SK442010A3 - New addition salts of tamsulosin and preparations containing them - Google Patents

Abstract

The invention relates to addition salts of sulfonic acids and tamsulosin as well as their hydrated or solvated form in a crystalline or an amorphous form. The invention also relates to a method for the preparation of said salts as well as to their use for therapeutic purposes.

Description

Technical field

The present invention relates to a process for the preparation of novel addition salts of Tamsulosin, the chemical name of which is (R) -5- (2- (2- (2-ethoxyphenoxy) ethylamino) propyl) -2-methoxybenzenesulfonamide.

Field of the invention

Tamsulosin of formula (I) is a selective alpha blocker used in the treatment of problems caused by benign prostatic hyperplasia (enlarged prostate). Tamsulosin belongs to a group of medicines known as alpha-adrenergic blockers. Tamsulosin was marketed by Yamanouchi Pharmaceuticals. Tamsulosin in the form of its addition salt as the hydrochloride is used in the form of capsules under the trademark e.g. Flomax.

BACKGROUND OF THE INVENTION

Tamsulosin in the form of salts such as hydrochloride and hydrobromide is disclosed in U.S. Pat. US 5447958

Patent application WO 2005/056521 discloses a process for preparing optically pure R - (-) Tamsulosin hydrochloride.

U.S. Patent Application Publication 2003/0109752 discloses the partial purification of Tamsulosin as a camphorsulfone salt which is enriched in the (R) isomer.

US 2006079714 describes a process for resolving a mixture of (R) and (S) isomers of tamsulosin or salts thereof using S - (+) - BPA. (R, S) -Tamsulosin oxalate is characterized. Other racemic tamsulosin addition salts such as oxalates, salicylates, fumarates, tartrates, maleates are mentioned without being characterized.

The above salts are not intended for oral administration and are characterized by reduced solubility when used in the form of solutions.

Among all known salts, the salt of tamsolusin in the form of the hydrochloride is preferred, which has also been the subject of numerous patents for various dosage forms and preparations.

EP 1088551 mentions various dosage forms in which Tamsulosin hydrochloride is used as the active ingredient.

European patent application EP-A-0 661 045 is directed to a tablet adsorption system. In particular, it describes sustained release hydrogel compositions. The additives ensure the necessary penetration of water into the formulations. The presence of a hydrogel-forming polymer is required.

None of the aforementioned patents and patent applications solves the problem of improving the solubility of tamsulosin in the form of its sulfonic acid addition salts as well as the subsequent controlled release of the drug.

In short, there is still a need for the development of stable addition salts of Tamsulosin and corresponding solvates with a satisfactory drug release profile, the manufacture of which is a simple and fast process and does not require the use of expensive excipients. Such a requirement, i. improving the solubility of tamsulosin has been successfully reflected in the present invention. SUMMARY OF THE INVENTION The present invention provides novel tamsolusin addition salts with increased water solubility and significantly lower hygroscopicity compared to known forms.

The present invention solves the problems with reference to previous publications in that the novel sulfonic acid and Tamsolusin addition salts are set forth in claim 1.

SUMMARY OF THE INVENTION

The present invention solves the above problems by preparing novel addition salts of Tamsulosin in order to achieve the following objects:

A first object of the invention are sulfonic acid addition salts of tamsulosin and solvates thereof which are substantially more soluble than the known salts described in the patents cited in the prior art.

A second object of the present invention is a process for the preparation of the addition salts of the active compound Tamsulosin, which have a significantly lower hygroscopic character and good flowability in processing.

It is a further object of the invention to provide alternative Tamsulosin addition salts suitable for use in solid release formulations, in particular for use in the form of tablets.

It is a further object of the present invention to provide a process suitable for the preparation of the novel addition salts described herein.

The free base serves as the active ingredient and a lot of effort is being made to improve its therapeutic effect, for example toxicity, hygroscopicity, fluidity, stability, solubility and the like. A disadvantage of the hitherto known compounds of Tamsulosin is, inter alia, that they are hygroscopic, which affects their stability and bioavailability and thus disadvantages the route for preparation and their use for aqueous and non-aqueous forms of suspension.

It is another object of the invention to provide formulations comprising Tamsolusin addition salts generally administered in solid form.

The invention also relates to solvates of addition salts and polymorphic modifications thereof. The discovery of new salts as pharmaceutically useful compounds provides new opportunities for improving the properties and effects of pharmaceutical products. This extends the repertoire of the formulations the scientist has available for formulation design.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel addition salts of Tamsulosin and sulfonic acids selected preferably from the group of acids: 1,2-ethanedisulfonic acid, sulfoacetic acid, 2-hydroxyethanesulfonic acid, 1,3-benzenedisulfonic acid, 1,2-benzenedisulfonic acid, 1,2-dimethyl -benzenesulfonic acid, 2,5-dihydroxybenzenesulfonic acid, 3-sulfobenzoic acid, 4-sulfobenzoic acid, 2-hydroxy-3-sulfobenzoic acid, 4-hydroxy-1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid and solvates thereof. These salts are substantially better soluble and have a lower hygroscopicity as compared to known salts.

A further advantage of the sulfonic acids used to prepare addition salts in the present invention is that when said acids are used in manufacturing processes, in view of increasing production safety, environmental impact as well as safety at work, the process offered is preferable to using hydrochloric acid.

The synthesis of a pharmaceutically acceptable addition salt of Tamsulosin is generally carried out by reacting Tamsulosin (as the free base) with a solution of an organic sulfonic acid in an organic solvent or water or mixtures thereof.

The present inventors have surprisingly found that especially the addition salts of Tamsulosin and 4sulfobenzoic acid and 5-sulfosalicylic acid selected from the list of acids used in the present invention provide considerable advantages. They exhibit low hygroscopicity and good solubility suitable for use in solid dosage forms, especially in the form of capsules or tablets.

According to the present invention, one substantially non-toxic and non-hygroscopic addition salt as mentioned above is, for example, Tamsulosin 4-sulfobenzoate, prepared by the reaction of

Tamsulosin of the free base (I) with 4-sulfobenzoic acid in the presence of organic solvents or water, or mixtures thereof. Preferably, solvents selected from the group such as: methanol, ethanol, isopropanol, ethyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, hexane, cyclohexane, cyclohexane, cyclohexane, cyclohexane, dichloromethane, cyclohexane, cyclohexane, cyclohexane, cyclohexane, water and mixtures thereof. Of the solvents mentioned above, solvents selected from the group which are inert under the reaction conditions such as e.g. ethyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, hexane, heptane, acetonitrile, dichloromethane, chloroform, water and mixtures thereof. According to the invention, Tamsulosin is capable of forming salts without undesired by-products.

Another aspect of the invention is the molar ratio of Tamsulosin to sulfonic acid, which ranges from 2: 1 to 1: 1. In general, disulfonic acid and Tamsulosin yield a mixed product with different molar ratios of disulfonic acid and Tamsulosin. According to the invention, defined addition salts of Tamsulosin sulfonic acids are preferred in which the molar ratios of Tamsulosin to disulfonic acid are 1: 1 and 2: 1. For simplicity, the combination of two Tamsulosin molecules and one disulfonic acid molecule is hereinafter referred to as a 2: 1 addition salt.

Another aspect of the invention is the addition salt of Tamsulosin and 4-sulfobenzoic acid, as well as the addition salt of Tamsulosin and 5-sulfosalicylic acid prepared by reacting Tamsulosin hydrochloride with an appropriate sulfonic acid salt e.g. an ammonium salt in the presence of an organic solvent or water, or mixtures thereof.

The compounds of the present invention have excellent water solubility and stability and can be expected to have the proper absorption properties of the drug.

To illustrate the solubility of the desolvated form of Tamsulosin ethanedisulfonate 2: 1 (salt I), dehydrated form of Tamsulosin salicyl 5-sulfonate (salt II), crystalline form of Tamsulosin 4-sulfobenzoate (salt III), and crystalline form of Tamsulosin hydrochloride (salt III). ) was tested under the conditions below (Table 1). Tests for solubility were carried out in a standard manner by the banking method with stirring at 22 ± 0.5 ° C, in deionized water, respectively. at pH 4.5 (Britton-Robinson buffer). The solubility of Tamsulosin hydrochloride was chosen as a reference value.

Table no. 1 Relative solubility test results

compound Solubility in water (%) Solubility pH 4.5 (%) Solly 147.6 158.5 Salt II 167.5 172.6 Salt III 101.1 110.2 Salt IV 100 100

Ultimately, the new addition salts and in particular their hydrates are less hygroscopic than the Tamsolusin hydrochloride salt as shown in Table 1. In addition, the crystalline hydrates of the addition salts of Tamsulosin and 4-sulfobenzoic acid, respectively. Sulfosalicylic acids also have good rheological properties due to low hygroscopicity and a suitable solid phase form.

For better illustration, Table 2 shows the behavior of the addition salts: Tamsulosin 1,2-ethanedisulfonate 2: 1, desolvated form (salt I), Tamsulosin 5-sulfosalicylate dehydrated form (salt II), Tamsulosin 4-sulfobenzoate crystalline form (salt III) , and Tamsulosin hydrochloride crystalline form (salt IV) upon exposure to moisture. These salts were left in the stability chamber to the point where equilibrium was reached (Table 2). The water content was measured for each salt by the Karl Fischer method.

No dramatic weight gain was found after exposure of the sample at 45% relative humidity. However, it has been found that desolvated or anhydrous salts (dehydrated) are hygroscopic in an area with relative humidity up to 75%. However, experiments carried out to absorb water showed that the above salts (I, II, III) were gradually transformed into defined hydrates.

Varying relative humidity RH values for salts indicate that water begins to absorb to the amorphous component (acting as a plasticizer).

Experiments have shown that further moisture sorption produces corresponding crystalline hydrates of the addition salts of tamsolusin and sulfonic acids, which are surprisingly stable over the entire relative humidity range (95%) versus tamsolusin hydrochloride, which absorbs moisture above the observed range and spills.

It can be stated that the new prepared hydrates of salts II and III are more stable at higher relative humidity values while salt IV already tends to flow (liquefaction).

Finally, the crystalline addition salt of Tamsolusin and 4-sulfobenzoic acid is less hygroscopic than the corresponding crystalline hydrochloride. Overall, therefore, greater stability can be expected, as illustrated in Table 2.

Measurement of the hygroscopicity of the salts was made in a chamber at 25 ° C and humidity as shown in Table 2. The water content was then determined (% of the final value of the water content is determined in terms of the dried substance). Test samples at 95% RH were allowed to crystallize freely.

Table 2 Exposure Exposure to Addition Salts of Relative Humidity

relative humidity (%) Final water content after absorption Sol' Salt II Salt III Salt IV 45 0.65 1:36 12:14 12:18 75 1.99 2.85 12:49 12:18 95 4.15 1.3 1:49 reflow

According to the invention, the aforementioned salts may be unsolvated or may form solvates, for example hydrates. The number of water molecules is not limited, for example 0.5 molecules, 1 molecule or 2 molecules. These salts also form non-stoichiometric hydrates.

The lower hygroscopicity of the hydrates of the novel salts is advantageous for their processing and storage in crystalline form. One of the advantages of the new addition salts is, in particular, their more compact crystal form, which results in a substantially improved flowability. Therefore, in view of the above findings, it can be concluded that the Tamsulosin addition salts presented in the present invention have at least better properties in terms of their hygroscopicity, in particular Tamsulosin-4-sulfobenzoic acid addition salt hemihydrate and Tamsulosin-5- addition salt hydrate. sulfosalicylic.

At the same time, it was found that Tamsulosin 5-sulfosalicylate hemihydrate at elevated temperature under vacuum forms a material having low crystallinity, an ongoing process leading to dehydration and amorphization to the salt II.

According to the invention, the addition salts of Tamsulosin include not only crystalline forms but can also be in the form of amorphous salts. It is well known that one of the most important physical properties of drugs (amorphous form versus crystalline form) is their solubility. (Konno T., Chem. Pharm. Bull., 1990, 38, 2003). In some therapeutic terms, the term bioavailability is one of the key parameters that determines the form of the substance for use in a pharmaceutical composition. There are many advantages where amorphous forms of drug are used in a drug. Better solubility and bioavailability are essential. It has been found that the crystalline form is less soluble than its amorphous forms, that is, procedures which have also been developed have also focused on the preparation of amorphous forms.

According to another point, compositions comprising novel sulfonic acid and Tamsulosin addition salts are disclosed, by way of illustration, in the example of the invention. The method of preparation according to the invention depends on the skill of the person skilled in the art. The addition salts of the present invention can advantageously be formulated into pharmaceutical compositions. In this case, the principal active ingredient is used in combination with some of the elements such as binders, fillers, diluents, disintegrants, lubricants and paints, as desired. Solid oral dosage forms, such as hard gelatin capsules and tablets, are preferred. In the compositions of the invention, the amount of salt ranges from 2% to 75%, most preferably 4% to 15% by weight.

Diluents that can be incorporated according to the present invention are preferably selected from the group of natural or artificial carbohydrates such as lactose, sucrose, glucose, starches, sorbitol and micro crystalline cellulose. Of the binders, similarly, preferably starches, sugars, cellulose and its derivatives, gelatin and polyvinylpyrrolidone are selected. Starch and micro crystalline cellulose are preferred in use as good disintegrants. Particularly preferred is Avicel (TM), a type of commercial microcrystalline cellulose.

Lubricants used for solid dosage forms are selected from the group consisting of talc, silica, magnesium stearate, glidant, aerosol, stearic acid and stearin.

Magnesium stearate is particularly preferred.

Brief description of the pictures

Figures 1 to 4 are Fourier transform infrared spectra of FTIR addition salts of Tamsulosin and sulfonic acids measured on a Spectrometer Nicolet, Impact 410. ATR measurement technique, Omnic version 5.2 program was used.

Figure 5 is an illustrative diffractogram (XRPD-X-ray powder diffraction) for addition salts. The measurement was performed on a Phillips PW3040 / 60 X'Pert PRO diffractometer powder diffractometer, CuKa radiation 1.541874 L.

The following examples describe the process for preparing the sulfonic acid and Tamsulosin addition salts of the invention. The following examples serve to further illustrate the present invention without limiting its scope to the examples described herein.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of the desolvated form of Tamsulosin-1,2-ethanedisulfonic acid addition salt (2: 1) To a solution of Tamsulosin (0.4 g) in 2-propanol (6 mL) at 85 ° C was added 1,2-ethanedisulfonic acid (0.1 g) in solution. water / 2-propanol (1: 3 ratio, 2ml). The reaction mixture was stirred at 20 ° C for 12 hours, then the reaction mixture was cooled and the resulting crystalline product was filtered off and dried. A solvate of the addition salt of Tamsulosin and 1,2-ethanedisulfonic acid (2: 1) containing three molecules of 2-propanol was obtained. [α] -1.5 ° (c 1, methanol). Elemental analysis for C 51 H 86 N 4 O 2 S 4 (1187.5) theory: C, 51.58; H, 7.30; N, 4.72; S, 10.80. Found: C, 50.80; H, 7.85; N, 4.90, S, 10.48. The desolvated form of the addition salt of Tamsulosin and 1,2-ethanedisulfonic acid (2: 1) was obtained by drying the solvate at 95100 ° C for 4 hours under an inert nitrogen atmosphere under vacuum. Drying loss determined by TGA

0.035%. The dried substance was stored in a desiccator over P2O5.

Example 2

Preparation of the addition salt of Tamsulosin and sulfoacetic acid

Tamsulosin (0.4 g) was added to a solution of sulfoacetic acid (0.16g) in tetrahydrofuran / water (4 mL, 3: 1). After stirring at gentle reflux for 12 hours, the reaction mixture was cooled and filtered. The white substance obtained after washing with tert. butyl methyl ether (MTBE, 2 mL) was an addition salt of Tamsulosin and sulfoacetic acid. IR (cm ^-1 ) 1719, 1592, 1495, 1455, 1390,

1327, 1283, 1252, 1211, 1155, 1126, 1073, 1033, 92,814,748.

Example 3

Preparation of the amorphous form of the 2-naphthalenesulfonic acid addition salt of Tamsulosin

A solution of 2-naphthalenesulfonic acid (0.23 g) in 2-propanol (10 mL) was quickly filtered through a nylon filter (0.22 µm). The filtrate was transferred to a 20 mL flask. While stirring, Tamsulosin (0.4 g) was added to the solution and the reaction mixture was refluxed for two hours with stirring. Addition of MTBE (7 mL) to the reaction mixture with stirring gave a solid which was filtered. The material was washed with MTBE. 0.4 g of Tamsulosin 2-naphthalenesulfonic acid addition salt was obtained in amorphous form confirmed by XRPD measurement.

Example 4

Preparation of the anhydrous form of the addition salt of Tamsulosin and 5-sulfosalicylic acid

Tamsulosin (0.4 g) was added to a solution of 5-sulfosalicylic acid dihydrate (0.26 g) in ethanol (10 mL). The reaction mixture was stirred at 70 ° C for 12 hours and then cooled to 5 ° C. To the cooled solution was added 1 mL of MTBE. Filtration gave

0.55 g of white crystalline Tamsulosin 5-sulfosalicylate hemihydrate. Elemental analysis for C27H33N2O10.5S2 (635.70) theory: C, 51.01; H, 5.23; N, 4.41; S, 10.09. Found: C, 51.00; H, 5.30; N, 4.45, S, 10.00. The anhydrous form of Tamsulosin 5-sulfosalicylate was obtained by drying the hemihydrate at 105 ° C under an inert nitrogen atmosphere under vacuum for 4 hours. Drying loss determined by TGA 0.028%. The dried substance was stored in a desiccator over P2O5. By exposing the sampled anhydrous sample at 95% RH and 22 ° C for 142 hours, it is possible to obtain a crystalline hydrated form, a loss on drying determined by K.F. 3.01%.

Examples 5-18

In analogy to Example 3, the sulfo acids shown in Table 3 were used. Third

Table 3

Example # Sulfo acid [α] D, (c, MeOH) * Example 5 3-sulfobenzoic -1.5 (l, MeOH) Example 6 4-sulfobenzoic -1.5 (l, MeOH) Example 7 1,2-ethanesulfonic acid (1: 1) -1.4 (1, MeOH) Example 8 1,2-ethanesulfonic acid (2: 1) -1.5 (0.7, MeOH) Example 9 xylene sulfonic -1.5 (l, MeOH) Example 10 5-sulfosalicylic -1.5 (l, MeOH) Example 11 Sulfooctová -1.5 (l, MeOH) Example 12 2-hydroxyethanesulfonic acid -1.5 (l, MeOH) Example 13 Hydrochinónsulfónová -2.0 (1.05, MeOH) Example 14 1,3-benzenedisulfonic acid (1: 1) -1.5 (l, MeOH) Example 15 1,3-benzenedisulfonic (2: 1) -1.7 (0.7, MeOH) Example 16 1,2-benzenedisulfonic acid -1.5 (l, MeOH) Example 17 4-hydroxy-1-naphthalenesulphonic -1.5 (l, MeOH) Example 18 2-Naphthalenesulfonic acid -1.5 (l, MeOH)

(* MeOH methanol)

Example 19

Preparation of the addition salt of Tamsulosin and 1,2-ethanedisulfonic acid

To a solution of 1,2-ethanedisulfonic acid (0.21 g) in 2-propanol (12 mL) was added Tamsulosin (0.4 g) with stirring. The reaction mixture was stirred for 14 hours under gentle reflux, then the reaction mixture was cooled and the resulting crystalline product was filtered off and dried.

Since the product obtained was contaminated with an alternative salt of Tamsulosin, it can then be purified by crystallization. Crystallization was carried out as follows: the product was dissolved in ethanol (8.5 ml). The solution was filtered through a nylon filter (0.22 µm). The resulting filtrate was transferred to a 25-mL flask and heated to 70 ° C with stirring. Ethyl acetate was added to the solution under stirring with slight turbidity. The reaction mixture was stirred at reflux until clear. The reaction mixture was further stirred at room temperature for 8 hours while a white precipitate formed. The resulting product was filtered off, washed with ethanol-ethyl acetate (7

ΛΙ.

ml, 1: 1) and dried under vacuum at 15mbar and 55 ° C. 0.14 g of an acid addition salt of Tamsulosin and 1,2-ethanedisulfonic acid was obtained.

Elemental analysis for C 22 H 34 N 2 O 11 S 3 (598.71) theory: C, 44.13; H, 5.72; N, 4.68. S, 16.07. Found: C, 48.01; H, 5.85; N, 4.90, S, 16.48.

Example 20

Preparation of the anhydrous form of the addition salt of Tamsulosin and 4-sulfobenzoic acid

A solution of 4-sulfobenzoic acid (0.21 g) in 2-propanol (3 mL) was filtered through a nylon filter (0.22 µm). The resulting filtrate was transferred to a 20 mL flask. While stirring, Tamsulosin (0.4 g) dissolved in 2-propanol (6 mL) was added to the solution, and the reaction mixture was stirred under gentle reflux for 2 hours. The clear solution was further stirred at room temperature for 12 hours. The crystallized white solid was filtered and washed with MTBE. 0.4 g of crystalline addition salt of Tamsulosin and 4-sulfobenzoate salt, Form I, were obtained. The product was dried at 105 ° C under an inert nitrogen atmosphere under vacuum for 8 hours. Drying loss determined by TGA 0.14%. The dried substance was stored in a desiccator over P2O5. By exposing the sampled anhydrous form at RH 95% and 22 ° C for 154 hours, it is possible to obtain a crystalline hydrated form, a loss on drying determined by K.F. 1.49%.

A tablet form comprising one or more addition salts of the present invention, including excipients, provides the following formulation of the dosage form shown in Table 4.

Table 4. Pharmaceutical composition comprising Tamsulosin salt as active ingredient of the invention.

Ingredient in pill Amount in mg Tamsulosin-1,2-ethanedisulfonic acid addition salt (2: 1) 0.4 Microcrystalline cellulose (Avicel PH 102) 26.1 hypromellose 63.0 Magnesium stearate 1.5 Lactose anhydrous 2.5 crospovidone 3.5 Colloidal Silicone Dioxide (Cab-O-Sil) 0.6 carbomer 2.0

-0 ύύ 2-040

Claims (8)

PATENT CLAIMS: 1. Tamsulosin-sulfonic acid addition salts selected from 1,2-ethanedisulfonic acid, sulfoacetic acid, 2-hydroxyethanesulfonic acid, 1,3-benzenedisulfonic acid, 1,2-benzenedisulfonic acid, 2,5-dihydroxybenzenesulfonic acid, 3- sulfobenzoic acid, 4-sulfobenzoic acid, 2-hydroxy-3-sulfobenzoic acid, 2-naphthalenesulfonic acid, 4-hydroxy-1-naphthalenesulfonic acid, xylenesulfonic acid, and their respective solvates and hydrates. A process for the preparation of Tamsulosin addition salts according to claim 1, characterized in that it comprises reacting Tamsulosin with an acid selected from the group of 1,2-ethanedisulfonic acid, sulfoacetic acid, 2-hydroxyethanesulfonic acid, 1,3-benzenedisulfonic acid, 1,2-benzenedisulfonic acid, 2, 5-dihydroxybenzenesulfonic, 3sulfobenzoic, 4-sulfobenzoic, 2-hydroxy-3-sulfobenzoic, 2-naphthalenesulfonic, 4hydroxy-1-naphthalenesulfonic and xylenesulfonic. Process according to claim 1, characterized in that the reaction is carried out in the presence of an organic or inorganic solvent or mixtures thereof and the molar ratio of Tamsulosin to sulfonic acid in the addition salt ranges from 2: 1 to 1: 1. The process of claim 3 wherein the solvent is selected from the group of selected solvents methanol, ethanol, isopropanol, ethyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, hexane, cyclohexane, acetonitrile, dichloromethane, chloroform and water. Use of Tamsulosin and sulfoacid addition salts according to claim 1, characterized in that it is used for the preparation of a medicament for the treatment of benign prostatic hyperplasia (enlarged prostate). A composition comprising at least one addition salt according to claim 1. 7. A composition comprising at least one addition salt according to claim 6, wherein said formulation is a solid oral dosage form. Crystalline or amorphous sulfamic acid-Tamsulosin addition salts according to claim 1? 44