Technical Field

The present invention relates to the pharmaceutical compositions in the form of the lyophilized powder, which do not contain alcohol, comprises Levosimendan as an active ingredient or a pharmaceutically acceptable salt thereof, Kollidon PF- 17 as a solubilizing agent and tri-sodium citrate as a buffering agent, the preparation and use of these compositions.

State of the Art

Levosimendan, the (-) enantiomer of [[4-(l,4,5,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl) phenyl] hydrazono] propanedinitrile and the methods for the preparation thereof are described in EP 565546 Bl and WO 97/35841. Levosimendan is a highly effective cardiotonic that increases the sensitivity of the heart to calcium without causing an increase in the intracellular calcium. Levosimendan is potent in the treatment of the heart failure and exhibits a significant calcium-dependent binding to troponin. The maximum daily dose is 298 pg/kg. It is a yellow-orange powder.

The chemical formula of Levosimendan is and its molecular weight is 280.28 g/mol. Levosimendan compound is shown in Formula 1.

Currently, the commercial products, from Daiichi Sankyo company, named SIMDAX® CONCENTRATED SOLUTION VIAL FOR IV INFUSION 2.5 mg/ml containing Levosimendan, are commercially available. (EP 1210085 Bl, TR 2002/00620 B, WO 2001/019334)

Simdax concentrated solution in a 5 mL of glass vial is clear and yellow or orange in color, and each milliliter contains 2.5 mg of Levosimendan as an active ingredient, 785 mg of ethanol (anhydrous) as an auxiliary substance, 10 mg of povidone and 2 mg of citric acid (anhydrous). The storage condition of the pharmaceutical product in the market is between 2-8°C. The pH value is below 5.

The primary packaging materials for the pharmaceutical product named Simdax are 8 mL of type 1 glass vial, chlorobutyl rubber stopper coated with fluoropolymer, and flip- off aluminum cap. Secondary packaging material is a cardboard box.

Simdax is a pharmaceutical product developed for the intravenous use in the hospitalized patients with the acute heart failure. It is indicated for the acute decompensated chronic heart failure and for the supportive treatment after coronary bypass surgery when the inotropic support with its calcium sensitizing and potassium channel opener effect is required. It is used as an infusion up to 24 hours in the acute decompensated chronic heart failure and in the supportive treatment after bypass.

Simdax is diluted with 5% glucose solution before the administration. The pharmaceutical product is suitable for the hospital use only. The administration should be done in the hospitals that have the adequate monitoring facilities and expertise for the use of the inotropic agents.

The document CN 1470238 A describes the water-based pharmaceutical compositions of Levosimendan with a solubility in water increased with the hydroxypropyl-beta- cyclodextrin.

The document TR 2000/03101 describes the composition containing Levosimendan and alginic acid.

The document TR 2020/02333 describes the cyclodextrin-containing Levosimendan compositions for the intravenous administration as an infusion or injection and infusion concentrate.

W02020041180 document describes the cyclodextrin-containing compositions for the subcutaneous administration. The document WO2017037737 relates to a parenteral composition containing Levosimendan, povidone, triethanolamine HC1 and sodium citrate. The only example given as povidone in the patent is Kollidon PF- 12.

The document W02012093404 describes the preparation of a parenteral pharmaceutical product containing Kollidon PF- 12 and an alkalizing or buffering agent and stable at pH 6-8, with respect to Levosimendan.

Levosimendan is a crystalline powder at room temperature and has a pKa of 6.12. Levosimendan is unstable in the aqueous solutions at a physiological pH and is subject to the hydrolytic degradation. Therefore, Levosimendan, which has low solubility in water, can easily precipitate from the aqueous solutions. This situation poses a risk for the patient safety in the clinical practice for the intravenous solutions.

The poor water solubility of Levosimendan causes the difficulties especially in the compositions consisting of the aqueous solutions for the parenteral administration. Also, the solubility of Levosimendan drops dramatically as it falls below the neutral pH values, so the working with Levosimendan especially in the aqueous media with pH values below 7 is another major challenge.

In the product, commercially named Simdax, the anhydrous ethanol was used as a solvent and a rubber stopper coated with the fluoropolymer was used as a stopper. The presence of ethanol in the composition of the pharmaceutical product is a challenge for the manufacturing process. In addition, Simdax is a product that is transported by the cold chain and the storage condition is 2-8°C, bringing about the storage disadvantages and the like.

The present invention has been developed to overcome the disadvantages and difficulties of the injection manufacturing of Levosimendan in the ethanol medium.

The commercial product is a cold chain product with a storage condition of 2-8°C. For this reason, it has storage disadvantages and the like. Since the storage condition of the composition of the invention is the room temperature below 25°C, it eliminates the disadvantages of the cold chain. There is a need to develop a parenteral composition that overcomes the above- mentioned shortcomings in the state of the art and provides a more stable composition throughout the shelf life of the product.

Summary of the Invention

In order to eliminate the disadvantages of the products in the state of the art, the pharmaceutical compositions in the form of the lyophilized powder, have been developed, which do not comprise alcohol, but comprise Levosimendan as an active ingredient and Kollidon PF- 17 (Polyvinylpyrrolidone PF- 17) as a solubilizing agent.

Detailed Description of the Invention

The present invention is a pharmaceutical composition in the form of the lyophilized powder, which does not contain alcohol, wherein the composition comprises a. Levosimendan as an active ingredient or a pharmaceutically acceptable salt thereof, b. a polyvinylpyrrolidone (Kollidon PF- 17) as a solubilizing agent with a molecular weight of 7100-11000 calculated from the K value limit given in Ph.Eur, c. at least one pharmaceutically acceptable buffering agent, d. at least one pharmaceutically acceptable pH-adjusting agent, and e. water as a solvent.

The infusion application of the approved commercial product, Simdax, is carried out only with 5% glucose solution. The reconstitution solution of the pharmaceutical composition to be obtained with the present invention, which is prepared with water, is close to the physiological pH values and the solution can be diluted with the different standard infusion solutions. For example, it can be diluted with infusion solutions such as 0.9% NaCl or the Lactated Ringer’s solution.

Moreover, since the storage condition of the composition of the invention is the room temperature below 25°C, the difficulty for storing the current commercial product at 2- 8°C is also eliminated. In addition, the composition of the invention does not contain ethanol or any alcohol. Therefore, the risk of remaining as an organic solvent residue in the production equipment is also eliminated.

The composition preferably contains 10-20 mg of Levosimendan, more preferably 12.5 mg of Levosimendan.

The composition preferably contains 100-300 mg of Kollidon PF- 17, more preferably 125 mg of Kollidon PF- 17.

In one embodiment of the invention, the composition contains tri- sodium citrate as a buffering agent. The amount of tri-sodium citrate is preferably 20-350 mg, more preferably 50-100 mg.

The composition preferably contains sodium hydroxide as a pH-adjusting agent.

When Kollidon PF- 12 was used in the composition in the experimental activities related to the invention, it was determined that Levosimendan did not dissolve in 5 mL, but dissolved in 10 mL. This composition was filled into 10 mL of vials and lyophilized. When the reconstitution test was performed for the lyophilized powder, it was determined that the lyophilized powder (cake) did not dissolve in 5 mL, but dissolved in 10 mL. This caused the amount of Levosimendan of 1 mL to change. Surprisingly, it was found by the inventors that when Kollidon PF- 17 is used, Levosimendan composition of the invention provides the desired solubility and concentration (in 5 mL) both in the bulk solution and reconstitution.

Kollidon PF- 17, used in the composition as a solubilizing agent, is the name of a specific commercial product that mainly includes an excipient known as polyvinylpyrrolidone. The differences between Kollidon PF- 17 and Kollidon PF- 12 were published in the 9 ^th revised edition of “ Polyvinylpyrrolidone Excipients for the Kollidon Pharmaceutical Industry", March 2008, prepared by Volker Buhler.

In the document, the K values and Nitrogen contents determined for Kollidon PF- 12 and Kollidon PF- 17 are indicated in Table 2.3. In the document, Table 2.14 indicates that the bulk densities are different.

In the document, Table 2.18 indicates that the molecular weights are different.

On page 46 it is indicated that the osmotic pressures are different.

According to these data, the polyvinylpyrrolidone (Kollidon PF- 17) contained in the composition of the invention has the following features:

The exemplary unit composition of the pharmaceutical composition of the invention is given in Example 1.

Example 1

Preparation of the Composition of the Invention

An exemplary process for the preparation of the pharmaceutical composition of the invention is given below. 1. The water for injection of 70-80% of the total volume is taken at a temperature of

20-30°C.

2. Kollidon PF- 17, weighed in the amount determined according to the composition, is added into the water by mixing, and the mixing is continued until a clear solution is formed. When it is completely dissolved, the pH is measured. 3. pH is adjusted between 7.0 and 8.0, preferably 7.0, by 10% NaOH solution.

4. The active ingredient Levosimendan, weighed in the amount determined according to the composition, is added by mixing. 10% NaOH solution is added dropwise until the active ingredient is completely dissolved and a clear, yellow-orange solution is formed, providing the active ingredient to be solved. During the additions, the pH is instantly controlled so that the pH does not exceed the range of 7.0-8.0. When a clear solution is formed, the pH is measured by stopping the addition of NaOH.

5. Tri-sodium citrate, weighed in the amount determined according to the composition, is added by mixing, and the mixing is continued until a clear solution is formed. If the added tri-sodium citrate does not dissolve completely, the water for injection is added in such a way that it does not exceed the required final volume, and a clear solution is formed. pH is measured.

6. The pH value of the solution is adjusted to the target value (preferably 7.5) with 10% NaOH.

7. It is made up to its volume with the water for injection, mixed for 5-10 minutes to be homogeneous, and filtered by the sterile filtration.

8. 20 mL of Type 1 colorless glass vials are each filled with 5 mL of the filtered solution. It is lyophilized into a lyophilized powder form with a half-closed elastomeric lyophilized stopper.

The lyophilized powder form is obtained by the sterile filtration of the prepared solutions and filling them into a sterile vial and applying the freeze-drying method (lyophilization).

The lyophilization is a dehydration process typically used to preserve a degradable material or to make the material more suitable for the transportation. The freeze-drying works by freezing the material and then reducing the ambient pressure and adding enough heat to allow the frozen water in the material to sublimate directly from the solid phase to the gas phase.

The lyophilization operating parameters are as follows (Toffion LYO-05):

Example 2

Preparation of the Composition of the Invention An exemplary process for the preparation of the pharmaceutical composition of the invention is given below.

1. The water for injection of 70-80% of the total volume is taken at a temperature of 20-30°C. 2. Kollidon PF- 17, weighed in the amount determined according to the composition, is added into the water by mixing, and the mixing is continued until a clear solution is formed. When it is completely dissolved, the pH is measured.

3. With 10% NaOH solution, the pH is adjusted between 7.0 and 8.0, preferably 7.0.

4. The active ingredient Levosimendan, weighed in the amount determined according to the composition, is added by mixing. 10% NaOH solution is added dropwise until the active ingredient is completely dissolved and a clear, yellow- orange solution is formed, providing the active ingredient to be solved. During the additions, the pH is instantly controlled so that the pH does not exceed the range of 7.0-8.0. When a clear solution is formed, the pH is measured by stopping the addition of NaOH.

5. Tri-sodium citrate, weighed in the amount determined according to the composition, is added by mixing, and the mixing is continued until a clear solution is formed. If the added tri-sodium citrate does not dissolve completely, the water for injection is added in such a way that it does not exceed the required final volume, and a clear solution is formed. pH is measured.

6. The pH value of the solution is adjusted to the target value (preferably 7.5) with 10% NaOH.

7. It is made up to its volume with the water for injection, mixed for 5-10 minutes to be homogeneous, and filtered by the sterile filtration.

8. 20 mL of Type 1 colorless glass vials are each filled with 5 mL of the filtered solution. It is lyophilized into a lyophilized powder form with a half-closed elastomeric lyophilized stopper.

The lyophilized powder form is obtained by the sterile filtration of the prepared solutions and filling them into a sterile vial and applying the freeze-drying method (lyophilization).

The lyophilization is a dehydration process typically used to preserve a degradable material or to make the material more suitable for the transportation. The freeze-drying works by freezing the material and then reducing the ambient pressure and adding enough heat to allow the frozen water in the material to sublimate directly from the solid phase to the gas phase.

The lyophilization operating parameters are as follows (Toffion LYO-05):

Administration of the Composition of the Invention

A reconstitution solution of a pharmaceutical composition of the invention in the form of the lyophilized powder, which does not contain alcohol, is prepared, preferably with 5 mL of water for injection. The pH value of the resulting solution is between 7.5 and

8.0.

The pH of this solution is close to the physiological pH values and the solution can be diluted with the different standard infusion solutions.

For example, it can be diluted with infusion solutions such as 5% glucose solution, 0.9% NaCl or Lactated Ringer’s solution and administered intravenously.

Medical Use of the Composition of the Invention A pharmaceutical composition of the invention in the form of the lyophilized powder, which does not contain alcohol, can be used in the acute decompensated chronic heart failure or in the supportive treatment after the coronary bypass surgery.