MXPA01008293A - Spontaneously dispersible n-benzoyl staurosporine compositions - Google Patents

Abstract

Spontaneously dispersible N-benzoyl-staurosporine compositions are discussed for oral administration having high bioavailability levels and reduced variability of bioavailability levels of N-benzoyl-staurosporine, as well as their preparation and use in medical treatment.

Description

SEPARATELY DISPERSIBLE N-BENZOIL-ESTAUROSPOR1NA COMPOSITIONS The present invention relates to novel pharmaceutical compositions in which an active agent is N-benzoyl-staurosporine, as disclosed, for example, in U.S. Patent No. 5,093,330 and its equivalents. U.S. Patent No. 5,093,330 specifically discloses two tablet formulations based on mixtures of starch / lactose, in the presence of colloidal silica, talc, and magnesium stearate (Examples 52 and 53), and a formulation of capsule based on talc and colloidal silica (Example 54). We have found that N-benzoyl-staurosporine presents highly specific difficulties in relation to administration in general, and with pharmaceutical compositions in particular, including problems with the bioavailability of the drug and the variability in the response to the intra- and intra- patients, for example, with respect to U.S. Patent No. 5,093,330. We have found that it is very lipophilic and practically insoluble in water, in simulated gastric and intestinal fluids (solubility < 0.1 milligrams / liter). In particular, this exceptionally low solubility of the active substance necessitated the development of an unconventional dosage form. In accordance with the present invention, it has now been found in a surprising manner that stable pharmaceutical compositions can be obtained with N-benzoyl-staurosporine, which have particularly interesting bioavailability characteristics, and a reduced variability in the parameters of inter-bioavailability. intra-subjects, for example with respect to the Patent of the States United States Number US 5,093,330. It has been found that these novel N-benzoyl-staurosporine compositions substantially satisfy or reduce the previously encountered difficulties. It has been demonstrated that the compositions according to the present invention can make possible an effective dosage of N-benzoyl-staurosporine with a concomitant improvement, as well as a reduced variability of the levels of resorption / bioavailability for and between individual patients. These reductions in the variability in inter- and intra-subject bioavailability can be found particularly with respect to the specific formulations described. More particularly, it has been found that these compositions can contain N-benzoyl-staurosporine solubilized at a sufficiently high concentration to allow convenient oral administration without exhibiting precipitation of the active agent. Accordingly, the invention can achieve effective therapy with lower dosage levels of N-benzoyl-staurosporine, and may allow a closer standardization and optimization of daily dosing requirements for each individual. As a result, the occurrence of undesirable side effects is decreased, and the overall cost of therapy can be reduced. In one aspect, the present invention provides a pharmaceutical composition for oral administration, which comprises N-benzoyl-staurosporine having a high level of bioavailability, for example determined by measurement of plasma concentrations over time, as defined through the Area Under the Curve (AUC) in mass-time / volume units. In another aspect, the present invention provides a pharmaceutical composition for oral administration, which comprises N-benzoyl-staurosporine having a reduced variability of bioavailability. In preferred embodiments, the variability of bioavailability is reduced by providing N-benzoyl-staurosporine in the form of a spontaneously dispersible pharmaceutical composition. In another aspect, the present invention provides a spontaneously dispersible pharmaceutical composition for enteral administration., for example oral, which comprises N-benzoyl-staurosporine, for example, in the form of a micellar precursor. The term "spontaneously dispersible pharmaceutical composition", as used herein, is defined as a system which is capable of producing colloidal structures, for example colloids or analogous structures, for example droplets, particles, micelles, for example swollen micelles. , microemulsions, and / or aggregates, for example up to 1000 nanometers, for example in general of more than 5 nanometers, when diluted with an aqueous medium. These systems can be defined as consisting of a component or phase (the dispersed component or phase) finely divided and distributed through a second component or phase (the dispersion medium or the component or continuous phase), for example the systems that are from molecularly dispersed solutions, wherein the average size of the component or dispersed phase can be, for example, less than 200 nanometers, for example greater than 5 nanometers, up to macroemulsions, wherein the average size of the component or dispersed phase can be , for example, up to 1000 nanometers, for example greater than 200 nanometers. The aqueous medium can be, for example, water, for example when diluted, for example, to 1:10, or gastric juices, for example simulated conditions after oral application. Colloidal structures, for example colloids or analogous structures, for example droplets, particles, and / or micelles, are formed spontaneously or in a substantially spontaneous manner when the components of the dispersible pharmaceutical composition are contacted with an aqueous medium, for example by simple manual agitation for a short period of time, for example for 10 seconds. These spontaneously dispersible pharmaceutical compositions are thermodynamically stable, for example from at least 15 minutes or 4 hours up to 24 hours. Typically, they contain dispersed structures, for example colloidal, for example colloids or analogous structures, of a size less than about 200 nanometers, as measured by conventional light scattering techniques, for example using a Malvern Zetasizer 3000, preferably comprising droplets or particles that they have an average diameter of less than about 150 nanometers, typically less than 100 nanometers, generally greater than 5 nanometers. The micellar compositions or micellar part of these spontaneously dispersible compositions can be monophasic and substantially non-opaque, ie transparent or opalescent when viewed by optical microscopic elements. Alternatively, the pharmaceutically dispersible pharmaceutical composition can simultaneously form a mixture comprising aqueous micelles and nanoparticles. These nano-particles can have a particle size from 150 nanometers to approximately 1000 nanometers, generally in the range of 200 to 800 nanometers. It was found that the amount of nanoparticles produced may depend on the temperature, but still suitable bioavailability characteristics can be obtained. Although the invention has been described in particular with respect to a spontaneously dispersible pharmaceutical composition, an expert in the art will appreciate that other systems can be prepared.

In another aspect, the present invention provides a spontaneously dispersible pharmaceutical composition for oral administration, which comprises: 1) N-benzoyl-staurosporine, 2) a hydrophilic component, and 3) a surfactant. In yet another aspect, the invention provides a method for increasing the bioavailability of N-benzoyl-staurosporine, by mixing N-benzoyl-staurosporine with a carrier comprising a hydrophilic component, and a surfactant. In another aspect, the present invention provides a pharmaceutical composition for increasing the bioavailability of N-benzoyl-staurosporine, which comprises: 1) N-benzoyl-staurosporine, 2) a hydrophilic component, and 3) a surfactant. The spontaneously dispersible pharmaceutical composition (hereinafter encompassed by the term "pharmaceutical composition of the present invention") is preferably in the form of a colloidal structure, for example colloids or analogous structures, for example a micellar precursor. The N-benzoyl-staurosporine is also referred to herein as the active agent, and all other components of the spontaneously dispersible pharmaceutical composition can be referred to herein after as the vehicle of the spontaneously dispersible pharmaceutical composition. The components of the spontaneously dispersible pharmaceutical compositions can be described in Fiedler, H.P. "Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete", Editio Cantor, D-7960 Aulendorf, 4th revised and expanded edition (1996), whose content is incorporated herein by reference. In accordance with the present invention, N-benzoyl-staurosporine may be present in a weight amount of up to about 20 weight percent of the composition. Preferably, the active agent is present in an amount of 1 to 15 weight percent of the composition, for example about 5 to 10 percent, and more preferably 5 percent. The hydrophilic component preferably provides a rapid mixture of the active agent with water when mixed with water, and can be determined by routine experimentation, for example by different chromatography methods, for example Gas Chromatography (GC). The hydrophilic component may comprise a main or single component, for example an alcohol, for example ethanol, or alternatively may comprise a co-component, which may be selected from partial ethers or lower alkanols. Preferred lower alkanol components include ethanol, 1,2-propylene glycol, or a polyethylene glycol, for example of a molecular weight of 100 to 600 daltons, for example polyethylene glycol 400. When present in the invention, ethanol may comprise up to 60 weight percent of the hydrophilic component; preferably from 20 to about 55 weight percent, more preferably from about 25 to about 40 weight percent. Particularly preferred partial ethers are those known and commercially available, for example, as glycofurol (also known as polyethylene glycol ether tetrahydrofurfuryl alcohol). These co-components, when present, are, for example, a partial replacement of other components of the hydrophilic component, such that the effectiveness of the hydrophilic component as part of the N-benzoyl-staurosporine vehicle is not materially impaired. The hydrophilic component may further comprise triethyl citrate, Transcutol, N-methylpyrrolidone, dimethylisosorbide, or propylene carbonate. The total amount of the hydrophilic component present in the spontaneously dispersible pharmaceutical compositions of the present invention can comprise from 5 to 50 weight percent of the vehicle, for example from 10 to 50 percent; preferably from 10 to 40 percent by weight, more preferably from about 15 to 35 percent by weight. The pharmaceutical compositions of the present invention further comprise at least one pharmaceutically acceptable surfactant. The surfactants useful for the present invention may be of the anionic, cationic, amphoteric, or non-ionic type, or mixture thereof, and may generally have a hydrophilic-lipophilic equilibrium (HLB) value of about 3 to 20. Preferred are nonionic surfactants, in particular those nonionic surfactants having a hydrophilic-lipophilic equilibrium value, greater than 10, for example 14 to 20. Alternatively, the pharmaceutical compositions of the present invention they may encompass systems comprising a mixture of surfactants, for example a mixture of a first surfactant and one or more surfactant co-agents selected from any of the types of surfactants listed below. Especially preferred are specific combinations of a surfactant having a high hydrophilic-lipophilic equilibrium value, with a surfactant co-agent having a low hydrophilic-lipophilic equilibrium value, for example a combination of a castor oil derivative of polyoxyethylene, for example Cremophor RH 40 (HLB 14-16) and a transesterified ethoxylated vegetable oil, for example Labrafil M2125 CS (hydrophilic-lipophilic balance: 3-4). Particularly preferred hydrophilic-lipophilic equilibrium high-value surfactants, for example HLB > 10, are the following: (i) The reaction products of a natural or hydrogenated vegetable oil and ethylene oxide, ie natural or hydrogenated polyoxyethylene glycol vegetable oils, for example natural or hydrogenated polyoxyethylene glycolic castor oils. The natural or hydrogenated castor oil can be reacted with ethylene oxide in a molar ratio of about 1:35 to about 1:60, with the optional removal of the polyethylene glycol component of the products. Several of these surfactants are commercially available. Hydrogenated castor oils with polyethylene glycol available under the trade name CREMOPHOR are especially suitable (Fiedler loe, cit. 1, pages 392-395). Particularly suitable are CREMOPHOR RH 40, which has a saponification number of about 50 to 60, an acid number of less than about 1, a water content (Fischer) of less than about 2 percent, an nDβ0 of about 1,453 to 1,457. , and a hydrophilic-lipophilic balance of approximately 14 to 16; and CREMOPHOR RH 60, which has a saponification number of about 40 to 50, an acid number less than about 1, an iodine number less than about 1, a water content (Fischer) of about 4.5 to 5.5 percent a nD25 from about 1453 to 1457, and a hydrophilic-lipophilic balance of about 15 to 17. An especially preferred product of this class is CREMOPHOR RH40. Also suitable are polyethylene glycol castor oils, such as those available under the trade name CREMOPHOR EL, which has a molecular weight (by vapor osmometry) of about 1,630, a saponification number of about 65 to 70, a number of acid of about 2, a number of iodine of about 28 to 32, and a nD25 of about 1471, and a hydrophilic-lipophilic equilibrium value of about 12 to 14. Also suitable are the different surfactants available under the trade names NIKKOL (for example NIKKOL HCO-40 and HCO-60), MAPEG (for example, MAPEG CO-40h), INCROCAS (for example, INCROCAS 40), and TAGAT, for example fatty acid esters of polyoxyethylene glycerol, for example TAGAT RH 40, and polyoxyethylene glycerol trioleates, for example TAGAT TO having a hydrophilic-lipophilic equilibrium value of 11.3. These surfactants are further described in Fiedler loe, cit. (Ii) Related products belonging to the class of polyoxyethylene alkyl ethers are available under the tradename BRIJ, for example Brij 35, which has a hydrophilic-lipophilic equilibrium value. of approximately 16.9. (iii) Polyoxyethylene fatty acid esters, for example esters of polyoxyethylene stearic acid of the type known and commercially available under the tradename MYRJ (Fiedler, loe, cit., 2., pages 1042-1043). An especially preferred product of this class is MYRJ 52, which has a nD25 of about 1.1, a melting point of about 40 ° C to 44 ° C, a hydrophilic-lipophilic equilibrium value of about 16.9, an acid value of about 0 to 1, and a saponification number of about 25 to 35. Other related products include polyethoxylated saturated hydroxy fatty acids, which can be produced by the reaction of a saturated fatty hydroxy acid, for example from 18 to 20 carbon atoms, with, example, ethylene oxide or polyethylene glycol. Suitable examples for the present invention are known and are commercially available, for example from the BASF company under the trademark Solutol. Especially preferred is Solutol HS15 which is known, for example, from BASF's technical leaflet, MEF 151E (1986), which comprises about 70 percent polyethoxylated 12-hydroxystearate by weight and about 30 percent by weight of a non-esterified polyethylene glycol component. Solutol HS 15 has a hydrogenation value of 90 to 110, a saponification value of 53 to 63, a maximum acid number of 1, and a maximum water content of 0.5 weight percent. (iv) Polyoxyethylene sorbitan fatty acid esters (also called polysorbates), for example mono- and tri-lauryl-, pal-methyl-, stearyl-, and oleyl-esters of the type known and commercially available under the trade name TWEEN (Fiedler, loc. Cit., 2, pages 1615-1619), including the products TWEEN, 20 [polyoxyethylene sorbitan monoaurate (20)] with a hydrophilic-lipophilic balance of about 16.7, 21 [polyoxyethylene sorbitan monolaurate ( 4)] with a hydrophilic-lipophilic equilibrium of approximately 13.3, 40 [polyoxyethylene sorbitan monopalmitate (20)] with a hydrophilic-lipophilic balance of approximately 15.6, 60 [polyoxyethylene sorbitan monostearate (20)] with an equilibrium hydrophilic-lipophilic of about 14.9, 65. [polyoxyethylene sorbitan tristearate (20)] with a hydrophilic-lipophilic balance of about 10.5, 80 [polyoxyethylene sorbitan mono-oleate (20)] with a hydrophilic-lipophilic equilibrium of about 15.0, 81 [polyoxyethylene sorbitan mono-oleate (5)] with a hydrophilic-lipophilic equilibrium of about 10.0, 5. [polyoxyethylene sorbitan trioleate (20)] with a hydrophilic-lipophilic balance of approximately 11.0. Especially preferred products of this class are TWEEN 40 and TWEEN 80. (v) Hydrophilic tocopherol esters, for example d-alpha-tocopheryl-polyethylene glycol 1000 succinate. (Vi) Polyoxyethylene-polyoxypropylene block copolymers and copolymers, for example of the type known and commercially available under the trade names PLURONIC, EMKALYX and PO-LOXAMER (Fiedler, loe, cit. 2, pages 1198-1204). An especially preferred product of this class is PLURONIC F68 having a melting point of about 52 ° C, and a molecular weight of about 6,800 to 8,975. A further preferred product of this class is POLOXAMER 188, which has a hydrophilic-lipophilic equilibrium value of about 29. Particularly preferred surfactant co-agents having a low hydrophilic-lipophilic balance, for example HLB <; 10, are the following: (i) Sorbitan fatty acid esters, for example of the cone-like type and commercially available under the trade name Span, for example including sorbitan monolaurelester (HLB 8.6), sorbitan mono-palmitylester ( HLB 6.7), sorbitan monostearylester (HLB 4.7), sorbitan tristearylester (HLB 2.1), sorbitan mono-oleylester (HLB 4.3), and sorbitan trioleyl esters (HLB 1.8) (Fiedler loe, cit .. ^ pages 1430). (ii) Mono- and di-esters of propylene glycol fatty acid, such as propylene glycol dicaprylate (also known and commercially available under the tradename M IGLYOL 840), propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate , propylene glycol ricinoleate, propylene glycol stearate, etc. (Fiedler loe, cit. 2, pages 1008-1010). The propylene glycol monoesters of 8 carbon atoms include Sefsol 218 (Nikko Chemicals) and Capryol 90 (Gatte-fossé). (iii) transesterified ethoxylated vegetable oils, such as those obtained by the reaction of different natural vegetable oils (e.g. corn oil, palm kernel oil, almond oil, peanut oil, olive oil, soybean oil) , sunflower oil, saffron oil, and palm oil or mixtures thereof), with polyethylene glycols having an average molecular weight of 200 to 800, in the presence of an appropriate catalyst (in accordance with the known procedures described in the literature, for example in U.S. Patent No. 3,288,824). Particularly, the ethoxylated or transesterified maize oil is referred to. Various forms of transesterified ethoxylated vegetable oils are known and are commercially available under the tradename LABRAFI L (Fiedler loe, cit 2, page 880). Especially suitable examples are LABRAF ILM 21 25 CS (obtained from maize oil, and which has an acid concentration less than approximately 2, a saponification number from 155 to 175, a value of hydrophilic-lipophilic balance from 3 to 4, and an iodine number from 90 to 110), and LABRAFIL M 1944 CS (obtained from palm kernel oil, and having an acid number of approximately 2, a number of saponification from 145 to 175, and an iodine number from 60 to 90). LABRAFIL M 2130 CS (which is a transesterification product of a glyceride of 12 to 18 carbon atoms and polyethylene glycol, and having a melting point of about 35 ° C to 40 ° C, and an acid number less than about 2, a toad number from 185 to 200, and an iodine number less than about 3), can also be used. The preferred transesterified ethoxylated vegetable oil is LABRAFIL M 2125 CS which can be obtained, for example, from Gattefossé, Saint-Priest Cedex, France. (iv) Mono-, di- and mono / diglycerides, for example mono- and di-glycerides of fatty acids of 8 to 10 carbon atoms, include Capmul MCM, Akoline MCM (from the company Karlshamns), Imwitor 308 and Imwitor 988, which have a hydrophilic-lipophilic equilibrium value of approximately 3.8 (from the company Contensio), and especially the products of the esterification of caprylic or capric acid with glycerol. Preferred products of this class are, for example, those comprising or consisting essentially of mono- and di-glycerides of caprylic / capric acid. Mono-, diglycerides of 8 to 10 carbon atoms having from 6 to 10 mole percent of polyoxyethylene groups, for example Softigen 767 (available from Contensio Chemicals). Monoglycerides, for example mono-oleate, glycerol monopalmitate, and glycerol monostearate, for example as are known and commercially available under the tradenames Myvatex, Myvaplex, and Myverol (Fiedler loe, cit., 2, page 1044) and acetylated monoglycerides, for example mono- and di-acetylated, for example as they are known under the trade name Myvacet (Fiedler, loe, cit. 2., page 1043). (v) Esters of fatty acids of pentaerythritol and polyalkylene glycol ethers and polyalkylene glycol ethers, for example dioleate, distearate, monolaurate, polyglycol ether, and pentaerythritol monostearate, as well as fatty acid esters of pentaerythrityl (Fiedler, loc. cit., 2, pages. 1158-1160). (vi) Other suitable surfactants include glycerol triacetate or (1, 2,3) -triacetin (Fiedler, loe, cit. 2, page 1580); and sterols and their derivatives. Additional classes of ionic surfactants not represented by the categories described above include: (i) docusate salts, for example dioctyl sulfosuccinate or related compounds, for example di- [2-ethylhexyl] succinate (Fiedler, loe, cit. .. 1, page 500). (ii) Phospholipids, in particular lecithins (Fiedler, loe, cit., 2, pages 910-912). Lecithins suitable for use in the compositions of the invention include, in particular, soybean lecithins. Accordingly, in another aspect, the present invention provides a spontaneously dispersible pharmaceutical composition for oral administration, which comprises N-benzoyl-staurosporine and a surfactant selected from the group consisting of polyoxyethylenes, for example a castor oil polyoxyethylene, for example Cremophor RH40, a polyoxyethylene alkyl ether, for example Brij 35, polyglycerols and related polyols, for example a polysorbate, for example Tween 20, and polyalkylene oxide copolymers, for example Pluronic. Furthermore, in yet another aspect, the present invention provides a spontaneously dispersible pharmaceutical composition for oral administration, which comprises N-benzoyl-staurosporine and a surfactant having a high hydrophilic-lipophilic balance value greater than 10, for example selected from from the group consisting of a polyoxyethylene castor oil, for example Cremophor RH 40, a polyoxyethylene alkyl ether, for example Brij 35, and a polysorbate, for example Tween 20, and a surfactant co-agent having a low value of hydrophilic-lipophilic balance less than 10, for example a transesterified ethoxylated vegetable oil, for example Labrafil M2125 CS. The spontaneously dispersible pharmaceutical composition can be formulated in a conventional manner, and preferably it can be in a micellar precursor form, as described above. The total amount of the surfactant and the surfactant co-agent present in the pharmaceutical composition of the present invention may comprise from 5 to 80 weight percent of the vehicle; preferably from 10 to 70 weight percent, more preferably from 20 to 60 weight percent, and still more preferably from about 30 percent to 55 weight percent. The pharmaceutical compositions of the present invention may further comprise a lipophilic component. These compositions can produce emulsions and related systems, for example microemulsions, for example a system with an average particle diameter, for example, from 5 nanometers to 200 nanometers, for example from 5 nanometers to 100 nanometers, for example aqueous or oily microemulsions, preferably an aqueous microemulsion, when mixed with an aqueous medium. Preferably, the lipophilic component can be characterized by a low hydrophilic-lipophilic equilibrium value of less than 10, for example up to 8. The lipophilic component can comprise triglycerides of fatty acids, preferably triglycerides of medium-chain fatty acids. Especially suitable medium-chain fatty acid triglycerides are neutral oils, for example neutral plant oils, in particular fractionated coconut oils, for example those known and commercially available under the trade names Captex, Myritol, Capmul, Neobee and Mazol; Migiyol 812 being most preferred. Migiyol 812 is a fractionated coconut oil comprising triglycerides of caprylic-capric acid, and having a molecular weight = at about 520 daltons. Fatty acid composition = maximum C6 approximately 3 percent, C8 approximately 50 to 65 percent, C10 approximately 30 to 45 percent, C12 maximum 5 percent; acid number = approximately 0.1; saponification number from approximately 330 to 345; iodine number = maximum 1. The Migiyol 812 is available from the company Hüis. Other suitable triglycerides preferably comprise mixtures of triglycerides of fatty acids of 8 to 10 carbon atoms or of 12 to 20 carbon atoms, especially triglycerides of fatty acids of 16 to 18 carbon atoms. The fatty acid component of the triglycerides can comprise both saturated and unsaturated fatty acid residues. However, they are preferably predominantly comprised of unsaturated fatty acid residues; in particular, residues of unsaturated fatty acids of 18 carbon atoms. Suitably, the triglycerides comprise at least 60 percent, preferably at least 75 percent, more preferably at least 85 percent by weight of triglycerides of unsaturated fatty acids of 18 carbon atoms (eg, linic acid, linc , and c). Suitably, the triglycerides comprise less than 20 percent, for example about 15 percent or 10 percent by weight or less, of triglycerides of saturated fatty acids (e.g. palmitic and stearic acid). The lipophilic component may also comprise a transesterification product, generally obtained as described in Patent Numbers GB 2,257,359 or WO 94/09211, the content of which is incorporated herein by reference. Other particularly suitable triglycerides are the purified transesterification products of corn oil and glycerol, hereinafter referred to as corn oil glycerides, and produced according to the description of Patent Numbers GB 2,257,359, or WO 94/09211 . Accordingly, in another aspect, the invention provides a spontaneously dispersible pharmaceutical composition for oral administration, which comprises N-benzoyl-staurosporine and a surfactant having a hydrophilic-lipophilic equilibrium value greater than 10, and a fatty acid glyceride. as a lipophilic component. The total amount of the lipophilic component, when present in the spontaneously dispersible pharmaceutical compositions, can comprise from 5 to 85 weight percent of the vehicle, for example from 10 to 85 percent; preferably from 15 to 70 weight percent, more preferably from about 20 to about 50 weight percent. Accordingly, in yet another aspect, the present invention provides a spontaneously dispersible pharmaceutical composition for oral administration, which comprises N-benozoyl-staurosporine, a surfactant agent selected from the group consisting of a polyoxyethylene castor oil , for example Cremophor RH 40, a polyoxyethylene alkyl ether, for example Brij 35, and a polysorbate, for example Tween 20, and a lipophilic component selected from the group consisting of fatty acid glycerides, for example fractionated coconut oil , for example Migiyol 810 and 812, a glyceride of corn oil, and an acetylated mono- or diglyceride, respectively. This spontaneously dispersible pharmaceutical composition can be formulated in a conventional manner, and preferably it can be in a micellar precursor form as described above. When desired, the pharmaceutical compositions of the present invention may comprise additional additives or ingredients, for example thickening agents, suspending agents, solidifying agents, as well as antioxidants, for example tocopherols, ascorbyl palmitate, butylated hydroxyanis(BHA), butylhydroxy -toluene (BHT), antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, and the like. The total amount of these additives or ingredients, when present in the invention, may comprise from about 0.05 to 5 percent, preferably from 0.1 to 1 percent by weight of the total weight of the spontaneously dispersible pharmaceutical composition. The spontaneously dispersible pharmaceutical composition may also include sweetening or flavoring agents in an amount of up to about 2.5 or 5 weight percent, based on the total weight of the composition. Accordingly, in yet another aspect, the present invention provides a spontaneously dispersible pharmaceutical composition for oral administration, which comprises: (a) up to 20 weight percent N-benzoyl-staurosporine, (b) 5 to 50% by weight, weight percent of a hydrophilic component, (c) from 5 to 80 weight percent of a surfactant or a mixture of surfactants, (d) from 5 to 85 weight percent of a lipophilic component, and (e) ) from 0.05 to 5 percent by weight of an additive. Of course, any pharmaceutical composition of the present invention as described above, in the form of a micellar precursor, can, by itself, that is, before being diluted with an aqueous medium, or after dilution with an aqueous medium, is present. in the form of an aqueous micellar solution (possibly comprising nanoparticles), an oily or aqueous emulsion, preferably a microemulsion, and in accordance with the foregoing, exhibiting the characteristic structural features of these systems. Pharmaceutical formulations, for example those of the examples hereinafter, can show good stability characteristics, as indicated by conventional stability tests, for example having a shelf life stability of up to 1.2. , or 3 years, and even more. The pharmaceutical formulations of this invention produce aqueous microemulsions or aqueous micelles that are stable for up to a day or more.

The pharmaceutical compositions of the invention exhibit particularly convenient properties when administered orally. For example, in terms of reduced variability and high level of bioavailability, for example obtained in conventional biodisposability tests for example by measuring the area under the plasma concentration curve (AUC) -time from, for example, 0 to 48 hours, in units of mass-time / volume and average Cmax, defined as the highest concentration observed in plasma in units of mass / volume. These biopharmaceutical properties of the compositions of the invention, for example the compositions of the examples, can be determined in a conventional manner, for example in conventional animal tests, for example in rats or dogs, for example beagle dogs, or in clinical trials. Normally, beagle dogs can be used on an empty stomach, for example in groups of up to 8, for example 6 to 8, and blood drug levels are detected, for example using an HPLC method with fluorescence detection, or , for example, by ELISA using a specific monoclonal antibody. Typically, a dose, for example, of 25 milligrams or of 50 milligrams, for example 50 milligrams of the active agent, can be administered. For example, typical values of AUC / dose in the range of (h »nmol / L) / (mg / kg) from 960 to 1700 for Formulation A, from 380 to 1,760 for Formulation B, and from 840 to 1970 for Formulation C. Typical values of Cmax / dose in the range of (nmol / L) / (mg / kg) from 130 to 310 for Formulation A, from 60 to 280 for Formulation B, and from 140 to 310 for Formulation C. In one aspect, the invention provides a pharmaceutical composition for oral administration, which comprises N-benzoyl-staurosporine having an AUC value (0-48 hours) / dose (in h "nmol / L) / (mg / kg)) after administration of a dose (in milligrams / kilogram) to beagle dogs on an empty stomach, up to 2000, for example from 380 to 2000, for example from 840 to 2000. In another aspect, the invention provides a pharmaceutical composition for oral administration, which comprises N-benzoyl-staurosporine having a Cmax / dose (in (nmol / L) / (mg / kg)) after the administration of a dose (in milligrams / kilogram) to fasting beagle dogs of up to 310, for example from 60 to 310, for example from 140 to 310. Pharmacokinetic parameters, for example absorption and blood levels, also become surprisingly more predictable, and Administration problems can be eliminated or reduced with erratic absorption. It has been found that the compositions of this invention reduce the variability in the intra- and intra-patient dose response. Normally, the variability of bioavailability is approximately 10 percent for the Formulation A, approximately 17 percent for Formulation B, and approximately 14 percent for Formulation C. In another aspect, the invention provides a pharmaceutical composition for oral administration, which comprises N-benzoyl-staurosporine, and which has a bioavailability variability of N-benzoyl-staurosporine of less than 20 percent, for example from 5 percent to 17 percent, for example from 10 percent to 17 percent. In another aspect, the invention provides a method for in-increasing the bioavailability or for reducing the variability of the bioavailability levels of N-benzoyl-staurosporine, this method comprising orally administering a composition of the invention to beagle dogs on an empty stomach, example where N-benzoyl-staurosporine has an AUC value (0-48 hours) / dose (in h «nmol / L) / (mg / kg)) after the administration of a dose (in milligrams / kilogram) to fasted beagle dogs up to 2000, for example from 380 to 2000, for example from 840 to 2000. In another aspect, the invention provides a method to increase the bioavailability or to reduce the variability of the bioavailability levels of N-benzoyl -staurosporin, this method comprising orally administering a composition of the invention to beagle dogs on an empty stomach, for example where N-benzoyl-staurosporine has a Cmax / dose (in (nmol / L) / (mg / kg)) after administration of a dose (in mi-ligramos / kilogram) to beagle dogs in fasting up to 310, for example from 60 to 310, for example from 140 to 310. In another aspect, the invention provides a method for increasing the bioavailability or for reducing the variability of the bioavailability levels of N-benzoyl-staurosporine, this method comprising orally administering a composition of the invention to beagle dogs in fasting, for example where the variability of bioavailability is less than 20 percent, for example from 5 percent to 17 percent, for example from 10 percent to 17 percent. Additionally, the pharmaceutical compositions of the present invention are effective with tenside materials, for example bile salts, which are present in the gastrointestinal tract. That is, the pharmaceutical compositions of the present invention can be dispersed spontaneously in aqueous systems comprising such natural surfactants, and are therefore capable of providing aqueous micellar or aqueous microemulsion systems in situ that are stable. The function of the pharmaceutical compositions in the present invention after oral administration remains substantially independent of, and / or not impaired by, the relative presence or absence of bile salts at any particular time or for any given individual. In another aspect, the invention provides a process for the production of a spontaneously dispersible pharmaceutical composition as defined above, said process comprising placing the hydrophilic component and the surfactant (and additional components, if required) in intimate admixture, and add the active agent, ie, N-benzoyl-staurosporine. When required, the composition can be mixed in a unit dosage form, for example by encapsulation in soft or hard gelatin capsules. Optionally, additional components or additives, in particular a hydrophilic co-component, for example ethanol, can be mixed with the two components, or with or after the addition of the active agent. For example, although the use of ethanol in the compositions is not essential, ethanol may provide additional benefits, for example, it has been found to be of particular advantage when the compositions are to be manufactured in a soft gelatin encapsulated form. This is because the storage characteristics are improved, in particular the risk of precipitation of the active agent is reduced following the encapsulation procedures. Accordingly, the shelf life stability can be prolonged by the use of ethanol or some other co-component as an additional ingredient of the hydrophilic component. The utility of all the pharmaceutical compositions of the present invention can be observed in conventional clinical tests, for example, the known indications of the dosages of the active agent giving equivalent blood levels of the active agent; for example, using dosages in the range of 25 milli-grams to 300 milligrams, preferably 100 to 225 milligrams, for example 120 to 225 milligrams, for example 150 milligrams of active agent per day for a 75 kilogram mammal, per example an adult human, and in conventional animal models. The pharmaceutical profile, for example the increased bioavailability and reduced bioavailability volatility of the active agent, provided by the compositions, can be observed in conventional animal tests and in clinical trials, for example as described above. In another aspect, the invention provides a method for in-increasing the levels of bioavailability or for reducing the variability of bioavailability levels of N-benzoyl-staurosporine for patients during therapy with N-benzoyl-staurosporine, comprising this method orally administering a composition of the invention. In yet another aspect, the invention provides the use of N-benzoyl-staurosporine in the manufacture of a medicament suitable for oral administration, and having, for example, high levels of bioavailability and reduced variability of bioavailability of N-benzoyl-staurosporine. In yet another aspect, the invention provides the use of N-benzoyl-staurosporine in the manufacture of a medicament having high levels of bioavailability and reduced variability of bioavailability of N-benzoyl-staurosporine. The pharmaceutical compositions of the present invention are preferably mixed in a unit dosage form, for example by filling them into orally administrable capsule shells. The capsule covers can be covered with soft or hard gelatin capsules. When the pharmaceutical composition of the present invention is in a unit dosage form, each unit dosage will suitably contain from 25 to 100 milligrams of active agent, preferably between 25 and 75 milligrams of the active agent, for example 25 or 50 milligrams. These unit dosage forms are suitable to be administered from 1 to 5 times a day, depending on the particular purpose of the therapy, the component of the therapy, and the like. However, if desired, the pharmaceutical compositions of the present invention may be in a drinking solution form, and may include water or any other aqueous system, to provide suitable formulations for drinking. The pharmaceutical compositions of the present invention are particularly useful for the treatment and prevention of the conditions disclosed in U.S. Patent No. 5,093,330, the contents of which are incorporated herein by reference. Most notably, these compositions show high antiproliferative and antitumor activity, as a result of the inhibition of protein kinase C (PKC), which can be extremely useful for the treatment of cancer. Moreover, its highly selective and potent inhibition of PKC can lead to superior clinical outcomes for the patient (ie, delay or suppression of disease progression) with equally tolerable regimens. Potential applications include a variety of solid tumors, and more specifically, for example, breast cancer, colon cancer, ovarian cancer, and leukemia. In addition, other different indications that can be affected by PKC activity can be effectively treated with these compositions, including Multiple Drug Resistance (M DR), one of the main problems in cancer chemotherapy currently employed, and inflammatory diseases. in general. Accordingly, in another aspect, the present invention provides a method of treatment comprising administering a dispersible pharmaceutical composition according to the present invention to a subject in need of such treatment. Following is a description, by way of example only, of the compositions of this invention, and is not intended to limit the scope of the present invention. Examples 1 to 4 Particle measurements were made, including measurement of the average size of the dispersed particles (diameter), measured at a dispersion angle of 90 ° and at a temperature of 20 ° C, using a Malvern Zetasizer 3000. The vehicle it was prepared by mixing the components with each other. The active agent N-benzoyl-staurosporine is then dissolved in the vehicle by stirring. No phase separation or precipitation is observed for any of the compositions 1 to 4 described, which are and remain transparent.

Table 1: Composition of Formulations 1 to 4 Example 5 The pharmacokinetic parameters and plasma profiles of N-benzoyl-staurosporine administered in the following three formulations A, B, and C (filled in hard gelatin capsules) were analyzed: A pre-concentrated in microemulsion containing Cremophor and EG, preconcentrated B in microemulsion containing Cremophor and Labrafil, C preconcentrated in microemulsion containing Solutol. Using a two-block Latin Square design, two hard gelatin capsules of each formulation A, B, or C containing N-benzoyl-staurosporine were placed deep in the throat of each of 8 male beagle dogs (from 3 to 5 years, from 10 to 14 kilograms). A subsequent throat rinsing was performed, using 20 milliliters of demineralized water to swallow. The nominal dose of 50 milligrams applied per animal corresponds to real doses between 3.5 and 4.9 milligrams / kilogram of body weight (see Table 2). The dogs were fasted for at least 15 hours before administration, but had free access to tap water throughout the experiment. Around 6 hours (range of 6.0 to 6.3) after oral administration, each animal received around 350 grams of granules. The blood (3 milliliters) of the cephalic vein was collected in 5 milliliter polystyrene tubes containing Li-heparin as anticoagulant (at least 15 international units of heparin per milliliter of blood), at the following points in time: 0 ( = before) and 0.17, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24, 30, 36, and 48 hours after the dose. The heparinized blood samples were centrifuged (approximately 2,150 g, 10 minutes, approximately 4 ° C), no more than 30 minutes after removal, and the supernatant plasma was collected in clean colored dark brown polystyrene tubes to avoid further exposure in the daylight. The plasma samples were frozen and stored below -18 ° C during the analysis. The concentrations of N-benzoyl-staurosporine in plasma were determined by a H PLC method with fluorescence detection. Table 2 lists the pharmacokinetic parameters Cmax (highest concentration observed in plasma); tmax (time to reach Cmax); and AUC (0-48 hours) (area below the plasma concentration curve - time from 0 to 48 hours, calculated by the linear trapezoidal rule, where concentrations below the limit of quantitation (LOQ) were taken as' zero '). In Figures 1, 2, and 3, respectively, the individual and average plasma concentrations (N = 6 *) of N-benzoyl-staurosporine are shown in dogs 1 to 8 after oral administration of individual doses of 50 milligrams. as the formulation A, B, or C (where T means the time after dosing, and M means the average concentration). Dogs No. 2 and 6 were excluded from the calculation of averages, because it was questionable whether they properly ingested the appropriate dosages. or Table 2: Individual and average pharmacokinetic parameters (N = 6 *) derived from plasma concentrations of N-benzoyl-staurosporine in 8 dogs after administration of individual doses of 50 mg of N-benzoyl-staurosporine in the form of 3 different formulations.

SEM standard error of the average.

Claims (13)

1. A spontaneously dispersible pharmaceutical composition for oral administration, which comprises: 1) N-benzoyl-staurosporine, 2) A hydrophilic component, and 3) a surfactant.

2. A composition according to claim 1, which further comprises a lipophilic component.

3. A composition according to claim 1, or in claim 2, wherein the hydrophilic component comprises ethanol, 1,2-propylene glycol, or a polyethylene glycol.

4. A composition according to any of the preceding claims, wherein the surfactant is selected from the group consisting of polyoxyethylenes, polyglycerols and related polyols, and polyalkylene oxide copolymers.

A composition according to any one of the preceding claims, wherein the surfactant is selected from the group consisting of a polyoxyethylene castor oil, a polyoxyethylene alkyl ether, and a polysorbate.

A composition according to any one of the preceding claims, wherein the surfactant has a hydrophilic-lipophilic equilibrium value greater than 10, and the composition further comprises a surfactant co-agent having a lower hydrophilic-lipophilic equilibrium value what 10

7. A composition according to claim 6, wherein the surfactant is selected from the group consisting of a polyoxyethylene castor oil, a polyoxyethylene alkyl ether, and a polysorbate, and the surfactant co-agent comprises an ethoxylated vegetable oil transesterified.

A composition according to claim 2, wherein the surfactant has a hydrophilic-lipophilic equilibrium value greater than 10, and the lipophilic component comprises a fatty acid glyceride.

9. A spontaneously dispersible pharmaceutical composition for oral administration, which comprises: (a) up to 20 weight percent of N-benzoyl-staurosporine, (b) from 5 to 50 weight percent of a hydrophilic-CO component, (c) from 5 to 80 percent of a surfactant or a mixture of surfactants, (d) from 5 to 85 percent of a lipophilic component, and (e) from 0.05 to 5 percent of an additive.

10. A method of treatment for treating subjects in need of therapy with N-benzoyl-staurosporine, which comprises administering a dispersible pharmaceutical composition according to any of the preceding claims, to a subject in need of such treatment.

11. A pharmaceutical composition for oral administration, which comprises N-benzoyl-staurosporine, and which has: (a) a variability of the bioavailability levels of N-benzoyl-staurosporine from 5 to 17 percent. (b) an AUC value (0-48 hours) / dose (in (h «nmol / L) / (mg- / kg)) from 380 to 2000, or (c) a Cma? / dose (in (nmol) / L) / (mg / kg)) from 60 to 310, after the administration of a dose (in milligrams / kilogram) of N-benzoyl-staurosporine to beagle dogs on an empty stomach.

12. A method for increasing the levels of bioavailability or for reducing the variability of the bioavailability levels of N-benzoyl-staurosporine, by mixing N-benzoyl-staurosporine with a vehicle comprising a hydrophilic component, and an agent surfactant.

13. A method for increasing the levels of bioavailability or for reducing the variability of the levels of bioavailability of N-benzoyl-staurosporine, this method comprising administering orally a composition according to any of the preceding claims, to beagle dogs on an empty stomach.