Masking agent in powder form for pharmaceutical tastes

Details Masking agent in powder form for pharmaceutical tastes Masking agent in powder form for pharmaceutical tastes

2001-10-24

2003-07-29

Azpuru, Carlos (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S464000, C424S484000, C424S485000, C424S400000

Reexamination Certificate

active

06599534

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a masking agent in powder form intended to mask unpleasant pharmaceutical tastes of medicaments whenever necessary.
2. Description of the Prior Art
Traditionally, masking agents for unpleasant pharmaceutical tastes are used whenever the patient, especially a young child, has to take the medicament orally. The substances used are of various types and are generally added to the pharmaceutical formulation as an excipient. For example, we can cite sweeteners including saccharine and its derivatives.
Numerous studies on this subject aim more particularly to discover and exploit new substances rather than the way in which such substances can be incorporated in the final pharmaceutical composition. Numerous patents can be cited for example EP 0 351 566, EP 0 350 667, EP 0 351 567, relating to a taste modifier derived from a vegetable
Curculigo latifolia
called curculin, or EP 0 753 296 which indicates how to make an anti-inflammatory steroid, ibuprofen, which has a particularly strong bitter taste.
However, the principal problem is not to find new chemical substances, either natural or synthetic, for masking unpleasant tastes, but rather to develop the manner in which these new or known masking agents will be used.
It is in fact important that the masking effect should be constant and uniform from one administration of the medicament to the next, failing which the sought-after effect with the patient could not be guaranteed. This is precisely not so with traditional masking agents that are either powders statistically distributed in the final medicament formulation, or statistical mixtures of powders.
This is in particular the case when the masking agent contains a sweetener as sapid agent and a potentiator (or enhance) having very different particle sizes, namely a powder of a sweetener having a relatively large grain size mixed with a potentiator in the form of a much finer powder. The sweetener, that is to say the agent which provides the sweet taste, is usually saccharine or sodium or calcium saccharinate which themselves have a bitter of metallic taste, or sometimes other intense sweeteners of natural or synthetic origin.
The primary role of the sweetener or more generally of the sapid agent is to replace the unpleasant pharmaceutical taste of the final medicament.
The potentiator (or reinforcer, or enhancer) has a double role. Firstly, as its name indicates, it has the effect of extending the time of the perception of the taste of the sapid agent which, in its absence, would be too short. A good potentiator, as those classically used, allows for example an increase of the perception time, in particular the sweetness perception time (by 4 to 5 times). The other effect of the potentiator, and not the least, is to hide the secondary or parasitic taste of the sweetener, e.g. the bitter, metallic taste of saccharine or its sodium or calcium salts.
To avoid any ambiguity in the terminology used herein, we will used the term “masking agent” to designate the mixture of the sapid agent/potentiator, which is the subject of this invention, as well as traditional corresponding products serving for comparative purposes, whereas we will use the expression “masking formulation” or “masking premix”, when the masking agent itself is dispersed in a support.
Traditional masking agents of the sapid agent/potentiator type are statistical mixtures of one or more sweeteners and of one or more potentiators which have, as stated before, very different particles sizes, In spite of the care which can be brought to their realization, this can only result in very heterogeneous mixtures. They will therefore be named hereafter “coarse masking agents”.
DETAILED DESCRIPTION OF THE INVENTION
The problems evoked hereinabove are solved by the invention, in a surprisingly simple way, the invention consisting in proposing a powdered masking agent for pharmaceutical tastes in the form of an intimate mixture of a sapid agent and a potentiator. This mixture is in the form of an intimate mixture with a substantially uniform, non-statistical sapid agent/potentiator distribution, and wherein the proportion of sweetener to potentiator is substantially constant in all particles.
When reference is made to “a sapid agent”, or “a potentiator”, it should be understood that this is intended to comprehend “at least one sapid agent”, or “at least one potentiator”, respectively.
Preferably, the powdered masking agent according to the invention has a particle size comprised between 10 and 100 &mgr;m, with a Gaussian distribution. Preferably too, the proportion sapid agent/potentiator(s) is comprised between 97/3 and 90/10, expressed in parts by weight.
Particles are substantially spherical in shape and they do not segregate in bags. Their density is individually above 1, whereas the powder itself, due to the empty spaces between particles, has an apparent density between 0.7 and 0.8.
As indicated above and as will be seen below, because the proportion of sapid agent to sweetener is substantially constant and equal from one particle to the other, it will be constant from one granule to the other in the masking formulation wherein the masking agent is dispersed in a support, and consequently in the final medicament. This guarantees for the patient not only an acceptable taste, but above all a constant taste from one administration of the medicament to another administration.
According to one of the preferred embodiments of the invention, the masking agent according to the invention can be a powder with a Gaussian distribution and a mean particle diameter comprised between 10 and 100 &mgr;m, comprising between 65,000,000 and 85,000,000, for example around 75,000,000 particles per gram, compared to saccharine of 40-80 mesh having a particle size comprised between 100 and 1000 &mgr;m and comprising only 50,000 to 70,000, with a mean of about 60,000 particles per gram.
As sapid agent, a sweetener can be used or other substances such as methyl-, ethyl- or carboxyl(m)ethylcelluloses, pectins, carraghenates or alginates, all of which are able to excise an effect on the taste buds. Advantageously, one of several sweeteners will be used, for example sodium or calcium saccharinate or saccharine, already mentioned above, as well as other sweeteners such as aspartyl-phenylalanine, acesulfam and cyclamates and stevioside which is a glycoside of natural origin.
As potentiators, one can use thaumatin, which is a protein of vegetable origin, and glycosides such as neohesperidine dihydrochalcone (NHDC), glycyrrhizin, glutamate, etc., alone or mixtures thereof. These substances insure a great lingering of the sweet taste and cover the bitter and metallic aftertaste of saccharine and its salts.
The powdered masking agent according to the invention can also contain other ingredients in small quantities, such as taste enhancers, sodium glutamate, nucleotides (sodium inosinate and guanylate), maltol and ethylmaltol, etc. These ingredients are included in “microingredients” which can enter the intermediate formulation of the medicament or premix which can also contain vitamins, oligo-elements, or even other medicinal substances administered preventively or prophylactically. These substances are generally calculated to be present in an amount of 75 to 150 g per kg in the final medicament.
To prepare the masking agent according to the invention, its various constituents may be dissolved together in water at a temperature between 40 and 70° C., or alternatively, dissolution may be carried on in two separate batches which are thereafter mixed together, temperature being maintained in the above range.
Typical parameters for spray-drying at atmospheric pressure are as follows:
incoming air temperature: 175 to 200° C.
outgoing air temperature: 75 to 100° C.
incoming pressure (nozzle or turbine): 150 to 180 bars
flow rate of nozzle: 250 to 290 l/h
nozzle opening diameter: 1.15 to 1.25 mm
The powder falling down to the bottom of the spay-drying tower may be collected on a flui

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