MXPA00000754A - Pharmaceutical compositions containing an effervescent acid-base couple - Google Patents

Abstract

A pharmaceutical composition in form of effervescent tablets comprising an active ingredient and an effervescent blend, wherein the effervescent blend comprises an acidic component and sodium glycine carbonate as alkaline components. Preferred acid component are fumaric acid, maleic acid and their salts. Tablets are prepared by direct compression in normal thermo-hygrometric conditions and with standard tabletting equipment.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING AN ACID-EFFERVESCENT BASE DESCRIPTION OF THE INVENTION The present invention relates to fast-dissolving, solid pharmaceutical compositions administered orally, containing an effervescent acid-base pair, suitable for dissolving in water or in an aqueous solution and for sucking. Effervescent tablets occupy an important position among pharmaceutical forms, being the form of choice not only for adults, but also for children. Many drugs, and in particular analgesics, vitamins and antibiotics, were designed in this type of formulations. Effervescent tablets, when added to cold water, generate a gas that causes effervescence and produces a clear foaming solution. The gas that produces the effervescence is always carbon dioxide, which is derived from the reaction between an acid and a base, such as a carbonate or dicarbonate. The effervescent tablet consists of at least three components: the active ingredient; an acid; - an alkaline compound (basic ingredient) constituted REF: 32618 by a carbonate or a bicarbonate. Acid and alkali are essential components that provide the effervescence and disintegration of the tablet when it comes into contact with water. As an acidic component, citric acid is frequently used, both in its hydrated form and in anhydrous form, but other edible acids such as tartaric, fumaric, adipic, malic acid can also be used. Carbonate, which represents the source of carbon dioxide that generates effervescence, is usually a water-soluble alkaline carbonate. The selection of carbonate is very important since, in addition to provoking effervescence, it can have an influence on the stability of the tablet. Sodium bicarbonate is one of the most used carbonates, because it is very soluble and inexpensive. Alternatively, modified sodium bicarbonate, obtained by heating common sodium bicarbonate in order to transform the surface of its particles into sodium carbonate, can be used to increase its stability. Other physiologically acceptable alkaline earth metal or alkali metal carbonates, such as potassium or calcium (bi) carbonate, sodium carbonate or sodium glycine carbonate may be used. The effervescent tablet compositions may also include a lubricant, which has to be selected from among the fully water-soluble compounds that form a clear solution. Examples of this type of lubricants are sodium benzoate, sodium acetate, fumaric acid, polyethylene glycols (PEG) greater than 4000, alanine and glycine. Conventional excipients such as diluents, ligands, pH regulators, sweeteners, flavors, colorants, solubilizers, disintegrants, wetting agents and other commonly used excipients can be added to the formulation. Effervescent tablets are easy-to-use, attractive and convenient pre-measured pharmaceutical forms. However, these advantages are balanced by some technological problems, the two most important being hygroscopicity and lubrication. The instability of the effervescent tablets, their tendency to absorb moisture and the loss of reactivity, are generally known. Due to this instability in the presence of water, conventional wet granulation and the subsequent compression of the granulate are very difficult to apply. Sometimes the granulation has to be carried out using very low amounts of water, for example by melting citric acid monohydrate, which on heating releases part of the water of crystallization, which acts as the granulating fluid. Then, the granulate has to be processed under controlled humidity conditions, usually less than 20%. Alternatively, anhydrous granulation techniques, in the absence of aqueous phases, have been applied using volatile organic solvents such as ethanol. However, some techniques require special manufacturing environments with strictly controlled conditions of relative humidity (usually below 20% and with explosion-proof equipment.) Another technique, which is more time consuming and laborious, is represented by wet granulation. separately from the acid granules and the alkali granules, which are subsequently mixed and compressed to obtain the final pharmaceutical composition.The direct compression of the simple physical mixture of the components of the formulation, represented an attempt to obviate the technological difficulties However, such operation has been carried out under controlled thermo-hygrometric conditions, for example at temperatures below 20-25 ° C and with a relative humidity less than 30%, using tabletting machines with tapered dies and punches lined with alloys of chromium due to operating and stabilized problems d, this type of manufacturing method can not be easily applied for the manufacture of effervescent tablets of particular active ingredients which can not be wet granulated or which contain a residual percentage of water of crystallization, which is difficult to remove. Typical examples of this type of drugs are cyclodextrin complexes, active ingredients, hydrates and their salts, which can present stability problems in the presence of water. Similar problems are encountered when the composition contains excipients that possess water of hydration or residual moisture difficult to remove. Typical examples of this type of excipients are cyclodextrins. • The other important technological problem that affects the manufacture of effervescent tablets is lubrication, since the lubricant must not only have lipophilic properties for a good lubrication, but it must also have a high solubility in water, to produce a disintegration adequate and quickly produce a clear solution. Most substances used as lubricants, such as magnesium stearate, are effective but insoluble in water. The resulting solution after disintegration is opaque and often has a soapy taste. Ideally, non-toxic lubricants with high water solubility and acceptable taste are required. In addition, the effervescent base is inherently difficult to lubricate, partly due to the nature of the raw materials used and partly due to the rapid disintegration of the tablet normally required, which limits the use of a high percentage of lubricants. It has now been found, and this is an object of the present invention, that effervescent tablets can be prepared by simple techniques having direct industrial application and which are based on the use of a particular effervescent mixture of acids and glycine carbonate. sodium, provided in an amount sufficient to disperse rapidly and aid in the dissolution of the components of the formulation. In particular, according to a second aspect of the present invention, it was found that the use of a mixture of certain acids with sodium glycine carbonate makes it possible to prepare effervescent tablets by direct compression under normal thermo-hygrometric conditions and with standard tabletting equipment. It has been found, even more surprisingly, that this technology also applies to active ingredients and / or excipients that can not be wet granulated because they contain a residual percentage of water of crystallization difficult to remove. In accordance with another aspect of the present invention, it was found that the use of certain acid mixtures / sodium glycine carbonate is particularly advantageous in the preparation of effervescent tablets containing a cyclodextrin as a component of a complex inclusion or as an excipient, despite the fact that cyclodextrins have water of hydration and tend to absorb moisture very easily. The characteristics of the excipients that can be used in the preparation of the effervescent tablets have been described in Aiache JM, Pharm. Acta Helv. 49 (5/6), 169-178, 1974; and in Boymond C, Labo-Phar to Probl. Tech. 25 (271), 987-995, 1977. In any case, Faguet JP et al. , in Labo-Pharma Probl. Tech. 26 (274), 207-210, 1978, after evaluating the effects of moisture on the stability of acids, carbonates and bicarbonates, concluded that when sodium glycine carbonate, which is inherently sensitive to moisture, is mixed with an acid, specifically citric acid, the resulting carbonate is very unstable to moisture, much more than sodium glycine carbonate alone. In some patents, sodium glycine carbonate is simply mentioned, among several different excipients, as a possible component of effervescent combinations that can be used in chewable tablets (European Patent EP 396335) in formulations that form a suspension when contacted with water (European Patent EP 524846), in compositions consisting of acid and alkali granules separately, which may also comprise a moisture trap (ZA 9307745), in oral, cold water soluble formulations of β-cyclodextrin complexes with drugs non-spheroidal anriinflammatories such as ibuprofen, naproxen or ketoprofen (International Publication WO 9504528). However, none of the above documents teaches the preparation of effervescent tablets using sodium glycine carbonate as the basic component, nor do they suggest the possible advantages of this. The use of sodium glycine carbonate in effervescent formulations is described in patent applications and in the scientific literature with respect to formulations containing amoxicillin hydrate (PCT International Publication WO 9115197), isosorbide-5-mononitrate (German Patent DE 4416769) and enzymes (French Patent FR 2305194). The acid component in these formulations consists of citric, tartaric, malic or adipic acid, and the manufacturing process includes steps of pulping, grinding the paste, mixing and compression, or the use of anhydrous excipients or, also, an external lubrication of the machine. Amela J. et al. , in the document "Drug Dev Ind Pharm 22 (5), 407-16, 1996", makes the analysis of several components that can be used in the preparation of effervescent tablets and conclude that the carbonate of sodium glycine is one of the carbonates that do not have favorable compression characteristics. The formulation of the present invention essentially comprises: an active ingredient; - sodium glycine carbonate; an acid capable of reacting rapidly with sodium glycine carbonate, to release carbon dioxide. One of the preferred acids is fumaric acid, which may be present in salt form such as monosodium or monopotassium fumarate. Certain types of formulations take advantage of the lubricating properties of fumaric acid, which limits the amount of lubricant.

Another preferred acid is maleic acid, optionally present in salt form. The choice of acid is made according to the characteristics of the active ingredient. In some cases mixtures of acids and / or salts are particularly suitable for modulating either the strength of the acid or the lubricating properties. The use of fumaric acid in effervescent formulations is described in several documents that relate to various formulations, but never in combination with sodium glycine carbonate. Patents EP 44381, FR 2715849, WO 9300886, WO 9107174, WO 9104757 are examples of patents mentioning fumaric acid among other acids that are commonly used in effervescent pharmaceutical forms such as US Pat. Nos. 4153678, US 4812303 and US 4704269, which refer to formulations of particular active ingredients. In other documents (among which are for example British Patent GB 1178294, Rosheisen G. and Schmidt PC Eur J. Pharm. Biopharm, 41 (5), 302-308, 1995), fumaric acid is considered as a lubricant. Maleic acid has also been described as an acid component of effervescent pairs, but never in combination with sodium glycine carbonate.

In a particular embodiment of the present invention, the active ingredient of the formulation contains a residual percentage of moisture or water of crystallization difficult to remove. Examples of this type of active ingredients are drug complexes such as the piroxicam-β-cyclodextrin complex, the levodopa methyl ester and the carbidopa hydrate. The piroxicam-β-cyclodextrin complex. it has been described in European Patent EP 153998, where an effervescent tablet formulation is also exemplified. In this case, citric acid and sodium glycine carbonate represented the effervescent mixture. However, the tablets that correspond to the formulation exemplified in European Patent EP 153998, have unfavorable characteristics such as opacity of the solution produced, high dimension and weight and low fluidity of the weighted mixture to be consumed. In addition, the presence of sucrose as a diluent and of sweetening agents compromises the stability of the same formulation, as has been proved later. The formulation may comprise other excipients such as: a lubricant which is selected from the group consisting of PEG greater than 4000 and preferably PEG 6000, sodium benzoate, sodium and potassium fumarate, leucine, alanine; a sweetening agent that is selected from the group consisting of aspartame, saccharin, cyclamate, sugars, preferably aspartame; a diluent selected from the group consisting of lactose, mannitol, sorbitol or mixtures thereof and preferably spray-dried lactose (SD) and optionally flavoring agents, ligands, preservatives and others. As a diluent, lactose SD is particularly preferred as it facilitates the fluidity of the mixture, to improve the compressibility and the machinability of the formulation. The particular effervescent mixture of the present invention, together with the aforementioned additives, makes it possible to obtain highly soluble, stable, small-size effervescent tablets by direct compression of the mixture of components, which can be worked under the standard thermo-hygrometric conditions of the normal pharmaceutical production facilities, using standard compression machines with normal punches and dies. Likewise, the subsequent processing, storage and packaging of the tablets, can be carried out under normal conditions of temperature and humidity. The effervescent compositions of the present invention are solubilized on contact with water and produce a clear solution for oral administration. Solutions are favored over suspensions for oral administration, since drugs in solution are absorbed more quickly. The solutions are often also more acceptable for patients, in terms of tastability. However, in some cases the active ingredient does not dissolve and the composition does not result in a clear solution, but in a suspension. For this type of active ingredients, the possibility of preparing a tablet by direct compression and obtain rapid disintegration, in any way, represents a remarkable improvement of the formulation. Other advantages of the composition are the low content of sodium ions, due to the use of sodium glycine carbonate, with respect to the other sodium carbonates and to a less bubbling effervescence, which is more pleasing for the patient. In addition, the composition of the present invention, due to its small size, its low effervescence and rapid disintegration, can also be prepared as a fast-dissolving or mouth-sucking tablet. In fact, when it is introduced into the mouth and comes in contact with saliva, the tablet disintegrates and quickly forms an aqueous solution or dispersion that is easy to swallow. The following Examples further illustrate the present invention. EXAMPLE 1 Composition of an effervescent tablet having a piroxicam content of 20 mg. Piroxicam-ß-cyclodextrin (1: 2.5 191.2 mg Sodium glycine carbonate 260.0 mg Fumaric acid 180.0 mg PEG 6000 20.0 g Spray-dried lactose (SD) 208.8 mg Lemon flavor 25.0 mg Aspartame 15.0 mg The piroxicam-β-cyclodextrin, the lactose SD, the sodium glycine carbonate, the lemon flavoring, the aspartame and the PEG 6000 are sieved and premixed. The fumaric acid is added and the components are mixed until a homogenous mixture is obtained. Afterwards, the mixture is compressed in a standard tabletting machine equipped with chromed punches. The process is carried out at room temperature and with a relative humidity not higher than 55-60%. The dimensions of the tablets produced are approximately 13 mm in diameter, 5 mm in thickness, and weighing approximately 900 mg. EXAMPLE 2 Test of the active ingredient solution. The analysis of the tablets prepared according to Example 1 was carried out in order to determine the percentage of the active ingredient dissolved at the end of the effervescence. The maximum dissolution time with effervescence is 1.5 minutes. The experimental conditions simulated the taking of the effervescent tablets by the patient. The effervescent tablet was dissolved in three types of water. At the end of the effervescence (1.5 minutes) the amount of piroxicam-β-cyclodextrin in solution was determined. The data obtained, which are reported in Table 1, show that the concentration of the active ingredient in the solution is always greater than 70% of the nominal content, per tablet. Table 1. Piroxicam-ß-cyclodextrin solution in 50 ml of water Type of water% of active ingredient dissolved demineralized water 72.4 drinking water 85.6 non-natural non-carbonated water 77.0 EXAMPLE 3 Speed of dissolution of effervescent tablets containing piroxicam-β-cyclodextrin complex, in comparison with standard tablets. The dissolution rate of the effervescent tablets prepared in Example 1 was compared with that of standard piroxicam-β-cyclodextrin tablets, using USP Apparatus 2 (without pallets) in distilled water, at a temperature of 37 ° C. . Piroxicam time dissolved solution (minutes) (%) standard tablets of 20 mg 5 65% 10 100% effervescent tablets of 20 mg 100% EXAMPLE 4 The absorption profile of the piroxicam released from the effervescent tablets of piroxicam-β-cyclodextrin complex (β-CD) prepared according to the present invention was compared to that of standard piroxicam-β-CD tablets available in the Commerce. The test was carried out after a single oral dose of the two formulations, equivalent to 20 mg of piroxicam, in 16 healthy volunteers according to a randomized two-way crossover design. The results, reported in Table 2, confirmed the behavior of the two compositions in the dissolution test, demonstrating a more rapid absorption of the active ingredient after the administration of the effervescent formulation of the present invention. Compared to the standard formulation, the effervescent tablet produces markedly higher plasma concentrations (Cp of 1.93 μg / ml vs. 0.77 μg / ml, respectively) 15 minutes after administration, as well as increased exposure to the drug during the first hour after administration. administration, as shown in the ABC data (ABC = Area Under the Curve, ie the area under the plasma concentration vs. time curve), collected after 1 hour. Table 2. Main pharmacokinetic parameters (geometric mean ± standard deviation), statistical comparison and 90% confidence intervals standard (90% CI). Parameters Tablet Tablets Cl 90% pharmacokinetics Piroxicam-ß-CD effervescent P * Piroxicam-ß-CD (n = 16) (n = 16) Cp 15 min 0.77 1.93 160% -389% lμg / ml) (0. 310 -1.90) (1. .33-2.80) 0.003 Cp 30 min 2.01 2.26 100% -127% (μg / ml) (1 .47-2.73) (i .64-3.10) 0.106 Cp 45 min 2.15 2.22 94% -114% (μg / ml) (1.76-2.62) (i., 66-2.97) 0.570 Cp 1 h 2.08 2.09 93% -109% (μg / ml) (1. .75-2.46) (i .58-2.77) 0.845 Cmax 2.23 2.35 96% -116% (μg / ml) (i .83-2.72) (i .74-3.16) 0.330 ABC 1 h 1.55 1.88 107% -138% (μg / ml) (i .19-2.01) (i .40-2.53) 0.018 * Level of significance calculated by the analysis of variance (ANOVA) Cmax = Maximum plasma concentration. EXAMPLE 5 The stability of the effervescent mixture and tablets prepared according to Example 1 was tested at 25 ° C and at different relative humidity conditions. Both in the effervescent mixture and in the tablets stored at a relative humidity of 11%, 33%, 52% and 75% showed an increase in weight at the beginning of the study and then a slight weight decrease (see Tables 3 and 4) . This behavior is due to two correlated phenomena: the absorption of moisture and the subsequent loss of carbon dioxide.

The absorption of moisture prevails during the first days with respect to the release of carbon dioxide. The loss of carbon dioxide, however, was so low that the effervescence characteristics of the tablets were not affected. Table 3. Variation of% by weight of the mixture at room temperature (approximately 25 ° C), under different conditions of relative humidity (RH). HR Days 1 2 3 4 ~ 7 9 11 11% 0.06 0.09 0.11 0.09 0.08 0.07 0.07 33% 0.22 0.24 0.23 0.22 0.21 0.20 0.20 52% 0.30 0.30 0.29 0.29 0.27 0.27 0.27 75% 0.42 0.42 0.41 0.40- 0.35 0.33 0.34 Table 4. Variation of% by weight of tablets at room temperature (approximately 25 ° C), under different conditions of relative humidity (RH). HR Days 11 11% 0.05 0.10 0.14 0.10 0.08 0.07 0.07 33% 0.19 0.20 0.20 0.18 0.17 0.16 0.16 52% 0.26 0.25 0.24 0.23 0.21 0.21 0.20 75% 0.17 0.15 0.13 0.12 0.08 0.07 0.07 The effervescent mixture and tablets according to the present inven absorb a very low amount of water (3.5% for the mixture and 3.0% for the tablets) even in very unfavorable storage conditions, for example 11 days at 75% relative humidity ). Under these particular unfavorable conditions, the chemical, technological and effervescence characteristics of the tablets are not substally modified, as shown in Tables 5 and 6. Table 5.% humidity and purity of the mixture after 11 days of storage in different conditions of relative humidity. Test Value Values at day 11 Initial HR 11- HR 33 * HR 52 * HR 75? 1) Humidity (r) 2.4 3.6 4.1 4.5 5.9 2) Purity < 0.005 < 0.005 < 0.005 < 0.005 < 0.005 Table 6. Chemical and technological characteristics of the tablets after 11 days of storage under different relative humidity conditions. Test Value Values at day 11 Initial HR 11: HR 33? HR 52% HR 75% Characteristics complies compliance complies fulfill effervescence compliance (disintegration < 5 minutes) 1) Humidity (%) 2.5 3.3 3.9 4.4 5.5 2) Purity < 0.005 < 0.005 < 0.005 < 0.005 < 0.005 1) The percentage of moisture absorption was determined by the Karl Fischer method. 2) The purity was estimated by determining the percentage of 2-. aminopyridine, which is the main degradation product of piroxicam. EXAMPLES 6 TO 14 With processes analogous to that described in Example 1, the following tablet formulations were prepared: EXAMPLE 6 Ambroxol hydrochloride. a) Ambroxol Hydrochloride 30 mg Lactose SD 800 mg Sodium glycine carbonate 400 mg Fumaric acid 260 mg PEG 6000 40 mg Aspartame 30 mg The mixture was compressed directly into tablets with a diameter of 17 mm and a thickness of 5.5 mm. b) Ambroxol Hydrochloride 60 mg Lactose SD 600 mg Sodium glycine carbonate 400 mg Maleic acid 250 mg PEG 6000 40 mg Aspartame 30 mg The mixture was compressed directly into tablets with a diameter of 17 mm and a thickness of 5.0 mm. EXAMPLE 7 Paracetamol. Paracetamol (acetaminophen) 500 mg Sodium glycine carbonate 260 mg 180 mg fumaric acid PEG 6000 10 mg The mixture was compressed directly into tablets with a diameter of 13 mm and a thickness of 5.1 mm. EXAMPLE 8 Combination of paracetamol / domperidone maleate. Paracetamol (acetaminophen) 500 mg Domperidone Maleate 10 mg Sodium glycine carbonate 400 mg Fumárico acid 300 mg PEG 6000 10 mg Aspartame 20 mg The mixture was compressed directly into tablets with a diameter of 15 mm and a thickness of 5.7 mm. EXAMPLE 9 Nimesulide. a) Nimesulide 50 mg Lactose SD 500 mg Sodium glycine carbonate 800 mg 180 mg fumaric acid PEG 6000 40 mg The mixture was compressed directly into tablets with a diameter of 17 mm and a thickness of 5.2 mm. b) Nimesulide 50 mg Betacyclodextrin 300 mg Lactose SD 50 mg Sodium glycine carbonate 300 mg 180 mg fumaric acid PEG 6000 20 mg The mixture was compressed directly into tablets with a diameter of 13 mm and a thickness of 4.98 mm. EXAMPLE 10 Ibuprofen.

Ibuprofen 200 mg Lactose SD 610 mg Sodium glycine carbonate 600 mg Fumaric acid 360 mg PEG 6000 30 mg The mixture was compressed directly into tablets with a diameter of 20 mm and a thickness of 5.2 mm. EXAMPLE 11 Morniflumate. Morniflumate 175 mg Lactose? D 300 mg Sodium glycine carbonate 650 mg Fumárico acid 800 mg PEG 6000. 50 mg The mixture was compressed directly into tablets with a diameter of 20 mm and a thickness of 5.0 mm. EXAMPLE 12 Levodopa Methyl Ester (MELD) MELD 314 mg Lactose SD 146 mg Sodium glycine carbonate 650 mg Fumárico acid 260 mg The mixture was compressed directly in tablets with a diameter of 13 mm and a thickness of 5.0 mm.

EXAMPLE 13 Carbidopa monohydrate. Carbidopa monohydrate 27 mg Lactose SD 433 mg Sodium glycine carbonate 260 mg fumaric acid 180 mg The mixture was compressed directly into tablets, with a diameter of 13 mm and a thickness of 5.0 mm. EXAMPLE 14 Combination of MELD / Carbidopa monohydrate. a) MELD 314 mg Carbidopa monohydrate 27 mg Lactose SD 539 mg Sodium glycine carbonate 520 mg Fumaric acid 360 mg PEG 6000 40 g The mixture was compressed directly into tablets with a diameter of 17 mm and a thickness of 5.0 mm. EXAMPLES 15, 16 and 17 The dissolution rate of the formulations of Examples 6, 7 and 14 was determined using Apparatus 2 of the USP (with paddles). EXAMPLE 15 Ambroxol hydrochloride. Conditions: medium = 0.1 N HCl; volume = 750 mi; speed = 50 rpm (revolutions per minute); temperature = 37 ° C. Time: 5 minutes. % of the dissolved drug: 98%. EXAMPLE 16 Paracetamol. Conditions: medium = distilled water; volume = 900 mi; speed = 50 rpm (revolutions per minute); temperature = 37 ° C. Time: 5 minutes. % of the dissolved drug: 90.9%. EXAMPLE 17 Combination MELD / Carbidopa Monohydrate. Conditions: medium = 0.1 N HCl; volume = 750 mi; speed = 50 rpm (revolutions per minute); temperature = 37 ° C. Time: 5 minutes. % of Carbidopa dissolved: 94%. % dissolved MELD: 99% EXAMPLE 18 The oral absorption profile of levodopa and carbidopa released from the effervescent tablets of the combination MELD / carbidopa monohydrate prepared in accordance with Example 14, was compared with that of standard levodopa / carbidopa monohydrate tablets available commercially (Sinemet ©). The study was carried out after a single oral dose administration of the two formulations, in six healthy volunteers according to a cross-over design. The results, reported in Tables 7 and 8, show a faster absorption and a higher exposure of the active ingredients during the first hours after the administration of the effervescent formulation, in comparison with the standard commercial formulation. In the Table: Cp = plasma concentration; Cmax = maximum plasma concentration; T ax = time to maximum concentration; ABClh, ABC2h, ABCt = area under the curve of plasma concentration vs time, after 1 hour, 2 hours and total, respectively. Table 7. Main pharmacokinetic parameters of levodopa (geometric mean ± standard deviation) after oral administration of effervescent tablets of the combination MELD / carbidopa monohydrate of Example 14 vs commercial standard tablets of the combination levodopa / carbidopa monohydrate (Sine et ©) , in six healthy volunteers. Parameters Tablets of effervescent Sinemet® pharmacokinetic tablets of levodopa MELD / carbidopa Cp 15 min 1292 ± 321 2787 ± 1338 (ng / ml) Cp 30 min 965 ± 304 1705 ± 989. (ng / ml) Cp 45 min 1158 ± 703 1339 ± 882 (ng / ml) Cp 1 h 999 ± 541 1023 ± 691 (ng / ml) Cmax 2218 ± 1289 3000 ± 1592 (ng / ml) Tmax 0.6 ± 0.3 0.3 ± 0.2 (h) AUC 1 h 986 ± 466 1683 ± 1074 (ng-hr / ml) AUCt 5473 ± 4678 5123 ± 4485 (ng-hr / ml) Table 8. Main pharmacokinetic parameters of carbidopa (geometric mean ± standard deviation) after oral administration of effervescent tablets of the combination MELD / carbidopa monohydrate of Example 14 vs commercial standard tablets of the combination levodopa / carbidopa monohydrate (Sinemet ©), in six healthy volunteers. Parameters Tablets of effervescent Sinemet® carbodynamic tablets of carbidopa MELD / carbidopa Cp 30 min 52 ± 31 46 ± 33 (ng / ml) Cp 45 min 52 ± 32 63 ± 46 (ng / ml) Cp 1 h 59 ± 39 66 ± 45 (ng / ml) Cp 1.5 h 69 ± 47 72 ± 46 (ng / ml) Cp 2 h 49 ± 32 68 ± 42 (ng (ml) Cmax 75 ± 51 88 ± 65 (ng / ml) Tmax 2.6 ± 1.7 1.5 ± 65 (h) AUC 1 h 44 ± 12 1.5 ± 0.8 (ng-h / ml) AUCt 230 ± 144 255 ± 168 (ng-h / ml) It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (12)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. A pharmaceutical composition in the form of effervescent tablets comprising an active ingredient and an effervescent couple, wherein the pair comprises an acid component and a component alkaline, characterized because the alkaline component is sodium glycine carbonate.
2. 2. A pharmaceutical composition according to claim 1, characterized in that the acid component is fumaric acid or its salts.
3. 3. A pharmaceutical composition in accordance with the. claim 1, characterized in that the acid component is maleic acid or its salts.
4. 4. A pharmaceutical composition according to any of claims 1 to 3, characterized in that the active ingredient is unstable in the presence of water.
5. 5. A pharmaceutical composition according to any of claims 1 to 4, characterized in that it comprises an unstable excipient in the presence of water.
6. 6. A pharmaceutical composition according to any of claims 1 to 5, characterized in that it also comprises a cyclodextrin.
7. 7. A pharmaceutical composition according to any of claims 1 to 6, characterized in that the active ingredient is a piroxicam-β-cyclodextrin complex.
8. 8. A pharmaceutical composition according to any of claims 1 to 7, characterized in that the active ingredient is a combination of levodopa methyl ester and carbidopa monohydrate.
9. 9. A pharmaceutical composition according to any of claims 1 to 8, characterized in that it comprises at least one additional excipient that is selected from the group consisting of ligands, agents, lubricants, sweeteners, solubilizers, colorants, flavorings, diluents, disintegrants, humectants and mixtures thereof.
10. 10. A pharmaceutical composition according to any of claims 1 to 9, characterized in that the diluent is spray-dried lactose.
11. 11. A pharmaceutical composition in the form of effervescent tablets according to any of claims 1 to 10, characterized in that the effervescent couple is activated by water or saliva, wherein the tablet is substantially completely disintegrable both in water and directly in the mouth. .
12. 12. A pharmaceutical composition according to any of claims 1 to 11, characterized in that the effervescent tablets are prepared by direct compression under normal thermo-hygrometric conditions and with standard compression equipment.