Dispersible and soluble galenic paracetamol formulation,...

Details Dispersible and soluble galenic paracetamol formulation,... Dispersible and soluble galenic paracetamol formulation,...

2002-07-03

2003-09-16

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S489000, C424S464000, C424S470000, C424S044000

Reexamination Certificate

active

06620433

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention fits in the pharmaceutical sector and, more specifically in the field of the galenic formulation of analgesics, specifically paracetamol which is widely used in human medicine and veterinary medicine. The present invention provides a new galenic formulation of paracetamol with improved properties in comparison with the formulations presently existing on the market.
PRIOR ART
Paracetamol is N-(4-hydroxyphenyl) acetamide. It is a widely used analgesic that exists on the market under numerous brands in different galenic forms. Likewise, paracetamol is an active drug capable of being combined with other active ingredients for different uses. There are also numerous preparations on the market in which paracetamol is combined with other drugs. Therefore, there is a large number of pharmaceutical patents related to paracetamol.
According to the information provided by The Merck Index, 1996, 12
th
Ed., it is a product which in its pure form crystallizes from water in the form of large monoclinic prisms, has a melting point of 169-170.5° C. and a specific density at 21° C. of 1.293 g/cm
3
. It has a maximum UV absorption (ethanol) at 250 nm with an &egr; of 13,800.
Paracetamol is a solid which is barely soluble in cold water, a solubility which increases considerably in hot water. Likewise, it is soluble in methanol, ethanol, dimethylformamide, ethylene dichloride, acetone and ethyl acetate. It is barely soluble in ether and practically insoluble in petroleum ether, pentane and benzene. Its LD
50
in mice (mg/Kg) is 338 when administered orally and 500 when its administration is interperitoneal.
Paracetamol is therapeutically catalogued as an analgesic and antipyretic, although at high doses it can also have anti-inflammatory action.
Paracetamol can be prepared from p-nitrophenol [Morse, Ber 11, 232 (1878); Tingle, Williams Am. Chem. J. 37, 63 (1907)], from p-amino-phenol [Lumiere et al., Bull. Soc. Chim. France [3] 33, 785 (1905); Fierz-Davil, Kuster, Helv. Chim. Acta 22, 94 (1939); Wilbert, De Angelis, U.S. Pat. No. 2,998,450 (1961 of Warner Lambert); Bergmann, German patent 453,577; Chem, Zentr. 1928.I, 2663; Frdl. 16, 238]; from p-hydroxyacetophenone hydrazone [Pearson et al., J. Am. Chem. Soc. 75, 5907 (1953)].
Data concerning its toxicity can be found in G. A. Starmer et al., Toxicol. Appl. Pharmacol 19, 20 (1971) and D. C. Dahlin, S. D. Nelson, J. Med. Chem. 25, 885 (1982); an evaluation of its effects on the kidneys can be found in D. P. Sandler et al. N. Engl. J. Med. 320, 1238 (1989); an extensive description of the product can be found in J. E. Fairbrother, Anal. Profiles Drug Subs. 3, 1-109 (1974); a compilation of its pharmacology can be found in B. Ameer, D. J. Greenblatt, Ann. Int. Med 87, 202-209 (1977); a compilation of studies regarding hepatotoxicity induced by paracetamol can be found in J. A. Hinson, Rev. Biochem. Toxicol. 2, 103-129 (1980); idem, Life Sci. 29, 107-116 (1981); and a compilation on protective agents is proposed in M. Davis, Sem. Liver. Dis. 6, 138-147 (1986).
European patent appln. no. 96942064, regarding formulations with a high paracetamol content, directly compressible, especially suitable to provide tablets with a high paracetamol content (>80%) with respect to the total weight of the tablet; and European patent E97936739 regarding stable liquid paracetamol formulations especially suitable to obtain antialgic injectable preparations; and European patent E90907166 regarding an ophthalmic paracetamol formulation and European patent 92301558 regarding compositions of sustained release of paracetamol among other drugs, can be cited among patents regarding special forms of paracetamol.
There are also numerous patents regarding pharmaceutical preparations in which paracetamol is combined with one or several active drugs, for different uses, among which the following stand out:
Spanish patent n
o
530359 refers to the obtainment of an analgesic preparation made of paracetamol and tizamidine.
Spanish patent n
o
551584 refers to the obtainment of a pharmaceutical preparation that contains flupirtine and paracetamol, especially appropriate for treating inflammatory diseases, degenerative articular diseases, arthrosis deformans, dysmenorrhea, post-operative pain, etc.
European patent application n
o
E90903746 refers to a preparation, among others, containing coumarin or calcium dibesilate and paracetamol, effective for treating arthrosis.
European patent application n
o
E92307474 refers to pharmaceutical cough preparations that comprise dextromethorphan and paracetamol.
European patent application n
o
E94908449 refers to pharmaceutical compositions that contain paracetamol and L-cysteine or a precursor thereof.
European patent application n
o
E95401290 refers to a powder-form formulation for drinkable solutions that contain metochlopramide and paracetamol, for uses in different therapies.
European patent application n
o
E95909789 refers to coated tablets that contain as active ingredients paracetamol and dompesidone (an antiemetic), with analgesic and antiemetic properties.
European patent application no. E96402580 refers to pharmaceutical compositions useful for treating migraines, compositions which contain paracetamol and metochlopramide.
Despite a lot of research, scientific publications and patents concerning paracetamol, it is certain that there is still not a galenic formulation thereof that is dispersible and soluble in water, with minimum effervescent effects and a high paracetamol content per pharmaceutical dose (tablet or packet of granulate) on the market.
Paracetamol has the physicochemical behavior characteristic of a fine powder barely soluble and dispersible in water. This is why the preparations currently existing on the market are practically insoluble and barely dispersible in cold water, which is the normal liquid medium which is used to swallow drugs. Only the Efferalgan brand tablets and effervescent packets of powder are soluble in cold water, but they do so rather slowly.
Nonetheless, it is well known that many consumers do not use effervescent preparations because they produce flatulence or prove to be unpleasant to take.
Besides, the weight ratio of paracetamol per dose in these cases is very low, because a rather large tablet, or a high granulate mass, is required in order to swallow a low dose of the active drug. This even makes it necessary to take two dose forms each time in order to achieve the threshold required for the desired effect.
Therefore, research still continues on new galenic formulations of paracetamol that overcome these inconveniences and that are easy to take.
The present inventors have focused their research efforts along these lines, achieving a new galenic formulation of paracetamol with excellent properties of dispersibility and solubility in cold water, which is the object of the present invention.
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° C. 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, th

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