MXPA99004552A - Pharmaceutical compositions containing 3-iodo-1,2-propanediol having mucolytic activity - Google Patents

Abstract

The present invention relates to pharmaceutical compositions containing 3-iodo-1,2-propanediol which are effective in increasing the output of thin respiratory tract fluid and liquefying tenacious mucus in the bronchial tree.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING 3-Y0D0-l, 2 ~ PROPANODIOL, WITH MUCOLYTIC ACTIVITY The present invention relates to pharmaceutical compositions containing 3-iodo-l, 2-propanediol, which have mucolytic activity and to a therapeutic method to increase the elimination of fluid from the thin respiratory tract and will liquefy tenacious mucus in the bronchial tree, which comprises administering orally a pharmaceutical composition containing a therapeutically effective amount of 3-iodo-1,2-propanediol in admixture with one or more pharmaceutically acceptable carriers. For a long time it has been believed that iodine is beneficial in the treatment of respiratory states, although the clinical test has not been developed to the level required by government authorities to obtain approval for the use of iodides in this treatment. . Probably, the most widely used iodide, mucolytic product has been iodinated glycerol, as described in U.S. Patent No. 2,872,378. Iodization of glycerol, according to this patent, results in an isomeric mixture of iodized dimers of glycerol. The precise structures and chemical formula resulting from the iodination of glycerol have not been fully established, however, it is generally accepted that it is an isomeric mixture of 67-75% of 2 (1-iodoethyl) -1,3-dioxolan-4 -methanol or 3-, 3- (2-iodopropylidenedioxy) propanol and 25-33% of 2- (2-iodoethyl) -1,3-dioxolan-4-methanol or 2, 3- (3-iodopropylidenedioxy) propanol. We have now found that the organic iodide 3-iodo-1,2-propanediol as a unique mucolytic agent is approximately 90 times as effective as iodized glycerol in increasing the elimination of the fluid from the small respiratory tract and in liquefying the tenacious mucus in the bronchial tree as determined by the tracheal secretion of phenol red in male mice. The stimulated tracheal secretion of phenol red is characteristic of such mucolytic activity. The 3-iodo-1,2-propanediol is prepared by the reaction of 3-chloro-l, 2-propanediol with sodium iodide and the recovery of the desired product in the manner set forth in the following example. The process for preparing 3-iodo-1,2-propanediol is usually carried out in a solvent selected from, for example, methyl ethyl ketone, dichloro methane, 1,2-dichloroethane, trichloroethane and mixtures of two or more. of these solvents. The temperatures at which the different steps of preference are carried out are within a range of ± 5 ° C of the temperature used in the examples.

The invention will now be further described with reference to the following examples: EXAMPLE 1 3-iodo-1, 2-propanediol 300 g of 3-iodo-1,2-propanediol, 500 g of anhydrous sodium iodide and 2 liters of methyl ethyl ketone are placed in a 3-necked round bottom flask of 5 liters, equipped with a condenser, condenser and drying tube.The mixture is stirred with reflux heating for 24 hours.The sodium chloride formed is then filtered and the filtrate is washed with 2 x 250 ml of acetone. The filtrate is then concentrated at 50 ° C in a Rotovap to approximately 500 ml or until no more solvent is evolved.The resulting oil and solid are dissolved in 1.5 liters of ethyl acetate and 100 ml of water.The organic layer is separated and Wash with 3 100 ml [sic] of water containing 10 g of thiosulfate per 100 ml of water.The organic layer is then concentrated at 50 ° C in a Rotovap 15 g of Dowex 50 H is added and the mixture The mixture is filtered and concentrated at 50 ° C in a Rotovap using toluene to allow the mixture to stir at room temperature for 48 hours. When the water is removed, the resulting oil is dissolved in 250 ml of chloroform at 50 ° C and cooled overnight in a refrigerator with seeded. The material is filtered and the cake is recovered and washed with 2 x 125 ml of ice-cold chloroform and 50 ml of toluene and dried to air at constant weight. The performance in 287.9. The material is recrystallized by dissolving 1250 ml of toluene [sic] containing 2% n-butanol at 90 ° C. 25 g of carbon are added and the material is filtered through Celite and rinsed with 150 ml of water containing 10 g of thiosulfate x 100 ml of water. The material is placed in an ice bath with good agitation and refrigerated overnight. The material is filtered and the cake is washed with 2 x 100 ml of water and 3 x 150 ml of toluene. The material is air dried at constant weight, the yield is 236 g of 3-iodo-l, 2-propanediol as a whitish crystalline powder with a purity of 99.5%, the organically bound iodine not less than 62.5% w / w and not more than 0.1% w / w of iodine free. The following example demonstrates the effect of glycerol iodine and 3-iodo-1,2-propanediol on the tracheal secretion of [lacuna].EXAMPLE 2 Adult male mice weighing 14-40 g were used in this investigation.The animals were acclimated to the laboratory environment for a maximum of 5 days before their use in the experimental procedures. controlled in which temperature, humidity and ventilation were regulated based on the needs of the species.The practices of administration and veterinary care were in accordance with Guide for Care and Use of Laboratory Animáis (NIH Publication No. 85-236) The tracheal secretion in mice, expressed by the amount of phenol red dye secreted in the lumen of the trachea was measured in accordance with the method of Engler and Szelenyi.The male mice were randomly placed in appropriate treatment groups. every day of the experiment, from 1 to 4 mice in a group received by vehicle (distilled water or 1% acacia, 0.1 ml / 10 g per body weight) _ or a medicine. Each medication was tested at a minimum of 3 different dose levels. Each dosage of the medication was tested on at least 6 animals. The drugs were administered orally (0.1 ml / 10 g of body weight) 30 minutes before the intraperitoneal injection of phenol red 8500 mg / kg: 5% solution in physiological saline, 0.1 ml / 10 g of body weight). 30 minutes after the phenol red injection the animals were sacrificed by exposure to C02. The entire trachea was carefully separated and washed in__1.0 ml of physiological saline for a period of 30 minutes. Subsequently, 0.1 ml of ÍM NaOH was added to the tracheal washings to stabilize the pH of the wash fluid. The amount of phenol red was measured photometrically at 546 nM in a Bechman model 25 spectrophotometer. The amount of phenol red secreted in the lumen of the trachea, expressed in μg / 10 g body weight / hour was determined by the Graziani formula and Cazzulani: VS = sx 10 W where: S = phenol red secreted by 10 g of body weight per hour (μg / lOg / hour). S = intensity of phenol red emission contained in 1.0 ml of tracheal wash as determined from the standard phenol red curve (0.5, 1, 5 and 10 μg / ml). V = volume of the tracheal wash (1.0 ml). W = body weight of the mice expressed in grams. The results were expressed as mean ± S.P.M. The statistical significance was evaluated using the t test for independent meaning, where P < 0.05 is considered significant compared to adequate control. The percent increase in tracheal secretion of phenol red for each dose of a drug was determined by the use of the following formula: T - C increment = -x 100 C T = tracheal secretion of phenol red (μg / lOg / hour) in treated mice, every day, C = tracheal secretion of phenol red (μg / lOg / hour) in untreated mice every day. The line of the best fit was calculated from the dose-response curve of each drug and the ED50 (mg / kg), that is, the dose that stimulates the secretion of the trachea from phenol red by 50% over the level of control, was determined and 95% of the confidence limits were also calculated. Iodized glycerol, 3-iodo-l, 2-propanediol, potassium iodide, N-acetylcysteine and albuterol exerted a dose-dependent increase in the secretion of the phenol red trachea in mice (Table 1). The ED 50 calculated (mg / kg, po, 30 minutes) were as follows: glycerol iodine = 68.3; 3-iodo-l, 2-propanediol = 0.75, albuterol = 0.18; N-acetylcysteine = 61.8) and potassium iodide = i > 00. Bromhexine (3, 30 and 100-- mg / kg, po, 30 minutes) exerted a weak to moderate effect not related to the dose (ED50 => 100 mg / kg) table 1. The data obtained show that iodinated glycerol and 3-iodo-1, 2-propanediol stimulates the tracheal secretion of phenol red that is characteristic of mucolytic activity. The 3-iodine-l, 2-propanediol is approximately 90 times as effective as iodized glycerol in stimulating the secretion of the trachea from phenol red in mice. Albuterol and potassium iodide also stimulated the [lacuna] tracheal mg / kg / respectively. Previously, others have reported an oral ED50 of approximately 4 and 4000 mg / kg for albuterol and potassium iodide, respectively. Prohexine produced a significant increase in tracheal secretion of phenol red alone at 100 mg / kg p.o. but with 3 or 30 mg / kg. In the same way, others have reported little or no bronchosecretagogic activity of bromhexine at 40 mg / kg p.o. in mice. The subcutaneous administration of bromhexine at 20-80 mg / kg, 15 minutes before the phenol red injection has been reported to exert a dose-dependent increase (from 10 to 42%) in tracheal secretion in mice. The expectorant / mucolytic drugs have been known to exert antitussive activity improving the elimination of fluid from the respiratory tract. 3-iodo-1,2-propanediol and iodinated glycerol have been shown to exert an antitussive effect against cough responses induced by citric acid (aerosol) in guinea pigs and after mechanical or electrical stimulation in cats. The ability of 3-iodo-1, 2-propanediol and iodinated glycerol to improve the waxy secretions of the trachea may also play a role in their antitussive activity reported in guinea pigs and cats. The results of the aforementioned research are set forth in Table I and clearly demonstrate the following: - 3-iodo-1, 2-propanediol and iodinated glycerol exerted dose-dependent stimulation of tracheobronchial secretion of phenol red in mice with a Oral ED50 of 0.75 and 68.3 mg / kg, respectively. The results demonstrate its mucolytic activity in this animal model system; y The results obtained show that 3-ydo-l, 2-propanediol and iodized glycerol are effective in stimulating the tracheal secretion of phenol red in mice, however, 3-iodo-l, 2-propanediol is approximately 90 times as effective as iodized glycerol.

Table 1 Effect of 3-iodo-l, 2-propanediol, iodinated glycerol, bromhexine, albuterol, potassium iodide and N-acetylcysteine on tracheal secretion of phenol red in mice 1 Organidin® available from Wallace Laboratories, Cranbury, New Jersey values are average ± SEM * P < 0.05 compared to the respective controls the numbers in the parentheses indicate the number of observations t dose of a drug that stimulates tracheal secretion by 50% over the control.

The pharmaceutical compositions according to the present invention are administered orally mixed with carriers, diluents, etc., compatible, normal. The active ingredient, 3-iodo-l, 2-propanediol can be formed into tablets in the normal form with other ingredients such as corn starch, calcium dibasic phosphate, red No. 40 FD &C, magnesium stearate, microcrystalline cellulose, tribasic calcium phosphate, etc., according to the following formulation: microcrystalline cellulose mg 3.5 starch _ mg 1.0 tribasic calcium phosphate mg 12.0 3-iodo-l, 2-propanediol mg 30.0 magnesium stearate mg 2.0 calcium dibasic phosphate mg 12.0 red FD &C No. 40 mg 0.5 An elixir formulation contains: 3-iodo-l, 2-propanediol mg 30 ethyl alcohol 21.75% by volume and glucose, sodium saccharin, purified water, natural and artificial flavors to produce 60 mg 3-iodo-l, 2-propanediol per 5 ml of elixir The examples Specific features have been provided illustrating the practice of the invention, however, the invention is not limited to the specific examples provided but is limited only by the scope of the appended claims.

Claims (3)

2. A pharmaceutical composition with mucolytic activity containing a therapeutically effective amount of 3-iodo-1,2-propanediol in admixture with one or more pharmaceutically acceptable carriers and diluents. The pharmaceutical composition as mentioned in claim 1, which consists of a tablet. The pharmaceutical composition as mentioned in claim 1, which consists of an elixir. A therapeutic method for increasing the elimination of fluid from the small respiratory tract and for liquefying the tenacious mucus in the bronchial tree, which consists in orally administering a pharmaceutical composition containing a therapeutically effective amount of
3. 3-iodo-1,2-propanediol. in admixture with one or more pharmaceutically acceptable carriers and diluents.