MXPA01001172A - Pharmaceutical composition for injection based on paracetamol - Google Patents

Abstract

A pharmaceutical composition, characterized in that:a) it comprises i) paracetamol, ii) from 1 to 4 parts by volume of a low molecular weight alcohol for each part by weightof paracetamol, and iii) from 1 to 5 parts by volume of a polyethylene glycol for each part by weight of paracetamol;b) it is substantially anhydrous;and c) it forms a clear solution for injection with 4-10 parts by volume of water for each part by weight of paracetamol.

Description

PHARMACEUTICAL COMPOSITION FOR INJECTION BASED ON PARACETAMOL.

The present invention relates to a pharmaceutical composition for injection based on paracetamol. In particular, in a first aspect, the present invention relates to a pharmaceutical composition for injection comprising paracetamol, a low molecular weight alcohol and a polyethylene glycol. For a long time it has been known in practice to use paracetamol as an analgesic and an antipyretic. By virtue of its very satisfactory tolerability, paracetamol is, in some cases, preferred for NSAIDs (non-spheroidal anti-inflammatory drugs) and, in particular, on aspirin. In effect, acetaminophen, like aspirin, exhibits its activity by inhibiting the synthesis of prostaglandins produced by cyclooxygenase. However, unlike many NSAIDs, its inhibition is practically exerted. exclusively in the brain and, on a smaller level, in the peripheral tissues (stomach, kidneys and platelets of the blood). For this reason its use does not produce side effects typical of NSAIDs such as, for example, heartburn and gastric lesions with possible blood loss. The only possible complication associated with its use is cytolysis of the liver, although this occurs only in case of overdose (Flo er RJ, Vane JR, "Nature", 240, 410-411, 1972, Lanza R., Poster P., "J. Pharmacol", 130, 105-109, 1986, Black M., "Annual Reviews of Medicine", 35, 577-593, 1984). It is also known that paracetamol is very slightly soluble in water ("The Merck Index", 12th edition, page 9, No. 45, 1996). This characteristic represents a greater obstacle to its administration by injection, even more, in the presence of water, paracetamol undergoes degradation, which gives an increase in coloration of rose to coffee derivatives. The most common types of degradation are hydrolysis to aminophenol and / or oxidation, for example, by oxygen dissolved in water. This second reaction seems to be responsible for the formation of the mentioned derivatives. The application of WO 98/05314 attempts to overcome the aforementioned disadvantages by means of a composition containing a solution of paracetamol in an aqueous solvent in combination with a regulator having a pH ranging from 4 to 8 and an agent capable of capture free radicals Furthermore, the aforementioned document recommends removing any oxygen that may be present in said solvent by means of discharge with an inert gas insoluble in water.

Among the pharmaceutical compositions given as an example in the application in the aforementioned patent, those capable of dissolving most paracetamol contain, in addition to water, PEG-400 and propylene glycol. In particular, in accordance with the above-mentioned document, a solution consisting of 30 percent propylene glycol, 40 percent PEG-400 and 30 percent water is capable of dissolving up to about 200 milligrams / milliliter of water. paracetamol at 20 ° C (WO 98/05314, page 9, lines 7-12). However, this solvent mixture is very viscous (see Comparative Example 1) and thus is unsuitable for administration by injection. That is why there is still a great need for a composition based on paracetamol which, in addition to containing therapeutic levels of paracetamol, can be injected easily and does not increase the welts. It has been found, surprisingly, that low molecular weight alcohols promote the dissolution of paracetamol in a polyethylene glycol. As can be seen in the examples, the dissolved amount of paracetamol is greater by a mixture of a low molecular weight alcohol and a polyethylene glycol (Example '..) than that dissolved, for an equal volume, by only alcohol of low molecular weight and polyethylene glycol. Comparative Examples 2 and 3). This is all the more surprising, if one considers that, in accordance with the aforementioned Patent application WO 98/05314, the sum of ethanol does not increase the solubility of paracetamol in a polyethylene glycol (page 11, last line). In a first aspect, the present invention provides a pharmaceutical composition characterized in that: a) it comprises i) paracetamol, ii) from 1 to 4 parts by volume of ethanol per part by weight of paracetamol, and iii) from 1 to 5 parts by volume of a polyethylene glycol per part by weight of paracetamol. b) is substantially anhydrous, c) forms a clear solution for injection with 4 to 10 parts by volume of water per part by weight of paracetamol. In a second aspect, the present invention relates to a pharmaceutical composition consisting of a clear solution for injection, characterized in that it comprises paracetamol and, for each part of paracetamol: i) from 1 to 4 parts by volume of ethanol, ii) from 1 to 5 parts by volume of a polyethylene glycol, and iii) from 4 to 10 parts by volume of water, and does not contain any preservatives, stabilizers, surfactants, pH regulators, agents to capture free radicals and antioxidants . In the description and in the claims that follow, it is understood that the term "substantially anhydrous" means a composition containing less than 0.1 weight percent water. Preferably, for each part by weight of paracetamol, the parts by volume of ethanol are between 1.5 and 3, and even more preferably between 2 and 2.5. In turn, for each part by weight of paracetamol, the volume parts of polyethylene glycol are preferably between 1.5 and 4, and even more preferably between 2 and 3. Finally, the parts by volume of water for each part by weight of Paracetamol are preferably between 5 and 8.

Preferably, the polyethylene glycol is selected from the group comprising PEG-200, PEG-300, PEG-400, PEG-1,000, PEG-1,540, PEG-4,000 and PEG-8,000. Typically, polyethylene glycol is PEG-400. The organic paracetamol solution is very stable according to the first aspect of the present invention, since paracetamol does not precipitate or undergo degradation, even after sterilization at 121 ° C for 30 minutes followed by storage at 30 ° C. or constant lighting at 11,000 lux for at least a month. This stability is found even in the absence of preservatives, stabilizers, surfactants, pH regulators, agents to capture free radicals and / or antioxidants. By adding water and a simple manual whipping. , this form then immediately a clear aqueous solution, in accordance with the second aspect of the present invention.

Typically, the clear aqueous solution for injection thus obtained has a viscosity of between 2 and 10 mPa-s. Preferably, the amount of low molecular weight alcohol, polyethylene glycol and water are adjusted so that that viscosity is between 4 and 7 mPa-s. According to another aspect, the present invention thus relates to a clear pharmaceutical solution for injection, characterized in that it comprises ethanol, PEG-400, water and from 10 to 25 percent (weight / volume) of paracetamol and in that the amounts of ethanol, PEG-400 and water are adjusted so that the viscosity of said solution is between 4 and 7 mPa-s. This solution also has the additional advantage that it does not contain any preservatives, stabilizers, surfactants, pH regulators, agents to capture free radicals and / or antioxidants. The pharmaceutical composition of the present invention can be prepared in accordance with techniques that are well known in pharmaceutical chemistry, comprising mixing, dissolving, sterilizing and the like. The present invention will be further described by the following examples, which are given for purely illustrative purposes and should not be construed in a limiting sense.

EXAMPLE 1 Solutions of organic paracetamol. Solution A Component Quantity Paracetamol 50 g Absolute ethanol 100 ml PEG-400 100 ml Absolute ethanol and PEG-400 were added to paracetamol at room temperature. This mixture was then stirred until the paracetamol completely dissolved (about 33 minutes). Some of the solution thus obtained was divided among 63 bottles of 5 milliliters in a proportion of 3 milliliters per bottle. In some samples, freshly prepared (time 0), the following controls were carried out: paracetamol title: HPLC (milligrams / milliliter). p-aminophenol title: HPLC (milligrams / milliliter) and revision for any coloration degradation product: spectrophotometry at 476 nm. and the following results were obtained: average paracetamol title: 214.1 P-aminophenol: absent. average absorption: 0.0075 The aforementioned samples were then stored for one month under the following conditions: at 4 ° C (Samples A). -At room temperature (Samples B). -A at 30 ° C in a room under the illumination of 11,000 lux (Samples C). The results obtained are given in the table below.

Table 1 Other samples (Samples D), freshly prepared (time 0), showed the following characteristics: paracetamol title: 204.0 - P-aminophenol: absent, absorption: 0.0062. They were stored for one month at 30 ° C in a room under the illumination of 11,000 lux and showed the following characteristics: - paracetamol title: 203.0 P-aminophenol: absent, absorption: 0.0162 Finally, another group of samples (Samples E), freshly prepared (time 0) and after sterilization (121 ° C for 30 minutes), showed the following characteristics: paracetamol title: 202.8 P-aminophenol: absent, absorption: 0.0100 They were stored for a month 30 ° C in a low room the illumination of 11,000 lux and showed the following characteristics: paracetamol title: 202.0 P-aminophenol: absent, absorption: 0.0104 BYC SOLUTIONS Similar results were obtained with samples I had the following compositions: Solution B Component Quantity Paracetamol 50 g Absolute ethanol 100 ml PEG-400 150 ml Solution C Component Quantity Paracetamol 80 g Absolute ethanol 200 ml PEG-400 200 ml EXAMPLE 2 Aqueous solution for injection Solution A (8 ml), prepared as described in Example 1 above, was introduced into a bottle (20 ml). Distilled water for injection (12 ml) was added. The bottle was then shaken manually until a clear solution was obtained (about 10-40 seconds). The solution thus obtained showed the following physicochemical characteristics: Appearance: clear, without color.

Viscosity *: 5.068 mPa-s Calculated osmolarity: 529.2 mOsmol / liter Density **: 1.02600 g / cm3 * measured with a Carri-Med Rheometer Meter CSL 50. ** measured with a Mettler Toledo DA-310 M densitometer.

COMPARATIVE EXAMPLE 1 Aqueous solution for injection in accordance with the application of Patent WO 98/05314 Component Quantity Paracetamol 1,600 mg Propylene glycol 2.7 ml PEG-400 3.6 ml Sodium acetate 20 mg Reduced glutathione 20 mg Hydrochloric acid cs pH 6 The aforementioned composition, prepared as described in the application of WO 98/05314, was introduced into a 15 ml bottle. Distilled water for injections (3.7 ml) was added thereto and left stirring until a clear solution was obtained (30 minutes). The solution thus obtained showed the following physicochemical characteristics: Appearance: clear, without color.

Viscosity *: 37.40 mPa-s Calculated osmolarity: 1,088.8 mOsmol / liter Density **: 1.09685 g / cm3 When working in a manner similar to that described above, a second composition containing 8 OD milligrams of paracetamol was prepared instead of 1,600 mg. This solution showed the following physicochemical characteristics: Appearance: clear, without color. Viscosity *: 26.34 mPa-s Calculated osmolarity: 560 mOsmol / liter Density **: 1.09433 g / cm3 COMPARATIVE EXAMPLE 2 Solution of organic paracetamol free of alcohol Component Quantity Paracetamol 5 g PEG-400 10 ml The PEG was added to paracetamol at room temperature. Then the mixture was kept stirring at room temperature for 2 hours. 4 milliliters of the aforementioned suspension were centrifuged in an Eppendorf tube at 25 ° C for 30 minutes at a speed of 7,000 rpm. The HPLC analysis of the supernatant thus obtained showed that the solubility of paracetamol was 18-19%.

COMPARATIVE EXAMPLE 3 PEG-free organic paracetamol solution Component Quantity Paracetamol 5 g Absolute ethanol 10 ml Absolute ethanol was added to paracetamol at room temperature. Then the mixture was kept stirring at room temperature for 2 hours. 4 milliliters of the aforementioned suspension were centrifuged in an Eppendorf tube at 4 ° C for 40 minutes at a speed of 7,000 rpm. HPLC analysis of the supernatant thus obtained showed that the solubility of paracetamol was 9-10 percent.

Claims (10)

1. A pharmaceutical composition characterized in that: a) comprises i) paracetamol, ii) from 1 to 4 parts by volume of ethanol per part by weight of paracetamol, and iii) from 1 to 5 parts by volume of a polyethylene glycol for each part by weight of paracetamol, b) is substantially anhydrous, c) forms a clear solution for injecting with 4 to 10 parts by volume of water per part by weight of paracetamol.

2. A pharmaceutical composition consisting of a clear solution for injection characterized in that it comprises paracetamol and, for each part by weight of paracetamol: i) from 1 to 4 parts by volume of ethanol, ii) from 1 to 5 parts in volume of a polyethylene glycol, and iii) from 4 to 10 parts by volume of water, and does not contain any preservatives, stabilizers, surfactants, pH regulators, capture agents :: free radicals or antioxidants.

3. A pharmaceutical composition according to claim 1 or 2, characterized in that for each part by weight of paracetamol, the volume parts of ethanol are between 1.5 and 3.

4. A pharmaceutical composition according to claim 3, which is characterized in that for each part by weight of paracetamol, the parts by volume of ethanol are between 2 and 2.

5. 5. A pharmaceutical composition according to claim 1 or 2, characterized in that for each part by weight of paracetamol, the volume parts of polyethylene glycol are between 1.5 and 4.

6. A pharmaceutical composition according to the claim 5, which is characterized in that for each part by weight of paracetamol, the volume parts of polyethylene glycol is between 2 and 3, and does not contain any preservatives, stabilizers, surfactants, pH regulators, agents to capture free radicals or antioxidants . A pharmaceutical composition according to claim 1 or 2, characterized in that the parts by volume of water per part by weight of paracetamol are between 5 and 8. A pharmaceutical composition according to claim 1 or 2 , which is characterized in that the polyethylene glycol is selected from a group comprising PEG-200, PEG-300, PEG-400, PEG-1,000, PEG-1,540, PEG-4,000 and PEG-8,000. 9. A pharmaceutical composition according to claim 8, characterized in that the polyethylene glycol is PEG-400. 10. A clear pharmaceutical solution for injection, characterized in that it comprises ethanol, PEG-400, water and from 10 to 25 percent (weight / volume) of paracetamol and in that amounts of ethanol, of PEG-400 and of Water are adjusted so that the viscosity of said solution is between 4 and 7 mPa-s.