RS51179B - LIQUID INJECTABLE PARACETAMOL FORMULATIONS - Google Patents

Abstract

Aqueous paracetamol solution for use in perfusion, having a pH between 4-5 and 6.0, characterized in that the solution contains a stabilizing substance of paracetamol in a solution consisting of glucose at a concentration between 0.4% w / v and 3.3% w / v. The application contains 9 more dependent claims.

Description

LIQUID INJECTABLES

PARACETAMOL FORMULATIONS

Technical field

This invention relates to injectable liquid mixtures of paracetamol according to the preamble of patent claim 1.

State of the art

Paracetamol (n-acetyl-4-aminophenol) is an active ingredient that has been widely used in the last four decades in pharmaceutical preparations thanks to its action as an analgesic and antipyretic, which was introduced by Von Mering back in 1893. In addition, people tolerate it well and it does not change the acid-base balance, which is why it is widely used to relieve pain in adults, children and the elderly. A large number of pharmaceutical preparations are known that are applied orally or even topically. However, it is difficult to obtain a pharmaceutical preparation for injection and, in particular, a ready-to-use solution for intravenous perfusion, due to the fact that paracetamol is not very soluble in water and that its solutions in aqueous media are unstable in the presence of oxygen and/or light, because they are degraded through various degradation pathways that are well known and described, for example, in the article "Stability of aqueous solutions of N-acetyl-p-aminophenol" by K.T. Koshvija and J.L. Lachi in Pharmaceutical Sciences, Vol 50 (2) (February 1961), at p. 113-118. This instability in the aqueous medium is shown by the appearance of degradation substances that cause the solution to color. Various substances that cause the solution to color include benzoquinomines, which are hepatotoxic to humans.

However, the development of color in pharmaceutical solutions and especially in injectable formulations that must be completely transparent, involves serious problems because the presence of said color indicates the presence of unwanted compounds in the formulation and therefore leads to discarding the injectable product out of use.

One of the causes of paracetamol degradation is based on chemical oxidation reactions in which oxygen present in the solution is the main precursor of this degradation. Another cause of degradation may be deacetylation of the amino group to form p-aminophenol which degrades just as rapidly to produce p-benzoquinoneimine. Then when the phenolate form is present, this deacetylation occurs in both acidic pH (much faster) and basic pH.

In vivo, most paracetamol is metabolized through the formation of these phenolates from derivatives, mainly through gluconate derivatives and through sulfonate derivatives:

Obtaining stable paracetamol solutions in an aqueous medium can be achieved through several combined actions. 1) By establishing the optimal pH at which the formation of 4-aminophenol is prevented or minimized, as indicated by K. Thomas Koshy and Jon L. Lach in the aforementioned reference: "Stability of aqueous solutions of N-acetyl-p-aminophenol" J. of Phar. Sci., Vol 50 No.2 (1961), 113-118, hydrolysis of the acetate group of paracetamol is minimized between pH=4.5 and pH=6.0. 2) Preventing the presence of oxygen in the solution. This procedure is described in Spanish patent no. 2,201,316, confirmed in Spanish and European patent EP 858,329 B1 issued to Pharmatop SCR. This document describes a procedure by which the oxidation of paracetamol is prevented by removing the main cause of activation of the reaction, oxygen, by nitrogen purging. By further storing the solution in a hermetically sealed bottle, the stability of the paracetamol in the solution is ensured for longer periods of time, with minimal levels of impurities and complete absence of color in the solution. It can be concluded from the characteristics of the SCR Pharmatop product that it must be stored in suitable bottles that will prevent the incorporation of oxygen into the solution and therefore these solutions cannot be stored in individual bottles permeable to oxygen, such as those made of plastic material.

The joint action of the two previous factors allows obtaining a stable paracetamol solution that does not develop color over long periods of time.

International patent application VVO2004/071502 A1, issued to Nguyen-Xuan, describes a paracetamol formulation containing a buffering agent with a pKa between 4.5 and 6.5, an isotonic agent and a paracetamol dimer. The stability of paracetamol in solution is contributed by the presence of paracetamol dimer of formula I, produced by in situ treatment of the solution with a temperature between 100°C and 130°C for at least 5 minutes. This formulation does not require oxygen removal and can be stored in some of the plastic materials. However, it has the following disadvantages: 1. Considering that it does not contain factors that prevent the oxidation of paracetamol, over time impurities are created, such as the mentioned dimer, which creates a color in the solution and turns it into a product that is not safe for use because at the time of its use it is not possible to know whether the color comes from the formation of paracetamol polymers or benzoquinonemine or other substances of unknown origin. 2. The stability of these solutions is reduced when stored in plastic materials, such as PVC, a mixture that does not use antioxidants. In other words, they must be stored in plastic materials such as polypropylene, polyolefins, polyethylene, polyethylene vinyl acetate, having antioxidants and preventing or hindering the entry of oxygen into the solution. These materials usually contain several of the following antioxidants: 1. butylhydroxytoluene; 2. pentaerythritol tetrakis(3,5-di-tert-butyl-4-hydroxyphenyl)propionate; 3. 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-s-triazine-2,4,6(1H,3H,5H)-trione; 4. octadecyl 3-(3,5-di-tert-butyl-4-hydroxybenzyl)propionate; 5. ethylenebis[3,3-bis[3-(1,1-dimethylethyl)-4-hydroxyphenyl]butanoate]; 6. dioctadecyl disulfide; 7. 2,2,2',6,6'6"-hexa-tert-butyl-4,4')4"-[(2,4,6-trimethyl-1,3,5-benzenetrile)trismethylenetriphenol 8. 2,2'-bis(octadecyloxy)-5,5'-spirobi[1,3,2-dioxaphosphinan]; 9. didodecyl 3,3'-thiodipropionate; 10. dioctadecyl 3,3'-thiodipropionate; 11. tris(2,4-di-tert-butylphenyl)phosphate; 12. 5 different substances containing a phenyl phosphinite group;

13. butylhydroxyanisole.

FR-A1-2 751 875 describes aqueous solutions of paracetamol for use in perfusion with a pH between 5 and 7. The pH value is maintained using a buffer system comprising an acid and an alkali metal acetate or phosphate. It further includes stabilizing substances, such as derivatives of the sulfate acid group, for example, formaldehyde sulfoxylate.

FR-A1-2 809 619 describes aqueous solutions of paracetamol for use in perfusion with a pH between 5 and 6, preferably 5.5. The pH value is maintained using a buffer system, such as a citric acid/trisodium citrate mixture. It further includes stabilizing substances, such as sulfite or its derivatives in a concentration between 0.00001%-0.1% m/v.

US-A-6 028 222 describes the use of aqueous solutions of paracetamol for use in perfusion comprising stabilizing substances such as glucose polyols or mannitol. However, the concentration range for glucose is not mentioned in this document.

Thus, the problem that this invention aims to solve is to provide an alternative stable injectable solution of paracetamol preventing the development of an unwanted color in the solution over time.

The solution to this problem is based on the fact that the authors determined that when using substances that can react with the p-acetyl aminophenolate form, an intermediate chemical species in both degradation and deacetylation and oxidation, these paracetamol degradation pathways are significantly reduced and highly stable injectable solutions of paracetamol with a minimum content of impurities are obtained. The reason for this is that the formation of intermediate products, such as gluconate or sulfonate derivatives with a phenolate form, although they may be unstable in solution, still significantly reduce the breakdown of paracetamol. Sulfate, gluconate or furfural ions can be found in solution as side products created by this decomposition.

Therefore, the aqueous paracetamol solutions of the invention for their use by perfusion contain a substance that can react with phenolates converting them to their O-derivatives or related compounds. In a preferred embodiment of the invention, these agents are selected from the following group, which is composed of reducing sugars, such as: glucose, galactose, fructose; acid forms of these sugars or their salts, such as: gluconate, glucuronate, glucoheptanoate, galactate; of chemical species containing sulfur in an oxidized state of less than +6, sodium formaldehyde sulfoxylate, sulfites or thiourea or any combination of the preceding substances. These mixtures produce a solution with greatly reduced levels of impurities and the absence of color in the solution for longer periods of time, which allows them to be stored in plastic materials without antioxidants.

In the prior art, it is possible to find aqueous formulations of paracetamol for perfusion containing antioxidants. However, there is not a single known document that investigated the different antioxidant power of different substances through the reactivity of phenolates in aqueous solution or possible practical consequences. The authors have now concluded that the action on this intermediate product in the process of hydrolysis/oxidation of paracetamol allows providing a different degree of protection of paracetamol from oxidation in the same pH conditions, so that it is possible to obtain a solution with the above-mentioned advantages by a suitable choice of antioxidants or substances that can react with the intermediate phenolate form.

A very important factor to consider is that a balance must be achieved between the color of the solution/impurities from the degradation of paracetamol and the impurities originating from the degradation of the substances used as stabilizers: although the prior art described aqueous solutions of paracetamol for perfusion containing glucose, fructose or gluconate as an isotonic agent, it is still necessary to use amounts of 5% w/v to ensure isotonicity in the solution, with which amount color is obtained in the solution after several months from production, and thus these solutions would not be suitable for this invention. Therefore, it is necessary to use an appropriate amount of each stabilizing compound so that said compound exerts its stabilizing effect without developing any intrinsic color over time. In the paracetamol solutions of the invention, this is achieved by adding at least one paracetamol stabilizing substance to the solution, which is selected from the group consisting of: glucose, fructose or gluconate in a concentration of 0.4% m/v to 3.3% m/v and sodium formaldehyde sulfoxylate, sodium sulfite or sodium dithionite in a concentration between 0.0008%-0.02% m/v. The addition of the aforementioned stabilizing substances is not intended to ensure the isotonicity of the solution of the invention and, moreover, would be insufficient for that purpose. On the contrary, their addition is intended to provide the exposed technical effect, i.e., stabilization of paracetamol in the solution, thus delaying the development of color in the solution over time. This effect is not obvious and cannot be expected from the disclosure of the existing prior art.

The last factor to consider is that the solubility of paracetamol in an aqueous medium is about 12 mg/ml at a temperature of 20°C and 8 mg/ml at 4°C, so the production or composition of the solution must prevent crystallization of paracetamol. This effect is resolved by filtering the solution through pore sizes of 0.45 microns or smaller or, by adding a solubilizing agent as described in international publication VVO03033026, issued by BIOREN SA, which is an aqueous solution of paracetamol obtained by mixing paracetamol and propylene glycol in a citrate medium at a pH between 4.5 and 6.5 and heating that solution at a temperature between 70°C-130°C.

EXAMPLES

In order to examine the protective effect of different substances that can have antioxidant activity to ensure the stability of paracetamol solutions, solutions with various compositions were made, all in the presence of oxygen, without prior dehydrogenation of the solvent medium, and were stored in glass and PVC materials

(poly(vinyl chloride)) until later subjected to wet sterilization, which is currently the safest recognized procedure for injectable solutions.

1) Solutions stored in glass containers

It has been confirmed that the most stable pH range for 0.1% m/v solutions of paracetamol is between 4.5 and 6.0 and, this is the pH range used to perform the tests, buffering agents with a pKa close to this pH range are preferable as they allow the maintenance of optimum pH values in a much more consistent manner. Thus, it is possible to use buffering agents based on citrate, malate, acetate, lactate, gluconate; and those that exhibit a synergistic antioxidant effect, such as citrate or malate, are preferred.

The following tests were performed to test the stability of the solution:

- visual appearance,

- absorbance measurement at 320 nm and 500 nm in 10 mm thick quartz cuvettes,

- the content of impurities was determined by liquid chromatography based on the chromatographic conditions of the European Pharmacopoeia (5th edition), by comparing the relative surfaces with external standards of paracetamol with known concentrations.

After sterilization with moist heat, the resulting solutions were subjected to a heating treatment at 100°C for solutions in glass bottles and at 70°C for solutions stored in plastic.

The stability of the solutions at room temperature for product storage (25°C) can be predicted by observing the characteristics of the solutions subjected to these heating treatments at different times, because, as noted by K. Thomas Koshy, the kinetics of degradation follows the Arrhenius law of temperature/time dependence.

The three investigated characteristics, visual appearance, absorbance at different wavelengths and the content of impurities are interdependent. Absorbance at 350 nm (yellow) is caused by p-aminophenol, polymerization products, impurities associated with the synthesis of paracetamol and benzoquinonemine; absorbance at 500 nm (pinkish brown) is caused by benzoquinonimines and their polymerization. Table 1 shows the maximum values of impurities corresponding to the area of the chromatographic peak with the highest value, expressed as a % relative to paracetamol. The sum of all impurities is indicated as % value of total impurities.

It was noticed that not all antioxidants stabilize the solution in the same way. After sterilization, visually, neither ascorbates nor nitrites protect paracetamol. The solution without antioxidants retains its colorless appearance, however, the solution without antioxidants is, among the colorless solutions, the one that contains the highest values of impurities. The effect of these substances as antioxidants, which they are, is obviously not enough to stabilize the solution.

After 16 hours of treatment at 100°C, it was observed that those solutions containing dithionite, glucose or sodium formaldehyde sulfoxylate were those with less color, having absorbances at 350 nm less than 0.100 absorbance units and at 500 nm less than 0.020 absorbance units.

After 24 hours at 100°C, it can be observed that a formulation containing oxygen in an aqueous medium and sodium sulfoxylate at a concentration of 0.02% m/V can match the stability of the commercial formulation Perfalgan® (obtained according to the process described in the SCR Pharmatop patent), which formulation, stored in its original glass bottle at 100°C for 24 hours, remains colorless with absorbances virtually zero at 350 nm and 500 nm.

2) Solutions stored in plastic material

The same conclusions can be drawn if the test of paracetamol solution in plastic material is observed:

Both color and impurity content are significantly lower in paracetamol solutions containing oxygen with an associated suitable antioxidant. These suitable antioxidants are so not because of their antioxidant activity but because they neutralize the degradation of paracetamol via the p-acetaminophenolate pathway, which despite their minimal presence in an acidic medium, their reactivity is significantly higher.

The tested mixtures have a much higher stability compared to Perfalgan® when stored in plastic materials. Perfalgan® solution in PVC thus has an intense grayish brown color after storage at 70°C for 67 hours, with an absorbance of 0.267 AU at 350 nm and 0.38 AU at 500 nm.

3) Comparison of solutions stored in different types of materials

In the following example, the effect on the color of the same chemical mixture was observed depending on its storage in different plastic materials (polyolefins and PVC), where polyvinyl chloride is the favorite.

The concentration of antioxidants plays an important role in stabilizing the solution because the breakdown of such antioxidants in turn creates impurities that lead to color in the solution. In the case of sugar, they can produce other derivatives of furfural and gluconate, in the case of reducing substances with sulfur, they can produce sulfonate derivatives of paracetamol which, in turn, can also give color in solution, or inorganic forms of sulfate. Depending on the type of stabilizing substance in the solution, its optimal concentration varies: in a preferred embodiment of the invention, the mixtures contain at least one stabilizing substance of paracetamol in the solution, which is glucose in a concentration of 0.4% to 3.3% m/v; in an even more preferred embodiment of the invention, the formulation contains glucose in a concentration of 0.5% to 3.0% m/v; in the most preferred embodiment of the invention, the formulation contains glucose in a concentration between 1.0% and 3.0%.

When using sodium formaldehyde sulfoxylate as a stabilizing substance of paracetamol in solution, in a preferred embodiment of the invention, the formulations of the invention contain sodium formaldehyde sulfoxylate in a concentration between 0.008% and 0.02%; in a more preferred embodiment of the invention, the formulation contains sodium formaldehyde sulfoxylate in a concentration between 0.001% and 0.02%.

It has also been observed that the use of the acid form of glucose also prevents the appearance of color when the solution is produced in the presence of oxygen.

As a result, it is possible to obtain a stable solution of paracetamol by incorporating antioxidant substances into the solution, which can react with p-aminophenolates increasing their O-derivatives or related compounds, above all selected from the group composed of reducing sugars, such as glucose, galactose, fructose; acid forms of sugar or their salts, such as lactobionate, gluconate; glucuronate; glucoheptanoate, galactate, lactobionate or lactone, such as gluconolactone; chemical species containing sulfur in an oxidation state less than +6, sodium formaldehyde sulfoxylate, sulfites or thiourea and, it is possible that these substances produce derivatives with the phenolate form of paracetamol. In this way, injectable solutions of paracetamol with an impurity content of less than 0.1% can be obtained. The solutions of the invention further have the advantage that they can be kept in glass bottles or bottles of any plastic material, including PVC, and can be sterilized by heat or filtration.

The amount of paracetamol present in the solution is also a decisive factor because the content of impurities is constant in relation to the content of paracetamol, independent of the content of paracetamol, however, the intensity of the color increases proportionally with the concentration for the same content of impurities (see Table 4).

At the maximum tested concentration of 0.15%, the solution is stable under cooling conditions of 2-8°C, no crystallization was observed.

Lower color values are obtained by reducing the concentration of paracetamol in the solution.

Claims (10)

1. An aqueous solution of paracetamol for use in perfusion, with a pH between 4-5 and 6.0, indicated by the fact that the solution contains the stabilizing substance of paracetamol in a solution consisting of glucose in a concentration between 0.4% m/v and 3.3% m/v. 2. An aqueous solution of paracetamol for use in perfusion, as in claim 1, wherein the glucose is present in a concentration between 0.5% w/v and 3.0% w/v. 3. An aqueous solution of paracetamol for use in perfusion, as in any one of claims 1-2, wherein the glucose is present at a concentration between 1.0% w/v and 3.0% w/v. 4. An aqueous solution of paracetamol, as in any of the preceding claims, where the pH is between 4.7 and 5.5 and, the solution is buffered with a buffer mixture selected from at least one acid form and ionized form: citric, malonic, succinic, acetic, sorbic, phosphoric, fumaric, lactic, gluconic and tartaric acids or mixtures thereof. 5. An aqueous solution of paracetamol for perfusion, as in claim 4, wherein the buffer is sodium citrate-acetate. 6. An aqueous solution of paracetamol for perfusion, as in any of the preceding claims, further comprising a chelating agent. 7. An aqueous solution of paracetamol for perfusion, as in any of the preceding claims, further comprising sugar acid derivatives or sulfates or furfurals. 8. An aqueous solution of paracetamol for perfusion, as in any of the preceding claims, which can be sterilized by heat or filtration. 9. An aqueous solution of paracetamol for perfusion, as in any of the preceding claims, wherein the concentration of paracetamol is between 0.25% and 1.5% w/v. 10. An aqueous solution of paracetamol for perfusion, as in any of the preceding claims, wherein the concentration of paracetamol is between 0.5% and 1.5% w/v.