DE102010010360A1 - Taurolidine formulations and process for its preparation - Google Patents

Abstract

A composition comprises taurolidine and / or its hydrolysis products as well as a (e) biodegradable (s) (co) polymer or inorganic matrix for use as an implant for the treatment of local infections of the skeleton and soft parts. A lozenge as well as a spray or gargle solution also includes taurolidine and / or its hydrolysis products and is used in the treatment of sore throat, sore throat with difficulty swallowing, inflammation of the throat and larynx. A method of making taurolidine is also disclosed.

Description

The invention relates to a composition comprising taurolidine and / or its hydrolysis products, as well as their use as an implant for the treatment of local infections of the skeleton and of soft tissues. It also relates to a lozenge and a spray or gargle solution comprising taurolidine and / or its hydrolysis products and their use in the treatment of throat inflammation, sore throat with difficulty swallowing, inflammation of the oropharynx and laryngeal inflammation. Furthermore, the invention relates to a process for the preparation of taurolidine.

Taurolidine was first synthesized in Switzerland in 1965 (Patentschrift CH 482 713 Swiss Confederations with priority GB 40734/64 ). It is decomposed hydrolytically rapidly into taurultam and methylol-taurultam (hydroxymethyl taurultam). The biotransformation then proceeds enzymatically to taurinamide and methylol-taurinamide (hydroxymethyltaurinamide) (see 1 concerning the structural formulas of these compounds). All compounds act as a chemotherapeutic agent with bactericidal activity against Gram-negative and Gram-positive bacteria and against anaerobic bacteria. It is also known that taurolidine and its hydrolysis products are capable of inactivating bacterial endo- and exotoxins. Methylol group transfer should occur on the surface of the bacterial cell wall, thereby reducing microbial adhesion. This results in an outstanding property of these substances: they do not cause any resistance.

Recently, it has been discovered that taurolidine also has an anti-tumor effect.

There are only a few therapeutic applications of taurolidine and its hydrolysis products. The present invention extends the scope of application thereof.

The in the patent CH 482 713 described synthesis route for the preparation of taurolidine is relatively cumbersome and leads to numerous by-products. This disadvantage is in the process of the German patent DE 195 15 976 C1 eliminated, but the potential explosion tendency of the β-Azidoethansulfonylazides used there is not optimal. In the process of EP 0863133 B1 For example, safer 2-aminoethanesulfonyl azide hydrochloride is used and other starting compounds (e.g., cysteamine) are used.

The present invention provides a five-step synthesis method which dispenses entirely with the use of azides.

A first aspect of the invention is a composition which comprises at least one polymer or copolymer or inorganic matrix which is biodegradable in the human body, into which or the taurolidine and / or one or more hydrolysis products thereof, which consists of taurultam, Methylol taurultam (hydroxymethyl taurultam), taurine amide and methylol taurine amide (hydroxymethyl taurine amide) are selected embedded. It is useful as a medical implant in the local treatment of bone skeletal or soft tissue infections.

Another object of the invention is a lozenge comprising taurolidine and / or one or more hydrolysis products thereof, which are selected from taurultam, hydroxymethyl taurultam, taurine amide and hydroxymethyl taurinamide, and at least one suitable pharmaceutical carrier or excipient.

Yet another object of the invention is an aqueous-alcoholic spray or gargle solution comprising taurolidine and / or one or more hydrolysis products thereof selected from taurultam, hydroxymethyl taurultam, taurine amide and hydroxymethyl taurine amide.

The lozenge or spray solution is used to treat throat infections, sore throat with difficulty swallowing, mouth and throat infections and laryngeal inflammation.

• 1. Umsetzung von Taurin mit einer Verbindung, die eine Amin-Schutzgruppe liefert, bevorzugt Phthalsäureanhydrid, in Gegenwart einer ein Metallion enthaltenden Base zur Herstellung eines Metallsalzes, bevorzugt des Kaliumsalzes, von geschütztem Taurin;
  
• 2. Umsetzung des Salzes von geschütztem Taurin mit einem Säurechlorid zur Herstellung von geschütztem Taurinchlorid;
  
• 3. Überführung des geschützten Taurinchlorids in das geschützte Taurinamid;
  
• 4. Entschützen des geschützten Taurinamids;
  
  und
• 5. Umsetzung von Taurinamid mit Formaldehyd zur Herstellung von Taurolidin
  

Furthermore, the invention relates to a process for the preparation of taurolidine, which comprises the following steps:

• 1. reaction of taurine with a compound which provides an amine protecting group, preferably phthalic anhydride, in the presence of a base containing a metal ion to produce a metal salt, preferably the potassium salt, of protected taurine;
  
• 2. Reaction of the salt of protected taurine with an acid chloride to produce protected taurine chloride;
  
• 3. transfer of the protected taurine chloride into the protected taurine amide;
  
• 4. deprotection of the protected taurine amide;
  
  and
• 5. Reaction of taurine amide with formaldehyde to produce taurolidine
  

Short description of the drawing

1 shows the structural formulas of taurolidine, taurultam, hydroxymethyl taurultam (methylol taurultam), taurine amide and hydroxymethyl taurine amide (methylol taurine amide).

In 2 the glass transition temperatures of formulations of Example 1 are plotted against the extrusion temperatures.

3 shows release profiles of various taurolidine formulations of Example 1.

4 shows release curves of formulations with 30% taurolidine and 5% PEG with 5 extrudate cylinders (30% Tau, 5% PEG) and with 10 extrudate cylinders (30% Tau, 5% PEG - x2) in 3 ml release medium (phosphate buffer) in absolute representation.

5 shows the mass loss of extrudates in percent in a release trial.

6 shows the release of formulations with 30% taurolidine and 0% PEG 400 before and after sterilization with gamma-rays.

Biodegradable polymers or copolymers or inorganic matrices which form the matrix for the taurolidine or its hydrolysis products embedded in the implantable composition of the present invention are hydrolysed and / or enzymatically degradable. These may be naturally occurring polymers and copolymers such as starch and egg whites, polymers and copolymers made from natural polymers such as starch derivatives, polymers and copolymers made from renewable resources such as polylactides, copolymers of lactic acid and Glycolic acid and polyhydroxy fatty acids, or polymers and copolymers derived from fossil fuels, such as certain polyacrylates, polyurethanes, polyesters, polyesteramides, polyvinyl alcohol and polycaprolactone. In the case of inorganic matrices, z. B. hydroxyapatite or CaSO ₄ · 2H ₂ O (gypsum) act.

The preferred biodegradable polymer or copolymer in the human body is a copolymer of lactic acid and glycolic acid in the ratio of about 80:20 to about 20.80, preferably about 50:50.

The proportion of taurolidine in the composition according to the invention is generally about 5-60 wt .-%, more preferably about 20-50 wt .-%, preferably about 25-35 wt .-%, more preferably about 30 wt .-%, based on the weight of the composition.

In addition to taurolidine and the biodegradable polymer or copolymer, the composition according to the invention preferably also contains a parenterally usable plasticizer. It can be used hydrophilic plasticizers, for. As polyhydric alcohols such as polyethylene glycol and polypropylene glycol, with polyethylene glycols having molecular weights between 50 and 1000, in particular with an average molecular weight of about 400 (PEG 400), are particularly preferred. Also, lipophilic plasticizers such as dibutyl sebacate, glycerol monostearate, stearyl alcohol, phthalic acid esters, eg. As diethyl phthalate and dibutyl phthalate, citrates, z. Triethyl citrate, tribuyl citrate and acetyl tributyl citrate, and glycerol triacteate may be used.

The plasticizers may be used in amounts of from about 1 to about 50 weight percent, more preferably from about 5 to about 10 weight percent, based on the weight of the composition.

A particularly preferred composition according to the invention comprises about 30% by weight of taurolidine and / or one or more hydrolysis products thereof, about 65% by weight of a copolymer of lactic acid and glycolic acid in the ratio of about 50:50, and about 5% by weight. % Plasticizer.

To prepare the implant, taurolidine, the biodegradable polymer and optionally the plasticizer are intimately mixed. For example, first taurolidine and the polymer are mixed with a high-speed mixer and then granulated with the addition of the plasticizer.

The formation of the implant can, for. B. by extrusion of the granules and cutting the extrudate into cylinders or by calendering the granules into spheres or other forms. Furthermore, extrudates can be comminuted again and then pressed into compacts.

The implant is primarily used for the local treatment of bone skeletal or soft tissue infections, by implanting it into the affected tissue through or after surgery. There, the taurolidine is then slowly released from the polymer matrix dissolving it or from the inorganic matrix into the tissue.

The lozenges of the invention which form the second object of the invention contain taurolidine and / or one or more hydrolysis products thereof selected from taurultam, methylol-taurultam (hydroxymethyltaurultam), taurinamide and methylol-taurinamide (hydroxymethyltaurinamide), usually in an amount of 1 to 50 mg, especially 5 to 10 mg per dose or tablet.

Suitable carriers for lozenges are, in particular, sugar alcohols, such as sorbitol, xylitol, mannitol and isomalt, and sugars, such as sucrose, glucose and fructose. Sorbitol, optionally in combination with mannitol, is particularly preferred.

Suitable tablet weights are z. 500 mg, 750 mg, 850 mg, 1000 mg or 2000 mg.

The lozenge may contain other active ingredients in small amounts to help alleviate the symptoms of throat inflammation, sore throat with difficulty swallowing (which is often an alarm of an incipient cold), oropharyngeal inflammation and laryngeal inflammation. These include local anesthetics with surface anesthetic action, such as benzocaine, tetracaine, butoxycaine and Fomocain, antiseptics that are orally used, such as antiseptics from the group of N-containing heterocycles, such as oxine, clioquinol, ethacridine and hexetidine, guanidine compounds, such as chlorhexidine and Ambazon, as well as quaternary ammonium compounds, for example cetylpyridinium chloride and benzalkonium chloride.

Further, the lozenges can be added to other customary formulation ingredients, eg. For example, lubricants such as calcium arachinate and talc and flavors such as peppermint flavor.

The tablets are pressed in the usual way.

The aqueous-alcoholic spray or gargle solution of the present invention contains taurolidine and / or one or more hydrolysis products thereof selected from taurultam, methylol-taurultam (hydroxymethyltaurultam), taurinamide and methylol-taurinamide (hydroxymethyltaurinamide), usually in an amount of about 1 to about 10% by weight, based on the weight solution. Preferably, 1 to 5 wt .-%, in particular about 2 wt .-% are used.

Ethanol is usually used as the alcohol. However, it is also possible to use polyhydric alcohols, such as ethylene glycol and / or propylene glycol, optionally in combination with ethanol. The total amount of alcohol is usually about 2 to about 12 weight percent, based on the weight of the solution, preferably about 4 to about 9 weight percent, e.g. B. about 4 wt .-% ethanol and 3 wt .-% propylene glycol.

In addition, other auxiliaries, for example the already mentioned in the lozenges local anesthetics and antiseptics and common flavors and sweeteners may be included.

The process according to the invention for the preparation of taurolidine, which forms the third object of the invention, is distinguished by its simplicity, high yield and ready accessibility of the starting materials and intermediates.

In the first stage, the β-amino group is protected by taurine. For this purpose, it is possible to use all compounds which give the customary customary amino-protecting groups known to the person skilled in the art, eg. Carboxybenzyl (Cbz), t-butoxycarbonyl (Boc), Fmoc, trifluoroacetyl and phthaloyl. The phthaloyl protecting group is preferred. They are preferably prepared by reacting phthalic acid hydride with the metal salt prepared in situ using a metal ion-containing base, in particular the potassium salt, of taurine. Suitable reaction media are the combination of lower carboxylic acid metal salts, eg. As potassium acetate, with their associated acids.

In the second step, the protected salt of taurine is converted into the protected taurine chloride. This is done using conventional acid chlorides such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride, which is preferred. Suitable reaction media are aprotic solvents, eg. As toluene.

In the third step, the protected taurine chloride is converted to the protected taurinamide. This is preferably done in concentrated aqueous ammonia solution (25-30% by weight).

In the fourth step, the amine is deprotected, preferably with hydrazine hydrate in ethanol to give free taurine and by-product phthalic acid hydrazide. Taurine is isolated after usual workup as taurine hydrochloride.

In the last step, taurine hydrochloride is reacted in the presence of a base, preferably sodium bicarbonate, with formaldehyde, preferably in the form of formalin in aqueous solution. Taurolidine is formed by a threefold reaction with formaldehyde.

The workup of the individual stages is carried out in the usual manner, for example by evaporation, extraction, filtration, washing and crystallization, as z. As indicated in the examples.

The invention will now be described in more detail by way of examples.

EXAMPLES

example 1

A. Product Manufacturing: Formulation of Biologically degradable Polymer Implants (PLGA)

For the preparation of the extrudates, the solid components taurolidine (previously passed through a screen 90) and PLGA (Resomer ^® RG 503 H) were initially in a Turbula mixer (Willy A. Bachofen AG, Muttenz, Switzerland) was homogenized for 15 minutes. Then the liquid plasticizer PEG 400 (Lutrol ^® E 400) was added and granulated by hand for at least five minutes. The finished mixtures were then extruded at the lowest possible temperature using a co-rotating twin-screw extruder (Minilab II Haake Rheomex CTW5 from ThermoFisherScientific, Karlsruhe, Germany). The cooled extrudate strands were cut into uniform pieces weighing 10 ± 0.2 mg.

The compositions of the formulations are summarized in Table 1 below with the extrusion temperature used, each formulation being made three times. Table 1: Composition of the formulations charge polymer Taurolidine in% PEG 400 in% Extrusion temperature in ° C 00C-701 Resomer ^® RG 503 H 30 - 110 00C-702 Resomer ^® RG 503 H 40 - 110 00C-703 Resomer ^® RG 503 H 30 5 95 00C-705 Resomer ^® RG 503 H 30 10 85

The plasticizer PEG 400 was added firstly in order to lower the extrusion temperature and thus the temperature load on the drug and the polymer, and secondly in order to possibly positively influence the release behavior.

The extrusion temperature of a polymer blend is determined primarily by the glass transition temperature (Tg) of the polymer. Thus, the extrusion temperature is generally 40-100 ° C above the glass transition temperature. This can be lowered for example by adding a plasticizer, as was done in these studies. The influence of the components, taurolidine (Taur.) And PEG 400, on the glass transition temperature was determined by DSC (DSC 7, Perkin Elmer, Norwalk, USA) and are listed in Table 2. The characteristic variable used to describe the glass transition temperature was the temperature of the center point of the turning tangent (half step height between onset and end temperature) projected onto the measurement curve (half-step glass transition temperature). Table 2: Glass transition temperatures of the formulations charge Taur. (%) PEG (%) Tg 1 (° C) Tg 2 (° C) Tg 3 (° C) Average St. abw. 701 30 0 45.28 43.23 42.86 43.79 1.30 702 40 0 44.85 43.67 44.31 44.28 0.59 703 30 5 31.17 30.61 31.22 31.00 0.34 705 30 10 26.03 24,49 23.41 24.64 1.32

In 2 the glass transition temperatures of the formulation are plotted against the extrusion temperatures. It can be clearly seen that lowering the glass transition temperature by the plasticizer makes it possible to use lower extrusion temperatures. At the same time, this reduces the temperature load on the drug and the polymer during the manufacturing process.

B. In Vitro Release Studies

For determination of in vitro release, five extrudates weighing 10 ± 0.2 mg were selected from each lot and incubated in 3 ml of release medium (phosphate buffer pH 7.4) at 37 ° C with shaking. Every 72 hours, the phosphate buffer was removed and replaced. The sampled sample was deep-frozen by HPLC until analysis. The results of the release studies are in the 3 shown graphically.

All 30% taurolidine batches exhibit a sigmoidal release pattern, the less the higher the plasticizer level. Despite the overall sigmoidal course, the batches release the drug evenly after the burst effect for about two weeks. However, for the 30% taurolidine-free plasticizer batch, the second release phase, the erosion release of the polymer, starts somewhat earlier, after about 13 days, than the 30% taurolidine and 5% and 10% PEG 400 batches, where the erosion phase only after 16 days begins. The onset of erosion release is evidenced by an increase in the release curve. After about three weeks, the curves flattened, releasing the entire amount of drug. The release process of the batch is different with 40% taurolidine, which shows an exponential curve. The higher drug content results in a higher burst effect where about 30% of the taurolidine was released. The dissolved taurolidine gives rise to pores, which in turn trigger the penetration of the water and thus the release of the drug and the degradation of the polymer.

The release curves do not change when 10 cylinders in 3 ml of phosphate buffer instead of only 5 extrudate cylinders. A difference only becomes apparent from the non-cumulative presentation of the released quantity in 4 clear. In the release experiment with a doubling of the number of test cylinders, twice the amount of drug is released, which clearly exceeds the minimum inhibitory concentration of Staphylococcus aureus. In addition, almost completely over a period of three weeks, the minimum bactericidal concentration is exceeded.

This proves that increasing the number of extrudate cylinders also increases the amount of drug released to the same extent without altering the release process. This makes it possible to adapt the dose to the volume of the infected tissue.

C. Mass loss of the extrudates during release

To determine the mass loss of the extrudates during the course of the release, the samples were dried to determine the swelling after wet weighing. To dry the extrudates, a freeze dryer (freeze dryer Alpha 1-4 LDC-1M Martin Christ Gefrierrocknungsanlagen GmbH, Osterode, Germany) was used. The glass transition temperature was -20 ° C (about 4 hours) and the primary drying was carried out at -5 ° C and a pressure of 0.2 mbar for about 24 hours. The secondary drying was carried out at 15 ° C and 0.08 mbar. After drying, the extrudates were weighed again to determine the mass loss. However, this process was only possible as long as the extrudates remained in shape and did not disintegrate when touched. The mass in percent is in 5 played.

In the first release phase, release by diffusion, the mass loss of the extrudates is approximately equal to the mass of drug released. This means, for example, in the formulation with 30% taurolidine and 5% PEG 400 after seven days a mass loss of about 12%, which corresponds to the released amount of drug with a percentage mass of 12.3% based on the total mass. After 12 days, the mass of the extrudates drops more sharply, the second release phase begins, and polymer fragments are released by erosion.

D. Influence of radiation sterilization

Since drug forms have to be sterilized for parenteral use, the influence of radiation sterilization on the extrudates was investigated. The samples were irradiated with gamma rays at a surface dose of 28 kGy. The selected formulation and its radiation dose are listed in Table 3. Table 3: Radiation sterilization charge Taurolidine in% PEG in% Irradiation in kGy 701 30 0 28 702 40 0 28 703 30 5 28

Release experiments after sterilization:

When formulated with 30% taurolidine and 0% PEG 400 no changes are seen by the treatment of gamma rays ( 6 ).

Example 2

A. Formulation of lozenges

• a) For the preparation of lozenges, the following formulation ingredients according to Table 4 were used:

Table 4: Recipe of lozenges ingredients Shares (%) sorbitol 76.25 mannitol 20 calcium arachinate 0.7 talc 0.3 Natural spray-dried peppermint flavor 1.5 taurolidine 1 benzalkonium chloride 0.1 benzocaine 0.15

The lozenges were prepared by direct tabletting since the taurolidine decomposes in aqueous medium to taurultam and hydroxymethyl taurultam. For the preparation, all components were first passed through a sieve (355) and then weighed. The inner phase, that is the sorbitol, mannitol, peppermint flavorings and the active ingredients were added together and homogeneously mixed for 15 minutes in a Turbula mixer (Willy A. Bachofen AG, Muttenz, Switzerland). The outer phase, consisting of calcium arachinate and talc, was added and also mixed in the Turbula mixer for 5 minutes.

• b) In einer weiteren Formulierung wurde auf den Zusatz von Mannitol verzichtet. Es wurden folgende Bestandteile in den angegebenen Konzentrationen verwendet (Tabelle 5). Darüber hinaus wurde nun mit einer Anmischung von Benzalkoniumchlorid und Benzocain mit 10% Sorbitol gearbeitet. Die resultierenden Tabletten weisen ein gutes Lutschgefühl durch sehr glatte Tablettenoberflächen auf.

Tabelle 5: Rezeptur der Lutschtabletten ohne Mannitol Bestandteile Anteile (%) Sorbitol 96,25 Calciumarachinat 0,7 Talkum 0,3 Natürliches sprühgetrocknetes Pfefferminzaroma 1,5 Taurolidin 1 Benzalkoniumchlorid 0,1 Benzocain 0,15 This powder mixture was pressed on an eccentric press (Korsch, EK0) into tablets with a diameter of 15 mm and a mass of about 850 mg.

• b) In another formulation, the addition of mannitol was omitted. The following ingredients were used at the concentrations indicated (Table 5). In addition, it was now worked with an admixture of benzalkonium chloride and benzocaine with 10% sorbitol. The resulting tablets have a good sucking sensation due to very smooth tablet surfaces.

Table 5: Formulation of lozenges without mannitol ingredients Shares (%) sorbitol 96.25 calcium arachinate 0.7 talc 0.3 Natural spray-dried peppermint flavor 1.5 taurolidine 1 benzalkonium chloride 0.1 benzocaine 0.15

B. Lozenge tests

Uniformity of mass

The tablets were tested for uniformity of mass according to the European Pharmacopoeia (Ph. Eur. 6.0, 2.9.4). The determined mean weight of the lozenges gave the following value:
Mean: 846.1 mg
Standard deviation: 5.9 mg
Maximum deviation: 1.7%

friability

The friability of the tablets was tested according to the European Pharmacopoeia (Ph. Eur. 6.0) according to 2.9.7 Friability of uncoated tablets. 10 tablets were tested and an abrasion of 0.2% was determined.

The tablets thus have only a low abrasion and thus meet the requirements of the pharmacopoeia.

breaking strength

The breaking strength was measured with a break strength tester according to Dr. med. Schleuniger (Model 6D Tablet Tester, Pharmatron) tested. On 20 tablets a breaking strength of 202 N + 12.7 N was determined.

This rather high breaking strength causes the tablet does not disintegrate in the mouth, but that it slowly dissolves. You can suck them thus. The high breaking strength also causes the surfaces of the tablets by "melting" (cold flow) of sorbitol have only an extremely low porosity, or have completely closed surface. As a result, water can penetrate only poorly, making the tablets relatively insensitive to atmospheric moisture.

Example 3

Formulation of a spray and gargle solution

The following ingredients were used at the concentrations indicated (all parts are by weight): taurolidine 2.0 parts cetylpyridinium 0.02 parts propylene glycol 3.0 parts ethanol 4.0 parts peppermint oil 0.3 parts Sodium saccharine 0.2 parts Distilled water to 100 parts

Example 4

Preparation of taurolidine

1st stage: Preparation of the protected taurine

¹H-NMR (300 MHz, D₂O, 300 K): δ (ppm) = 7,86-7,80 (m, 4H, CH-Arom.), 4,07 (t, 2H, ³J = 6,90 Hz, C-2), 3.28 (t, 2H, ³J = 6.55 Hz, C-1).
¹³C-NMR (300 MHz, D₂O, 300 K): δ (ppm) = 169,4 (C-3), 134,3 (C-6), 130,8 (C-4), 122,9 (C-5), 47,3 (C-1), 33,0 (C-2).
ESI-MS: m/z = 332,1 [M+2K]⁺⁺, 256,040.5 g (0.232 mol) of taurine were suspended in glacial acetic acid and treated with 41.3 g (0.429 mol) of potassium acetate. The reaction mixture was heated under reflux, wherein 20 minutes after reaching the boiling temperature 52.7 g (0.356 mol) of phthalic anhydride was added and refluxed for a further 4 h. After cooling the reaction mixture, the precipitate formed was filtered off with suction and washed three times each with 20 ml of glacial acetic acid and ethanol. Subsequent filtration and drying provided 76.26 g of a colorless solid.
Yield: 76.26 g (92%)

¹ H-NMR (300 MHz, D ₂ O, 300 K): δ (ppm) = 7.86-7.80 (m, 4H, CH-Arom.), 4.07 (t, 2H, ³ J = 6.90 Hz, C-2), 3.28 (t, 2H, ³ J = 6.55 Hz, C-1).
¹³ C-NMR (300 MHz, D ₂ O, 300 K): δ (ppm) = 169.4 (C-3), 134.3 (C-6), 130.8 (C-4), 122, 9 (C-5), 47.3 (C-1), 33.0 (C-2).
ESI-MS: m / z = 332.1 [M + 2K] ⁺⁺ , 256.0

2nd stage: Preparation of the protected chloride

¹H-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 7,88-7,76 (m, 4H, CH-Arom.), 3,87-3,82 (m, 2H, C-2), 2,85-2,80 (m, 2H, C-1).
¹³C-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 167,7 (C-3), 134,3 (C-6), 131,8 (C-4), 123,0 (C-5), 48,7 (C-1), 34,4 (C-2).
ESI-MS: m/z = 274,0 [M+H]⁺ 76.7 g (0.262 mol) of the potassium salt were suspended in a little dry toluene and treated with 42.0 g (0.236 mol) of phosphorus pentachloride. The reaction mixture was refluxed for one hour, followed by a second addition of 42.0 g (0.236 mole) of phosphorus pentachloride. After a further 2 h, the reaction mixture was cooled and the solvent removed in vacuo. The remaining solid was carefully introduced into ice-water and stirred there for at least 5 minutes. The solid was then filtered off with suction, washed with water and dried. There were obtained 88.24 g of a yellowish solid.
Yield: 88.24 g (92%)
R _f = 0.7 (EE)

¹ H-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 7.88-7.76 (m, 4H, CH-Arom.), 3.87-3.82 (m, 2H, C -2), 2.85-2.80 (m, 2H, C-1).
¹³ C-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 167.7 (C-3), 134.3 (C-6), 131.8 (C-4), 123.0 ( C-5), 48.7 (C-1), 34.4 (C-2).
ESI-MS: m / z = 274.0 [M + H] ⁺

3rd stage: Preparation of the amide

¹H-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 7,89-7,82 (m, 4H, CH-Arom.), 7,00 (s, 2H, NH₂), 4,00-3,95 (m, 2H, C-2), 3,37-3,32 (m, 2H, C-1).
¹³C-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 167,4 (C-3), 134,3 (C-6), 131,7 (C-4), 123,0 (C-5), 51,6 (C-1), 32,6 (C-2).
ESI-MS: m/z = 401,0.1 [M+2Na]⁺⁺, 277,1 [M+Na]⁺, 255,1 [M+H]⁺ 88.0 g (0.322 mol) of the acid chloride were concentrated in 770 ml. Ammonia was suspended and stirred for 48 h at room temperature, which was checked by means of TLC control for completeness of the reaction. After the reaction, the suspension was evaporated to dryness and the residue was triturated intimately with glacial acetic acid / water (3: 2). The solid was then filtered off, washed with a little glacial acetic acid / water (3: 2) and dried over phosphorus pentoxide. There were obtained 52.17 g of an ocher solid.
Yield: 52.71 g (64%)
R _f = 0.6 (EE)

¹ H-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 7.89-7.82 (m, 4H, CH-Arom.), 7.00 (s, 2H, NH ₂ ), 4 , 00-3.95 (m, 2H, C-2), 3.37-3.32 (m, 2H, C-1).
¹³ C-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 167.4 (C-3), 134.3 (C-6), 131.7 (C-4), 123.0 ( C-5), 51.6 (C-1), 32.6 (C-2).
ESI-MS: m / z = 401.0.1 [M + 2Na] ⁺⁺ , 277.1 [M + Na] ⁺ , 255.1 [M + H] ⁺

4th stage: deprotection to taurinamide

¹H-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 3,38 (m, 2H, C-1), 3,17 (m, 2H, C-2)
ESI-MS: m/z = 125,0 [M+H]⁺ 51.9 g (0.204 mol) of the 2- (N-phthalimido) ethanesulfonic acid amide were suspended in ethanol and heated to reflux. Then, 10.2 ml (0.204 mol) of 35% hydrazine hydrate solution was added and the reaction was refluxed for another 45 min. After cooling, the resulting precipitate was filtered off, suspended in water and heated to reflux. Thus, until the formation of a clear solution of water, then 29 ml of conc. Hydrochloric acid was added and the solution was cooled to room temperature. The resulting precipitate was filtered off and washed with a little water. The filtrate was concentrated in vacuo to give more precipitate. After removal, the mixture was concentrated to dryness and the crude product recrystallized in 95 percent methanol. Taurinamide hydrochloride was obtained as a white solid.
Yield: 20.93 g (83%)

¹ H-NMR (300 MHz, DMSO, 300 K): δ (ppm) = 3.38 (m, 2H, C-1), 3.17 (m, 2H, C-2)
ESI-MS: m / z = 125.0 [M + H] ⁺

5th stage: Preparation of taurolidine

5.00 g (31.3 mmol) of taurinamide hydrochloride are dissolved in 30 ml of water and cautiously treated with 3.15 g (1.2 equiv., 37.5 mmol) of sodium bicarbonate. After checking the adjustment of the pH to pH = 8 and cooling the batch by means of an ice bath, 3.00 ml (1.3 equiv., 40.6 mmol) of 37-38% formalin solution slowly (10 drops every 10 min.) With a syringe. The resulting precipitate is filtered off and the remaining solution is spent for further crystallization in a refrigerator. There are obtained 3.12 g (10.9 mmol, 81%) of a white powder.
Melt .: 174 ° C;
R _f value: 0.41 (EtOH / MeOH (3/1))
¹ H NMR (300 MHz, d ₆ -DMSO) δ (ppm) = 7.26 (s, 2H, NH), 4.12 (s, 4H, NCH ₂ NHSO ₂ ), 3.56 (s, 2H, NCH ₂ N), 3.32 (m, 4H, CH ₂ CH _2), 2.99 (m, 4H, CH ₂ CH _2).

QUOTES INCLUDE IN THE DESCRIPTION

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Cited patent literature

• CH 482713 [0002, 0005]
• GB 40734/64 [0002]
• DE 19515976 C1 [0005]
• EP 0863133 B1 [0005]

Claims (13)

A composition comprising at least one polymer or copolymer or inorganic matrix biodegradable in the human body into which the taurolidine and / or one or more hydrolysis products thereof, selected from taurultam, methylol-taurultam (hydroxymethyltaurultam), Taurinamide and methylol-taurinamide (hydroxymethyltaurinamide) are selected embedded. The composition of claim 1 wherein the biodegradable polymer or copolymer in the human body is a copolymer of lactic acid and glycolic acid in the ratio of about 80:20 to about 20:80, preferably about 50:50. The composition of claim 1 or 2, wherein the taurolidine and / or the one or more hydrolysis products thereof in an amount of about 5-60 wt .-%, more preferably about 20-50 wt .-%, preferably about 25-35 wt .-%, more preferably about 30 wt .-%, based on the weight of the composition, are present. A composition according to any one of claims 1 to 3, further comprising a plasticizer. A composition according to any one of claims 1 to 4, wherein the plasticizer is polyethylene glycol having an average molecular weight of 400 Da in an amount of about 1 to about 50% by weight, more preferably about 5 to about 10% by weight, by weight the composition is. A composition according to any one of claims 1 to 5, comprising about 30% by weight of taurolidine and / or one or more hydrolysis products thereof, about 65% by weight of a copolymer of lactic acid and glycolic acid in the ratio of about 50:50, and about 5% by weight of plasticizer. Composition according to one of claims 1 to 6 as a medical implant. Use of a composition according to any one of claims 1 to 7 as an implant for local treatment of infections of the skeleton or soft tissues. A lozenge comprising taurolidine and / or one or more hydrolysis products thereof selected from taurultam, hydroxymethyl taurultam, taurine amide and hydroxymethyl taurine amide, and at least one suitable pharmaceutical carrier or excipient. Aqueous alcoholic solution for spraying or gargling comprising taurolidine and / or one or more hydrolysis products thereof selected from taurultam, hydroxymethyl taurultam, taurine amide and hydroxymethyl taurine amide. A lozenge or spray or gargle solution according to claim 9 or 10, further comprising an antiseptic and / or a surface-active local anesthetic. Use of the lozenge or spray or gargle solution of any one of claims 9 to 11 for treating throat infections, sore throat with difficulty swallowing, mouth and throat infections and laryngeal inflammation. A process for the preparation of taurolidine which comprises the steps of: 1. reacting taurine with a compound which provides an amine protecting group, preferably phthalic anhydride, for the preparation of a salt, preferably the potassium salt of protected taurine;

2. Reaction of the salt of protected taurine with an acid chloride to produce protected taurine chloride;

3. transfer of the protected taurine chloride into the protected taurine amide;

4. deprotection of the protected taurine amide;

and 5. Reaction of taurine amide with formaldehyde to produce taurolidine

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