MX2008005641A - Formulations comprising jorumycin-, reni eramycin-, safracin- or saframycin-related compounds for treating proliferative diseases - Google Patents

Abstract

Jorumycin, renieramycin, safracin and saframycin related compounds formulations, methods of preparing the same, articles of manufacture and kits with such formulations, and methods of treating proliferative diseases with the same formulations are provided.

Description

FORMULATIONS CONTAINING COMPOUNDS RELATED TO JORUMYCIN, RENIERAMYCIN, SAFRACINE OR SAFRAMYCIN FOR THE TREATMENT OF PROLIFERATIVE DISEASES Field of the Invention The present invention relates to formulations. More particularly, it relates to compositions and formulations of compounds related to jorumicin, renieramycin, safracin and saframycin, such as the compounds PM00104 and PM00121. Background of the Invention Jorumicin is a natural compound isolated from the skin and mucus of the peaceful nudibranchs Jorunna funebris (Fontana A., et al., Tetrahedron (2000) 56, 7305-8). In addition, the family of renieramicin is described as isolated from sponges and tunicates (James MF et al., J. Am. Chem. Soc. (1982), 104, 265-269; Oku N., et al. Journal Natural Products (2003 ), 66, 1 136-9). The safracin and saframycin compounds are described by Manzanares I., et al Curr. Med. Chem. Anti-Cancer Agents (2001), 1, 257-276, as well as in WO 00/18333 and WO 01/87894. Due to the detailed description provided in those references and to the citations given there, the structural characteristics of these compounds are not explicitly presented here; Anyone with a common knowledge of this technology is able to obtain that information directly from the sources cited here and from related sources. At least two of those compounds PM00104 and PM00121 will be specifically referred to herein to illustrate the features of this invention. PM00104 and PM00121 are synthetic alkaloids related to jorumicin and renieramicins, and also to safracin and saframycin compounds. They show the following chemical structures: A pharmaceutical composition containing PM00104 or PM00121 together with a pharmaceutically acceptable carrier is described in WO 01/87894. PM00104 has shown significant in vivo activity against human xenografted cell lineages in mouse such as breast and prostate. Preliminary studies on the mechanism of action of PM00104 suggest changes in cell cycle, DNA binding properties and transcriptional inhibition. In addition, phase I clinical trials are currently in process with PM00104. More details on the activity data of PM00104 and PM00121 see WO 01/87894. PM00104 and PM00121 as well as the related compounds are complex chemical entities as revealed by their structural characteristics. In addition, they have a limited solubility in water, and their stability, particularly in biocompatible forms and formulations, is difficult to predict and achieve. These characteristics challenge the common experience and conventional methodologies in this technology, particularly when it comes to the preparation of formulations of these compounds that must be used for medicinal purposes. These uses are preferably based on formulations whose characteristics include one or more of the following: biocompatibility, stability under environmental conditions, or under conditions that are as close as possible to environmental conditions, with a shelf life that is as long as possible, and an easy reconstitution capacity to form reconstituted solutions that are stable under ambient conditions, for as long as possible. In view of the potential of these compounds as antitumor agents, there is a need to provide a formulation that can solve the problems that conventional formulations and manufacturing methodologies do not touch or do not fully resolve. These problems include the problem of the stability of these compounds. Modalities of PM00104, PM00121 and the related compound formulations should preferably have favorable lyophilization properties, should preferably be amenable to easy reconstitution, and preferably exhibit dilution properties, such as after dilution with an infusion fluid., while at the same time presenting many of the desirable characteristics of the formulations for medical use as indicated herein. As indicated above, the modalities of these formulations must be stable during long-term storage. In addition, the formulation and its manufacturing methodology must meet the standards of biocompatibility and therefore must allow the effective use of a vehicle of the formulation that is not toxic, at least at the concentrations used for the infusion. A general review of the excipient-drug interactions in parenteral formulations is provided by Akers M.J., in Journal of Pharmaceutical Sciences, 91, 2002, 2283-2300. This reference provides among other things a section of volumetric and lyoprotective agents, including this subject in the context of lyophilization. It is envisioned that the methodologies and formulations developed in the context of this invention are applicable to other related compounds in addition to PM00104 and MP00121. Brief Description of the Invention Specifically, the invention relates to compositions and formulations of the general formula (I): Ri is selected from the group consisting of -CH2-N (Ra) 2 and -CH2-ORa, wherein each Ra is independently selected from the group consisting of H, alkyl-CO-, haloalkyl-CO-, cycloalkylalkyl-CO-, haloalkyl -O-CO-7 arylalkyl-CO-, arylalkenyl-CO-, heteroaryl-CO-, alkenyl-CO-f alkyl, alkenyl and amino acid acyl, or the two Ra groups together with the N atom of -CH2-N (Ra ) 2 form a heterocyclic group; R2 is selected from alkyl-CO-, cycloalkyl-CO- and haloalkyl-CO-; and R3 is OH or CN; or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof. The different groups may be substituted or unsubstituted. Thus the present invention provides stable formulations of compounds of the general formula (I), and methods for producing those formulations. It is an object of this invention to provide a new formulation of compounds of the general formula (I): In particular, a formulation with high stability during storage is required. In addition there is a special need to avoid impurities in the formulation. SUMMARY OF THE INVENTION In accordance with the present invention there are provided compositions containing a compound of the general formula (I) and a disaccharide, and methods for preparing such compositions. Preferred embodiments of those compositions are preferably of pharmaceutical purity. Some embodiments of these compositions are provided by means of lyophilized formulations containing a compound of the general formula (I) and a disaccharide. Methods are provided to prepare these formulations. Detailed Description of the Invention We have found in the context of this invention that the disaccharides stabilize the formulations of the compounds of the general formula (I) as defined above. In the compounds the substituents can be selected according to the following guidance: The alkyl groups preferably have from 1 to 12 carbon atoms. A more preferred class of alkyl groups has from 1 to about 6 carbon atoms, and more preferably 1, 2, 3 or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl are preferably preferred alkyl groups in compounds of the present invention. As the term "alkyl" is used herein unless it is otherwise modified, it refers to both cyclic and non-cyclic groups, although the cyclic groups comprise ring members with at least three carbons. Preferred alkenyl groups in the compounds of the present invention have one or more unsaturated bonds and 2 to about 12 carbon atoms. A more preferred class of alkenyl groups has from 2 to about 6 carbon atoms, and more preferably 2, 3 or 4 carbon atoms. The term "alkenyl" as used herein refers to cyclic and non-cyclic groups. Suitable aryl groups in the compounds of the present invention include one-ring or multi-ring compounds including multi-ring compounds containing separate and / or fused aryl groups. Typical aryl groups contain from 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms. Especially preferred aryl groups include substituted or unsubstituted phenyl, naphthyl, biphenyl, phenanthryl and anthracyl. Suitable heterocyclic groups include include heteroaromatic and heteroalicyclic groups. Preferred heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, for example, coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazole. Preferred heteroalicyclic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include for example tetrahydrofuranyl groups, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl. Phthalimido is another candidate heterocyclic group. Acyl amino groups include alanyl, arginyl, aspartyl, cystyl, glutamyl, glutaminyl, glycyl, histidyl, hydroxyprolyl, isoleucyl, leucyl, lysyl, methionyl, phenylalanyl, prolyl, seryl, threonyl, thironyl, tryptopyl, tyrosyl, vally, as well as other amino acid groups, which can be L- or D-. The groups mentioned herein may be substituted in one or more available positions by means of one or more suitable groups such as R ', OR', = 0, SR ', SOR', S02R ', N02, NHR', N (R) 2, = N-R ', NHCOR, N (COR) 2, NHS02R', CN, halogen, C (= 0) R ', C02R, OC (= 0) R where each of the R groups is independently selected of the group consisting of hydrogen, OH, N02, NH2, SH, CN, halogen, = 0, C (= 0) H, C (= 0) alkyl, C02H, alkyl with 1 to 12 carbon atoms substituted or unsubstituted, alkenyl with 2 to 12 carbon atoms substituted or unsubstituted, alkynyl with 2 to 12 carbon atoms substituted or unsubstituted and substituted or unsubstituted aryl. Suitable halogen substituents in the compounds of the present invention include F, Cl, Br and I. Where those groups are substituted, the substituents may be selected from the above list. The term "pharmaceutically acceptable salts, derivatives, prodrugs" refers to any pharmaceutically acceptable salt, ester, solvate, hydrate or any other compound, which after administration to the recipient is capable of providing (directly or indirectly) a compound as described here. However, it will be appreciated that pharmaceutically unacceptable salts also fall within the scope of the invention as they may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the art. For example, such pharmaceutically acceptable compounds provided herein are synthesized from a parent compound, containing a basic or acid ratio, by means of conventional chemical methods. Generally, these salts are prepared, for example, by reacting the acidic or basic free forms of these compounds with a stoichiometric amount of the base or the appropriate acid in water or in an organic solvent or in a mixture of the two. Generally non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or mineral acid addition salts, such as for example hydrochloride, bromohydrate, iodohydrate, sulfate, nitrate, phosphate and acid salts of organic acid such as for example acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of the alkaline addition salts include inorganic salts such as for example sodium, potassium, calcium and ammonium salts and organic alkali salts such as for example ethylene diamine, ethanolamine, N, N-dialkylene ethanolamine, triethanolamine and salts of basic amino acids. The compounds of the invention may be in the form of either free compounds or solvates (for example hydrates) and both forms are intended to be within the scope of the present invention. Solvation methods are generally known in the art. Any compound that is a prodrug of a compound of the formula (I) is within the scope and spirit of the invention. The term "pordrug" is used in its broadest sense and includes those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would be apparent to those skilled in the art, and include for example compounds in which a free hydroxy group is converted to an ester derivative. The compounds of the present invention represented by the formula described above (i) may include enantiomers depending on their asymmetry or diastereoisomers. Stereoisomerism around the double bond is also possible, therefore in some cases the molecule could exist as an isomer (E) or an isomer (Z). The simple isomers or mixtures of the isomers fall within the scope of the present invention. Examples of compounds of the present invention include those described for example in WO 00/18233 and WO 01/87894. We incorporate as a specific reference each of the compounds identified in the respective examples of these PCT presentations. More generally we incorporate by means of specific reference the content of those two PCT presentations for the description of the compounds of the present formula (I). Best to mention the preferred groups given in those texts, particularly since they apply to the present groups R and R2, especially R1. R3 is usually OH The preferred compounds of this invention are those with the following chemical structure: The compounds of the formula (I) including PM00104 and PM00121, are complex chemical entities whose behavior in the formulation is not predictable in terms of the behavior of other unrelated chemical substances. Such behavior is even more difficult to predict when at least one compound of the general formula (I) is included as the active substance in a formulation that is to meet biocompatibility standards, including medical standards. We have further found in this regard that the use of disaccharides as bulking agents can drastically reduce the formation of impurities during the lyophilization process and the storage of compositions PM00104 and PM00121. In addition, the use of disaccharides also improves storage conditions by allowing long-term storage of the lyophilized formulation over a wide temperature range, including cooling conditions and room temperature. The term "stable" is used herein for example in the expression "a stable formulation P 00104 or PM00121", refers to a formulation which satisfies the stability characteristics reported herein and their equivalents, which do not possess the conventional formulations and which do not achieve when the formulation is prepared by means of conventional manufacturing methodologies. Examples of embodiments of the present invention are provided by means of novel pharmaceutically acceptable compositions containing a compound of formula (I) and a disaccharide. Examples of suitable disaccharides include lactose, trehalose, sucrose, and combinations thereof. Additional examples of disaccharides can be used in some embodiments of this invention include at least one of maltose, isomaltose, cellobiose, isosaccharose, isotrehalosa, sorbose, turanosa, melibiose, gentiobiose, and mixtures thereof. Sucrose is the one that is currently preferred. In other embodiments of the invention, the composition contains a compound of the general formula (I) and a lactose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and a trehalose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and a sucrose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and a maltose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and an isomaltose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and a cellobiose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and an isosucrase-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and an isotrehalose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and a sorbose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and a turanose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and a melibiose-free disaccharide. In other embodiments of the invention, the composition contains a compound of the general formula (I) and a gentobiose-free disaccharide. Thus in some embodiments, the composition of this invention contains less than 2% or less than 1% or less than 0.5% or less than 0.2% or less than 0.1% by weight of at least one, and preferably each of lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, sosaccharose, isotrehalosa, sorbose, turanosa, melibiosa, and gentiobiose. The terms "their mixtures" and "their combinations" as used herein refer to at least two entities that provide the antecedent basis for the terms "their mixtures" and "their combinations". By way of illustration but not limitation, the terms "products comprising at least one of A, B, C and their mixtures" refer to the product modalities for which one of the following is satisfied: A is in the product; B is in the product; C is in the product; A and B are in the product; A and C are in the product; B and C are in the product; and A, B and C is in the product. It is further understood that terms such as "react", "form", and related terms applied to a chemical entity refer to one of: (a) the chemical entity such as, and (b) the chemical entity in the way in which that entity is present in the reaction medium. Similarly, naming the chemical entity or giving its formula in the context of an operation or reaction stage, or naming it or giving its formula as a solid or liquid medium, including products, formulations and combinations, refers here to one of: ( a) the entity as such and (b) the entity in the form in which that entity is present in the medium. For example, the name of the acid chemical entity refers here to the form or forms in which that entity is present in the context in which it is named. By way of illustration but not as limitation, the name of the chemical entity as "sodium chloride" or its formula herein refers to the NaCl entity as such a diatomic molecule, if it is in the form in which the Sodium is present in the relevant medium; it also refers to the collection of non-associated and / or dissociated chemical species if the sodium chloride in the relevant medium is totally or partially dissociated, including species in those media that are solvated, part of envelopes, are associated with other species, etc. . To provide a more concise description, some of the qualitative expressions given here are not qualified with the term "approximately". It should be understood that if the term is used explicitly or not, each quantity given here is intended to refer to the given actual value, and it is also intended to refer to the approximation of that given value that would be reasonably inferred based on normal experience in the technique, including equivalents and approximations due to the experimental and / or measurement conditions for that given value. The substance or active substances in the context of this invention may be of natural, semi-synthetic or synthetic origin, including combinations of origins. In embodiments in which the active substance is a compound such as PM00104 or PM00121, those compounds are of synthetic or semi-synthetic origin and can be prepared following the description of WO 01/87894, which is incorporated by reference.

The proportion of active substances to the volumetric agent in embodiments of this invention is determined according to the solubility of the volumetric agent and when the formulation is lyophilized, this is in accordance with the capacity of lyophilization of the volumetric agent. It is anticipated that the ratio (w / w) may be approximately 1: 1 in some modalities, approximately 1.5 in other modalities, approximately 1:10 in other modalities, while other modalities illustrate provide in the range of approximately 1:10 a approximately 1: 1. Other modalities are expected to have proportions in the range of about 1:10 to 1:80, and still other modalities in the range of about 1:80 to 1: 1500. When the active compound is PM00104 or PM00121, the ratio (w / w) of active ingredient to bulking agent is typically from about 1: 80 to about 1: 1500, preferably from about 1: 100 to about 1: 800, more preferably from about 1: 100 to about 1: 400, and even more preferably about 1: 200. The lyophilized material is usually presented in a bottle containing a specific amount of active compound. When the active compound is PM00104, the active amounts are illustrated by 2.5 mg / vial. When the active compound is PM00121, the active amounts are illustrated in 1 mg / vial. The present invention is not limited to specific container shapes or designs as long as the container is acceptable for its intended use and standards. The embodiments of this invention are provided with a formulation contained in bottles. The lyophilized formulations of this invention can be reconstituted and diluted to give a composition of this invention in the form of a solution ready for intravenous injection. The actual amounts of reconstituting fluid are not limiting characteristics of the embodiments of this invention. By way of illustration, but not as limitation, the embodiments of the lyophilized formulations according to this invention are reconstituted with a volume of water. Most of these volumes do not exceed about 20 ml, with preferred volumes in the range of about 1 ml to about 15 ml, more preferably in the range of about 1 ml to about 10 ml, and even more preferably in the range of about 3 ml. my at about 8 mi, and even more preferably about 5 mi. When the active substance is represented by PMOO 104, the solution reconstituted in these embodiments contains at a concentration of PMOO 104 up to 5 mg / ml, with concentrations of about 2.5 mg / ml, about 1 mg / ml, and about 0.5 mg / ml being preferred. . The reconstituted embodiments of the present invention can be diluted if this prior dilution is desired is not a limitation of the present invention. Thus the subsequent dilution is preferably carried out with an aqueous system which is usually 0.9% sodium chloride or 5% glucose. The reconstituted solution will be diluted depending on the concentration in the reconstituted solution and the desired concentration in the diluted solution. The embodiments of the formulations of the compounds of the formula (I) according to this invention can be used in the treatment of a variety of cancer. It is understood that "treatment" in this context refers to an action that leads to an improvement of the condition (s). In addition, the embodiments of the formulations according to the invention can be used in tests with laboratory tissues, including but not limited to clinical tests, analytical tests and modeling tests. The embodiments of this invention comprising compounds of the formula (I) are preferably administered by infusion. The infusion step is typically repeated on a cyclic basis, which can be repeated as appropriate for 1 to 20 cycles. The cycle includes an infusion phase, a formulation of a compound of the formula (I) and usually also a non-infusion phase of the active substance. Typically the cycle is elaborated in weeks and thus the cycle usually comprises one or more weeks of a phase of infusion of active substance, and one or more weeks to complete the cycle. We prefer that times of up to 24 hours are used, more preferably 1-12 hours, with 1-6 hours being most preferred. The short infusion times that allow the treatment to be performed without a night stay in the hospital are especially desirable. However, the infusion can be 12 to 24 hours or even more if required. The embodiments of the formulations of this invention which contain a compound of the formula (I) can be made by lyophilizing a composition of this invention in the form of a volumetric solution including a compound of the formula (I) and disaccharide. Usually the volumetric solution will be buffered for example at a pH of about 4. Suitable buffering agents include phosphate buffer, citrate buffer, phosphate buffer / citrate (a mixture of phosphate buffer and citrate buffer), lactate buffer, buffer of ascorbate, tartaric / citrate buffer, bicarbonate / hydrochloric acid buffer, acetate buffer, succinate buffer and glycine / hydrochloric acid buffer. Mixtures of buffers can be used. Biocompatible shock absorbers that allow pH control at a desired value provide additional embodiments of this invention. Other components can be included in the volumetric solution for example surface active agents such as polyoxyethylene sorbitan monooleate (also known as polysorbate) or polyoxyl 40 stearate. Other possible surface active agents include dosfolipids, such as a lecithin.; polyoxyethylene-polyoxypropylene copolymers, such as a pluronic surfactant, polyoxyethylene esters of 12-hydroxystearic acid. such as a solutol surfactant: cholesterol ethoxylates, such as diacyl glycerol, dialkyl glycerol; bile salts such as sodium cholate, sodium deoxycholate; sucrose esters such as sucrose monolaurate, sucrose monooleate; polyvinylpyrrolidone (PVP), or polyvinyl alcohol (PVA). The formulation is usually supplied as a bottle containing the lyophilized product. This form of supply, however, is not a limitation of the present invention. To provide a bottle containing the lyophilized product, the volumetric solution is added to the bottle and lyophilized. Freeze-drying is performed in some embodiments of this invention using reduced secondary drying times. A preferred protocol includes cooling to a temperature from about -40 ° C to about -50 ° C, primary drying at 80 to 85 pbar for 25 to 50 hours, and secondary drying at a lower pressure and above 0 ° C. for 3 to 20 hours. The embodiments of this invention comprise freeze-drying to cool the product to below -40 ° C. The primary drying is performed at a temperature of about -20 ° C to about -27 ° C and a pressure of about 85 pbar for about 35 to 46 hours. The secondary drying is carried out at a temperature from about 20 ° C to about 25 ° C for about 30 to 45 hours.

The formulations embodiments of this invention are suitable for storage at temperatures significantly greater than the storage temperatures of conventional formulation. Examples of storage temperatures for formulations according to this invention are about + 5 ° C. These temperatures are easily provided by ordinary refrigerators. Brief Description of the Drawing of the Invention Figure 1. Shows the evolution of comparative percentage purity of PM00103 of two formulations of PM00104, one containing sucrose and the other mannitol, stored at 40 ° C / 70% RH for 3 months. EXAMPLES Example 1 This example describes a comparative stability study of two PM00104 formulations, one uses mannitol as the volumetric agent and the other uses sucrose, which is a disaccharide and illustrates the present invention. The composition of the volumetric solution for each of the formulations was as follows (Table I): Table I Bulky solutions were prepared and lyophilized by means of the standardized process. Formulation of mannitol A volume of 50 ml of mannitol formulation was prepared: 40 ml of a 0.05M potassium dihydrofosphate solution (pH 4) was added to 5,493 mg of PM00104, and the mixture was kept under stirring for 1 hour. Then 2.5 g of mannitol was added, washing the plate with 5 ml of a phosphate buffer solution (pH 4). The mixture was stirred for an additional hour. After this the pH of the solution was adjusted to pH 4 with 1N phosphoric acid and the solution was brought to a final weight of 52g with 0.05 phosphate buffer (pH 4). The solution was filtered through a PVDF filter and the solution was introduced into 2 ml glass bottles dispensing 2 ml / vial and the bottles were lyophilized according to the following procedure (Table II): Table II After lyophilization the bottles were sealed and transferred to a refrigerated area (-20 ° C). Sucrose formulation: A volume of 300 ml of sucrose formulation was prepared: 32. 615 ml of PM00104 were added to 100 ml of a 0.05M potassium dihydrofosphate solution (pH 4), washing the plate with an additional 110 ml of the 0.05M potassium dihydrofosphate solution (pH 4). Then the mixture was kept under stirring for 1 hour. 30 g of sucrose were added, washing the plate with 30 ml of a phosphate buffer solution (pH 4). The mixture was stirred for an additional hour.

After that the pH of the solution was adjusted to pH 4 with 1 M phosphoric acid and the solution was brought to a final weight of 300 g with water for injection. The solution was filtered through a Milipore-Optiscale filter and the filtered solution was introduced into 2 ml glass flasks dispensing 2 ml / flask and the flasks were flushed. The stability tests were carried out at temperatures of 5 ° C, 25 ° C / 60% RH and 40 ° C / 75% RH in the case of the sucrose formulation and 40 ° C / 75% RH in the case of the formulation of mannitol. Table III and the figure show the evolution of the chromatographic purity PM00104 of the formulation studied: Table III The data in Table III and Figure 1 show the sucrose-containing formulation showed better stability at 40 ° C and 75% RH with an insignificant reduction in purity. This reduction is significantly lower than the reduction observed with the mannitol formulation. Example 2 A formulation of PM00121 was prepared with sucrose as the volumetric agent and its stability was evaluated at temperatures of 5 ° C, 25 ° C / 60% RH and 40 ° C / 75% RH. For each flask the composition of the volumetric solution was as follows (Table IV): Table IV The formulation of PM00121 was prepared as follows: 100 ml of 0.1% polysorbate 80 solution (pH 2.5) were added to 161.04 mg of PM0121, and subsequently 110 ml of 0.1% polysorbate 80 solution was also added (pH 2.5). The mixture was kept under stirring for 1 hour. Then, 2.04 g of potassium dihydrophosphate was added, washing the plate with 15 ml of polysorbate 80 to 0.1 solution (pH 2.5). Then they were weighed and added 30 g of sucrose, washing the plate with 15 ml of a polysorbate 80 to 0.1 solution (pH 2.5). The mixture was stirred for another hour. After that the pH of the solution was adjusted to pH 4 with 1 M phosphoric acid and the solution was brought to a final weight of 300 g with water for injection. The solution was filtered through a Milipore-Optiscale filter and the filtered solution was introduced into 2 ml glass bottles dispensing 2 ml / vial and kept at 20 ° C until the lyophilization process.

The lyophilization process was carried out according to the following table V: Table V After lipophilization, the bottles were sealed and transferred to a refrigerated area (-20 ° C). The stability tests were carried out at a temperature of 5 ° C, 25 ° C / 60% RH and 40 ° C / 75% RH. Table VI describes the chromatographic purity of PM00121 of the formulation under study: Table VI It was observed that the formulation containing the disaccharide is stable at 5 ° C and 25 ° C / 60% RH. Example 3 Two formulations PM00104, 104-F and 104-FB, containing sucrose as volumetric agent were prepared and their stability was evaluated at a temperature of -20 ° C, 5 ° C, 25 ° C / 60% RH and 45 ° C / 75% RH. For each formulation, the composition of the volumetric solution for each bottle was as follows (Table VII): Table VII Volumetric solutions were prepared and lyophilized using the following particular protocols: Formulation 04-F To 1759 I of volumetric solution was prepared as follows: 153.125 ml of 0.05 N phosphoric acid were added to 905.61 mg of PM00104. The mixture was stirred for 15 minutes. Then 1400 ml of water for injection were added, then by the addition of 11.9 g of potassium dihydrophosphate and 175 g of sucrose. The mixture was kept stirring again for 1 hour 15 minutes. The pH of the solution does not need to be adjusted 3.8 < pH < 4, since the pH value was 3.91. The solution was brought to a final weight of 1820 g with water for injection. Then, the solution was filtered through a Millipack® 20 filter of 0.22pm. And the filtered solution was introduced into 25 ml flasks in a 5.4 ml volumetric solution / flask distribution and kept at -20 ° C until the lyophilization process. The lyophilization process was carried out according to the following table VIII: Table VIII Formulation 104-F B 2.271 g of PM00104 were added to 100 ml of 0.05 N phosphoric acid, washing the plate with 265 ml of 0.05 N phosphoric acid. The mixture was stirred for 15 minutes. Then 3360 ml of water for injection were added, followed by the addition of 28.56 g of potassium dihydrophosphate. The mixture was stirred for 3 minutes and 420 g of sucrose. The mixture was again kept under stirring for 1 hour 15 minutes.

The pH of the solution does not need to be adjusted 3.8 < pH < 4, since the pH value was 3.84. The solution was brought to a final weight of 4369 g with water for injection. Then, the solution was filtered through a 0.22 pm filter. And the filtered solution was introduced into 25 ml flasks in a 5 ml distribution of volumetric solution / flask and kept at -20 ° C until the lyophilization process. The lyophilization process was carried out according to the following table IX: Table IX After lyophilization, the bottles were sealed and transferred to a refrigerated area (-20 ° C). Stability tests were performed for both formulations at a temperature of -20 ° C + 5 ° C, 5 ° C + 3 ° C, 25 ° C + 2 ° C / 60% RH + 5% RH and 40 ° C + 2 ° C / 75% RH + 5% RH. Table X shows the chromatographic purity evolution of PM00104 of formulation 104-FA during storage at -20 ° C, 5 ° C, 25 ° C / 60% RH and 45 ° C / 70% RH. Table X Table XI shows the chromatographic purity evolution of PM00104 of formulation 104-FB during storage at -20 ° C, 5 ° C, 25 ° C / 60% RH and 45 ° C / 70% RH.

Table XI The data in tables X and XI show that the purity evolution of the formulations stored at 5 ° C and 25 ° C / 60% RH is comparable to that of the formulation stored at -20 ° C. Therefore no major degradation was found at 5 ° C and 25 ° C / 60% RH showing that formulations containing a disaccharide can be stored at least + 5 ° C for a prolonged period of time. All references cited herein are incorporated by reference in their entirety. The features and advantages of this invention are evident in light of the description provided herein. Based on this description modifications and adaptations to different conditions and uses can be made generating modalities within the scope of the invention.

Claims (23)

1. CLAIMS 1. A pharmaceutical composition containing a compound related to jorumicin, renieramycin, safracin and saframycin and a disaccharide. 2. A composition according to claim 1, wherein the compound related to jorumicin, renieramycin, safracin and saframycin has the general formula (I)
2. Ri is selected from the group consisting of -CH2-N (Ra) 2 and -CH2-ORa, wherein each Ra is independently selected from the group consisting of H, alkyl-CO-, haloalkyl-CO-, cycloalkylalkyl-CO-, haloalkyl -O-CO-7 arylalkyl-CO-, arylalkenyl-CO-, heteroaryl-CO-, alkenyl-CO-f alkyl, alkenyl and amino acid acyl, or the two Ra groups together with the N atom of -CH2-N (Ra ) 2 form a heterocyclic group; R2 is selected from alkyl-CO-cycloalkyl-CO- and haloalkyl-CO-; and R3 is OH or CN; or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer.
3. 3. A composition according to claim 2, wherein the compound is selected from PM00104 and PM00121.
4. 4. A composition according to any of the preceding claims, wherein the disaccharide is selected from the group consisting of lactose, trehalose, sucrose, and mixtures thereof.
5. 5. A composition according to claim 4, wherein the disaccharide is sucrose.
6. 6. A composition according to any of the preceding claims, wherein the ratio (w / w) of the compound to the disaccharide is from about 1: 800 to about 1: 1500.
7. 7. A composition according to claim 6, wherein the ratio (w / w) of the compound to the disaccharide is from about 1: 100 to about 1: 1400.
8. 8. A composition according to claim 7, wherein the ratio (w / w) of the compound to the disaccharide is about 1: 200.
9. 9. A composition according to any of the preceding claims, further comprising a buffering agent.
10. 10. A composition according to claim 9, wherein the buffering agent is a phosphate buffer.
11. 11. A composition according to any of the preceding claims, which also contains a surfactant agent.
12. 12. A composition according to claim 11, wherein the surfactant is a polyoxyethylene sorbitan monooleate.
13. 13. A composition according to any of the preceding claims, wherein the composition is in the form of a lyophilized formulation.
14. 14. A composition according to claim 13, wherein the lyophilized formulation is in a bottle and includes an amount of PM00104 and PM00121.
15. 15. A composition according to claim 14, wherein the amount of PM00104 is about 2.5 mg.
16. 16. A composition according to claim 15, wherein the bottle contains a formulation containing: about 2.5 mg PM00104, about 500 mg of sucrose, and about 34 mg of phosphate, the 34 mg of phosphate being calculated as potassium phosphate .
17. 17. A method for producing a bottle containing a lyophilized formulation of a compound according to any of claims 1 to 3, which consists of drying by lyophilization a volumetric solution containing the compound and a disaccharide.
18. 18. A method according to claim 17, wherein the compound is PM00104.
19. 19. A method for reducing the formation of impurities in a formulation of a compound according to any one of claims 1 to 3, which consists in lyophilizing a volumetric solution containing the compound and a disaccharide.
20. 20. A method according to claim 19, wherein the compound is PM00104.
21. 21. A method for preparing a solution for intravenous infusion, which consists of: providing a bottle containing a lyophilized compound according to any of claims 1 to 3 and a disaccharide, adding water to form a reconstituted solution and diluting the solution reconstituted with an aqueous system.
22. 22. A method according to claim 21, wherein the compound is PM00104.
23. 23. A method for treating cancer consisting of the intravenous infusion of a solution prepared by means of a method according to any one of claims 21 or 22.