Title:  Dispersible and soluble galenic paracetamol formulation, method for its preparation and its applications

United States Patent:  6,620,433

Issued:  September 16, 2003

Inventors:  Martin; Luis Carvajal (Madrid, ES); Asensio; Juan Carlos Asensio (Zaragoza, ES); Tirado; Francisco Javier Sevilla (Zaragoza, ES)

Assignee:  Laboratorios Belmac, S.A. (San Sebastian de los Reyes, ES)

Appl. No.:  188680

Filed:  July 3, 2002

Abstract

The new galenic formulation of paracetamol is comprised of a base mixture of paracetamol and citric acid in a proportion of 85:15 to 90:10 w/w among other pharmaceutically acceptable components, in an exsiccation state corresponding to a water activity of less than 0.6 and it is in the form of a powder, granulate or tablet. The process comprises obtaining said exsiccated base mixture up to a water activity of less than 0.6 in order to obtain a powder, that can be granulated in order to obtain a granulate dispersible and soluble in water, whose granulate can also be compressed in order to obtain a tablet dispersible and soluble in water. Said new formulation is useful in human and veterinary medicine.

DETAILED DESCRIPTION OF THE INVENTION

As indicated in its title, the present invention refers to a new galenic formulation of paracetamol dispersible and soluble in water. The present invention also refers to the process for the preparation of said new formulation and to its pharmaceutical uses.

The new galenic formulation of the present invention essentially consists of paracetamol and citric acid, irrespective of the fact that it may include other types of products selected from among vehicles, binding agents, disaggregating agents, etc. commonly used in conventional pharmaceutical practice.

For the preparation of said formulation paracetamol is treated with a hot saturated citric acid solution, in a high speed mixer (at 500-1,000 rpm) for approximately 3-10 minutes, heating the mass to a temperature of about 45-55^oC. Then, the stirring rate is reduced to approximately 10-120 rpm and a vacuum is applied to the mixing basin up to a pressure of approximately 10-30 mbar that contains a moist paracetamol and citric acid mass. Under these conditions, by effect of the latent heat of vaporization of the mass, the temperature thereof drops to about 30-35^oC., which prevents degradation of the paracetamol. Besides, the citric acid tends to form its monohydrate, for which reason it sequesters the water from the mass during this drying period, making it possible to achieve a semi-dry state of the mass in which the water activity is less than 1 (Aw<1). Within the context of the present invention, the term semi-dry is understood as the property that the paracetamol:citric acid mass has to capture water forming hydrates at temperatures lower than 45-55^oC. It is known that citric acid forms hydrates below this temperature, the free water becoming bound water. Therefore, the referred mass will have a moist appearance (Aw>1) at temperatures higher than 45^oC., whereas below 45^oC., the mass will have a dry appearance (Aw<1). The drying rate depends on the intensity of the vacuum applied, achieving faster drying as the vacuum increases, that is to say, when the pressure drops inside the basin.

The amounts of paracetamol and citric acid that are used in the mixture are 85-90% (weight/weight) of paracetamol and 15-10% (weight/weight) of citric acid. Citric acid is used in the form of a 55-60% (weight/volume) aqueous solution. In order to dissolve the citric acid in water, it is necessary to preheat it to 60-80^oC., after which the citric acid is added under continuous stirring until it completely dissolves (the dissolving temperature of citric acid normally varies between 60 and 65^oC.).

The product resulting from the above-cited process is a dry mass of paracetamol and citric acid in powder form. A dry mass is understood to be one that does not have adherence due to moisture. For this reason the Aw should be lower than 0.6 and the water content determined by the Karl-Fisher method should be lower than 2%

Said dry paracetamol:citric acid mass has an apparent density of approximately 0.6-0.8 g/ml. Besides, it is rapidly soluble in cold water (approximately at 12-20^oC., which is the normal temperature of tap water). "Rapidly soluble" is understood to be when a dose of paracetamol of 500-1,000 mg dissolves in a proportion higher than 90%, in 60 ml of said cold water, with stirring, in less than 3 minutes.

Another characteristic of said dry mass is that its solution has a pH of 2.1-2.5 (measured by solubilizing 1 g thereof in 100 ml of cold water). Said dry mass in powder form constitutes the base mixture of the formulation of the present invention, which has excellent fluidity properties and a high compacting and compressing capacity. However, it has the inconvenience that its pH is too low, so as to be able to be used as such in highly dispersible soluble tablets.

In order to overcome this inconvenience, a weak alkali is added to the mass, together with an appropriate carrier. Hence, the composition of the formulation of the invention is essentially the following:

Formulation I

weight (mg)

per dose unit

Base mixture of paracetamol/citric acid 715-765

(in a ratio of 85:15 to 90:10 % w/w)

Weak alkali qsp pH 5-5.5

Pharmaceutically acceptable carrier 3-6

The buffers sodium bicarbonate/sodium carbonate, sodium citrate alone or mixed with other weak organic acid salts are examples of the weak alkali that can be used.

In the event of using sodium bicarbonate/sodium carbonate, the amounts thereof would be of 15-30 mg and 2-10 mg, respectively, and in the event of using sodium citrate the amount thereof would be of 150-250 mg, all of these amounts referring to a dose unit.

The pharmaceutically acceptable carrier is selected among Sucroester 15, sodium lauryl sulfate and sodium ethyl sulfosuccinate.

This formulation, upon including bicarbonate and carbonate, in the presence of citric acid, has slightly effervescent properties when it comes in contact with water, for which reason it should be kept away from moisture during its handling and preservation.

However, the proportion of carbon anhydride that this mixture produces is minimum, if it is compared with that which is produced by the preparations currently existing on the market. Thus for example, while a dose of the mixture of the invention, corresponding to 650 mg of paracetamol gives off about 17-18 mg of CO₂, the effervescent preparations existing up until now give off approximately 550-650 mg of CO₂.

The above-described formulation I can be dosed directly in single dose packets for direct consumption as said powder, or else it can be subjected to a granulation process in order to obtain a granulated product. Said granulation process is carried out conventionally in a roller compactor.

The granulate thus obtained can be dosed in single dose packets, with some excellent dispersing and solubilizing characteristics of the granulate in cold water by gentle stirring by hand.

It is also possible to obtain tablets from the granulated product thus obtained. For this purpose, conventional products of galenic formulations in tablets, such as for example, taste correctors, sweeteners, flavoring agents, disaggregating agents, etc. can be added to the granulated mixture.

In accordance with the above, the starting formulation to obtain the tablet would essentially be the following:

Formulation II

weight (mg)

per dose unit

Paracetamol granulate 735-811

Flavor 30-50

Sweetener 15-20

Disaggregating agent 15-20

Lubricating agent 10-20

Aspartame, saccharine, or mixtures thereof can be cited as examples of sweeteners. Crosspovidone, crosscaramellose or mixtures thereof can be mentioned as disaggregating agents. Magnesium stearate and/or polyethylene glycol can be used as examples of lubricating agents.

The tablet is obtained by direct dry compression of Formulation II.

The tablets obtained in accordance with the present invention are characterized in that they are soluble and weigh approximately 800-900 mg, which is approximately the weight of the unsoluble tablets currently existing on the market, for a dose of paracetamol of 500-650 mg Besides, they have the advantage of weighing less and being smaller than the presently marketed effervescent soluble tablets, that tend to weigh 2-5 g.

The tablets of the invention are additionally characterized in being stable at the temperature and moisture when they are packaged in a blister or jar, for a period of no less than 3 years; and in that they comply with the pharmacotechnical specifications for this type of drug, complying with the specifications for swallowable tablets as well as with the specifications for dispersible and soluble tablets. Therefore, the present invention presents tablets with the property of being swallowed directly or of being dispersed and solubilized in water in order to be taken. Obviously it has to be pointed out that the external disaggregating agent is not water soluble, but it represents a minimum amount of the total weight of the tablet (in the neighborhood of 15-20 mg).

The pharmacological advantage of the formulations of the invention is that since they are soluble, they provide a higher paracetamol absorption rate, which allows the symptoms to be alleviated much quicker.

The uses of the formulations of the present invention are the same as those of the other galenic preparations of paracetamol, and they are basically centered on its analgesic, antipyretic and anti-inflammatory activity useful in humans and animals, that is to say, in human medicine and veterinary medicine.

EMBODIMENTS OF THE INVENTION

The present invention is additionally illustrated by means of the following example, which in no way seeks to restrict its scope of protection.

EXAMPLE

A mixture of 1 kg of paracetamol and 225 ml of an aqueous 50% citric acid solution was prepared. The mixture was placed in the basin of a high speed mixer, where it was kept for 10 minutes, at a temperature of 45-55^oC. (achieved by means of a heating sleeve at 65^oC.) and subjected to a stirring rate of 600 rpm. After 10 minutes, the stirring rate is reduced to 120 rpm and the vacuum was produced in the basin up to a pressure of 10 mbars keeping the sleeve at 65^oC., in order to dry the mixture until a water activity of less than 0.6 is achieved.

Then 720 mg of this dry paracetamol (650 mg) and citric acid (70 mg) mixture are mixed with 30 mg of sodium bicarbonate, 5 mg of sodium carbonate and 1 mg of sodium lauryl sulfate. The mixture thus obtained is subjected to a dry granulation process in a roller compactor with the following conditions:

Roller pressure: 90 KN

Feed: continuous

Cooling of the rollers: at 10-14^oC.

Granulator sieve: 1.5 mm perforation diameter in order to obtain a granulate, that can be used as such, being dosed in single dose packets.

On the other hand, 756 mg of the granulate thus obtained are mixed with 50 mg of orange flavoring agent, 15 mg of aspartame and 15 mg of crosscaramellose and subjected to a direct dry compression process to obtain a tablet.

Claim 1 of 25 Claims

What is claimed is:

1. Galenic formulation of paracetamol dispersible and soluble in cold water comprising:

a base mixture of paracetamol and citric acid in a proportion between 85:15 and 90:10 w/w,

having a water content of less than 2% as measured by the Karl-Fisher method,

said formulation being in a form selected from the group consisting of a powder, a granulate, a tablet and in packets.

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