WO2011137894A1

WO2011137894A1 - Melting tablet comprising a triptane or atypical neuroleptic

Info

Publication number: WO2011137894A1
Application number: PCT/DE2011/001022
Authority: WO
Inventors: Staša Vuković; Biljana Stupar; Tijana Mihajlović
Original assignee: Stada Arzneimittel Ag
Priority date: 2010-05-04
Filing date: 2011-05-03
Publication date: 2011-11-10
Also published as: DE102010019416A1; EP2566452A1

Abstract

The invention relates to a melting tablet, comprising a triptane or an atypical neuroleptic as a pharmaceutical active ingredient. The aim of the invention is to provide a tablet that can be applied both as a melting tablet and as a tablet for swallowing. This is achieved by virtue of a melting tablet comprising a triptane or an atypical neuroleptic as a pharmaceutical active ingredient, said melting tablet having a breaking strength greater than/equal to 25 N.

Description

Orodispersible tablet comprising a triptan or an atypical

neuroleptic

The present invention relates to an orodispersible tablet comprising a triotan or an antiviral neuroleic acid as a pharmaceutical active ingredient. Orodispersible tablets are tablets that dissolve relatively quickly in the mouth. They have the advantage that they are also used by persons with dysphagia as well as lying down

can be taken without problems and that the

Under certain circumstances, active substance can also be absorbed via the oral mucosa, which is why the pharmaceutical effect can occur relatively quickly in the case of orodispersible tablets. In addition, orodispersible tablets have the advantage that for their ingestion a Nachtrinken of water is usually not required, so that orodispersible tablets for the

Taking on the road are particularly well suited.

Filmt bletten - in the art as well

Lacquer tablets are called - are tablets for

To swallow. Film-coated tablets consist of a tablet core coated with a very thin layer of polymer. The

For example, the polymer layer can improve the

Applicability by facilitating the swallowability or masking of an unpleasant taste serve.

confirmation copy Triptans and atonic neuroleptics are known in the art. They are used in particular for the treatment of migraine or for the treatment of psychotic symptoms, especially in schizophrenics.

Triptans and atypical neuroleptics are offered both in the form of film and coated tablets. For example, the triptans zolmitriptan and

Rizatriptan under the brand name AscoTop ^® or Maxalt ^{® offered} as a melt and film tablet. The atypical

Antipsychotics olanzapine and aripiprazole, for example, are considered under the brand name Zyprexa ^® and Abilify ^®

Melted and film-coated tablets. The subject melt and film tablets of an active ingredient are formulated differently from each other, wherein the film, in contrast to the tablets are still coated with a Poiymerfilm. The separate production of enamel and film-coated tablets is complicated and cost-intensive.

Thus, there is a need to include a tablet

To provide triptan or an atypical neuroleptic drug as a pharmaceutical agent, which can be administered both as orodine tablet as well as a conventional tablet for swallowing.

It is therefore an object of the present invention to provide a tablet comprising a triptan or an atypical neuroleptic as a pharmaceutical active substance, which can be used both as a fused tablet and as a tablet for swallowing.

This object is achieved by a fused tablet,

comprising a triptan or an atypical neuroleptic as pharmaceutical active ingredient, wherein the orodispersible tablet has a breaking strength F of greater than or equal to 25 N. Surprisingly, it was found that the

Orodispersible tablet according to the invention can be administered both as a fused tablet and as a conventional swallow tablet. Presumably, the relatively high mechanical strength of the orodispersible tablet according to the invention causes a

temporal shift of the beginning of their relatively rapid melting. A separate production of

Melted tablet and film tablet can therefore be omitted, which is why the tablet according to the invention is relatively inexpensive to produce.

The orodispersible tablet according to the invention also has the advantage of being bioequivalent both to corresponding ones

Melted tablets and corresponding film tablets can be configured.

In addition, the orodispersible tablet according to the invention has the advantage that, as evidenced by its relatively high breaking strength F, it is relatively stable mechanically and therefore less, as is usual with orodispersible tablets, too

Damage tends. The melt tablet according to the invention can therefore be offered, for example, in blister packs by blistering and does not have to be packaged in unpractical blisters with a peel film, as is otherwise customary, which increases patient acceptance.

The tablet according to the invention is an orodispersible tablet. The European Pharmacopoeia {Ph.Eur) defines orodispersible tablets as uncoated tablets that are kept in the mouth where they quickly disperse before being swallowed, with orodispersible tablets having a disintegration time according to Ph. Eur. 2.9.1 of less than or equal to 3 minutes. The orodispersible tablet according to the invention satisfies this definition, although alternatively it can also be swallowed before it spreads in the mouth. Accordingly, in the context of the present invention, the term "orodispersible tablet" is understood to mean an uncoated tablet which is retained in the mouth, where it is rapidly distributed, before it is swallowed, or swallowed before it has spread in the mouth, being a

Decay time according to Ph.Eur. 2.9.1 less than or equal to 3 minutes.

In the tablet according to the invention, a triptane can be contained as an active ingredient. Triptans are known in the art (see Mutschier et al.

Textbook of Pharmacology and Toxicology. 9th Edition, 2008. (ISBN 978-3-8047-1952-1)). Triptans are 5-HT _{1B / 1D} receptor agonists and are preferably used for the acute treatment of migraine and cluster headache. Their mechanism of action is based on selective stimulation of Serotoni (5-hydroxytryptamine (5-HT)) receptors of subtype 5

HTIB / ID · Alternatively, an atypical neuroleptic may be included as an active ingredient in the orodispersible tablet according to the invention.

Atypical neuroleptics are known in the art (see Mutschier et al., Arzneimittelwirkungen, Lehrbuch der

Pharmacology and Toxicology, 9th Edition 2008, {ISBN 978-3-8047-1952-1)). Atypical neuroleptics are thereby

characterized that they compared with the older ones

tricyclic neuroleptics and the 3-propyltronenes and

Diphenylbutylpiperidinen either barely or at least

cause significantly less extrapyramidal motor side effects and also the negative symptoms favorable

influence .

The triptane or atypical antipsychotic may be in the form of the free base or in the form of a pharmaceutically acceptable Salt in the fusible tablet according to the invention

be.

The orodispersible tablet according to the invention has a

Breaking strength F of greater than or equal to 25 N on. The

Breaking strength F is according to Ph.Eur. 2.9.8 to determine. It is inventively preferred that the breaking strength F is measured by means of a tablet hardness tester by uniaxial vertical load between two horizontal jaws with plane-parallel surfaces by recording a controlled force-displacement curve, wherein placed in the measurement, the sample on the lower jaw and whereupon the upper jaw is progressively lowered. According to the invention, it is particularly preferred that the breaking strength F is determined by means of a tablet hardness tester from ERWEKA International AG, Switzerland,

Device type: TBH 250 IC, is determined. Round tablets, i. Tablets having a circular cross-section such as e.g. round flat biplane tablets, are used at the

Breaking strength measurement over the web {i.e. radial)

broken.

As stated above, the inventive

Orodispersible tablet a fracture strength F according to Ph.Eur. 2.9.8 greater than or equal to 25N. In this context it is

preferred that the extreme values in determining the

Breaking strength F measured forces are in a range of 20 N to 60 N, more preferably in a range of 25 N to 55 N. According to a preferred embodiment of

fused tablet according to the invention, it is provided that the orodispersible tablet has a breaking strength F of greater than or equal to 25 N to 55 N, preferably a breaking strength F of 27 N to 45 N and particularly preferably a breaking strength F of 30 N to 40 N. The breaking strength F of invention For example, Schrne1 z abletfce can be sorted by type and. Amount of binder used and the size of the

applied pressing force can be adjusted in the tableting.

The breaking strength F of a tablet may depend on its shape and dimensions. It may therefore be preferred according to the invention, the mechanical strength of

Tablet according to the invention as compressive strength σ indicate, since the compressive strength σ the geometry of the tablet

and thus one of them, in principle, independent

Size represents. The compressive strength σ is calculated by means of the experimentally determined fracture strength F. For example, for cylindrical tablets

Compressive strength σ by means of the following mathematical

Compound calculated (see "The Tablet ^" ', A. itschel et al., 2nd edition, Editio-Cantor-Verlag, 2002, ISBN 3-87193-228-0):

2F

σ =

nDt in which

- σ is the compressive strength;

- F is the breaking strength;

- π is the number pi;

D is the tablet diameter;

- t is the tablet thickness.

For curved tablets, for example, the compressive strength σ is calculated by means of the following mathematical relationship (see "The tablet", A. Ritschel et al., 2nd edition, Editio-Cantor-Verlag, 2002, ISBN 3-87193 -228-0): IOF

(2.84-- 0.126- + 3.15- + 0.01j

TTD ² in which

- σ is the compressive strength;

- F is the breaking strength;

- π is the number pi;

D is the tablet diameter;

- the thickness over everything

- W is the thickness of the central cylinder.

According to the invention, it is preferable for the orodispersible tablet to have a compressive strength σ of greater than or equal to 0.55 N / mm ² , preferably a compressive strength σ in a range of 0.55 ii A * - in a range of 0.60 N / mm ² to 1.50 N / mm ² and more preferably a compressive strength σ in a range of 0.70 N / mm ² to 1.30 N / mm ² .

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the orodispersible tablet is cylindrical.

According to a further preferred embodiment of the

melting tablet according to the invention, it is provided that the orodispersible tablet has a disintegration time of less than or equal to 60 s, preferably a disintegration time of 10 s to 30 s and more preferably a disintegration time of 10 s to 20 s. The decay time is according to Ph.Eur. 2.9.1, preferably using water as the medium.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the orodispersible tablet has a friability of less than or equal to 1%. and most preferably a friability of 0.1% to 0.4%. The friability is according to Ph.Eur. 2.9.7 to determine. According to a further preferred embodiment of the

According to the invention orodispersible tablet, it is provided that the triptane is selected from the group consisting of

Almotriptan, avitriptan, donitriptan, eletriptan,

Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan and

Zolmitriptan.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the triptane is selected from the group consisting of

Zolmitriptan and rizatriptan.

According to a further preferred embodiment of the

According to the invention orodispersible tablet it is provided that the atypical neuroleptic is selected from the group

consisting of clozapine, olanzapine, quetiapine, zotepin,

Sulpiride, amisulpride, risperidone, ziprasidone and aripiprazole.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the atypical neuroleptic is selected from the group

consisting of olanzapine, risperidone and aripiprazole.

According to a further preferred embodiment of the

It is contemplated that the atypical antipsychotic drug is aripiprazole.

If a tablet is prepared by mixing a granulate with pharmaceutical excipients and the resulting mixture is compressed into a tablet, so in this formulation type between an inner phase (granules) and cinci uuc cn rriicitn-; (nii L ü l L unc, _i_.ii nc ^ ucii

Granules embedded) is differentiated. According to a further preferred embodiment of the invention

Melt tablet it is envisaged that the orodispersible tablet comprises an inner phase and an outer phase, wherein the inner phase contains the active ingredient.

According to a further preferred embodiment of the

melting tablet according to the invention, it is provided that the inner phase comprises a water-soluble and a water-insoluble pharmaceutical filler. Fillers serve the purpose of increasing the volume of tablets to a suitable size, especially for low-dose tablets. The

The amount of filler depends on its nature, the size of the tablet and the amount of the active ingredient. Water-soluble is understood as meaning a solubility in water at a temperature of 15 ° C. to 25 ° C. of more than 33 mg per ml, preferably one

Water solubility from 100 mg per ml to 1000 mg per ml. Under water insoluble becomes a water solubility at a

Temperature of 15 ° C to 25 ° C understood of less than 1 mg per ml, preferably a water solubility of less than 0, 1 mg per ml.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the water-soluble filler is selected from the group consisting of a sugar and a sugar alcohol.

According to a further preferred embodiment of the

melting tablet according to the invention, it is provided that the sugar or the sugar alcohol is selected from the group consisting of dextrose, lactose, mannitol, sorbitol,

Sucrose and xylitol. According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the water-soluble filler is mannitol. According to a further preferred embodiment of the

fused tablet according to the invention, it is provided that the water-insoluble filler is selected from the group consisting of aluminum hydroxide, barium sulfate,

Calcium carbonate, calcium phosphate, calcium sulfate,

Magnesium carbonate, magnesium trisilicate, kaolin, cellulose, preferably microcrystalline cellulose, and starch.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the water-insoluble filler is microcrystalline cellulose.

According to a further preferred embodiment of the

melting tablet according to the invention, it is provided that the weight ratio of water-soluble to water-insoluble filler in the inner phase is in a range of 1 to 10, preferably in a range of 6 to 10 and more preferably in a range of 8 to 10.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the proportion of the inner phase of water-soluble and

.? τ.τΐι ί _* ώ ^ ι ΙΤΊΙ AEE l ^■ ii ~ -_ _* Vi m T i 'i 1 1 o f ^ nf Γΐ Πο _* ϊ _ S- Κϊ n Q f ow _Sr Ήι o † - τ ~ -i rr † - based on the total weight of the inner phase, preferably 80 wt .-% to 90 wt .-%.

According to a further preferred embodiment of the

fused tablet according to the invention, it is provided that the inner phase is a wet granules, ie a dried granules which has been produced by means of a wet granulation process. According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the moist granules are a binder granules.

According to a further preferred embodiment of the

melting tablet according to the invention it is provided that the binder granules contain a hydrophilic polymer as a binder.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the hydrophilic polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose and salts thereof, methylcellulose, hydroxyethylcellulose,

Ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low substituted HPC), polyvinyl pyrrolidone,

Polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate Copoly er, gelatin, guar gum, partially hydrolyzed starch, especially maltodextrin, alginates and xanthan gum.

According to a further preferred embodiment of the

fused tablet according to the invention, it is provided that the hydrophilic polymer is maltodextrin.

According to a further preferred embodiment of the melt tablet according to the invention, it is provided that the proportion of the internal phase in the binder is from 1% by weight to 20% by weight, based on the total weight of the internal

Phase, preferably 3 wt .-% to 10 wt .-%.

According to a further preferred embodiment of the

According to the invention orodispersible tablet, it is provided that the proportion of the ore tablet to internal phase 20 wt .-% to 80 Orodispersible tablet, preferably 30% to 70% by weight and

more preferably from 40% to 60% by weight. The remaining weight fraction is outer phase.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the outer phase comprises a water-soluble filler and binder suitable for direct tabletting, as well as a

water-insoluble, suitable for direct tableting filler and binder. Under water becomes a

Water solubility at a temperature of 15 ° C to 25 ° C of more than 33 mg per ml understood, preferably one

Temperature of 15 ° C to 25 ° C understood of less than 1 mg per ml, preferably a water solubility of less than 0, 1 mg per ml. According to a further preferred embodiment of the

melting tablet according to the invention, it is provided that the water-soluble filler and binder is selected from the group consisting of lactose and mannitol. According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the mannitol is in the form of a mannitol granule.

According to a further preferred embodiment of the

fused tablet according to the invention, it is provided that

Weight ratio of water-soluble filler and binder to water-insoluble filler and binder in a range of 2 to 0.5, preferably in a range of 1.5 to 1. EiltSprec ed 61Π6Γ Welte! It is provided that the water-insoluble filling and binding agent is microcrystalline

Cellulose is.

According to a further preferred embodiment of the

fused tablet according to the invention, it is provided that the proportion of the outer phase of water-soluble and

50% by weight to 95% by weight, based on the total weight of the outer phase, preferably 75% by weight to 85% by weight, of water-insoluble filling and binding agent.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the orodispersible tablet comprises one or more pharmaceutical excipients selected from the group consisting of a

Disintegrants, lubricants, flow control agents and a taste masking agent. According to a further preferred embodiment of the

According to the invention orodispersible tablet it is provided that the pharmaceutical excipient is contained in the outer phase.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the taste-masking agent comprises a sweetener and / or a flavoring agent.

According to a further preferred embodiment of the

melting tablet according to the invention it is provided that the sweetener is selected from the group consisting of saccharin, saccharin sodium, saccharin calcium and saccharin potassium. The sweeteners mentioned have no adverse effect on the stability of the active pharmaceutical ingredient. According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the sweetener is free of aspartame. Aspartame may have an adverse effect on the stability of the active pharmaceutical ingredient.

A typical orodispersible tablet provided by the present invention

- includes zolmitriptan, rizatriptan or aripiprazole as a pharmaceutical active substance;

has a breaking strength F in a range of 25 N to 55 N;

- has a compressive strength σ in a range of 0.7

N / mm ² to 1.3 N / mm ²

- has a decay time of 10 s to 30 s;

- has a friability of 0.1% to 0.4%;

- comprises an inner phase and an outer phase, the inner phase containing the active substance;

the proportion of internal phase is 40% by weight to 60%

Wt .-% based on the total weight of the orodispersible tablet;

the outer phase comprises a water-soluble,

Direct tableting suitable filling and binding agent as well as a water-insoluble filling and binding agent suitable for direct tabletting;

- Is the weight ratio of water-soluble filler and binder to water-insoluble filling and

Binder in a range of 2 to 0.5;

is preferably cylindrical. The present invention further relates to a method for

Production of a tablet according to the invention comprising the steps: or an atypical neuroleptic as a pharmaceutical agent;

- Mixing the granules with a filling and

A binder suitable for direct tabletting, whereby a mixture is obtained;

- Pressing the mixture with such a large force that a compact having a breaking strength F of greater than or equal to 25 N is obtained.

The breaking strength of the compact, i. the orodispersible tablet according to the invention can, for example, the nature and amount of the binder used and the size of the

applied pressing force can be adjusted in the tableting.

According to a preferred embodiment of the

According to the invention it is provided that the granules provided are a binder granules, wherein the used for the preparation of the granules

Granulating liquid maltodextrin as a binder in a proportion of 35% (w / v) to 45% (w / v) comprises. It is further preferred that the granulating liquid is an aqueous granulating liquid.

The following embodiments serve to explain the invention.

Embodiment 1

Orodispersible tablets containing 7.26 mg of rizatriptan benzoate (equivalent to 5.0 mg of rizatriptan) were prepared. The

Melt tablets had the values given in Table 1

Composition on: Substance amount per function of

Tablet [mg] substance

inner phase (granules)

Rizatriptan benzoate 7, 265 active ingredient

Mannitol 58, 0 filler

microcrystalline 8.0 filler

cellulose

Maltodextrin 5.0 Binder fumed 1.0 flow control silica medium

ü

uoci c rii sc

Mannitol (pre-granulated) 29.0 fill and

Binding microcrystalline 23, 0 filling and

Cellulose binder

Crospovidone 8.0 disintegrant fumed 1.0 flow-regulating silica medium

Saccharin sodium 0.5 sweetener

Menthol 3.0 flavoring

Magnesium stearate 3.0 lubricant

The weight of the

orodispersible tablet

The preparation of the orodispersible tablets was carried out as described below.

Commercially available rizatriptan benzoate, mannitol, microcrystalline cellulose, and fumed silica were sieved, weighed, and blended in a mixer to

Homogeneity mixed together. The resulting mixture was then flashed using a 40% (w / v, ie wet granulated.

From the moist granules thus obtained, a granulate fraction 2 mm) was separated by means of a sieve of 2 mm mesh size. The separated granule fraction was dried in a fluid bed dryer and the resulting dried granules further selected by means of a sieve of 1 mm mesh size to give a final

Active ingredient granules 1 mm).

The final active ingredient granules were mixed with the outer phase substances, i. Mannitol (pre-granulated), microcrystalline cellulose, crospovidone, fumed silica,

Saccharin sodium, menthol and magnesium stearate, mixed and the resulting mixture by means of a conventional

Tablet press to round flat biplane tablets with a diameter of 8.0 mm and a ridge height (= thickness) of 2.3 mm (+ 0.2 mm) pressed.

The tablets thus obtained had the following properties:

Breaking strength F (Ph. Eur. 2.9.8): Mean: 36 N

(Extreme values: (min)

N and (Max)

Compressive strength σ: 1.25 N / mm ²

Decay time (Ph.Eur 2.9.1): mean: 25 s

(Individual values from 20 s to 30 s)

Friability {Ph.Eur. 2.9.7): 0.3%

The breaking strength P of the tablets according to Ph.Eur. 2.9.8 was determined by means of a tablet hardness tester from ERWEKA

International AG, Switzerland, Device type: TBH 250 IC, measured. The orientation of the tablets during measurement was such that they were broken across the web (ie radially).

Embodiment 2:

Melted tablets containing 14.53 mg of rizatriptan benzoate (equivalent to 10.0 mg of rizatriptan) were prepared. The orodispersible tablets had the values given in Table 2

Composition on:

Table 2:

Substance Menne- nr-o- Function of

Tablet [mg] substance

inner phase (granules)

Rizatriptan benzoate 14, 53 active ingredient

annitol 116, 0 filler

microcrystalline 16, 0 filler

cellulose

Maltodextrin 10, 0 Binder fumed 2.0 flow control silica medium

outer phase

Mannitol (pre-granulated) 58, 0 fill and

Binder microcrystalline 46.0 filling and

Cellulose binder

Crospovidone 16, 0 disintegrant fumed 2.0 flow control silica medium

Saccharin sodium 1.0 sweetener

Menthol 6.0 flavoring

Magnesi mstearat 6.0 Lubricant

Total weight of the 293, 53

orodispersible tablet The preparation of the orodispersible tablets was carried out analogously to Example 1, wherein the final mixture by means of a conventional tablet press into round flat biplane tablets with a diameter of 10.0 mm and a ridge height (= thickness) of 3.2 mm (+ 0.2 mm) pressed has been.

The tablets thus obtained had the following properties:

Breaking strength F (Ph. Eur. 2.9.8) Mean: 39 N

(Extreme values: (Min) N and (Max) 55 N)

Compressive strength σ: 0.78 N / mm ²

Decay time (Ph.Eur 2.9.1) Average: 22 s

(Individual values from 20 to 25 s)

Friability (Ph.Eur 2.9.7) 0.1% The breaking strength F of the tablets according to Ph.Eur. 2.9.8 was determined by means of a tablet hardness tester from ERWEKA

International AG, Switzerland, Device type: TBH 250 IC, measured. The orientation of the tablets at measurement was such that they were broken across the ridge (i.e., radially).

Embodiment 3;

Orodispersible tablets containing 2.5 mg zolmitriptan were prepared. The orodispersible tablets had the composition given in the table:

Table 3:

Substance amount per function of

Tablet [mg] substance ximcx c ruaoc imauu aLj

Zolmitri tan 2.5 active substance

Mannitol 60, 0 filler

microcrystalline 8.0 filler

cellulose

Maltodextrin 5, 0 Binder fumed 1.0 flow control silica medium

outer phase

Mannitol (pregranulated) 28, 0 fill and

Binders of microcrystalline rUJLX-UHU.

Cellulose binder

Crospovidone 8,0 disintegrants

Sodium hydrogen carbonate 5.0 disintegrant

Citric acid 3.0 disintegrants

(anhydrous)

highly dispersed 1.0 flow-regulating silica medium

Saccharin atrium 0.5 sweetener

Menthol 3.0 flavoring

Magnesium stearate 3.0 lubricant

Gesaintge icht de J.D X, U

orodispersible tablet

The preparation of the orodispersible tablets was analogous

Embodiment 1, wherein the final mixture by means of a conventional tablet press into round flat biplane tablets with a diameter of 8, 0 mm and a ridge height {= thickness) of 2.4 mm (+ 0.2 mm) was pressed.

The tablets thus obtained had the following properties: π-. , ^ "" * - -Ί- _Η 4- mn τη,, - * Ί η α \

Di Lii-JUi-Gö i_y.is.t_x ι_ c r-n. UJ. , ^, 7, oj

(Extreme values: (Min) 27 N and (Max) 45 N)

Compressive strength σ: 1, 06 N / mm ³

Decay time (Ph.Eur 2.9.1) Average: 15 s

Friability (Ph. Eur. 2.9.7):

The breaking strength F of the tablets according to Ph.Eur. 2.9.8 was determined by means of a tablet hardness tester from ERWE A

International AG, Switzerland, Device type: TBH 250 IC, measured. The orientation of the tablets at measurement was such that they were broken across the stea (i.e., radially).

Embodiment 4

There were manufactured Schmeiztabietten containing 5.0 mg Zoimitriptan. The orodispersible tablets had the composition given in Table 4: TABLE 4

Substance amount per function of

Tablet [mg] substance

inner phase (granules)

Zoimitriptan 5.0 active ingredient

Mannitol 120, 0 filler

microcrystalline 16, 0 filler

cellulose

Maltodextrin 10, 0 binder highly dispersed 2.0 flow control silica medium

outer phase

Mannitol (pre-granulated) 56.0 fill and

Binder microcrystalline 46.0 filling and Bindemi el

Crospovidone 16, 0 disintegrant

Sodium hydrogen carbonate 10, 0 disintegrant

Citric acid 6.0 disintegrant

(Anhydrous)

fumed 2.0 flow control silica medium

Saccharin sodium 1.0 sweetener

Menthol 6.0 flavoring

Magnesium stearate 6.0 lubricant

Total weight of 302, 0

Π _ J 1_ Ί

OJIIV £ L> CLJw) JLt3 L. L _*

The preparation of the orodispersible tablets was analogous

Embodiment 1, wherein the final mixture by means of a conventional tablet press into round flat biplane tablets with a diameter of 10.0 mm and a ridge height (= thickness) of 3.2 mm (+ 0.2 mm) was pressed.

The tablets thus obtained had the following properties:

Breaking strength F {Ph.Eur. 2.9.8): mean: 35 N

(Extreme values: (Min) 28 N and (Max) 51 N)

Compressive strength σ: 0.70 N / mm ²

Decay time (Ph.Eur 2.9.1): mean: 15 s

Friability (Ph.Eur 2.9.7): 0.3%

The breaking strength F of the tablets according to Ph.Eur. 2.9.8 was determined by means of a tablet hardness tester from ER EKA

International AG, Switzerland, Device type: TBH 250 IC, measured. The orientation of the tablets during measurement was such that they were broken across the web (ie, radially). On the other hand, opius

Orodispersible tablets containing 5.0 mg of aripiprazole were prepared. The orodispersible tablets had the composition given in the table:

Table 5:

Embodiment 1, wherein the final mixture by means of a conventional tablet press into round flat biplane tablets with a diameter of 6 mm and a web height (= thickness) of 2.1 mm {+ 0.2 mm) was pressed.

The tablets thus obtained had the following properties: Breaking strength F (Ph. Eur. 2.9.8) Mean value: 25 N

(Extreme values: (Min) 22 N and (Max) 31 N)

Compressive strength σ: 1.26 N / mm ²

Decay time (Ph.Eur 2.9.1) Mean: 18 s

Friability (Ph.Eur 2.9.7): 0.1%

Embodiment 6; Melt tablets containing 10.0 mg of aripiprazole were prepared. The orodispersible tablets had the in Table 6

Table 6

Substance amount per function of

Tablet [mg] substance

inner phase (granules)

Aripiprazole 10, 0 active ingredient

Manni ol 52, 6 filler 1 4-

Lu i k ukj. iötallinc u Γ U1 1S UUL 1

cellulose

Maltodextrin 4.2 Binders Colloidal 0.70 Flow Control Silica Medium

outer phase

Manni ol (pre-granulated) 26.3 fill and

Binder microcrystalline 21.0 filling and

Cellulose binder

Crospovidon 7.0 explosives

Natrxumhy ogenca o at -1

X, o o Sprengmi e1

Tartaric acid 2, 8 disintegrant highly dispersed 0.7 flow-regulating silica medium

Saccharin sodium 0, 28 sweeteners

Color 0, 14 colorants

Aroma 2,8 Aroma

Magnesium Stearate 2.8 Lubricant

Total weight of 140, 0

orodispersible tablet

The He a elluny the

cj-fulyte Siialuy

Embodiment 1, wherein the final mixture by means of a conventional tablet press into round flat biplane tablets with a diameter of 8 mm and a ridge height (= thickness) of 2.3 mm (+ 0.2 mm) was pressed.

The tablets thus obtained had the following properties:

Breaking strength F (Ph. Eur. 2.9.8): mean: 30 N

(Extreme values: (Min) 25 N and (Max) 38 N) Druukfestiykeit u: 2

I / 111111

Decay time (Ph. Eur. 2.9.1) Average

Friability (Ph.Eur 2.9.7): 0, 14% The breaking strength F of the tablets according to Ph.Eur. 2.9.8 was determined by means of a tablet hardness tester from ERWEKA

Embodiment 7;

Orodispersible tablets containing 15.0 mg of aripiprazole were prepared. The orodispersible tablets had the composition given in the table:

Table 7:

Substance amount per function of

Tablet [mg] substance

inner phase (granules)

Aripiprazole 15, 0 active ingredient

Mannitol 78, 9 filler

microcrystalline 10, 5 filler

cellulose

Maltodextrin 6.3 Binder fumed 1, 05 flow control silica medium

outer phase

Mannitol (pregranulated) 39.45 filling and

Binder microcrystalline 31.5 filling and

Cellulose binder

Crospovidone 10, 5 disintegrants

Sodium bicarbonate 2, 52 disintegrants Tartaric acid sulphonating agent fumed 1, 05 flow-regulating silica

Saccharin sodium 0.42 Sweetener

Color 0, 21 colorants

Aroma 4.2 flavoring

Magnesium Stearate 4.2 Lubricant

Total weight of 210, 0

orodispersible tablet

The preparation of the orodispersible tablets was analogous

Embodiment 1, wherein the final mixture by means of a conventional tablet press into round flat biplane tablets with a diameter of 10.0 mm and a ridge height (= thickness) of 2.35 mm (+ 0.2 mm) was pressed.

The tablets thus obtained had the following properties:

Breaking strength F (Ph. Eur. 2.9.8) Mean: 35 N

(Extreme values: (Min) 28 N and (Max) 39 N)

Compressive strength σ: 0.95 N / mm ²

Decay time {Ph.Eur. 2.9.1) Average: 15 s

Friability (Ph.Eur 2.9.7): 0.0%

The breaking strength F of the tablets according to Ph.Eur. 2.9.8 was determined by means of a tablet hardness tester from ERWEKA

Embodiment 8: Melt tablets containing 30.0 mg of aripiprazole were prepared. The orodispersible tablets had the composition given in Table 8: TABLE 8

The preparation of the orodispersible tablets was analogous

Application example Conventional tablet press to round flat iplanen tablets with a diameter of 13.0 mm and a web height (= thickness) of 2.8 mm (± 0.2 mm) was pressed. The tablets thus obtained had the following properties:

Breaking strength F (Ph. Eur. 2.9.8) Mean: 40 N

(Extreme values: (Min) N and (Max) 49 N)

Compressive strength σ: 0.70 N / mm ²

Decay time (Ph.Eur 2.9.1) Average: 15 s

Friability (Ph.Eur 2.9.7): 0, 18%

The breaking strength F of the tablets according to Ph.Eur. 2.9.8 was determined using a Tabietten hardness tester from ER EKA

Claims

claims

Orodispersible tablet comprising a triptan or an atypical neuroleptic as a pharmaceutical active ingredient, characterized in that the orodispersible tablet has a

Breaking strength of greater than or equal 25 N has.

Melt tablet according to claim 1, characterized in that the orodispersible tablet has a breaking strength of 25 N to 55 N.

Orodispersible tablet according to one of the preceding claims, characterized in that the orodispersible tablet is a

Compressive strength greater than or equal to 0.55 N / mm ² .

Disintegration time of less than or equal to 60 s has.

Friability of less than or equal to 1%.

Orodispersible tablet according to one of the preceding claims, characterized in that the triptane is selected from the group consisting of zolmitriptan and rizatriptan.

Orodispersible tablet according to one of the preceding claims, characterized in that the atypical neuroleptic is aripiprazole.

Orodispersible tablet according to one of the preceding claims, characterized in that the orodispersible tablet has an inner Phase and an outer phase, wherein the inner phase contains the active ingredient.

Orodispersible tablet according to claim 8, characterized in that the proportion of the ore tablet to inner phase 20 wt .-% to 80 wt .-% is based on the total weight of the orodispersible tablet. Orodispersible tablet according to claim 8 or 9, characterized

in that the outer phase comprises a water-soluble filling and binding agent suitable for direct tabletting, and is suitable for use with a PTTI s R fisnin ls lps hps _t . Tiu Di r ^ k: tabl e- i snmo_ _! suitable filling and binding agent. Melt tablet according to one of claims 8 to 10, characterized in that the weight ratio of

water-soluble filler and binder to water-insoluble fillers and binders in a range of 2 to 0.5. Melt tablet according to one of claims 8 to 11, characterized in that the proportion of the outer phase

water-soluble and water-insoluble filling and

Binder 50 wt .-% to 95 wt .-% is based on the total weight of the outer phase. A process for preparing a orodispersed tablet according to any one of claims 1 to 12, comprising the steps of:

- Providing a granule containing a triptan or an atypical neuroleptic as a pharmaceutical agent;

- Mixing the granules with a filling and

A binder suitable for direct tabletting, whereby a mixture is obtained; Pressing the Getnxsch.es tnxt such a large force that a compact with a breaking strength of greater than or equal to 25 N is obtained.