MINI TABLET CONTAINING LOSARTAN FOR PEDIATRIC USE

Description

[0001] Losartan is the international nonproprietary name (INN) for 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-methanol.

[0002] Losartan blocks the interaction of angiotensin II and its receptor and is mainly used to treat high blood pressure, heart failure, ischemic peripheral circulatory disorders, and myocardial ischemia ( Angina pectoris Losartan is used to treat diabetic neuropathy and glaucoma, as well as to prevent the progression of heart failure after myocardial infarction. It is also approved for the treatment of essential hypertension in adults and in children and adolescents aged 6 to 18 years.

[0003] Losartan has also shown beneficial effects in the treatment of diseases such as... Marfan Syndrome, the brittle bone disease ( Osteogenesis ImperfectaOl) or fibrotic diseases such as butterfly disease ( Epidermiolysis Bullosa, EB). Many of these diseases typically occur in children, and treatment must therefore begin in childhood.

[0004] A dosage form containing losartan suitable for pediatric use must therefore meet the requirement that the dose of the therapeutic agent grows with the children, i.e., can be adjusted in the smallest possible steps.

[0005] A formulation of losartan potassium intended for pediatric use, in the form of 2.5 mg / ml powder and solvent for oral suspension, was approved in 2014 under the trade name LORZAAR ®<.

[0006] This formulation contains, in addition to the active ingredient losartan, a variety of other ingredients, namely a powder containing microcrystalline cellulose (E 460), lactose monohydrate, pregelatinized maize starch, vegetable magnesium stearate (E 572), and Opadry WHITE consisting of hyprolose (E 463), hypromellose (E 464), and titanium dioxide (E 171), as well as a solvent containing microcrystalline cellulose (E 460), carmellose sodium, citric acid, water, xanthan gum (E 415), methylparaben (E 218), sodium dihydrogen phosphate monohydrate, potassium sorbate, carrageenan, calcium sulfate, sodium phosphate, glycerol, sweet berry-lemon flavouring, propylparaben (E 216), sodium citrate, saccharin sodium, sorbitol (E 420), and a Defoaming AF emulsion consisting of water, dimethicone, glycerol mono / di [-palmitate, -stearate], macrogol stearate and macrogol.

[0007] According to the LORZAAR® product information, the recommended daily initial dose of losartan potassium for patients aged 6 to 18 years is 0.7 mg / kg, which corresponds to a daily dose of 14 mg to 35 mg of active ingredient for a body weight between 20 kg and 50 kg.

[0008] The LORZAAR® suspension has several disadvantages. Preservatives must be added to maintain its stability. Furthermore, precise dosing is quite cumbersome and virtually impossible without additional aids. Suspensions tend to sediment and therefore must be shaken repeatedly with each use. To mask the extremely bitter taste of losartan, viscosity enhancers such as carrageenan and xanthan gum, as well as several sweeteners and flavorings, are added.

[0009] EP 2 836 207 A1 discloses potassium losartan mini-tablets containing 4 mg losartan.

[0010] An object of the present invention can be seen in providing an oral dosage form containing losartan suitable for pediatric use, which avoids the disadvantages of the dosage form known in the prior art.

[0011] The problem is solved by the mini-tablets containing losartan as defined in the claims.

[0012] The mini-tablets suitable for pediatric applications according to the present invention contain losartan or one of its pharmaceutically acceptable salts. Due to the low active ingredient content, the mini-tablets according to the invention offer the advantage that they are suitable for both precise individual dose adjustment and incremental dose increases, thus allowing flexible adaptation of the dosage to the changing body weight of children by administering whole units.

[0013] For example, in a child weighing 20 kg, the daily dose to be administered is 0.7 mg Losartan per kg body weight, which corresponds to 14 mg Losartan mini-tablets of 1 mg each, 10 mini-tablets of 1.4 mg each or 7 mini-tablets of 2 mg each.

[0014] An increase in body weight of just 2 kg can easily be accommodated by administering an additional mini-tablet of 1.4 mg.

[0015] For easier dosing, mini-tablets according to the present invention can be administered via individually adjustable dosing dispensers. One aspect of the invention therefore relates to a kit comprising 50 to 2,000 losartan mini-tablets according to the invention and a dosing dispenser.

[0016] The mini-tablets according to the invention have a surface area to volume ratio of 2:1 to 6:1 mm -1<.

[0017] The mass of the mini-tablets is preferably 3 mg to 15 mg, preferably 4 mg to 10 mg, and particularly preferably 5 mg to 9 mg.

[0018] Furthermore, preferred mini-tablets according to the invention have a diameter and height of 1 mm to 3 mm, more preferably 1.5 mm to 2.5 mm. This results in a further advantage, namely improved swallowability of these numerous small and therefore easily swallowable units. In addition, mini-tablets with a diameter of up to 3 mm can be safely used in children from the age of two.

[0019] Another advantage of the mini-tablets according to the invention is the improved physical and chemical stability compared to the suspension, so that no preservatives need to be added.

[0020] The pharmaceutical minitablets of the present invention contain the active ingredient losartan, preferably in the form of one of its salts, preferably the potassium salt, with each unit containing a single dose of 1 mg to 3 mg of the active ingredient. Due to the small dimensions of minitablets, losartan must be present in relatively high proportions. Furthermore, minitablets have an increased surface area to volume ratio. Since losartan has poor flow properties and tends to cause tool clogging during formulation, the development of minitablets with a high losartan content presents a particular challenge. Moreover, due to the smaller die openings, special attention must be paid to ensuring good flowability of the formulations during their production.

[0021] The pharmaceutical mini-tablets of the present invention contain, in addition to the active ingredient, one or more excipients, for example one or more fillers, one or more binders, one or more disintegration accelerators and / or one or more lubricants.

[0022] Pharmaceutically acceptable fillers according to the present invention include cellulose derivatives such as microcrystalline cellulose (MCC), methylcellulose, starches, sugar alcohols such as mannitol, sorbitol, or xylitol, acrylate polymers and copolymers, dextrates, dextrin, dextrose, maltodextrin, pectin, and gelatin. Silicified microcrystalline cellulose is a preferred filler. The total amount of fillers is in the range of 20% to 80% by weight, preferably in the range of 30% to 60% by weight, based on the total weight of the composition.

[0023] Pharmaceutically acceptable binders according to the present invention include vinylpyrrolidone-vinyl acetate copolymers (copovidone), hydroxypropylcellulose (HPC), dihydroxypropylcellulose, hydroxyethylcellulose, polymethacrylates, sodium alginate, polyvinylpyrrolidone (povidone), pregelatinized starch, and mixtures thereof. Copovidone is the preferred binder. The total amount of binder is in the range of 0.5 wt% to 10 wt%, preferably in the range of 3 wt% to 7 wt%, based on the total weight of the composition.

[0024] Pharmaceutically acceptable disintegration accelerators according to the present invention include crospovidone, croscarmellose, carboxymethylcellulose, carboxymethyl starch, and mixtures thereof. Crospovidone is the preferred disintegration accelerator. The total amount of disintegration accelerator is in the range of 1 wt.% to 10 wt.%, preferably in the range of 1 wt.% to 4 wt.%, based on the total weight of the composition.

[0025] Pharmaceutically acceptable lubricants according to the present invention include talc, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hexanedioic acid, sodium stearyl fumarate, glycerol fumarate, and mixtures thereof. Preferred lubricants are magnesium stearate and talc. The total amount of lubricant is in the range of 1% to 5% by weight, preferably in the range of 2% to 4% by weight, based on the total weight of the composition.

[0026] Furthermore, the mini-tablets according to the invention may optionally contain brittle excipients to increase the compressive strength of the tablet during compression. Pharmaceutically acceptable brittle excipients according to the present invention include calcium phosphate, tricalcium citrate, mannitol, sucrose, xylitol, and lactitol, as well as mixtures thereof. A preferred brittle excipient is anhydrous dicalcium phosphate. The total amount of brittle excipients, if present, is in the range of 10 wt.% to 30 wt.%, preferably in the range of 15 wt.% to 25 wt.%, based on the total weight of the composition.

[0027] The LORZAAR® suspension known from the prior art contains, in addition to sweeteners, the viscosity enhancers carrageenan and xanthan gum. These excipients contribute to taste masking by increasing the viscosity of the suspension and thus prolonging the time the active ingredient needs to reach the taste receptors on the tongue. In other words, this shortens the contact time of the active ingredient with the taste receptors on the tongue before swallowing. However, this type of taste masking is limited to liquid dosage forms such as suspensions and is therefore not applicable to the solid dosage forms according to the invention.

[0028] The inventors of the present application have found that for pediatric formulations of losartan, which is not only extremely unpleasant-tasting but also highly soluble, the creation of a physical barrier around the losartan is advantageous for optimal taste masking. The mini-tablets according to the invention therefore have a physical barrier that delays the release of the losartan and ideally suppresses the very bitter taste until the mini-tablet has been swallowed by the patient.

[0029] According to the invention, the physical barrier consists of a coating that initially delays the release of the active ingredient. The coating preferably consists of a pharmaceutically acceptable, water-soluble film-forming agent.

[0030] Film formers according to the invention comprise polymers such as hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carmellose, polyvinylpyrrolidone, polyvinyl alcohol or gastro-soluble coatings of polyacrylic acid derivatives such as copolymers of butyl methacrylate, methyl methacrylate and dimethalyminoethyl methacrylate.

[0031] A preferred film former according to the present invention is the water-soluble polymer hydroxypropylmethylcellulose (HPMC).

[0032] In addition, the films may optionally contain plasticizers, such as polyethylene glycol (PEG).

[0033] Film formers and plasticizers are preferably used in a ratio of 20 to 1 to 5 to 1, preferably from 12 to 1 to 8 to 1.

[0034] For pediatric applications, a one-minute delay in the release of losartan from the mini-tablet is usually sufficient. The delay in drug release has been found to correlate with the film thickness.

[0035] Thus, a coating (mass coverage) of 5 mg / cm² resulted in a film thickness of 35 µm to 45 µm and a one-minute delay in drug release. With a doubled amount, i.e., 10 mg / cm², the film thickness was 75 ± 10 µm, and the release of losartan from the minitablets occurred accordingly only after two minutes in significant quantities.

[0036] Another aspect of the present invention therefore relates to mini-tablets containing losartan and a coating, wherein the release of losartan in a significant amount occurs at the earliest after 30 seconds after administration of the dosage form, preferably at the earliest after between 1 minute and 5 minutes, and particularly preferably after between 2 minutes and 5 minutes.

[0037] Another aspect of the present invention relates to mini-tablets containing losartan and a coating, wherein the thickness of the coating is between 20 µm and 100 µm, preferably between 35 µm and 85 µm and particularly preferably between 65 µm and 85 µm.

[0038] To mask or improve the taste of the mini-tablets according to the invention, complexing agents such as cyclodextrins or ion exchangers, lipoproteins with a high affinity for taste receptors such as adenosine monophosphate, and taste-enhancing agents such as sweeteners and flavorings can also be added.

[0039] The mini-tablets according to the invention can be produced by a process in which, in a first step, granules are produced from losartan and one or more fillers. In a second step, the granules obtained in the first step are mixed with one or more binders and one or more disintegration accelerators. Optionally, the binder can already be contained in the granules. In a third step, one or more lubricants are added to the mixture obtained in the second step. In a fourth step, the mixture is compressed into tablet cores, and in a fifth step, the tablet cores are coated. Further details of the manufacturing process are given in the examples.

[0040] The mini-tablets according to the invention are particularly suitable for pediatric applications such as the treatment of essential hypertension, the MarfanThe inventive mini-tablets are suitable for the treatment of syndromes, osteogenesis imperfecta, and fibrotic diseases, as they ensure both a low initial dose and the ability to adjust the dose to body weight in small increments. A preferred application is in the treatment of epidermolysis bullosa, where the mini-tablets contain 1 mg to 2 mg, preferably 1.3 mg to 1.7 mg, of losartan potassium.

[0041] Another preferred embodiment of the present invention relates to a mini-tablet for pediatric applications with a surface area to volume ratio of 2:1 to 6:1 mm -1< , containing losartan or one of its pharmaceutically acceptable salts, one or more excipients and a coating, whereby the release of the active ingredient after ingestion is delayed by 30 seconds or longer.

[0042] Another preferred embodiment of the present invention relates to a mini-tablet for pediatric applications with a surface area to volume ratio of 2:1 to 6:1 mm -1< , containing 0.5 mg to 4 mg losartan or one of its pharmaceutically acceptable salts, 20 wt.% to 80 wt.% of one or more fillers and a coating containing one or more film-forming agents, whereby the release of the active ingredient after ingestion is delayed by between 1 and 5 minutes.

[0043] Another preferred embodiment of the present invention relates to a mini-tablet for pediatric applications having a surface area to volume ratio of 2:1 to 6:1 mm⁻¹, a total weight of 3 mg to 15 mg, containing 1 mg to 3 mg of losartan or one of its pharmaceutically acceptable salts, 20 wt.% to 80 wt.% of one or more fillers, 0.5 wt.% to 10 wt.% of one or more binders, 1 wt.% to 10 wt.% of one or more disintegration accelerators, 1 wt.% to 5 wt.% of one or more lubricants, and a coating containing one or more polymers and optionally one or more plasticizers, whereby the release of the active ingredient is delayed by between 1 and 5 minutes after ingestion.

[0044] Another preferred embodiment of the present invention relates to a mini-tablet for the treatment of epidermolysis bullosa with a surface area to volume ratio of 2:1 to 6:1 mm², a total weight of 5 mg to 8 mg, and a diameter and height of 1.5 mm to 2.5 mm, containing 1.3 mg to 1.7 mg of losartan potassium, 30 wt.% to 60 wt.% microcrystalline cellulose, 3 wt.% to 7 wt.% copovidone, 1 wt.% to 4 wt.% crospovidone, 2 wt.% to 4 wt.% of a mixture of magnesium stearate and talc, and a coating consisting of hydroxypropyl methylcellulose (HPMC), whereby the release of the active ingredient after ingestion is delayed by between 2 and 4 minutes. EXAMPLE 1

[0045] In a first step, losartan potassium (42.7%) and silicified microcrystalline cellulose (57.3%) are mixed and a dry granulate is produced using a roller compactor.

[0046] The particle size of the granules is one of the factors that influence their flowability. Generally, flowability increases with increasing particle size, with particles larger than 250 µm considered free-flowing, particles smaller than 100 µm considered cohesive, and particles smaller than 10 µm considered extremely cohesive.

[0047] Table 1 shows that the mean particle size increases with increasing specific compaction force (SCC). For granules compacted with an SCC of 6 kN / cm², only 10% of all particles are smaller than 100 µm. Particle size determination was performed using a Camsizer XT with compressed air dispersion (x-jet, dispersion pressure: 30 kPa, digital image processing with a two-camera system; measuring range 1 µm - 3 mm). Table 1: Particle diameter of the granules SSK = 2 kN / cm SSK = 4 kN / cm SSK = 6 kN / cm Average particle diameter [µm] D 10 59 ± 1 75 ± 1 101 ± 14 D 50 634 ± 12 799 ± 8 832 ± 12 D 90 1135 ± 4 1183 ± 4 1204 ± 4

[0048] A preferred embodiment of the present invention therefore relates to a granulate containing losartan, characterized in that only 10% of all particles (D 10 ) are smaller than 100µm.

[0049] Another parameter for flow behavior is the so-called Hausner factor. The smaller the Hausner factor, the better the flow behavior (see Table 2). A triple determination of the Hausner factor according to Ph.Eur. 2.9.36 for granules produced at a flow coefficient of 6 kN / cm² yielded a Hausner factor of 1.33 ± 0.03, which corresponds to moderate flow behavior but is considered sufficient under the given difficult conditions. Hausner factor Table 2: according to Ph.Eur. 2.9.36 Flow behavior Hausner factor Compressibility index excellent 1,00-1,11 1-10% Good 1,12-1,18 11-15% satisfactory 1,19-1,25 16-20% moderate 1,26-1,34 21-25% bad 1,35-1,45 26-31% very bad 1,46-1,59 32-37% insufficient > 1,60 > 38%

[0050] A preferred embodiment of the present invention therefore relates to the production of a losartan-containing mini-tablet from a granulate with a Hausner -factor of 1.34 or lower.

[0051] In a second step, the granules obtained in step 1 are first mixed with the copovidone and the crospovidone. Magnesium stearate and talc are then added, and the resulting mixture is tableted using a rotary tablet press, with sieving steps being incorporated if necessary. The composition of the resulting mini-tablets is shown in Table 3. Table 3. Composition of the mini-tablets material function Amount [mg] per unit Crowd [%] Losartan potassium Active ingredient 2,50 38.46 Silicified microcrystalline cellulose Filler 3,34 51.54 Copovidon binder 0,33 5.00 Crospovidone decay accelerator 0,13 2.00 Magnesium stearate lubricant 0,13 2.00 talc 0,07 1.00 In total: 6,50 100

[0052] To withstand the subsequent coating step, the mini-tablets must possess sufficient breaking strength. Breaking strength increases with increasing compression pressure during tableting. The mini-tablets according to the invention already exhibited sufficient breaking strength of approximately 0.9 MPa at a compression pressure of 100 MPa. A further preferred embodiment of the present invention therefore relates to mini-tablets containing losartan that have an average breaking strength of 0.9 MPa or higher.

[0053] Friability can also be used as a parameter for assessing the mechanical properties of minitablets. Therefore, a friability test of the minitablets according to the invention was carried out in accordance with Ph. Eur. 2.9.7. The minitablets showed a friability of 0.14 ± 0.03%, which is well below the limit of 1.0% according to the European Pharmacopoeia. A further preferred embodiment of the present invention therefore relates to minitablets containing losartan that exhibit a friability of less than 1%, preferably less than 0.5%, and even more preferably less than 0.2%.

[0054] The average active ingredient content of the mini-tablets according to the invention was determined in accordance with Ph.Eur. 2.9.40. Table 4. Active ingredient content of the mini-tablets (n=10) Average [%] s [%] rsd [%] Acceptance value Limit (Ph.Eur. 2.9.40) 100,8 4,8 4,7 11,5 15

[0055] Table 4 shows that the mean content of losartan, taking into account the standard deviation, is within the acceptance value specified by the pharmacopoeia.

[0056] The uncoated mini-tablets obtained in step 2 are coated in a fluidized bed using bottom spraying in a third step. The coating solution contains demineralized water, 12 wt% hydroxypropyl methylcellulose (HPMC), and 1.2 wt% polyethylene glycol (PEG 6000). After a heating step, the spraying process is followed by a drying step. The equipment settings for the coating process are shown in Table 5. Table 5: Coating process - Device settings Device Mycrolab fluid analyzer (Hüttlin, Germany) Inner diameter of the nozzle 0.8 mm Spray pressure 1.0 bar microclimate 0.15-0.25 bar supply air temperature 48°C supply air volume 13 m³ / h Pump rate 1.3g / min

[0057] Some parameters of the mini-tablets produced in this way are listed in Table 6. Table 6. Dimensions of the mini-tablets (n=20) Diameter [mm] Height [mm] Mass [mg] 2,15 ± 0,01 2,21 ± 0,03 7,96 ± 0,32

[0058] Figure 1 shows a size comparison of the mini-tablets produced in this way.

[0059] Dissolution studies of the mini-tablets produced in this manner were carried out in phosphate buffer pH 6.0 at 37 ± 0.5°C using a basket apparatus according to Ph.Eur. Drug release was measured by HPLC with a UV-Vis detector.

[0060] How Figure 4 The release of the active ingredient from uncoated minitablets is virtually immediate. In contrast, the release profiles of coated minitablets exhibit an initial delay in drug release. Compared to uncoated minitablets, this avoids the bitter taste of losartan while the minitablets remain in the patient's mouth.

[0061] The initial delay in drug release increases with increasing polymer deposition. A mass deposition of 5 mg / cm², corresponding to a film thickness of 35 µm to 45 µm, resulted in a delay in the release of losartan of over one minute. At a mass deposition of approximately 10 mg / cm², corresponding to a film thickness of 75 ± 10 µm, the drug was released with a delay of over two minutes.

[0062] SEM image of a cross-section of a mini-tablet coated with 5 mg / cm² polymer in Figure 2 as well as the micro-computed tomography (µCT) scan of a cross-section of a mini-tablet coated with 10 mg / cm² polymer in Figure 3 Each shows a uniform coating with a complete and intact film.

[0063] As from Figure 4It is also evident that there is no further delay beyond the initial delay, so that over 90% of the active ingredient is released equally from both film-coated and unfilm-coated mini-tablets after 20 minutes.

[0064] The coating according to the invention thus ensures a taste-masking effect, which can be elegantly controlled via the mass coverage or layer thickness of the film.

[0065] As can be seen from Table 7, the film-coated mini-tablets according to the invention exhibit very good storage stability. Film-coated mini-tablets were stored for 6 months under two different standard conditions under various packaging conditions (open, polyethylene (PE) and aluminum foil (Alu)) and subsequently the impurities were removed according to USP 39 Monograph on losartan tablets as determined as follows: Table 7. Stability data 6 M25 °C / 60 % rh 6 m 40 °C / 75 % rh pollution Open PE Aluminum Open PE Aluminum "1H Dimer" ND ND ND < 0.1 % < 0.1 % < 0.1 % "2H Dimer" ND ND ND ND ND < 0.1 % Other impurities ND ND ND < 0.1 % < 0.1 % ND Total unknown impurities < 0,1 % 0,10 % < 0,1 % 0,11 % 0,13 % 0,.13 % Total impurities < 0,1 % 0,10 % < 0,1 % 0,11 % 0,13 % 0,13 % EXAMPLE 2

[0066] Table 8. Composition of the mini-tablets material function Amount per mini tablet Portion [%] Losartan potassium Active ingredient 1,5 27,27% Silicified microcrystalline cellulose Filler 2,16 39,27% Dicalcium phosphate anhydrous Brittle auxiliary material 1,3 23,64% Copovidon binder 0,26 4,73% Crospovidone decay accelerator 0,11 2,00% Magnesium stearate lubricant 0,11 2,00% talc 0,06 1,09% In total: 5.5 mg 100,00

[0067] The inventive mini-tablets are produced by first mixing losartan, silicified microcrystalline cellulose, calcium phosphate, and copovidone, and producing a dry granulate using a roller compactor. In a further step, the dry granulate obtained in step 1 is mixed with crospovidone. Subsequently, magnesium stearate and talc are added in two separate mixing steps. The resulting mixture is tableted on a rotary press. The resulting mini-tablets are coated using bottom spraying in a fluidized bed. For the composition of the spray solution, see Example 1. After a heating step, the spraying process is followed by a drying step.

[0068] The mini-tablets according to example 2 are particularly suitable for use in the treatment of the disease Epidermolysis Bullosa due to their active ingredient content.

Claims

1. A minitablet for the use in the treatment of pediatric diseases which contains Losartan or one of its pharmaceutically acceptable salts and is characterized by a ratio of surface to volume of 2:1 to 6:1 mm-1, characterized in that it contains 1 mg to 3 mg of Losartan or one of its pharmaceutically acceptable salts, and further comprises a coating which after taking delays the release of the active ingredient Losartan by 1 minute or longer.

2. The minitablet for the use according to claim 1 characterized by a total weight of 3 mg to 15 mg, preferably 4 mg to 10 mg, particularly preferred 5 mg to 8 mg.

3. The minitablet for the use according to any of the preceding claims, characterized by a diameter as well as a height of 1 mm to 3 mm, preferably 1.5 mm to 2.5 mm.

4. The minitablet for the use according to any of the preceding claims further comprising one or more fillers selected from the group consisting of microcrystalline cellulose (MCC), methylcellulose, starches, sugar alcohols such as mannitol, sorbitol or xylitol, dextrates, dextrin, dextrose, maltodextrin, pectin, and gelatin.

5. The minitablet for the use according to any of the preceding claims further comprising one or more binders selected from the group consisting of vinylpyrrolidone vinylacetate copolymers (copovidone), hydroxypropylcellulose (hpc), dihydroxypropylcellulose, hydroxyethylcellulose, polymethacrylates, sodium alginate, polyvinylpyrrolidone (povidon), pregelatinized starch.

6. The minitablet for the use according to any of the preceding claims further comprising one or more disintegrators selected from the group consisting of crospovidone, croscarmellose, carboxymethylcellulose as well as carboxymethyl starch.

7. The minitablet for the use according to any of the preceding claims further comprising one or more lubricants selected from the group consisting of magnesium stearate, talcum, calcium stearate, sodium stearate, stearic acid, hexanedioic acid, sodium stearyl fumarate, calcium behenate, sodium glyceryl behenate as well as glycerin fumarate.

8. The minitablet for the use according to any of the preceding claims wherein the coating contains one or more polymers.

9. The minitablet for the use according to any of the preceding claims wherein the thickness of the coating is between 20 µm and 100 µm, preferably between 35 µm and 85 µm and particularly preferred between 65 µm and 85 µm.

10. The minitablet for the use according to any of the preceding claims wherein the pediatric disease is selected from the group consisting of the essential hypertension, the Marfan's syndrome, imperfect osteogenesis as well as fibrotic diseases.

11. The minitablet for the use according to claim 10 wherein the fibrotic disease is bullous epidermolysis and the minitablet contains 1 mg to 2 mg, preferably 1.3 mg to 1.7 mg of Losartan potassium.

12. A kit for individually adjusting the dose comprising a dosing dispenser as well as 50 to 2000 minitablets for the use according to any of the preceding claims.

13. A method for preparing a minitablet for the use according to claims 1 to 12 which comprises the process steps of i. preparing a granulate of Losartan, at least one or more fillers as well as optionally further excipients, ii. mixing the granulate obtained in the first step with one or more disintegrators as well as optionally one or more excipients, iii. mixing the mixture obtained in the second step with one or more lubricants as well as optionally one or more excipients, iv. compacting the mixture to minitablets, v. coating the minitablets.