RU2370268C2 - Method of obtaining pharmaceutical composition for oral introduction possessing improved bioaccessibility of biologically active effective medicinal substance, and pharmaceutical composition obtained by said method - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method of obtaining tablets containing crystalline-form-free alprazolam, includes at preliminary stage of granulation operation obtaining alprazolam solution in pharmacologically acceptable solvent together with crystallisation-inhibiting agent, formed by mixture of binding substance and from 20 to 60% wt of total amount of lubricating substance, impregnation with obtained solution of mixture of diluent and 25% reticular carboxymethylcellulose as disintegrating agent until homogeneous granulated mass is obtained and grinding of obtained granulated mass, preliminarily dried, until grinded granulometrically homogeneous mass is obtained. At the second stage of granulation operation, 100% of remaining lubricating agent and remaining reticular carboxymethylcellulose and aromatising additives are added to dried and grinded mass, obtained at preliminary stage of granulation operation; aromatised mass is finally mixed and pressed. Non-crystalline state of alprazolam improves its solvability and bioaccessibility.

EFFECT: alprazolam tablets have smaller size than traditional tablets, and disintegration time less than 1 minute, preferably, less than 30 seconds.

11 cl, 7 dwg, 3 tbl, 3 ex

Description

FIELD OF THE INVENTION

The present invention relates to a method for producing pharmaceutical compositions in the form of rapidly disintegrating oral tablets, preferably for buccal or sublingual administration, among other routes of administration, containing a biologically active active drug substance substantially free of crystalline form, preferably directed to the treatment of panic disorder or acute attacks of severe anxiety. Also provided are pharmaceutical compositions prepared by this method.

BACKGROUND OF THE INVENTION

Benzodiazepines are a heterogeneous group of chemical compounds having a common basic 5-aryl-1,4-benzodiazepine core. Among them, alprazolam, clonazepam and bromazepam can be distinguished.

Pharmacodynamic and pharmacokinetic differences determine various therapeutic applications in accordance with the intensity of the manifestation of sedative, hypnotic muscle relaxant, anxiolytic or anticonvulsant activity.

Alprazolam, 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (l, 4) benzodiazepine, is often prescribed as an anxiolytic agent. In recent years, its use in distress conditions such as panic disorder has been investigated. There are many scientific papers on this topic and among them:

Ballenger JC, Burrows D, DuPont, RL Jr. - ARCH. GEN. PSYCHIATRY 45: 413-422, 1988.

Spiegel DA-PSYCOPHARAMOL. BULL. 1988, 34 (2): 191.

Noyes R., Burrows GD, Reich JH, Judd FK, Gravy MJ et al - J. CLIN. PSYCHIATRY 1996, 57 (8): 349.

Gleman James H, - Treatment of Panic Disorder with Alprazolan - U.S. Patent 4,504,826 (1985).

Due to the fact that the disorders caused by patients with this type of pathology are such as anxiety, a sense of impending death, disorientation, it is essential that the therapeutic effect occurs as quickly as possible at the time and place where the crisis began.

However, to date, there is no appropriate drug alprazolam, which produces a therapeutic effect as quickly as required by the symptoms of the disease.

Studies by several authors have shown that sublingual administration could be an alternative and effective route of administration for some benzodiazepines. Therefore, this possibility was evaluated using lorazepam (Gale GD, Gallon S, Porter WR. Sublingual Lorasepam: a better premedication. - BR. J. ANAETH. 1983: 55: 761-5), Greenblatt DJ, Divoll M, Harmatz JS et al. Pharmacokinetic comparisons of sublingual lorazepam with intravenous, intramuscular and oral lorazepam, J. PHARM. SCL. 1982; 71: 248-252); triazolam (Scavone JM, Greenblatt DJ, Friedman H, et al. Enhanced bioavailability of triazolam following sublingual versus oral administration. J. CLIN.PHARMACOL. 1986; 26: 208-10) and flunitrazepam (Huttel MS, Bang U. Sublingual flunitrazepam for premedication, ACTA ANAETH. SCAND. 1985; 29: 209-11).

In 1987, Joseph Scavone, David Greenbaltt and Richard Shader (J. CLIN. PSUCHOPAHARMACOLOGY Vol. 7 No. 5, Oct. 1987) demonstrated in healthy patients who were voluntarily treated with commercially available oral tablets that sublingual absorption of alprazolam is possible . Such affordable commercially available tablets, being kept under the tongue of volunteers for 15 minutes who starved for the previous 8 hours and then starved for 3 hours after drug administration, have been shown to be absorbed sublingually as quickly and without statistically significant differences as with oral absorption after fasting.

Peaks in plasma concentrations after sublingual administration were higher than those observed after the experiment with oral administration (17.3 compared with 14.9 ng / ml). The time required to achieve maximum concentration was 1.17 hours for sublingual administration and 1.73 hours for normal or digestive administration.

In 1992, the same authors (Scavone JM, Greenblatt DJ, Goddard JE, Friedman H, Harmatz JS and Shader RI - EUR. J. CLIN. PHARMACOL. (1992) 42: 439-443) examined the effect of nutrition on oral or sublingual absorption of alprazolam. They confirmed that sublingual absorption occurring after ingestion while holding 1 mg alprazolam tablets under the tongue for 15 minutes was lower than absorption observed by the same authors in starving patients. They observed that with the administration following a meal, the plasma concentrations reach peak values with the sublingual route of administration later than with the oral route of administration (2.8 hours, compared to 1.8 hours, P <0.01). Moreover, they confirmed that after 15 minutes no remaining tablet pieces were found under the tongue.

It is well known that disintegration is an essential property of tablets intended for oral administration, and this is even more true for sublingual tablets, because active active drug substances are preferably absorbed into the oral cavity through buccal or sublingual mucous membranes.

In addition, it is known that the higher the rate of disintegration, the faster the absorption of the drug, which is absorbed by the environment. For drugs with a wide range of applications in human therapy, various pharmacopoeias set the maximum disintegration time of a tablet in order to verify its effectiveness. For example, for sublingual tablets of isosorbide or nitroglycerin dinitrate, the US Pharmacopoeia XXIII sets a maximum disintegration time of no more than 2 minutes, and for ergotamine tartrate, the disintegration time is no more than 5 minutes. Other products with longer disintegration times are also listed. The prior art described above emphasizes the practical relevance of disintegration times directly related to the therapeutic activity and effectiveness of each product.

The results obtained by the researchers in the above studies indicate that the sublingual route of administration is actually an alternative route that deserves study. However, these studies, in addition, confirm the fact that the use of an oral tablet that must be kept under the tongue for 15 minutes in order to achieve absorption of the active active substance does not find practical application in the field of therapy. As in the case when such a tablet requires long-term fasting conditions both before and after its administration for absorption of benzodiazepine.

In particular, when benzodiazepine, such as alprazolam, is used in the treatment of panic disorder or acute attacks of severe anxiety, the severe fasting conditions that precede the introduction of the product or follow its introduction in order to verify the effectiveness of the product, and, moreover, the practical inconvenience of retention tablets in the buccal pocket for a long period of time (from 10 to 15 minutes) until it completely disintegrates, as described in the above scientific literature, make it difficult for patients to perform the scheme and Modes of treatment.

Suck Won Kim et al. (ANNALS OF CLINICAL PSYCHIATRY-Vol. 4 No. 2, June 1992), it is believed that the patient will have a beneficial effect on the quick action of the product, which can neutralize the symptoms that precede the panic attack (prodromal symptoms), including the panic disorder itself.

Therefore, in the case of patients suffering from panic attacks or acute bouts of severe anxiety, a quick effect of the drug is desirable. This effect can be achieved through the use of oral administration of the drug, preferably the sublingual route of administration.

A similar advantageous criterion is applied to other therapeutic formulations of benzodiazepines when the pharmaceutical composition provides fast delivery and exposure to the active active drug substance contained therein.

It is well known that for most active medicinal substances, an amorphous state is the most convenient physical form that promotes their dissolution and absorption.

Solid crystalline substances have a certain shape corresponding to the established crystallographic systems, which they retain even after fine crushing, as was shown by Aiache JM et al {BIOFARMACIA - Ed. El Manuel Moderno, Mexico, 1983), who believe that the arrangement of molecules in the structural network remains unchanged.

On the other hand, substances in an amorphous state do not have a definite structure, they have an disordered structure in three dimensions and are thermodynamically less stable, however, this state is the form of the active drug substance with the highest solubility. There are a number of links that confirm the above information. Mullins and Macek (Mullins, JD, Macek, TJ - J. PHARM. SCI., 49, 425 (I960)) disclose that amorphous novobiocin is ten times more soluble than its crystalline form and has oral absorption. The crystalline form is not bioavailable with this route of administration.

Higuchi and col. (Higuchi, WI, Lau, PK, Higuchi, T, Schell, JW - J. PHARM. SCI., 52, 150 (1963)) indicate that the solubility of amorphous methylprednisolone is 20 times higher than the solubility of the same substance in crystalline form.

In 1972, Monkhouse et al. (Monkhouse, DC and Lach, JL - PHARM. SCI. 1431-vol. 61 (9) 1972) describe a method for increasing the solubility of poorly soluble drugs by increasing the contact surface of the active active drug substance with the medium. They mix and shake the drug with an inert substance (silica) and solvent for a period of time, then remove the solvent and grind the mixture. The demonstrated method is suitable for a significant increase in the dissolution of substances.

However, the method has the disadvantage that there is no linear relationship between the amount of inert substance used and the amount of free active active drug substance previously deposited on its surface. Moreover, an inert carrier is not always suitable for a pharmaceutical composition.

Therefore, there is still a need to obtain tablets for oral administration, preferably sublingual administration, for the treatment of panic disorder or acute attacks of severe anxiety, which have better solubility and bioavailability of the active active drug substance of the composition, preferably alprazolam, which makes it possible to quickly act.

SUMMARY OF THE INVENTION

Therefore, the aim of this invention is to provide a method for producing pharmaceutical compositions in the form of tablets for oral, preferably buccal or sublingual administration, for the treatment of distress conditions, panic disorder or acute attacks of severe anxiety.

Another objective of the present invention is the provision of a simple and economical method of producing pharmaceutical compositions in the form of tablets for oral administration, preferably sublingual administration, having rapid disintegration, containing a biologically active active drug substance, which is essentially free of crystalline form.

Another objective of the present invention is the provision of a method of obtaining pharmaceutical compositions for oral, preferably buccal or sublingual routes of administration, with rapid disintegration and containing a biologically active active drug substance, which is essentially free of crystalline form and which do not add agents that inhibit crystallization .

An additional objective of this invention is the provision of a method for producing pharmaceutical compositions in the form of tablets for oral, preferably buccal or sublingual routes of administration, containing a biologically active active drug substance, which is essentially free of crystalline form, with rapid disintegration and general digestibility of the biologically active active drug substances.

Another objective of this invention is the provision of a method for producing pharmaceutical compositions in the form of tablets for oral, preferably buccal or sublingual routes of administration, having rapid disintegration, containing a biologically active active drug substance, which is essentially free of crystalline form, homogeneously distributed throughout the tablet .

Another objective of this invention is the provision of a method for producing pharmaceutical compositions in the form of tablets for oral, preferably buccal or sublingual routes of administration, of a reduced size, which contributes to the low tablet strength in the oral cavity.

Another objective of this invention is the provision of a method for producing pharmaceutical compositions in the form of tablets for oral, preferably buccal or sublingual routes of administration, containing alprazolam, which is essentially free of crystalline form, for the treatment of distress conditions, panic disorders or acute attacks of severe anxiety.

An additional objective of the present invention is the provision of a method for producing pharmaceutical compositions in the form of tablets having rapid disintegration for oral, preferably buccal or sublingual routes of administration, containing a biologically active active drug substance, which is essentially free of crystalline form.

Another objective of this invention is the provision of a method for producing pharmaceutical compositions in the form of tablets with rapid disintegration for oral, preferably buccal or sublingual routes of administration, containing alprazolam, which is essentially free of crystalline form.

Surprisingly, it was found that in the case when the sequence of adding excipients in the preparation of a pharmaceutical preparation is changed, tablets containing a biologically active active drug substance, preferably alprazolam, which is essentially free of crystalline form and possessing the required solubility characteristics, can be obtained. and bioavailability without the need for additional agents, such as crystallization inhibitors.

It has now been found that such tablets are prepared when the active active drug substance of a pharmaceutical composition for preparing a solution is dissolved in a solvent or an appropriate solvent mixture together with a binder and part of a lubricant, from 20% to 60%. The remaining components of the composition are impregnated with this solution, then the solvent is removed and, ultimately, the flavored mass is pressed.

Thus, they promote the homogeneous dispersion of the active active drug substance over the surface of all components of the pharmaceutical composition and, surprisingly, it was found that the presence of agglutinating and lubricating agents in the solvent acts similarly to crystallization inhibitors, preventing complete restoration of the initial crystalline form of the active active drug substance in the resulting a pill.

Both characteristics, uniformity of distribution and non-crystalline state, remarkably improve the solubility and bioavailability of the active active drug substance of the composition.

This sequence is not only new, but also very convenient, since it prevents the active active drug substance from restoring its original crystalline form after it is dissolved in the selected solvent.

Moreover, these tablets exhibit a significant advantage compared to traditional tablets formulated with the same active active drug substances because of their small size, their remarkable disintegration rate and the reduced stability of the entire tablet or its fragments in the oral cavity or during sublingual localization. Such characteristics also contribute to the patient's effective adherence to prescribed therapeutic treatment.

Moreover, the pharmaceutical compositions obtained by the method of the present invention, due to their reduced size and rapid dissolution, do not require the use of liquids, for example water, when administered, which allows the patient to use the product anytime, anywhere.

Brief Description of the Figures

1-5, included as illustrative examples, show and confirm changes in the crystal structure of the active agent, alprazolam, used in the preparation of the pharmaceutical compositions of the present invention.

Figures 1 and 2 correspond to differential thermal analysis curves obtained using DSC (differential scanning calorimetry) of alprazolam (Figure 1) and alprazolam treated with lubricants and binders, in accordance with the preparation used in the following examples I and II according to this invention respectively.

Figure 3 correspond to the differential thermal analysis curves for physical mixtures of the same components (alprazolam, povidone and stearic acid), with the same mass ratio as used to obtain the curves of figure 2.

4 shows an X-ray diffraction spectrum of alprazolam.

Figure 5 shows the X-ray diffraction spectrum of a mixture of alprazolam treated with lubricants and binders, in accordance with the methodology presented in the present invention and described in examples I and II, which, in comparison with Figure 4, shows a spectrum with wide diffraction lines and diffuse highs.

FIG. 6 shows the X-ray diffraction spectrum of a physical mixture of alprazolam, povidone and stearic acid obtained by simple mixing of the same components that were used in the sample for which FIG. 5 was obtained.

Fig.7 is a characteristic curve of the plasma level (mg / ml ± SD *) of alprazolam tablets containing a single dose (0.5 mg (sublingual route of administration)) obtained in accordance with the method of the present invention.

*) SD stands for standard deviation

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the unexpected discovery that it is possible to prevent or slow down the crystallization of the bioactive component in the manufacture of medicament tablets and to produce tablets having faster disintegration, faster delivery and faster bioavailability of the active ingredient than tablets commercially available and commercially available if the preliminary granulation operation of such a dissolved component is carried out in combination with a binder and a part of the lubricating substances; and in the second granulation operation, the obtained granular substance, previously ground, is treated in a mixture with other components and the remaining part of the lubricant.

In a preferred embodiment of the present invention, a method for producing pharmaceutical compositions of tablets intended for oral administration, having rapid disintegration, which contain a biologically active active drug substance, which is essentially free of crystalline form, includes:

- obtaining a solution of biologically active active drug substance in a pharmaceutically acceptable solvent together with a crystallization inhibiting agent, which is obtained by mixing a binder and from 20 to 60 wt.% of the total amount of lubricant;

- impregnation with the above solution of a mixture of loaded components and excipients of the composition to obtain a homogeneous granular mass;

- grinding pre-dried granular mass to obtain a crushed mass of a homogeneous particle size distribution;

- adding to the dried ground mass 100% of the remaining lubricant and the remaining components and optional flavoring agents; mixing and pressing such flavored masses.

In yet another preferred embodiment of the present invention, a method for preparing pharmaceutical compositions of tablets having fast disintegration for oral administration, which contain alprazolam, which is substantially free of crystalline form, comprising:

- obtaining a solution of a biologically active active drug substance in a pharmaceutically acceptable solvent together with a crystallization inhibiting agent obtained by mixing a binder and from 20 to 60 wt.% of the total amount of lubricant;

- impregnation with the above solution of a mixture of loaded components and excipients of the composition to obtain a homogeneous granular mass;

- grinding pre-dried granular mass to obtain a crushed mass of a homogeneous particle size distribution;

- adding to the dried ground mass 100% of the remaining lubricant and the remaining components, optional flavoring agents; mixing and pressing such flavored masses.

The method of the present invention allows to obtain and use pharmaceutical compositions, the following characteristics of which completely distinguish them from compositions of the prior art.

The first difference is that the same excipients of the pharmaceutical composition function as carriers of active active drug substances. Thanks to the preliminary dissolution of the active agent in a solvent and the subsequent impregnation of all excipients of the pharmaceutical preparation, a homogeneous distribution of the active drug substance over the entire initial mass is guaranteed.

Another significant difference is that the introduction of the binder and part of the lubricant in the preliminary granulation stage, which act as crystallization inhibitors in the solvent medium, preventing the restoration of the initial crystalline form and structure of the active agent on the surface of the granular components that form the mass of each tablet.

The changes observed among the differential thermal analysis curves confirm the disorder and partial loss of crystal structure of alprazolam in tablets obtained in accordance with the method of the present invention (Figure 2), compared with alprazolam separately (Figure 1).

Moreover, comparing the curves obtained in FIGS. 2 and 3, a stronger perturbing effect on the crystal structure of alprazolam treated according to the method of the present invention can be seen, since the endothermic peak of alprazolam is shifted from 228.64 ° C (FIG. 1) to 208 , 61 ° C (Figure 2); while for a simple physical mixture of alprazolam, povidone and stearic acid, a shift from 228.64 ° C to 213.03 ° C is observed (Figure 3).

The loss of crystal structure of alprazolam in tablets obtained according to the method of the present invention can also be observed by X-ray diffraction spectra (Figures 4, 5 and 6). Alprazolam does not lose the crystalline structure in the physical mixture of components having a spectrum (Figure 6), similar in its characteristics (well-defined sharp peaks) to the spectra of alprazolam as such (Figure 4). However, alprazolam treated according to the method of the present invention exhibits a spectrum with large distortions, with wide diffraction lines and diffuse maxima.

Such process characteristics, the homogeneous distribution of the active active drug substance, contribute to its overall “digestibility” in the oral cavity for a remarkably short period of time and therefore guarantee the absorption of the drug, preferably through the oral and sublingual mucous membranes. Such absorption is stimulated by the suggestion that the patient put a tablet under the tongue. Moreover, as can be observed in the following examples of embodiments, after less than 15 seconds, the whole tablet is practically absent in the oral cavity. Both facts guarantee maximum absorption of the described original composition through the sublingual and oral mucous membranes. This absorption characteristic provides another additional advantage over other oral tablets containing the same active active drug substance, since the patient is freed from the need to follow the fasting regimen recommended before and after product administration in order to guarantee the effectiveness of the product, and, in addition, is absent the disadvantage of having to keep the tablet in the oral cavity for a long period of time (10 to 15 minutes) until it completely disintegrates, like This was described in the above scientific literary works.

The digestibility of the active active drug substance in a non-crystalline state is also increased. As indicated above, such a condition would contribute to its solubility and bioavailability.

The tablets obtained according to the method of the present invention have a “short disintegration period” of less than 1 minute and preferably in the range of 8 to 15 seconds. It is remarkable how this can be observed in the following examples of embodiments that the commercially available and commercially available tablets have a longer disintegration time than the resulting tablets containing pharmaceutical compositions of the invention. Oral, buccal and sublingual tablets, which are the object of the present invention, allocates them a significantly short disintegration time. So, for example, the full assimilation of a drug that is to be absorbed, preferably through the mucous membrane, takes place in less than 1 minute and, preferably, from 8 to 15 seconds after each drug is placed in the mouth, in each In this case, the disintegration time varies in accordance with the nature of the active substance contained, but is within the limits indicated above.

The fact that the same components act as inhibiting the crystallization of the biologically active component eliminates the need for additional inhibitory agents, thereby simplifying the preparation process.

Another advantage that the tablets obtained according to the method of the present invention have demonstrated is that the tablets have a “very small size”. They have a mass of approximately 75 mg and preferably 30 and 40 mg. They contain the smallest possible number of excipients that are not active substances. This minimum allowable amount, however, is necessary and sufficient to guarantee an adequate stable pharmaceutical composition. This is confirmed by the physicochemical determinations that are given in the examples of embodiments of the present invention. A significant decrease in the excipient content provides the best interaction between the active active drug substance and the sublingual or oral mucous membranes after tablet disintegration, which promotes absorption of the active active drug substance. The final weight of the tablets that are the object of the present invention is actually 2-6 times less than the mass of other traditional tablets containing the same active active drug substance.

In addition, the tablets of the present invention exhibit better “bioavailability” of the biologically active active ingredient. As shown in detail in the following biological analyzes, the biologically active active substance, alprazolam, enters the plasma faster than 15 minutes after its administration, and the plasma peak is obtained earlier (at 45 minutes) than with pharmaceutical compositions. Plasma levels obtained with tablets of the present invention containing 0.5 mg of alprazolam are equivalent to plasma levels obtained with tablets described in the literature, but containing 1 mg of alprazolam.

The following components are required in the preparation of tablets having fast disintegration: a diluent, a binder, disintegrating and lubricating agents and a granulating solvent.

The solvents may be inorganic, such as water, or organic, such as dichloromethane or ethanol. The latter can be easily removed. Ethanol is the preferred solvent, because after its removal it is unlikely that any contaminants remain.

In addition, it is possible to use combinations of ethanol and water, or ethanol and dichloromethane in accordance with the nature of the active active drug substance, which is dissolved.

Microcrystalline cellulose, lactose monohydrate, sorbitol, mannitol and xylitol can be used as diluents.

The most common binding agents are acacia, gelatin, sucrose, povidone, methyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, starch paste. Preferably, povidone is selected as the binder in the method of the present invention.

Disintegrating agents are starch, modified starch, alginic acid, microcrystalline cellulose, colloidal silicates.

Lubricants include metal stearates such as magnesium stearate, stearic acid, stearic acid esters such as sodium stearyl fumarate, hydrogenated vegetable oils and talc.

The pharmaceutical composition described in the present invention is applicable to drugs intended for buccal and sublingual absorption, compatible with excipients of the developed composition and the described production technology. It is specifically designed for effective medicines, even in very small doses.

Examples

The following examples are presented to further illustrate the preparation of the claimed invention. Examples I and II describe preferred methods of carrying out the invention and some properties of the pharmaceutical composition, such as disintegration time, weight, brittleness, strength and active drug content of the pharmaceutical composition obtained by the method of the present invention. Example III describes the preparation of buccal or sublingual tablets in the absence of a biologically active active drug substance using lactose as an inert substance.

Example 1

Composition for producing 10,000 tablets of sublingual or buccal alprazolam

Alprazolam 5 g Reticular carboxymethyl cellulose 3.5 g Flavoring q.s. Lactose 200 mesh 82 g Povidone 3.5 g Stearic acid 1.7 g Macrocrystalline cellulose q.s.p. 350 g

To a solution of 5 g of alprazolam and 3.5 g of povidone in a mixture of ethanol: dichloromethane (1: 1) was added 60% of the amount of stearic acid indicated in the composition (Solution A).

A mixture of 0.880 g of reticular carboxymethyl cellulose (25% of the amount given in the composition) and the indicated amounts of microcrystalline cellulose and lactose were impregnated with solution A in a granulator mixer (Collete type) until a homogeneous granular mass was obtained. The granular mass was dried in a fluidized bed dryer (type Glatt) until the solvent was completely removed.

Then the granular mass was transferred to the same collector of the mixer-granulator and impregnated with 30 ml of ethanol. The solvent was again removed by drying in a fluidized bed dryer. The dried granular mass was ground in a Quadro Comil type apparatus to obtain particles of uniform size. A flavoring agent and 75% of the calculated amount of reticular carboxymethyl cellulose were added and the components were mixed for 20 minutes. After adding the remaining stearic acid and stirring for 5 minutes, the mass was pressed.

Tests

Weight 35 mg Disintegration (tablets for sublingual use, US Pharmacopoeia XXII) <15 seconds Fragility (apparatus, Pharmacopoeia of the USA XXII) <0.5% Strength 5 to 8 kg / inch ² Content (determined by HPLC) 0.501 mg

Example II

Composition for producing 10,000 tablets of sublingual or buccal alprazolam

Alprazolam 5 g Reticular carboxymethyl cellulose 3.5 g Flavoring q.s. Lactose 200 mesh 90 g Povidone 3.5 g Stearic acid 1.7 g Macrocrystalline cellulose q.s.p. 350 g

A solution of 5 g of alprazolam, 3.5 g of povidone and 60% of the amount of stearic acid from the previous composition (1.02 g) in 270 ml of ethanol was obtained. The solvent was removed and the mass was dissolved in 60 ml of ethanol (solution A).

A mixture of 25% of the calculated amount of reticular carboxymethyl cellulose and the indicated amounts of microcrystalline cellulose and lactose was impregnated with solution A in a granulator mixer (Collete type) until a homogeneous granular mass was obtained. The granular mass was dried in a fluidized bed dryer (type Glatt) until the solvent was completely removed.

The dried granular mass was ground in a Quadro Comil type apparatus to obtain particles of uniform size. A flavoring agent and 75% of the calculated amount of reticular carboxymethyl cellulose were added and the components were mixed for 20 minutes. After adding the remaining stearic acid and stirring for 5 minutes, the mass was pressed.

TEST

Weight 35 mg Disintegration (tablets for sublingual administration, US Pharmacopoeia XXII) <10 seconds Fragility (apparatus, Pharmacopoeia of the USA XXII) <0.5% Strength 5 to 8 kg / inch ² Content (determined by HPLC) 0.51 mg

Example III

Composition for producing 10,000 tablets sublingual or buccal lactose

Reticular carboxymethyl cellulose 3.0 g Flavoring q.s. Lactose 200 mesh 72.5 g Povidone 3.0 g Stearic acid 1.0 g Macrocrystalline cellulose q.s.p. 300 g

A solution of 3.0 g of povidone and 60% of the calculated amount of stearic acid in 50 ml of ethanol and 10 ml of water was obtained (solution A).

A mixture of 25% of the calculated amount of reticular carboxymethyl cellulose and the indicated amounts of microcrystalline cellulose and lactose was impregnated with solution A in a granulator mixer (Collete type) until a homogeneous granular mass was obtained. The granular mass was dried in a fluidized bed dryer (type Glatt) until the solvent was completely removed.

The dried granular mass was ground in a Quadro Comil type apparatus to obtain particles of uniform size. A flavoring agent and 75% of the calculated amount of reticular carboxymethyl cellulose were added and the components were mixed for 20 minutes. After adding the remaining stearic acid and stirring for 5 minutes, the mass was pressed.

TESTS

Weight 30 mg Disintegration (tablets for sublingual administration, US Pharmacopoeia XXII) <30 seconds Fragility (apparatus, Pharmacopoeia of the USA XXII) <0.5% Strength 5 to 8 kg / inch ²

Benchmarking

The following table I shows a comparison of the differences in weight and disintegration time of oral tablets and buccal or sublingual tablets obtained using the method of the present invention. The average weight and disintegration time of a tablet not containing an active active drug substance obtained according to the method shown in example III are shown in table II.

TABLE I
Tablets containing 0.5 mg alprazolam A drug Administration form Average weight Disintegration time Product manufactured by industry Oral 130 mg <10 minutes Example I Buccal /
sublingual 35 mg <15 seconds Example II Buccal /
sublingual 35 mg <10 seconds

The following table II shows the average weight and disintegration time of the tablets obtained in accordance with example III.

TABLE II
Lactose Pills A drug Administration form Average weight Disintegration time Example III Buccal /
sublingual 30 mg <30 seconds

In addition, it was demonstrated that the pharmaceutical composition and method of preparation can be used to obtain larger tablets, intended exclusively for oral use. In such tablets, the maximum disintegration time was less than 10 minutes, and preferably less than 5 minutes.

Biological tests

I. The study of plasma levels

The aim of this study was to determine the plasma levels of alprazolam in 12 healthy volunteers observed after administration of a single dose of alprazolam (0.5 mg) in the pharmaceutical composition of the present invention, the preparation of which was described in the above examples of embodiments.

The study was carried out on 12 healthy volunteers aged 21 to 50 years, with experience of irregular doses of benzodiazepine, without harmful side effects, with normal psychophysical examination, and biochemical control without abnormalities (blood count, blood glucose, creatinemia , uremia, proteinogram, bilirubinemia, TGO, TGP, alkaline phosphatase, cholesterol, urinalysis, Wasserman reaction, reaction to hepatitis Ag virus, response to HIV).

A tablet containing 0.5 mg of alprazolam, specially formulated for rapid disintegration, suitably flavored, was administered sublingually to healthy volunteers after signing the relevant informed consent document.

20 ml of blood was taken from each volunteer in the following time periods: 0; 5; fifteen; 45; 60; 120; 180 and 240 minutes.

A time marked with zero is considered the moment immediately preceding the administration of a sublingual tablet.

After plasma separation by centrifugation, it was stored at -20 ° C until analysis was carried out by HPLC (HP 1100 chromatograph from Hewlett Packard).

The results are shown in Fig.7 and are presented in the following table III:

Table III
Time in minutes (n) 0 (12) 5 (12) 15 (12) 30 (12) 45 (12) 60 (12) 120 (12) 180 (12) 240 (12) - 0.5 1.24 ±
0.90 8.71 ± 3.96 10.73 ± 1.63 9.87 ± 1.73 7.38 ± 1.31 6.59 ± 1.26 6.18 ± 1.1

The area under the curve, in the range from 0 to 4 hours, was 2608.85 mg / ml.h ^-1

As can be seen in FIG. 7, plasma levels were determined 15 minutes after sublingual administration, obtaining a maximum peak at 45 minutes (10.73 mg / ml).

Healthy volunteers stated that in less than 30 seconds they no longer had a whole pill in their mouth.

These values were compared with the values of the maximum plasma peaks of alprazolam, which are reported in the literature. So, for example, after the administration of oral tablets containing 1 mg alprazolam, Garzone, PD et al. received levels of 14.4 to 19 ng / ml in the range of 1.17 to 1.73 hours after administration (Garzone, PD and Kroboth PD Pharmacokinetics of the newer benzodiazepines CLIN. PHARMACOKIN .; 1989; 16: 337-364 )

A comparison was made with the data obtained after the administration of 1 mg of alprazolam by the sublingual route, which occurs after ingestion, but when using the usual pharmaceutical preparation for oral administration. In this case, the plasma peak was 11.3 ng / ml at 2.8 hours after drug administration (Scavone, JM et al. - The Pharmacokinetics and Pharmacodynamics of Sublingual and Oral alprazolam in the Postprandial State - EUR. J. CLIN. PHARMACOL .; 1992; 42: 439-443).

In addition, a standard pharmaceutical composition for oral administration containing 1 mg of alprazolam was studied after its administration in a fasting regimen by sublingual administration.

In this case, the plasma peak was 17.3 ng / ml at 1.17 hours (Scavone, JM at al - Alprazolam Kinetic Following Sublingual and Oral Administration - J. CLIK PSYCHOPHARMACOL; 1987; 7: 332-334).

From this comparison it follows that the new pharmaceutical composition alprazolam of the present invention makes it possible:

i. drug to get into the plasma earlier than 15 minutes after its administration;

ii. a plasma peak (obtained at 45 minutes) appears faster compared to plasma peaks obtained by buccal or sublingual administration of an oral pharmaceutical composition, which was previously referred to in the literature;

iii. in accordance with clinical results, plasma levels obtained with the new pharmaceutical composition prove to be therapeutically effective;

iv. the indicated plasma levels are actually equivalent to the plasma levels described in the studies described herein, since the new pharmaceutical composition contains only 0.5 mg of alprazolam, and the levels given in the literature relate, in particular, to oral tablets containing 1 mg of alprazolam, but introduced by the sublingual route. A study of the levels described confirms the benefits of the new composition of the present invention and the significant difference between the new composition (in which the concentration of alprazolam is only 0.5 mg per tablet) and the published composition intended for tablets containing 1 mg alprazolam.

II. The study of the therapeutic effect

The clinical use of alprazolam tablets administered by a sublingual group of patients has confirmed that:

i. negative thoughts that trigger classic symptoms and signs associated with panic disorder disappear in a short period of time;

ii. general symptoms of a panic attack, such as tachycardia, high blood pressure, palpitations, shortness of breath, excessive sweating, dry mouth and so on, also weaken or disappear within a short period of time;

iii. after about 15 minutes, patients overcome a state of crisis or a panic attack, being able to return to the responsibilities that they performed.

Suppressing a bout of crisis or panic attack and associated symptoms for such a short period of time (about 15 minutes) confirms the extremely high rate at which useful therapeutic levels of active active drug substance are achieved using the pharmaceutical composition of the present invention. This therapeutic result is combined with the presence of plasma levels of alprazolam, determined at 5 minutes, and the maximum level of alprazolam, achieved in the range from 30 to 45 minutes after administration of the tablet.

In conclusion, the studies were carried out with the involvement of healthy volunteers and test patients using the pharmaceutical composition of the present invention containing 0.5 mg of alprazolam in one tablet, the use of which is described below, suggests that:

After less than 30 seconds, the tablet remains in the mouth. This means that all the active drug substance of the pharmaceutical composition is absorbed, absorbed through the mucous membrane of the mouth.

The plasma level of benzodiazepine is determined 15 minutes after the administration of the pharmaceutical form.

Peak maximum absorption is obtained 45 minutes after administration of the pharmaceutical composition.

Clinical results were satisfactory.

The active drug substances, preferred methods and directions of action of the present invention have been described herein.

However, the invention to be protected is not limited to the individual embodiments described, and therefore should be considered as illustrative and not restrictive. Changes and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention.

Claims (11)

1. A method of obtaining a pharmaceutical composition of oral tablets having rapid disintegration, containing alprazolam, free of crystalline form, characterized in that the granulation operation consists of
A) a preliminary step in a granulation operation, consisting of a) obtaining a solution of alprazolam in a pharmacologically acceptable solvent, together with a crystallization-inhibiting agent formed by a binder mixture and from 20% to 60 wt.% Of the total amount of lubricant; b) soaking in the above solution of a mixture of diluent and 25% cross-linked carboxymethyl cellulose as a disintegrating agent until a uniform granular mass is obtained; c) grinding the resulting granular mass, previously dried, to obtain a crushed granulometric homogeneous mass;
C) the second stage of the granulation operation, consisting of adding to the dried and crushed mass obtained in the preliminary stage of the granulation operation A, 100% of the remaining lubricant and the remaining net carboxymethyl cellulose, and flavoring agents; and finally mixing and pressing this flavored mass. 2. The method according to claim 1, characterized in that the solvent is selected from water, ethanol, dichloromethane, a mixture of ethanol-dichloromethane and a mixture of ethanol-water. 3. The method according to claim 1, characterized in that the binding component is selected from carboxymethyl cellulose, polyethylene glycol, gelatin, starch, povidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and cellulose derivatives. 4. The method according to claim 1, characterized in that the flavoring agent is selected from powdered essences, aspartame or a bitter eliminator, and the lubricating component is stearic acid, magnesium stearate and sodium stearyl fumarate, and the diluents are selected from lactose, microcrystalline cellulose, xylitol, mannitol and sorbitol. 5. The method according to claim 1, characterized in that in addition to the sequence of stages, the following ingredients contribute to non-crystallization of alprazolam: 20-60% lubricant and 100% binder. 6. The method according to claim 1, characterized in that receive tablets for sublingual administration having a weight of less than 50 mg. 7. The method according to claim 6, characterized in that the obtained tablets, when administered orally, have a disintegration time of less than 1 minute, preferably less than 30 seconds. 8. The method according to claim 7, characterized in that the biologically active substance alprazolam is present in an amount of from 0.125 to 2 mg per tablet. 9. The pharmaceutical composition of tablets having rapid disintegration obtained by the method according to claim 1, characterized in that it is essentially free of crystals of the biologically active active substance alprazolam obtained by direct conversion in the process of obtaining. 10. The pharmaceutical composition according to claim 9, characterized in that the obtained tablet for sublingual administration has a mass of less than 50 mg and a disintegration time of less than 30 s. 11. The pharmaceutical composition according to claim 9, characterized in that alprazolam is present in an amount of from 0.125 to 2 mg per tablet.

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