WO2020025986A1

WO2020025986A1 - Injectable combination of diclofenac sodium and thiocolchicoside

Info

Publication number: WO2020025986A1
Application number: PCT/GR2019/000053
Authority: WO
Inventors: Marios KOSMIDIS; Spyridon MAVROKORDOPOULOS
Original assignee: Win Medica Pharmaceutical S.A.; Pharmaplot Private Company
Priority date: 2018-08-02
Filing date: 2019-07-31
Publication date: 2020-02-06
Also published as: GR1009729B; ZA202003508B; GR20180100359A

Abstract

The present invention relates to stable injectable solutions comprising diclofenac sodium and thiocolchicoside as active ingredients and a liquid carrier comprising propylene glycol, benzyl alcohol and a polydentate ligand. The solutions may be stored for a prolonged period of time in a wide range of temperatures, without sedimentation of the active ingredients and / or chemical degradation thereof.

Description

INJECTABLE COMBINATION OF DICLOFENAC SODIUM AND

THIOCOLCHICOSIDE

TECHNICAL FIELD

The present invention relates to pharmaceutical solutions for parenteral injectable administration which include diclofenac sodium and thiocolchicoside. The injectable solutions of the present invention can be administered intramuscularly for the treatment of acute musculoskeletal pain.

BACKGROUND OF THE INVENTION

Diclofenac is a non-steroidal anti-inflammatory active pharmaceutical ingredient with proven anti-inflammatory and analgesic properties.

Diclofenac is poorly soluble in water, and thus for the preparation of pharmaceutical solutions the sodium salt, i.e. diclofenac sodium is used (Chemical Formula I), which ensures better water solubility.

Chemical Formula I

Thiocolchicoside (Chemical Formula II) is a semi-synthetic sulfate derivative of colchicoside and presents muscle relaxant pharmacological activity. Muscle relaxants represent one of the many treatments currently used to manage undifferentiated back pain. Thiocolchicoside is indicated for the treatment of painful muscle spasm in various cases. It is widely prescribed in many Member States of the European Union, and the benefits of thiocolchicoside-containing medicinal products are already recognized in clinical practice. Beyond the relaxing, it also has anti-inflammatory, analgesic action that helps alleviating painful muscle spasms.

Chemical Formula II

The injectable sodium diclofenac preparation as well as the injectable thiocolchicoside preparation as monotherapies have the therapeutic advantage of almost immediate bioavailability and very rapid patient relief compared to the oral administration.

Sodium diclofenac injectable medicinal products are commercially available in many countries.

For example, Voltarol^® and Voltaren^® injectable solutions in ampoules are marketed in the United Kingdom and in Greece, respectively, by Novartis Pharmaceuticals. These products contain 75 mg of diclofenac sodium per 3 ml of solution. Mannitol, sodium metabisulfite, benzyl alcohol, propylene glycol, sodium hydroxide and water for injection, are also included as excipients. Injectable thiocolchicoside pharmaceutical solutions are also commercially available in many countries.

An example of a commercially available product is Muscoril^® solution for injection that is marketed in Greece by Sanofi Aventis. Muscoril^® contains 4 mg of thiocolchicoside per 2 ml of solution. It also contains sodium chloride and water for injections as excipients.

Although there are no published data for the Greek population, combined intramuscular administration of diclofenac sodium and thiocolchicoside for the treatment of back pain seems to be a widespread practice in Primary Health Care with very good results in rapid and effective pain relief.

Considering that no diclofenac sodium and thiocolchicoside combination formulation is available, the patient should undergo two consecutive intramuscular injections or the healthcare professional would mix the two drugs into a syringe and then would administer it intramuscularly to the patient, which could cause unknown effects, as the compatibility and stability of the combined solution is not known.

The first practice causes additional discomfort to the patient and increases the risk of complications arising from the two consecutive intramuscular injections, requires more time for the medical/nursing staff to spend with the patient and more consumables are used, resulting in increased cost and environmental burden.

The latter practice of mixing the two solutions with the unknown compatibility and stability additionally involves the risk of infections as the procedure is not aseptic but also of the patient's discomfort due to the increased bolus intramuscular dose of the solution (5 ml).

Therefore, taking into account the above-mentioned concerns about the medical practices of combined administration of diclofenac sodium and thiocolchicoside monotherapies, the development of a stable, ready-to-use pharmaceutical solution for injection of the combination of diclofenac sodium and thiocolchicoside is definitely an existing need.

The prior art demonstrates that diclofenac sodium is a substance that is relatively unstable in solution and that therefore the liquid preparations of the said substance require the presence of a stabilizing agent.

Thiocolchicoside also presents stability problems when in solution. The chemical and physical compatibility of thiocolchicoside with other injectable drugs often associated with it, including anti-inflammatory agents, is described in Farmaco, 2002, 57 (1 ), 925- 930.

Therefore, it is challenging to develop stable injectable solutions of the combination of diclofenac sodium and thiocolchicoside since both active ingredients exhibit stability problems.

WO-A-2014/064030 describes a pharmaceutical composition in the form of an injectable aqueous solution comprising diclofenac sodium and thiocolchicoside as active ingredients and butylated hydroxyanisole as a stabilizer.

Butylated hydroxyanisole is used by the drug industry as an antioxidant, possessing also antimicrobial properties.

However, there is a dispute over the safety of butylated hydroxyanisole. The Food and Drug Administration (FDA) of the United States of America (USA) classifies this pharmaceutical excipient as GRAS - generally recognized as safe, which means that it is generally considered to be safe for its intended use in specific quantities. However, a subsequent review by an independent panel, although supporting the overall safety of the butylated hydroxyanisole, has come to the conclusion that "there are uncertainties that require further studies." [FDA/SCOGS-Report Number: 55^*/ ID Code: 25013-16-5]

Other health organizations have also expressed concerns about the safety of butylated hydroxyanisole. For example, the National Toxicology Program in the US has concluded, based on animal studies, that butylated hydroxyanisole "is reasonably expected to be a carcinogen to humans." [NTP/Report on Carcinogens, Fourteenth edition]

Thus, butylated hydroxyanisole in the United States of America is referred by the Science Center for the Public Interest as well as by a consumer groups as an additive to "be avoided".

Therefore, a technically greater challenge in the development of stable injectable solutions of the combination of diclofenac sodium and thiocolchicoside is the development of such solutions using excipients with minimum toxic activity at the lowest achievable concentrations without compromising the physicochemical stability of the respective formulations.

The present invention addresses the above problems known in the prior art by describing a combination injection solution of diclofenac sodium and thiocolchicoside, ready for use, which exhibits as little chemical modification as possible of the active ingredients, and a lower percentage of known and unknown impurities during the preparation and storage, including excipients with minimum toxic effects.

SUMMARY OF THE INVENTION

The present invention provides an injectable pharmaceutical solution comprising diclofenac sodium and thiocolchicoside as active ingredients. Advantageously, the present invention provides an injectable pharmaceutical solution comprising diclofenac sodium and thiocolchicoside which exhibits excellent physicochemical stability.

The injectable pharmaceutical solution according to the invention includes diclofenac sodium, thiocolchicoside and a liquid carrier comprising propylene glycol, benzyl alcohol and a polydentate ligand.

The diclofenac sodium and thiocolchicoside injectable solution according to the invention may also optionally contain further excipients commonly used in the preparation of parenteral pharmaceutical compositions, such as co-solvents, substances that make the solution isotonic with the blood and pH-adjusting agents.

The injectable solution of diclofenac sodium and thiocolchicoside according to the invention exhibits excellent physicochemical stability while allowing the use of excipients with minimum toxic activity at the lowest achievable concentrations without compromising the stability of the respective formulations.

The diclofenac sodium and thiocolchicidal sodium injectable solution of the present invention effectively addresses the dosing and administration problems of the individual active ingredients, helping to simplify the scheme and improve overall patient compliance.

The diclofenac sodium and thiocolchicoside solution for injection of the present invention can be administered intramuscularly to treat acute musculoskeletal pain as initial shortterm therapy or after per os treatment failure.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new physicochemically stable combination of diclofenac sodium and thiocolchicoside.

The present invention provides an injectable pharmaceutical solution comprising diclofenac sodium and thiocolchicoside as active ingredients in combination with a pharmaceutically acceptable liquid carrier.

According to the general chapters of the European Pharmacopoeia, the parenteral injectable formulations are sterile formulations containing one or more active ingredients intended for administration by injection into the body.

Parenteral formulations may require the use of excipients, for example to make the formulation isotonic with respect to blood, to adjust pH, to increase solubility or prevent chemical modification of the active ingredients.

Excipients are substances without pharmaceutical activity, which are added to the pharmaceuticals in order to improve their characteristics (staining, touch, odor, appearance, taste) or to assist in the better absorption, distribution, dissolution, stability and activity of the active ingredients .

The addition of excipients to the injectable solutions should be kept to a minimum. Where excipients are used, they should not adversely affect the stability, bioavailability, safety and efficacy of the active ingredients, or cause toxicity or undue local irritation. There should also be no incompatibility between any of the components of the solution for injection.

It has surprisingly been found that a combination of propylene glycol, benzyl alcohol and a polydentate compound as excipients at specific concentration ranges with simultaneous pH adjustment in the range of 7.0 to 8.5 leads to stable compositions of the combination of diclofenac sodium and thiocolchicoside. It is important that such compositions are not required to include additional excipients, such as ethanol, polyethylene glycol, ethyl lactate, sorbitol, tocopherol, sodium metabisulphite, propyl- fumaric acid ester, butylated hydroxyanisole and butylated hydroxytoluene which may raise additional safety issues and toxicity.

The injectable pharmaceutical solution of the present invention includes diclofenac sodium and thiocolchicoside as active ingredients, 100 mg / ml to 300 mg / ml propylene glycol, 10 mg / ml to 50 mg / ml benzyl alcohol, 0.05 mg / ml to 2 mg / ml polydentate ligand and water for injection, wherein the pH of the solution is 6.5 to 8.5.

Preferably, the concentration of propylene glycol in the solution of the present invention is 150 mg / ml to 250 mg / ml.

Preferably, the concentration of benzyl alcohol in the solution of the present invention is 20 mg / ml to 40 mg / ml.

Preferably, the concentration of the polydentate ligand in the solution of the present invention is 0.1 mg / ml to 0.5 mg / ml.

Preferably the pH of the solution of the present invention is 7.3 to 8.1.

Preferably, the polydentate ligand is selected from edetate (ethylenediaminetetraacetic), glutamate, histidine or malate. More preferably, the polydentate ligand is disodium edetate. Disodium edetate is the most well-known and most typical representative of a series of compounds, which are generally called aminopolycarboxylic acids and are characterized by an extremely intense ability to complex most metals. It is important that disodium edetate is considered a safe excipient, non-carcinogenic and generally non- toxic when used in quantities approved by international drug organizations. The diclofenac sodium and thiocolchicoside injectable solution according to the invention may also optionally contain additional excipients commonly used in the preparation of parenteral pharmaceutical compositions such as co-solvents, substances that make the solution isotonic with blood, and pH buffering agents.

Co-solvents which may be used in the present invention include, but are not limited to, glycerol, glucose, ethyl carbonate, dioxolanes and any combination thereof.

The substances making the solution isotonic with blood may include, but are not limited to, lactose, mannitol, dextrose, sodium chloride and sodium sulfate.

The pH-adjusting agents may include, but are not limited to, citrate buffers, glutamate buffers, lactate buffers, carbonate buffers, bicarbonate buffers, gluconate buffers, tris(hydroxymethyl)aminomethane (TRIS) buffer, acetic acid buffer, phosphate buffers, amino acids such as arginine, alanine, histidine, glycine, lysine, and corresponding salts or mixtures thereof.

Compared to the injectable solutions described in the prior art, the use of excipients is prevented which, when entering at relatively large amounts in the body, may raise patient safety and safety issues.

In a preferred embodiment of the invention, the injectable pharmaceutical solution according to the invention is free of ethanol, polyethylene glycol, ethyl lactate, sorbitol, tocopherol, sodium metabisulfite, propyl-gallic acid ester, butylated hydroxytoluene and butylated hydroxyanisole.

In a more preferred embodiment the injectable pharmaceutical solution is free of ethanol, polyethylene glycol, ethyl lactate and butylated hydroxyanisole. The injectable pharmaceutical solution of the present invention exhibits excellent stability and extended shelf life. In particular, it remains physicochemically stable when stored for at least three months at a temperature of 40° C and a relative humidity of 75%.

The injectable pharmaceutical solution of the present invention remains physicochemically stable when stored for at least two weeks in a refrigerator, i.e. at a temperature of 2 to 8 ° C, without sedimentation of the active ingredients. This enables the short term storage of the product at 2 to 8 ⁰ C, which is essential for the microbiological protection, after the ampoule opening, if not administrated immediately.

The present invention provides a novel injectable pharmaceutical solution which is intended to substitute, for the treatment of acute, painful musculoskeletal syndromes such as back pain, the parenteral administration of the respective injectable monotherapies, i.e.. non-steroidal anti-inflammatory sodium diclofenac and muscle relaxant thiocolchicoside.

The diclofenac sodium and thiocolchicoside injectable solution of the present invention effectively addresses the problems associated with the dosing and the practices of the concurrent dosing of the individual active ingredients, contributing to the simplification of the scheme and to improving the overall compliance of the patient.

The injectable solution of the present invention can be administered intramuscularly to treat acute musculoskeletal pain as initial short-term therapy or after per os treatment failure. Thus, the present invention also provides an injectable pharmaceutical solution for use in the treatment of acute musculoskeletal pain by intramuscular administration.

The present invention also provides a simple and efficient process for the preparation of a combination solution of diclofenac sodium and thiocolchicoside. Manufacturers will appreciate the simplicity and cost-effective manufacturing process, while doctors and consumers will appreciate a stable solution for injection, the dosage of which is easily adjusted according to the patient's needs.

The susceptibility of the proposed product to the thermal stresses of liquid sterilization, even when milder sterilization temperatures are applied, provides the rationale for the use of sterile filtration as the most effective means of achieving sterility without adversely affecting the quality of the solution.

The compositions of the present invention can be prepared by, for example, using the following procedure:

Water for injection is added to a master container. The specified amount of propylene glycol is added while stirring until it is completely dissolved. Then, benzyl alcohol is added to the main vessel while stirring until complete dissolution. Sodium diclofenac is also added to the solution of the previous step under continuous stirring. In an auxiliary container, water for injection, together with the polydentate ligand, is added under stirring until complete dissolution. The specified amount of thiocolchicoside is added to the auxiliary container and stirred until it is completely dissolved. The premix of this step is transferred to the main vessel under continuous stirring. The pH of the solution is adjusted with sodium hydroxide solution (1 N) at pH 6.5 to 8.5. Finally, the volume is adjusted with water for injection.

The final solution is filtered through a 0.22 pm pore size microbial retain filter and filled under aseptic conditions in defined Type I glass ampoules of 2 to 8 ml.

EXAMPLES EXAMPLE 1

The following example shows the effect of the proposed carrier according to the invention on the physicochemical stability of diclofenac sodium and thiocolchicoside. The compositions were prepared by the following procedure: Water for injection was added to a master container. The specified amount of propylene glycol was added while stirring until it was completely dissolved. Then, benzyl alcohol was added to the main vessel while stirring until complete dissolution. Sodium diclofenac was also added to the solution of the previous step under continuous stirring. In an auxiliary container, water for injection, together with disodium edetate, were added under stirring until complete dissolution. The specified amount of thiocolchicoside was added to the auxiliary container and stirred until it was completely dissolved. The premix of this step was transferred to the main vessel under continuous stirring. The pH of the solution was adjusted with sodium hydroxide solution (1 N) at pH 7.6 to 7.8. Finally, the volume was adjusted with water for injection. The final solution was filtered through a 0.22 pm pore size microbial retain filter.

The stability of the following compositions was studied at a temperature of 40° C and a relative humidity of 75% for three months and at refrigerator temperature for two weeks.

The assay of the active substances, before and after storage, was performed using suitable validated liquid chromatographic analytical methods.

Table 1

RH.: Relative Humidity

According to the data of Table 1 , compositions A, B and C, which are not part of the invention, exhibited precipitation and/ or chemical degradation of the active substances.

On the other hand, composition I, which belongs to the present invention, is a stable preparation, without precipitation of solids and / or chemical degradation of the active substances, at both storage conditions that were studied.

EXAMPLE 2

This example shows a preferred composition according to the present invention.

The compositions were prepared by the following procedure: Water for injection was added to a master container. The specified amount of propylene glycol was added while stirring until it was completely dissolved. Then, benzyl alcohol was added to the main vessel while stirring until complete dissolution. Sodium diclofenac was also added to the solution of the previous step under continuous stirring. In an auxiliary container, water for injection, together with disodium edetate, were added under stirring until complete dissolution. The specified amount of thiocolchicoside was added to the auxiliary container and stirred until it was completely dissolved. The premix of this step was transferred to the main vessel under continuous stirring. The pH of the solution was adjusted with sodium hydroxide solution (1 N) at pH 7.6 to 7.8. Finally, the volume was adjusted with water for injection. The final solution was filtered through a 0.22 pm pore size microbial retain filter.

The stability of following compositions was studied at a temperature of 30° C and a relative humidity of 75% for three months and at refrigerator temperature for two weeks.

The assay of the active substances and their impurities profile, before and after storage, was performed using suitable validated liquid chromatographic analytical methods.

Table 2

RRT: Relative Retention Time RH.: Relative Humidity LOQ: Limit of Quantitation

Claims

1. Injectable pharmaceutical solution comprising diclofenac sodium and thiocolchicoside, 100 mg / ml to 300 mg / ml propylene glycol, 10 mg / ml to 50 mg / ml benzyl alcohol, 0.05 mg / ml to 2 mg / ml polydentate ligand and water for injection, wherein the pH of the solution is 6.5 to 8.5.

2. An injectable pharmaceutical solution according to claim 1 , wherein the polydentate ligand is selected from edetate, glutamate, histidine or malate.

3. An injectable pharmaceutical solution according to claim 2, wherein the polydentate ligand is disodium edetate.

4. An injectable pharmaceutical solution according to any one of claims 1 to 3, wherein the propylene glycol concentration is 150 mg / ml to 250 mg / ml.

5. An injectable pharmaceutical solution according to any one of claims 1 to 4, wherein the concentration of benzyl alcohol is 20 mg / ml to 40 mg / ml. 6. An injectable pharmaceutical solution according to any one of claims 1 to 5, wherein the concentration of the polydentate ligand is 0.1 mg / ml to 0.5 mg / ml.

7. An injectable pharmaceutical solution according to any one of claims 1 to 6, wherein the pH of the solution is 7.3 to 8.1.

8. An injectable pharmaceutical solution according to any one of claims 1 to 7, wherein the solution further comprises any one of a co-solvent, a substance that makes the solution isotonic with blood and a pH-adjusting agent.

9. An injectable pharmaceutical solution according to any one of claims 1 to 8, wherein the solution is free of ethanol, polyethylene glycol, ethyl lactate, sorbitol, tocopherol, sodium metabisulfite, propyl-fumaric acid ester, butylated hydroxytoluene, and butylated hydroxyanisole.

10. Injectable pharmaceutical solution according to any one of claims 1 to 9, wherein the solution is free of ethanol, polyethylene glycol, ethyl lactate, and butylated hydroxyanisole.

1 1. An injectable pharmaceutical solution according to any one of claims 1 to 10, which comprises:

18.75 mg / ml diclofenac sodium,

1.0 mg / ml thiocolchicoside,

200 mg / ml propylene glycol,

40 mg / ml benzyl alcohol,

0.5 mg / ml disodium edetate,

sodium hydroxide and water for injection, wherein the pH of the solution is 7.6 to 7.8. 12. An injectable pharmaceutical solution according to any one of claims 1 to 11 , for use in the treatment of acute musculoskeletal pain by intramuscular administration.