WO2001008662A1

WO2001008662A1 - Liquid pharmaceutical composition based on paracetamol

Info

Publication number: WO2001008662A1
Application number: PCT/EP2000/006871
Authority: WO
Inventors: Mario Pinza; Giovanni Cavallo; Vilma Rossi; Alberto Campana
Original assignee: Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.
Priority date: 1999-07-30
Filing date: 2000-07-18
Publication date: 2001-02-08
Also published as: ITMI991697A1; ITMI991697A0; AR024959A1; AU6565100A; IT1313579B1

Abstract

A liquid pharmaceutical dosage form consisting of a solution comprising at least 10 % (w/v) of paracetamol in anhydrous PEG-200.

Description

"Liquid pharmaceutical composition based on paracetamol"

* * * * * _* *

The present invention relates to a liquid pharmaceutical composition based on paracetamol. More particularly, the invention relates to an anhydrous liquid pharmaceutical composition based on paracetamol.

It is known that paracetamol is used extensively as an analgesic and antipyretic agent by virtue of its good tolerability. In a number of cases, it is also preferred to non-steroidal antiinflammatory drugs (NSAID) such as, for example, acetylsalicylic acid, since it does not produce the typical side effects of NSAIDs such as, for example, heartburn and gastric lesions. The only possible complication associated with its use is hepatic cytolysis, which, however, occurs only in cases of overdosing. It is also known that paracetamol is generally administered in solid pharmaceutical dosage forms because its solubility in water is of about 1 % (w/v). In addition, in aqueous medium, paracetamol is hydrolysed relatively rapidly, with formation of para-aminophenol and/or is oxidized by the action, for example, of the oxygen dissolved in the water. This second reaction appears to be responsible for the formation of pink- to brown-coloured derivatives. To overcome these drawbacks, attempts have been made to dissolve paracetamol in anhydrous pharmaceutically acceptable solvents and/or to potentiate its activity, particularly in the case of pharmaceutical forms for nasal administration, with many types of potential enhancers having been investigated, but, as far as the Applicant is aware, satisfactory practical results have not been obtained to date.

Thus, there is still a great need for anhydrous liquid pharmaceutical dosage forms which are suitable, for example, for nasal, ocular, otological and parenteral administration. Moreover, liquid dosage forms are also very useful for oral administration both because they allow greater accuracy in dosing the drug as a function of the body weight, as well as of the type and seriousness of the pathology to be treated, but also because they are suitable in all cases in which the patient displays difficulty in swallowing, such as, for example, children and the elderly.

Effervescent tablets have been proposed to overcome this last drawback. However, they are relatively complex and expensive to produce and package since they require special machinery and suitable premises for processing powders with a controlled moisture content. In addition, the type of packaging required consists of aluminium blister packs coupled with plastic films that are impermeable to air and moisture. Furthermore, this particular type of packaging contributes towards making these effervescent tablets even more expensive. It has now been found, surprisingly, that it is possible to obtain high concentrations of paracetamol in PEG-200, up to a maximum concentration of about 22% (w/v).

As is known, PEG-200 is a mixture of ethylene glycols with an average molecular weight of about 200, a density of about 1.1 -1.3 g/cm³ and a viscosity of about 40-50 cp. Typically, commercial PEG-200 has the following percentage composition: monoethylene glycol, 0.1 %; diethylene glycol, 3.4%; triethylene glycol, 21.2%; tetraethylene glycol, 31.2%; pentaethylene glycol, 24.4%; hexaethylene glycol, 14.0%; heptaethylene glycol, 5.4%; octaethylene glycol, 0.3%. The present invention thus relates to a liquid pharmaceutical dosage form, characterized in that it consists of a solution comprising at least 10% (w/v) of paracetamol in anhydrous PEG-200.

Preferably, the amount of paracetamol in the solution of the present invention ranges from 15 to 22% (w/v). Even more preferably, this amount ranges from 18 to 22% (w/v). The advantages of the present invention are particularly great when the amount of paracetamol is between 20 and 22% (w/v).

The solution of the present invention can readily be sterilized with steam. In addition, the solution has good stability at room temperature. Depending on the route of administration selected and the pathology which it is intended to treat, the solution of the present invention may further contain other active principles and/or additives of conventional type, such as, for example, preserving agents, flavourings, colorants, sweeteners and the like. According to another advantageous aspect of the present invention, in the case of preserving agents, the amount required is less than the norm. For example, in the case of benzalkonium chloride, the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually between 0.005 and 0.01 % (w/v). In the case of methyl paraben, the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually between 0.005 and 0.25% (w/v). In the case of a mixture of ethyl, propyl and butyl paraben, the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually between 0.005 and

0.03% (w/v). In the case of sodium edetate (EDTA), the amount which may be present in the solution of the present invention will range from 0.001 to 0.0025% (w/v), whereas it is usually 0.005% (w/v). In the case of Thiomerosal, the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually 0.01 % (w/v).

The absence or, at most, the presence of small amounts of preserving agents is particularly advantageous in the case of nasal and ocular administration. Another particularly advantageous aspect of the present invention is that PEG is not hygroscopic, even in the presence of high humidity (Bϋhler V., Vademecum for Vitamin Formulations, Stuttgart 1988, pp. 57 and 87). Yet another advantage of the present invention is that PEG-200 does not compromise the good gastric tolerability of paracetamol.

Moreover, the LD₅₀ (mg/kg) of PEG-200 is

- orally: > 29,000 in rats and mice, and > 19,000 in rabbits;

- intraperitoneally: > 13,000 in rats and mice; - intravenously: > 7,000 in rats and mice.

Depending on the route of administration chosen, the solution of the present invention can be dispensed using suitable known devices which allow the administration of accurate doses, such as, for example, mechanical pumps, medical droppers, spray dispensers and the like. The solution of the present invention can also be used for preparing syrups, at the time of use, by mixing it, before use, with suitable diluents such as, for example, aqueous or aqueous-alcoholic diluents, optionally comprising conventional additives such as, for example, preserving agents, flavourings, colorants, sweeteners and the like. In the case of nasal administration with mechanical spray systems, the dose will be, for example, 200 μl per nostril (1 spray) of a 20% (w/v) solution, equal to 80 mg of paracetamol. If necessary, the amount of paracetamol administered may be increased by increasing the number of sprays in each nostril, optionally sufficiently quickly one after the other, or by administering a more concentrated solution.

In the case of otological and ocular administration, the solution of the present invention may be administered as it is or added before use with a suitable diluent capable of giving a final solution having preselected isotonicity and/or pH. The examples and tests below serve to illustrate the present invention without, however, limiting it.

EXAMPLE 1 Preparation of a 22% (w/v) solution Paracetamol (2.2 g) was added to PEG 200, making up to a volume of 10 ml with magnetic stirring at room temperature.

The characteristics of the final solution were: titre (w/v): 22% density^* (g/cm³) 1.4606 viscosity^** (cp) 168.4

^* the density was measured using a Mettler Toledo DA310M machine; ^** the viscosity was measured using a Cammed CSL50 rheometer.

EXAMPLE 2 Sterilization The degradative effect of water was also evaluated in the sterilization tests on a number of embodiments of the present invention.

Batch A consisted of an anhydrous 20% (w/v) paracetamol solution prepared as described in Example 1 above.

Batch B consisted of a 20% (w/v) solution of paracetamol in a 99/1 (v/v) PEG 200/water mixture.

The possible degradation of the paracetamol was evaluated by subjecting the test samples to 4 cycles of sterilization at 121 °C for 25 minutes/cycle and determining the amount of p-aminophenol (PAP) formed due to degradation of the paracetamol. This quantitative analysis of the p-aminophenol was carried out by the reverse-phase

HPLC method with UV detection.

The results are given in Table 1 below, in which PAP0 indicates the amount of p-aminophenol found in fresh solutions prepared before sterilization; PAP1 indicates the amount of p-aminophenol found in the solutions after the first sterilization cycle; PAP2 indicates the amount of p-aminophenol found in the solutions after the second sterilization cycle; PAP4 indicates the amount of p-aminophenol found in the solutions after the fourth sterilization cycle. The amount of p-aminophenol is expressed in μg/ml.

TABLE 1

These results show that the degradation of the paracetamol is also promoted by small amounts of water.

TEST 1 Tolerabilitv of paracetamol solutions in rabbits The intranasal tolerability of paracetamol in rabbits was evaluated using the method of Frattola et al. ("Arch. Toxicol.", Suppl. 14, 272-275, 1991 ).

The following solutions were used: Solution A: paracetamol (20% w/v) in PEG 200; Solution B: PEG 200;

Solution C: paracetamol (20% w/v) in PEG 200 and phosphatidylcholine

(5% w/v); Solution D: PEG 200 and phosphatidylcholine (5% w/v); Solution E: sodium taurocholate (5% w/v) (positive control). The test solution was administered to male New Zealand White rabbits by means of nasal instillation of a total volume of 0.8 ml divided into four doses (100 μl) per nostril, at intervals of 90 minutes in one day. One group of animals received no treatment (negative control). Each treatment group consisted of 3 animals. All the animals were weighed and examined to evaluate any side reactions to the treatment. Three days before the administration and 24 and 72 hours after the final dose (on days -3, 1 and 3, respectively, of the study) nasal cells were taken from all the animals by means of interdental toothbrushes soaked with Hank's solution supplemented with bovine serum albumin (0.1% w/v).

After taking the samples, the brushes were immersed in the abovementioned solution (1 ml) and agitated to separate the cells. The following parameters were evaluated: differential and total number of cells (epithelial cells and leukocytes). Table 2 shows that the intranasal instillation of solutions A and C did not induce any intolerance reactions, caused no increase of the nasal cells or, in particular, of the leukocytes which generally increase by the action of migration towards inflamed regions, as did occur, however, in the case of the animals treated with solution E containing sodium taurocholate, a known mucosal irritant.

TABLE 2

co

TEST 2 Bioavailabilitv of paracetamol solutions in rabbits The study was carried out using the following solutions:

- solution 1 having the following composition: paracetamol (4.16 g), Tween 20 (20 g), absolute ethanol (20 ml), water (qs 100 ml); (titre:

4.16% (w/v));

- solution 2 having the following composition: paracetamol (20.3 g), PEG 200 (qs 100 ml) and phosphatidylcholine (5 g); (titre: 19.7% w/v)); and - solution 3 having the following composition: paracetamol (20.8 g),

PEG 200 (qs 100 ml); (titre: 22% w/v)).

The study was carried out by administering 5 mg/kg of paracetamol to male New Zealand White rabbits by means of intranasal instillation of solutions 2 and 3. The volumes administered corresponded to 25.4 μl/kg for solution 2 and 22.5 μl/kg for solution 3.

The bioavailability was calculated with reference to the intravenous administration of 120 μl/kg of solution 1 , equivalent to 5 mg/kg of paracetamol, to male New Zealand White rabbits.

At 0, 5, 15 30, 45, 60, 90, 120, 150, 180, 210 and 240 minutes after the treatment, blood samples were taken using heparinized syringes.

The samples were centrifuged at 1600 g/min for 15 minutes at 0°C (Heraeus Sepatech centrifuge). The plasma was transferred into polypropylene test tubes and stored at -20°C until the time of analysis. The paracetamol concentrations in the plasma samples were determined using an HPLC/MS/MS method.

The pharmacokinetic parameters were calculated using the Siphar™ programme release 4.0 (Simed). The bioavailability (F%) was calculated according to the following equation: F = (average AUC(o-_m)i-n./average AUC(o-_tn)i.v.)x(i.v. dose/i.n. dose)x100 The results obtained are given in Table 3 and can be summarized as follows: a) solution 2 gave a maximum plasma concentration (C_maχ) equal to 1.41 μg/ml in 16.25 minutes, an area under the curve (AUC(o-inf)) equal to 89 μg^*min/ml, half-life time (t1/2) of 87 minutes and a bioavailability (F) of 21%; and b) solution 3 gave a maximum plasma concentration (C_max) equal to

2 μg/ml in 16.25 minutes, an area under the curve (AUC(o-inf)) equal to 157.9 μg^*min/ml, half-life time (t1/2) of 74.8 minutes and a bioavailability (F) of 37%.

Thus, Table 3 shows that both solutions 2 and 3 are rapidly absorbed in the nose and that the solution of paracetamol in PEG 200 (solution 3) also has better bioavailability than solution 2 containing phosphatidylcholine.

TABLE 3

Claims

CLAIMS 1. A liquid pharmaceutical dosage form, characterized in that it consists of a solution comprising at least 10% (w/v) of paracetamol in anhydrous PEG-200. 2. A pharmaceutical dosage form according to the preceding claim 1 , characterized in that it comprises from 15 to 22% (w/v) of paracetamol. 3. A pharmaceutical dosage form according to the preceding claim 1 or 2, characterized in that it comprises from 20 to 22% (w/v) of paracetamol.