WO2018108884A1

WO2018108884A1 - Pharmaceutical tablet formulation

Info

Publication number: WO2018108884A1
Application number: PCT/EP2017/082379
Authority: WO
Inventors: Peter Serno; Katrin IDE; Carmen Lobback; Michael Pfeffer; Christine Schwer; Anke Stroyer
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2016-12-16
Filing date: 2017-12-12
Publication date: 2018-06-21
Also published as: AR110371A1; UY37525A; TW201836592A

Abstract

The present invention relates to a stable pharmaceutical tablet formulation containing 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-L-alanyl-L-alaninate (neladenoson bialanate) in the form of one of its salts, characterized in that said pharmaceutical tablet formulation releases the active ingredient rapidly, and to a method for the preparation thereof, to the use thereof as medicament, and to the use thereof for the prophylaxis and/or treatment of cardiovascular diseases such as, for example, worsening chronic heart failure, heart failure with reduced or with preserved ejection fraction (HFrEF or HFpEF), angina pectoris and ischemic injury during an acute coronary syndrome.

Description

Pharmaceutical Tablet Formulation

The present invention relates to a stable pharmaceutical tablet formulation containing 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyano-6 - (pyrrolidin-1-yl) pyryl] phenoxy} ethyl-L-alanyl-L-alaninate (Neladenoson bialanat) in the form of one of its salts, characterized in that it releases the active ingredient quickly, and processes for their preparation, their use as a medicament, as well as its use for the prophylaxis and / or treatment of cardiovascular diseases such as worsening chronic heart failure, heart failure with impaired or preserved left ventricular ejection fraction (heart failure with reduced or ejection fraction, HFrEF or HFpEF), angina pectoris and ischemic injury during acute coronary syndrome.

Neladenoson bialanate is the compound 2- {4- [2 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyano-6- (pyrrolidine 1-yl) pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate of the formula (I)

Neladenoson bialanat is used in the form of one of its salts. Preference is given to using the hydrochloride (II), in particular the monohydrochloride (IIa).

Neladenosone is the compound 2 - [[2- (4-chlorophenyl) thiazol-4-yl] methylsulfanyl] -4- [4- (2-hydroxyethoxy) phenyl] -6-pyrrolidin-1-ylpyridine-3 , 5-dicarbonitrile of the formula (III)

Neladenosone, the bialanate and the hydrochloride or the monohydrochloride of the bialanate are known (see WO 2010/086101 and WO 2016/188711). The compounds of the formulas (I), (II) and (III) act as partial adenosine A1 receptor agonists and can be used, for example, as agents for the prophylaxis and / or treatment of cardiovascular disorders such as, for example, chronic heart failure, heart failure with impaired or preserved left ventricular ejection fraction (HFrEF or HFpEF), angina pectoris, and ischemic injury during acute coronary syndrome.

A preferred route of administration for these agents is oral administration. As a result of the very low water solubility of neladenosone (III), it is not sufficiently bioavailable after oral administration. For this reason, WO 2010/086101 describes not only neladenosone (III) but also prodrugs of neladenosone, such as neladenoson bialanate (I) (ibid., Compare Examples 1 and 44).

Prodrugs of pharmaceutical agents are often developed to increase the solubility of the drug, to overcome limited intestinal uptake, or to reduce its metabolism in the gastrointestinal tract. Most of the prodrugs available on the market are esters, which are cleaved in vivo mostly by esterase-mediated hydrolysis into the actual active ingredient, which can then develop its intended pharmacological effect. On the one hand, the chemical lability is a desired property of the biological activity of prodrugs, which, on the other hand, at the same time considerably impairs the stability in the pharmaceutical dosage form.

In order to stabilize the prodrug brivanib alaninate, the authors suggest optimizing the production conditions and, in particular, as dry as possible process conditions for coating the tablet cores and the use of high-density polyethylene (HDPE) bottles with desiccant as primary packaging [Kestur et al., Int. J. Pharm. 476, 93-98 (2014) and Badawy et al., Int. J. Pharm. 469, 1111-120 (2014)]. The proposed formulation of the tablet cores consists in addition to the active ingredient of microcrystalline cellulose, hydroxypropyl cellulose, the disintegrant croscarmellose sodium and the lubricant magnesium stearate and contains no lactose.

For the likewise hydrolysis-sensitive active ingredient trimebutin maleate, the authors use D-mannitol as filler and succinic acid as stabilizer [Cho et al., Int. J. Pharm. 400, 145-152 (2010)]. Crospovidone was not used, lactose proved detrimental.

DMP 754 is an ester prodrug of a fibrinogen glycoprotein IIb / IIIa receptor antagonist. It shows as pure active ingredient after storage for 3 months at 40 ° C and 75% relative humidity, a low degradation. In the case of preformulation work with respect to a solid oral dosage form, it was found that the compound decomposes significantly in the presence of anhydrous lactose and the content of degradation products increases dramatically. The stability problem could be solved by addition of acids such as disodium citrate [SIF Badawy et al., Pharm. Dev. Tech. 4, 325-331 (1999)]. The mixtures or tablets did not contain crospovidone. To stabilize the prodrug A ⁹ -Tetrahydrocannabinol also pH modifying excipients such as citric acid and antioxidants are proposed [S. Thumma et al., Int. J. Pharm. 362, 126-132 (2008)].

Fesoterodine is an unstable drug that substantially decomposes in a humid environment and at elevated temperature. The stability of this active ingredient in solid oral dosage forms depends on the excipients used. A particularly preferred filler MicroceLac ^® has been described in a proportion of 20-40% of the tablet 100 (paragraph [0262] of US 2010/0130606 A1), which is a co-processed mixture of 75% α-lactose monohydrate and 25% microcrystalline cellulose , This corresponds to a content of α-lactose monohydrate in the tablet of 15-30%. It should be noted that lactose destabilizes the drug (paragraph [0334] of US 2010/0130606 A1). Furthermore, stabilization was possible by addition of a stabilizer from the group xylitol, sorbitol, polydextrose, isomalt or dextrose.

Other active ingredients are not subject to decomposition in tablet formulations, but a phase transformation occurs in a hydrate form of the active ingredient. Measures that prevent this reaction of active ingredients with water could be used in the broadest sense to avoid the degradation of prodrugs during storage of tablets. In this context, it is described that the use of the filler a-lactose monohydrate accelerates the formation of hydrate, while when using microcrystalline cellulose as a filler no change in the active ingredient occurred [M. Otsuka and Y. Matsuda, Chem. Pharm. Bull. 42, 156-159 (1994)]. This finding was confirmed by other active substances of S. Airaksinen [Role of Excipients in Moisture Sorption and Physical Stability of Solid Pharmaceutical Formulations, Dissertation Helsinki (2005)].

Neladenoson bialanate hydrochloride (II) and the monohydrochloride (IIa) is also an unstable compound, but can not be formulated into a stable tablet with the known methods of formulating prodrugs and other unstable drugs. It decomposes in common tablet formulations even with most extensive exclusion of water. Neladenosone (III) forms as the degradation product. This is undesirable since neladenosone (III) is almost not bioavailable after oral administration and thus the decomposed active ingredient portion for the desired pharmacological effect on the patient is no longer available. Also for regulatory reasons, tablets with partially decomposed active ingredient are undesirable because the permissible amount of degradation products and the decrease in the active ingredient content of tablets are limited. Tablets, whose active substance is already clearly decomposed, are therefore no longer marketable.

In addition, conventional tablet formulations of neladenosone bialanate hydrochloride (II) or the monohydrochloride (IIa) leave something to be desired in the release of the active ingredient. Although such tablets disintegrate rapidly, drug release is sometimes slow and variable. However, the release of active ingredient, ie the dissolution of the active ingredient in an aqueous medium, which corresponds to the conditions in the upper gastrointestinal tract, is a prerequisite for the absorption of the drug into the bloodstream and the unfolding of a pharmacological action. After taking Neladenoson bialanate hydrochloride tablets, it is desirable that the active ingredient in the aqueous environment of the upper gastrointestinal tract is released as soon as possible. Low-speed tablets of drug release have the risk that the drug dissolves only in deep sections of the gastrointestinal tract where it encounters adverse conditions of stability or absorption or is excreted without absorption into the body.

It is therefore an object of the present invention, bialanat (I), in particular for Neladenoson bialanate hydrochloride (II) or Neladenoson bialanat monohydrochloride (IIa) to find tablet formulations for salts of Neladenoson, in which the active ingredient is as stable as possible, ie in tablet formulations As slowly as possible to Neladenoson (III) decomposes, and from which the release of the drug takes place as quickly as possible. The monohydrochloride contains the hydrochloride in exactly defined stoichiometric content. The use of monohydrochloride (IIa) represents in the context of this invention is a preferred embodiment, although not always explicitly mentioned in detail.

Surprisingly, it has now been found that stable and rapidly releasing tablets containing 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5- dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate [Neladenoson bialanat (I)] can be obtained in the form of one of its salts when the excipient content of the tablets to 68 -95% (w / w) of lactose monohydrate or anhydrous lactose, and the excipient portion of the tablets contains 5-20% (w / w) crospovidone as disintegrant. This dosage form has the advantage of being sufficiently stable, rapidly disintegrating and rapidly releasing the drug. The dosage form does not require additional pH modifiers and antioxidants and can be coated using aqueous suspensions.

The dosage form of the tablet is generally described in European Pharmacopoeia 9.3 (Chapter 07 Dosage Forms - Tablets). For the present invention, uncoated and coated tablets are preferred.

In detail, the tablets contain the active ingredient Neladenoson bialanate hydrochloride (II) or the monohydrochloride (IIa). But there are also other salt forms of Neladenoson bialanat (I) possible. Preference is given to dosages of 1 to 100 mg, in particular 2.5 to 60 mg, very particularly preferably 2.5 to 45 mg per tablet [amount stated as neladenosone bialanate (I)].

Based on the mass of the tablets, the amount of active ingredient is 2-50%, depending on the dosage and size of the tablets.

Apart from the active ingredient, the tablets contain excipients. Amounts of the excipients are understood to mean the proportions by weight of a single excipient of the total mass of excipients of the tablet ("excipient content") of lacquer substance is also an adjuvant and is included in the calculation of the total mass of excipients of the coated tablet.

Tablets usually contain a filler. For example, are common: sugars or sugar alcohols such as mannitol, carbohydrates, such as microcrystalline cellulose or maltodextrin, inorganic fillers such as calcium hydrogen phosphate or calcium carbonate, and mixtures or coprocessed excipient mixtures such as MicroceLac ^® (eg MicroceLac ^® 80 from Meggle consisting of 75% α-lactose monohydrate and 25% microcrystalline cellulose), or Cellactose ^® (for example Cellactose ^® 80 from Meggle consisting of 75% α-lactose monohydrate and 25% Pulvercellu- loose). However, most of these fillers are unsuitable because the active ingredient Neladenoson bialanate hydrochloride (II) decomposes rapidly in the tablets produced therefrom or the release of active ingredient from the tablets is slow.

By contrast, the tablets according to the invention contain as fillers at least 68, preferably at least 75, up to a maximum of 95 percent by weight (based on all excipients of the tablet) lactose in one of its forms, such as anhydrous lactose or lactose monohydrate or mixtures thereof. The lactose may be made of different modifications, such as a-lactose monohydrate, beta-lactose or amorphous lactose, or have been prepared by different methods such as the commercial grades SUPERTAB ^® 21 is ON or SUPERTAB ^® 24an, Pharmatose ^®, Supertab ^® 1 1 SD or 14SD, Tablettose ^® or FlowLac ^® 90 or 100th

The tablets also contain a disintegrant. Typical examples are: alginic acid, low-substituted hydroxypropylcellulose, corn starch, carboxymethyl starch sodium, carmellose calcium, croscarmellose sodium and other starch or cellulose derivatives. However, these disintegrants are unsuitable because they adversely affect the stability of the active ingredient (I) in the form of one of its salts in the tablet.

The tablets of the invention contain as disintegrants crospovidone. Crospovidone is described in the monograph "Crospovidone" of European Pharmacopoeia 9.0 Particularly preferred are tablet formulations containing 5 to 20% by mass (based on all excipients of the tablet) of crospovidone, in particular Crospovidone of type A. Crospovidone of type A is coarser than that of the type B and has according to the method described in the US Pharmacopoeia USP39 method of wet screening a mass fraction of more than 15% of particles> 63 m.

Further, the tablets may contain any of the known lubricants, dry binders, flow control agents or coating materials.

As the lubricant, there may be used, for example, magnesium stearate, sodium stearyl fumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fats or oils, polyethylene glycols or talc. External lubrication of the tablets is also possible. As a flow control agent, for example, fumed silica is suitable.

As coating materials for coated tablets according to the European Pharmacopoeia 9.0 (monograph "Coated tablets" of the European Pharmacopoeia 9.0) are the known pharmaceutical paints, which polymers such as hypromellose, hydroxypropyl cellulose, macrogol-poly (vinyl alcohol) graft copolymer, polyvinyl alcohol or poly (meth) acrylates, color pigments such as iron oxides, titanium dioxide or indigo carmine lacquer, plasticizers such as macrogols, tributyl citrate, tributyl acetyl citrate, dibutyl sebacate, triacetin or glycerol monostearate, as well as talc, etc. Coating materials with further functional properties can also be used, such as film formers for modified release of active substances such as ammonium methacrylate copolymers, cellulose acetate, Cellulose acetate butyrate, chitosan, ethyl cellulose, polyacrylates, poly (vinyl acetate) or enteric polymers such as cellulose acetate phthalate, hypromellose acetate succinate, hypromellose phthalate, methacrylic acid-methacrylic at-copolymers, poly (methacrylate-co-methyl-methacrylate-co-methacrylic acid) or polyvinyl acetate phthalate.

The pharmaceutical tablet formulations according to the invention are characterized in that

(a) it is 1-100 mg, especially 2.5-60 mg, most preferably 2.5-45 mg (w / w) 2- {4- [2- ({[2- (4-chlorophenyl) - 1, 3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate [ Neladenoson bialanat (I)] in the form of one of its salts, preferably in the form of the hydrochloride,

(b) as the filler lactose monohydrate or anhydrous lactose in an amount of 68-95% (w / w), more preferably 75-95% (w / w) of the excipient moiety, and

(c) Crospovidone as disintegrant in an amount of 5-20% (w / w) of the excipient moiety, and

(D) optionally further auxiliaries in an amount of 0-27% (w / w) of the excipient content.

The tablets consist of active ingredient such as Neladenoson bialanat hydrochloride (II) or another salt of Neladenoson bialanat (I) and excipients. The stated percentage of active ingredient refers to the mass of the tablet. The stated percentages of lactose monohydrate or anhydrous lactose, as well as crospovidone and optionally further excipients, are based on the sum of the masses of all adjuvants of the tablet, without the active ingredient. The tablets are produced by mixing, sieving and compressing the powder components (direct tabletting method). Alternatively, the powder mixture or parts thereof may be first dry granulated and then compressed into tablets. The tablets may be coated by spraying on an aqueous or organic solvent based lacquer suspension. It is advantageous if the preparation of the tablets takes place in the absence of moisture. All excipients are used in a dry form, all manufacturing steps are carried out in a dry atmosphere and the tablets are packed in such a way that moisture is prevented. For this purpose, for example, an addition of desiccants such as silica gel or molecular sieve for packaging or blinding the tablets with moisture-proof films containing a layer of aluminum are suitable. If a production step is carried out with the addition of water or other solvents, such as the coating of unpainted tablets, the solvent must be removed again as quickly as possible and completely by drying.

The achievable stability of the tablets according to the invention depends on the type of packaging and, associated therewith, the residual moisture during storage and the storage temperature. Packaging forms with desiccants remove moisture from the tablets and lead to a particularly low rate of degradation of the salts of active ingredient (I) to neladenosone (III). In the case of packaging forms without desiccant, the achievable stability of the tablets according to the invention depends on the residual moisture of the tablets at the time of packaging. Furthermore, the degradation rate of the salts of active ingredient (I) to neladenosone (III) at low storage temperature is lower than at higher storage temperature.

The tablets of the invention have a very good chemical stability. The increase in the degradation product neladenosone (III) in these tablets when stored for 3 months at 40 ° C and a relative humidity of 75% at less than 0.32 percentage points, measured after packaging of 10 tablets in a 45 ml HDPE bottle , which in each case contains a desiccant capsule with 3 g desiccant of molecular sieve. A synthetic zeolite is in this case with a pore size of 3A used (Tri-Sorb ^® from Clariant) as a molecular sieve.

The tablets of the invention have a rapid release of active ingredient. Under the conditions described in the Experimental Section, at least 90%, preferably 95%, of the active ingredient is released within 15 minutes.

The embodiments of the invention are described below:

(A) The subject of the invention is thus a pharmaceutical tablet formulation containing 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5- dicyano-6- (pyrrolidin-1-yl) -pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate [neladenoson bialanate (I)] in the form of one of its salts, characterized in that the excipient moiety

(a) to 68-95% (w / w) of lactose monohydrate or anhydrous lactose or

Mixtures thereof,

(b) to 5-20% from crospovidone and

(c) 0-27% from other pharmaceutical excipients

consists. (B) The invention further provides a pharmaceutical tablet formulation comprising 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5- dicyano-6- (pyrrolidined-1-yl) pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate [neladenoson bialanate (I)] in the form of one of its salts, characterized in that the increase in the Decomposition product 2- [[2- (4-chlorophenyl) thiazol-4-yl] methylsulfanyl] -4- [4- (2-hydroxyethoxy) phenyl] -6-pyrrolidin-1-ylpyridine-3,5-dicarbonitrile [ Neladenosone (III)] when stored for 3 months at 40 ° C and a relative humidity of 75%, measured after packaging of 10 tablets in a 45 ml HDPE bottle, each containing a desiccant capsule with 3 g desiccant desiccant, less is 0.5, preferably less than 0.32, more preferably less than 0.30 percentage points.

(C) The invention also provides a pharmaceutical tablet formulation comprising 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5- dicyano-6- (pyrrolidined-1-yl) pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate [neladenoson bialanate (I)] in the form of one of its salts, characterized in that the increase in the Decomposition product 2- [[2- (4-chlorophenyl) thiazol-4-yl] methylsulfanyl] -4- [4- (2-hydroxyethoxy) phenyl] -6-pyrrolidin-1-ylpyridine-3,5-dicarbonitrile [ Neladenosone (III)] when stored for 3 months at 40 ° C and a relative humidity of 75%, measured after packaging in blister films containing an aluminum layer as a water vapor-impermeable layer, less than 1, 5, preferably less than 1, 0 , more preferably less than 0.8 percentage points.

(D) The invention furthermore relates to pharmaceutical tablet formulations as described in embodiments (A), (B) or (C), which are each characterized in that the excipient fraction

(a) to 75-95% (w / w) of lactose monohydrate or anhydrous lactose or mixtures thereof,

(b) to 5-12% from crospovidone and

(c) to 0-20% from other pharmaceutical excipients

consists.

E) The invention furthermore relates to pharmaceutical tablet formulations as described in embodiments (A), (B), (C) or (D), which are each additionally characterized in that the active ingredient (I) is at least 90% effective after 15 minutes. is released.

(F) The invention also relates to pharmaceutical tablet formulations as described in embodiments (A), (B), (C) or (D), which are each further characterized in that the active ingredient (I) after 15 minutes to at least 95 % is released. (G) The invention also relates to pharmaceutical tablet formulations as described in the embodiments (A), (B), (C), (D), (E) or (F), each of which is additionally characterized in that the active ingredient in Form of the hydrochloride (II) is present.

(H) The invention also relates to pharmaceutical tablet formulations as described in the embodiments (A), (B), (C), (D), (E), (F) or (G), which are each further characterized in that a type A crospovidone is chosen as the disintegrant.

(I) The invention also relates to pharmaceutical tablet formulations as described in the embodiments (A), (B), (C), (D), (E), (F), (G) or (H), each of which additionally characterized in that they contain 5-25% (w / w) 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) - 3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] -phenoxy} ethyl-L-alanyl-L-alaninate hydrochloride [neladenoson bialanate hydrochloride (II)].

(J) The invention also relates to pharmaceutical tablet formulations as described in the embodiments (A), (B), (C), (D), (E), (F), (G), (H) or (I) , which are each further characterized in that the tablet has a film coating.

(K) The invention further provides a process for preparing a pharmaceutical tablet formulation comprising 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate

[Neladenoson bialanate (I)] in the form of one of its salts and (a) 68-95% (w / w) lactose monohydrate or anhydrous lactose or mixtures thereof, (b) 5-20% crospovidone and (c) 0-27% further pharmaceutical excipients, characterized in that the powder components are mixed, sieved and pressed into tablets.

(L) The invention further relates to the method mentioned above under (K), characterized in that the powder mixture or parts thereof are first dry granulated and then pressed into tablets.

(M) The invention further relates to the method mentioned above under (K) or (L), characterized in that it is carried out in the absence of moisture.

The discovered possibility of stabilizing the active ingredient in tablet form is surprising since, in contrast to the methods mentioned at the outset, it stands for the formulation of prodrugs and other labile active substances. So far, the fillers microcrystalline cellulose, mannitol or MicroceLac ^{® were} used. α-Lactose monohydrate was found to be rather disadvantageous. Stabilizers such as sugar alcohols or acids were added. Croscarmellose sodium was described as a disintegrant. Also, one skilled in the art would expect that the use of lactose monohydrate due to the water content of this adjuvant for the Formulation of a moisture-sensitive agent is less suitable, as well as the use of lactose types such as Flowlac ^® 90, which contains a proportion of amorphous lactose (see Example 14). In amorphous adjuvant mixtures, the free mobility of the molecules is not limited by binding into a solid crystal lattice, which generally reduces the stability of co-processed active ingredients.

How inadequate these findings of the prior art for the formulation of tablets with salts of Neladenoson bialanat (I), will become apparent from a number of comparative examples. As usual or as recommended, mannitol or microcrystalline cellulose as fillers, disintegrants in the usual manner and amount as well as various acids have been used as stabilizers. However, as Comparative Examples 1, 3, 4 and 5 show, these tablets are unstable. Already after 1 to 3 months storage at 40 ° C in HDPE bottles with desiccant from molecular sieve, the degradation product neladenosone (III) increases by 2.9 to 17.8 percentage points or the content of active ingredient (II) drops significantly. An addition of basic stabilizers such as sodium carbonate or calcium carbonate was also tested in a binary compatibility test and resulted in very rapid degradation rates. Comparative Examples 37 to 39 show the poor stability of neladenosone bialanate hydrochloride (II) tablets with xylitol or pregelatinized cornstarch as a bulking agent. Even with the application of Cho et al. [Int. J. Pharm. 400, 145-152 (2010)] and Mika et al. (US 2010/0130606 A1) described formulation to unstable Neladenoson bialanate hydrochloride (II) tablets (Comparative Examples 41 and 42) with degradation rates of 0.56 and 0.44 percentage points after storage for 3 months at 40 ° C in HDPE Bottles with molecular sieve desiccant.

For the objective proof of the effects of the invention, the stability of tablets with Neladenoson bialanat hydrochloride (II) in comparative stability tests at the same moisture content of the tablets, the same packaging and the same storage temperature of 40 ° C was also tested. As the examples and comparative examples 15-19 show, the stability of the tablets depends on the one hand on the lactose content of the tablets, even if the disintegrating agent has already been selected according to the findings of the invention. Thus, the breakdown product increases by 0.13 percentage points in the case of a lactose content of the tablet excipients of about 85% in the measurement period (see Example 15). In contrast, with a lactose content of about 64% of the tablet adjuvants, the rate of degradation is 2.7 times higher with an increase of 0.35 percentage points over the same period (see Comparative Example 19).

On the other hand, the stability of the tablets depends on the disintegrant, even if the filler has already been selected according to the findings of the invention. Thus, the examples and comparative examples 20, 21, 12 and 22 show a significantly reduced rate of formation of the degradation product under otherwise identical conditions when the disintegrant crospovidone according to the invention is used. However, it is not enough to formulate tablets that are stable because of a low rate of formation of neladenosone (III). After ingestion and disintegration of the tablets in the aqueous environment of the gastrointestinal tract, they must release the active ingredient rapidly and completely as possible. Otherwise, there is the risk that the drug, which has not been dissolved in time, will not be absorbed and excreted. The rate of onset may be disadvantageously slow in slowly releasing tablets. As shown in the examples of individual tablet formulations, the tablets according to the invention have the advantage of very rapid and complete release. This is in the examples 1 1, 12, 13, 14, 22 and 24-31 each at 97% to 100%, in Example 23 at 93.0%. In contrast, conventional tablets have partially lower (Comparative Examples 1, 2, 21) or significantly lower release rates (Comparative Examples 5, 8 and 10). This advantage is surprising, since the tablets each contained active ingredient of the same particle size and would not be predictable or explainable due to the disintegration times of tablets according to the invention and conventional tablets. Thus, the tablets of Comparative Example 10 show a very rapid disintegration within 0.17 minutes and yet an unsatisfactory slow release of the active ingredient of only 55.1% in 15 minutes. In the tablets according to the invention of Example 12, the disintegration time is 0.58 minutes and the release rate is 99.8% in 15 minutes. A particularly slow release rate has the tablet composition proposed in WO 2010/086101 (ibid., Page 187). As shown in Comparative Example 43, these tablets release only 7.1% of the active ingredient within 15 minutes.

Comparative Examples and Examples

The release of the active ingredient from the tablets is determined by the method of US Pharmacopoeia USP 39 (Chapter <71 1> Dissolution) using the apparatus 2 (Paddle Test). To determine the release rate, a tablet is introduced into each beaker of the USP apparatus 2 and the amount of neladenoson bialanate (I) which has gone into solution is determined after filtering off the undissolved constituents by means of HPLC. The release medium used is acetate buffer pH 4.5 with addition of 0.1% Brij 35 and the blade stirrer of USP Apparatus 2 has a rotational speed of 50 revolutions per minute. Unless otherwise stated, the rate of release of six specimens is determined. In each case, the mean value of the amount of active ingredient released after 15 minutes is given.

The disintegration time of the tablets is determined by the method of the European Pharmacopoeia 9.0 (Chapter 2.9.1 Disintegration of Tablets and Capsules) with disk to 6 tablets and the median of the disintegration times of the individual tablets is given.

The breaking strength of the tablets is determined by the method of European Pharmacopoeia 9.0 (Chapter 2.9.8 Resistance to crushing of tablets) and the mean of the individual determinations is stated. The flexural strength of oval tablets is determined with a commercial tablet break strength tester containing two inserts with a total of three break mandrels. The measurement principle is described in [Bauer KH, Frömming KH and Guide C, Textbook of Pharmaceutical Technology, Stuttgart 1999 on page 352, Figure 14.54c]. The tablet to be tested is placed on the bridge side, so that the top and bottom of the tablet points to the test jaws. The fracture mandrels of the test jaws are adjusted so that they roughly triple the top of the tablet. It determines the force necessary to break the tablet when the test jaws move together and gives the mean of the individual determinations.

The content of neladenosone (III) is determined by high pressure liquid chromatography. For analysis, the tablets are prepared as follows: 5 tablets are used e.g. with 25 ml of 10 mmolar aqueous phosphoric acid. After disintegration of the tablets, 60-70 ml of acetonitrile are added and sonicated for 10 minutes. The suspension is shaken overnight, treated with ultrasound for a further 10 min, brought to room temperature and made up to 100 ml. After shaking, an aliquot is centrifuged and, depending on the tablet thickness, diluted with a mixture of 1 part by volume phosphoric acid (10 mmol / L) and 3 parts by volume acetonitrile and finally chromatographed. For the subsequent HPLC determination of the content of the active ingredient neladenosone bilanate (I), possible synthesis secondary components and the degradation products, in particular of neladenosone (III), a highly selective analytical method was developed. The stationary phase used is a commercially available Triart C18 HPLC column (1, 9 μΓΤΐ particles, column dimensions 50 mm 2.0 mm). The mobile phase used is a solvent mixture which

A: from 1.5 g ammonium acetate / 1 L water (adjusted to pH 6.1 with acetic acid) and

B: consists of acetonitrile with 5% (v / v) methanol (B).

The solvent mixture of A and B is changed with a gradient during the chromatographic run according to the following time scheme.

The column temperature is 20 ° C and the chromatographic run time 40 minutes. The degradation product neladenosone (III) appears at a relative retention time of approximately 1.48. Since the separation capacity of HPLC columns can vary, there are small deviations possible. The content of neladenosone (III) is related in area percent to the sum of the peak areas of neladenoson bialanate (I) and the by-products and degradation products present. The increase in the content of the degradation product neladenosone (III) is expressed as the difference between the percentage content at the start of storage and at the end of storage in percentage points. For example, when the level of neladenosone (III) is increased from, for example, 0.1% to 0.3%, the increase is 0.2 percentage points.

As a desiccant capsule in HDPE bottles each Tri-Sorb ^® Clariant was used, which contains 3 g desiccant of molecular sieve. The molecular sieve used here is a synthetic zeolite having a pore size of 3 Å.

Comparative Example 1

242.54 g of micronized Neladenoson bialanate hydrochloride (II), 2562.46 g of mannitol (Parteck ^® M 200) and 150.0 g of croscarmellose sodium were mixed and sieved and mixed with 45.0 g of magnesium stearate. The mixture was compressed on a tablet press into round tablets of 130 mg mass, 7 mm diameter, breaking strength of about 64 N and containing 10.51 mg of Neladenoson bialanate hydrochloride (II).

Each 20 of these tablets were packaged in a HDPE bottle with desiccant of molecular sieve and subjected to 40 ° C and 75% humidity a durability test.

After storage for 3 months, the content of the decomposition product neladenosone (III) increased from initially 0.5% to 3.4%, ie by 2.90 percentage points and thus by 580%. After 6 months, the content of this decomposition product was 9.8% and thus increased by 1860%. The active ingredient was thus unstable in the tablet formulation.

The release rate of the tablets was 86.0% in 15 minutes.

Comparative Example 2

210.2 g of micronized Neladenoson bialanat hydrochloride (II), 65.0 g of crospovidone of type B (Polyplasdone ^® XL 10), 2306.6 g StarLac ^® (coprozessierte mixture of 85% α-lactose mono- hydrate and 15% corn starch) were mixed and sieved and mixed with 18.2 g of magnesium stearate. The mixture was compressed on a tablet press into round tablets of 130 mg mass, 7 mm diameter, breaking strength of about 64 N and containing 10.51 mg of Neladenoson bialanate hydrochloride (II).

The tablets thus contained only 2.7% of type B crospovidones in the excipient portion. The release rate of the tablets was 74.8% in 15 minutes.

Comparative Example 3

3.09 g of micronized Neladenoson bialanat hydrochloride (II), 5.00 g croscarmellose sodium (Ac-Di-Sol ^®), 75.4 g mannitol (Parteck M ^®) and 15.00 g of succinic acid were mixed and sieved with 1 , 51 g magnesium stearate mixed. The mixture was placed on a tablet pressed into round tablets of 85 mg mass, a diameter of 6 mm, a breaking strength of about 62 N and a content of 2.63 mg Neladenoson bialanat hydrochloride (II). The tablets were packed in HDPE bottles with molecular sieve desiccant and subjected to a shelf life test at 40 ° C and 75% humidity.

After 1 month of storage, the content of neladenosone bialanate hydrochloride (II) in the tablets decreased by 8.2% and by 35.3% after storage for 6 months. The active ingredient was thus unstable in the tablet formulation.

Comparative Example 4

9.28 g of micronized Neladenoson bialanat hydrochloride (II), 15.00 g of croscarmellose sodium (Ac-Di-Sol ^®), 226.2 g mannitol (Parteck ^® M) and 45.00 g of fumaric acid were mixed and sieved and 4 , 52 g magnesium stearate mixed. The mixture was compressed on a tablet press to round tablets of 85 mg mass, 6 mm diameter, a breaking strength of about 65 N and a content of 2.63 mg Neladenoson bialanat hydrochloride (II). The tablets were packed in HDPE bottles with molecular sieve desiccant and subjected to a shelf life test at 40 ° C and 75% humidity.

After storage for 2 months, the content of the decomposition product neladenosone (III) increased from 0.963% to 18.8%, or 17.84 percentage points. This corresponds to an increase of the initial level of neladenosone (III) by 1852%. The active ingredient was thus unstable in the tablet formulation.

Comparative Example 5

9.28 g of micronized Neladenoson bialanat hydrochloride (II), 15.00 g of croscarmellose sodium (Ac-Di-Sol ^®), 228.6 g of a coprocessed mixture of 85% α-lactose monohydrate and 15% maize starch (StarLac ^®) and 45.00 g fumaric acid were mixed and sieved and mixed with 2.12 g magnesium stearate. The mixture was compressed on a tablet press to round tablets of 85 mg mass, 6 mm diameter, a breaking strength of about 65 N and a content of 2.63 mg Neladenoson bialanat hydrochloride (II). The tablets were packed in HDPE bottles with molecular sieve desiccant and subjected to a shelf life test at 40 ° C and 75% humidity.

After storage for 2 months, the content of the decomposition product neladenosone (III) increased from 1.77% to 12.26% and thus by 10.49 percentage points. This corresponds to an increase of the initial content of neladenosone (III) by 593%. The active ingredient was thus unstable in the tablet formulation.

The release rate of the tablets was 63.6% in 15 minutes (mean of three tablets studied). Composition of the tablets

Comparative Examples 6 to 10

There were prepared unpainted tablets containing per tablet 10.51 mg micronized Nela- denoson bialanat hydrochloride (II), 150.23 mg filler, 18.00 mg crospovidone and 1, 26 mg magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 150 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 80 N. Each 10 tablets were packed in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. When using microcrystalline cellulose as filler, the proportion of the degradation product neladenosone (III) during the test period increased by 2.66 percentage points. The release rate was 93.8% in 15 minutes (Comparative Example 6).

When using mannitol as a filler, the proportion of the degradation product neladenosone (III) during the test period increased by 0.35 percentage points. The release rate was 102% in 15 minutes (Comparative Example 7).

When maltodextrin was used as filler, the proportion of the degradation product neladenosone (III) increased by 0.30 percentage points over the test period. The release rate was only 47.5% in 15 minutes (Comparative Example 8).

When using a mixture of agglomerated α-lactose monohydrate and microcrystalline cellulose in a ratio of 3: 1 as filler, the proportion of the degradation product neladenosone (III) in the test period increased by 0.57 percentage points. The release rate was 100% in 15 minutes (Comparative Example 9).

When using calcium hydrogen phosphate dihydrate as a filler, the proportion of the degradation product neladenosone (III) only increased by 0.09 percentage points in the test period. The disintegration time of the tablets was 0.17 minutes and the release rate was only 55.1% in 15 minutes (Comparative Example 10).

Comparative Examples 6-10 show that even using the optimal disintegrants found in this invention, crospovidone tablet formulations using conventional bulking agents are either unstable or too slow to release.

Examples 1 1 to 14

Under the same conditions as Comparative Examples 6-10, unpainted tablets were prepared containing per tablet 10.51 mg of micronized Neladenoson bialanate hydrochloride (II), 150.23 mg of bulking agent, 18.00 mg of crospovidone and 1.26 mg of magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 150 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 80 N. Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. When using a coprocessed mixture of 85% α-lactose monohydrate and 15% corn starch as filler, the proportion of the degradation product neladenosone (III) increased by 0.25 percentage points in the test period. The release rate was 100% in 15 minutes (Example 11).

When using anhydrous ß- / a-lactose (Supertab ^® 24AN) as a filler, the proportion of the degradation product neladenosone (III) during the test period only increased by 0.13 percentage points. The Disintegration time of the tablets was 0.58 minutes and the release rate was 99.8% in 15 minutes (Example 12).

When using α-lactose monohydrate as filler, the proportion of the degradation product neladenosone (III) only increased by 0.1 1 percentage points in the test period. The release rate was 97.8% in 15 minutes (Example 13).

When using α-lactose monohydrate with fractions of amorphous lactose (FlowLac ^® 90) as a filler increased the percentage of the degradation product Neladenoson (III) in the check period only by 0.09 percentage points. The release rate was 100% in 15 minutes (Example 14).

Composition of the tablets

Comparative Examples Inventive Examples

6 7 8 9 10 11 12 13 14

Active ingredient (II) in mg per tablet 10.51 10.51 10.51 10.51 10.51 10.51 10.51 10.51 10.51

Excipients in mg per tablet 169.49 169.49 169.49 169.49 169.49 169.49 169.49 169.49 169.49

Mass of a tablet in mg 180 180 180 180 180 180 180 180 180 180

mannitol

88.64

in% of the excipient content

Microcrystalline cellulose

88.64 22.16

in% of the excipient content

maltodextrin

88.64

in% of the excipient content

a-lactose monohydrate

66.48 75.34 88.64% of the excipient content

corn starch

13,30

in% of the excipient content

Calcium hydrogen phosphate

Dihydrate 88.64

in% of the excipient content

SS / a-lactose (Supertab ^® 24an)

anhydrous, 88.64

in% of the excipient content

α-lactose monohydrate with

Proportions of amorphous lactose

88.64 (FlowLac ^® 90)

in% of the excipient content

Crospovidone (Polyplasdone ^®

10.62 10.62 10.62 10.62 10.62 10.62 10.62 10.62 10.62 XL) in% of the excipient content

magnesium stearate

0.74 0.74 0.74 0.74 0.74 0.74 0.74 0.74 0.74 in% of the excipient content

Diameter (mm) 8 8 8 8 8 8 8 8 8

Breaking strength (N) -80 -80 -80 -80 -80 -80 -80 -80 -80

Increase in salary

Compound (III) after 3 months

2.66 0.35 0.30 0.57 0.09 0.25 0.13 0.1 1 0.09 at 40 ° C / 75% humidity

(in percentage points)> Comparative Examples Inventive Examples

6 7 8 9 10 11 12 13 14

Release of active substance after 15

93.8 102 47.5 100 55, 1 100 99.8 97.8 100 min (in%)

Decay time (min) 0.17 0.58

^ Packaging in HDPE bottles with molecular sieve desiccant

Examples 15-18

There were prepared unpainted tablets containing per tablet 21, 02 mg micronized Neladenoson bialanat hydrochloride (II), 139.76 mg filler, 17.96 mg crospovidone and 1, 26 mg magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 180 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 80 N. The tablets were coated with 5 mg of lacquer solids per tablet, which consisted of 2.528 mg hypromellose 5 cP, 0.506 mg talc, 1.958 mg titanium dioxide and 0.008 mg red iron oxide. For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity.

When using anhydrous .beta. / a-lactose (Supertab ^® 24an) as a filler was the lactose content of the tablets 85.23%, the loss on drying of the tablets and 0.7% the equilibrium relative humidity 23.5%. The proportion of the degradation product neladenosone (III) only increased by 0.13 percentage points in the test period (Example 15).

When using a mixture of 95% anhydrous .beta. / a-lactose (Supertab ^® 24an) and 5% of microcrystalline cellulose as a filler of lactose content of the tablets was 80.97%, the loss on drying of the tablets 0.6%, and the equilibrium relative humidity 23, 6%. The proportion of the degradation product neladenosone (III) increased by 0.15 percentage points in the test period (Example 16).

When using a mixture of 90% anhydrous .beta. / a-lactose (Supertab ^® 24an) and 10% microcrystalline cellulose as a filler was the lactose content of the tablets 76.71%, the loss on drying of the tablets 0.7%, and the equilibrium relative humidity 24, 0%. The proportion of the degradation product neladenosone (III) increased by 0.19 percentage points in the test period (Example 17).

When using a mixture of 80% anhydrous .beta. / a-lactose (Supertab ^® 24an) and 20% microcrystalline cellulose as a filler was the lactose content of the tablets 68.18%, the loss on drying of the tablets 0.8%, and the equilibrium relative humidity 21, 8th %. The amount of the degradation product neladenosone (III) increased by 0.25 percentage points in the test period (Example 18).

It is particularly noteworthy that the stability of the active ingredient (II) in the tablet core can be increased so far by the excipient combination according to the invention that a short-term exposure of the cores to an aqueous coating suspension is possible.

Examples 15-18 further show that the best results of the stability test are found in the preferred use of only lactose as the filler. Small amounts of other fillers are still tolerable, but already worsen the stability of the tablets.

Comparative Example 19

Under the same conditions as in Examples 15-18, unpainted tablets containing micronized 21, 02 mg of neladenoson bialanate hydrochloride (II), 139.76 mg of filler, 17.96 mg of crospovidone and 1, 26 mg of magnesium stearate per tablet were prepared. For this purpose, the ingredients corresponding to a batch size of 180 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 80 N. The tablets were coated with 5 mg of lacquer solids per tablet, which consisted of 2.528 mg hypromellose 5 cP, 0.506 mg talc, 1.958 mg titanium dioxide and 0.008 mg red iron oxide. For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity.

When using a mixture of 75% anhydrous .beta. / a-lactose (Supertab ^® 24an) and 25% microcrystalline cellulose as a filler of lactose content of the tablets was 63.92%, the loss on drying of the tablets 0.2%, and the equilibrium relative humidity 21, 6%. The proportion of the degradation product neladenosone (III) increased by 0.35 percentage points during the test period. Thus, the rate of increase of the degradation product was 2.7 times higher than in Example 15.

Composition of the tablets

comparably

Examples according to the invention

example

15 16 17 18 19

Active ingredient (II) in mg per tablet 21, 02 21, 02 21, 02 21, 02 21, 02

Excipients in mg per tablet 163.98 163.98 163.98 163.98 163.98

Mass of a tablet in mg 185 185 185 185 185 SS / a-lactose (Supertab ^® 24an)

85.23 80.97 76.71 68, 18 63.92 anhydrous in% of the excipient content

Microcrystalline cellulose

4.26 8.52 17.05 21, 31 in% of the excipient content comparably

Examples according to the invention

example

15 16 17 18 19

Crospovidone (Polyplasdone ^® XL)

10,95 10,95 10,95 10,95 10,95 in% of excipient content

magnesium stearate

0.77 0.77 0.77 0.77 0.77% of the excipient content

Lacquer dry matter ⁾

3.05 3.05 3.05 3.05 3.05% of the excipient content

Diameter (mm) 8 8 8 8 8

Breaking strength (N) -80 -80 -80 -80 -80

Drying loss (%) 0.7 0.6 0.7 0.8 0.2 rel. Equilibrium (%) 23.5 23.6 24 21, 8 21, 6

Increase in the content of compound

(III) after 3 months at 40 ° C (in 0, 13 0.15 0.19 0.25 0.35 percentage points) ²⁾

> consisting of 50.56% hypromellose 5cP, 10.12% talc, 39, 16% titanium dioxide and 0.16% iron oxide red ^ Packaging in HDPE bottles with molecular sieve desiccant

Comparative Examples 20 and 21

Uncoated tablets were prepared, which bialanat Noson per tablet 10.51 mg of micronized Nelade- hydrochloride (II), 150.23 mg of anhydrous .beta.-l - Lactose (Supertab ^® 24an), 18.00 mg disintegrating agent and 1, 26 mg of magnesium stearate contained. For this purpose, the ingredients corresponding to a batch size of 150 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 80 N. Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity.

With the use of carboxymethyl starch sodium (Primojel ^®) as the disintegrating agents as determined by the Karl Fischer method of water content of the tablets was 0.60%. The proportion of the degradation product neladenosone (III) increased by 0.41 percentage points in the test period. The release rate was 90.6% in 15 minutes (Comparative Example 20).

When croscarmellose sodium (Ac-Di- ^Sol® ) was used as the disintegrant, the water content of the tablets determined by the Karl Fischer method was 0.81%. The proportion of the degradation product neladenosone (III) increased by 0.50 percentage points in the test period. The disintegration time of the tablets was 0.75 minutes and the release rate was 87.7% in 15 minutes (Comparative Example 21).

Both comparative examples show the poor stability of Neladenoson bialanat hydrochloride (II) in tablets with non-inventive disintegrants. The release rate is lower and thus worse than tablets with disintegrants according to the invention (Examples 12 and 22). Example 22

Under the same conditions as in Comparative Examples 20 and 21 uncoated tablets were prepared containing per tablet 10.51 mg of micronized Neladenoson bialanat hydro- chloride (II), 150.23 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an) 18.00 mg disintegrant and 1, 26 mg magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 150 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 80 N. Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity.

With the use of crospovidone (Polyplasdone ^® XL), the tablets described in Example 12 were obtained. The water content of the tablets determined by the Karl Fischer method was 0.73%. The proportion of the degradation product neladenosone (III) only increased by 0.13 percentage points in the test period. The disintegration time of the tablets was 0.58 minutes and the release rate was 99.8% in 15 minutes.

With the use of crospovidone (Kollidon CL ^®) as the disintegrating agents as determined by the Karl Fischer method of water content of the tablets was 0.92%. The proportion of the degradation product neladenosone (III) only increased by 0.1 1 percentage points in the test period. The release rate was 100% in 15 minutes (Example 22).

Composition of the tablets

invention

Comparative Examples

Examples

20 21 12 22

Active ingredient (II) in mg per tablet 10.51 10.51 10.51 10.51

Excipients in mg per tablet 169.49 169.49 169.49 169.49

Mass of a tablet in mg 180 180 180 180 SS / a-lactose (Supertab ^® 24an), anhydrous

88.64 88.64 88.64 88.64% of the excipient content

Carboxymethyl starch sodium (Primojel ^®) 10.62

Croscarmellose sodium (Ac-Di- ^Sol® )

10.62

in% of the excipient content

Crospovidone (Polyplasdone ^® XL)

10.62

in% of the excipient content

Crospovidone (Kollidon CL ^®)

10.62% of the excipient content

magnesium stearate

0.74 0.74 0.74 0.74% of the excipient content

Diameter (mm) 8 8 8 8

Breaking strength (N) -80 -80 -80 -80 invention

Comparative Examples

Examples

20 21 12 22

Water content (Karl Fischer method) (%) 0.6 0.81 0.73 0.92

Increase in the content of compound (III) after

3 months at 40 ° C / 75% rel. Humidity 0,41 0,50 0,13 0,1 1 (in percentage points)>

Decay time (min) 0.75 0.58

Release of active ingredient after 15 min (%) 90.6 87.7 99.8 100

^ Packaging in HDPE bottles with molecular sieve desiccant

Example 23

Were prepared film coated tablets, which per tablet 2.63 mg micronized Neladenoson bialanat hydrochloride (II), 73.275 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 8.5 mg Crospo- vidone (Polyplasdone ^® XL) and 0,595 mg Magnesium stearate contained. For this purpose, the ingredients corresponding to a batch size of 2125 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 85 mg mass and a diameter of 6 mm and a breaking strength of about 40 N. A partial batch of 656.8 g of the tablets was coated with a coating of 3 mg of dry lacquer substance per tablet, which consisted of 1.518 g of hypromellose 5 cP, 0.3036 mg of talc, 1.1748 mg of titanium dioxide and 0.0048 mg of red iron oxide , For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) only increased by 0.31 percentage points. The drug release from the tablets was 93.0% in 15 minutes.

Example 24

Were prepared film coated tablets, which per tablet 5.25 mg micronized Neladenoson bialanat hydrochloride (II), 155.49 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 18 mg CROS povidone (Polyplasdone ^® XL) and 1, Contained 26 mg of magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 4250 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 62 N. A partial batch of 3640 g of the tablets was coated with 5 mg of lacquer dry matter per tablet, which consisted of 2.528 mg hypromellose 5 cP, 0.506 mg talc, 1.958 mg titanium dioxide and 0.008 mg red iron oxide. For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. Each 10 film-coated tablets were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) only increased by 0.22 percentage points. The drug release from the tablets was 100% in 15 minutes.

Example 25

Were prepared film coated tablets, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 150.23 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 18 mg CROS povidone (Polyplasdone ^® XL) and 1, Contained 26 mg of magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 12500 tablets were first mixed and sieved without magnesium stearate, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 74 N. The tablets were coated with 5 mg of lacquer solids per tablet, which consisted of 2.528 mg hypromellose 5 cP, 0.506 mg talc, 1.958 mg titanium dioxide and 0.008 mg red iron oxide. For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. Each 10 film tablets were packed in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) only increased by 0.23 percentage points. The drug release from the tablets was 100% in 15 minutes.

Example 26

Were prepared film coated tablets, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 150.23 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 18 mg CROS povidone (Polyplasdone ^® XL) and 1, Contained 26 mg of magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 2000 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 65 N. The tablets were coated with 5 mg of lacquer solids per tablet, which consisted of 2.528 mg hypromellose 5 cP, 0.506 mg talc, 1.958 mg titanium dioxide and 0.008 mg red iron oxide. For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. The film-coated tablets were packed in aluminum / aluminum blisters and stored for 3 months at 40 ° C. and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) increases by 0.74 percentage points. In a stability test for 12 months at 25 ° C, the proportion of the degradation product neladenosone (III) increased from 0.291 to 0.663%, corresponding to 0.372 percentage points. The drug release from the tablets was 98.0% in 15 minutes. Example 27

Were prepared film coated tablets, which bialanat per tablet 21, 02 mg of micronized Neladenoson hydrochloride (II), 139.72 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 18 mg CROS povidone (Polyplasdone ^® XL) and 1, Contained 26 mg of magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 4000 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 78 N. A partial feed of 1500 g of the tablets was coated with 5 mg of lacquer solids per tablet, which consisted of 2.528 mg of hypromellose 5 cP, 0.506 mg of talc, 1.958 mg of titanium dioxide and 0.008 mg of red iron oxide. For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) only increases by 0.19 percentage points. Over a storage period of 9 months at 25 ° C and 60% relative humidity, the proportion of the degradation product neladenosone (III) increased from 0.36% to 0.45%, corresponding to 0.09 percentage points. The drug release from the tablets was 100% in 15 minutes.

Example 28

A portion of the film-coated tablets, the preparation of which is described in Example 27, was packaged in aluminum / aluminum blisters. In the course of a stability test for 3 months at 40 ° C and 75% relative humidity, the proportion of degradation product neladenosone (III) increased by 0.80 percentage points. The drug release from the tablets was 100% in 15 minutes.

Example 29

Were prepared film coated tablets, which per tablet 42.04 mg of micronized Neladenoson bialanat hydrochloride (II), 118.16 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 18 mg CROS povidone (Polyplasdone ^® XL) and 1, 80 mg magnesium stearate contained. For this purpose, the ingredients corresponding to a batch size of 500 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 76 N. Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) only increased by 0.06 percentage points. The drug release from the tablets was 100% in 15 minutes.

Example 30

Were prepared film coated tablets, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 150.23 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 18.00 mg CROS povidone and 1, 26 mg magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 2250 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 71 N. A partial batch of 875.8 g of the tablet cores was coated with a coating of 5 mg of dry lacquer substance per tablet, which consisted of 2.2 mg of hydroxypropylcellulose, 1.22 mg of titanium dioxide, 0.72 mg of hypromellose 3cP, 0.42 mg of propylene glycol, 0, There was 04 mg of red iron oxide and 0.40 mg of yellow iron oxide. For this purpose, the paint components were sprayed as a dispersion of 8% paint dry substance, 82.8% isopropanol and 9.2% water in a paint spray on the tablet cores. 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) only increased by 0.13 percentage points. Drug release from the tablets was 97.0% in 15 minutes.

Example 31

Film-coated tablets were prepared containing per tablet 10.51 mg micronised Neladenoson bialanat hydrochloride (II), 150.23 mg anhydrous ß- / a-lactose (Supertab ^® 24AN), 18.00 mg crospovidone and 1, 26 mg magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 2550 g were first mixed and sieved without magnesium stearate and granulated dry on a roll granulator at a specific pressing force of 6 kN / cm and a mesh width of 1 mm. The granules were mixed with 1, 26 mg magnesium stearate and pressed into round tablets of 180 mg mass, a diameter of 8 mm and a breaking strength of about 82 N. Drug release from the tablets was 98.0% in 15 minutes (mean of five tablets).

Example 32

Film-coated tablets were produced containing per tablet 2.63 mg micronised Neladenoson bialanat hydrochloride (II), 73.275 mg anhydrous ß- / a-lactose (Supertab ^® 24AN), 8.50 mg crospovidone and 0.595 mg magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 2125 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 85 mg mass and a diameter of 6 mm and a breaking strength of about 42 N. A partial charge of 656.8 g of the tablet cores was coated with 3 mg of lacquer solids per tablet consisting of 1.32 mg of hydroxypropylcellulose, 0.732 mg of titanium dioxide, 0.432 mg of hypromellose 3cP, 0.252 mg of propylene glycol, 0.024 mg of red iron oxide and 0.24 mg of yellow iron oxide. For this purpose, the paint components were sprayed as a dispersion of 8% Lacktrockensub- dance, 82.8% isopropanol and 9.2% water in a Lackiergerät on the tablet cores. 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity. in the As a result of this stability test, the proportion of the degradation product neladenosone (III) only increased by 0.16 percentage points. The drug release from the tablets was 97% in 15 minutes.

Composition of the tablets

> consisting of 50.56% hypromellose 5cP, 10, 12% talc, 39, 16% titanium dioxide and 0.16% iron oxide red ²⁾ consisting of 14.4% hypromellose 3cP, 24.4% titanium dioxide, 8% iron oxide yellow, 0.8% iron oxide red, 44% hydroxypropyl cellulose and 8.4% 1.2-propylene glycol

Example 33

Were prepared film coated tablets, which per tablet 5.26 mg micronized Neladenoson bialanat hydrochloride (II), lactose monohydrate 155.48 mg (Supertab ^® 1 1 SD), 18 mg Crospovi- contained done of the type A (Polyplasdone ^® XL) and 1, 26 mg of magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 180 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 71 N. 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) only increased by 0.22 percentage points.

Example 34

Were prepared film coated tablets, which per tablet 5.26 mg micronized Neladenoson bialanat hydrochloride (II), lactose monohydrate 155.48 mg granulated (30GR Supertab ^®), crospovidone 18 mg of type A (Polyplasdone ^® XL) and 1, 26 mg of magnesium stearate contained , For this purpose, the ingredients corresponding to a batch size of 180 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 72 N. 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) only increased by 0.22 percentage points.

Example 35

Were prepared film coated tablets, which bialanat per tablet 31, 53 mg of micronized Neladenoson hydrochloride (II), 209.58 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 27 mg Crospovidone of type A (Polyplasdone ^® XL) and 1 , 89 mg magnesium stearate. For this purpose, the ingredients corresponding to a batch size of 3240 g unpainted tablets were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into oval tablets of 270 mg mass, a length of 12 mm and a width of 6 mm and a flexural strength of about 55 N. A partial batch of 1350 g of unpainted tablets was coated with 7 mg of lacquer solids per tablet consisting of 3.5 mg hypromellose 5 cP, 0.7 mg talc, 2.1 mg titanium dioxide and 0.7 mg red iron oxide. For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. Drug release from the tablets was 98% in 15 minutes.

Example 36

There were film-coated tablets prepared which per tablet 42.04 mg of micronized Neladenoson bialanat hydrochloride (II), 279.44 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 36 mg Crospovidone of type A (Polyplasdone ^® XL) and 2 , 52 mg magnesium stearate. For this The ingredients corresponding to a batch size of 4680 g unpainted tablets were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into oval tablets of 360 mg mass, a length of 14 mm and a width of 6 mm and a flexural strength of about 57 N. A partial batch of 3960 g of unpainted tablets was coated with 8.5 mg of dry paint per tablet, which consisted of 4.25 mg of 5 mg hypromellose, 0.85 mg of talc, 2.55 mg of titanium dioxide and 0.85 mg of red iron oxide. For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. The drug release from the tablets was 100% in 15 minutes.

Composition of the tablets

) consisting of 50% hypromellose 5cP, 10% talc, 30% titanium dioxide and 10% iron oxide red

Comparative Example 37

Tablets were prepared, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 150.23 mg xylose (Xylitab ^®), crospovidone 18 mg of type A (poly- Plasdone ^® XL) and 1, containing 26 mg of magnesium stearate. The tablets are thus not in accordance with the present invention. For this purpose, the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 104 N. Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) increased significantly by 0.78 percentage points. Further, drug release from the tablets was insufficient at only 12.8% after 15 minutes.

Comparative Example 38

Tablets were prepared, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 48.54 mg xylose (Xylitab ^®), 101, 69 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 18 mg Crospovidone of type A (Polyplasdone ^® XL) and 1, 26 mg of magnesium stearate contained. The tablets are thus not in accordance with the present invention. For this purpose, the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 73 N. Each 10 tablets were packed in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) increased significantly by 0.56 percentage points. Furthermore, drug release from the tablets was slow at 83.8% after 15 minutes.

Comparative Example 39

Tablets were prepared, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 150.23 mg pregelatinized starch (Lycatab ^® CLM), 18 mg Crospovidone of type A (Polyplasdone ^® XL) and 1, 26 mg of magnesium stearate contained , The tablets are thus not in accordance with the present invention. For this purpose, the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 29 N. Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) increased significantly by 0.59 percentage points. Further, drug release from the tablets was insufficient at only 27.7% after 15 minutes. Comparative Example 40

Tablets were prepared, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 150.23 mg of calcium sulfate dihydrate (Compactrol ^®), crospovidone 18 mg of type A (Polyplasdone ^® XL) and 1, 26 mg of magnesium stearate contained , The tablets are thus not in accordance with the present invention. For this purpose, the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 77 N. Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) increased only slightly by 0.165 percentage points. However, drug release from the tablets was insufficient at only 58.2% after 15 minutes.

Composition of the tablets

Comparative Example 41

Tablets according to the teaching of Mika et al. (US 2010/0130606 A1). These relate to fesoterodine and contain xylitol as stabilizer, for example in the ratio 1: 1 to 1: 9 (fesoterodine / stabilizer, see claim 51). In detail, therefore, neladenoson bialanate hydrochloride (II) tablets were prepared, which per tablet 10.51 mg micro Nes nadesoson bialanat hydrochloride (II), 52.55 mg xylitol, 97.14 mg co-processed mixture of 75% α-lactose monohydrate and 25% microcrystalline cellulose (MicroceLac ^®), crospovidone 18 mg of type A (Polyplasdone ^® XL) and 1, 8 mg of magnesium stearate contained. Thus, the tablets are not in accordance with the present invention as they had only a low level of 43% lactose (w / w, based on the mass of all the excipients of the tablet). For this purpose, the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 73 N. Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) increased significantly by 0.56 percentage points. Furthermore, drug release from the tablets was slow at only 82.9% after 15 minutes.

Comparative Example 42

Tablets made using the teachings of Cho et al. for trimebutine maleate and macrapride citrate dihydrate [KH Cho et al., Int. J. Pharm. 400, 145-152 (2010), Table 1, Composition V on page 146]. For this purpose, the said active ingredients were exchanged for micronized Neladenoson bialanate hydrochloride (II) and added to the compression required for tablets usual lubricant. Specifically, tablets were prepared containing bialanat per tablet 21, 02 mg of micronized Neladenoson hydrochloride (II), 4.18 mg hydroxypropyl cellulose (L-HPC), 4.18 mg of silicon dioxide (Aerosil ^®), 8.36 mg of croscarmellose sodium ( Ac-Di-Sol ^®) 67.63 mg D-mannitol (Pearlitol SD 100 ^®), 10.45 mg citric acid and 4.18 mg of magnesium stearate contained. The tablets are thus not in accordance with the present invention. For this purpose, the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 120 mg mass and a diameter of 7 mm and an average breaking strength of about 80 N. Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) increased significantly by 0.44 percentage points. Furthermore, drug release from the tablets was slow at only 86.7% after 15 minutes. Comparative Example 43

Tablets were produced as proposed in WO 2010/086101 A1 (page 187). Specifically, tablets were prepared containing per 100 mg of Micronized Neladenoson Bialanate Hydrochloride (II), 50 mg of Lactose Monohydrate, 50 mg of Corn Starch (native), 10 mg of Polyvinylpyrrolidone (PVP 25) and 2 mg of Magnesium Stearate. Thus, the tablets are not in accordance with the present invention as they had only a low level of 44.6% lactose (w / w, based on the mass of all the excipients of the tablet). For this purpose, 200 g of active ingredient, 100 g of corn starch and 100 g of lactose were premixed in a mixed granulator. The powder mixture was granulated with a solution of 20 g of polyvinylpyrrolidone in 380 g of water, dried, sieved and mixed with 4 g of magnesium stearate. This press-ready mixture was pressed on an eccentric press into round tablets of 212 mg mass and a diameter of 8 mm and an average breaking strength of about 40 N. Drug release from the tablets was insufficient at only 7.1% after 15 minutes.

Comparative Example 44

Were prepared film coated tablets, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 163.73 mg of anhydrous .beta. / a-lactose (Supertab ^® 24an), 4.5 mg of crospovidone (Polyplasdone ^® XL) and 1, Contained 26 mg of magnesium stearate. Due to the low proportion of 2.6% (w / w) Crospovidone of the type A (Polyplasdone ^® XL) in the adjuvant portion of the tablet, these tablets do not correspond to the present invention. For this purpose, the ingredients corresponding to a batch size of 1000 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on a rotary press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 73 N. A partial charge of 750 g of the tablets was applied to a paint application of 5 mg of lacquer substance per tablet, which consisted of 2.528 mg of 5 mmoles of Hypromellose, 0.506 mg of talc, 1.958 mg of titanium dioxide and 0.008 mg of red iron oxide. For this purpose, the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. In contrast to film tablets according to the invention, the release of active ingredient from the film-coated tablets of this comparative example spread strongly and was only 79.4 and 84.2% in 15 minutes for two out of twelve tablets. In comparison, the drug release of the film-coated tablets from Example 26 was also more than 96% in 15 minutes for each individual film-coated tablet. Composition of the tablets

¹⁾ consisting of 50.56% hypromellose 5cP, 10.12% talc, 39.16% titanium dioxide and 0.16% iron oxide red

Claims

claims

1. A pharmaceutical tablet formulation comprising 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyano-6- (pyrrolidine) 1-yl) pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate [Neladenoson bialanat (I)] in the form of one of its salts, characterized in that the excipient fraction

(a) to 68-95% (w / w) of lactose monohydrate or anhydrous lactose or mixtures thereof,

(b) to 5-20% from crospovidone and

(c) 0-27% from other pharmaceutical excipients

consists.

2. Pharmaceutical tablet formulations according to claim 1, characterized in that the excipient fraction

(b) to 5-12% from crospovidone and

(c) to 0-20% from other pharmaceutical excipients

consists.

3. Pharmaceutical tablet formulations according to any one of claims 1 or 2, each further characterized in that the active ingredient (I) is released after 15 minutes to at least 90%.

4. Pharmaceutical tablet formulations according to any one of claims 1, 2 or 3, which are each further characterized in that the active ingredient (I) after 15 minutes to at least 95% is released.

5. Pharmaceutical tablet formulations according to any one of claims 1, 2, 3 or 4, which are each further characterized in that the active ingredient in the form of

Hydrochloride (II) is present.

6. Pharmaceutical tablet formulations according to claim 5, characterized in that the active ingredient in the form of the monohydrochloride (IIa) is present.

7. Pharmaceutical tablet formulations according to any one of claims 1, 2, 3, 4, 5 or 6, which are each further characterized in that as a disintegrating agent

Crospovidone type A is selected.

Pharmaceutical tablet formulations according to any one of claims 1, 2, 3, 4, 5, 6 or 7, each further characterized by being 5-25% (w / w) 2- {4- [2 - ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyano

pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate hydrochloride [Neladenoson bialanate hydrochloride (II)].

Pharmaceutical tablet formulations according to any one of claims 1, 2, 3, 4, 5, 6, 7 or 8, each further characterized in that the tablet has a film coating.

A process for the preparation of a pharmaceutical tablet formulation according to claim 1, containing 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5 - dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate [neladenosonbialanate (I)] in the form of one of its salts and (a) 68-95% ( w / w) lactose monohydrate or anhydrous lactose or mixtures thereof, (b) 5-20% crospovidone and (c) 0-27% further pharmaceutical excipients, characterized in that the powder ingredients are mixed, sieved and compressed into tablets.

1 1. A method according to claim 10, characterized in that Neladonoson bialanat in the form of the hydrochloride (II) or the monohydrochloride (IIa) is used.

12. The method according to claim 10 or 1 1, characterized in that the powder mixture or parts thereof are first dry granulated and then pressed into tablets.

13. The method according to claim 10, 1 1 or 12, characterized in that it is carried out in the absence of moisture.