MXPA06005378A - Novel compound, corresponding compositions, preparation and/or treatment methods - Google Patents

Abstract

Disclosed is a novel crystalline form of topotecan monohydrochloride pentahydrate, which is a pentahydrate of 10-[(dimethylamino) methyl]-4-ethyl -4, 9-dihydroxy -1H-pyrano[3’,4’:6,7]indolizino[1, 2-b]quinoline-3, 14(4H,12H)dione monohydrochloride, corresponding pharmaceutical compositions, methods preparation and/or use thereof to treat anti-viral and/or cancer-related diseases.

Description

COMPOSITE NOVEDOSO, CORRESPONDING COMPOSITIONS, PREPARATION AND / OR TREATMENT METHODS FIELD OF THE INVENTION The present invention relates to a novel crystalline form of a topotecan pentahydrate rhine, corresponding pharmaceutical compositions, methods of preparation and / or uses thereof for treating antiviral and / or cancer-related diseases.

BACKGROUND OF THE INVENTION A fundamental step in the processes of replication and transcription of cellular DNA is associated with the separation of helical strands of DNA. The helical DNA structure of eukaryotic cells dictates specific topological properties that can guide problems that a cellular apparatus must resolve to use the genetic material as a template for cellular replication processes. Eukaryotic DNA strands, organized within the chromatin by chromosomal proteins, are restricted in such a way that those strands can not be unrolled without the help of enzymes that alter their topology. In light of this, it has been recognized for a long time that the advancement of a transcription or replication complex along a DNA helix would be facilitated by a pivot point that would eliminate the overall conformation torque during such processes. Topoisomerases are important enzymatic components in cellular functions capable of altering the DNA topology in eukaryotic cells and in cell proliferation processes. Topoisomerases alter the DNA binding number (that is, equal to the number of times a strand of DNA coils in the direction of the helical axis in the right direction) by catalyzing a three-step process: the cleavage of one or both strands of DNA , the passage of a DNA segment through such break (s) and the resealing of the DNA break. Two classes of topoisomerases have been associated with eukaryotic cells: topoisomerase type I and topoisomerase type II. The topoisomerases type I and type ll play important roles in the replication, transcription and recombination of DNA. In general, inhibition of topoisomerase has been the main goal of oncological, antineoplastic, antiviral agents, etc. The inhibition of topoisomerase II is the main goal of important commercial oncolytic agents (for example etoposide, doxorubicin and mitoxantrone) as well as other oncolytic agents that are still being developed. An example of a class of DNA topoisomerase I inhibitor compounds include camptothecin and its corresponding analog or related derivatives. Camptothecin is a water-insoluble cytotoxic alkaloid produced by plants such as trees of Camptotheca accuminata native to China and the trees Nothapodytes foetida native to India. Camptothecins generally (such as topotecan) are discussed in Cancer Chemotherapy and Biotherapy (see, pp. 463-484, 2nd edition, Eds. Bruce A. Chabner and Dan L: Longo, Lippincott-Raven Publishers, Philadelphia, 1996). Examples of derivatives of camptothecin analogs include topotecan, ironotecan and 9-aminocamptothecin. U.S. Patent No. 5,0047,758 describes topotecan, (S) -10 - [(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1 H-pyran monohydrochloride [3 ', 4 ': 6,7] indolizine [1, 2-b] quinoline-3,14 (4H, 12H) dione (also known as 9-dimethylaminomethyl-10-hydroxycamptothecin, etc.), as illustrated by the following chemical structure: (S) - Topotecan Topotecan is also listed in The Merck Index (see 12th Ed., Monograph No. 9687, Merck &Co., Inc., 1996). Clinical trials have shown that topotecan has efficacy against several cancers of solid tumors, in particular ovarian cancer, esophageal cancer and non-small cell lung carcinoma in humans.

Hycamtin® (sold by GlaxoSmithKine, Brentford, UK), which contains topotecan hydrochloride, is formulated as a lyophilized mixture, which is suitable for intravenous administration after reconstitution. Typically, this product is administered by medical professionals in a hospital, clinic or in a doctor's office environment. This dosage requires that patients move to such facilities, sometimes daily, for treatment. It would be desirable to develop a pharmaceutical form of topotecan hydrochloride that could be manufactured easily and safely and that would be useful in the preparation of a pharmaceutical composition that could be administered to patients in any environment, for example at home. In general, such self-administrable dosage forms are solid orally administrable forms.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound which is a topotecan pentahydrate monohydrochloride characterized by the substantially same pattern of powder X-ray diffraction (XRPD) as Figure 1. The present invention also relates to a compound which is a monohydrochloride of topotecan pentahydrate characterized by a powder X-ray diffraction pattern (XRPD) that has peak positions in 4.5 + 0.1 (2T), 6.4 + 0.1_ (2T), 7.1 0.1 (2T), 9.0 0.1. ° 2T), 10.1 ± 0.1 (° 2T), 11.5 + 0.1 (° 2T), 12.6 + 0.1 (° 2T), 13.1 + 0.1 (° 2T), 14.1 + 0.1 (° 2T), 15.5 ± 0.1 (° 2T) ), 17.9 ± 0.1 (° 2T), 18.7 + 0.1 (° 2T), 20.0 + 0.1 (° 2T), 20.3 ± 0.1 (° 2T), 21.1 ± 0.1 (° 2T), 21.8 + 0.1 (° 2T), 23.0 + 0.1 (° 2T), 24.8 + 0.1 (° 2T), 25.6 + 0.1 (° 2T), 26.6 ± 0.1 (° 2T), 27.2 ± 0.1 (° 2T), and 28.9 ± 0.1 (° 2T). The present invention relates to a compound, which is a topotecan pentahydrate monohydrochloride characterized by a solid state spectrum FT-IR (KBr) which provides a second inverse derivative spectrum for the spectral region of 1800 cm "1 to 1500 cm" 1 which is substantially the same as that of Figure 3. The invention further relates to a compound, which is topotecan pentahydrate monohydrochloride, characterized by a second solid-state spectrum derived FT-IR (KBr) having peaks in 1754 + 2 cm "1, 1745 ± 2 cm" 1, 1740 ± 2 cm "1, 1658 ± 2 cm" 1, 1649 ± 2 cm "1, 1596 + 2 cm" 1584 ± 2 cm "1, and 1507 + 2 cm "1. The present invention also relates to pharmaceutical compositions, comprising the topotecan pentahydrate monohydrochloride of this invention. The compositions of this invention further comprise one or more pharmaceutically acceptable carriers, including adjuvants, diluents, excipients, etc. The invention relates to a process for preparing the topotecan pentahydrate monohydrochloride of this invention, wherein the process comprises the steps of: (a) forming an aqueous mixture of organic solvent containing topotecan monohydrochloride; (b) recrystallizing the topotecan monohydrochloride from and / or suspending the topotecan monohydrochloride with the aqueous mixture of organic solvent to precipitate and / or form the topotecan pentahydrate monohydrochloride product; and [c] collecting, by filtration, topotecan pentahydrate monohydrochloride. The present invention further relates to a method of treating cancer comprising administering to a subject in need thereof an effective amount of the topotecan pentahydrate monohydrochloride of this invention. The present invention relates to a method of treating cancer comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising the topotecan pentahydrate monohydrochloride of this invention. The present invention further provides the topotecan pentahydrate monohydrochloride of this invention for use in therapy. The present invention also provides the use of topotecan pentahydrate monohydrochloride of this invention in the preparation of a medicament for the treatment of cancer and the use of topotecan pentahydrate monohydrochloride of this invention in the preparation of a medicament for improving one or more of the symptoms associated with cancer.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a powder X-ray diffractogram of a polymorphic form of topotecan pentahydrate monohydrochloride illustrating substantially identified characteristic peaks of the 0o-2-theta region (° 2T) at 35 ° 2-theta (° 2T). Figure 2 is a FT-IR (KBr) spectrum of a polymorphic form of topotecan pentahydrate monohydrochloride. Figure 3 is a second inverse derivative spectrum of the region 1800 cm "1 to 1500 cm" 1 of the FT-IR spectrum (KBr) of a polymorphic form of topotecan monohydrochloride pentahydrate.

DETAILED DESCRIPTION OF THE INVENTION Topotecan (salts), hydrates, and / or solvates thereof) suitable for use in the present invention, which include the starting materials (ie, as topotecan monohydrochloride pentahydrate), intermediates or products, are prepared as described herein, and / or by applying or adapting known methods, which may be methods previously used or described in the literature. The patent of the U.S.A. No. 5,004,758 discloses water-soluble camptothecin analogs, including topotecan (9-dimethylaminomethyl-10-hydroxycamptothecin), preferably (S) -topotecan, more preferably the hydrochloride salt. The patent of the U.S.A. No. 5,734,056 discloses analogues of water-soluble camptothecin compounds (including topotecan), a process for the preparation of such analogs and / or intermediates useful therein. The patent of the U.S.A. No. 5,155,225 generally describes methods for making pyran [3 ', 4': 6,7] indolizine- [1,2-B] quinolinones. The patents of the U.S.A. No. 5,405,963, 5,468,859, 5,541, 329, 5,700,939, 5,663,177 and 5,670,500 describe general procedures for the total asymmetric synthesis of camptothecin analogues and / or intermediates of corresponding compounds, pharmaceutical compositions and / or methods for the manufacture and / or use of analogs . The patent of the U.S.A. No. 5,674,872 and the US patent. No. 5,756,512 disclose methods for the treatment of ovarian cancer and non-small cell lung carcinoma, respectively, comprising administering an effective amount of a compound of the class of water-soluble camptothecin analogs, including topotecan. The patent of the U.S.A. No. 5,633,016 discloses combination chemotherapy related to the use of a compound of the class of camptothecin analogues (ie, topotecan) and a platinum coordination compound. The patent of the U.S.A. No. 6,582,689 discloses compositions, comprising enhancers, an interferon-gamma inducing factor (IGIF).; as IL-18), in combination with a chemotherapeutic agent (which may include topotecan), methods for making such compositions, the use of such compositions to inhibit the growth of tumors or cancer cells and / or to prevent or treat cancer in mammals . The topotecan monohydrochloride and solvates thereof (in particular hydrates) exhibit polymorphism. As conventionally understood in the art, polymorphism is defined as a capacity of a compound to crystallize as more than one distinct crystalline or "polymorphic" species. A polymorph is defined as a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state. The polymorphic forms of any given compound are defined by the same chemical formula and / or composition but are as different in chemical structure as crystal structures from two different chemical compounds. Such compounds may differ in agglomeration, geometric arrangement of the corresponding crystal lattices, etc. Accordingly, the chemical and / or physical properties or characteristics vary with each distinct polymorphic form, which may include variations in solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure, stability, etc. . The polymorphic forms of any given compound can be distinguished from one another using different characterization or identification techniques. For example, conventional organic chemistry identification techniques can be used to distinguish different polymorphic forms. Such identification techniques may include, without restriction, infrared spectroscopy (IR), nuclear magnetic resonance (NMR) (ie, proton magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), nuclear magnetic resonance 31P (31P NMR), electron microscopy, powder X-ray diffraction (XRPD), optical crystallography, differential scanning calorimetry (DSC), differential thermal analysis, dilatometry, etc. The novel topotecan pentahydrate monohydrochloride of this invention is a specific crystalline polymorphic form of 10 - [(dιmethylamine) methy1] -4-ethyl-4,9-dihydroxM H-pyrano [3 ', 4': 6,7] indolizine monohydrochloride [1, 2 -b] quinolin-3,14 (4H, 12H) dione (or 9-dimethylaminomethyl-10-hydroxylcamptothecin monohydrochloride pentahydrate) This topotecan pentahydrate monohydrochloride can be easily isolated and shows uniformity, reproducibility, ease and safety of handling in its manufacture and stability when isolating and drying. The topotecan pentahydrate monohydrochloride of this invention is characterized by substantially the same XRPD pattern as that illustrated in Figure 1. The XRPD pattern of Figure 1 is expressed in terms of 2-theta angles and is obtained with a diffractometer using radiation with X-ray copper Ka. Those skilled in the art will understand that an XRPD pattern will be considered to be substantially the same as the XRPD pattern of Figure 1 if the difference in peak positions of the XRPD standards is not greater than ± 0.1 (° 2T).

The topotecan pentahydrate monohydrochloride is further characterized by an XRPD pattern having peak positions at 4.5 ± 0.1 (° 2T), 6.4 ± 0.1 (° 2T), 7.1 + 0.1 (° 2T), 9.0 ± 0.1 (° 2T), 10.1 ± 0.1 (° 2T), 11.5 ± 0.1 (° 2T), 12.6 + 0.1 (° 2T), 13.1 ± 0.1 (° 2T), 14.1 ± 0.1 (° 2T), 15.5 ± 0.1 (° 2T), 17.9 ± 0.1 (° 2T), 18.7 ± 0.1 (° 2T), 20.0 ± 0.1 (° 2T), 20.3 ± 0.1 (° 2T), 21.1 ± 0.1 (° 2T), 21.8 ± 0.1 (° 2T), 23.0 ± 0.1 (° 2T), 24.8 ± 0.1 (° 2T), 25.6 ± 0.1 (° 2T), 26.6 ± 0.1 (° 2T), 27.2 ± 0.1 (° 2T) and 28.9 ± 0.1 (° 2T). The location (2T values) of these peaks was obtained from an XRPD pattern expressed in terms of 2-theta angle and was obtained with a diffractometer using X-ray radiation Ka of copper. The topotecan pentahydrate monohydrochloride of this invention is also characterized by substantially the same solid state spectrum as the second reverse derivative FT-lR (KBr) for the spectral region of 1800 cm "1 to 1500 cm" 1 as in FIG. It will be understood by those skilled in the art that a second reverse drift spectrum FT-lR (KBr) of 1800 to 1500 cm "1 will be considered as substantially the same as the FT-lR (KBr) spectrum of Figure 3 if the difference in peak positions of the FR-IR spectra is not greater than ± 2 cm "1. The topotecan pentahydrate monohydrochloride of this invention is further characterized by a second derivative solid state spectrum FT-lR (KBr) having peaks at 1754 ± 2 cm "1, 1745 ± 2 cm" \ 1740 ± 2 crn "1 , 1658 ± 2 cm "1, 1649 ± 2 cm" 1, 1596 ± 2 cm "1, 1584 ± 2 cm" 1, and 1507 ± 2 cm "1.

The topotecan pentahydrate monochlorhydrate of this invention may have a water content scale of between about > 10% p / p to around < 17 p / p. The water content associated with the topotecan pentahydrate monohydrochloride can be on a scale of about 3.5% by weight to about 20% by weight. Specifically, the topotecan pentahydrate monohydrochloride of this invention can have a water content on a scale of about 10.5% by weight to about 16.5% by weight. The topotecan pentahydrate monohydrochloride product of this invention can exist in the same crystal form whether it has 3, 4 or 5 water molecules associated with the crystal form (i.e., each of the trihydrate, tetrahydrate and pentahydrate of the monohydrochloride of topotecan of this invention provides substantially the same XRPD pattern as that of Figure 1). The topotecan pentahydrate monohydrochloride product of the present invention has a crystal lattice structure incorporating these three water molecules attached to the crystal lattice (the trihydrate state). The topotecan pentahydrate monohydrochloride product can also incorporate two labile channel water molecules linked in a coordinated manner; its removal from the grid to form the trihydrate state does not affect the crystallinity of the material as measured by powder X-ray diffraction techniques and infrared spectroscopy. If the topotecan monohydrochloride product is dried to the trihydrate state, then it is allowed to absorb additional water molecules (for example from moist air), it will pick up two channel water molecules. If the topotecan pentahydrate monohydrochloride product is incompletely dried, the analysis may indicate that the product contains more than five water molecules. However, of these, three will be water molecules attached to the crystal lattice, two will be channel water molecules and any additional water will be surface water molecules (attached to the surface of the crystal, but which otherwise does not affect the crystallinity of the topotecan monohydrochloride product). The topotecan monohydrochloride product of this invention is described as a pentahydrate because, in environments of a relative humidity of about 40 to about 90%, this product will equilibrate to contain 5 molecules of water. The invention also relates to a process for preparing the topotecan pentahydrate monohydrochloride product of this invention, wherein the process comprises the steps of: [a] forming a mixture of aqueous organic solvent containing topotecan monohydrochloride; [b] recrystallizing the topotecan monohydrochloride from and / or suspending the topotecan monohydrochloride with the aqueous mixture of organic solvent to precipitate and / or form the topotecan monohydrochloride pentahydrate product; and [c] collecting, by filtration, the monohydrochloride product of topotecan pentahydrate.

Suitable organic solvents for use in the methods of the present invention for forming aqueous mixtures of organic solvent include, without restriction, acetone, tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, dimethyl sulfoxide and N, N-dimethylformamide and mixtures thereof. . Other solvents that may be useful in the process of this invention include ethyl acetate, acetonitrile and dichloromethane and / or mixtures thereof and / or mixtures with one or more of the organic solvents mentioned above. Particularly useful solvents include acetone, tetrahydrofuran and n-propanol, more particularly acetone and tetrahydrofuran. The "aqueous" portion of the aqueous mixture of organic solvent is an aqueous solvent which may be water or a solution of aqueous mineral acid. Conveniently, the aqueous mixture of organic solvent comprises a solution of aqueous mineral acid. In one embodiment, the mineral acid solution is a solution of aqueous hydrochloric acid (aqueous HCl), wherein the acid solution is aqueous HCl 0.05 N. For the recrystallization procedures identified in step [b], the aqueous solution mixture of organic solvent may comprise a mixture of an organic solvent and an aqueous solvent in a ratio (v / v) of from 1.5: 1 to about 3: 1, wherein the aqueous solvent is preferably a solution of aqueous mineral acid . A preferable scale for the ratio (v / v) of organic solvent to aqueous solvent, for the recrystallization process, is from 1.5: 1 to about 2: 1.

For the slurry forming processes that are identified in step [b], an aqueous mixture of organic solvent solution useful in a previously mentioned process of the present invention may have an organic solvent to aqueous solvent ratio (v / v) from 2: 1 to around 8: 1. A preferable ratio of organic solvent to aqueous solvent for the suspension formation process is about 8: 1. The mixture of aqueous organic solvent solution is used in the process of this invention such that the mixing ratio of organic solvent solution (volume / milliliters) to topotecan monohydrochloride (weight / grams) is from 7: 1 to around 13: 1. A preferable scale useful for the recrystallization process is a mixing ratio of aqueous organic solvent solution (volume / milliliters) to topotecan monohydrochloride (weight / grams) from 10.6: 1 to about 13: 1, more preferably 12: 1. A preferable scale useful for the suspension formation process is a mixing ratio of organic solvent solution (volume / milliliters) to topotecan monohydrochloride (weight / grams) of from 7: 1 to about 12: 1, more preferably 12: 1. The topotecan pentahydrate monohydrochloride product can be dried after filtration to remove any remaining traces of the recrystallization solvents. The drying process can be performed in a manner that does not reduce water / topotecan stoichiometry to less than 3 water molecules / 1 HCl molecule of topotecan; that is, the water / topotecan stoichiometry of the topotecan pentahydrate monohydrochloride product is at least 3 water molecules / 1 HCl molecule of topotecan. Generally, the topotecan pentahydrate monohydrochloride product obtained by the process of this invention should not be dried at pressures of less than about 30 mm Hg or at temperatures greater than about 37 ° C. In one embodiment of the process of this invention, the topotecan pentahydrate monohydrochloride of this invention can be first prepared by dissolving topotecan monohydrochloride in a mixture of aqueous solution of heated organic solvent. In a specific embodiment of this invention, the aqueous mixture of heated organic solvent solution is a mixture of acetone and 0.05 N aqueous hydrochloric acid heated at a temperature of about 58 ° C and the ratio of the volume of acetone to aqueous hydrochloric acid is of about 2: 1. The crystallization / recrystallization of topotecan pentahydrate monohydrochloride from the heated solution can be achieved by cooling the solution, filter the topotecan pentahydrate monohydrochloride product and dry. Conveniently, the cooling process can be carried out by cooling the heated topotecan monohydrochloride solution with stirring. The cooling ratio should generally be in the range of about 0.1 ° C / min to about 1 ° C / min. In a specific embodiment, the cooling ratio is around 0.25 ° C / min. In the crystallization process (recrystallization), the solution / mixture can be cooled to a temperature from about room temperature to about 0 ° C. After filtering the topotecan monohydrochloride product from the recrystallization solvent, the collected / filtered product can be dried to remove any remaining traces of the crystallization / recrystallization solvents. Examples of useful drying conditions include drying at 20-25 ° C at 165-300 mm Hg for up to 14 days or 28-32 ° C at 150-200 mm Hg per >24 hours, with a nitrogen purge. This invention is also directed to pharmaceutical compositions comprising the topotecan pentahydrate monohydrochloride of this invention. The compositions of this invention further comprise one or more pharmaceutically acceptable carriers. If desired, the pharmaceutical compositions of this invention may further comprise other additive ingredients. The pharmaceutical compositions of the present invention may further include these ingredients as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a deleterious effect on the therapeutic action of the compositions. snapshots The forms of the pharmaceutical compositions of the present invention include either a solid form (ie, tablets, capsules, powders, etc.) or a liquid form (i.e., suspensions or emulsions, etc.), wherein the monohydrochloride of topotecan pentahydrate is present in the pharmaceutical composition in a crystalline form defined above. In general, the pharmaceutical compositions of the present invention were prepared using known conventional materials and techniques, which may include, without restriction, mixing, blending and the like. The percentage of topotecan pentahydrate monohydrochloride in pharmaceutical compositions of the present invention can be varied to provide a desired amount of active compound in such therapeutically useful compositions, such that a suitable dose will be had. The topotecan pentahydrate monohydrochloride and / or the pharmaceutical compositions of the present invention may be useful in treatment methods that provide antiviral and / or antineoplastic activity. For example, various cancers treatable using the topotecan pentahydrate monohydrochloride and / or pharmaceutical compositions of the present invention include solid-type tumors (ie, which may include, without restriction, ovarian cancer, breast cancer, endometrial cancer, esophageal cancer, cancer small and non-small cell lung, cervical cancer, colorectal cancer, neuroblastomas, glioma and the like) and non-solid type tumors (which may include, but are not limited to, myelodysplastic syndrome, acute myelogenous leukemia, chronic myelomonocytic leukemia and the like) in mammals , as humans. The topotecan pentahydrate monohydrochloride and / or pharmaceutical compositions of the present invention have a human and veterinary utility. If a veterinary use is intended, the topotecan pentahydrate monohydrochloride and / or pharmaceutical compositions of the present invention may be formulated with a carrier that may be a liquid, or aspersion, or may be formulated in a solid, non-degradable or degradable form for insertion in the rumen. Selected carriers, such as those described herein, may be employed to prepare compositions acceptable or adaptable for veterinary use. Accordingly, this invention relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of topotecan pentahydrate monohydrochloride of this invention. The invention also relates to a method of treating cancer comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an effective amount of topotecan pentahydrate monohydrochloride of this invention. This invention also relates to a method for using the topotecan pentahydrate monohydrochloride of this invention and / or a pharmaceutical composition comprising the same as a palliative for improving one or more of the symptoms associated with cancer, which comprises administering to a subject an effective amount of topotecan pentahydrate monohydrochloride of this invention and / or a pharmaceutical composition comprising the same. Improving the symptoms associated with cancer can improve the quality of life of cancer patients, especially with lung cancer. Examples of cancer symptoms that can be improved by treatment with topotecan pentahydrate monohydrochloride and / or pharmaceutical compositions comprising the same include, without restriction, fatigue, pain, insomnia, interference with daily activity and specific symptoms in disease (e.g., for lung cancer). : dyspnea, chest pain, hemoptysis and hoarseness). The topotecan pentahydrate monohydrochloride and / or corresponding pharmaceutical compositions can be used in a single agent therapy for any of the treatments described above or uses or can be reused in combination with other active treatment modalities such as radiation therapy, conventional antineoplastic agents, which include unrestricted paclitaxel, docetaxel, doxorubicin, ara-c (cytarabine), 5-fluorouracil, etoposide, and organometallic coordination compounds, such as cisplatin and carboplatin, and meta-biological therapeutic approaches, including without restriction gefitinib, erlotinib, lapatinib, bortezimib, elacridar, and erbitux The term "effective amount" means the amount of the monohydrochloride of topotecan pentahydrate and / or a pharmaceutical composition containing the same, which when administered to a mammal (such as a human being) that needs it, provides a clinically desirable result in the treatment of various diseases; that is, as viral and / or cancer diseases (ie, the latter may include antineoplastic treatment, which includes, without restriction, inhibition of tumor cell growth, remission, cure, improvement of symptoms, etc.).

It will be appreciated that the current preferred therapy course will vary in accordance with, for example, the particular formulation of the topotecan pentahydrate monohydrochloride used, the mode of administration and the host being treated in particular. Those skilled in the art can elucidate an optimal therapy course for a given set of conditions using tests for determination of conventional therapy course by virtue of the information set forth herein and the disclosures of the US patents. No. 5,004,758, 5,633,016, 5,674,872 and 5,756,512. It will be noted that current preferred doses of the compound used in the compositions and methods of treatment of the present invention will vary in accordance with the particular formulated composition, the mode of administration and the particular site, such as the host and type of tumor that is present. being treated, etc. Additionally, those skilled in the art can elucidate optimal doses for a specific pathological condition in a particular patient as in antiviral or antineoplastic techniques, using conventional dose determination tests by virtue of the experimental data. In accordance with the present invention, the components of each pharmaceutical composition and selection of the suitable one or more pharmaceutically acceptable carriers, will depend on the treatment carried out and / or intended route of administration. Another embodiment of this invention is directed to the use of topotecan pentahydrate monohydrochloride of this invention to prepare a wide variety of pharmaceutical compositions containing topotecan, including solid forms (tablets, capsules, powders including lyophilized powders, etc.) or liquid forms (ie say solutions, suspensions or emulsions, etc.). Accordingly, a process for the preparation of such pharmaceutical compositions comprises using conventional materials and techniques known in the art, which may include without restriction, mixing, combining and the like, of the topotecan monohydrochloride pentahydrate of this invention with one or more pharmaceutically acceptable carriers. . The topotecan pentahydrate monohydrochloride, pharmaceutical compositions of the present invention and / or compositions containing topotecan can be administered by intravenous and intramuscular injection, parenterally, topically, orally or by inhalation. The topotecan pentahydrate monohydrochloride, pharmaceutical compositions of the present invention and / or compositions containing topotecan can also be administered in injectable doses by dissolving or suspending these materials in a physiologically acceptable diluent with one or more pharmaceutically acceptable carriers. Suitable pharmaceutically acceptable carriers, including adjuvants, diluents, excipients, surfactants and the like, contemplated for use in the pharmaceutical compositions of the present invention include those known in the pharmaceutical formulating arts. For example, a reference to useful materials can be found in compilatory textbooks of well-known pharmaceutical formulations, such as Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Suitable carriers include, without restriction, sterile liquids such as water and oils, with or without the addition of a surfactant and / or other pharmaceutically and physiologically acceptable carriers, including adjuvants, excipients or stabilizers, etc. In general, liquid carriers, in particular, as used in injectable solutions, may include without restriction, water, saline, aqueous dextrose and related sugar solution, pharmaceutically acceptable glycols, such as propylene glycol or polyethylene glycol, and the like. Oils suitable for use in the present invention may include, without petroleum restriction, animals, vegetable oils or oils of synthetic origin (eg, peanut oil)., soybean oil, hydrogenated vegetable oil or mineral oil and the like). The pharmaceutical compositions may optionally contain a preservative to prevent the growth of microorganisms under ordinary conditions of storage and use. If a liquid carrier is used, the pharmaceutical composition may be in the form of an emulsion, soft gelatin capsule, sterile injectable suspension or a solution in an ampule or bottle or non-aqueous liquid suspension. If a desired pharmaceutical composition is in the form of a solution or suspension (which may also be encapsulated), examples of suitable pharmaceutical carriers include: for aqueous systems, water; for non-aqueous systems: ethanol, glycerin, propylene glycol, vegetable oils (such as olive oil, corn oil, cottonseed oil, peanut oil, sesame oil, hydrogenated vegetable oil), liquid paraffins, glyceryl monostearate, mixtures of these and mixtures of these with water; for solid systems: lactose, alabaster, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, kaolin and mannitol; and for aerosol systems: dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Pharmaceutical compositions that can be prepared using the topotecan pentahydrate monohydrochloride of the present invention that are available for injectable use can include, without restriction, sterile aqueous solutions or sterile dispersions and powders for extemporaneous preparation (reconstitution) as sterile injectable solutions or dispersions and Similar. The pharmaceutical compositions of this invention include sterile dispersions and / or sterile powders comprising the topotecan pentahydrate monohydrochloride of this invention, wherein, prior to injection, such dispersions or powders are reconstituted (for example by dissolving in water, saline, etc.) to form a sterile injectable solution or dispersion. In all cases, each injectable / reconstituted solution / dispersion must be sterile and fluid to the extent that it has an application character by syringe. The pharmaceutical forms must be stable under manufacturing and storage conditions, which must be protected against the contaminating action of microorganisms, such as bacteria and fungi. For example, a carrier can be a solvent or dispersion medium which can include, without restriction, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, suitable mixtures thereof, and the like. For parenteral administration, an injectable pharmaceutical composition containing topotecan may include, without restriction, the form of a sterile injectable liquid, such as a reconstituted lyophilized formulation or a nonaqueous or aqueous liquid suspension and the like. Suitable solutions or suspensions of active compounds of the present invention can be prepared in water by suitably mixing with a surfactant, such as hydroxypropylcellulose. Suitable dispersions can also be prepared in, without restriction, glycerol, liquid polyethylene glycols and oil mixtures thereof and the like. The patents of the U.S.A. No. 5,814,335, No. 5,552,156, No. 5,837,282, No. 5,543,152 and No. 5,741, 516 and the U.S. patent publications. No. 2002/0110586, No. 2002/0119990, No. 2004/0071768 and No. 2004/0170678 describe liposomes and / or mycelium which can be used with the topotecan pentahydrate monohydrochloride of this invention in the preparation of liposomal injectable compositions and / or micelles that contain topotecan. A variety of lipids are known in the art that can be used for general such liposomes. In general, single-layer liposomes have a membrane and are referred to as "unilamellar". Multilayer liposomes are known as "multilaminares". Suitable lipids include, without restriction, phospholipids or negatively charged and neutral sphingolipids and sterols such as cholesterol. Specific liposome compositions comprise various sphingomyelin and cholesterol ratios. Other lipids may also be included in such liposome compositions as necessary, such as to prevent the oxidation of lipid or ligands on the liposome surface. Such liposomal compositions containing topotecan may also be lyophilized (such as PCT / US2004 / 020592, the disclosure of which is incorporated herein by reference). In particular, topotecan pentahydrate monohydrochloride can be used to prepare sterile lyophilized formulations, suitable for parenteral administration, after reconstitution with (solution in) water or saline. One embodiment of this invention is directed to a process for the preparation of a lyophilized composition comprising topotecan hydrochloride, mannitol and tartaric acid, wherein the process comprises the steps of forming a mixture of aqueous solution by dissolving the topotecan monohydrochloride pentahydrate of This invention, mannitol and tartaric acid in water, and lyophilize the solution mixture to form a solid mixture. Optionally, prior to lyophilization, the pH of the solution mixture can be adjusted to about 2.5 to about 3.5. Additionally, the solution mixture can optionally be placed in jars prior to lyophilization. After lyophilization, the resulting solid mixture can be sealed inside the flasks to keep the mixture as a sterile powder.

The topotecan pentahydrate monohydrochloride of this invention or topotecan hydrochloride (Hycamtin) is administered in doses based on the weight of the topotecan free base (molecular weight: 421.4), not on the weight of topotecan pentahydrate monohydrochloride (molecular weight 548.0) or topotecan monohydrochloride (molecular weight 457.9). For example, a 4 mg dose of topotecan is provided by 4.35 mg of topotecan monohydrochloride. For parenteral administration, a course of therapy employed is generally from about 0.5 mg topotecan / m2 to about 25 mg topotecan / m2 of body surface area per day for about a day to about 7 consecutive days. In one embodiment, the course of therapy employed for a patient is from about 0.75 mg topotecan / m2 to about 2 mg topotecan / m2 of body surface area per day for about 5 to 7 consecutive days. In another modality, the course of therapy employed is about 1.5 mg topotecan / m2 of body surface area per day for about 5 consecutive days. The course of therapy may be repeated at least once around a range of 7 to about 21 days (from the date of initiation of therapy) depending on the initial dosing schedule and the patient's recovery from normal tissues. In one modality, the therapy course can be repeated at 21-day intervals. If topotecan pentahydrate monohydrochloride is used in combination therapy (e.g., in some dosage in combination with cisplatin, carboplatin, etoposide, paclitaxel or docetaxel), the amount of topotecan pentahydrate monohydrochloride can be reduced (e.g. by about 0.25-0.5). mg topotecan / m2 of body surface area per day, or potentially more), depending on the needs and / or tolerance of the therapy by the patient. Other useful dosage regimens suitable for use with the topotecan pentahydrate monohydrochloride of this invention are possible. The course of parenteral therapy can be repeated based on the tumor response in cancer-related diseases. Parenteral administration can be by short (for example 30 minutes) or prolonged (for example 24-72 hours) intravenous infusion. In general, injectable pharmaceutical compositions containing topotecan can be administered by intravenous fusion in 30 minutes. For continuous intravenous administration, the dose that can be used is around 0.5 mg topotecan / m2day for 5 days to 21 days. For topical administration, a compound and / or pharmaceutical composition of the present invention may include, without restriction a form of a cream, ointment, liniment, lotion, paste, spray or drops suitable for administration to the skin, ear, eye, nose or genital area and the like. If a solid carrier is used, the preparation can be made into tablets, placed in a capsule of hard gelatin powder or pellet form or in the form of a pellet or troche. Additionally, solid carriers can be used to formulate compassions that can be inhaled. The amount of solid carrier will vary widely but will preferably be from about 25 mg to about 1 gram. Suitable formulations for administration by inhalation include powders or mists of fine particles that can be generated by various types of pressure aerosols with metered doses, nebulizers or insufflators. For pulmonary administration via the mouth, the powder or droplet particle size is typically in the range of 0.5-10μM, preferably 1-5μM, to ensure delivery to the bronchial tree. For nasal administration, particle size on the 10-500μM scale is preferred to ensure retention in the nasal cavity. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more cosolvents, for example surfactants. For oral administration, the pharmaceutical compositions of the present invention and / or the topotecan containing compositions may have a form that includes, without restriction, a tablet, capsule, powder, pellet, troche, lozenge, syrup, suspension, elixir, liquid or emulsion and / or other solid unit dosage forms as conventionally known in the art and the like. For example, topotecan pentahydrate monohydrochloride, pharmaceutical compositions of the present invention and / or compositions containing topotecan can be administered orally with an inert carrier, an edible assimilable carrier, surrounded by hard or soft shell capsules compressed into tablets and / or incorporated directly with the food, et cetera. In one embodiment, the pharmaceutical composition of the invention, comprising the topotecan pentahydrate monohydrochloride described above is in the form of an orally administrable solid tablet or capsule. The solubility of the topotecan pentahydrate monohydrochloride described herein can facilitate the provision or development of a dosage form from which the drug substance (topotecan) becomes more available for its bioabsorption. As a result, it may be possible to develop stable and controlled release dosage forms, in particular oral dosage forms, containing the topotecan pentahydrate monohydrochloride and / or corresponding pharmaceutical compositions of the present invention, for once a day dosing, regimens of pulsatile release or controlled or delayed release, etc., to optimize therapy by matching pharmacokinetic performance with pharmacodynamic requirements. Alternatively, the dosage form (a pharmaceutical composition of this invention or a composition containing topotecan) may be administered in combination with or may contain a compound that improves the bioavailability of topotecan. Examples of compounds that can improve the bioavailability of topotecan are described in PCT / N LOO / 00331, published as WO00 / 69390, the disclosure of which is incorporated herein by reference.

A solid form suitable for use in the present invention may include, without restriction, a capsule (i.e. as an ordinary type of gelatin) containing the topotecan monohydrochloride pentahydrate of this invention and one or more pharmaceutically acceptable carriers. Conventional pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions described herein include, without restriction, lactose, sucrose, or corn starch and the like, binders (i.e., acacia, gum, tragacanth, corn starch, or gelatin, etc.), excipients (i.e. dicalcium phosphate) disintegrating agents (e.g. corn starch, potato starch or alginic acid), lubricants (i.e., stearic acid, magnesium stearate, etc.); surfactants (ie, sodium laurel sulfate, sodium dodecyl sulfate, and glyceryl monostearate) and a sweetening agent (i.e., sucrose, lactose or saccharin, etc.). Many other materials may be present as coatings or to modify the physical forms of each dosage unit. For example, the tablets may be coated with materials, which may include without restriction shellac and / or sugar, a syrup (i.e. which may include, without restriction an active ingredient, a sweetening agent (i.e., as sucrose), preservatives ( that is, as methyl and propylparaben), a dye and flavoring (ie, cherry or orange flavors), and the like When the unit dosage form used is a capsule, it may also contain a liquid carrier (i.e., as an oil fatty), etc. The pharmaceutically acceptable carrier may also include one or more materials that can provide a delayed release of the topotecan pentahydrate monohydrochloride Such delayed release materials are well known in the art and include glyceryl monostearate or glyceryl distearate alone or with a wax, ethyl cellulose, hydroxypropylmethylcellulose, methyl methacrylate and the like. The pharmaceutical composition of this invention is a hard gelatin capsule which encapsulates a dispersion of the topotecan pentahydrate monohydrochloride of this invention in a mixture of glyceryl monostearate and hydrogenated vegetable oil. For administration of the topotecan pentahydrate monohydrochloride of this invention, the course of therapy comprises the administration of a single dose of topotecan pentahydrate monohydrochloride, wherein the dosage is from 0.5 mg topotecan / m2 to about 25 mg topotecan / m2 of body surface area per day for about one or 21 consecutive days with courses of treatment repeated at appropriate intervals. In one embodiment, the course of therapy employed for oral administration is generally from about 1 mg topotecan / m2 to about 2 mg topotecan / m2 of body surface area per day for about 5 consecutive days. In general, the course of therapy is repeated at least once in about a range of 7 to about 28 days (from the date of initiation of therapy) depending on the initial dosing schedule and the recovery of normal tissues in the patient. The course of therapy may be repeated based on the response of the tumor. In one modality the therapy course can be repeated at 21-day intervals. Other useful and suitable dosage regimens for use with the topotecan pentahydrate monohydrochloride of this invention are possible. The examples below illustrate the present invention and are not intended to limit, in any way, the scope of the present invention.

EXAMPLE 1 Preparation of topotecan pentahydrate monohydrochloride Topotecan hydrochloride (2.9 g) is suspended in a mixture of acetone (23.2 ml, 8 volumes) and 0.05 N HCl (11.6 ml, 4 volumes). The reaction mixture mentioned above is heated to 58 ° C to dissolve the solid topotecan hydrochloride. The reaction mixture solution is cooled, resulting in the formation of a monohydrochloride suspension of topotecan pentahydrate. The monohydrochloride of topotecan pentahydrate is crystallized at 37 ° C. The suspension is further cooled to room temperature whereby the reaction product, the crystalline topotecan monohydrochloride pentahydrate, is isolated by filtration and dried.

EXAMPLE 2 Preparation of topotecan pentahydrate monohydrochloride Topotecan monohydrochloride (6.00 kg) was dissolved in a mixture of acetone (50.4L, 8.4 volumes) and 0.05N HCl (26.1L, 4.4 volumes) upon heating to 58 ° C. The resulting solution was cooled at a rate of about 1 ° C / min, with agitation, at 40 ° C, was spread with topotecan monohydrochloride pentahydrate spreader material (5.9 g) and maintained at 35 ° C for 1 h, time during which the crystallization occurred. The resulting suspension was cooled to 0 ° C at a rate of about 0.25 ° C / min. The reaction product, topotecan pentahydrate monohydrochloride, was isolated by filtration and dried at 32 ° C and -0.76 barG for 62 hours while introducing a vigorous stream of nitrogen through the vessel. Yield: 4,597 kg of yellow powder. This process produces topotecan pentahydrate monohydrochloride of this invention with or without the step of spreading in the material solution for spreading of topotecan monohydrochloride pentahydrate.

EXAMPLE 3 Diffraction data with X-ray and infrared FT for topotecan pentahydrate monohydrochloride X-ray diffraction, general procedure The X-ray powder diffraction pattern for the topotecan pentahydrate monohydrochloride, which is prepared according to the procedure of Example 1 or 2, is recorded or scanned using a Philips X'Pert Pro Diffractometer instrument , where the following procedures and / or techniques for sample preparation are used to obtain the X-ray diffraction pattern with the following acquisition parameters. The mixture is added with a few milligrams of Si powder (internal standard), and mixed in a mortar and pestle. Approximately 30 mg are gently flattened on a zero-depth silicon sample holder. The stand is placed in a designated position in the 15-position sample changer and programmed to the computer with the correct sample information immediately to prevent confusion in the sample position. The sample containing the topotecan pentahydrate monohydrochloride is flushed using the instrument or acquisition parameters provided in Table 1.

TABLE 1 X-ray diffraction acquisition parameters for topotecan monohydrochloride crystalline pentahydrate The powder X-ray diffraction pattern obtained for a sample of the topotecan pentahydrate monohydrochloride according to this invention is shown in Figure 1. The diffraction angles (° 2T) and d-separations (Angstroms) calculated from the Acquisition data are provided in Table 2.

TABLE 2 X-ray diffraction data for topotecan pentahydrate monohydrochloride (° 2T diffraction angles and d-separations (Angstroms)) Using 1 k-alpha copper radiation.

Infrared, general procedure: The sample for FT-lR analysis is prepared by diluting approximately 2 mg of a sample of the topotecan pentahydrate monohydrochloride of this invention with 300 mg of dry potassium bromide (KBr). The resulting mixture is subjected to grinding with a mortar and pestle and then transferred to a die that is placed under high pressure for 3 minutes. At least 100 scans are collected using a FT-lR spectrometer equipped with a dTGS detector with a resolution of 4 cm "1. The full range spectrum of the crystal form of the topotecan pentahydrate monohydrochloride of this invention may vary to some degree. In the region from 3700 cm "1 to 2500 cm" 1 due to varying levels of water present in the sample, a full-spectrum spectrum FT-lR obtained for a sample of the topotecan pentahydrate monohydrochloride is shown in FIG. in accordance with this invention.

The second derivative spectrum (or second reverse derivative spectrum) of the IR region from 1800 cm "1 to 1500 cm" 1 can be used for the characterization of the crystalline form. This spectrum can be obtained by converting the ordinary scale to absorbance units, expanding the spectral region of 1800 cm "1 to 1500 cm" 1 and taking a second derivative of the resulting spectrum. The spectrum of the second derivative is multiplied by a factor of one negative to produce a second inverse derivative spectrum. Figure 3 illustrates the second inverse derivative spectrum for the 1800 cm "1 to 1500 cm" 1 spectral region for the topotecan pentahydrate monohydrochloride of this invention. The IR bands of topotecan pentahydrate monohydrochloride of this invention appear in approximately 1754 cm "1, 1745 cm" 1, 1740 cm "1, 1658 cm" 1, 1596 cm "1, 1584 cm" 1, and 1507 cm "1 (with an experimental variation of + 2 cm "1). In some cases the characteristic bands appear as transitions. The presence of a transition in one or more of the positions identified above is satisfactory to confirm the identity. The above description fully describes how to make and use the present invention. However, this invention is not limited to the particular embodiments described above, but includes all modifications thereof within the scope of the appended claims and their equivalents. Those skilled in the art will recognize by routine experimentation that various changes and modifications may be made without departing from the scope of this invention, so that the right is reserved to the illustrated embodiments and all online modifications within the scope of the claims. following. Each of the various patents, patent applications and patent application publications cited herein are incorporated by reference in their entirety as if they had been fully established herein.

Claims (26)

NOVELTY OF THE INVENTION CLAIMS

1. - An isolated compound which is topotecan pentahydrate monohydrochloride, said compound has an X-ray diffraction pattern which is substantially the same as that of figure 1.

2. An isolated compound which is topotecan pentahydrate monohydrochloride, said compound has a FT-lR spectrum of second inverse derivative for the spectral region of 1800 cm "1 -1500 cm" 1 which is substantially the same as that of figure

3. 3.- An isolated compound which is topotecan pentahydrate monohydrochloride, wherein said compound provides an X-ray diffraction pattern that has peaks at 4.5 ± 0.1 (° 2T), 6.4 ± 0.1 (° 2T), 7.1 ± 0.1 (° 2T), 9.0 ± 0.1 (° 2T), 10.1 ± 0.1 (° 2T), 11.5 ± 0.1 (° 2T), 12.6 ± 0.1 (° 2T), 13.1 ± 0.1 (° 2T), 14.1 ± 0.1 (° 2T), 15.5 ± 0.1 (° 2T), 17.9 ± 0.1 (° 2T) , 18.7 + 0.1 (° 2T), 20.0 ± 0.1 (° 2T), 20.3 ± 0.1 (° 2T), 21.1 ± 0.1 (° 2T), 21.08 ± 0.1 (° 2T), 23.0 ± 0.1 (° 2T), 24.8 ± 0.1 (° 2T), 25.6 ± 0.1 (° 2T), 26.6 ± 0.1 ( ° 2T), 27.2 ± 0.1 (° 2T), and 28.9 ± 0.1 (° 2T).

4. An isolated compound that is topotecan pentahydrate monohydrochloride, wherein said compound provides a spectrum to the FT-IR having peaks in 1754 ± cm "1, 1745 ± 2 cm" 1, 1740 ± 2 cm "1, 1658 ± 2 cm "1, 1649 ± 2 cm" 1, 1596 ± cm "1, 1584 ± 2 cm" 1, and 1507 ± 2 cm "1.

5. - The isolated compound according to any of claims 1-4, further characterized in that the topotecan monohydrochloride pentahydrate has a water content scale from from > 10% p /% p to around < 17 p /% p.

6. The compound isolated according to any of claims 1-5, further characterized in that the topotecan pentahydrate monohydrochloride has a water content in the range of about 10.5% p about 16.5% p.

7. The compound isolated according to any of claims 1-6, further characterized in that the topotecan pentahydrate monohydrochloride has a crystal lattice structure incorporating three water molecules attached to the crystal lattice within it.

8. The compound isolated according to any of claims 1-7, further characterized in that the topotecan pentahydrate monohydrochloride has a crystalline lattice structure incorporating two molecules of labile channel water coordinately.

9. A pharmaceutical composition comprising the compound according to any of claims 1-8 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, further characterized in that the pharmaceutical composition is a hard gelatin capsule and the pharmaceutically acceptable carrier comprises glyceryl monostearate and hydrogenated vegetable oil.

11. A process for preparing the isolated compound according to any of claims 1-8, wherein the method comprises the steps of: (a) forming an aqueous mixture of organic solvent containing topotecan monohydrochloride; (b) recrystallizing the topotecan monohydrochloride from and / or suspending the topotecan monohydrochloride with the aqueous mixture of organic solvent to precipitate and / or form the topotecan monohydrochloride pentahydrate product; and (c) collecting, by filtering said compound.

12. The process according to claim 11, further characterized in that the aqueous mixture of organic solvent comprises a mixture of acetone and a solution of aqueous hydrochloric acid 0.05 N.

13. The process according to claim 12, further characterized because the ratio of the volume of acetone to aqueous hydrochloric acid is about 2: 1.

14. The process according to claim 11, further characterized in that the aqueous mixture of organic solvent is heated to a temperature of about 58 ° C.

15. The process according to claim 14, further characterized in that the aqueous mixture of heated organic solvent is mixed at a rate in the scale of about 0.1 ° C / min to about 1 ° C / min.

16. - The method according to claim 15, further characterized in that the cooling rate is around 0.25 ° C / min.

17. The process according to claim 11, further characterized in that the aqueous mixture of organic solvent comprises an organic solvent and an aqueous solvent in a ratio of about 2: 1.

18. The use of the topotecan pentahydrate monohydrochloride isolated according to any of claims 1-8 in the preparation of a medicament for the treatment of cancer.

19. The use of the pharmaceutical composition according to claim 9, for preparing a medicament for treating cancer.

20. The use as claimed in claim 18 or 19, wherein said cancer is selected from the group of solid type tumors and non-solid type tumors.

21. The use as claimed in claim 18 or 19, wherein said cancer is selected from the group consisting of ovarian cancer, breast cancer, endometrial cancer, esophageal cancer, small and non-small cell lung cancer, cervical cancer. , colorectal cancer, neuroblastomas and glioma.

22. The use as claimed in claim 18 or 19, wherein said cancer is selected from the group consisting of myelodysplastic syndrome, acute myelogenous leukemia and chronic myelomonocytic leukemia.

23. The use of isolated topotecanpentahydrate monohydrochloride according to any of claims 1-8 in the preparation of a medicament for improving one or more symptoms associated with cancer.

24. The use of the pharmaceutical composition according to claim 9 for preparing a medicament for improving one or more of the symptoms associated with cancer.

25. The use as claimed in claim 23 or 24, wherein the one or more symptoms associated with cancer is selected from the group consisting of pain, fatigue, insomnia, interference with daily activity, dyspnea, chest pain, hemoptysis and hoarseness. 26.- Topotecanpentahydrate monohydrochloride isolated according to any of claims 1-8 for use in therapy.