TW201836592A - Pharmaceutical tablet formulation - Google Patents

Abstract

The present invention relates to a stable 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) in the form of one of its salts, characterized in that it releases the active ingredient rapidly, and to processes for production thereof, to the use thereof as a medicament, and to the use thereof for prophylaxis and/or treatment of cardiovascular disorders, for example worsening chronic heart failure, heart failure with reduced or preserved (HFrEF or HFpEF), angina pectoris and ischaemic injury during an acute coronary syndrome.

Description

   Pharmaceutical lozenge formulations   

The present invention relates to a stable pharmaceutical lozenge formulation containing 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} hydrothio ) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine-yl-L-alanine (Niladsondi Alanine (neladenoson bialanate), one of the various salt forms, characterized by its rapid release of the active ingredient, as well as its method of manufacture, its use as a medicine, and its use in the prevention and / or treatment of cardiovascular diseases, For example, heart failure that worsens chronic heart failure, and has reduced or maintained left ventricular ejection rate (HFrEF or HFpEF), angina pectoris, and ischemic injury during acute coronary syndrome.

Niradsson dipropylamine ester is a compound of formula (I) 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} hydrogen sulfide Group) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine acetyl L-propylamine ester Neladeson dipropylamine ester is used in one of its various salt forms. The hydrochloride (II), especially the monohydrochloride (IIa), is preferably used.

Neladenoson is a compound of formula (III) 2-[[2- (4-chlorophenyl) thiazol-4-yl] methylhydrothio] -4- [4- (2-hydroxyethoxy Yl) phenyl] -6-pyrrolidin-1-ylpyridine-3,5-dicarbonitrile The hydrochloride or monohydrochloride salts of nalaradexone, dipropylamine and dipropylamine are known (see WO 2010/086101 and WO 2016/188711).

Compounds of formula (I), (II) and (III) act as partial adenylate A1 receptor agonists and can be used, for example, to prevent and / or treat cardiovascular disorders (e.g. exacerbating chronic heart failure, with reduced or maintained left Reagents for ventricular ejection fraction (HFrEF or HFpEF) of heart failure, angina pectoris and ischemic injury during acute coronary syndrome.

The preferred route of administration of these active ingredients is oral administration. Due to the extremely low water solubility of Niladsson (III), it has only insufficient bioavailability after oral administration. For this reason, WO 2010/086101 also describes nelaradexone (III), a prodrug of nelaradexone such as nelaradexone dipropylamine (I) (for the same source, see Examples 1 and 44).

Active medicinal ingredients are often developed before driving drugs to increase the solubility of the active ingredient to overcome limited absorption in the intestine or reduce metabolism in the gastrointestinal tract. Most of the prodrugs available on the market are esters, which are usually cleaved in vivo by esterase-mediated hydrolysis to provide actual active ingredients that can exhibit the expected pharmacological effects. Therefore, on the one hand, chemical instability (chemical lability) is a property required for the biological activity of the prodrug, but on the other hand, it also considerably weakens the stability of the pharmaceutical administration pattern.

Regarding the stabilizing effect of the prodrug brivanib alaninate, the authors suggest that the production conditions are optimized, and especially the extremely dry processing conditions for the coating of the core and the use of high-density polyethylene (HDPE) ) Bottles and desiccants are used as primary packaging methods [Kestur et al., Int. J. Pharm. 476, 93-98 (2014) and Badawy et al., Int. J. Pharm. 469, 111-120 (2014)]. The proposed ingot core formulation and active ingredients consist of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium disintegrant and magnesium stearate lubricant, and do not contain any lactose.

Similarly for the hydrolysis-sensitive active ingredient trimebutin maleate, the authors used dextromannitol as a filler and succinic acid as a stabilizer [Cho et al., Int. J. Pharm. 400, 145- 152 (2010)]. Crospovidone was not used; lactose was found to be disadvantageous.

DMP 754 is an ester prodrug of fibrinogen glycoprotein IIb / IIIa receptor antagonist. In pure active ingredient form, it exhibits low degradation after storage at 40 ° C and 75% relative air humidity for 3 months. In the case of pre-formulation studies, with regard to solid oral administration forms, it was found that the compound decomposed significantly in the presence of anhydrous lactose and the content of decomposition products increased dramatically. The stability problem is solved by adding an acid such as disodium citrate [S.I.F. Badawy et al., Pharm. Dev. Tech. 4, 325-331 (1999)]. The mixture or lozenge does not contain any crospovidone.

For the stabilizing effect of the prodrug △ ⁹ -tetrahydrocannabinol, pH adjustment aids such as citric acid and antioxidants are also proposed [S. Thumma et al., Int. J. Pharm. 362, 126-132 (2008)].

Fesoterodine (Fesoterodine) is an unstable active ingredient that decomposes greatly in humid environments and high temperatures. The stability of this active ingredient in solid oral administration forms depends on the adjuvant used. MicroceLac ^® 100 used in a tablet ratio of 20% to 40% is described as a particularly preferred filler (US 2010/0130606 A1, paragraph [0262]), which is a 75% α-lactose monohydrate and 25% micro Co-processed mixture of crystalline cellulose. This corresponds to the content of α-lactose monohydrate in tablets of 15% -30%. It is pointed out here that lactose destabilizes the active ingredient (US 2010/0130606 A1, paragraph [0334]). Furthermore, by adding stabilizers from the group of xylitol, sorbitol, polydextrose, isomalt or glucose, stabilization is possible.

The other active ingredients are not subject to any decomposition in the lozenge formulation; instead, a phase transition of the active ingredient in the form of a hydrate occurs. In order to avoid the degradation of the prodrug during the storage of the lozenge, the broadest measure to prevent such reaction between the active ingredient and water can be adopted. In this regard, it states that the use of the filler α-lactose monohydrate can accelerate the formation of hydrates, while in the case of using microcrystalline cellulose as a filler, the active ingredient has not changed [M. Otsuka and Y. Matsuda, Chem . Pharm. Bull. 42, 156-159 (1994)]. This finding was confirmed by S. Airaksinen's further active ingredients [Role of Excipients in Moisture Sorption and Physical Stability of solid Pharmaceutical Formulations, Thesis, Helsinki (2005)].

Niradsson dipropylamine hydrochloride (II) or monohydrochloride (IIa) is also an unstable compound, but it cannot be formulated using known methods of prodrug formulations and other unstable active ingredients Into stable lozenges. It breaks down in standard lozenge formulations, even if very much water is excluded. This formed Nailedsson (III) as a degradation product. This is undesirable because Niladecone (III) after oral administration is actually non-bioavailable, so the proportion of the active ingredient that has been decomposed is no longer available for the patient's desired pharmacological effect. For regulatory reasons, lozenges containing partially decomposed active ingredients are undesirable because the allowable amount of degradation products and the reduction in the active ingredient content of lozenges are limited. Lozenges whose active ingredients have undergone significant decomposition are therefore no longer suitable for sale.

In addition, the standard lozenge formulations of naladesone dipropylamine hydrochloride (II) or monohydrochloride (IIa) have yet to be improved in terms of active ingredient release. Even if the corresponding lozenge breaks down quickly, the active ingredient release is slow and variable in some cases. However, the release of the active ingredient, i.e. the dissolution of the active ingredient in an aqueous medium corresponding to the conditions of the upper gastrointestinal tract, is a prerequisite for the absorption of the active ingredient into the blood stream and the pharmacological utility. After taking lozendox dipropylamine hydrochloride lozenges, it is desired that the active ingredient be rapidly released in the aqueous medium of the upper gastrointestinal tract. Lozenges with a slower active ingredient release rate risk that the active ingredient will only dissolve in the deep part of the gastrointestinal tract, where they will encounter unfavorable stability and absorption conditions, or will be excreted without absorption into the body by absorption.

Therefore, it is an object of the present invention to find lozenge formulations for the salt of naladesone dialanine (I), especially for naladesone dialanine hydrochloride (II) or Radsson dialanine monohydrochloride (IIa), in which the active ingredient has the greatest stability, that is, it is decomposed very slowly into Neladexone (III) in the lozenge formulation, and the release of the active ingredient is very rapid. Monohydrochloride contains a precisely defined stoichiometric amount of hydrochloride. The use of the monohydrochloride salt (IIa) is a preferred embodiment in the context of the present invention, even in individual cases that has not been explicitly stated repeatedly.

It has been found that, surprisingly, when the content of the auxiliary ingredients of the lozenges is 68% -95% (w / w) of lactose monohydrate or anhydrous lactose, and the auxiliary ingredients of the lozenge contain cross-linked poly When veterone is used as a disintegrant to the extent of 5% -20% (w / w), 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazole- 4-yl] methyl} hydrothio) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine amide-L -Alanine [Niladexone Dialanine (I)] One of the various salt forms for stable and fast-release lozenges. This form of application has the advantage of being sufficiently stable, quickly decomposing and quickly releasing the active ingredient. This form of application does not require any additional pH adjusters or any antioxidants and can be applied using an aqueous suspension. Tablet administration forms are generally described in the European Pharmacopoeia 9.3 (Chapter 07 Dosage Forms-Tablets). For the present invention, uncoated and coated tablets are preferred.

In particular, the lozenges contain the active ingredient nelaradexone dipropylamine hydrochloride (II) or monohydrochloride (IIa). Alternatively, other salt forms of naladesone dialanine (I) are also possible. The preferred dosage of each lozenge [specified as naladesone dialanine (I)] is 1-100 mg, especially 2.5-60 mg, and most preferably 2.5-45 mg.

Based on the quality of the lozenges, depending on the dosage and size of the lozenges, the quality of the active ingredient is 2% -50%.

In addition to the active ingredients, lozenges contain auxiliary agents. The use amount of the auxiliary agent should be understood to mean the mass ratio of a single auxiliary agent in the total mass of the auxiliary agent (“secondary component”) in the lozenge. The amount of coating material applied to the coated tablets is like an auxiliary and is included in the calculation of the total amount of auxiliary in the coated tablets.

Lozenges usually contain fillers. Typical examples are: 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 co-processing aid mixtures such as MicroceLac ^® (eg from Meggle is composed of 75% α-lactose monohydrate and 25% microcrystalline cellulose MicroceLac ^® 80) or Cellactose ^® (eg from Meggle, composed of 75% α-lactose monohydrate and 25% cellulose powder Cellactose ^® 80) However, these fillers are due to the rapid decomposition of the active ingredient Niladson dipropylamine hydrochloride (II) in the lozenges produced therefrom, or the slow release of the active ingredient from the lozenges. Mostly not applicable.

Conversely, the lozenges according to the invention contain at least 68, preferably at least 75, and at most 95% by mass (based on all adjuvants in the lozenge) of lactose in one of its various forms (eg anhydrous lactose or lactose monohydrate or Its mixture) as a filler. The lactose may be composed of various variants (Modifications), for example, α - lactose monohydrate, β - amorphous lactose or lactose, or may be prepared by various methods, such as commercial grade SuperTab ^® 21AM or SuperTab ^® 24AN, Pharmatose ^®, Supertab ^® 11SD or 14SD, Tablettose ^® or Flowlac ^® 90 or 100.

Lozenges also contain disintegrating agents. Typical examples are: alginic acid, low-substituted hydroxypropyl cellulose, corn starch, sodium carboxymethyl starch, calcium carboxymethyl cellulose, croscarmellose sodium and other starch or cellulose derivatives. However, these disintegrating agents are not suitable because they adversely affect the stability of one of the various salt forms of the active ingredient (I) in the lozenge.

The lozenges of the present invention contain crospovidone as a disintegrant. Cross-linked povidone is described in the "cross-linked povidone" monograph of the European Pharmacopoeia 9.0. For the excellent tablet formulation, the content of crospovidone is 5-20% by mass (based on all additives in the tablet), especially A-type crospovidone. Type A crospovidone is rougher than Type B, and in the wet screening method described in USP 39, correspondingly has a mass ratio of more than 15% of particles> 63 μm.

In addition, lozenges may contain one of known lubricants, dry binders, flow regulators or coating materials.

The lubricant used may be, for example, magnesium stearate, sodium stearate, stearic acid, glycerol monostearate, glyceryl monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylene glycol Or talc. External lubrication of lozenges is also possible.

An example of a suitable flow regulator is finely divided silica.

Suitable coating materials for coating tablets according to European Pharmacopoeia 9.0 (the monograph "Coated Tablets" in European Pharmacopoeia 9.0) are known pharmaceutical coatings, which may contain polymers such as hydroxypropylmethyl Cellulose, hydroxypropyl cellulose, polyethylene glycol-poly (vinyl alcohol) graft copolymer, polyvinyl alcohol or poly (meth) acrylate, color pigments such as iron oxide, titanium dioxide or indigo carmine coating, plastic Chemical agents such as polyethylene glycol, tributyl citrate, tributyl citrate, dibutyl sebacate, glycerol triacetate or glycerol monostearate, and talc. It is also possible to use coating materials with more functional properties, such as film-forming agents for modified release of active ingredients, such as ammonium methacrylate copolymer, cellulose acetate, cellulose acetate butyrate, chitosan, ethyl Cellulose, polyacrylate, poly (vinyl acetate) or gastric juice-resistant polymers, such as cellulose acetate phthalate, hypromellose acetate succinate, hypromellose phthalate, Acrylic acid-methacrylate copolymer, poly (methacrylate-co-methyl methacrylate-co-methacrylic acid) or polyvinyl acetate phthalate.

The pharmaceutical lozenge formulation according to the present invention is characterized in that (a) it contains 1-100 mg, especially 2.5-60 mg, even preferably 2.5-45 mg (w / w) of 2- {4- [2-({[ 2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} hydrothio) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridine-4- [Phenoxy] phenoxy} ethyl-L-propylamine amide-L-alanine [Niladsone dipropylamine (I)] one of various salt forms, preferably the hydrochloride salt form, (b ) As a filler, lactose monohydrate or anhydrous lactose, the amount of which is 68% -95% (w / w) of the auxiliary ingredient, preferably 75% -95% (w / w), and (c) as a collapse Powder, the amount of crospovidone is 5% -20% (w / w) of the auxiliary ingredient, and (d) the amount of other auxiliary agents is 0% -27% (w / w) of the auxiliary ingredient ).

Lozenges are composed of another salt of an active ingredient such as nelaradexone dialanine hydrochloride (II) or nelaradexone dialanine (I) and adjuvants. The percentage of active ingredient is based on the mass of the lozenge. The mentioned percentages of lactose monohydrate or anhydrous lactose and crospovidone and optionally further adjuvants are based on the sum of the masses of all the adjuvants in the lozenge, without active ingredients.

Lozenges are produced by mixing, sieving and compressing powder components (direct tableting method). Alternatively, the powder mixture or a part thereof can be granulated in a dry form and then compressed into tablets. Lozenges can be packaged by spraying aqueous coating suspensions or organic solvent-based coating agents. Lozenges can be coated by spray application of aqueous coating suspensions or organic solvent-based coating suspensions.

It is advantageous when the lozenges are produced without moisture. All auxiliaries are used in dry form, all production steps are carried out in a dry atmosphere and the tablets are packed in a way that moisture cannot enter. Examples of suitable means for this purpose include the addition of desiccants such as silicone or molecular sieves to the packaging, or the blister packaging of the tablets with a moisture-impermeable film containing an aluminum layer. If the production step is achieved by adding water or other solvents, such as film formation of uncoated tablets, the solvent must be removed as quickly and completely as possible by drying.

The achievable stability of the lozenges according to the invention depends on the nature of the packaging and the relevant residual moisture content and storage temperature during storage. The packaging form using a desiccant absorbs moisture from the lozenges and causes the degradation rate of the salt of the active ingredient (I) to be naradesson (III) to be particularly low. In the absence of a packaging form of desiccant, the achievable stability of the lozenge according to the invention depends on the residual moisture content of the lozenge at the time of packaging. In addition, the degradation rate of the salt of the active ingredient (I) to Niladson (III) at a low storage temperature is lower than that at a higher storage temperature.

According to the present invention, lozenges have good chemical stability. When stored at 40 ° C for more than 3 months and a relative air humidity of 75%, the increase in the degradation product Niladson (III) in these lozenges is less than 0.32 percentage points. Ten lozenges are packed in 45ml HDPE bottles and measured. In each case, they contain desiccant capsules with 3g of desiccant composed of molecular sieves. The molecular sieve used here is a synthetic zeolite with a pore size of 3Å (Tri-Sorb ^® from Clariant).

The lozenges according to the invention have a rapid release of active ingredients. Under the conditions described in the experimental section, at least 90%, preferably 95% of the active ingredient is released within 15 minutes.

The following describes an embodiment of the present invention:

(A) The present invention thus provides a pharmaceutical lozenge formulation comprising 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} Thiol) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine amide-L-propylamine ester [naira Desong Dialanine (I)] One of various salt forms, characterized in that the auxiliary ingredient is composed of: (a) 68% -95% (w / w) lactose monohydrate or anhydrous lactose Or a mixture thereof, (b) crospovidone reaching 5% -20%, and (c) additional medical aids reaching 0% -27%.

(B) The present invention also provides a pharmaceutical tablet formulation comprising 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} Thiol) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine amide-L-propylamine ester [naira Desong dialanine (I)] One of many salt forms, characterized by degradation products 2-[[2- (4 when stored at 40 ° C for more than 3 months and a relative air humidity of 75% -Chlorophenyl) thiazol-4-yl] methylhydrosulfanyl] -4- [4- (2-hydroxyethoxy) phenyl] -6-pyrrolidin-1-yl-pyridine-3,5- The increase of dicarbonitrile [Niladsson (III)] is less than 0.5, preferably less than 0.32, and more preferably less than 0.30 percentage points, which is measured after packaging 10 lozenges in 45ml HDPE bottles in each case In each case, it contains a desiccant capsule with 3g of desiccant composed of molecular sieve.

(C) The present invention also provides a pharmaceutical lozenge formulation comprising 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} Thiol) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine amide-L-propylamine ester [naira Desong dialanine (I)] One of many salt forms, characterized by degradation products 2-[[2- (4 when stored at 40 ° C for more than 3 months and a relative air humidity of 75% -Chlorophenyl) thiazol-4-yl] methylhydrosulfanyl] -4- [4- (2-hydroxyethoxy) phenyl] -6-pyrrolidin-1-yl-pyridine-3,5- The increase of dicarbonitrile [Niladsson (III)] is less than 1.5, preferably less than 1.0, and more preferably less than 0.8 percentage points. This is a blister film containing an aluminum layer as a water vapor-impermeable layer in packaging After the measurement.

(D) The present invention also provides the pharmaceutical lozenge formulations described in Examples (A), (B) or (C), each of which is characterized in that the auxiliary ingredients are composed of the following (a) up to 75% -95% (w / w) lactose monohydrate or anhydrous lactose or mixtures thereof, (b) crospovidone reaching 5% -12%, and (c) additional medical aids reaching 0% -20%.

(E) The present invention also provides the pharmaceutical lozenge formulations described in examples (A), (B), (C) or (D), each of which is also characterized by the active ingredient (I) after 15 minutes Release at least 90%.

(F) The present invention also provides the pharmaceutical lozenge formulations described in examples (A), (B), (C) or (D), each of which is further characterized by the active ingredient (I) after 15 minutes Release at least 95%.

(G) The present invention also provides the pharmaceutical lozenge formulations described in Examples (A), (B), (C), (D), (E) or (F), each of which is also characterized by activity The ingredients are in the form of hydrochloride (II).

(H) The present invention also provides the pharmaceutical lozenge formulations described in Examples (A), (B), (C), (D), (E), (F) or (G), their respective It is also characterized by the selection of type A crospovidone as a disintegrant.

(I) The present invention also provides pharmaceutical lozenge formulations as described in Examples (A), (B), (C), (D), (E), (F), (G) or (H) Substances, each of which is characterized in that it contains 5% -25% (w / w) of 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazol-4-yl ] Methyl} hydrothio) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine acetyl-L-alanine Ester hydrochloride [Niladexone dipropylamine hydrochloride (II)].

(J) The present invention also provides the medicines described in Examples (A), (B), (C), (D), (E), (F), (G), (H) or (I) The lozenge formulations are also characterized in that the lozenge has a film coating.

(K) The present invention also provides a method of preparing a pharmaceutical lozenge formulation, which contains 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazole -4-yl] methyl} hydrothio) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine amide- L-alanine [Niladsone dialanine (I)] one of various salt forms, and (a) 68% -95% (w / w) lactose monohydrate or anhydrous lactose or mixtures thereof, (b) 5% -20% crospovidone and (c) 0% -27% additional pharmaceutical adjuvants, characterized in that the powder components are mixed, sieved and compressed into tablets.

(L) The present invention further provides the method previously described in (K), characterized in that the powder mixture or part thereof is first granulated in dry form and then compressed into a lozenge.

(M) The present invention further provides the method previously described in (K) or (L), which is characterized in that the operation is carried out while excluding water.

The possibility of stabilizing the active ingredient in the form of a lozenge is surprising, as compared to the method of formulating the prodrugs and other unstable active ingredients originally detailed. To date, the fillers used have been microcrystalline cellulose, mannitol or MicroceLac ^® . α-lactose monohydrate was found to be relatively unfavorable. Stabilizers such as sugar alcohols or acids are added. Croscarmellose sodium is described as a disintegrant. Those with ordinary knowledge may also expect that the use of lactose monohydrate is not suitable for the formulation of moisture-sensitive active ingredients due to the water content of this additive, and the use of lactose types such as Flowlac ^® 90 also contains a certain proportion of amorphous Lactose (see Example 14). In amorphous admixtures, the free movement of molecules is not limited by their incorporation into a fixed crystal lattice, which usually reduces the stability of the co-processed active ingredients.

As far as the formation of lozenges with neradsone dialanine (I) salt is concerned, the deficiencies of these prior art findings become clear from a series of comparative examples. According to practice or recommendation, when mannitol or microcrystalline cellulose is used as a filler, the disintegrant is used in a standard manner and amount, and various acids are used as stabilizers. As shown in Comparative Examples 1, 3, 4 and 5, however, these lozenges are unstable. After storage at 40 ° C in HDPE bottles with desiccant composed of molecular sieves for only 1 to 3 months, the degradation product Niladson (III) increased by 2.9 to 17.8 percentage points or the content of active ingredient (II) decreased significantly. The addition of alkaline stabilizers, such as sodium carbonate or calcium carbonate, was also tested in the binary compatibility test and resulted in a very rapid degradation rate. Comparative Examples 37 to 39 show that the stability of lozendrosone dipropylamine hydrochloride (II) lozenges using xylitol or pregelatinized corn starch as a filler is poor. Even using the formulation principles described by Cho et al. [Int. J. Pharm. 400, 145-152 (2010)] and Mika et al. (US 2010/0130606 A1), HDPE bottles with a desiccant composed of molecular sieves at 40 ° C After medium storage for more than 3 months, it resulted in unstable naladesone dipropylamine hydrochloride (II) tablets (Comparative Examples 41 and 42), and their respective degradation rates were 0.56 and 0.44 percentage points, respectively.

In addition, as objective evidence of the effect according to the present invention, in a relative stability test with the same lozenge moisture content, the same packaging and the same storage temperature of 40 ° C., the inclusion of neradsone dipropylamine hydrochloride was tested (II) The stability of lozenges. As shown in Examples and Comparative Examples 15-19, even if the disintegrant has been selected based on the findings of the present invention, the stability of the lozenge depends first on the lactose content of the lozenge. Therefore, in the case where the lactose content of the lozenge adjuvant is about 85%, the degradation products increased by 0.13 percentage points during the measurement period (see Example 15). Conversely, when the lactose content is about 64% of the lozenge adjuvant, the rate of decrease increases by 0.35 percentage points during the same period, which is 2.7 times (see Comparative Example 19).

Secondly, even if the filler has been selected according to the findings of the present invention, the stability of the lozenge depends on the disintegrant. For example, Examples and Comparative Examples 20, 21, 12 and 22 show that when crospovidone disintegrant is used in accordance with the present invention, the rate of degradation product formation is significantly reduced under the same conditions.

However, on the basis of the low formation rate of Niladson (III), it is not sufficient to formulate lozenges that can be regarded as stable. After taking and dissolving the lozenges in the aqueous medium of the gastrointestinal tract, the active ingredient must be released as quickly and completely as possible. Otherwise, there is a risk that active ingredients that have not been dissolved in time will not be absorbed and excreted again. In the case of sustained-release tablets, the rate of onset of action may also be unfavorably slow. As shown by the examples of individual lozenge formulations, lozenges according to the invention have the advantage of being very fast and completely released. In Examples 11, 12, 13, 14, 22, and 24-31, the release in each case was 97% to 100%; in Example 23, it was 93.0%. In contrast, the release rate of standard lozenges is lower in some cases (Comparative Examples 1, 2, 21) or significantly reduced (Comparative Examples 5, 8, and 10). This advantage is surprising because the lozenges each contain active ingredients of the same particle size, and the decomposition time of lozenges based on the invention and the conventional is also unpredictable or interpretable. For example, the lozenge of Comparative Example 10 showed rapid decomposition in 0.17 minutes, however, it showed that only 55.1% of the active ingredient was not satisfactorily released slowly in 15 minutes. In the case of the inventive tablet from Example 12, the decomposition time was 0.58 minutes, and conversely, within 15 minutes, the release rate was 99.8%. The lozenge composition proposed in WO2010 / 086101 (ibid., P. 187) has a particularly slow release rate. As shown in Comparative Example 43, these lozenges released only 7.1% of the active ingredient in 15 minutes.

Comparative examples and examples

The release of the active ingredient from the lozenge is determined by the method of the United States Pharmacopoeia USP39 (Chapter <711> Dissolution) using device 2 (paddle test). To determine the release rate, a lozenge was added to each beaker of USP device 2, and the amount of neradixone dialanine (I) that had entered the solution was determined by HPLC after the undissolved ingredients had been filtered . The release medium used was 0.1% Brij 35 in acetate buffer pH 4.5, and the paddle stirrer of USP device 2 had a rotation speed of 50 revolutions per minute. Unless otherwise stated, the release rate of 6 samples was determined. In each case, the average amount of active ingredient released after 15 minutes is reported.

The disintegration time of lozenges is measured using a disc on 6 lozenges according to the method of the European Pharmacopoeia 9.0 (Chapter 2.9.1 "Disintegration of Lozenges and Capsules") and reports the median decomposition of a single lozenge time.

The crush resistance of the lozenge was measured by the method of the European Pharmacopoeia 9.0 (chapter 2.9.8 on the crush resistance of lozenges), and the average value of each measurement was reported.

The bending resistance of the oval tablets is measured with a commercial tablet crush resistance tester, which uses two inserts with a total of three crushing spikes. The measuring principle is described in [Bauer KH, Frömming KH and Führer C, Lehrbuch der Pharmazeutischen Technologie (Textbook of Medical Technology), Stuttgart 1999, p. 352, Figure 14.54c]. Place the lozenge to be tested on its side so that the top and bottom surfaces of the lozenge point towards the test jaws. The breaking peak of the test forceps was set so that the top surface of the lozenge was roughly divided into three equal parts. When the test jaws move together, test the force required to crush the lozenges and indicate the average value of each determination.

The content of Niladson (III) is determined by high pressure liquid chromatography. For analysis, lozenges are prepared as follows: For example, to 5 lozenges, 25 ml of 10 millimolar phosphoric acid aqueous solution is added. After the tablet is decomposed, 60-70 ml of acetonitrile is added and treated with ultrasound for 10 minutes. Stir overnight, then treat with ultrasound for 10 minutes, equilibrate to room temperature and make up to 100ml. After stirring, the aliquot was centrifuged and diluted with a mixture of 1 part by volume phosphoric acid (10 mmol / l) and 3 parts by volume acetonitrile according to the thickness of the tablet, and finally chromatographed. For the subsequent HPLC determination of the content of active ingredient naladesone dialanine (I), possible secondary synthesis components and degradation products (especially the degradation products of nalardsone (III)), a highly selective analysis was developed method. The stationary phase used was a commercially available Triart C18 HPLC column (1.9 μm particles, column size 50 mm × 2.0 mm). The mobile phase used was a solvent mixture consisting of: A: 1.5 g of ammonium acetate / 1 liter of water (adjusted to pH 6.1 with acetic acid) and B: acetonitrile and 5% (v / v) methanol (B).

The solvent mixture of A and B changes in a gradient during the chromatography according to the following time schedule:

The column temperature was 20 ° C, and the chromatography time was 40 minutes. The degradation product Niladson (III) appeared at a relative retention time of about 1.48. Since the separation capacity of the HPLC column may be different, a small deviation may occur. The content of nalared pine (III) is based on the area percentage and is based on the sum of the peak areas of the nalard pine dialanine (I) and the by-products and degradation products present. The increase in the content of the degradation product Niladson (III) was reported as a percentage difference in percentage content at the beginning of storage and at the end of storage. In the case where the content of Niladson (III) is increased from, for example, 0.1% to 0.3%, the increase is 0.2%.

The desiccant capsules used in HDPE bottles are in each case Tri-Sorb ^® from Clariant, which contains 3 g of desiccant composed of molecular sieves. The molecular sieve used here is a synthetic zeolite with a pore size of 3Å.

Comparative example 1

242.54g of micronized Naladesone dipropylamine hydrochloride (II), 2562.46g of mannitol (Parteck ^® M 200) and 150.0g of croscarmellose sodium were mixed and sieved, and then followed by 45.0 g magnesium stearate blend. The mixture was pressed in an ingot machine to provide a round lozenge with a mass of 130 mg, a diameter of 7 mm, and a crush resistance of about 64 N, and with a content of 10.51 mg of neradsone dipropylamine hydrochloride (II).

In each case, 20 of these lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and tested for stability at 40 ° C and 75% air humidity. After 3 months of storage, the content of the decomposition product Niladson (III) increased from the initial 0.5% to 3.4%, that is, 2.90 percentage points, so it was 580% times. After 6 months, the content of this decomposition product was 9.8%, so it increased by 1860%. Therefore, the active ingredient is unstable in lozenge formulations. The tablet release rate was 86.0% within 15 minutes.

Comparative example 2

210.2g micronized Niladsone dipropylamine hydrochloride (II), 65.0g B-type crospovidone (Polyplasdone ^® XL 10), 2306.6g StarLac ^® (85% α-lactose monohydrate The co-processed mixture with 15% corn starch) was mixed and sieved, and subsequently mixed with 18.2 g of magnesium stearate. The mixture was pressed in an ingot machine to provide a round lozenge with a mass of 130 mg, a diameter of 7 mm, and a crush resistance of about 64 N, and with a content of 10.51 mg of neradsone dipropylamine hydrochloride (II).

The lozenge therefore contains only 2.7% of type B crospovidone in the adjuvant component. The lozenge release rate was 74.8% within 15 minutes.

Comparative Example 3

Dipropylamine 3.09g micronised Nailadesong ester hydrochloride (II), 5.00g cross-linked sodium carboxymethylcellulose ^{(Ac-Di-Sol ®)} , 75.4g of mannitol (Parteck M ^®) and 15.00g Succinic acid was mixed and sieved, and subsequently mixed with 1.51 g of magnesium stearate. The mixture was pressed in a spindle machine to provide a round lozenge with a mass of 85 mg, a diameter of 6 mm, and a crush resistance of approximately 62 N, and with a content of 2.63 mg of neradsone dipropylamine hydrochloride (II). The lozenges are packaged in HDPE bottles with a desiccant composed of molecular sieves, and are tested for stability at 40 ° C and 75% air humidity.

After one month of storage, the content of nalaradeson dipropylamine hydrochloride (II) in the lozenges decreased by 8.2%, and after 6 months of storage, it decreased by 35.3%. Therefore, the active ingredient is unstable in lozenge formulations.

Comparative Example 4

Dipropylamine 9.28g micronised Nailadesong ester hydrochloride (II), 15.00g cross-linked sodium carboxymethylcellulose ^{(Ac-Di-Sol ®)} , 226.2g of mannitol (Parteck ^® M) and 45.00g The fumaric acid is mixed and sieved, and subsequently mixed with 4.52 g of magnesium stearate. The mixture was pressed in a spindle machine to provide a round lozenge with a mass of 85 mg, a diameter of 6 mm, and a crush resistance of about 65 N, and with a content of 2.63 mg of neradsone dipropylamine hydrochloride (II). The lozenges are packaged in HDPE bottles with a desiccant composed of molecular sieves, and are tested for stability at 40 ° C and 75% air humidity.

After 2 months of storage, the content of the decomposition product Niladson (III) increased from the initial 0.963% to 18.8%, or 17.84 percentage points. This corresponds to a 1852% increase in the initial content of Nailedsson (III). Therefore, the active ingredient is unstable in lozenge formulations.

Comparative Example 5

Dipropylamine 9.28g micronised Nailadesong ester hydrochloride (II), 15.00g cross-linked sodium carboxymethylcellulose ^{(Ac-Di-Sol ®)} , 85% α- and 15% lactose monohydrate Maize The 228.6 g co-processed mixture of starch (StarLac ^® ) and 45.00 g fumaric acid are mixed and sieved, and subsequently mixed with 2.12 g magnesium stearate. The mixture was pressed in a spindle machine to provide a round lozenge with a mass of 85 mg, a diameter of 6 mm, and a crush resistance of about 65 N, and with a content of 2.63 mg of neradsone dipropylamine hydrochloride (II). The lozenges are packaged in HDPE bottles with a desiccant composed of molecular sieves, and are tested for stability at 40 ° C and 75% air humidity.

After 2 months of storage, the content of the decomposition product Niladson (III) increased from the initial 1.77% to 12.26%, that is, 10.49 percentage points. This corresponds to a 593% increase in the initial content of Nailedsson (III). Therefore, the active ingredient is unstable in lozenge formulations.

The lozenge release rate is 63.6% within 15 minutes (the average of the three lozenges tested).

Composition of lozenges

Comparative Examples 6 to 10

An uncoated lozenge containing 10.51 mg of micronized Niladexone dipropylamine hydrochloride (II), 150.23 mg of filler, 18.00 mg of crospovidone, and 1.26 mg of magnesium stearate per tablet is manufactured. For this purpose, the components corresponding to the batch size of 150 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and compressed into a round ingot with a mass of 180 mg, a diameter of 8 mm and a crush resistance of about 80 N Agent. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months.

When microcrystalline cellulose was used as a filler, the proportion of degradation product Niladson (III) increased by 2.66 percentage points during the test. The release rate was 93.8% within 15 minutes (Comparative Example 6). When mannitol was used as a filler, the proportion of degradation product Niladson (III) increased by 0.35 percentage points during the test. The release rate was 102% within 15 minutes (Comparative Example 7).

When maltodextrin was used as a filler, the proportion of degradation product Niladson (III) increased by 0.30 percentage points during the test. The release rate was only 47.5% in 15 minutes (Comparative Example 8). When a 3: 1 mixture of cohesive α-lactose monohydrate and microcrystalline cellulose was used as a filler, the ratio of degradation product Niladson (III) increased by 0.57 percentage points during the test. The release rate was 100% within 15 minutes (Comparative Example 9).

When calcium hydrogen phosphate dihydrate is used as a filler, the proportion of degradation product Niladson (III) only increased by 0.09 percentage points during the test. The decomposition time of the lozenge was 0.17 minutes, but the release rate was only 55.1% in 15 minutes (Comparative Example 10).

Comparative Examples 6-10 show that even with the most desirable cross-linked povidone disintegrant found in the context of the present invention, lozenge formulations using standard fillers are either unstable or release too slowly.

Examples 11 to 14

Under the same conditions as Comparative Examples 6-10, each lozenge was manufactured to contain 10.51 mg of micronized nelaradesone dipropylamine hydrochloride (II), 150.23 mg of filler, 18.00 mg of crospovidone and 1.26 mg Uncoated lozenges of magnesium stearate. For this purpose, the components corresponding to the batch size of 150 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and pressed into round ingots with a mass of 180 mg, a diameter of 8 mm, and a crush resistance of about 80 N Agent. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months.

When a co-processed mixture of 85% α-lactose monohydrate and 15% corn starch was used as a filler, the proportion of degradation product Niladson (III) increased by 0.25 percentage points during the test period. The release rate was 100% within 15 minutes (Example 11).

When anhydrous β- / α-lactose (Supertab ^® 24AN) was used as a filler, the proportion of the degradation product Niladson (III) only increased by 0.13 percentage points during the test. The decomposition time of the lozenges was 0.58 minutes and the release rate was 99.8% within 15 minutes (Example 12).

When α-lactose monohydrate is used as a filler, the proportion of degradation product Niladson (III) only increased by 0.11 percentage points during the test. The release rate was 97.8% in 15 minutes (Example 13).

When α-lactose monohydrate and part of amorphous lactose (Flowlac ^® 90) were used as fillers, the ratio of degradation product Niladson (III) only increased by 0.09 percentage points during the test. The release rate was 100% within 15 minutes (Example 14).

Composition of lozenges

¹⁾ Packed in HDPE bottle with molecular sieve desiccant

Examples 15-18

An uncoated lozenge containing 21.02 mg of micronized neradsone dipropylamine hydrochloride (II), 139.76 mg of filler, 17.96 mg of crospovidone, and 1.26 mg of magnesium stearate per tablet is manufactured. For this purpose, the components corresponding to the batch size of 180 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and compressed into a round ingot with a mass of 180 mg, a diameter of 8 mm, and a crush resistance of about 80 N Agent. Tablets are provided with a coating application of 5 mg of dry coating material per tablet, which consists of 2.528 mg hydroxypropyl methylcellulose 5 cP, 0.506 mg talc, 1.956 mg titanium dioxide and 0.008 mg hematite oxide. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months.

When anhydrous β- / α-lactose (Supertab ^® 24AN) is used as a filler, the lactose content of the lozenges is 85.23%, the dry loss of the lozenges is 0.7% and the relative equilibrium moisture content is 23.5%. The proportion of degradation product Niladson (III) only increased by 0.1 percentage points during the test (Example 15). When a mixture of 95% anhydrous β- / α-lactose (Supertab ^® 24AN) and 5% microcrystalline cellulose is used as a filler, the lactose content of the lozenge is 80.97%, the drying loss of the lozenge is 0.6% and is relatively balanced The moisture content is 23.6%. The proportion of degradation product Niladson (III) increased by 0.15 percentage points during the test period (Example 16).

When a mixture of 90% anhydrous β- / α-lactose (Supertab ^® 24AN) and 10% microcrystalline cellulose is used as a filler, the lactose content of the lozenge is 76.71%, the drying loss of the lozenge is 0.7% and is relatively balanced The moisture content is 24.0%. The proportion of degradation product Niladson (III) increased by 0.19 percentage points during the test period (Example 17).

When a mixture of 80% anhydrous β- / α-lactose (Supertab ^® 24AN) and 20% microcrystalline cellulose is used as a filler, the lactose content of the lozenge is 68.18%, the drying loss of the lozenge is 0.8% and is relatively balanced The moisture content is 21.8%. The proportion of degradation product Niladson (III) increased by 0.25 percentage points during the test period (Example 18).

It is particularly noteworthy that the adjuvant combination according to the invention can increase the stability of the active ingredient (II) in the core of the tablet, so that the core can be briefly exposed to the aqueous coating suspension.

Examples 15-18 also show that the best results in the stability test are found when it is preferred to use lactose completely as a filler. A small proportion of other fillers is still tolerable, but it has deteriorated the stability of the tablets.

Comparative Example 19

Under the same conditions as in Examples 15-18, each lozenge was manufactured to contain 21.02 mg of micronized nelaradesone dipropylamine hydrochloride (II), 139.76 mg filler, 17.96 mg crospovidone and 1.26 mg hard Uncoated lozenges of magnesium fatty acid. For this purpose, the components corresponding to the batch size of 180 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and compressed into a round ingot with a mass of 180 mg, a diameter of 8 mm, and a crush resistance of about 80 N Agent. Tablets are provided with a coating application of 5 mg of dry coating material per tablet, which consists of 2.528 mg hydroxypropyl methylcellulose 5 cP, 0.506 mg talc, 1.956 mg titanium dioxide and 0.008 mg hematite oxide. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months.

When a mixture of 75% anhydrous β- / α-lactose (Supertab ^® 24AN) and 25% microcrystalline cellulose is used as a filler, the lactose content of the lozenges is 63.92%, the drying loss of the lozenges is 0.2% and is relatively balanced The moisture content is 21.6%. The proportion of degradation product Niladson (III) increased by 0.35 percentage points during the test period. Therefore, the increase rate of degradation products was 2.7 times higher than that of Example 15.

Composition of lozenges

¹⁾ Composed of 50.56% hydroxypropyl methylcellulose 5cP, 10.12% talc, 39.16% titanium dioxide and 0.16% red iron oxide ²⁾ Packaged in HDPE bottle with molecular sieve desiccant

Comparative Examples 20 and 21

Each lozenge contains 10.51mg micronized Niladexone dipropylamine hydrochloride (II), 150.23mg anhydrous β- / α-lactose (Supertab ^® 24AN), 18.00mg disintegrant and 1.26mg magnesium stearate Of uncoated lozenges. For this purpose, the components corresponding to the batch size of 150 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and pressed into round ingots with a mass of 180 mg, a diameter of 8 mm, and a crush resistance of about 80 N Agent. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months.

When sodium carboxymethyl starch (Primojel ^® ) is used as a disintegrant, the water content of the lozenge measured by the Karl Fischer method is 0.60%. The proportion of degradation product Niladson (III) increased by 0.41 percentage points during the test period. The release rate was 90.6% in 15 minutes (Comparative Example 20). When croscarmellose sodium (Ac-Di-Sol ^® ) is used as a disintegrant, the water content of the lozenge measured by the Kaffe method is 0.81%. The proportion of degradation product Niladson (III) increased by 0.50 percentage points during the test. The disintegration time of the lozenge is 0.75 minutes and the release rate is 87.7% in 15 minutes (Comparative Example 21).

The two comparative examples show that the stability of Naladesone dipropylamine hydrochloride (II) is poor in a tablet having a disintegrant other than the present invention. The release rate is low, so it is not as good as the case of tablets containing the disintegrant of the present invention (Examples 12 and 22).

Example 22

Under the same conditions as in Comparative Examples 20 and 21, each lozenge was manufactured to contain 10.51 mg of micronized neradsone dialanine hydrochloride (II), 150.23 mg of anhydrous β- / α-lactose (Supertab ^® 24AN), 18.00 mg of disintegrant and 1.26 mg of uncoated lozenges of magnesium stearate. For this purpose, the components corresponding to the batch size of 150 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and pressed into round ingots with a mass of 180 mg, a diameter of 8 mm, and a crush resistance of about 80 N Agent. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months.

When crospovidone (Polyplasdone ^® XL) was used, the lozenge described in Example 12 was obtained. The water content of the lozenge measured by the Kaffe method is 0.73%. The proportion of degradation product Niladson (III) increased by only 0.13 percentage points during the test period. The decomposition time of the tablets is 0.58 minutes and the release rate is 99.8% within 15 minutes.

When crospovidone (Kollidon ^® CL) is used as a disintegrant, the water content of the lozenge measured by the Kaffe method is 0.92%. The proportion of degradation product Niladson (III) only increased by 0.11% during the test period. The release rate was 100% within 15 minutes (Example 22).

Composition of lozenges

¹⁾ Packed in HDPE bottle with molecular sieve desiccant

Example 23

Each lozenge contains 2.63mg micronized Neradsone dipropylamine hydrochloride (II), 73.275mg anhydrous β- / α-lactose (Supertab ^® 24AN), 8.5mg crospovidone (Polyplasdone ^® XL ) Film-coated tablets with 0.595 mg of magnesium stearate. To this end, the components corresponding to the batch size of 2125g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and pressed into a round ingot with a mass of 85mg, a diameter of 6mm, and a crush resistance of about 40N Agent. 656.8g part-batch lozenges are provided with a coating application of 3mg dry coating substance per lozenge consisting of 1.5168mg hydroxypropyl methylcellulose 5cP, 0.3036mg talc, 1.1748mg titanium dioxide and 0.0048mg red Made of iron oxide. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased by only 0.31 percentage points. The active ingredient released from the lozenge was 93.0% within 15 minutes.

Example 24

Each lozenge contains 5.25mg micronized Neradsone dipropylamine hydrochloride (II), 155.49mg anhydrous β- / α-lactose (Supertab ^® 24AN), 18mg crospovidone (Polyplasdone ^® XL) Film-coated tablets with 1.26mg magnesium stearate. To this end, the components corresponding to the batch size of 4250g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and compressed into a round ingot with a mass of 180mg, a diameter of 8mm and a crush resistance of about 62N Agent. A 3640g portion of the bulk lozenges provided a coating application of 5mg dry coating material per lozenge, which consisted of 2.528mg hydroxypropyl methylcellulose 5cP, 0.506mg talc, 1.956mg titanium dioxide and 0.008mg hematite oxide. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) only increased by 0.22 percentage points. The active ingredient released from the lozenge is 100% within 15 minutes.

Example 25

Each lozenge contains 10.51mg micronized Neradsone dipropylamine hydrochloride (II), 150.23mg anhydrous β- / α-lactose (Supertab ^® 24AN), 18mg crospovidone (Polyplasdone ^® XL) Film-coated tablets with 1.26mg magnesium stearate. For this purpose, the component lozenges corresponding to the batch size of 12 500 are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and compressed into a mass of 180 mg, a diameter of 8 mm, and a crush resistance of about 74 N Round lozenges. Tablets are provided with a coating application of 5 mg of dry coating material per tablet, which consists of 2.528 mg hydroxypropyl methylcellulose 5 cP, 0.506 mg talc, 1.956 mg titanium dioxide and 0.008 mg hematite oxide. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased by only 0.23 percentage points. The active ingredient released from the lozenge is 100% within 15 minutes.

Example 26

Each lozenge contains 10.51 mg of micronized Niladexone dipropylamine hydrochloride (II), 150.23 mg of anhydrous β- / α-lactose (Supertab ^® 24AN), and 18 mg of crospovidone (Polyplasdone ^® XL) Film-coated tablets with 1.26mg magnesium stearate. For this purpose, the components corresponding to the batch size of 2000 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and compressed into a round ingot with a mass of 180 mg, a diameter of 8 mm, and a crush resistance of about 65 N Agent. Tablets are provided with a coating application of 5 mg of dry coating material per tablet, which consists of 2.528 mg hydroxypropyl methylcellulose 5 cP, 0.506 mg talc, 1.956 mg titanium dioxide and 0.008 mg hematite oxide. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. Film-coated tablets are packaged in aluminum / aluminum blister and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased by 0.74 percentage points. In the stability test at 25 ° C for more than 12 months, the proportion of degradation product Niladson (III) increased from 0.291% to 0.663%, corresponding to 0.372%. The active ingredient released from the lozenge was 98.0% within 15 minutes.

Example 27

Each lozenge contains 21.02 mg of micronized Niladexone dipropylamine hydrochloride (II), 139.72 mg of anhydrous β- / α-lactose (Supertab® 24AN), and 18 mg of crospovidone (Polyplasdone ^® XL) Film-coated tablets with 1.26mg magnesium stearate. For this purpose, the components corresponding to a batch size of 4000 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and compressed into a round ingot with a mass of 180 mg, a diameter of 8 mm, and a crush resistance of about 78 N Agent. A coating application of 5 mg dry coating material per lozenge was provided for a 1500 g portion batch lozenge consisting of 2.528 mg hydroxypropyl methylcellulose 5 cP, 0.506 mg talc, 1.956 mg titanium dioxide and 0.008 mg hematite oxide. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased by only 0.19 percentage points. At 25 ℃ and 60% relative air humidity for more than 9 months of storage time, the proportion of degradation product Niladson (III) increased from 0.36% to 0.45%, corresponding to 0.09 percentage points. The active ingredient released from the lozenge is 100% within 15 minutes.

Example 28

Part of the film-coated tablets manufactured as described in Example 27 was packaged in aluminum / aluminum blister. At 40 ° C and 75% relative air humidity, during the stability test over 3 months, the proportion of degradation product Niladson (III) increased by 0.80 percentage points. The active ingredient released from the lozenge is 100% within 15 minutes.

Example 29

Each lozenge contains 42.04mg micronized Niladoxone dipropylamine hydrochloride (II), 118.16mg anhydrous β- / α-lactose (Supertab ^® 24AN), 18mg crospovidone (Polyplasdone ^® XL) Film-coated tablets with 1.80mg magnesium stearate. For this purpose, the components corresponding to a batch size of 500 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and compressed into a round ingot with a mass of 180 mg, a diameter of 8 mm, and a crush resistance of about 76 N Agent. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) only increased by 0.06 percentage points. The active ingredient released from the lozenge is 100% within 15 minutes.

Example 30

Each lozenge contains 10.51mg micronized Neradsone dipropylamine hydrochloride (II), 150.23mg anhydrous β- / α-lactose (Supertab ^® 24AN), 18.00mg crospovidone and 1.26mg hard Film-coated tablets of magnesium fatty acid. To this end, the components corresponding to the batch size of 2250g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and pressed into a round ingot with a mass of 180mg, a diameter of 8mm, and a crush resistance of about 71N Agent. A coating application of 875.8g partial batch cores to provide 5mg dry coating substance per tablet, consisting of 2.2mg hydroxypropyl cellulose, 1.22mg titanium dioxide, 0.72mg hydroxypropyl methylcellulose 3cP, 0.42mg propylene glycol, 0.04mg red iron oxide and 0.40mg yellow iron oxide. For this purpose, in the coating system, the coating components are sprayed on the core with a dispersion consisting of 8% dry coating material, 82.8% isopropanol and 9.2% water. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased by only 0.13 percentage points. The active ingredient released from the lozenge was 97.0% within 15 minutes.

Example 31

Each lozenge contains 10.51mg micronized Neradsone dipropylamine hydrochloride (II), 150.23mg anhydrous β- / α-lactose (Supertab ^® 24AN), 18.00mg crospovidone and 1.26mg hard Film-coated tablets of magnesium fatty acid. For this purpose, the components corresponding to the batch size of 2550 g are mixed and sieved without magnesium stearate, and dried in a roller granulator with a specific pressure of 6 kN / cm and a mesh size of 1 mm of grinding sieve. grain. The granules were subsequently mixed with 1.26 mg of magnesium stearate and compressed into round lozenges with a mass of 180 mg, a diameter of 8 mm and a crush resistance of about 82N. The release of the active ingredient from the lozenges was 98.0% within 15 minutes (analysis of the average of five lozenges).

Example 32

Each lozenge contains 2.63mg micronized Neradsone dipropylamine hydrochloride (II), 73.275mg anhydrous β- / α-lactose (Supertab ^® 24AN), 8.50mg crospovidone and 0.595mg hard Film-coated tablets of magnesium fatty acid. For this purpose, the components corresponding to the batch size of 2125g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and compressed into a round ingot with a mass of 85mg, a diameter of 6mm and a crush resistance of about 42N Agent. A coating application of 36.8 mg of dry coating material per lozenge to 656.8 g of partial batch cores is made up of 1.32 mg hydroxypropyl cellulose, 0.732 mg titanium dioxide, 0.432 mg hydroxypropyl methylcellulose 3 cP, 0.252 mg propylene glycol, 0.024mg red iron oxide and 0.24mg yellow iron oxide. For this purpose, the coating component in the coating system is sprayed on the core with a dispersion consisting of 8% dry coating material, 82.8% isopropyl alcohol and 9.2% water. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased by only 0.16 percentage points. The active ingredient released from the lozenges is 97% within 15 minutes.

Composition of lozenges

¹⁾ Composed of 50.56% hydroxypropyl methylcellulose 5cP, 10.12% talc, 39.16% titanium dioxide and 0.16% red iron oxide ²⁾ Composed of 14.4% hydroxypropyl methyl cellulose 3cp, 24.4% titanium dioxide, 8% Composed of iron oxide yellow, 0.8% hematite oxide, 44% hydroxypropyl cellulose and 8.4% 1,2-propanediol

Example 33

Each contains 5.26mg tablets manufactured micronized Nailadesong dipropylamine ester hydrochloride (II), 155.48mg Lactose monohydrate (Supertab ^® 11SD), 18mg A crosslinked type crospovidone (Polyplasdone ^® XL) and 1.26mg film-coated tablets of magnesium stearate. To this end, the components corresponding to the batch size of 180g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and then compressed in an eccentric press to form a mass of 180mg, a diameter of 8mm and an average crush resistance Round lozenges of about 71N. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) only increased by 0.22 percentage points.

Example 34

Each contains 5.26mg tablets manufactured micronized Nailadesong dipropylamine ester hydrochloride (II), 155.48mg particulate monohydrate (Supertab ^® 30GR), 18mg A crosslinked type crospovidone (Polyplasdone ^® XL) Film-coated tablets with 1.26mg magnesium stearate. To this end, the components corresponding to the batch size of 180g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and then compressed in an eccentric press to form a mass of 180mg, a diameter of 8mm and an average crush resistance Round lozenges of about 72N. In each case, 10 film-coated tablets were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) only increased by 0.22 percentage points.

Example 35

Each lozenge contains 31.53mg micronized Neradsone dipropylamine hydrochloride (II), 209.58mg anhydrous β- / α-lactose (Supertab ^® 24AN), 27mg type A crospovidone (Polyplasdone ^® XL) Film-coated tablets with 1.89 mg magnesium stearate. For this purpose, the components corresponding to the batch size of 3240 g of uncoated tablets are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and compressed into a mass of 270 mg, a length of 12 mm and a width of 6 mm, and Elliptical lozenges with a bending resistance of about 55N. A 1350g portion bulk uncoated tablet is provided with a coating application of 7mg dry coating substance per tablet, which consists of 3.5mg hydroxypropyl methylcellulose 5cP, 0.7mg talc, 2.1mg titanium dioxide and 0.7mg red iron oxide Posed. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. The active ingredient released from the lozenge is 98% within 15 minutes.

Example 36

Each lozenge contains 42.04mg micronized Neradsone dipropylamine hydrochloride (II), 279.44mg anhydrous β- / α-lactose (Supertab ^® 24AN), 36mg type A crospovidone (Polyplasdone ^® XL) Film-coated tablets with 2.52 mg magnesium stearate. For this purpose, the components corresponding to the batch size of 4 680 g uncoated lozenges are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and compressed into a mass of 360 mg, a length of 14 mm and a width of 6 mm. With elliptical tablets of about 57N bending resistance. 3960g partial bulk uncoated tablets are provided with a coating application of 8.5 mg dry coating substance per tablet, which is oxidized by 4.25 mg hydroxypropyl methylcellulose 5 cP, 0.85 mg talc, 2.55 mg titanium dioxide and 0.85 mg hematite Constituted by things. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. The active ingredient released from the lozenge is 100% within 15 minutes.

Composition of lozenges

¹⁾ Composed of 50% hydroxypropyl methylcellulose 5cP, 10% talc, 30% titanium dioxide and 10% red iron oxide

Comparative Example 37

Manufacturing tablets contain 10.51mg per Nailadesong dipropylamine micronized ester hydrochloride (II), 150.23mg xylose (Xylitab ^®), 18mg A crosslinked type crospovidone (Polyplasdone ^® XL) with hard 1.26mg Lozenges of magnesium fatty acid. Lozenges are therefore not in accordance with the invention. For this purpose, the components corresponding to the batch size of 300 g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and then compressed in an eccentric press to form a mass of 180 mg, a diameter of 8 mm, and an average crush resistance Round lozenges of about 104N. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased significantly by 0.78 percentage points. Furthermore, after 15 minutes, the release of the active ingredient in the lozenge was only less than 12.8%.

Comparative Example 38

Each lozenge contains 10.51 mg of micronized Niladexone dipropylamine hydrochloride (II), 48.54 mg xylose (Xylitab ^® ), 101.69 mg anhydrous β- / α-lactose (Supertab ^® 24AN), 18 mg A Tablets of crospovidone (Polyplasdone ^® XL) and 1.26 mg magnesium stearate. Lozenges are therefore not in accordance with the invention. For this purpose, the components corresponding to the batch size of 300 g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and then compressed in an eccentric press to form a mass of 180 mg, a diameter of 8 mm, and an average crush resistance Round lozenges of about 73N. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased significantly by 0.56 percentage points. In addition, the release of the active ingredient from the lozenge slowed to 83.8% after 15 minutes.

Comparative Example 39

Manufacturing tablets contain 10.51mg per Nailadesong dipropylamine micronized ester hydrochloride (II), 150.23mg pregelatinized starch (Lycatab ^® CLM), 18mg A crosslinked type crospovidone (Polyplasdone ^® XL) and 1.26mg tablets of magnesium stearate. Lozenges are therefore not in accordance with the invention. For this purpose, the components corresponding to the batch size of 300 g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and then compressed in an eccentric press to form a mass of 180 mg, a diameter of 8 mm, and an average crush resistance Round lozenges of about 29N. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased significantly by 0.59 percentage points. In addition, the release of the active ingredient in the lozenge is only less than 27.7% after 15 minutes.

Comparative Example 40

Manufacturing tablets contain 10.51mg per Nailadesong dipropylamine micronized ester hydrochloride (II), calcium sulfate dihydrate 150.23mg (Compactrol ^®), 18mg A crosslinked type crospovidone (Polyplasdone ^® XL) and 1.26mg tablets of magnesium stearate. Lozenges are therefore not in accordance with the invention. For this purpose, the components corresponding to the batch size of 300 g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and then compressed in an eccentric press to form a mass of 180 mg, a diameter of 8 mm, and an average crush resistance Round lozenges of about 77N. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased only slightly by 0.165 percentage points. However, after 15 minutes, the release of the active ingredient in the lozenge was only less than 58.2%.

Composition of lozenges

Comparative Example 41

Tablets are produced according to the teachings of Mika et al. (US 2010/0130606 A1). These are based on fesoterodine (frosoterodine) and contain xylitol as a stabilizer, for example in a ratio of 1: 1 to 1: 9 (fesoterodine / stabilizer; see claim 51). In particular, therefore, each lozenge is manufactured to contain 10.51 mg of micronized neradsone dialanine hydrochloride (II), 52.55 mg of xylitol, 97.14 mg of 75% α-lactose monohydrate and 25% of microcrystalline fibers (MicroceLac ^® ) co-processed mixture, 18 mg of crospovidone A (Polyplasdone ^® XL) and 1.8 mg of magnesium stearate Neladexone dipropylamine hydrochloride (II) lozenges. These lozenges are therefore not in accordance with the invention, as they only have a low content of 43% lactose (w / w, based on the mass of all auxiliaries in the lozenge). For this purpose, the components corresponding to the batch size of 300 g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and then compressed in an eccentric press to form a mass of 180 mg, a diameter of 8 mm, and an average crush resistance Round lozenges of about 73N. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased significantly by 0.56 percentage points. In addition, the release of the active ingredient from the lozenge slowed to only 82.9% after 15 minutes.

Comparative Example 42

Production of lozenges using trimetine maleate and mosapride citrate dihydrate manufactured by the teaching of Cho et al. [KHCho et al., Int. J. Pharm. 400, 145-152 (2010), Table 1, composition Property V p. 146]. To this end, the active ingredient is replaced with micronized hydrochloride (II), and the conventional lubricant required for compression into a lozenge is added. In particular, each lozenge contains 21.02 mg of micronized Neradexone dipropylamine hydrochloride (II), 4.18 mg of hydroxypropyl cellulose (L-HPC), 4.18 mg of silica (Aerosil ^® ), A lozenge of 8.36 mg sodium cross-linked methyl cellulose (Ac-Di-Sol ^® ), 67.63 mg dextromannitol (Pearlitol ^® 100 SD), 10.45 mg citric acid and 4.18 mg magnesium stearate. Lozenges are therefore not in accordance with the invention. For this reason, the components corresponding to the batch size of 300g are mixed and sieved without magnesium stearate, and then mixed with magnesium stearate, and then pressed in an eccentric press to synthesize a mass of 120mg, a diameter of 7mm and an average crush resistance Round lozenges of about 80N. In each case, 10 lozenges were packaged in HDPE bottles with a desiccant composed of molecular sieves and stored at 40 ° C and 75% relative air humidity for 3 months. During this stability test, the proportion of degradation product Niladson (III) increased significantly by 0.44 percentage points. In addition, the release of the active ingredient from the lozenge slowed to only 86.7% after 15 minutes.

Comparative Example 43

The lozenges are prepared as proposed in WO 2010/086101 A1 (page 187). In particular, each lozenge contains 100 mg of micronized naladesone dipropylamine hydrochloride (II), 50 mg of lactose monohydrate, 50 mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP 25) and 2 mg of hard Lozenges of magnesium fatty acid. Lozenges are therefore not in accordance with the present invention, as they only have a low content of 44.6% lactose (w / w, based on the mass of all auxiliaries in the lozenge). For this purpose, 200 g of active ingredient, 100 g of corn starch and 100 g of lactose are pre-mixed in a mixing granulator. The powder mixture was granulated with a solution of 20 g polyvinylpyrrolidone in 380 g water, dried, sieved and subsequently mixed with 4 g magnesium stearate. This mixture, ready to be compressed, is compressed in an eccentric press to form a round lozenge with a mass of 212 mg and a diameter of 8 mm and an average crush resistance of about 40 N. After 15 minutes, the release of the active ingredient in the lozenge was only 7.1% insufficient.

Comparative Example 44

Each lozenge contains 10.51mg micronized Neradsone dipropylamine hydrochloride (II), 163.73mg anhydrous β- / α-lactose (Supertab ^® 24AN), 4.5mg crospovidone (Polyplasdone ^® XL ) Film-coated tablets with 1.26 mg magnesium stearate. Due to the low proportion of A-type crospovidone (Polyplasdone ^® XL) as low as 2.6% (w / w) in the adjuvant composition of the tablets, these tablets are not in accordance with the present invention. For this purpose, the components corresponding to a batch size of 1000 g are mixed and sieved without magnesium stearate, and subsequently mixed with magnesium stearate, and pressed with a rotary press to form a mass of 180 mg, a diameter of 8 mm, and an average crush resistance of about 73N round lozenges. A coating application of 5 mg dry coating material per lozenge was provided to a 750 g portion batch lozenge consisting of 2.528 mg hydroxypropyl methylcellulose 5 cP, 0.506 mg talc, 1.956 mg titanium dioxide and 0.008 mg hematite oxide. For this purpose, the coating components in the coating system are sprayed onto the core with a 15% aqueous dispersion. In contrast to the film-coated tablets of the present invention, the active ingredient release in the film-coated tablets from this comparative example was significantly dispersed, and within 15 minutes, for 2 of the 12 tablets, only 79.4% and 84.2%. In contrast, the active ingredient release of the film-coated tablets in Example 26 was more than 96% in 15 minutes per film-coated tablet.

Composition of lozenges

¹⁾ Composed of 50.56% hydroxypropyl methylcellulose 5cP, 10.12% talc, 39.16% titanium dioxide and 0.16% red iron oxide

Claims (13)

    A pharmaceutical lozenge formulation containing 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} hydrothio) -3,5 -Dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine acetyl-L-alanine [neladenoson (neladenoson bialanate) (I)] One of a variety of salt forms, characterized in that the auxiliary ingredients are composed of (a) lactose monohydrate or anhydrous lactose or mixtures thereof up to 68% -95% (w / w), ( b) crospovidone reaching 5% -20%, and (c) additional medical aids reaching 0% -27%.         The pharmaceutical lozenge preparation according to claim 1, characterized in that the auxiliary ingredient is composed of (a) lactose monohydrate or anhydrous lactose or a mixture thereof up to 75% -95% (w / w), (b ) Crospovidone reaching 5% -12%, and (c) additional medical aids reaching 0% -20%.         The pharmaceutical lozenge formulation according to any one of claims 1 and 2, each of which is characterized in that each of them is characterized in that the active ingredient (I) releases at least 90% after 15 minutes.         The pharmaceutical lozenge formulation according to any one of claims 1, 2 and 3, each of which is characterized in that the active ingredient (I) releases at least 95% after 15 minutes.         The pharmaceutical lozenge formulation according to any one of claims 1, 2, 3 and 4 is characterized in that the active ingredient is in the form of hydrochloride (II).         The pharmaceutical lozenge formulation according to claim 5, characterized in that the active ingredient is in the form of monohydrochloride (IIa).         The pharmaceutical lozenge formulation according to any one of claims 1, 2, 3, 4, 5 and 6, each of which is characterized in that the type A crospovidone is selected as the disintegrant.         The pharmaceutical lozenge formulation according to any one of claims 1, 2, 3, 4, 5, 6 and 7 is characterized in that it contains 5% -25% (w / w) of 2- {4- [2 -({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} hydrothio) -3,5-dicyano-6- (pyrrolidin-1-yl) Pyridin-4-yl] phenoxy} ethyl-L-propylamine amide-L-alanine ester hydrochloride [Niladexone dipropylamine hydrochloride (II)].         The pharmaceutical lozenge formulation according to any one of claims 1, 2, 3, 4, 5, 6, 7 and 8, each of which is characterized in that the lozenge has a film coating.         A method for manufacturing the pharmaceutical lozenge formulation as claimed in claim 1, the pharmaceutical lozenge formulation comprising 2- {4- [2-({[2- (4-chlorophenyl) -1,3-thiazole-4 -Yl] methyl} hydrothio) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-propylamine acetyl-L- Alanine [Niladsone Dialanine (I)] One of various salt forms and (a) 68% -95% (w / w) lactose monohydrate or anhydrous lactose or mixtures thereof, (b) 5% -20% crospovidone and (c) 0% -27% additional medicinal adjuvants, characterized in that the powder components are mixed, sieved and compressed into tablets.         The method according to claim 10, characterized in that the nairadsone dipropylamine ester is used in the form of hydrochloride (II) or monohydrochloride (IIa).         The method according to claim 10 or 11, characterized in that the powder mixture or a part thereof is first granulated in a dry form and then compressed into a lozenge.         The method as claimed in item 10, 11 or 12, which is characterized in that the operation is performed with the moisture removed.