HK1013623B - Aqueous concentrated solutions containing argatroban - Google Patents

Description

The present invention relates to a new galenic formulation of argatroban.

Argatroban, a synthetic thrombin inhibitor, is a compound that is poorly soluble in water (about 1 mg/ ml). However, in some indications, the dosage required is several hundred millilitres per day when argatroban is in the form of a simple aqueous solution.

To limit the volumes administered, certain agents may be used to increase the concentration of solutions.

For example, the possibility of using low amounts of ethanol, propylene glycol or polyethylene glycol or surfactants such as sorbitol esters or polyoxyethyl derivatives of castor oil has been investigated.

Some of these agents have been shown to increase the solubility of argatroban. However, for all solutions, significant problems of local tolerance and/ or general anaphylactic reactions have been reported.

A new galenic formulation of argatroban, improving its solubility in water, was therefore developed by adapting the mixed micelles technique.

This formulation combines argatroban, a mycelium forming agent, with a lipoid substance such as a phosphatide.

It may also contain additives normally used in the preparation of liquid pharmaceutical forms, such as osmolating agents, buffers, antioxidants and preservatives, or additives necessary for the preparation of a desiccated form (obtained by cryodesification, nebulization, atomisation, etc.) leading, after reconstitution, to a liquid form.

For example, cholic acid derivatives of general formula (I) are used as micelle forming agents. where R1, R2 and R3 are hydrogen atoms, hydroxy groups or exocyclic keto groups independently of each other and R4 is a carboxy group or a carboxy group linked by an amide bond to the amino group of an amino acid, and may contain one or two double bonds in the steroidal skeleton, e.g. at positions 7-8, 11-12 or 9-11.

In particular, compounds of formula (I) are used in which R1, R2, R3 and R4 have the following values: The following equation is used for the calculation of the CO2 emissions from the use of the fuel cell:

The compounds of formula (I) may also be used as salts, in particular alkaline metal salts, preferably sodium salts.

The following compounds are used as lipoids: phosphatidylcholinesphosphatidylethanolaminephosphatidylinositolphosphatidylserinesdiphosphatidylglycerolglycerine ether-phosphatidysplasma-generated phingomyelin sulphatides and monoglycerides, preferably phosphatides, and more specifically phosphatidylcholines.

The micelle forming agent may be a mixture of two or more cholic acid derivatives or a mixture of two or more lipoids.

The molar ratio between the lipoid part (pure compound or mixture) and the micellar part (pure compound or mixture) may vary from 0.1/1 to 2/1, preferably between 0.5/1 and 1.5/1.

The final concentration of micellic agent in the pharmaceutical formulation of the invention, which varies according to the target argatroban concentration, is generally between 0.01 and 0.5 M.

The argatroban solutions of the invention can be prepared by the following methods: 1. dissolution of all constituents in water under vigorous agitation.2. dissolution of the constituents of mixed micelles in a more or less diluted organic solvent, then evaporation of the solvent, recovery of the residue by water to which the other excipients necessary for adjusting the pH, osmolarity and/or stability of the solution have been added if necessary and finally incorporation of argatroban under agitation.3. dissolution of argatroban and the constituents of the micelles in an organic solvent then evaporation of the solvent and recovery of the residue by water to which the other excipients as mentioned in 2. have been added if necessary.

The resulting solutions have a argatroban concentration of more than 1 mg/ml and, more specifically, between 1 mg/ml and 21 mg/ml.

One or more substances such as bones, oligosaccharides, polyalcohols, amino acids, polymers such as polyvinylpyrrolidone, gelatine, dextran, albumin, etc. may be added to a solution obtained by one of the methods described above at concentrations between 0.1 and 20%. The preparation is then desiccated by atomization or freeze-drying. The resulting solid material, stored in a sealed container under controlled atmosphere, is extemporaneously solubilized by the addition of an appropriate solvent such as water for injections. This gives a clear solution with a concentration of 1 to 21 mg/ml.

The following examples illustrate the present invention:

Example 1

Dissolve 1.2 g of purified egg lecithin, 0.7 g of sodium glycocholate and 0.125 g of argatroban in 75 mg of 95% ethanol under magnetic agitation, then evaporate the ethanol at reduced pressure and then stir the residue at room temperature in 25 ml of phosphate buffer 0.06 M (pH = 6). This solution is stable for several weeks when stored at 4°C.

Example 2

Dissolve 0.750 g of purified egg lecithin and 0.490 g of sodium glycocholate in 10 ml of 95% ethanol. After evaporation of the solvent at reduced pressure, dissolve the residue in 15 ml of 0.06M phosphate buffer (pH = 6) and add 0.100 g of argatroban under vigorous agitation. Continue agitation for a few hours under nitrogen stirring and then adjust the volume to 20 ml by addition of phosphate buffer.

Example 3

Following the procedure in example 2, prepare a solution containing 0,1 M sodium glycocholate and 0,1 M phosphatidylcholine, add excess argatroban, agitate the suspension for 48 hours and filter over a membrane with a porosity of 0,22 μm to obtain a solution of 11,3 mg/ml.

Example 4

Following the method in example 3, a solution containing 0,075 M sodium glycocholate is obtained at a concentration of 9 mg/ml.

Example 5

Following the method in example 3, using a solution containing 0,15 M sodium glycocholate and 0,15 M phosphatidylcholine, a solution of 16,9 mg/ml is obtained.

Example 6

Following the method in example 3, a solution containing 0,15 M phosphatidylcholine and 0,15 M sodium taurcholate is obtained at a concentration of 13 mg/ml.

Example 7

Following the method in example 3, a solution of 20,6 mg/ml is obtained using 0,15 M of a mixture containing 65% sodium taurcholate and 35% sodium glycocholate and 0,15 M phosphatidylcholine.

Example 8

Following the method in example 3, using 0,15 M of sodium taurolate and 0,15 M of a mixture of phosphatidylcholine and phosphatidylethanolamine (in a ratio of 8,5/1), a solution of 20,1 mg/ml is obtained.

The argatroban solutions of the invention may be administered parenterally, orally, nasally, ocularly or retro-ocularly.

Claims (9)

1. Concentrated aqueous solution of argatroban, characterized in that it contains argatroban, one or more micelle-forming agents and one or more lipoid substances, the said micelle-forming agent being selected from cholic acid derivatives of general formula (I) in which R₁, R₂ and R₃ represent, independently of each other, hydrogen atoms, hydroxy groups or exocyclic keto groups, and R₄ represents a carboxy group or a carboxy group bonded by an amide bond to the amino group of an amino acid, and which may contain one or two double bonds in the steroid skeleton.
2. Solution according to Claim 1, characterized in that the cholic acid derivative is in the form of an alkali metal salt.
3. Solution according to any one of Claims 1 to 2, characterized in that the lipoid substance is a phosphatide.
4. Solution according to Claim 3, characterized in that the phosphatide is a phosphatidylcholine.
5. Solution according to any one of Claims 1 to 4, characterized in that it contains excipients as usually used in the preparation of liquid pharmaceutical forms or of dried pharmaceutical forms which lead after reconstitution to liquid forms.
6. Solution according to any one of Claims 1 to 5, characterized in that the molar ratio between the lipoid substance and the micelle-forming agent is between 0.1/1 and 2/1.
7. Solution according to any one of Claims 1 to 6, characterized in that the concentration of micelle-forming agent is between 0.01 and 0.5 M.
8. Solution according to any one of Claims 1 to 7, characterized in that the argatroban concentration is between 1 mg/ml and 21 mg/ml.
9. Solution according to any one of Claims 1 to 8, characterized in that it is prepared at the time of use from a solid material obtained by atomization or lyophilization of all or part of the components of the said solution.