BE1021320B1 - PHARMACEUTICAL COMPOSITION READY FOR USE - Google Patents

Abstract

The invention provides a pharmaceutical composition in the form of a ready-to-use, stable injectable aqueous solution comprising sotalol, acetic acid and at least one buffer comprising sodium acetate, wherein the pH of said composition is between 5 and 8.

Description

Ready-to-use pharmaceutical composition Field of the invention

The present invention relates to pharmaceutical compositions comprising an antiarrhythmic agent. In particular, the present invention relates to pharmaceutical compositions comprising sotalol.

Prior art

Medication treatment of cardiac arrhythmias has evolved rapidly over the last decade. Experimental studies have shown that drugs that act by delaying conduction but are able to suppress ventricular arrhythmias, increase the mortality rate especially in patients with heart disease.

Drugs such as flecainide, encainide and morizicin, which act by blocking sodium channels, have been shown to cause increased mortality in patients who have survived acute myocardial infarction, despite the clear suppression of premature ventricular contractions. Drugs such as quinidine, which has been used for a long time in antiarrhythmic therapy, increase mortality in a variety of settings. Amiodarone, an anti-arrhythmic agent that works by increasing cardiac repolarization time, is better than those that act by blocking sodium channels.

Suppression of arrhythmia does not necessarily decrease mortality. In addition, the most important determinant of arrhythmia mortality is the nature and degree of ventricular dysfunction. All of these factors lead to dramatic changes in the choice of anti-arrhythmic drugs for ventricular and supraventricular arrhythmias.

Sotalol, IM- {4- [1-hydroxy-2- (isopropylamino) ethyl] phenyl} methane sulfonamide, is emerging as one of the drugs of choice for its beta-blocking and anti-arrhythmic activity because it could reduce mortality in preventing ventricular fibrillation in patients with heart disease. Mason of ESVEM Investigators (N Engl J Med 1993; 329: 452-8) has shown that in patients with ventricular tachycardia (VT) and ventricular fibrillation (VF), sotalol is a beta-blocker with class-leading anti-arrhythmic activity. III is better than six other class I anti-arrhythmic compounds. One of the objects of the invention is to remedy at least in part the problems described above. The invention aims to provide a pharmaceutical composition of sotalol ready for use. Another object of the invention is to provide a more effective ready-to-use sotalol pharmaceutical composition. Summary Described herein are ready-to-use premixed pharmaceutical compositions of sotalol or its pharmaceutically acceptable salts, which are suitable for continuous intravenous infusion.

The present invention provides a pharmaceutical composition in the form of a stable injectable aqueous solution ready for use. The composition comprises sotalol or its pharmaceutically acceptable salts, acetic acid and at least one buffer comprising sodium acetate. The pH of said composition is between 5 and 8. The invention further provides a bag and / or a vial comprising said pharmaceutical composition. The invention also provides the use of said pharmaceutical composition for parenteral administration.

By providing pre-mixed pharmaceutical compositions ready for use with a buffered pH, these pharmaceutical compositions are stable at room temperature for at least one year. When stored at room temperature, the pharmaceutical compositions show a decrease from 0% to about 15% of the drug concentration and a formation of from 0% to about 3% (wt%) of total impurities over a period of time. eighteen to twenty-four months.

The other advantages of ready-to-use injectable premixed pharmaceutical compositions include convenience and ease of use over a dilution formulation, such as a vial or vial, improving safety for patients through elimination of dosage errors and solution contamination, reduction of medical waste, and ease of administration in emergency situations.

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

Methods of making the pre-mixed sotalol compositions suitable for intravenous administration include the steps of providing an effective amount of sotalol in a suitable buffer and optionally adding one or more tonicity agents. If necessary, the pH of the solution can be adjusted using a suitable pH adjusting agent. The compositions are dispensed in pharmaceutically acceptable containers for storage and direct delivery to patients.

detailed description

The premixed pharmaceutical compositions described herein include as the active ingredient sotalol or a pharmaceutically acceptable salt thereof. As used herein, the term "premixed" refers to a pharmaceutical composition that does not require reconstitution or dilution prior to administration to a patient. Unlike formulations (in ampoules or flasks) including sotalol which must be diluted before use in a diluent and a container or container selected by hospital staff, the pre-mixed ready-to-use pharmaceutical compositions provided above are stable at room temperature for 6 months or longer thanks to the integration of a buffer able to maintain the pH in an optimal pH range. Adjusters and / or co-solvents of suitable pH may be added to the pharmaceutical compositions.

Unless otherwise indicated, all terms used in the disclosure of the invention, including technical and scientific terms, have the meaning commonly understood by those skilled in the art to which this invention belongs. Through further information, definitions of terms are included to better appreciate the teaching of the present invention.

As used herein, the following terms have the following meanings: "One," "an," and "the," "," as used herein, refer to both singular and plural referents unless the context clearly indicates the opposite. For example, a "compartment" refers to one or more compartments. "Approximate" as used herein, referring to a measurable value such as a parameter, a quantity, a time duration, and the like, is intended to encompass variants of +/- 20% or less, preferably + / -10% or less, more preferably of +/- 5% or less, still more preferably +/- 1% or less, and still more preferably +/- 0.1% or less of and from the value specified, to the extent that such variations are appropriate for carrying out the disclosed invention. However, it should be understood that the value to which the "about" modifier refers is itself also specifically disclosed. "Understand", "understand" and "understand" and "include", as used herein, are synonymous with "include", "include", "include", "contain", "container", or "contains" and are inclusive or unlimited terms that specify the presence of the following, for example component and do not prohibit or exclude the presence of components, features, elements, members, steps, known in Tartou described therein, additional, not recited.

The recitation of numeric ranges or ranges by endpoints includes all the numbers and fractions encompassed in this range, as well as the recited endpoints. The term "% by weight" (percent by weight) herein and throughout the specification, unless otherwise indicated, refers to the relative weight of the respective component based on the total weight of the formulation.

The pharmaceutical composition provided by the invention is in the form of a stable injectable aqueous solution ready for use. The composition comprises sotalol, acetic acid and at least one buffer comprising sodium acetate. The pH of said composition is between 5 and 8.

In a preferred embodiment, the pH of said pharmaceutical composition is at least 5.1, at least 5.2, at least 5.3, at least 5.4, at least 5.5, at least 5.6, at least 5.7, at least 5.8, at least 6. The pH of said composition is not more than 7.9, not more than 7.8, not more than 7.7, not more than 7.6, not more than 7, 5, at most 7.4, at most 7.3, at most 7.2, at most 7.1, at most 7. The pH of the pharmaceutical composition may be between any of the values mentioned.

In a preferred embodiment, the premixed pharmaceutical compositions comprise at least one pH adjuster. Suitable pH adjusters typically include at least one acid or salt thereof, and / or a base or salt thereof. The acids and bases can be added on a base as needed to achieve a desired pH. For example, if the pH is above the desired pH, an acid can be used to lower the pH to the desired pH. Acids suitable for use in premixed pharmaceutical compositions include, but are not limited to, hydrochloric acid, phosphoric acid, citric acid, ascorbic acid, acetic acid, sulfuric acid, lactic acid and the like. carbonic acid and nitric acid. In some embodiments, hydrochloric acid is used to adjust the pH. As another example, if the pH is below the desired pH, a base can be used to adjust the pH to the desired pH. Bases suitable for use in premixed pharmaceutical compositions include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium citrate sodium acetate and magnesium hydroxide. In some embodiments, sodium hydroxide is used to adjust the pH.

The inventors have discovered that the pH, the concentration of the active ingredient and the composition of the container material affect the stability of the active ingredient and the formation of impurities. Thus, the development of a ready-to-use stable premixed pharmaceutical composition requires simultaneous optimization of pH and sotalol concentration, as well as the selection of a pharmaceutically compatible container. The ready-to-use pharmaceutical compositions described herein show a 0% to 15% decrease in drug concentration and 0% to 3% reduction in impurity formation when maintained at room temperature for 6 to at least 24 months . Typically, the pharmaceutical compositions are 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 compositions are also stable over extended periods of time when maintained at temperatures of about 2 ° C to 8 ° C. The term "stable" as used herein means to remain in a condition or condition that is appropriate for administration to a patient.

In a preferred embodiment, the premixed pharmaceutical compositions further comprise one or more tonicity agents. Tonicity agents are used to adjust the osmolarity of the premixed pharmaceutical compositions to bring it closer to the osmotic pressure of body fluids such as blood or plasma. Suitable tonicity agents include, but are not limited to, anhydrous or hydrated forms of sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium and other inorganic salts.

The amount of tonicity agent in the formulation can be expressed as mg / ml or g / L. In typical embodiments, the tonicity agent (s) is present from about 1 mg / ml to about 90 mg / ml. Thus, the premixed pharmaceutical compositions may comprise one or more tonicity agents at about 1-5 mg / ml, at about 5-10 mg / ml, at about 10-15 mg / ml, at about 15-25 mg / ml. ml, at about 25-50 mg / ml, at about 50-60 mg / ml, at about 60-70 mg / ml, at about 70-80 mg / ml, and at about 80 to 90 mg / ml, as well as combinations of the ranges above.

Alternatively, the tonicity agent concentration is measured in percent weight / volume. In typical embodiments, the tonicity agent (s) is present from about 0.1% to about 10%. For example, the appropriate tonicity agent concentrations include, but are not limited to, from about 0.1% to about 0.2%, from about 0.2% to about 0.3%, and from about 0.3% to about 0.4%, from about 0.4% to about 0.5%, from about 0.5% to about 0.6%, from about 0.6% to about 0%. , 7%, from about 0.7% to about 0.8%, from about 0.8% to about 0.9%, from about 0.9% to about 1%, from about 1% to about about 2%, about 2% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 7%, about 7% to about 8%, about 8% to about 9%, and about 9% to about 10%, as well as combinations of the above ranges.

In a preferred embodiment, the tonicity agent is a dextrose solution. Typically, the dextrose solutions suitable for use in the premixed pharmaceutical compositions are from about 2.5% to about 7.5% dextrose solutions. Suitable dextrose solutions include, but are not limited to, from about 2.5% to about 3%, from about 3% to about 3.5%, from about 3.5% to about 4%, from about 4% to about 4.5%, from about 4.5% to about 5%, from about 5% to about 5.5%, from about 5.5% to about 6%, about 6% to about 6.5%, from about 6.5% to about 7% dextrose solutions, as well as combinations of the above ranges.

In a preferred embodiment, the premixed pharmaceutical compositions comprise two, three, four, or more tonicity agents. In these embodiments, the concentration of each tonicity agent is generally less than the concentration that is used when only a single agent is present in the premixed formulation.

In a preferred embodiment, the pharmaceutical composition comprises a saline solution, a dextrose solution, a water solution or any combination thereof. Preferably, the pharmaceutical composition comprises a saline solution. Said saline solution has a minor risk of affecting other diseases of the patient such as diabetes.

In a preferred embodiment, said saline solution, dextrose solution, water solution or any combination thereof, is added so as to achieve the desired final volume of the pharmaceutical composition. Preferably, said final volume is at least 50 ml, preferably at least 60 ml, more preferably at least 80 ml, still more preferably at least 100 ml. Said final volume is at most 300 ml, preferably at most 250 ml, more preferably at most 220 ml, still more preferably at most 200 ml.

In a preferred embodiment, the premixed pharmaceutical formulation comprises a buffer that has sufficient buffering capacity to maintain the desired pH range throughout the shelf life of the product. Buffers suitable for use in the pharmaceutical compositions described herein include, but are not limited to, pharmaceutically acceptable salts and acids of acetate, glutamate, citrate, tartrate, benzoate, lactate, histidine or other amino acids, gluconate, phosphate, malate, succinate, formate, propionate, carbonate or any combination thereof. Preferably, the buffer comprises sodium acetate. "Pharmaceutically acceptable" is used herein in the sense and means to be compatible with the other ingredients of the formulation without being harmful to the recipient thereof. Accordingly, the term "pharmaceutically acceptable salt" refers to the salt forms of the active compounds that are prepared with counterions that are non-toxic under the conditions of use and are compatible with a stable formulation. The concentration of the buffer in the formulation can be expressed in mg / ml, g / L or as a molar concentration. In typical embodiments, from about 0.0001 mg / ml to about 100 mg / ml of a suitable buffer is present in the pharmaceutical compositions. Thus, the premixed pharmaceutical compositions may comprise from about 0.0001 to about 0.001 mg / ml of a suitable buffer, from about 0.001 to about 0.01 mg / ml of a suitable buffer, from about 0 0.1 to about 0.1 mg / ml of a suitable buffer, about 0.1 to 1 mg / ml of a suitable buffer, about 1 to about 5 mg / ml of an appropriate buffer, from about 5 to about 10 mg / ml of a suitable buffer, from about 10 to about 15 mg / ml of a suitable buffer, from about 15 to about 20 mg / ml of a suitable buffer, from about To about 25 mg / ml of a suitable buffer, from about 25 to about 50 mg / ml of a suitable buffer, from about 50 to about 75 mg / ml of a suitable buffer, and about 75 to about 50 mg / ml of a suitable buffer; at about 100 mg / ml of a suitable buffer.

Alternatively, the concentration of the buffer can be expressed as molar concentrations. In typical embodiments, about 0.1 to 100 mM of a suitable buffer is present in the pharmaceutical compositions. Thus, the premixed pharmaceutical compositions may comprise an appropriate buffer having a concentration of from about 0.1 to about 100 mM, from about 0.1 to about 0.5 mM, from about 0.5 to about 1, 0 mM, from about 1.0 to about 5 mM, from about 5 to about 10 mM, from about 10 to about 15 mM, from about 15 to about 25 mM, from about 25 to about 50 mM, from about 50 to about 75 mM, and from about 75 to about 100 mM.

In a preferred embodiment, the amount of acetic acid is between 0.04 and 1 mg / ml of buffer, preferably between 0.06 and 0.8 mg / ml of buffer, more preferably between 0.08 and 0.08. and 0.6 mg / ml buffer, still more preferably between 0.1 and 0.4 mg / ml buffer, still more preferably between 0.12 and 0.3 mg / ml buffer. Preferably, the amount of acetic acid is about 0.29 mg / ml buffer.

In a preferred embodiment, the final concentration of sotalol of the pharmaceutical composition is between 0.75 and 4 mg / ml, preferably between 1 and 3.5 mg / ml, more preferably between 1.2 and 3 mg / ml, more preferably between 1.4 and 2.5 mg / ml, still more preferably between 1.8 and 2 mg / ml. Preferably, the final concentration of sotalol is about 1.5 mg / ml.

The premixed pharmaceutical compositions may further comprise one or more co-solvents. A "co-solvent" is a solvent which is added to the aqueous formulation in an amount by weight which is less than that of water and aids solubilization of sotalol and / or a pharmaceutically acceptable salt thereof, improves the stability of the premixed formulation and / or adjusts the osmolarity of the premixed pharmaceutical compositions. Co-solvents suitable for use in the premixed pharmaceutical compositions include, but are not limited to, glycols (eg, polyethylene glycol, propylene glycol), ethanol, and polyhydric alcohols (eg, sorbitol) , mannitol, xylitol).

The amount of co-solvent used in the formulation may be expressed in mg / ml or g / L. In typical embodiments, the cosolvent (s) is present from about 1 mg / ml to about 100 mg / ml. Thus, the premixed pharmaceutical compositions may comprise one or more cosolvent (s) at about 1 to about 2 mg / ml, at about 2 to about 3 mg / ml, at about 3 to about 4 mg / ml, at about 4 at about 5 mg / ml, at about 5 to about 10 mg / ml, at about 10 to about 15 mg / ml, at about 15 to about 25 mg / ml, at about 25 to about 50 mg / ml, at about 50 at about 60 mg / ml, at about 60 to about 70 mg / ml, at about 70 to about 80 mg / ml, at about 80 to 90 mg / ml, and at about 90 to 100 mg / ml, and combination of the ranges above.

In a preferred embodiment, the pharmaceutical 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 and / or phenol or its derivatives. The order in which the various components of the compositions are added to the buffered solution is not critical, provided that the resulting compositions are stable and are suitable for continuous intravenous infusion. Dextrose and / or saline, however, must be the last component to be added in order to achieve the desired final volume of the composition. Preferably, said final volume is at least 50 ml, preferably at least 60 ml, more preferably at least 80 ml, still more preferably at least 100 ml. Said final volume is at most 300 ml, preferably at most 250 ml, more preferably at most 220 ml, still more preferably at most 200 ml. If necessary, the pH can be adjusted to reach the desired pH range.

The pharmaceutical compositions can be packaged for use in a variety of containers. Preferably, the compositions are packaged in a pharmaceutically acceptable container, such as bags, bottles, vials, intravenous syringes. The intravenous bags and syringes are preferably polymer based while the intravenous bottles and bottles are preferably glass. It is also preferable that the container components that come into contact with the pharmaceutical composition do not contain polyvinyl chloride (PVC). The most preferred container is an intravenous bag which has no PVC-containing components in contact with the pharmaceutical composition. It is also desirable to protect the pharmaceutical compositions from light. Therefore, the container may optionally further comprise a light barrier. A preferred light barrier is an overpack or an aluminum packaging pocket.

In a preferred embodiment, the premixed pharmaceutical compositions are dispensed into intravenous bags, such as premix bags and admix bags. Intravenous bags are well known in the art and commercially available. Examples of intravenous bags include, but are not limited to: GALAXY (R), INTRAVIA (R), SOLOMIX (R), STEDIM (R) 71, STEDIM (R) 100, VIAFLEX (R), EXCEL (R) , VISIV (R), VIAFLO (TM), ADDEASE (R), ADD-VANTAGE (R), DUPLEX (TM), FIRST CHOICE (TM), PROPYFLEX (TM) and B FS (TM).

In a preferred embodiment, the components of the bag that come into contact with the pharmaceutical compositions should not contain polar polymers such as polyvinyl chloride (PVC) and ethylene vinyl acetate (EVA). Examples of bags that do not contain the polar polymers and, therefore, are preferred for use include, but are not limited to, GALAXY (R), EXCEL (R), VISIV (R), and VIAFLO (TM) .

Procedures for filling pharmaceutical compositions into pharmaceutically acceptable containers, and their subsequent processing, are known in the art. These procedures can be used to produce sterile drug and / or pharmaceutical products often required for health care. See, for example, the Center for Drug Evaluation and Research (CDER) and Center for Veterinary Medicine (CVM), "Guidance for Industry for the Submission of Documentation for Sterilization Process Validation in Human Drug Applications", (November 1994) . Examples of suitable procedures for the production of sterile pharmaceutical drug products include, but are not limited to, wet heat end-point sterilization, ethylene oxide, radiation (e.g., gamma and electron beam) , and aseptic processing techniques. Any of these sterilization procedures can be used to produce sterile pharmaceutical compositions described herein.

In a preferred embodiment, the sterile pharmaceutical compositions can be prepared using aseptic processing techniques. Sterility is maintained using sterile equipment and a controlled work environment. All containers and apparatus are sterilized, preferably by heat sterilization, prior to filling. Then, the container is filled under aseptic conditions, for example by passing the composition through a filter and filling the units. Therefore, the compositions can be filled in a container in a sterile manner to avoid the heat stress of the terminal sterilization.

In some embodiments, the compositions are sterilized by wet heat. Terminal sterilization can be used to destroy all viable microorganisms within the sealed final container and containing the pharmaceutical composition. An autoclave is generally used to carry out terminal heat sterilization of medicinal products in their final packaging. Typical autoclaving cycles in the pharmaceutical industry for terminal sterilization of the final product are 121 ° C for at least 10 minutes. The invention further provides a bag comprising a pharmaceutical composition according to any embodiment of the invention. Preferably, said bag is as described above. The bag comprising the composition is preferably a disposable bag. The invention further provides a vial comprising a pharmaceutical composition according to any embodiment of the invention. Preferably, said flask is as described above. The vial comprising the composition is preferably a disposable vial. The invention further provides the use of a pharmaceutical composition according to any one embodiment of the invention for parenteral administration to a patient.

Although the present invention has been described with reference to the preferred embodiments thereof, many modifications and changes can be made by one skilled in the art without departing from the scope of the present invention which is defined by the claims. attached.

Claims (14)

claims A pharmaceutical composition in the form of a stable, injectable and ready-to-use aqueous solution comprising sotalol, acetic acid and at least one buffer comprising sodium acetate, wherein the pH of said composition is included between 5 and 8. The pharmaceutical composition according to claim 1 wherein the pH of said composition is at least 5.2, preferably at least 5.4, more preferably at least 5.6, still more preferably at least 5.8, further more preferably at least 6. 3. The pharmaceutical composition as claimed in any one of the preceding claims, in which the pH of said composition is at most 7.8, preferably at most 7.6, more preferably at most 7.4, still more preferably at most 7.4. , 2, even more preferably at most 7. The pharmaceutical composition according to any one of the preceding claims, further comprising a dextrose solution, a saline solution, a water solution or any combination thereof. A pharmaceutical composition according to any one of the preceding claims wherein the volume of said saline solution, dextrose solution, water solution or any combination thereof is added so as to achieve a desired final volume. which is at least 50 ml, preferably at least 60 ml, more preferably at least 80 ml, still more preferably at least 100 ml. The pharmaceutical composition according to any one of the preceding claims wherein said final volume is at most 300 ml, preferably at most 250 ml, more preferably at most 220 ml, still more preferably at most 200 ml. The pharmaceutical composition of any one of the preceding claims wherein said dextrose solution is a 5% dextrose solution. 8. The pharmaceutical composition as claimed in any one of the preceding claims, in which the amount of acetic acid is between 0.04 and 1 mg / ml of buffer, preferably between 0.06 and 0.8 mg / ml of buffer, still more preferably between 0.08 and 0.6 mg / ml of buffer, still more preferably between 0.1 and 0.4 mg / ml of buffer, still more preferably between 0.12 and 0.3 mg / ml of buffer. A pharmaceutical composition according to any one of the preceding claims, wherein the final concentration of sotalol is between 0.75 and 4 mg / ml, preferably between 1 and 3.5 mg / ml, more preferably between 1, 2 and 3 mg / ml, more preferably between 1.4 and 2.5 mg / ml, even more preferably between 1.8 and 2 mg / ml. The pharmaceutical composition according to any one of the preceding claims, comprising at least one pH adjuster selected from the group consisting of hydrochloric acid, sodium hydroxide or a mixture thereof. 11. Pharmaceutical composition according to any one of the preceding claims, 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: as sodium mercurothiolate, chlorobutanol and / or phenol or its derivatives. 12. Bag comprising a pharmaceutical composition according to any one of claims 1 to 11. 13. Bottle comprising a pharmaceutical composition according to any one of claims 1 to 11. 14. Use of a composition according to any one of claims 1 to 11 for parenteral administration.