FR2631831A1 - Syrups based on xylitol, ribitol or arabitol - Google Patents

Abstract

The invention relates to the use of a pentitol, chosen from xylitol, ribitol or adonitol, and arabitol, both in the racemic form and in the form of one of its optically active isomers, in the preparation of non-cariogenic syrups for the oral administration of therapeutically active principles having a symptomatic action, the aforementioned active principle being chosen from those of antitussive, anti-inflammatory, analgesic and antipyretic medicaments.

Description

 The present invention relates to pharmaceutical compositions in the form of an orally administrable syrup and more particularly to pharmaceutical compositions whose absorption of the active ingredient (s) is improved, accelerated, and whose therapeutic effect is more effective.

 A major general problem encountered in the preparation of orally administrable pharmaceutical compositions is that of ensuring the best possible absorption of the active ingredient.

 Many efforts have been made, however, to improve the bioavailability of pharmaceutical substances and, in this connection, we cite as an example German Patent Application No. 206137 which describes a pharmaceutical composition in the form of tablets whose ingredients The active ingredients are calcium compounds, in which the use of xylitol as a component to improve oral calcium absorption has been anticipated.

 Indeed, it is known that the therapeutic effect of a drug, the onset of its action and its duration of action are related to the pharmaceutical formulation.

 Therapeutically, the benefits of improving the bioavailability and rate of asbestos of an active ingredient are obvious, especially if it is a substance used for symptomatic treatments; indeed, the sooner the effective hematic concentration thresholds of the drug are reached, the sooner the therapeutic effect will begin.

 In the case of syrups that are used in the pediatric field, the most common excipient is sucrose, known to have some side effects, including a slowing of gastric transit (Elias E. et al., J. Physiol. , 317, 1968), an incompatibility for the treatment of certain patients (diabetics, for example) and a carbogenic action.

 In connection with these last two contraindications, it is proposed in various publications to replace sucrose with xylitol.

 Surprisingly, it has been found that the use of certain pentols, in substitution for sucrose and / or other monosaccharides, in the formulation of excipients suitable for the preparation of medicaments in the form of syrup, makes it possible to improve absorption of the active ingredient, especially in terms of speed.

 Suitable pentols for this purpose are: xylitol, ribitol or adonitol, arabitol in the racemic form, or in the form of one of its optically active isomers, ie D- and L- arabitol.

 Indeed, it has been found - and this is the main object of the present invention - that by administering a medicinal syrup based on xylitol, the rate of absorption of the associated active ingredients was significantly increased, as demonstrated by the considerable reduction in the time at which the haematic concentration reaches its maximum level.

 In addition, the bioavailability of the active ingredients was superior.

possède un pouvoir édulcorant similaire à celui du saccharose et présente une excellente solubilité dans l'eau (64.2 g/100 g de solution).Xylitol or xylite (xylo-pentano-1,2,3,4,5-pentol) having the general formula C5H1205:

has a sweetening power similar to that of sucrose and has excellent solubility in water (64.2 g / 100 g of solution).

 Xylitol, itself, is well suited for the preparation of medicinal syrups as it has been found to be a very light, emollient base and to accentuate delicate weapons. In addition, it has been observed that xylitol gives concentrated and brilliant solutions, comparable to ordinary syrups or those containing glycerine, and that it does not tend to ferment or crystallize. In the context of the applications of the present invention, concentrated xylitol solutions of up to 64% can be used, the preferred concentrations being preferably between 10 and 60% by weight.

 The active principles conveyed by xylitol solutions at the appropriate concentration may be all those which are adapted to the desired therapeutic purpose.

 In the case of antitussive syrups, the active ingredients may be, for example, dextromorphan hydrobromide, diphenhydramine hydrochloride, hydrochloride and cloperastine fendizoate and codeine in the form of its various salts.

 The appropriate dosages are those usually employed for the active ingredients that can be used alone or in combination with others, in order to complete and enhance their effectiveness.

 These active ingredients can be decongestants (eg pseudo ephedrine hydrochloride), sedatives (eg doxylamine succinic), balsamics (eg terpine hydrate, d1-transoberol, or its levogyre or dextrorotatory optical antipodes) , mucolytics (e.g.

 acetylcysteine), antibiotics and other appropriate active ingredients.

 Other active ingredients can be usefully transmitted by xylitol, including anti-inflammatory and analgesic drugs (eg piroxicam, diclofenac, ibuprofen, etc.), analgesics and antipyretics (eg acetaminofen, paracetamol, etc.), bronchodilators (ex theophylline, procaterol, broxaterol, etc.).

 The active ingredients exemplified do not limit the scope of the present invention to any orally active drug specifically having a symptomatic action, administered by means of xylitol syrup or other pentols.

 Among the additives to the xylitol solutions used for the purposes described above, it is possible, for example, advantageously to employ, in concentrations of between 0.1 and 10%, xanthan gum and gum tragacanth, etc. ; polysaccharides (such as Konjak), ciclodextrin, etc.); mucilages like pectin, etc. ; proteins with a high molecular weight such as gelatin, etc.

 The interest of the present invention is illustrated by comparative experimental tests conducted on volunteers taking two syrups containing the same active ingredients, the first, prepared using xylitol and the second, using sucrose.

 A first experiment was carried out on two groups of 5 volunteers (3 women and 2 men aged between 25 and 46 years), the diphenhydramine hydrochloride being prepared respectively in a syrup of xylitol and a syrup of sucrose (Tab. I).

 The dose of diphenhydramine administered was 50 mg and the blood levels were determined using a flame ionization gas chromatograph (Bilzer et al., J. Clin, Pharmacol.6.268, 1973).

 The administration of the product took place on fasting.

During the examination, the subjects did not take any food or drink. Diphenhydramine administered in a xylitol-based syrup was found to be absorbed in a much shorter time than the delay observed when diphenhydramine was administered in a sucrose-based syrup.

 The haematological concentrations shown in Table I show that the maximum level is reached at the third hour with xylitol (but at the fourth with sucrose), and that the haemal concentration of the active ingredient is significantly higher with xylitol.

A second experiment was conducted on an identical group of volunteers, by age (between 29 and 46 years) and sex (3 women and 2 men) with cloperastine fendizoate, a substance with antitussive activity, syrups being TABLE I
Haematological levels and dispersion per dose of diphenhydramine (40 mg), cloperastine fendizoate
(40 mg) and piroxicam (40 mg) administered to volunteers as a syrup
based on xylitol and saocharose

<SEP> 0.30 <SEP> min <SEP> 1 <SEP> hour <SEP> 2 <SEP> hours <SEP> 3 <SEP> hours <SEP> 4 <SEP> hours <SEP> 5 <SEP> hours <SEP> 6 <SEP> hours <SEP> 7 <SEP> hours <SEP> 8 <SEP> hours
<tb> Diphenhydramine <SEP> (ng / ml)
<tb> - <SEP> Xylitol <SEP> 15.4 # 4.9 <SEP> 20.2 # 7.2 <SEP> 37.6 # 12.8 <SEP> 44.6 # 14.4 <SEP> 38 , 2 # 15.7 <SEP> 31.8 # 12 <SEP> 23.4 # 8.6 <SEP> 17.4 # 7.1 <SEQ> 11.4 # 6.1
<tb> - <SEP> Sucrose <SEP> 14 <SEP># 4.5 <SEP> 18.8 # 6.1 <SEP> 37.2 # 14.5 <SEP> 38.8 # 14.2 <MS> 40.4 # 14.8 <SEP> 32 <SEP># 10.5 <SEP> 24.8 # 8.3 <SEP> 19.2 # 7.1 <SEP> 12.8 # 6.4
<tb> Fendizoate <SEP> of
<tb> Cloperastine
<tb> (g / ml)
<tb> - <SEP> Xylibol <SEP> 0.014 <SEP>#<SEP> 0.030 <SEP>#<SEP> 0.019 <SEP>#<SEP> 0.014 <SEP>#
<tb><SEP> 0.003 <SEP> 0.007 <SEP> 0.002 <SEP> 0.004
<tb> -Sucharose <SEP> 0.013 <SEP>#<SEP> 0.019 <SEP>#<SEP> 0.029 <SEP>#<SEP> 0.017 <SEP>#
<tb><SEP> 0.003 <SEP> 0.002 <SEP> 0.007 <SEP> 0.004
<tb> Piroxicam
<tb> (ng / ml)
<tb> - <SEP> Xylitol <SEP> 1.7 # 0.6 <SEP> 3.9 # 1.1 <SEP> 3.5 <SEP>#<SEP> 1.1 <SEP> 3.3 <SEP>#<SEP> 1,2
<tb> - <SEP> Sucrose <SEP> 1.5 # 0.96 <SEP> 2.8 # 1.03 <SEP> 3.4 <SEP>#<SEP> 1.0 <SEP> 3.3 <SEP>#<SEP> 0.8
<tb> respectively prepared with xylitol and sucrose.

The dose of fasting fendizoate of cloperastin administered to volunteers was, in both cases, 40 mg.

 The hematic concentrations of cloperastin were evaluated using a flame ionization gas chromatograph. The corresponding results are also reported in Table I.

 In this experiment, it was also found that cloperastin administered in xylitol syrup was absorbed more rapidly than cloperastin administered in a sucrose syrup.

 A third experiment was carried out with an anti-inflammatory active ingredient with analgesic activity, piroxicam, prepared as in the previous experiments, either in a syrup of xylitol, or in a syrup of sucrose. It was conducted on groups of 5 subjects, under the same experimental conditions as in previous tests.

 Patients treated with xylitol syrup were 3 men and 2 women, aged 29 to 71, while patients treated with sucrose syrup were 4 men and 1 woman aged 38 to 62 years.

 The dose of piroxicam administered was 40 mg in both cases and the active ingredient was dosed by a fluorometric method (Hobbs, K. et al., J. Clin.

Pharm.19, 270, 1979). The results have also been reported in Table I.

 As in the other two experiments, it was found that xylitol allowed to obtain a faster absorption of the active ingredient.

 The improvement of therapeutic activities, object of the present invention, is demonstrated by an experiment carried out on volunteers. A 6 volunteers (4 men and 2 women aged between 36 and 60 years), with an inflammatory condition of the upper airways and very severe symptoms of cough, were administered two syrups containing cloperastoin fendizoate at the same concentration per dose but prepared, one with xylitol, the other with sucrose.

 The evaluation of the cough was done objectively with a device able to measure coughing accesses according to the method described by Oldini et al. (Curr Ther Ther 42, 99, 1987).

 The corresponding results have been reported in Table II. Cloperastoin, administered at a dose of 20 mg in the xylitol syrup, causes a markedly earlier onset of antitussive activity than is achieved when cloperastol fendizoate is administered in a sucrose syrup.

TABLE II
Cough access measured in 6 patients with inflammatory conditions of the upper airways before and after 20 mg of cloperastine fendizoate prepared in xylitol and sucrose syrup.

<Tb>

<SEP> TIME <SEP> (in <SEP> minutes)
<tb><SEP> - <SEP> 15 <SEP> 0 <SEP> 15 <SEP> 30 <SEP> 45 <SEP> 50
<tb> Xylitol <SEP> 32.2 <SEP> 36.2 <SEP> 21.3 <SEP> 18.5 <SEP> 13.7 <SEP> 14.2 <SEP>
<tb><SEP> 10.8 <SEP> 7.6 <SEP> 4.2 <SEP> 10.6 <SEP><SEP> 6.6 <SEP> 4.3
<tb> Sucrose <SEP> 34.8 <SEP> 28.5 <SEP> 33 <SEP> 26.3 <SEP><SEP> 21.8 <SEP><SEP> 18.8 <SEP>
<tb><SEP> 12.1 <SEP> 9.3 <SEP> 10.0 <SEP> 7.9 <SEP> 5.0 <SEP> 4.0
<Tb>
Finally, a pharmacological demonstration of the greater speed of action obtained with the pharmaceutical preparations object of the present invention is provided by the experimentation of an anti-inflammatory active ingredient in rats, in the test of carrageenan.

 The experiment is carried out on two groups of rats (Charles River) weighing between 110 and 130 grams.

 The carrageenan edema inhibition test was performed according to the method described by Wiseman (Arzneim-Forsch 26, 1300, 1978).

 The evaluation of the inhibition of edema was made 30 minutes, 1 and 3 hours after the oral administration of 4 mg / kg of piroxicam in solution, either in xylitol or in sucrose.

 The values of the corresponding inhibition have been reported in Table III.

TABLE III
Percutaneous inhibition of carrageenin edema in rats after administration of piroxicam (4 mg / kg) in either xylitol or sucrose.

<SEP> TIME
<tb><SEP> 30 <SEP> minutes <SEP> 1 <SEP> hour <SEP> 3 <SEP> hours
<tb><SEP> Xylitol <SEP> 32.2 <SEP>#<SEP> 7.6 <SEP> 50.5 <SEP>#<SEP><SEP> 7.3 <SEP> 55.8 <SEP>#<SEP><SEP> 5.6
<tb> Sucrose <SEP> 5.0 <SEP>#<SEP> 5.6 <SEP> 36.3 <SEP>#<SEP><SEP> 8.9 <SEP> 54.0 <SEP>#<SEP><SEP> 4.6
<Tb>
In this test, it was further found that the xylitol syrup had earlier effects over time.

 In addition to improving the therapeutic effect of greater bioavailability and faster uptake, preparations formulated in a syrup containing xylitol as an excipient have no cariogenic effect and can be administered to diabetic or overweight patients.

 The compositions according to the present invention are prepared according to the pharmaceutical techniques usually employed for the preparation of syrups, using the appropriate ingredients, solvents, stabilizers, preservatives, anti-oxidants, weapons, buffers, salts, ingredients to correct or cover the bitter taste. etc. These techniques and substances are familiar to those skilled in the art.

The invention will be better understood thanks to the description of the examples which follow, given in a non-limiting manner.

EXAMPLE 1
Cloperastine fendizoate syrup
Fendizoate cloperastine 7.08 g
Xylitol 200 g
Xanthan gum 2 g methyl p-hydroxybenzoate 1,2 g propyl p-hydroxybenzoate 0,2 g
Citric acid 250 mg
Strawberry aroma 250 mg
Distilled water qs 1000 mi
The xanthan gum is dissolved in 100 ml of water.

All other ingredients, except for cloperastine fendizoate, are dissolved in 300 ml of water, and each solution is filtered. The two solutions are then mixed and the volume is made up to 1000 ml with distilled water. To the final solution, finally cloperastine fendizoate is added with stirring.

 A suspension is obtained which is packaged in glass flasks of the desired capacity.

EXAMPLE 2
Codeine syrup
Codeine Phosphate lg l-transobrerol lg
Glycerine 20 ml
Xylitol 300 g
Cherry weapon 500 mg
Distilled water qs 500 ml
The finely pulverized l-transobrerol is mixed with the glycerin until a solution is obtained. This is then added to 200 ml of water in which the codeine phosphate has previously been dissolved.

 The xylitol and the aroma are added successively with stirring until a solution is obtained, warming slightly if necessary. The volume is made up to 500 ml with distilled water, filtered and conditioned as before.

EXAMPLE 3
Expectorant syrup with diphenhydramine
Diphenhydramine Hydrochloride 2.5 g
Ammonium chloride 18 g
Xylitol 550 g
Xanthan gum 1 g
Sodium benzoate 1.5 g
Citric acid 135 mg
Raspberry flavor 350 mg
Distilled water qs 1000 ml
This syrup is prepared as described in Example 1.

EXAMPLE 4
Mucolytic syrup
Acetylcysteine 20 g
Xylitol 550 g
Glycerin 50 g
Xanthan gum 1 g
Sodium benzoate 1.5 g
Saccharin 0.5 g
Citric acid 0.25 g
Concentrated aroma of lemon 1 g
Distilled water qs 1000 ml
The xanthan gum is dissolved in 100 ml of water.

 Saccharin and the concentrated aroma of lemon are dissolved in glycerine while warming slightly. All other ingredients are dissolved in 300 ml of water. The three previous solutions are thoroughly mixed and the volume is made up to 1000 ml with distilled water.

 Filter and condition as before.

EXAMPLE 5
Anti-inflammatory and analgesic syrup
Piroxicam 2 g
Xanthane gum 2 g
Xylitol 200 g
Polyoxyl-40 stearate 1 g methyl p-hydroxybenzoate 1.22 g propyl p-hydroxybenzoate 0.18 g
Orange essence 0.003 g
Distilled water qs 1000 ml
Methyl propyl p-hydroxybenzoate is dissolved in 450 ml of water brought to 80-90C.

 It is allowed to cool to 60 ° C. and xylitol and xanthan gum are added. Polyoxyl-40 stearate and piroxicam are dissolved in 50 ml of 45wu water. Both solutions are mixed and the orange essence is added at room temperature.

 The volume is then supplemented to 1000 ml and stirred for 30 minutes. We control by analysis and filter.

EXAMPLE 6
Analgesic and antipyretic syrup
Paracetamol 50 g AvicelORC 591 15 g
Xylitol 300 g
Polyoxyl-40 stearate 1 g methyl p-hydroxybenzoate 1.22 g propyl p-hydroxybenzoate 0.18 g
Orange essence 0.3 g
Purified water qs 1000 ml
In 450 ml of purified water, the preservatives are dissolved under heat and, successively, while still maintaining the temperature between 60 ° and 70 ° C., the xylitol is added, with stirring, until complete dissolution is obtained.

 To this solution is added successively the Avicele RC-591, maintaining the stirring until complete homogeinization, then allowed to cool to 25 ° C.

 A purified water-based emulsion, polyoxyl-40 stearate and paracetamol are separately prepared. The solution and the emulsion are mixed until homogeneity, the orange essence is added and then the volume is made up to 1000 ml with purified water. Stirring is maintained until complete homogenization and filtration.

EXAMPLE 7
Formulations based on arabitol
In the compositions of the preceding examples, an equivalent amount of arabitol is substituted for xylitol. The procedures are the same as those previously described for xylitol.

 As has been indicated above, the present invention finds a similar application in the administration, by means of a syrup, of other active ingredients with a symptomatic effect, which are, for example, anti-inflammatory analgesics, antipyretics, sulfonamides, antibiotics; it is not necessary to expand further on the benefits of this type of administration for pediatric medicines.

Claims (7)

1. Using a pentol selected from xylitol, ribitol or adonitol, arabitol both in the racemic form and in the form of one of its optically active isomers, in the preparation of non-cariogenic syrups for oral administration of therapeutically active principles with symptomatic action, said active principle being chosen from those of antitussive, anti-inflammatory, analgesic and antipyretic drugs. Use of xylitol according to claim 1, in the preparation of non-carbogenic syrups for the administration of therapeutically active principles with symptomatic action orally. 3.- Use of xylitol according to claim 2, characterized in that said xylitol is in the form of an aqueous solution whose xylitol concentrations reach up to 64%. 4.- The use of xylitol according to claim 2, characterized in that said active ingredient is a antitussive drug. 5.- Use of xylitol according to claim 4, characterized in that said antitussive drug is selected from the hydrobromide of destromorphan, diphenhydramine hydrochloride, codeine and its pharmaceutically acceptable salts, the hydrochloride and cloperastine fendizoate. 6.- The use of xylitol according to claim 2, characterized in that said active ingredient is an anti-inflammatory analgesic. 7.- Use of xylitol according to claim 2, characterized in that said active ingredient is an antipyretic 8.- Use of xylitol according to claim 2, characterized in that associated with the syrup, additives to increase the viscosity of the solution and / or to increase the sweetening power and / or promote the suspension of insoluble active ingredients. Syrups obtained using xylitol according to any one of the preceding claims. 10.- Use of arabitol according to claim 1.  11. Syrups obtained according to one of claims 2 to 8, using arabitol instead of xylitol. 12. Syrups obtained according to claim 10.