MX2008002988A - Morphous solid dispersions of 7-chloro-n,n, 5-trimethyl-4-oxo-3-phenyl-3, 5,-dihydro-4h-pyridazino [4, 5-b]indole-1-acetamide - Google Patents

Abstract

Disclosed are amorphous solid dispersion formulations comprising 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide.

Description

SOLID DISPERSIONS AMORPHAS OF 7-CHLORINE-N.N.5- TRIMETHYL-4-OXO-3-PHENYL-3.5-DIHYDRO-4H-PIRIDAZINEr4.5- B1INDOL-1 -ACETAMIDE The present invention relates to amorphous solid dispersions of 7-chloro-? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4 - / - pyridazino [4,5-D] indol-1 -acetamide, a pharmacological agent that possesses a high affinity for peripheral type benzodiazepine receptors. This invention also relates to processes for the preparation of these amorphous solid dispersions, to pharmaceutical compositions including these dispersions, and to methods for their use for the prevention and treatment of diseases related to peripheral type benzodiazepine receptors.

BACKGROUND OF THE INVENTION 7-Chloro -? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1 -acetamide, which has the structure of formula (I): (I), has a high affinity for peripheral type benzodiazepine receptors. The preparation, physical properties and beneficial pharmacological properties of 7-chloro -? /,? /, 5-tri-methyl-4-oxo-3-phenyl-3, 5-dihydro-4H-pyridazino [4, 5-ft] Indole-1 -acetamide are described, for example, in the E. U. No. 6,262,045, and in particular in the Patent of E. U. No. 6,395,729, both of which are incorporated by reference in their entirety. The limited solubility of 7-chloro -? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-D] indol-1 -acetamide, prepared according to example 1 of the U.S. Patent No. 6,395,729, in aqueous solutions and solvents of non-aqueous formulations presents difficulties for the administration and preservation of formulations containing this compound. Preliminary studies performed with conventional formulations using this crystalline solid (such as formulations prepared by wet granulation or dry mixing processes using conventional excipients well known to those skilled in the art) have led to limited absorption of the drug. Attempts to improve the solubility of the pure drug substance, such as the preparation and use of amorphous forms of 7-chloro-? ,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pipdazino [4,5-b] indol-1 -acetamide, have produced a drug substance with limited physical stability. For example, this drug substance crystallized with time.

It has now been discovered that certain polymers are useful for preparing dispersions of 7-chloro-γ / γ /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5- £ > ] solid amorphous indole-1-acetamide having significant improvements in solubility against conventional formulations, and also possess significant improvements in physical stability against the amorphous drug substance alone. It is known that amorphous solid dispersions in polymers of poorly soluble drugs generally improve the solubility of drug products. However, these dispersions, in general, are unstable over time. Amorphous drug dispersions in polymers tend to become crystalline forms over time, which can lead to inappropriate dosing due to differences in the bioavailability and solubility of the crystalline drug material compared to the amorphous drug material. One skilled in the art can not predict which polymers, if any, will be useful in preparing stable amorphous dispersions for a particular drug product. The present invention, however, provides these stable amorphous dispersions with better solubility.

Brief Description of the Invention The present invention provides stable amorphous solid dispersions of the active agent, 7-chloro-γ / γ /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4 , 5-í > ] indole-1 -acetamide.

The present invention also provides processes for preparing and compositions comprising the amorphous solid dispersions of the present invention, and methods for their use.

Brief Description of the Drawings Figure 1 is a diffractogram of X-ray powder of a solid amorphous dispersion of 7-chloro -?,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4-pyridazino [4,5-b] indole-1 -acetamide in hydroxypropylmethylcellulose phthalate under stressful and non-stressing conditions. Figure 2 is an X-ray powder diffractogram of an amorphous solid dispersion of 7-chloro-? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4] , 5-b] indole-1-acetamide in hydroxypropylmethylcellulose acetate succinate under stressful and non-stressing conditions. Figure 3 is an X-ray powder diffractogram of an amorphous solid dispersion of 7-chloro-? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4 / - / - pyridazino [4,5-b] indole-1-acetamide in cellulose acetate phthalate under stressful and non-stressing conditions.

Figure 4 is a X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4 - / - pyridazino [4,5-í > ] indole-1-acetamide in polymeric polymethacrylate, EUDRAGIT® L 100, under stressful and non-stressing conditions.

Figure 5 is an X-ray powder diffractogram of an amorphous solid dispersion of 7-chloro-γ / γ /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4] , 5-b] indole-1-acetamide in hydroxypropylcellulose under stressful and non-stressing conditions. Figure 6 is an X-ray powder diffractogram of a solid amorphous dispersion of 7-chloro-? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4] , 5-f > ] indole-1 -acetamide in polyvinylpyrrolidone under stressful and non-stressing conditions. Figure 7 is a diffractogram of X-ray powder of a solid amorphous dispersion of 7-chloro-? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4] , 5-b] indole-1 -acetamide in polyvinylpyrrolidine plus 10% citric acid under stressful and non-stressing conditions. Figure 8 is a diffractogram of X-ray powder of a solid amorphous dispersion of 7-chloro-? ,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4-pyridazino [4,5-b] indole-1 -acetamide in polyvinylpyrrolidone-vinyl acetate copolymer under stressful conditions and not stressful Figure 9 is an X-ray powder diffractogram of an amorphous solid dispersion of 7-chloro-γ / γ /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4 / - / - pyridazino [4,5-b] indol-1 -acetamide in hydroxypropylmethylcellulose phthalate. Figure 10 shows the results of the dissolution test showing the solubility / dissolution rate of amorphous solid dispersions of the invention, of comparative amorphous solid dispersions, and of the pure crystalline drug substance in aqueous 0.25% sodium lauryl sulfate / 0.01 M phosphate buffer pH 7.

Figure 11 shows the results of the dissolution test comparing the solubility / dissolution rate of an amorphous solid dispersion of 7-chloro-? /,? /, 5-trimethyl-4-oxo-3-phenyl-3, 5- dihydro-4 - / - pyridazino [4,5-b] indole-1-acetamide in hydroxypropylmethylcellulose phthalate of the present invention and pure crystalline drug substance in aqueous 0.25% sodium lauryl sulfate / 0.01M phosphate buffer pH 7 Detailed Description of the Invention Definitions and Abbreviations As used above and throughout the description of the invention, it will be understood that the following abbreviations, unless otherwise indicated, have the following meanings: CAP phthalate acetate cellulose CA citric acid DCM dichloromethane EtOH ethanol HPC hydroxypropylcellulose HPMCAS acetate hydroxypropylmethylcellulose succinate HPMCP hydroxypropylmethylcellulose phthalate PVP polyvinylpyrrolidone As used above and throughout the description of the invention, it will be understood that the following terms, unless otherwise indicated, have the following meanings: The term "drug substance," as used herein. used herein, refers to 7-chloro -? /, /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4-pyridazino [4,5-b] indole-1 - acetamide. In general, the term "solid dispersion" refers to a system in the solid state comprising at least two components, wherein one component is dispersed through the other component or components. The term "solid amorphous dispersion", as used herein, refers to stable solid dispersions comprising the amorphous drug substance and a stabilizing polymer. By "amorphous drug substance" it is meant that the amorphous solid dispersion containing the drug substance in an amorphous substantially solid form, which constitutes at least 80% of the drug substance in the dispersion, is in amorphous form. More preferably at least 90%, and most preferably at least 95% of the drug substance in the dispersion is in amorphous form. A solid that is in an "amorphous" solid state form means that it is in a non-crystalline state. Amorphous solids in general have a short-range molecular arrangement of crystalline type, but not the long-range order molecular compaction found in crystalline solids. The solid state form of a solid, such as the drug substance in the amorphous dispersion, can be determined by polarized light microscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), or other conventional techniques known from the art. those skilled in the art. The amount of drug substance in the amorphous dispersions of the present invention ranges from about 0.1% to about 30% by weight relative to the stabilizing polymer. In a preferred embodiment, the amount of drug substance ranges from about 1% to about 25%, more preferably from about 5% to about 20% by weight relative to the stabilizing polymer. The term "stabilizing polymer", as used herein, including the claims, refers to any hydroxypropylmethyl cellulose phthalate (also known as HPMCP and / or hypromellose phthalate), cellulose acetate phthalate (also known as CAP) , hydroxypropylmethylcellulose acetate succinate (also known as HPMCAS) and polymeric polymethacrylates, such as EUDRAGIT® L 100. It is also understood that the term means mixtures of any two or more of the polymers mentioned above. Preferred polymers of the invention include hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and polymeric polymethyl methacrylate. In the particularly preferred amorphous dispersions of the present invention, the drug substance is present in an amount of about 5% to about 20% by weight relative to the stabilizing polymer, and the stabilizing polymer is hydroxypropylmethylcellulose phthalate. The amorphous solid dispersions are preferably prepared by dissolving the drug substance and the stabilizing polymer in a suitable solvent to form a feed solution, and then spray drying the feed solution to form the solid amorphous dispersion as a powder. A "suitable solvent," as used herein, is a solvent or mixture of solvents in which the drug substance and the polymer have the appropriate solubility, for example, a solubility greater than about 1 mg / ml. A mixture of solvents is preferred if the drug substance and the stabilizing polymer require different solvents to obtain the desired solubility. Examples of suitable solvents include dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water or mixtures thereof. A preferred solvent is a mixture of dichloromethane and ethanol. Spray drying is a process well known to those skilled in the art for preparing solid dispersions. In a preferred spray drying process of the present invention, the amorphous dispersion is formed by dispersing or dissolving the drug substance and the stabilizing polymer in a suitable solvent to form a feed solution, by pumping the feed solution through a spray towards a drying chamber, and removing the solvent to form the powder of the solid amorphous dispersion in the drying chamber. A drying chamber uses hot gases, such as forced air, nitrogen, air enriched with nitrogen, or argon, to dry the particles. The feed solution can be atomized by conventional means well known in the art, such as two fluid sonication nozzles and two fluid no sonication nozzles. Although the amorphous dispersions of the present invention are preferably prepared using conventional spray drying techniques, it will be understood that appropriate amorphous solid dispersions can be formed using other conventional techniques known to those skilled in the art, such as melt extrusion, lyophilization, rotary evaporation, drum drying or other solvent removal process. In another aspect of the invention, the pharmaceutically acceptable excipients used in the art are generally combined with the powder of the isolated amorphous solid dispersion to form a pharmaceutical composition. These pharmaceutically acceptable excipients may include one or more fillers; diluents, for example, microcrystalline cellulose, lactose, mannitol, pregelatinized starch and the like; disintegrants, for example, sodium starch glycolate, crospovidone, croscarmellose sodium and the like; lubricants, for example, magnesium stearate, sodium stearyl fumarate and the like; sweeteners, for example, sucrose, saccharin and the like; flavoring agents, for example, peppermint, methyl salicylate, orange flavor and the like; colorants; preservatives; tampons; and / or other excipients depending on the dosage form used. The pharmaceutical compositions of the present invention preferably contain a therapeutically effective amount of the drug substance. The term "therapeutically effective amount," as used herein, refers to an amount of the drug substance present in the amorphous dispersion or pharmaceutical composition being administered that is sufficient to prevent development or alleviate to some degree one. or more symptoms of the disease that is being treated. Similarly, a therapeutically effective amount of a pharmaceutical composition refers to an amount of said composition that is sufficient to prevent the development or alleviate to some degree one or more symptoms of the disease being treated. To determine the effective amount or dose, the attending physician considers a number of factors including, but not limited to, the mammalian species; its size, age and general health; the specific disease involved; the degree of commitment or severity of the disease; the response of the individual patient; the concrete dispersion that is being administered; the route of administration; the bioavailability characteristics of the preparation administered; the selected dose regimen; the use of concomitant medication; and other relevant circumstances. The pharmaceutical compositions of the present invention are generally administered orally to patients including, but not limited to mammals, e.g., humans, in the form, for example, of a hard or soft gelatin capsule, a tablet. , an oblong tablet, pills, granules or a suspension. In another embodiment, the present invention relates to dosage forms comprising the pharmaceutical compositions described herein. Dosage forms include, but are not limited to those selected from the group consisting of pills, hard or soft capsules, oblong tablets, tablets, granules and suspensions. Each dosage must contain the amount of drug substance calculated to produce the desired therapeutic effect. Typically, the pharmaceutical compositions will be administered in dosage units containing from about 2 mg to about 2000 mg of the drug substance by weight of the composition, with a range of about 10 mg to about 1000 mg being preferred. Those skilled in the art will also appreciate that the pharmaceutical compositions of the present invention can be administered with other therapeutic and / or prophylactic agents and / or drugs that are not medically incompatible therewith.

All components of the present compositions must be pharmaceutically acceptable. As used herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or other animals without undue side effects (such as toxicity, irritation and allergic responses) which corresponds to a reasonable risk of benefit / risk. The present invention also relates to the use of the pharmaceutical compositions of the invention in medicine. 7-Chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1 -acetamide is a selective and potent ligand of the receptor of peripheral benzodiazepine (PBR) and, as such, can be used for the prevention or treatment of peripheral neuropathies of different types, such as ischemic or trauma-related neuropathies, infectious neuropathies, alcohol-related, drug-related or genetic-related disorders motor neurons, such as spinal amyotrophies and amyotrophic lateral sclerosis. The 7-chloro-? ,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] ndol-1 -acetamide can also be used for the prevention or treatment of neurodegenerative diseases of the central nervous system, acute type such as cerebrovascular accidents and cranial and spinal injuries, or chronic type such as autoimmune diseases (multiple sclerosis), Alzheimer's disease, Parkinson's disease and other diseases from which the administration of neurotrophic factors is expected to have a therapeutic effect. The 7-chloro- / v,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1 -acetamide can also be used for prevention or treatment of acute or chronic renal failure, glomerutonephritis, diabetic nephropathy; for the treatment or prevention of heart diseases or disorders such as chronic heart failure, ischemia and heart failure, myocardial infarction, ischemia of the lower extremities, coronary vasospasm, angina pectoris, pathological disorders associated with heart valves, inflammatory heart diseases, effects secondary due to cardiotoxic drugs, or the subsequent effects of cardiac surgery, atherosclerosis and its thromboembolic complications, restenosis, rejection of grafts, disorders linked to proliferation or incorrect migration of smooth myocytes. The 7-chloro-? , / v, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1 -acetamide has demonstrated a pharmacological activity in animal models of rheumatoid arthritis by modulation of the immune response and, therefore, is also useful for the prevention or treatment of rheumatoid arthritis. The data from the literature indicate that the peripheral type benzodiazepine receptor can play a fundamental role in the regulation of cell proliferation and cancerization processes. In general, and in comparison with normal tissues, a higher density of peripheral type benzodiazepine receptors is observed in various types of tumors and cancers. Therefore, 7-chloro-? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indol-1 -acetamide also It can be used for the prevention or treatment of tumors and cancers.

Peripheral type benzodiazepine receptors are also present in the skin and, by virtue of these, 7-chloro-? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H -pyridazino [4,5 ~ b] indol-1 -acetamide can be used for the prophylaxis or treatment of skin stresses. It is understood that the term "cutaneous stress" means the various situations that can cause damage, in particular in the epidermis, independently of the agent causing this stress. This agent can be inside and / or outside the body, such as a chemical or free radical agent, or in another part of the outside, such as ultraviolet radiation. The present invention, therefore, relates to a method for treating and / or preventing diseases related to peripheral type benzodiazepine receptors, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention. , or a therapeutically effective amount of a pharmaceutical composition of the present invention. In one embodiment, the present invention relates to a method for treating or preventing neurodegenerative disease, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount of a pharmaceutical composition of the present invention. Another embodiment of the present invention is a method for treating or preventing neuropathy, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount of a pharmaceutical composition. of the present invention. In another embodiment, the present invention relates to a method for treating or preventing cancer or tumors, which comprises administering to a patient in need of said treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective of a pharmaceutical composition of the present invention. Another embodiment of the present invention is a method for treating or preventing cutaneous stresses, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount of a pharmaceutical composition of the present invention.

A preferred embodiment of the invention is a method for treating or preventing rheumatoid arthritis, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount of a composition pharmaceutical of the present invention. Another preferred embodiment of the invention is a method for treating or preventing a cardiac disease or a cardiac disorder, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of an amorphous dispersion of the present invention, or a therapeutically effective amount thereof. effective of a pharmaceutical composition of the present invention. One issue of the present invention is the use of an amorphous solid dispersion of the present invention in the manufacture of medicinal products for the treatment of diseases related to peripheral-type benzodiazepine receptors, such as neurodegenerative diseases, neuropathies, cancer or tumors, stresses cutaneous, heart disease or cardiac disorders, or rheumatoid artitis. The following examples will further illustrate the invention, without limiting it to them. Example 1 Preparation of an amorphous dispersion of the 20% drug substance in hydroxypropylmethylcellulose phthalate 3.2 grams of hydroxypropylmethylcellulose phthalate (HPMCP, commercially available as HP-55, Shin-Etsu Chemical Co. Ltd., Tokyo, was added. Japan) and 0.8 g of the drug substance (which can be prepared by methods known in the art, for example, as described in U.S. Patent No. 6,395,729) to a mixture of 72 ml of dichloromethane (DCM) and 72 ml of ethanol (EtOH). The resulting clear feed solution was pumped through an ultrasonic atomizer (commercially available from Sonotek, making it operate at a frequency of 60 Hz in the top spray mode with a gas inlet temperature of 20 ° C and a temperature of gas outlet of 18 ° C) to a drying chamber using a Harvard syringe pump with a feed rate of 2.2 ml / min. The solvent was removed to provide an amorphous solid dispersion.

Examples 2 to 4 The amorphous solid dispersions of Examples 2, 3 and 4 were prepared essentially according to the procedure described in Example 1, above, using the parameters listed in Table 1. Table 1: Amorphous dispersions Comparative Examples 5 to 8 The amorphous solid dispersions of Comparative Examples 5, 6, 7 and 8 were prepared essentially according to the procedure described in Example 1, above, using the parameters listed in Table 2. Table 2: Comparative amorphous dispersions EXAMPLE 9 20% Amorphous Drug Substance dispersed in HPMCP Hydroxypropylmethylcellulose phthalate (approximately 400 g) and the drug substance (approximately 100 g) were added to a mixture of dichloromethane (approximately 3.56 I) and ethanol (approximately 3.55 I). ). The resulting clear feed solution was pumped through a two fluid nozzle atomizer with a gas inlet temperature of 44 ° C and a gas outlet temperature of 25 ° C and into a drying chamber with a speed of feed of approximately 35 g / min. The solvent was removed to provide approximately 500 g of the amorphous dispersion, wherein the composition of the product was 20% drug substance / 80% HPMCP (HP-55).

Experimental data X-ray powder diffractometry (XRPD) (figures 1 to 9) The XRPD standards of examples 1 to 4 and 9 (figures 1 to 4 and 9, respectively) and comparative examples 5 to 8 (figures 5 to 8, respectively) were obtained with a Bruker D8® ADVANCE X-ray powder diffratrometer using K-alpha copper radiation. The instrument was equipped with an optical system of parallel beams, and the voltage and amperage of the tube were adjusted to 40 kV and 40 mA, respectively. The samples were swept at a speed of 0.1 degrees / minute or 1.0 degrees / minute at a 2-teta angle. The initial (unstressed) XRPD patterns obtained for Examples 1 to 4 and 9, and Comparative Examples 5 to 8 all indicate that the drug substance is substantially in amorphous form.

Stability studies (Figures 1 to 8) The stabilities of Examples 1 to 4, and of Comparative Examples 5 to 8 were determined after preservation of the samples at 40 ° C / relative humidity at 15% for three months. Other samples were also stored in a high humidity chamber at 40 ° C / 75% relative humidity for three months. A saturated aqueous solution of sodium chloride was used to generate the desired humidity for the high humidity chamber. The amorphous solid dispersions were placed in size 0 hard gelatin capsules, then placed in high density polyethylene bottles, which were placed in the chamber at 40 ° C. Figures 1 to 8 show the patterns of XRPD for the examples obtained initially, after 3 months at 40 ° C / relative humidity at 15%, and after 3 months at 40 ° C / relative humidity at 75%. These patterns indicate that Examples 1 to 4 (Figures 1 to 4), unpredictably, remained stable (ie, did not crystallize appreciably) even under stressful conditions, while Comparative Examples 5 to 8 began to crystallize under stressors, as shown in the XRPD patterns of Figures 5 to 8.

Dissolution study (Figures 10 and 11) The pure crystalline drug substance used in the following dissolution studies was prepared by dissolving 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro -4H-pyridazino [4, 5-b] indol-1 -acetamide in hot N-methyl-2-pyrrolidinone (NMP), adding ethanol to form a precipitate, and isolating the solid.

The dissolution tests of Examples 1 to 4, and Comparative Examples 5 to 8, and the pure crystalline drug substance were performed with a paddle-type drug dissolution test bath (available from Distek Inc.) at 75 rpm, and an HP 8453 UV spectrophotometer at a wavelength of 320 nm. The following parameters were used: the concentration of drug substance was 20 mg / 500 ml of medium, in which the medium was 0.25% sodium lauryl sulfate in water / 0.01 M phosphate buffer pH 7; the temperature was 37 ° C; and the sampling time interval was 10 minutes. Two containers were used for each sample. The results of the dissolution test, shown in Figure 10, indicate that the amorphous solid dispersions of the present invention have significantly higher dissolution rates, compared to the pure crystalline drug substance and comparative examples 5 to 8. The studies of solution were repeated for Example 9 using essentially the same procedure as described for the dissolution studies of Examples 1 to 4 and Comparative Examples 5 to 8. The solid amorphous dispersion of Example 9 shows a marked increase in the speed of dissolution compared to the pure crystalline drug substance. The results of this experiment are shown in figure 11.

Bioavailability study The following study was conducted to determine the bioavailability of a solid dispersion formulation according to the present invention, relative to a conventional formulation under fasting conditions. A conventional formulation and a solid dispersion of the present invention were prepared as follows: Conventional formulation Material Quantity (mg / capsule) Active drug substance (micronized) 20 Polysorbate 80 2.00 Microcrystalline cellulose 125 Pregelatinized starch 249 Croscarmellose sodium 2.00 Magnesium stearate 2.00 This formulation The conventional material was used as reference material and was manufactured using a conventional wet granulation process and introduced into a hard gelatin capsule of size 0. Solid dispersion Material Quantity (mg / capsule) Hydroxypropylmethylcellulose phthalate 100 Active drug substance 25 Dispersion The solid was prepared according to example 9, above, and introduced into a hard gelatin capsule of size 0. 100 mg of the active drug substance was administered in a single oral dose of the conventional formulation (n = 7) or the solid dispersion. (n = 8) to humans, and blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours. The samples were analyzed by LC / MS (liquid chromatography / mass spectrometry). The results are indicated in Table 3. The Cmax (maximum blood concentration) and the AUC (area under the concentration vs. time in the diagram) were significantly higher for the solid dispersions, when compared to the conventional control formulation, indicating, with it, the best bioavailability of the amorphous dispersions of the present invention. Table 3: Results of the bioavailability study: Serum blood levels in humans after oral administration Example 10 Tablets and capsules containing the pharmaceutical compositions of the present invention having the following composition can be produced in a conventional manner: mg per tablet or capsule Dispersion prepared according to example 9 300 Microcrystalline cellulose 80 Sodium starch glycolate 16 Magnesium stearate 4 Total weight of the tablet or capsule 400

Claims (33)

1. CLAIMING IS 1. A solid dispersion comprising substantially amorphous 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1 -acetamide and a stabilizing polymer. The solid dispersion according to claim 1, wherein said stabilizing polymer is one or more polymers selected from the group consisting of hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, and a polymethacrylate. 3. The solid dispersion according to claim 2, wherein said stabilizing polymer is hydroxypropylmethylcellulose phthalate. 4. The solid dispersion according to claim 2, wherein said stabilizing polymer is cellulose acetate phthalate. 5. The solid dispersion according to claim 2, wherein said stabilizing polymer is a polymethacrylate. 6. The solid dispersion according to claim 5, wherein the polymethacrylate is EUDRAGIT® L 100. 7. The solid dispersion according to claim 1, wherein the 7-chloro-N, N, 5-trimethyl-4-oxo-3 -phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole-1 -acetamide is present in an amount of about 0.1% to about 30% by weight relative to the weight of the stabilizing polymer. The solid dispersion according to claim 7, wherein 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole -1-Acetamide is present in an amount of about 1% to about 25% by weight relative to the weight of the stabilizing polymer. 9. The solid dispersion according to claim 8, wherein the 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b] indole -1-Acetamide is present in an amount of about 5% to about 20% by weight relative to the weight of the stabilizing polymer. 10. The solid dispersion according to claim 9, wherein the stabilizing polymer is hydroxypropylmethylcellulose phthalate. The solid dispersion according to claim 1, wherein at least 80% of the 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4] , 5-b] indole-1 -acetamide is in amorphous form. 12. The solid dispersion according to claim 1, wherein at least 90% of the 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4] , 5-b] indole-1 -acetamide is in amorphous form. The solid dispersion according to claim 12, wherein at least 95% of the 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4, 5-b] indole-1 -acetamide is in amorphous form. 14. A pharmaceutical composition comprising a solid dispersion according to claim 1, and one or more pharmaceutically acceptable excipients. 15. A pharmaceutical composition comprising a solid dispersion according to claim 10, and one or more pharmaceutically acceptable excipients. 16. A method for the treatment or prevention of a disease or disorder linked to a peripheral-type benzodiazepine receptor dysfunction, which comprises administering to a patient in need of said treatment or prevention a therapeutically effective amount of a solid dispersion according to the claim 17. A method for the treatment or prevention of a disease or disorder linked to a dysfunction of peripheral type benzodiazepine receptors, which comprises administering to a patient in need of said treatment or prevention a therapeutically effective amount of a pharmaceutical composition according to claim 14. 18. A method for the treatment or prevention of a neurodegenerative disease, comprising administering to a patient in need of said treatment or prevention a therapeutically effective amount of a solid dispersion according to claim 1. 19. A method for the treatment or prevention of a neurodegenerative disease, which comprises administering to a patient in need of said treatment or prevention a therapeutically effective amount of a pharmaceutical composition according to claim 14. 20. A method for the treatment or prevention of neuropathy, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of a solid dispersion according to claim 1. twenty-one . A method for the treatment or prevention of neuropathy, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of a pharmaceutical composition according to claim 14. 22. A method for the treatment or prevention of cancer or tumors , which comprises administering to a patient in need of said treatment or prevention a therapeutically effective amount of a solid dispersion according to claim 1. 23. A method for the treatment or prevention of cancer or tumors, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a pharmaceutical composition according to claim 14. 24. A method for the treatment or prevention of a cutaneous stress, which comprises administering to a patient in need of said treatment or prevention a therapeutically effective amount of a solid dispersion according to claim 1. 25. A method for the treatment or prevention of skin stress, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a pharmaceutical composition according to claim 14. 26. A method for the treatment or prevention of rheumatoid arthritis, which comprises administering to a patient in need of said treatment or prevention a therapeutically effective amount of a solid dispersion according to claim 1. 27. A method for the treatment or prevention of rheumatoid arthritis, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of a pharmaceutical composition according to claim 14. 28. A method for the treatment or prevention of a heart disease or a cardiac disorder, comprising administering to a patient in need of said treatment or prevention a therapeutically effective amount of a solid dispersion according to claim 1. 29. A method for the treatment or prevention of a heart disease or a cardiac disorder, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a pharmaceutical composition according to claim 14. 30. A process for preparing the solid dispersion according to claim 1 comprising the steps of: a) dissolving 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5- b] indole-1 -acetamide and a stabilizing polymer in a suitable solvent to form a feed solution; b) pumping the feed solution through an atomizer; and c) removing the solvent to form the solid dispersion. 31 The process according to claim 30, wherein the suitable solvent is one or more solvents selected from the group consisting of dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, and water. 32. The process according to claim 30, wherein said stabilizing polymer is selected from the group consisting of hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, and polymethacrylate. 33. The process according to claim 30, wherein the stabilizing polymer is hydroxypropylmethylcellulose phthalate, and the suitable solvent is a 50:50 mixture by volume of dichloromethane and ethanol.