EP3618812A1

EP3618812A1 - Orodispersible tablet containing an h1 antihistamine

Info

Publication number: EP3618812A1
Application number: EP18721783.1A
Authority: EP
Inventors: Sarah-Lena GREBE
Original assignee: Stada Arzneimittel AG
Current assignee: Stada Arzneimittel AG
Priority date: 2017-05-02
Filing date: 2018-05-02
Publication date: 2020-03-11
Also published as: WO2018202700A1; EP3398590A1

Abstract

The present invention relates to an orodispersible tablet, especially for treating sleep disorders, which comprises, as the active pharmaceutical ingredient, an H1 antihistamine selected from the group consisting of doxylamine and the pharmaceutically acceptable salts thereof, and diphenhydramine and the pharmaceutically acceptable salts thereof. The present invention further relates to the orodispersible tablet according to the invention for use in the treatment of sleep disorders and to a method for producing the orodispersible tablet according to the invention.

Description

The present invention relates to an orodispersible tablet, in particular for the treatment of insomnia, comprising as active pharmaceutical ingredient a hi antihistaminic agent selected from the group consisting of doxylamine and its

pharmaceutically acceptable salts and diphenhydramine and its pharmaceutically acceptable salts.

Doxylamine ((RS) -N, N-dimethyl-2 - [1-phenyl-1- (2-pyridyl) ethoxy] -ethylamine)

and diphenhydramine (2-benzhydryloxy-N, N-dimethyl-ethylamine)

are antihistamines Hi, so drugs that by a

Blockade of ΗΊ receptors inhibit the effect of histamine and thus have an anti-allergic effect. Doxylamine and diphenhydramine are among the first generation antihistamines of Hi and are well absorbed into the central nervous system. Due to the blockade of central Hi receptors, these antihistamines additionally have a sedating and antihistamines

antiemetic effect and therefore mainly in these indication areas, namely as sedative (sleep and

Tranquillizer} or antiemetic (anti-nausea and vomiting agent).

Doxylamine-containing drugs are e.g. for the immobilization of nex'vos patients, for the treatment of restlessness and

Conditions of excitement in children and medicinal

required treatment of sleep disorders. In addition, doxylamine-containing contents

Medicines as antiallergic for the treatment of allergic reactions of the upper and lower respiratory tract including hay fever and allergic bronchospasm, as well as

allergic skin diseases and itching used. Further Applications in combination with Vitarain B6 are the treatment of nausea and vomiting and in combination with paracetamol, dextromethorphan and optionally ephedrine the symptomatic treatment of colds.

Diphenhydramine is also used to treat single and

Sleep through disorders used. In addition, the active substance in question for the prevention and symptomatic treatment of nausea and vomiting is different

Cause used, especially in motion sickness, Next diphenhydramine ^' use in the treatment of

allergic symptoms and in relieving itching. Furthermore, diphenhydramine has FDA approval

symptomatic treatment of Parkinson's and extrapyramidal dyskinesia.

For example, a doxylamine supplement for the treatment of sleep disorders is marketed under the name Hoggar 'Night. These are tablets that are swallowed whole with swallowed liquid. A diphenhydramine preparation for the treatment of sleep disorders is marketed under the trade name Hemodorm. These are also tablets, which are swallowed whole with liquid by swallowing.

On this basis, the object is to provide a dosage form containing a Hi-Antihistaminika selected from the group consisting of doxylamine and diphenhydramine, which can be relatively easily taken and thus has a higher patient acceptance.

This object is achieved by a

Orodispersible tablet, in particular for the treatment of

Insomnia, comprising as active pharmaceutical ingredient a hi antihistamines selected from the group consisting of Diphenhydramine and its pharmaceutically acceptable salts.

The orodispersible tablets according to the invention are tablets which dissolve relatively quickly in the mouth. They have the advantage that they can also be taken without problems by persons with dysphagia and when lying down and that the active substance may also be resorbed via the oral mucosa, which is why the pharmaceutical effect can occur comparatively quickly in the melting tablets according to the invention. In addition, the

Schmelztabietten according to the invention has the advantage that for their intake a Nachtrinken of water usually not

is required, so that the orodispersible tablets are particularly well suited for taking on the go.

As already stated above, the inventive

Tablet a orodispersible tablet, for which the term

"Orodispersible tablet" is used in the art The European Pharmacopoeia (Ph.Eur.) Defines

Schmelz tabietten in the 8th edition, Grundwerk 2014, Volume 1, on page 1206 as uncoated tablets, which are kept in the mouth, where they spread quickly before being swallowed, with Schmelz tabietten a disintegration time according to Ph.Eur., 8th Edition, Grundwerk 2014, Volume 1, page 397 ff., Item 2.9.1 "Decay time of tablet. and capsules according to the invention: The fused tablet according to the invention comprises as active ingredient a Hi antihistamine selected from the group consisting of doxylamine and its pharmaceutically acceptable salts and diphenhydramine and the pharmaceutic thereof In this case, the active ingredient in the enamel tablet is in non - ion exchanger bound form, preferably in free form cost-effective provision of the orodispersible tablet according to the invention allows. The fact that the active ingredient in the orodispersible tablet according to the invention is preferably in free unbound form means in particular that the active ingredient is present as such in the orodine tablet and not in chemically bound form such as complex (coordinatively) bound form,

For example, complex-bound form on a

Ion exchange material such as a. Ion exchange resin.

According to a preferred embodiment of

fused tablet according to the invention, it is provided that the fused tablet has a fracture strength F in a range of 30 N to 120 N, preferably a fracture strength F in a range of 40 N to 110 N, more preferably one

Breaking strength F in a range of 50 N to 100 K, more preferably a breaking strength F in a range of 60 N to 100 N and more preferably a breaking strength F in a range of 70 N or SO N to 100 N. This ensures that that the orodispersible tablet according to the invention is relatively stable mechanically and therefore less susceptible to damage, as would otherwise be the case with orodispersible tablets. The inventive. Therefore, orodispersible tablet can be offered, for example, in blister packs by blistering and does not have to be packed with a peel film in otherwise impractical blisters, as is customary in the art

Patient acceptance of the orodispersible tablet according to the invention further increased.

The breaking strength F is to be determined in accordance with the European Pharmacopoeia, 8th Edition, Grundwerk 2014, Volume 1, page 412, Item 2.9.8 "Breaking strength of tablets" a tablet hardness tester by uniaxial vertical

Load between two horizontal jaws with plane-parallel surfaces is measured by taking a controlled force-displacement curve, during which the sample is placed on the lower jaw and the progressively lowered upper jaw. It is particularly preferred according to the invention that the breaking strength F is determined by means of a tablet hardness tester with the designation Dr. med. Schleuniger Pharmatron Model 6 D is determined. Round tablets, i. Tablets having a circular cross-section such as e.g. round flat biplane, biconvex or biconcave tablets, are used in the

Breaking strength measurement over the web (i.e., radial)

broken. The fracture strength F of the orodispersible tablet according to the invention can - as known to those skilled in the art, for example, on the type and amount of the pharmaceutical

Adjuvants such as the binder used and on the size of the applied pressing force can be adjusted in the tableting.

The fracture strength F of a fused tablet may depend on its shape and dimensions. It can therefore

According to the invention, it is preferable to specify the mechanical strength of the orodispersible tablet according to the invention as compressive strength σ, since the compressive strength σ is the geometry of the

Taken into account and thus one of them in principle independent size represents. The compressive strength σ is determined by means of the experimentally determined fracture strength F

calculated. For example, for cylindrical orodispersible tablets, the compressive strength σ will be determined by the following

calculated mathematical relationship (see "The Tablet", A. Ritschel et al., 2nd edition, Editio-Cantor-Verlag, 2002, ISBN 3 - 87193-228-0): 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 example, for domed orodispersible tablets

Compressive strength σ calculated by the following mathematical relationship {see "The Tablet", A. Ritschel et a 2nd edition, Editio-Cantor-Verlag, 2002, ISBN 3-87193-228-0)

15 in which

20

25

According to a further preferred embodiment of the

erfzt. According to the invention orodispersible tablet, it is provided that the Schrveiztabiette a compressive strength σ greater than or equal to 0.4 30 N / mm ² exhibit ", preferably a compressive strength o in one

Range of 0.45 N / mnr to 2.5 N / mm ~, more preferably a compressive strength c in a range of 0.5 D / rrnn- to 1.50 W / mm ² Range from 0.70 N / mm ² to 1.30 N / mm ² .

According to a further preferred embodiment of the

erfzt according to the invention orodispersible tablet, it is provided that the orodispersible tablet has a disintegration time in a range of 20 s or 60 s to 180 s, preferably a disintegration time in a range of 70 s to 150 s and more preferably a disintegration time in a range of 80 s to 120 s, The

Zerfaliszeit is according to Ph.Eur. , 8th edition, basic work 2014,

Volume 1, page 397 et seq., 2.9.1 "Disintegration time of tablets and capsules" shall be determined using as medium preferably

Water is used. According to a further preferred embodiment of the ^¬ erf indungsgemäßen orodispersible tablet, it is provided that the orodispersible tablet has a friability of less than / equal to 1%, preferably a friability of less than / equal to 0.5% and most preferably a friability of 0.1% to 0 , 4%. The friability is to be determined according to Ph.Eur, 8th Edition, Grundwerk 2014, Volume 1, page 411 ff., Item 2.9.7 "Friability of Uncoated Tablets".

According to a further preferred embodiment of the

According to the invention orodispersible tablet it is provided that the fusible tablet is directly tabletted. This will provide a relatively low cost of the

erf indungsgemäßen enamel fablette guaranteed. According to a further preferred disclosed embodiment of the

erfzt in accordance with the invention orodispersible tablet, it is provided that the orodispersible tablet is free of an ion exchange material, in particular free of an ion exchange resin. to

extensive suppression of the bitter taste of the

Active ingredient in the composition according to the invention is the Use of a relatively expensive ion exchange material to which the active ingredient is complexed, not necessary.

According to a further preferred embodiment of the

fused tablet according to the invention, it is envisaged that the enamel tablet is free of pyridoxine and free of a salt of pyridoxine.

According to a further preferred embodiment of the

Schmelztabiette invention, it is envisaged that the active ingredient of the only active pharmaceutical ingredient in the

Orodispersible tablet is. This will disable the use of

Composition of the invention for the treatment of

Insured sleep.

According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the active ingredient is doxylamine succinate, in particular

Doxy1aminesuccinate - hemihydrate. Doxylamine succinate exhibits a relatively high chemical stability in the hot-melt tab according to the invention, which is why the hot-melt tab is characterized by a relatively long shelf life.

According to a further preferred embodiment of the

fused tablet according to the invention, it is provided that the active substance Diphenhydraminhydrochoride is.

Diphenhydramine hydrochloride has a relatively high chemical stability in the orodispersible tablet according to the invention, which is why the melting point is characterized by a relatively long shelf life.

According to a further preferred embodiment of the

Schmelztabiette invention is provided that the active ingredient in the Schmelztabiette in crystalline form.

is present. In crystalline form, the active ingredient in the According to the invention orodispersible tablet has a relatively high chemical stability, which is why the orodispersible tablet is characterized by a relatively long shelf life. According to a further preferred embodiment of the form

According to the invention, the tablet is intended _» that the active ingredient in the orodispersible tablet in an amount in one

Range from 1 mg to 500 mg, preferably in an amount ranging from 5 mg to 100 mg, more preferably in an amount ranging from 10 mg to 50 mg, and more preferably in an amount of 25 mg or 50 mg,

According to a further preferred embodiment of the form

The tablet according to the invention is intended _» that the enamel tablet comprises a taste masking agent.

This will largely suppress the bitter

Taste of the active ingredient in the inventive

Composition ensured. According to a further preferred embodiment of the orodispersible tablet according to the invention, it is provided that the taste-masking agent comprises at least one cyclodextrin

preferably at least one cyclodextrin and at least one sweetening agent, more preferably at least one cyclodextrin and at least one flavoring agent and more preferably at least one cyclodextrin, at least one sweetening agent and at least one flavoring agent. It has been found that the mentioned alternatives of taste masking agents are particularly suitable for largely suppressing the bitter taste of the active ingredient in the present invention

Orodispersible tablet. In this context it is

Particularly preferred when the taste masking agent is a combination of β - cyclodextrin, sucralose and a

Äromastoff comprises, more preferably a combination of β-cyciodextrin, sucralose, strawberry flavor, and rhababer-vanilla flavor.

According to a further preferred embodiment of the

fused tablet according to the invention, it is provided that the

Orodispersible 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 amount of filler depends on its nature, the size of the tablet and the amount of the active ingredient. Under

water-soluble is a water solubility at a temperature of 15 ° C to 25 ° C of more than 33 mg per ml understood, preferably a water solubility of 100 mg per ml to 1000 mg per ml. Under water insoluble becomes a water solubility at a temperature of 15 ° C. up to 25 ° C of less than 1 rag per ml understood, 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 orodispersible 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 starch.

According to a further preferred embodiment of the

According to the invention orodispersible tablet, it is provided that the water-soluble and the non-aqueous pharmaceutical

Filler mixed together in the form of granules.

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

Orodispersible tablet suitable for direct tableting

Binder comprises, preferably microcrystalline cellulose.

According to a further preferred embodiment of the

According to the invention, the orodispersible tablet comprises one or more pharmaceutical excipients selected from the group consisting of a

Disintegrants, Lubricants and a Flow Control Agent A typical orodispersible tablet provided by the present invention is a orodispersible tablet for the treatment of sleep disorders, comprising as the sole pharmaceutical agent

Active ingredient 10 mg to 50 mg doxylamine succinate in non-ion exchange bound form, preferably in free unbound form, as well as a taste masking agent111, in particular comprising a taste masking agent

at least one Cycl.ode.xtrin, at least one sweetening agent and at least one flavoring agent, preferably one

Taste masking agent comprising β-cyclodextrin,

Sucralose and a flavoring agent, more preferably one

Taste masking agent comprising β-cyclodextrin,

Sucralose, strawberry flavor, and rhababer-vanilla flavor, wherein the ore tablet has a fracture toughness F in a range of 50 N to 100 N.

Another typical, by the present invention

An orodispersible tablet is an orodispersible tablet for the treatment of insomnia, comprising only one

pharmaceutical agent 25 mg to 75 mg

Diphenhydramine hydrochloride, preferably in non-ion exchange bonded form, preferably in free

unbound form, and a taste masking agent, especially a taste masking agent

at least one cyclodextrin _. , at least one sweetener and at least one flavoring agent, preferably one

Taste masking agent comprising β-cyclodextrin,

Sucralose and a flavoring agent, more preferably one

Taste masking agent comprising β-cyclodextrin,

Sucralose, strawberry flavor, and rhababer-vanilla flavor, wherein the orodispersible tablet has a fracture toughness F in a range of 50 N to 100 N.

The present invention further relates to a

Orodispersible tablets according to the invention for use in the treatment of sleep disorders.

The present invention also relates to a

Process for the preparation of an inventive

Orodispersible tablet, comprising the steps: - Provision of the active substance;

Mixing the active ingredient with a pharmaceutical excipient suitable for direct tabletting to obtain a mixture;

- Pressing the mixture to obtain a

Orodispersible tablet.

The following embodiments serve to explain the invention.

Embodiment 1;

It orodispersible ^tablets' were prepared containing as active ingredient 25 mg doxylamine succinate. The orodispersible tablets have the composition given in Table 1:

The melting ranges according to Table 1 were as follows

First, the active ingredient doxylamine succinate and the taste masking agent β-cyclodextrin were each sieved and then mixed with each other to obtain a drug mixture. Thereupon, the filler in the form of mannitol / corn starch composition (Peariitoi ¹ Flash), the flow control agent silicon dioxide, the binder microcrystalline cellulose, the disintegrant crospovidone and the taste masking agents sucralose, strawberry flavor and rhababer-vanilla flavor j each sieved and then also mixed together to obtain an auxiliary material mixture.

The active ingredient and adjuvant mixtures prepared as described above became a final one with the addition of the lubricant sodium stearyl fumarate

Blended tablet mixture by means of a conventional

Tablet press to round biplane orodispersible tablets with a diameter of 12.7 mm and a thickness of 4.5 mm

was directly tableted.

Breaking strength F (Ph ... Eur. 2,9.8) Mean: 98,1 N

(Extreme values: (Min) 88 N and (Max) 106 N)

The breaking strength F of the tablets according to Ph.Eur. 2.9.8 was determined by means of a tablet hardness tester with the name Dr. Measure Schleuniger Pharmatron Model 6 D. The orientation of the tablets at measurement was such that they were broken across the ridge (i.e., radially). The decay time according to Ph.Eur. 2.9.1 was determined by means of the medium of water.

Example 2: Orodispersible tablets containing 50 mg as active ingredient were obtained

Diphenhydramine hydrochloride prepared. The orodispersible tablets have the composition given in Table 2;

The orodispersible tablets according to Table 2 were analogous

Made example 1 - to obtain round biplane orodispersible tablets with a diameter of 12.7 mm and a thickness of 4.5 mm and analog Ausführungsbei play measured.

Embodiment 3s

Orodispersible tablets containing 25 mg of doxylamine succinate were prepared as the active ingredient. The orodispersible tablets have the composition given in Table 3: Table 3:

Substance amount per function of

Tablet [mg] substance

Doxylamine succinate 25, 0 active ingredient

Fearlitol ^' Flash (a 345, 1 filler

Mannitoi / Corn Starch -

Composition)

Sodium tearylfumarate 9.0 lubricant highly dispersed 4.5 flow control

Silica medium

microcrystalline 80, 0 binder

cellulose

Crospovidone 25, 0 explosives

Sucralose 1, 5 Taste masking - ΐ

! medium

(Sweetener)

Strawberry - Flavor 4.2 Taste masking agent

(Flavoring agent)

Rhababer - Vani 1 le -Aroma 5 7 Taste masking agent

1

(Flavoring) i ß - Cyclodextrin 100,0 Taste - masking agent

(Cyclodextrin)

Total weight of 600.0

Orodispersible tablet 1

The orodispersible tablets according to Table 3 were analogous

5 Embodiment 1 produced -. To obtain round

biplane orodispersible tablets with a diameter of 12.7 mm and a thickness of 4.5 mm - and measured analogously to Example 1.

Embodiment 4

Melt tablets containing 50 mg of diphenhydramine hydrochloride were prepared as active ingredient. The orodispersible tablets have the composition given in Table 4:

Table 4:

rungsm e (flavoring)

The enamel tablets according to Table 4 were analog

Embodiment 1 prepared - to obtain round biplane orodispersible tablets with a diameter of 12.7 mm and a thickness of 4.5 mm - and measured analogously to the embodiment.

Embodiment 5:

Melt tablets containing as active ingredient 25 mg

Doxylaminsuccmat produced. The painkillers have the composition given in Table 5:

Table 5:

The enamel tablets according to Table 5 were analog

Embodiment 1 prepared - to obtain round biplane orodispersible tablets with a diameter of 12.7 mm and a thickness of 4.5 mm - and measured analogously to Example 1.

Embodiment 6;

There were orodispersible tablets containing as active ingredient 50 mg

Diphenhydraminhydrochoride prepared. The orodispersible tablets have the. Composition given in Table 6:

The orodispersible tablets according to Table 6 were analogous

Embodiment 1 prepared - to obtain round biplane orodispersible tablets with a diameter of 12.7 mm and a thickness of 4.5 mm - and analog out of game play 1 game measured.

Embodiment 7:

Orodispersible tablets containing as active ingredient 25 mg

Doxylaminsucc inat produced. The orodispersible tablets have the composition given in Table 7.

Table 7

highly dispersed 3.0 l flow-regulating silica j medium

- microcrystal 60.0 l binder

cellulose

Crospovidcn 30,0 disintegrant

The orodispersible tablets according to Table 7 were analogous

From management example i produced - to obtain round biplane orodispersible tablets with a diameter of 12.7 mm and a thickness of 4.5 mm - and measured analogously to Example 1.

Embodiment 8;

Orodispersible tablets containing 25 mg of doxylamine succinate were prepared as the active ingredient. The orodispersible tablets have the composition given in Table S:

The orodispersible tablets according to Table 8 were analogous

Embodiment 1 produced - measured to obtain round biplanar 5 orodispersible tablets with a diameter of 12.7 mm and a thickness of 4, 5 mm ^■ ^■ · · and analog Embodiment 1. FIG. (Extreme values: (min) 84

N and (Max) 102 N)

Compressive strength σ: 1.02 N / rrtiiv

Decay time (Ph.Eur 2.9.1): 93 s

Claims

claims

Schmelztablet te, in particular for the treatment of

Insomnia comprising as active pharmaceutical ingredient a Ki antihistamine selected from the group consisting of doxylamine and its pharmaceutically acceptable salts and diphenhydramine and its pharmaceutically acceptable salts.

Melt tablet according to claim 1, characterized in that the orodispersible tablet has a breaking strength F in a range of 30 N to 120 N, preferably one

Breaking strength F in a range of 40 N to 110 N, more preferably a breaking strength F in a range of 50 N to 100 N, even more preferably a breaking strength F in a range of 60 N to 100 N, and more preferably a breaking strength F in one Range from 70 N or 80 N to 100 N.

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

Compressive strength σ of greater than or equal to 0.4 N / mm ^; preferably, has a compressive strength σ in a range of: 0.45 N / mm to 2.5 N / mm ² , further preferably a compressive strength, o in a range of 0.5 N / mm ^: to 1.50 N / mm ^2, and more preferably "compressive strength σ in a range of 0.70 N / mm ^: to 1.30 N / mm-.

Decay time in a range of 20 s or 60 s to 180 s, preferably a disintegration time in a range of 70 s to 150 s and more preferably a disintegration time in a range of 80 s to 120 s.

5 .. orodispersible tablet according to one of the preceding claims, characterized in that the orodispersible tablet

Friability of less than or equal to 1%. 6.. Orodispersible tablet according to one of the preceding claims, characterized in that the orodispersible tablet

is directly tableted. 7 .. orodispersible tablet according to one of the preceding claims, characterized in that the orodispersible tablet is free of an ion exchange material. 8 .. orodispersible tablet according to one of the preceding claims, characterized in that the active ingredient is the only active pharmaceutical ingredient in the orodispersible tablet. 9 .. orodispersible tablet according to one of the preceding claims, characterized in that the active ingredient is Doxylaminsuccinat or Diphenhydraminhydrochlorid. 1 00 .. orodispersible tablet according to one of the preceding claims, characterized in that the active ingredient in the

Melt tablet is present in crystalline form. 1 1. orodispersible tablet according to one of the preceding claims, characterized in that the active ingredient in the

Orodispersible tablet is contained in an amount ranging from 1 mg to 500 mg, preferably in an amount ranging from 5 mg to 100 mg, more preferably in an amount ranging from 10 mg to 50 mg, and more preferably in an amount of 25 mg or 50 mg. characterized in that the lubricating ztablette a

Taste masking agent. 13. enamel tablet according to claim 12, characterized in that the taste masking agent at least one

Cyciodextrin, at least one sweetener and at least one flavoring comprises. 14. Orodispersible tablet according to one of claims 1 to 13 for

Use for the treatment of sleep disorders.

15. A method for producing a orodispersible tablet according to any one of claims 1 to 13, comprising the steps:

- providing the active substance;

- Pressing the mixture to obtain a

Orodispersible tablet.