BE1021328B1 - PHARMACEUTICAL COMPOSITION READY FOR USE - Google Patents

Abstract

The invention provides pharmaceutical compositions for parenteral administration comprising sotalol, at least one buffer comprising sodium acetate and acetic acid, said compositions are provided in the form of stable injectable aqueous solutions ready for use. A composition according to one embodiment of the present invention may be contained in a pocket or bag.

Description

Ready-to-use pharmaceutical composition

The present invention relates to pharmaceutical compositions for the parenteral administration of sotalol.

Prior art

Drug therapy for cardiac arrhythmias has undergone rapid changes over the last decade. Experimental studies have shown that drugs capable of suppressing ventricular arrhythmias increase the mortality rate especially in patients with heart disease.

Sotalol, or IM- [4- [I-hydroxy-2 - [(1-methylethyl) amino] ethyl] phenyl] methanesulfonamide, has emerged as one of the drugs of choice for its antiarrhythmic and beta-blocking activity, because it reduces mortality by preventing ventricular fibrillation in patients with heart disease. It has been shown that in patients with ventricular tachycardia (VT) and ventricular fibrillation (VF), sotalol with class III anti-arrhythmic anti-arrhythmic activity, is better than six other class I anti-arrhythmic drugs (N Engl J Med 1993; 329: 452-8).

Sotalol in solution is marketed in ampoules. When used, the practitioner must dissolve and / or transfer the solution from the ampoules to a suitable administration device. This step increases the risk of contamination as well as the time of operation, disadvantages to avoid especially in case of emergency. The object of the invention is to provide a solution to the problems described above. One of the objectives of the invention is to provide pharmaceutical compositions for the parenteral administration of sotalol. Said compositions are ready for use. SUMMARY OF THE INVENTION The invention provides pre-mixed pharmaceutical compositions ready for use. The compositions are adapted for continuous intravenous infusion and include sotalol or its pharmaceutically acceptable salts.

In a first aspect, the invention provides pharmaceutical compositions for parenteral administration comprising sotalol, at least one buffer comprising sodium acetate and acetic acid, said compositions are in the form of stable injectable aqueous solutions ready to work.

In a second aspect, the invention provides a pouch comprising a pharmaceutical composition as described by the present invention. Said pocket is preferably formed by a material free of polar polymers. The invention also provides a vial comprising a pharmaceutical composition as described by the present invention.

In a third aspect, the invention provides the use of said pocket for parenteral administration of sotalol.

The compositions of the invention are in the form of injectable aqueous solutions ready for use. Said solutions have a buffered pH which makes the compositions stable at room temperature for at least six months, preferably at least one year.

The other advantages of the ready-to-use compositions of the invention are the convenience and ease of use compared to the same compositions provided in ampoules, improving patient safety by eliminating dosage errors. and the contamination of solutions, the reduction of medical waste, and the ease of administration in emergency situations.

Description The invention relates to pre-mixed pharmaceutical compositions ready for use. The compositions are adapted for continuous intravenous infusion and include sotalol or its pharmaceutically acceptable salts.

As used herein, the term "about" refers to a measurable value such as a parameter, a quantity, a time duration, and the like, and is intended to encompass variations of +/- 20% or less, of preferably of +/- 10% or less, more preferably of +/- 5% or less, still more preferably of +/- 1% or less, and still more preferably +/- 0.1% or less of and from the specified value, insofar as such variations are appropriate for carrying out the disclosed invention. The value to which the "about" modifier refers is itself also specifically disclosed.

The terms "the compositions" and "the composition" are used as synonyms and refer to a pharmaceutical composition according to one embodiment of the invention.

The terms "bag" and "bag" are used as synonyms and refer to a container that may contain a pharmaceutical composition according to one embodiment of the invention.

In a first aspect, the invention provides pharmaceutical compositions for parenteral administration comprising sotalol, at least one buffer and acetic acid. The compositions are in the form of stable injectable aqueous solutions ready for use. In a preferred embodiment, the amount of sotalol or its pharmaceutically acceptable salts is between 50 and 200 mg, preferably between 75 and 150 mg, more preferably between 100 and 120 mg, more preferably between 112 and 120 mg .

In a preferred embodiment, the volume of the buffer is between 5 and 20 ml, preferably between 10 and 15 ml. The buffer may be chosen from salts and acids or acetate, sodium acetate, glutamate, citrate, tartrate, benzoate, lactate, histidine or other amino acids, gluconate, phosphate, malate, succinate, formate, propionate, carbonate or any mixture thereof. Preferably, the buffer is sodium acetate.

In a preferred embodiment, the amount of acetic acid is between 1 and 5 mg / ml of buffer, preferably between 2 and 4 mg / ml of buffer, more preferably between 2.5 and 3 mg / ml of buffer, still more preferably about 2.9 mg / ml buffer.

In a preferred embodiment, the concentration of sotalol in the final composition is between 10 mg / ml and 25 mg / ml, preferably between 12 mg / ml and 20 mg / ml, more preferably between 14 mg / ml and 18 mg / ml. Preferably, the concentration of sotalol in the final composition is about 15 mg / ml.

In a preferred embodiment, the pH of the composition is between 5 and 8, preferably between 6 and 7. The pH of the composition can be adjusted using at least one pH adjuster. Said pH adjuster typically comprises at least one acid or salt thereof and / or a base or a salt thereof. The acids include, but are not limited to, hydrochloric acid, phosphoric acid, citric acid, ascorbic acid, acetic acid, sulfuric acid, carbonic acid and nitric acid . The bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium citrate, sodium acetate and magnesium hydroxide .

In a preferred embodiment, the composition comprises at least one antimicrobial preservative which comprises one or more substances selected from esters or salts of p-hydroxybenzoic acid, benzyl alcohol, mercurial compounds such as sodium mercurothiolate , chlorobutanol, phenol or its derivatives or any mixture thereof.

In one embodiment, the composition comprises one or more tonicity agents. Typically, tonicity agents are used to adjust the osmolarity of the premixed pharmaceutical compositions to bring them closer to the osmotic pressure of body fluids such as blood or plasma. The tonicity agent may be chosen from the group comprising anhydrous or hydrated forms or sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride, other inorganic salts or any mixture thereof. Preferably, the amount of tonicity present in the composition is from about 1 mg / ml to about 90 mg / ml. The composition may comprise between 1 and 5 mg / ml, between 5 and 10 mg / ml, between 10 and 15 mg / ml, between 15 and 25 mg / ml, between 25 and 50 mg / ml, between 50 and 60 mg / ml. ml, between 60 and 70 mg / ml, between 70 and 80 mg / ml, and between 80 and 90 mg / ml of tonicity agent.

In some embodiments, the tonicity agent is dextrose. The concentration of dextrose is 2.5% (which is equivalent to about 25 mg / ml), 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6 , 5% or 7%, as well as combinations of the ranges above.

In some embodiments, the tonicity agent is sodium chloride. The concentration of sodium chloride is about 0.1% (equivalent to 1 mg / ml), 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0, 7%, 0.8%, 0.9%, 1%, 1.2%, 1.4%, 1.6% or about 1.8%.

In a preferred embodiment, the pharmaceutical composition of the invention comprises one or more co-solvents. A "co-solvent" is a solvent which is added to the aqueous composition and which can help solubilize sotalol and / or a pharmaceutically acceptable salt thereof and / or improve the stability of the formulation. Said cosolvents include, but are not limited to, glycols (eg, polyethylene glycol, propylene glycol), ethanol, and polyhydric alcohols (eg, sorbitol, mannitol, xylitol) or any mixture thereof. them.

In a preferred embodiment, the method of preparing a premixed and suitable sotalol composition for intravenous administration comprises the steps of providing an effective amount of sotalol in a solution comprising one or more tonicity agents and / or a buffer and / or or one or more co-solvents. Sufficient water is added to reach a predetermined final volume. If necessary, the pH of the solution can be adjusted using at least one suitable pH adjusting agent. The compositions are dispensed into pharmaceutically acceptable bags or pouches for storage and direct delivery of the compositions to patients. The order in which the various components of the composition are added to the buffered solution is not critical, provided that the compositions obtained are stable and are suitable for intravenous infusion. Accordingly, the compositions described above can be prepared in a variety of ways. For example, in some embodiments, the compositions may be prepared by adding to a buffer of acetic acid, optionally a tonicity agent and / or a co-solvent; an adequate amount of sotalol; a pH regulator to achieve the desired pH; and water in sufficient quantity to reach a predetermined final volume. If necessary, the pH can be readjusted after the addition of water to reach the desired pH. As another example, the compositions may be prepared by adding buffer and sotalol or a pharmaceutically acceptable salt thereof to water; optionally adding a tonicity and / or co-solvent, adjusting the pH to reach the desired pH; and adding enough water to reach a predetermined final volume. Preferably, the predetermined final volume is between 5 and 25 ml, preferably between 8 and 20 ml, more preferably between 10 and 15 ml.

The pharmaceutical composition of the invention may be packaged in a variety of containers. Preferably, said composition is packaged in a pharmaceutically acceptable container such as a bag, an intravenous bag or bottle. Intravenous bags are well known to those skilled in the art and are commercially available.

In a second aspect, the invention provides a pouch comprising a pharmaceutical composition according to one embodiment of the invention. Preferably, said pocket is formed of a material free of polar polymers such as polyvinyl chloride and ethylene vinyl acetate. The invention also provides a vial comprising a pharmaceutical composition as described by the present invention. The bottle may be glass or plastic or any other material known to those skilled in the art. The total volume of the flask is between 5 and 20 ml, preferably between 8 and 15 ml, more preferably about 10 ml.

The compositions according to one embodiment of the invention are filled in bags or bags adapted. The filling procedures are known to those skilled in the art and may be selected from the following procedures: wet heat sterilization, ethylene oxide sterilization, radiation sterilization (gamma and electron beam) or any another procedure.

The ready-to-use pharmaceutical compositions according to one embodiment of the present invention exhibit a 0% to 15% decrease in drug concentration, and 0% to 3% impurity formation when the composition is maintained at room temperature. for at least 6 to 24 months. Typically, the pharmaceutical composition is stable when maintained at room temperature for at least 6 months, at least 12 months, at least 18 months, and at least 24 months. The composition is stable over even longer periods when maintained at temperatures of about 2 ° to 8 ° C. The term "stable" as used herein means to remain in a state suitable for administration to a patient. Said stability of the ready-to-use composition of the invention is achieved by selecting a pharmaceutically compatible container or pouch. The optimization of the pH of the composition as well as the concentration of sotalol also contribute to the stability of the final composition.

The pharmaceutical compositions of the invention do not require any dilution prior to administration. The compositions may be administered parenterally, including subcutaneously, intramuscularly, intravenously, intra-aurally, or by continuous intra-arterial infusion to a patient.

Examples:

Example 1

Pharmaceutical composition comprising: - Sotalol: 150 mg, - Sodium acetate as buffer: 10 ml, - Acetic acid: 2.9 mg / ml buffer, - pH between 6 and 7.

Example 2

Pharmaceutical composition comprising: - sotalol: 75 mg, - sodium acetate as buffer: 10 ml, - acetic acid: 2.9 mg / ml buffer, - pH between 6 and 7.

Example 3

Pharmaceutical composition comprising: - sotalol: 112.5 mg, - sodium acetate as buffer: 10 ml, - acetic acid: 2.9 mg / ml buffer, - pH between 6 and 7.

Each of the compositions shown in Examples 1, 2 and 3 is filled in a pouch as described above. The filling procedure was carried out under sterile conditions.

The embodiment described in the foregoing is an example given for illustrative purposes and the invention is not limited to this example. Any modification, variation or equivalent arrangement should be considered as part of the invention.

Claims (12)

Amended Claims - Amendments Accepted A pharmaceutical composition for parenteral administration comprising sotalol, at least one buffer comprising sodium acetate and acetic acid, said composition is in the form of a stable injectable aqueous solution ready for use having a pH between 5 and 8. 2. Pharmaceutical composition according to claim 1 wherein the amount of sotalol is between 50 and 200 mg, preferably between 75 and 150 mg, more preferably between 100 and 120 mg. 3. Pharmaceutical composition according to any one of claims 1-2 wherein the volume of the buffer is between 5 and 20 ml, preferably between 10 and 15 ml. 4. Pharmaceutical composition according to any one of claims 1-3 wherein the amount of acetic acid is between 1 and 5 mg / ml buffer, preferably between 2 and 4 mg / ml buffer, more preferably between 2.5 and 3 mg / ml buffer, more preferably about 2.9 mg / ml buffer. Pharmaceutical composition according to any one of claims 1-4 wherein the concentration of sotalol is between 10 mg / ml and 25 mg / ml, preferably between 12 mg / ml and 20 mg / ml, more preferably between 14 mg / ml and 18 mg / ml. The pharmaceutical composition according to any one of claims 1-5 wherein the concentration of sotalol is about 15 mg / ml. Pharmaceutical composition according to any one of claims 1-6 having a pH of between 6 and 7. 8. Pharmaceutical composition according to any one of claims 1-7, comprising at least one pH adjuster selected from the group consisting of hydrochloric acid, sodium hydroxide or a mixture thereof. 9. Composition according to any one of claims 1 to 8, comprising at least one antimicrobial preservative which comprises one or more substances selected from esters or salts of p-hydroxybenzoic acid, benzyl alcohol, mercurial compounds. such as sodium mercurothiolate, chlorobutanol and / or phenol or its derivatives. A pouch comprising a pharmaceutical composition according to any one of claims 1-9. The pouch of claim 10 formed of a material free of polar polymers. 12. Vial comprising a pharmaceutical composition according to any one of claims 1-9.