable disintegrants are cross-linked polyvinyl pyrrolidone, croscarmellose sodium, cross-linked Na carboxymethyl starch, or L-hydroxypropyl cellulose (L-HPC). L-HPC is a low-substituted hydroxypropylcellulose having a degree of substitution of 5-16% (after drying at 105 ° C. for 1 hour). Mixtures of these disintegrants can also be used.

  A preferred disintegrant is cross-linked polyvinyl pyrrolidone. The cross-linked polyvinyl pyrrolidone is water-insoluble (less than 1 part per 10000 parts of solvent) but does not form a film. The cross-linked polyvinyl pyrrolidone can have an average particle size (volume average) of 2 to 60 μm, preferably 2 μm or more and less than 50 μm, particularly preferably 2 μm or more and less than 30 μm. Cross-linked polyvinyl pyrrolidone having a hydration capacity of more than 6.5 g / g is very particularly preferred. Here, the hydration capacity is measured according to the following method.

  Weigh 2 g of polymer in a centrifuge tube and fill with 40 ml of water for 15 minutes. The mixture is then centrifuged at 2000 rpm for 15 minutes and the supernatant is discarded as thoroughly as possible. The measurement is performed at 20 ° C.

Hydration capacity = (final weight-tare) / initial weight The high hydration capacity of the cross-linked polyvinylpyrrolidone causes it to disintegrate very rapidly in the formulation, producing a particularly smooth feel in the mouth.

  As component d), the water-insoluble film-forming polymer can optionally be used in an amount of 0 to 10% by weight, preferably 0 to 6% by weight, particularly preferably 1 to 5% by weight. Polymers that are insoluble in the pH range of 1-14, i.e., have pH independent insolubility in water at any pH are preferred. However, more suitable are polymers that are insoluble in water at any pH in the pH range of 6-14.

  The polymer should be a film-forming polymer. In this context, film-forming means that the polymer in the aqueous dispersion has 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 copolymer, ethyl acrylate-methyl methacrylate-trimethylammonium methyl terpolymer, or butyl methacrylate-methyl methacrylate-dimethylaminoethyl methacrylate. Terpolymer.

  Acrylic acid-methacrylic acid copolymers are described in more detail in the European Pharmacopoeia as 30% polyacrylic acid dispersion, USP as methacrylic acid ammonio copolymer, and JPE as aminoalkyl-methacrylic acid copolymer E.

  Ethylcellulose is used as a preferred component d). Suitable ethylcellulose usually has an ethoxyl content of 45-50%. The measurement of the ethyl cellulose and ethoxyl content is also described in various pharmacopoeias such as USP34 (2011). The viscosity of ethylcellulose, measured as a 5% strength by weight solution in toluene / ethanol 8: 2, is 3 to 400 mPas, preferably 4 to 200 mPas, particularly preferably 5 to 100 mPas. Here, the measurement is carried out at 25 ° C. in an Ubbelohde viscometer.

  If necessary, it is obtained from the formulation by adding auxiliary agents (component e) customary for medicines, e.g. acidifying agents; buffer substances, sweeteners, fragrances, seasonings and dyes in amounts of 0 to 15% by weight. The flavor and appearance of the resulting tablet can be further improved. The following substances are particularly suitable here: citric acid, tartaric acid, ascorbic acid, sodium dihydrogen phosphate, cyclamate, sodium saccharin, aspartame, menthol, peppermint flavor, fruit flavor, vanilla flavor, glutamate, riboflavin, Beta-carotene, water-soluble dye, fine powder coloring lake.

  By adding a water-soluble polymer, smoothness and quantity can be increased to further improve the sensation in the mouth. Suitable materials are, for example, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyethylene glycol, ethylene glycol-propylene glycol block copolymer, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carrageenan Pectin, xanthan, alginate.

  Furthermore, surfactants can also be added as component e). Suitable surfactants include, for example, sodium lauryl sulfate, dioctyl sulfosuccinate, alkoxylated sorbitan esters such as polysorbate 80, castor oil such as Cremophor® RH40 or polyalkoxylated derivatives of hydrogenated castor oil, alkoxylated fatty acids , Alkoxylated hydroxy fatty acids, alkoxylated fatty alcohols, alkali metal salts of fatty acids, and lecithin.

  In addition, finely divided pigments can be added to further improve disintegration because the pigments expand the internal interface and thus water penetrates more rapidly into the tablet. These pigments, such as iron oxide, titanium dioxide, colloidal silica or precipitated silica, calcium carbonate, calcium phosphate, must inherently be sufficiently finely divided, otherwise a gritty flavor is produced again.

  In a mixer, fluid bed apparatus, paddle dryer or spray tower, the agglomeration can be increased and the preparation according to the invention in the form of granules. In contrast, the solid starting material and the granulating liquid are first brought into contact with each other and the wet material is dried simultaneously or subsequently. According to the invention, the granulating liquid used is an aqueous solution of the film-forming sugar or sugar alcohol which is component b).

  In the example of agglomeration, a fluidized bed is used to granulate an aqueous solution of film-forming sugar or sugar alcohol, non-film-forming sugar or sugar alcohol, and cross-linked PVP and optionally further polymer or auxiliary fluid. Spray onto the initially charged powder, which is a chemical mixture, thereby agglomerating the microparticles.

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

  According to a further embodiment of the invention, the insoluble film-forming polymer is suspended in an aqueous granulating liquid comprising a film-forming sugar or sugar alcohol.

  According to a further embodiment of the invention, the disintegrant, preferably cross-linked PVP, and the insoluble film-forming polymer are suspended in an aqueous granulating liquid comprising a film-forming sugar or sugar alcohol.

  When producing in a spray tower, preferably the so-called FSD technology or SBD technology (FSD: fluidized spray drying; SBD: spray bed drying) is used. Here, an aqueous film-forming sugar or sugar alcohol solution is first spray-dried, and in the lower part of the spray dryer or in the attached fluidized bed, cross-linked PVP is added to form an aqueous film-forming sugar or sugar alcohol solution. Spraying as a spray solution causes the particles to agglomerate. The fine particles can be blown again into the front of the spray nozzle of the sugar or sugar alcohol solution, and can also be aggregated. In the spray tower, the FSD or SBD treatment procedure can also be started from a crystal form of non-film-forming sugar or non-film-forming sugar alcohol. Here, crystalline sugar or sugar alcohol is added to the top of the spray tower or added to the recycle stream of finely divided material. By spraying an aqueous solution of a film-forming sugar or sugar alcohol, the non-film-forming sugar (alcohol) crystalline solid aggregates into granules in the tower.

  Spray drying of a non-film-forming sugar (alcohol) is usually performed from an aqueous solution having a concentration of 10 to 50% by weight.

  The film-forming sugar alcohol is usually used in the form of an aqueous solution having a concentration of 1 to 40% by weight. The concentration of the film-forming sugar alcohol in the aqueous spray solution can vary between two or more processing steps.

  For all of the embodiments described for the granulation treatment, the treatment conditions are such that the outlet air relative humidity reaches an upper limit of 99.5%, more than 85%, preferably more than 90%, particularly preferably more than 95%. The choice is crucial. An outlet air relative humidity greater than 85% is ensured by adjusting spray rate, inlet air temperature, inlet air volume, and inlet air humidity. The two main adjustment parameters are spray rate and inlet air temperature. An increase in spray rate and a decrease in inlet air temperature also cause an increase in outlet air humidity.

  The spray rate can be selected in the range of 3 to 35 g / min / kg of the initial charge powder, preferably 5 to 30 g / min / kg of the initial charge powder.

  The inlet air temperature is 20 to 80 ° C, preferably 30 to 60 ° C.

  The outlet air temperature is 10 to 60 ° C, preferably 10 to 40 ° C, and particularly preferably 15 to 30 ° C.

  Preferably, granulation is performed by combining a spray rate of 5-30 g / min / kg of the initial charge powder with an inlet air temperature of 30-60 ° C and an outlet air temperature of 10-40 ° C.

  Particularly preferably, the granulation is performed in combination with a spray rate of 6-18 g / min / kg of the initial charge powder and an inlet air temperature of 35-50 ° C. and an outlet air temperature of 15-25 ° C.

  In all of the embodiments described in the specification, the inlet air humidity can be capped at 99.5% relative humidity.

  It can prove that it is preferable to perform a multi-stage spraying process for the granulation process. Here, the concentration of the film-forming sugar or sugar alcohol spray solution varies in two or more steps. Initially, the concentration may be kept very low and even 0% by weight (sprayed with water) to moisten the initial charge and ensure a high outlet air humidity. During this time, it does not start to agglomerate and granulate. The concentration of the film-forming sugar or sugar alcohol spray solution is then increased, thereby agglomerating the initial charge and granulating. In each stage, the processing conditions can vary within the limits described above.

  A two-stage process in which the spray rate of the first stage is 1.5 to 3 times the spray speed of the second stage is preferred. The two-stage treatment as described above, in which pure water is used as the spray solution in the first stage, is particularly preferred. The mass ratio of the spray solution in the first stage and the second stage can vary from 1: 5 to 5: 1, preferably from 1: 2 to 2: 1.

  Granule size can be adjusted by the amount of film-forming sugar or sugar alcohol in the product. The more this material that is introduced, the larger the granules.

  Further adjustment parameters for the granule size can be considered the fineness of the spray droplets of the binder solution (adjustable by the pressure of the spray gas), the nozzle profile and the distance between the nozzle and the product bed. The finer and more uniform the spray performed, the finer and more uniform the resulting granules. The greater the distance from the product bed to the nozzle, the less the agglomeration behavior. Usually, the pressure of the atomizing gas is in the range of 0.5-5 bar, preferably 1.0-3.0 bar. The nozzle used is generally a two-substance nozzle. The nozzle diameter is usually 0.5 to 4.0 mm, preferably 0.8 to 3.0 mm. The distance between the nozzle and the product bed depends on the size of the spray device. Appropriate distances in each case can be confirmed by several routine experiments by those skilled in the art. If the spray process is complete, dry the damp material. In contrast, the inlet air temperature is increased in order to increase the speed of the drying process. Here, the customary temperature is 30-100 ° C. It would be advantageous to reduce the amount of inlet air during the dry phase and thereby prevent wear of the granules due to high mechanical loads.

  In the example of manufacture in a paddle dryer, the initial charge is sprayed with an aqueous solution of a film-forming sugar or sugar alcohol and dried simultaneously or thereafter.

  Furthermore, the granules can also be produced in a mixer by continuously agglomerated mixed agglomeration. One such continuously operated form of mixed agglomeration is the so-called “Schugi granules”. In this case, the solid starting material containing the film-forming sugar or sugar alcohol and the granulating liquid are vigorously mixed (M. Bohnet, “ See also “Mechanische Verfahrenstechnik” [Mechanical process engineering], Wiley VCH Verlag, Weinheim 2004, p. 198 ff.).

  The granules produced by this method have an average particle size (volume average) of 100 to 600 μm, preferably 120 to 500 μm, particularly preferably 140 to 400 μm.

  Here, the film-forming sugar or sugar alcohol serves as an aggregating agent in order to agglomerate the non-film-forming sugar or sugar alcohol microcrystals and the crosslinked PVP particles.

  According to the invention, the granules can be tableted with a small amount of lubricant, but this does not have any effect on the disintegration time. Furthermore, the granules according to the invention do not stick to the punch, thereby increasing the tableting speed and shortening the tableting process.

  The preparation according to the invention is preferably suitable for the production of oral fast-disintegrating tablets.

  The preparation according to the invention can also be used advantageously for the manufacture of tablets which are disintegrated in glass water before use. Of course, it is possible to produce tablets that are swallowed as they are.

  Conventional methods can be used to produce tablets, and direct compression and roll compression are particularly advantageous. Since the formulation according to the invention is of special nature, in principle only the active ingredient, the formulation according to the invention and a lubricant are required. The tablet formulation is therefore very simple and sufficiently reproducible, and the method can be easily demonstrated.

  Surprisingly, it has been found that film-forming sugars or sugar alcohols can act as highly effective binders when properly managed, and further increase the rate of tablet degradation considerably. . In this way, granules containing neither water-soluble nor water-insoluble polymers as binders can be produced. By using water-soluble polymers, the disintegration time of the tablets is significantly increased, and by using water-insoluble polymers, rapidly disintegrating tablets are actually produced but stored at high temperature and / or high humidity. In some cases, the disintegration time is considerably prolonged.

  The disintegration time of the preparation according to the invention is not affected by the elevated temperature and humidity.

  Furthermore, the preparations according to the invention have exceptionally good flowability and compressibility, and the tablets are mechanically very stable. The breaking strength of the tablets produced using the pharmaceutical preparation according to the invention is> 50N. Even with active ingredients that are difficult to compress, the fracture strength is often over 80N. The friability is <0.2%. As a result, no damage occurs during the conventional handling of tablets.

  Since the cross-linked polyvinyl pyrrolidone is fine, the tablet exhibits substantially no change in the tablet surface when stored under humid conditions. In contrast to the coarsely cross-linked polyvinyl pyrrolidone, there is no pimpling due to severe swelling of the particles. Thus, the formulation according to the invention is very stable on storage and maintains a good looking appearance.

  As mentioned above, the granules are produced with an outlet air humidity of at least 85% relative humidity. Conventional formulations are completely agglomerated at the outlet air humidity and cannot be fluidized or processed, so the outlet humidity is not conventional at all. Surprisingly, it has been found that at a relative humidity of less than 85%, sufficient granulation does not occur, but above 85%, very uniform granules are formed and can be processed without problems.

Film formation test:
In order to measure the film-forming property, first, 30.0 g of an aqueous solution of sugar or sugar alcohol having a concentration of 15% by weight at 23 ° C. was prepared. The solution was poured into a hollow glass plate (dimensions: 20 cm × 6.5 cm, hollow 0.3 cm), dried at 45 ° C. for 4 hours, and then visually evaluated. The ambient air here was 23 ° C. and had a relative humidity of 40%. Drying was performed on the heating plate of Coatmaster 509 MC (Erichsen), a film stretching device.

  The following particle size measurements were performed using a Malvern Mastersizer.

  Examples A to H show the aggregation effect of film-forming sugars or sugar alcohols.

  Non-film-forming sugar / sugar alcohol and cross-linked PVP, further auxiliaries are also introduced into the fluidized bed as initial charge and agglomerated with an aqueous solution of film-forming sugar or sugar alcohol at a concentration of 3% by weight. It was sprayed into a fluid bed granulator (Glatt, GPCG 3.1) using the spray method.

The following manufacturing conditions were used:
Batch size: 2.5kg
Binder solution / dispersion concentration: 3% by weight
Inlet air temperature: 60 ℃
Outlet air temperature: 18-25 ° C
Spray rate: 70 g / min In all examples, outlet air with a relative humidity of more than 90% was achieved.

Kollicoat (registered trademark) MAE 100 P: powder, methacrylic acid-ethyl acrylate copolymer (1: 1) 97 wt%, polysorbate 80 2.3 wt%, sodium lauryl sulfate 0.7 wt%
Ethyl cellulose: 7 mPas, ethoxyl content 48.0-49.5%
Kollicoat® IR: 25% by weight of PEG6000 graft copolymer and 75% by weight of MW 45000D polyvinyl alcohol side chain
The granules produced have the following properties:

  The particle size was measured using light scattering, and the average particle size (volume average) used was the D (4,3) value.

  Granules produced in this way were mixed with 2.0 wt% lubricant (sodium stearyl fumarate) in a Tubla mixer for 5 minutes. These mixtures were then tableted at a rotational speed of 40 rpm in a rotary tableting machine (Korsch XL 100/8) fully equipped. The rotary tableting machine was equipped with 8 punches (10mm, double leaf, facet). The tablet weight was adjusted to 300 mg. The pressure was adjusted so that the breaking strength of the tablet was 50N.

Breaking strength (tablet tester HT-TMB-Cl-12F, Kraemer), friability (Roche friability tester, Erweka), and disintegration time in phosphate buffer at pH 7.2 (disintegration tester, ZT74, The tablets were analyzed for Erweka).

Comparative Example Example J (Comparative example of B)
Aggregation of mannitol and non-film-forming sugar Production was carried out as in Example B, but using a xylitol solution instead of a sorbitol solution.

  Substantially no aggregation occurred. The average particle size was 97 μm and the angle of repose was 44 °. Tableting was impossible due to poor fluidity.

Example K (Comparative example of B)
Aggregation at 70% (less than 85%) relative humidity Manufacture was carried out as in Example B, except that the spray rate was adjusted so that the outlet air relative humidity was 70%.

  Substantially no aggregation occurred. The average particle size was 89 μm and the angle of repose was 43 °. Tableting was impossible due to poor fluidity.

Example L (Comparative example of Example H of WO2007 / 071581)
Agglomeration of mannitol and water-insoluble film-forming polymer Manufacture was carried out in the same manner as Example H of the above published specification.

  The disintegration time of the tablet immediately after production was 30 seconds. The tablets were then stored at 40 ° C./75% r.h. and 60 ° C. for 4 weeks. During this time, the decay time increased to 180 seconds and 204 seconds, respectively.

Examples M-P
Examples M to P show the stability of fast disintegrating aids in active ingredient formulations.

The fast disintegrating aid is produced by agglomeration in a fluidized bed as in Example C. The direct tableting composition produced by this method is mixed with the active ingredient and 0.5-1.0% by weight lubricant (Mg stearic acid) and then compressed in a rotary tableting press (Korsch PH 100/6). As a result, a breaking strength 50N tablet was obtained.

Breaking strength (tablet tester HT-TMB-Cl-12F, Kraemer), friability (Roche friability tester, Erweka), disintegration time in phosphate buffer at pH 7.2 (disintegration tester, ZT74, Erweka) The tablets were investigated for.

Examples Q-S
Non-film-forming sugar / sugar alcohol and cross-linked PVP, and further auxiliaries are also introduced into the fluidized bed as initial charge, first desalted water, then 6% strength by weight film-forming sugar / sugar alcohol solution And sprayed into a fluid bed granulator (Glatt, GPCG 3.1) using the top spray method.

The following manufacturing conditions were used:
Batch size: 2.5kg
Binder solution / dispersion concentration: 6% by weight
Inlet air temperature: 45 ℃
Outlet air temperature: 16-23 ° C
Water spray rate: 150g / min Binder solution spray rate: 60g / min Water amount: 1.25kg
Amount of binder solution: 1.25 kg
In all examples, an outlet air relative humidity greater than 90% was achieved.

The granules produced had the following properties:

  The particle size was confirmed using light scattering, and the average particle size (volume average) used was the D (4,3) value.

Claims (23)

a) 60-96% by weight of a non-film-forming sugar or sugar alcohol,
b) 1-10% by weight of a film-forming sugar or sugar alcohol,
c) 3-25% by weight of disintegrant,
d) 0-10% by weight of a water-insoluble film-forming polymer,
e) 0 to 15% by weight of further auxiliaries customary for medicines, the sum of components a) to e) being 100% by weight,
Granular pharmaceutical preparation.   2. The preparation according to claim 1, wherein the average particle size of the granules is 100 μm to 600 μm.   The preparation according to claim 1 or 2, comprising mannitol, erythritol, xylitol, or a mixture thereof as a non-film-forming sugar alcohol.   The preparation according to claim 1 or 2, comprising sorbitol, lactitol, isomalt or maltitol, or a mixture thereof as the film-forming sugar alcohol.   4. The preparation according to any one of claims 1 to 3, comprising a cross-linked polyvinyl pyrrolidone having an average particle size of less than 50 μm as a disintegrant.   6. The preparation according to any one of claims 1 to 5, comprising a crosslinked polyvinylpyrrolidone having a hydration capacity of more than 6.5 g / g as a disintegrant.   7. Use of acidifying agents, sweeteners, fragrances, seasonings, dyes, binders, thickeners, surfactants and fine pigments as further substances customary for medicine. The preparation described in 1. a) 70-93% by weight of a non-film-forming sugar or sugar alcohol,
b) 2-8% by weight of a film-forming sugar or sugar alcohol,
c) 4-20% by weight of disintegrant,
d) 0-6% by weight of a water-insoluble film-forming polymer,
8. A formulation according to any one of claims 1 to 7, comprising 0) to 15% by weight of granules of further auxiliaries customary for medicines. a) 80-90% by weight of a non-film-forming sugar or sugar alcohol,
b) 2-6% by weight of a film-forming sugar or sugar alcohol,
c) 5-15% by weight of crosslinked polyvinylpyrrolidone,
d) 1 to 5% by weight of a water-insoluble film-forming polymer,
9. A formulation according to any one of the preceding claims, comprising e) 0-15% by weight of further auxiliary aggregates customary for pharmaceuticals.   10. A tablet obtained using a pharmaceutical formulation according to any one of claims 1 to 9 having a disintegration time of less than 30 seconds in an aqueous environment.   11. A tablet according to claim 10, having a breaking strength of more than 50N.   12. The tablet according to claim 10 or 11, comprising 20 to 99% by weight of the pharmaceutical preparation according to any one of claims 1 to 9 based on the total weight of the tablet.   The tablet according to any one of claims 10 to 12, comprising further auxiliaries.   10. The pharmaceutical preparation according to any one of claims 1 to 9, wherein the non-film-forming sugar or sugar alcohol particles and the crosslinked polyvinylpyrrolidone are aggregated with an aqueous solution of the film-forming sugar or sugar alcohol. Method.   17. The method according to claim 16, wherein the non-film-forming saccharide or sugar alcohol particles are aggregated with an aqueous solution of film-forming saccharide or sugar alcohol further comprising a crosslinked polyvinylpyrrolidone in suspension.   The non-film-forming sugar or sugar alcohol particles are aggregated with an aqueous solution of a film-forming sugar or sugar alcohol, further comprising a water-insoluble polymer and crosslinked polyvinylpyrrolidone in suspension. The method described in 1.   17. A process according to any one of claims 14 to 16, wherein the agglomeration is carried out in a fluid bed granulator, a mixer, a paddle dryer or a spray tower.   18. A method according to any one of claims 14 to 17, wherein the agglomeration is carried out at an outlet air relative humidity greater than 85%.   19. A method according to any one of claims 14 to 18, wherein the agglomeration is carried out at an outlet air relative humidity greater than 90%.   20. A method according to any one of claims 14 to 19, wherein the agglomeration is carried out at an outlet air relative humidity greater than 95%.   21. A method according to any one of claims 14 to 20, wherein the granulation is carried out in two stages and in the first stage water is sprayed onto the initially charged powder as a granulating liquid.   The granulation is carried out by combining a spray rate of 5-30 g / min per kg of the initial charge powder with an inlet air temperature of 30-60 ° C and an outlet air temperature of 10-40 ° C. The method described in 1.   The granulation is performed by combining a spray rate of 6 to 18 g / min / kg of the initial charge powder with an inlet air temperature of 35 to 50 ° C and an outlet air temperature of 15 to 25 ° C. The method described in 1.