MX2008008187A - Crystalline pyrimidine nucleoside derivatives suspensions in capsules - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation which comprises (i) a capsule, and (ii) a core comprising crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-l-β-D-arabinofuranosylcytosine and a liquid carrier.

Description

PE SUSPENSION DERIVATIVES OF CRYSTALLINE PYRIMIDINE NUCLEOSID IN CAPSULES Field of the Invention The present invention relates to a new pharmaceutical formulation. More specifically, the present invention provides a new formulation of capsules for a pyrimidine nucleoside derivative, 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine, which is therapeutically useful in the treatment and / or cancer prevention. Background of the Invention The therapeutic use of pyrimidine nucleosides in the treatment of proliferative disorders has been documented in the art. By way of example, commercially available anti-tumor agents of the pyrimidine series include 5-fluorouracil (Duschinsky, R., and associates, J. Am. Chem. Soc, 79, 4559 (1957)), Tegafur (Hiller, SA, and associates, Dokl Akad, Nauk USSR, 176, 332 (1967)), UFT (Fujii, S., and associates, Gann, 69, 763 (1978)), Carmofur (Hoshi, A., and associates , Gann, 67, 725 (1976)), Doxyfluridine (Cook, AF, and associates, J. Med. Chem., 22, 1330 (1979)), Cytarabine (Evance, JS, and associates, Proc. Soc. Exp. Bio. Med., 106. 350 (1961)), Ancytabine (Hoshi, A., and associates, Gann, 63, 353, (1972)) and Enocytabine (Aoshima, M., and associates, Cancer Res., 36, 2726 (1976)). Patent EP 536936 (Sankyo Company Limited) describes various 2'-cyano-2'-deoxy derivatives of 1-β-D-arabinofuranosylcytosine which have been shown to exhibit valuable anti-tumor activity. A particular compound described in EP 536936 is 2'-cyano-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine (hereinafter referred to as "CYC682"); this compound is currently under additional investigation. CYC682, also known as 1- (2-C-cyano-2-dioxy-β-D-arabino-pentofuranosyl) -N4-palmitoyl cytosine, (Hanaoka, K., and associates, Int. J. Cancer, 1999: 82 : 226-236; Donehower R, and associates, Proc Am Soc Clin Oncol, 2000: abstract 764; Burch, PA, and associates, Proc Am Soc Clin Oncol, 2001: abstract 364), is a 2-prodrug anti-metabolite prodrug. -no novel deoxycytidine that is administered orally of the nucleoside CNDAC, 1- (2-C-cyano-2-deoxy-β-D-arabino-pentafuranosyl) -cytosine.

CYC682 has a unique mode of action with respect to other nucleoside metabolites, such as gemcitabine, in cunato that has a spontaneous DNA strand breaking action, which results in potent antitumor activity in a variety of cancer cell lines, xenografts and metastatic cancer model. CYC682 has been the focus of a number of studies by virtue of its oral bioavailability and its improved activity with respect to gemcitabine (the leading nucleoside analogue in the market) and 5-FU (a widely used anti-metabolite drug) based on the pre-clinical data in solid tumors. Recently, the researchers reported that CYC682 exhibited strong anti-cancer activity in a colon cancer model. In the same model, CYC682 was found to be superior to either gemcitabine or 5-FU in terms of increasing survival and also avoiding the spread of colon cancer metastases to the liver (Wu M, et al., Cancer Research, 2003: 63: 2477-2482). To date, phase I data from patients with a variety of cancers suggest that CYC682 is well tolerated in humans, with myelosuppression as the dose-limiting toxicity. A number of different formulations of CYC682 have been investigated to date. The prior art formulations usually involve capsules filled with granulated powder prepared using the active agent in amorphous form. However, these formulations were difficult to manufacture and led to capsules containing various amounts of crystalline material formed as a result of water absorption from the formulation process. As a consequence, these capsules exhibited poor stability and required storage at low temperatures (4 ° C). The present invention seeks to provide a new formulation of CYC682 that solves one or more of the problems associated with the prior art formulations investigated to date. In particular, the present invention seeks to provide a formulation for CYC682 that allows for easier processing and that results in capsules exhibiting improved stability. Brief Description of the Invention A first aspect of the present invention relates to a pharmaceutical formulation comprising (i) a capsule, and (ii) a center comprising 2'-cyano-2'-deoxy-N4-palmitoyl-1- crystalline β-D-arabinofuranosilcitosina and a liquid transporter. Conveniently, the claimed formulation exhibits improved stability and can be stored at room temperature, compared to 4 ° C of the formulations filled with powder of the prior art. In addition, preliminary studies indicate that the liquid-filled formulation allows an equivalent absorption of the active agent in the bloodstream, and in the case of doses for humans, shows similar pharmacodynamic effects. Finally, the process for preparing the claimed formulation has manufacturing advantages since the handling of the cytotoxic active agent in the powder form is minimized, since once the mixing takes place, all the filling processes involve liquid handling in the need for extensive containment. A second aspect of the present invention relates to the use of a medium chain triglyceride such as a liquid transporter in crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine capsules. A third aspect relates to a liquid carrier for use in capsules of 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine, wherein the liquid carrier is fractionated coconut oil or caprylic glyceride / capric A fourth aspect of the present invention relates to a process for preparing the above-described pharmaceutical formulation comprising the steps of: (i) mixing in additions 2'-cyano-2'-deoxy-N-palmytoyl-1-β-D crystalline-arabinophuranosylcytosine and a medium chain triglyceride to form a suspension; (ii) transferring the mixture formed in step (i) into a preformed capsule; and (iii) sealing the capsule. Detailed Description of the Invention As mentioned above, in a first aspect, the present invention provides a new pharmaceutical formulation of 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine, which is in the form of a capsule filled with liquid. More specifically, the pharmaceutical formulation comprises (i) a capsule, and (ii) a center comprising crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabino-furanosylcytosine and a liquid carrier. Preferably, the pharmaceutical formulation is for oral administration. CAPSULA The pharmaceutical composition of the present invention comprises an outer capsule or shell having the ability to encapsulate the liquid center. Suitable capsule materials will be familiar to those skilled in the art, including, for example, any polymeric material (polymers or copolymers, natural or synthetic), possessing the desired physical characteristics to allow delivery of the active agent through oral administration. . By way of example, suitable capsules include those prepared from the water soluble cellulose derivatives, a gelatinization agent and a co-gelatinization agent (see for example, US Patent No. US 5,431,917). Other examples include capsules prepared from hydroxypropylmethylcellulose and an ammonium salt of cellulose acetate phthalate polymer, or capsules made of gelatin and an ammonium salt of a copolymer of methacrylic acid and methacrylic acid alkyl ester. Additional examples include polymers that can be obtained through the polymerization of at least one vinyl ester in the presence of one or more polyether-containing compounds, and when appropriate, one or more other copolymerized monomers (see for example North American Patent No. US 6,783,770). Other suitable capsule materials include polymers or copolymers obtained by polymerizing or copolymerizing at least one polymerizable vinyl monomer in the presence of vinyl alcohol and / or derivatives thereof (see for example, US Patent No. US20050186268). Unlike conventional capsules, hard capsules of this type are compatible with liquid or semi-liquid centers. Preferably, the capsule is a hard capsule, although soft capsules may also be used. In a preferred embodiment, the capsule is a gelatin capsule, more preferably a hard gelatin capsule. Gelatin capsules according to the present invention can be prepared using conventional techniques (see for example Theory Publication and Practice of Industrial Pharmacy, Ed. Lachman L. and Associates, Third Edition, Lea & Febiger, 1986, Philadelphia, pp. 398-412). In a particularly preferred embodiment, the gelatin capsule comprises one or more opacifying agents and / or one or more pigments. Preferably, the pigments and / or the opacifying agents are each in an amount of from about 0.1 to about 10% by weight. Suitable pigments include, for example, titanium dioxide, lacquered pigments (e.g., aluminum lacustrine FS &C or lacustrine D &C), iron oxide pigments, natural dyes, synthetic oxide, and the like, or a pigment selected from indigo, carmine, quinoline yellow, S orange yellow, curcumin, riboflavin and red pigment. A particularly preferred opacifying agent is titanium dioxide. More preferably, the titanium dioxide is present in an amount of about 2%. In addition, the capsule material may contain other additives. These include but are not limited to, absorbents, acids, adjuvants, anti-hardening agents, glidants, anti-sticking agents, anti-foaming agents, anticoagulants, anti-microbial, anti-oxidants, antilogistics, astringents, antiseptics, bases, linkers. , chelating agents, sequestrants, coagulants, coating agents, dyes, dyes, pigments, compatibilizers, compound lifting agents, softeners, crystal growth regulators, denaturants, desiccants, drying agents, dehydration agents, diluents, dispersants, emollients, emulsifiers, encapsulants, enzymes, fillers, extenders, flavor concealers, flavorings, fragrances, gelatinization agents, hardeners, stiffening agents, humectants, lubricants, humidifiers, buffers, pH control agents, classifiers, softening agents, emollients, retarding agents, dispersing agents, stabilizers, suspending agents, sweeteners, disintegrants, thickening agents, regulators of consistency, surfactants, opacifiers, polymers, preservatives, anti-gelatinizers, rheology control agents, UV absorbers, toners, and viscometers. One or more additives of any particular kind, as well as one or more kinds of different additives, can be found in the compositions. Specific examples of additives are well known in the art. Preferred additives include surfactants and polymers. In a particularly preferred embodiment, the gelatin capsule is sealed by a band of gelatin. LIQUID TRANSPORTER As mentioned above, the formulation of the present invention comprises a liquid or semi-liquid center comprising 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D- arabinofuranosyl-cytosine (referred to in the present invention as an active agent) and a liquid carrier. Preferably, substantially all of the active agent is suspended in the liquid carrier. However, in some cases, the active agent can be partially solubilized and partially suspended in the liquid carrier. In a particularly preferred embodiment, the active agent is suspended in the liquid carrier. In another embodiment, the active agent is partially or completely dissolved in the liquid carrier. In a particularly preferred embodiment, the liquid carrier is a medium chain triglyceride oil. In a highly preferred embodiment, the medium chain triglyceride is fractionated coconut oil or caprylic / capric triglyceride. Myglyol 812N commercially available is the particularly preferred. At room temperature, Myglyol 812N (may also be known as MCT, DAC, oil neutral, CTFA, caprylic / capric triglyceride (caprylic acid: C8, capric acid: Cio)) is a liquid lipid oil of low viscosity. Normally, the MCT fatty acid composition is dominated by C8 fatty acids (50 to 65%), followed by C10 (30 to 45%), C12 (max 5 %) and C6 (max 3%). Oil is known to be more biodegradable than liquids with fatty acid chains more long Due to the absence of toxicity in the skin and mucous membranes, MCT has applications in dermal products where it improves permeability and dispersion. MCT is also widely used in oral formulations as a lubricant, drug solvent, and as a solution enhancer in parenteral formulations. In an alternative embodiment, the liquid carrier comprises polychlorinated glycerides, for example, Gelucire®. Gelucire compositions are inert semi-solid wax materials that are amphiphilic in character and available with various physical characteristics. They are active surface by nature and are dispersed or solubilized in aqueous media that form micelles, microscopic globules, or vesicles. It is identified by its melting point / HLB value. The melting point is expressed in degrees Celsius and the HLB (Hydrophilic-Lipophilic Balance) is a numerical scale ranging from 0 to approximately 20. Lower HLB values denote more lipophilic and hydrophobic substances, and higher values denote more hydrophilic substances and lipophobic The affinity of the compound with water or with oily substances is determined and its HLB value is assigned experimentally. One or a mixture of different grades of Gelucire excipient can be chosen to achieve the desired melting point and / or HLB value characteristics. The Gelucires preferred for use in the present invention include Gelucire® 44/14, 53/10, 50/13, 42/12, and 35/10 from Gaftefosse company. The Gelucire 50/13 compositions are polyglucolized glycerides which are prepared by reaction of alcoholysis of natural oils with polyethylene glycols (PEG). They are mixtures of long chain fatty acid (C-? 2 to C18) glyceride monoesters, diesters and / or triesters, and long chain fatty acid (C12 to C18) PEG (mono and / or di) esters and can include free PEG Gelucire compositions are generally described in the present invention as fatty acid esters of glycerol and PEG esters or as polyglucolized glycerides. A large family of Gelucire compositions is characterized by a wide ranges of function points from about 33 ° C to about 64 ° C and more commonly from about 35 ° C to about 55 ° C, and through a variety of HLB values of about 1 to about 14, more commonly about 7 to about 14. For example, Gelucire 50/13 designates a melting point of about 50 ° C and an HLB value of about 13 for this degree of Gelucire. The proper choice of the melting point / HLB value of a Gelucire or a mixture of Gelucire compositions will provide the supply characteristics needed for a specific function, for example, immediate release, sustained release and the like. The low melting points of many of the solid Gelucire compositions provide a means for incorporating the pharmaceutically active ingredients therein, at temperatures from about 0 ° C to about 50 ° C above their respective melting points, and subsequently filling the function ( solution and / or dispersion) in hard gelatin capsules. The melt solidifies inside the capsules at the time of cooling to room temperature. In a highly preferred embodiment of the present invention, the liquid carrier comprises Gelucire 44/14. This transporter is a semi-solid excipient which is a mixture of glycerol and PEG 1500 esters of long chain fatty acids. Suffixes 44 and 14 refer to their hydrophilic / lipophilic function and balance point (HLB) respectively. Gelucire 44/14 is commercially available (CAS 121548-04-7) and is also known as glycerol laurate PEG 32. Gelucire 44/14 and Miglyol 812N can be used either alone or in combination with one or more other co-transporters or additives. In a preferred embodiment, Miglyol 812N is used in combination with colloidal silicon dioxide (Aerosil 200). Preferably, Miglyol 812N is used with up to 2% colloidal silicon dioxide in combination. Conveniently, the formulations comprising Myglyol 812N and Gelucire 44/14 both show excellent stability superior to the other formulations. Myglyol 812N is particularly preferred as a liquid carrier by virtue of its more oral viscosity properties. In one embodiment of the present invention, the center may further comprise additional ingredients, for example, one or more vegetable oils, especially arachidis oil or sesame oil, or other pharmaceutically acceptable diluents, excipients or carriers. The center may also contain one or more solubilizers, one or more surfactants and / or one or more co-surfactants. A preferred solubilizer is diethylene glycol monoethyl ether. Active surfactants include caprylocaproyl macrogolglycerides or polyoxyethylene castor oil derivatives. Particularly preferred polyoxyethylene castor oil derivatives are polyoxyl hydrogenated castor oil (40) or polyoxyl hydrogenated castor oil (35). A preferred co-surfactant is polyethylene glycol 400. A preferred viscosity dispenser is polyvinylpyrrolidone. A particularly preferred viscosity imparter is povidone (PVP K-30). Other examples of additional ingredients include colloidal silicon dioxide (e.g., Aerosil 200), Gelucire 44/11, PEG4005, Polyoxamersl88 and 124, Lipoid PPL, Captex 200 and Labrafil. In a preferred embodiment, the center consists of essentially in crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine and the liquid carrier. In a more preferred embodiment, the center consists of 2'-ci to n-2 '-deoxy-N4-pa I mito i 1-1-β-D-arabinofuranosilcitosina and the liquid transporter alone, ie without other ingredients present. In a preferred embodiment, the amount of liquid carrier is from 1 to 50 parts by weight relative to 1 part by weight of crystalline 2'-cyano-2'-deoxy-N -palmitoyl-1-β-D-arabinofuranosylcytosine. In a preferred embodiment, the amount of liquid carrier is from 2 to 50 parts by weight relative to 1 part by weight of crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine. In a preferred embodiment, the amount of liquid carrier is from 1 to 10 parts by weight relative to 1 part by weight of crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine. In a preferred embodiment, the amount of liquid carrier is from 2 to 10 parts by weight relative to 1 part by weight of crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine. In an even more preferred embodiment, the amount of liquid carrier is from 1 to 5 parts by weight relative to 1 part by weight of 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D- crystallin arabinofuranosilcitosina. In an even more preferred embodiment, the amount of liquid carrier is from 2 to 5 parts by weight relative to 1 part by weight of 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine crystalline In a highly preferred embodiment, the amount of liquid carrier is about 3 parts by weight relative to about 1 part by weight of crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine. In a highly preferred embodiment, the formulation comprises 25% w / w active agent and 75 w / w liquid carrier. Another aspect of the present invention relates to the use of a medium chain triglyceride in the form of a liquid transporter in crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine capsules. Preferably, the medium chain triglyceride is fractionated coconut oil or caprylic / capric triglyceride. Yet another aspect of the present invention relates to a liquid carrier for use in crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine capsules, wherein the liquid carrier is fractionated coconut oil. or caprylic / capric triglyceride. ACTIVE AGENT The formulation of the present invention contains 2'-cyano- 2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine in the form of the active ingredient. This compound is also known as 1- (2-C-cyano-2-dioxy-β-D-arabino-pentofuranosyl) -N 4-palmitoyl cytosine, and has the structure shown below and is referred to throughout of the description as "CYC682".

CYC682 was first described in Patent No. EP 536936 (Sankyo Company Limited, equivalent to JP 2569251) and was shown to have excellent anti-tumor activity. Subsequently, various forms of CYC682 crystal have been described (see for example EP Patent 1364959; European application derived from WO 02/64609 in the name of Sankyo Company Limited). These crystal forms exhibit improved storage stability and ease of handling, while retaining a desirable pharmacokinetic profile.

In a particularly preferred embodiment of the present invention, crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine comprises form-B. In an especially preferred embodiment, the 2'-cyano-2'- crystalline deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine consists essentially of the B-form. In a particularly preferred embodiment, crystalline 2'-cyano-2'-deoxy-N -palmitoyl-1-β-D-arabinofliranosylcytosine consists of the B-form. The B-form of CYC682 can be prepared according to the teachings of EP Patent 1364959. CYC682 by itself is prepared according to the teachings of EP 536936. By way of summary, 2'-cyano-2 'monohydrochloride is passed. -deoxy-1-β-D-arabinofuranosylcytosine through an ion exchange resin (CHCOO type ") to form 2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine This compound is subsequently reacted with 1, 3-dichloro-1,1, 3,3-tetraisopropyldisiloxane to form 2'-cyano-2'-deoxy-3 ', 5'-O- (1,1,3,3-tetraisopropyldisiloxane-1,3 -di-il) -1-β-D-arabinofuranosilcitosina, which in turn is reacted with palmitic acid to form 2'-cyano-2'-deoxy-N4-palmitoyl-3 ', 5'-O- ( 1, 1,3,3-tetraisopropyldisiloxane-1,3-di-yl) -1-β-D-arabinofuranosylcytosine The final step involves deprotection using tetrabutylammonium fluoride to form the desired product, 2'-cyano-2'- Deoxy-N4-palmitoyl-1-ß-D-arabinofyranosylcytosine (CYC682). Alternatively, CYC682 can be prepared by reacting 2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine with palmitic anhydride. Form B of CYC682 is prepared by adding methyl acetate containing water in about 2.5 vol% to CYC682 and heating to a temperature of about 55 ° C to prepare a clear solution. Subsequently, the solution is cooled under specific conditions and the crystals are separated from the plate of the solution. After further stirring, the separated crystals are collected by filtration and washed with methyl acetate containing 2.5 vol% water to produce the desired crystal B. In a preferred embodiment, the pharmaceutical formulation is a unit dosage form, preferably, the formulation comprises from about 0.1 to about 500 mg of the active agent, more preferably, from about 1 to about 200 mg, or more preferably, from about 1 to about 100 mg of active agent. In a highly preferred embodiment, the formulation comprises about 25 mg of active agent. In another highly preferred embodiment, the formulation comprises approximately 75 mg of active agent. PROCESS As mentioned above, another aspect of the present invention relates to a process for preparing a pharmaceutical formulation as described above, which comprises the steps of: (i) mixing crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosyl-cytosine and a medium chain triglyceride; (ii) transferring the mixture formed in step (i) into a preformed capsule; and (iii) sealing the capsule. Preferably, the CYC682 is measured in a mixing container and the liquid conveyor is added in increments to it that has been added to the correct amount. The components are mixed using a commercially available mixer, for example a Silverson mixer.

Preferably, the components are mixed at high speed for at least 2 minutes, more preferably at least 3 minutes, even more preferably at least 5 minutes. In an especially preferred embodiment, the components are mixed for from about 5 to about 8 minutes. Ideally, the components are mixed until homogeneity is achieved. Once the mixture is homogeneous, the gases are preferably extracted using a vacuum. Preferably, the still mixture is transferred to the capsule using a capsule filler fitted to provide the filling weight. At the end, the capsules seal to avoid filtration. Various methods are available for sealing the capsules (see, for example, Publication F. Wittner, "New Developments in Hermetic Sealing of Hard Gelatin Capsules," Pharm.Manuf.2: 24-27, 1985). In a preferred embodiment, step (iii) comprises sealing the gelatin capsule with a gelatin band. Normally, this involves grinding the capsules and passing them once or twice on a wheel that is stirred in a gelatin bath. A quantity of gelatin is captured through the closed wheel and applied to the lid and body joint. The capsules remain in individual conveyors for drying. In an alternative preferred embodiment, step (iii) comprises sealing the gelatin capsule by macro locking. Normally, this involves sealing using a hydroalcoholic solution and the principle of decreasing the melting point of the gelatin is used by applying moisture to the area between the body of the capsule and the lid. The process involves spraying each capsule with a micro amount of sealing fluid in the body and attaching the cap using a directed fluid jet. The capillary action extracts fluid between the body and the cap. Subsequently drying takes place by gently bouncing the capsules in a rotating drum. The process can be carried out using a commercially available machine such as LEMS ™ 30 (Liquid Encapsulation by MicroSpray, Capsugel Division of Warner Lambert Company).

The present invention will be described further by way of example. EXAMPLES Example 1 Form B of CYC682 is prepared according to the methodology described in Patent EP 536936 and EP 1364959, both in the name of Sankyo Company Limited. Preparation of CYC682 (according to EP 536936) 1 (a) 2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine A solution of 8.66 g (30 mmol) of monohydrochloride 2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine dissolved in 50 ml of water was passed through a column packed with 90 ml of Dowex 1X2 ion exchange resin (trade name) (CHCOO type) ), and the column was washed with 300 ml of water.The effluent and the washings were combined and lyophilized, to yield 7.23 g (yield 95.5%) of the title compound in the form of a colorless powder NMR spectrum (dimethyl sulfoxide) hexadeuterated, 270 MHz) d ppm: 7.28 (1H, broad singlet), 7.23 (1H, broad singlet), 7.83 (1H, doublet, J = 7.8 Hz), 6.17 (1H, doublet, J = 7.3 Hz), 6.17 ( 1H, doublet, J = 5.9 Hz), 5.77 (1H, doublet, J = 7.3 Hz), 5.12 - 5.16 (1H, multiplet *); 4. 36-4.44 (1H, multiplet *); 3.56 - 3.80 (4H, multiplet *). 1 (b) 2'-cyano-2'-deoxy-3 ', 5'-0- (1, 1,3,3-tetraisopropyldisiloxane-1,3-di-yl) -1-β-D-arabinofuranosylcytosine They were dried three times by azeotropic distillation with pyridine 5.045 g (20 mmole) of 2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine [prepared as described in step (a) above], and the residue was suspended in 200 ml of pyridine. 6.7 ml (21 mmole) of 1,3-dichloro-1,1,3-tetraisopropyldisiloxane was added to the suspension and the resulting mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere. The solution was concentrated to approximately half of its original volume by distillation under reduced pressure, and the concentrate was diluted with 200 ml of ethyl acetate. The diluted solution was washed twice, each time with 200 ml of a saturated aqueous solution of sodium hydrogencarbonate. It was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and a resulting residue was mixed with a mixture of toluene and methanol. The mixture was subjected to azeotropic distillation to yield 11.21 g of a residue. This was purified by column chromatography through 300 g of silica gel (230-400 mesh), using methylene chloride containing 5% by volume of methanol as the eluent, to yield 8.67 g (87% yield) of the composed of the title in the form of a foam. NMR (CDCl 3, 270 MHz) d ppm: 7.69 (1H, doublet, J = 7.26 Hz); 6.31 (1H, doublet, J = 7.26 Hz); 5.74 (1H, doublet, J = 7.26 Hz); 4.64 (1H, doublet of doublets, J = 7.26 and 7.26 Hz); 4.15 - 4.04 (2H, multiplet *); 3.84 (1H, triplet double, J = 7.26 &3.30 Hz); 3.67 (1H, doublet of doublets, J = 7.26 &7.26 Hz); 1.15 - 0.93 (28H, multiplet). 1 (c) 2'-Cyano-2'-deoxy-N4-palmitoyl-3 ', 5'-0- (1,1,3,3-tetraisopropyl siloxane-1,3-diyl) -1 - ß- D-arabinofuranosylcytosine A mixture of 1.48 g (3 mmole) of 2'-cyano-2'-deoxy-3 ', 5'-O- (1, 1,3,3-tetraisopropyldisiloxane-1,3-diyl) -1 -β-D-arabinofuranosylcytosine [prepared as described in step (b) above] and 3.07 g (12 mmole) of palmitic acid was dried by azeotropic distillation using 50 ml of benzene, and the residue was dissolved in 30 ml of tetrahydrofuran. 2.47 g (12 mmole) of dicycloxycarbodiimide and 120 mg (0.9 mmole) of 4- (N, N-dimethylamino) pyridine were added to the solution, and the resulting mixture was stirred at a temperature of 50 ° C for 2.5 hours in a nitrogen atmosphere. At the end of this, the insoluble materials were removed by filtration, and the filtrate was freed from the solvent by distillation under reduced pressure. The residue was divided between 100 ml of ethyl acetate and 50 ml of a 5% w / v aqueous solution of sodium hydrogencarbonate. The organic layer was washed with 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography through silica gel, using methylene chloride containing 1% v / v methanol as the eluent, to yield 1.85 g of the title compound in the form of a solid caramel type. NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) d ppm: 10.94 (1H, singlet); 8.02 (1H, doublet, J = 7.82 Hz); 7.30 (1H, doublet, J = 7.32 Hz); 6.21 (1H, doublet, J = 7.83 Hz); 4.69 (1H, singlet); 4.22 (2H, multiplet); 3.98 (1H, doublet, J = 2.45 Hz); 3.42 (1H, doublet, J = 3.92 Hz); 2.40 (2H, triplet, J = 7.32 Hz); 1.53 (2H, singlet); 0.82 - 1.23 (55H). 1 (d) 2'-cyano-2'-of soxy-N4 -palmitoi 1-1- ß-D-arabinofuranosilcitosina 0.31 ml (5.45 mmole) of acetic acid and 2.84 were added g (10.9 mmole) of tetrabutylammonium fluoride, cooling with ice and stirring at the same time, to a solution of 4.0 g (5.45 mmole) of 2, -cyano-2'-deoxy-N4-palmitoyl-3 ', 5'- O- (1,1-3,3-tetraisopropyldisiloxane-1,3-diyl) -1-β-D-arabinofuranosylcytosine [prepared as described in step (c) above] in 60 ml of tetrahydrofuran (which had been previously dried through a molecular sieve 3A), and the resulting mixture was stirred for 40 minutes in a nitrogen atmosphere. The reaction mixture was subsequently concentrated to dryness by evaporation under reduced pressure, and the residue was partitioned between 100 ml of methylene chloride and 50 ml of a saturated aqueous solution of sodium chloride. The organic layer was washed with 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residual caramel solid was purified by column chromatography through silica gel, using methylene chloride containing 4% v / v methanol as the eluent, to provide 2.25 g. of the title compound in the form of a colorless powder. NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) d ppm: 10.91 (1H, singlet); 8.36 (1H, doublet, J = 7.8 Hz); 7.29 (1H, doublet, J = 7.8 Hz); 6. 25 (1H, doublet, J = 5.4 Hz); 6.21 (1H, doublet, J = 7.3 Hz); 5.22 (1H, broad singlet); 4.43 (1H, multiplet); 3.61 - 3.93 (4H, multiplet); 2.40 (2H, triplet, J = 7.3 Hz); 1.54 (2H, triplet, J = 6.8 Hz); 1.24 (24H, singlet); 0.83 - 0.88 (3H, multiplet). Alternative preparation of 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine A mixture of 12.9 (51.1 mmole) of 2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine [prepared as described in example 1 (a) above] and 38.1 g (76.7 mmole) of palmitic anhydride was placed in a 1 liter round bottom flask, and 51 ml of dimethylformamide was added. The resulting mixture was stirred in an oil bath maintained at a temperature of 100 ° C for 20 minutes, taking care at the same time to protect it from moisture. The disappearance of the starting compound was confirmed by thin layer chromatography (using methylene chloride containing 5% v / v methanol as the developing solvent). When the starting compound disappeared, 513 ml of diisopropyl ether were added to the reaction mixture, stirring at the same time, and the mixture was allowed to settle for 1 hour, while cooling with ice. At the end of this time, insoluble materials were collected by filtration. The insoluble materials were completely dissolved in 513 ml of propanol, heating while stirring, and the solution was allowed to settle overnight in a refrigerator, to provide 18.0 g of the title compound in the form of a colorless powder, which has the same physicochemical properties that the product of 1 (d) above. Example 2 Preparation of B-form of CYC682 (according to patent EP 1364959) (a) A 2'-cyano-2'-deoxy-N -palmitoyl-1-β-D-arabinofuranosylcytosine (30 g), which is the compound described in Example 1 (1d) of Japanese Patent No. 2569251 and European Patent No. EP 536936 (described above in Example 1), was added methyl acetate containing water in 2.5 vol% (300 mL) , and the resulting mixture was heated to a temperature of about 55 ° C to prepare a clear solution. Subsequently, the solution was cooled to a temperature of 5 ° C in a range of approximately 0.5 ° C per minute. Upon cooling to a temperature of about 45 ° C, in the course of cooling, the coating crystals were separated from the solution. After stirring additionally at a temperature of 5 ° C for 20 minutes, the separated crystals were collected by filtration and washed with methyl acetate containing 2.5 vol% water (30 ml) to yield the desired crystal B (28.78 g, purity 97.9%) in a yield of 96.0% [N / N]. (b) A 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine (8.7 kg), which is the compound described in example 1 (1d) of Japanese Patent No No. 2569251 and European Patent No. EP 536936 (described above in Example 1), methyl acetate containing water in 1.9 vol% (80 L) was added, and the resulting mixture was stirred at a temperature of about 23 ° C. for 1.5 hours. The separated crystals were collected by filtration, washed with methyl acetate containing water in 1.9 vol% (20 L) and dried to produce the desired crystal B (7.7 kg, purity 97.3%) in a yield of 90.1% [N / N] ] and Example 3 Preparation of Capsule Capsules were prepared in two different concentrations: 25 mg and 75 mg of CYC682. The highest concentration was formulated to be filled in a size 1 capsule, while a lower concentration was formulated to fill in a size 3 capsule, as appropriate. All materials have pharmacopoeia quality. The formulation of the center for both concentrations contains: Ingredient Function% (w / w) CYC682 active agent 25 Migiyol 812N Ph. EUG / GRAS liquid transporter 75 The formulation of the center is a simple suspension prepared by mixing the active agent with Migiyol 812N. Migiyol 812N is also known as fractionated coconut oil and is described in Ph. Eur and in GRAS. These are the only ingredients in the formulation in addition to the capsule shell and fixing material. White capsule caps containing titanium dioxide USP / Ph were used. Eur. 2% (by weight) and Gelatin USP / Ph. Eur to 100%. The capsules were fixed in the union of the body and the lid to avoid filtration. The fixing material contains USP / Ph Gelatine. Eur. Both concentrations of the capsule were manufactured from the same mixture with doses that are differentiated in the filling weight. The capsules are prepared as follows: 1. Weigh the CYC682 in the mixing container. 2. Add in increments the Migiyol 812N until the correct total amount is added there. 3. Mix the two components using a mixer Silverson at high speed for 5 to 8 minutes. 4. Remove the sample and check the homogeneity. 5. If it is homogeneous, cause a vacuum to extract the gas from the mixture. 6. Prepare the Bosch 1500L capsule filler with change parts size 3 and adjust the filling pump to provide the desired filling weight for the 25 mg dose. 7. Fill the 25 mg capsules using the following objectives for the average of the 12 capsules, ie Pilot 2. 5%; Action 3.5%; Rejection 5.0% The limits in the individual capsules are 7.5%. 8. Repeat the 75 mg capsules replacing the size 3 change parts with size 1 change parts, and readjust the fill weights. All other conditions are the same. 9. At the end of the filling of all the capsules, the capsules were fixed using clear gelatine. The filling weights of the two capsule concentrations are 100 mg and 300 mg, respectively. The covers of the capsules and the gelatin for fixation are obtained with the following suppliers: Capsule - Capsulgel Bornem, Rijksweg 11, B-2880 Bornem, Belgium); Gelatin (to fix the capsule) - Stoess AG, Gammelsbacherstr. 2, 8412 Eberbach, Germany). Example 4 Stability Tests Capsules were prepared in polypropylene containers at a temperature of 40 ° C / 75% relative humidity (RH) and at a temperature of 25 ° C / relative humidity of 69% The first is considered to constitute accelerated storage conditions, while the latter is considered to constitute normal storage conditions. The study consisted of an initial evaluation under accelerated conditions for 6 months followed by a longer evaluation under normal storage conditions. 6 months is the accepted duration of accelerated stability tests. After 6 months under accelerated conditions and 18 months under normal storage conditions, the capsules showed no physical deterioration or any interaction with the packaging. In addition, the HPLC analysis showed that there is no significant change either in percentage of the compound of origin or in the percentage levels of impurities (allowed) over time. Those skilled in the art will appreciate various modifications and variations of the described aspects of the present invention, without departing from the scope and spirit thereof. Although the present invention has been described in relation to the specific preferred embodiments, it should be understood that the present invention as claimed, should not be unduly limited to said specific embodiments. In fact, various modifications of the modes described to carry out the present invention are obvious to those skilled in the relevant fields, they are designed to be within the scope of the following claims.

Claims (25)

1. CLAIMS 1. A pharmaceutical formulation comprising (i) a capsule, and (ii) a center comprising crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine and a liquid carrier.
2. 2. The pharmaceutical formulation as described in claim 1, characterized in that the crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine comprises the B-form.
3. 3. The pharmaceutical formulation as described in claim 1 or claim 2, characterized in that the crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine consists essentially of the B-form .
4. 4. The pharmaceutical formulation as described in any of the preceding claims, characterized in that the liquid carrier is a medium chain triglyceride oil.
5. 5. The pharmaceutical formulation as described in claim 1, characterized in that the medium chain triglyceride oil is fractionated coconut oil or caprylic / capric triglyceride.
6. 6. The pharmaceutical formulation as described in any of claims 1 to 3, characterized in that the liquid carrier is Gelucire 44/14.
7. 7. The pharmaceutical formulation as described in any of the preceding claims, characterized in that the capsule is a gelatin capsule.
8. 8. The pharmaceutical formulation as described in any of the preceding claims, characterized in that the capsule is a hard capsule.
9. 9. The pharmaceutical formulation as described in any of the preceding claims, characterized in that the capsule comprises one or more opacifying agents and / or one or more pigments.
10. 10. The pharmaceutical formulation as described in claim 9, characterized in that the pigments and / or opacifying agents are each present in an amount from about 0.1 to about 10%.
11. 11. The pharmaceutical formulation as described in claim 9 or claim 10, characterized in that the opacifying agent is titanium dioxide.
12. 12. The pharmaceutical formulation as described in claim 11, characterized in that the titanium dioxide is present in an amount of about 2%.
13. 13. The pharmaceutical formulation as described in any of the preceding claims, characterized in that the capsule is sealed by a gelatin band.
14. 14. The pharmaceutical formulation as described in any of the preceding claims, characterized because the center consists essentially of crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosilcitosina and the liquid transporter.
15. 15. The pharmaceutical formulation as described in any of the preceding claims, characterized in that the amount of liquid carrier is from 2 to 50 parts by weight relative to 1 part by weight of the 2'-cyano-2'-deoxy- N -palmitoyl-1-β-D-arabinofuranosylcytosine crystalline.
16. 16. The pharmaceutical formulation as described in any of the preceding claims, characterized in that the amount of liquid carrier is from 2 to 10 parts by weight in relation to 1 part by weight of the 2'-cyano-2'-deoxy- N -palmitoyl-1-β-D-arabinofuranosylcytosine crystalline.
17. 17. The pharmaceutical formulation as described in any of the preceding claims, characterized in that the amount of liquid carrier is from 2 to 5 parts by weight in relation to 1 part by weight of the 2'-cyano-2'-deoxy- N4-palmitoyl-1-β-D-arabinofuranosylcytosine crystalline.
18. 18. The pharmaceutical formulation as described in any of the preceding claims, characterized in that the amount of liquid carrier is about 3 parts by weight relative to 1 part by weight of the 2'-cyano-2'-deoxy-N4 -palmitoyl-1-β-D-arabinofuranosilcitosina crystalline.
19. 19. The pharmaceutical formulation as described in any of the preceding claims, characterized in that it is for oral administration.
20. 20. The use of a medium chain triglyceride in the form of a liquid transporter in crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine gelatin capsules.
21. 21. The use as described in claim 20, characterized in that the medium chain triglyceride is coconut oil or caprylic / capric triglyceride fractionated.
22. 22. A liquid carrier for use in capsules of crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine, wherein the liquid carrier is fractionated coconut oil or caprylic / capric triglyceride.
23. 23. A process for preparing a pharmaceutical formulation as described in any of claims 1 to 19, characterized in that it comprises the steps of: (i) mixing 2'-cyano-2'-deoxy-N -palmitoyl- 1-ß-D-arabinofuranosilcitosina crystalline and a medium chain triglyceride. (ii) transferring the mixture formed in step (i) into a preformed capsule; and (iii) sealing the capsule.
24. 24. A process as described in claim 23, characterized in that step (iii) comprises sealing the capsule with a band of gelatin.
25. 25. A process as described in claim 23, characterized in that step (iii) comprises sealing the capsule by micro-spraying.