MXPA00004456A - Pharmaceutical compositions containing cyclodextrins and taxoids - Google Patents

Abstract

The present invention relates to water-soluble solid pharmaceutical compositions and their solutions in aqueous solvents, said compositions containing a) as an active ingredient a finely dispersed large surface area amorphous preferably lyophilized taxoid such as paclitaxel or docetaxel, their salts or their polymorphic hydrates or solvates such as solvates formed with ethanol and b) finely dispersed large surface area amorphous preferably lyophilized acetyl-&ggr;-cyclodextrin or hydroxy-propyl-&bgr;-cyclodextrin (cyclodextrin) whereby the weight ratio of said taxoid:said cyclodextrin ranges between 1:25 and 1:400;c) and optionally other water-soluble auxiliary materials usual in pharmaceuticals for parental purposes.

Description

INJECTABLE PHARMACEUTICAL COMPOSITIONS CONTAINING C I CLODEXTRINS DESCRIPTIVE MEMORY The present invention relates to new solid and water-soluble pharmaceutical compositions and their aqueous solutions intended for parenteral administration, containing taxoids and certain substances and which are free of noxious solvents and / or detergents. In particular, it relates to new solid and water soluble pharmaceutical compositions and to their solutions in aqueous solvents, compositions which A) as an active ingredient contain a taxoid such as paclitaxel and docetaxel, and in the same way in the form of their salts or its polymorph hydrates or solvates, such as, for example, solvates formed with ethanol; and B) contain a ce 111 -? - cic 1 ode xti na or hydroxypropyl-β-cyclodextrm ("ciclodextpna") of great surface area being the weight ratio between the mentioned taxoid and the mentioned "ciclodextpna" from 1:25 to 1: 250; C) and that eventually contain other auxiliary materials soluble in water and usually used in medicines intended for parenteral administration. The invention also relates to the preparation and use of these injectable pharmaceutical compositions. Both the descriptive memory and the indications are used the following definitions: Paclitaxel = taxal A; docetaxel = [N - must z 011 - N - t e r bu t ox i ca rb on 11) - 10-deacet? l-pacl? taxel; "aqueous solvents" = water of injectable quality or an aqueous solution containing a dissolved isotonizer in an amount and concentration effective as to isotonize said aqueous solution, such as, for example, sodium chloride, glucose; "amorphized" = that presents an amorphous structure when analyzed by r a and o s X CD = ci c 1 odex t r i na? - ciclodextpna = cic 1 orna 11 ooctaosa ß-cyclodextrin = ci c 1 orna 11 ohep taosa Ac? CD = a ce 111 -? - cic 1 odex trina HPßC = hydr ox ipr op 11 - ß - cic 1 odextrin (approximately 2 a approximately 8 groups of hi dr ox ipr op 11 or per CD unit) DIMEß = h ep takis - 2, 6 - di - o - me 111 - ß - cic 1 odex tri na (average) Taxoid is the generic name for the paclitaxel related substances structure lmen te with him. Pacitaxel is a compound that is extracted primarily from the bark of Taxus brevifolia and is known for its activity at a significant level, as it acts as a mitotic poison and as a potent inhibitor of cell replication. It is also known to have a low solubility in water of about 0.0005 mg / ml at room temperature and to be unstable in solution during storage (Anal.Chem 1997. 69, pages 72 to 77) as a consequence of the solvolysis of its ester bond that causes the loss of cytotoxic activity (Biochem.

Biophys. Res. Comm. 1982. 105, pages 1082-1089). There is a report on precipitation during the clinical use of infusions with a formulation based on a cremophor EL / ethanol vehicle (Am. J. Hosp. Pharm. 1993. 50. pages 2518-2521). The solutions containing mixtures of cremophor EL / ethanol exhibit a certain opalescence which, added to the possible aggregation of paclitaxel during storage, can result in a slight turbidity of the formulation (Am. J. Hosp. Pharm. 1992. 49., pages 1716-1719). It is also known that paclitaxel binds to the plastic or glass surfaces of the containers, thus varying its concentration during the storage of concentrated solutions and during infusion upon contact with the surfaces of the infusion set (J. Pharm, Sci. 85, pages 29-31). Cremofor EL has been implicated in some adverse reactions (hypertension, histamine release) during intravenous treatment, which is why in the past decade various attempts have been made to develop new drug delivery systems. . These attempts include the development of liposomes, the mi cro emul si uno s type of oil in water and the systems of release based on 1 ve nte / tensoactiv vo such as the use of micromicela composed by phosphatidyl-ta ta no 1 ami na s, ene ap s ul aci on is liposomes, mu liposomes 1111 ame 1 ares (PCT Intl. Appl. WO 9426253) which are characterized by increasing the solubility of various drugs including paclitaxel. It has also been reported on the preparation of my 1 st asys ubmi cr oemu 1 1 s stable tablet containing paclitaxel and where the vehicle is composed of oil, po 11 eti 1 en g 11 co 1 attached to fat and some other polar components (USP 5478860). Nanoparticle formulations containing paclitaxel are described in combination with Tween-20 and zirconium oxide, and the nanoparticles are prepared by grinding all the components together at high energy and for eleven days (US Patent No. 64832). When paclitaxel is formulated in the form of a solution in the organic solvents ethanol and chaste oil, it is administered as a water-in-water emulsion and diluted rapidly in the blood, which is a medium aqueous rich in hydrophobic domains and provided with lipids and proteins. Paclitaxel passes through the hydrophobic medium of the plasma membrane when entering and leaving the cells by diffusion. In non-polar solvents such as trichloroethane, concentration-dependent autoaggregation of paclitaxel does not occur and a precipitate is obtained that is stabilized by the effects of four functional groups (OH- and NH-) of the molecule with hydrogen bonds. These groups with hydrogen bonds can coordinate simultaneous interactions between the molecules on both major faces of paclitaxel and thus propagate the aggregation to obtain very ordered solid particles (S athy ama n ga 1 am, V. B a 1 as ub r ama niany col J Pharm, Sci. 1994. 83, pages 1470-1475). The propensity of paclitaxel to a u t t a g r e g e s depending on the solvent and concentration has been an obstacle to efforts to formulate this drug poorly soluble in pharmaceutically acceptable excipients intended for clinical administration. It is also known that docetaxel, a taxoid s emi s i n t e t i c o, is highly lipophilic and more soluble in water than paclitaxel (USP 4814470). The docetaxel for injectable concentrate that is purchased in stores is a sterile solution of the drug in polysorbate 80, accompanied by a diluent of ethanol 13% (w / w) in water for injection. The maximum concentration of the drug that could be used was 0.3 to 0.9 mg / ml. Concentrations higher than 0.9 mg / ml should be avoided due to precipitation problems. The hydrophobic reactions in s ib 111 da d associated with polysorbate 80 can cause problems for commercial formulations. Various formulation attempts have been made, including the use of vehicles with hydrophobic characteristics; These include lipos, polymers, c odi ods 1 and emulsions (Revie ed m Ph a rm Re s .1987, 4., pages 162-165, and Cancer Res.1993, 54., pages). 5877-5881). Most of these types of formulations appear to show initially an acceptable ubiquity of the taxoid, but at high concentrations of the drug, physical instability is imposed and the taxoid usually precipitates implicitly from c i b 1 e. In most of the vehicles, the taxoid is formulated in the millimolar concentration range that is comparable to the concentrations at which the taxon was observed, which culminates in the precipitation. The modification of the taxoi interactions of ta xo i in solution was achieved both by synthesis of congeners with substitutes and new entities that did not have hydrogen bonding and by design of formulations with specific additives to reduce the tendency of the precipitation of the drug, obtaining more stable and effective forms of the taxoid. Other suggestions on this topic are based on the interaction between the taxoid (mainly paclitaxel) and the c i c 1 ode x t r i na s. By studying the mobility of the taxoid in thin-layer chromatography and in the presence of dextrin cycle (Int.J. Pharm. 1994. 108, pages 64 to 75) it was first discovered that the interaction between the taxoid and the cyclodexdex na was very weak. Later (AU-B 35544 / 93,645,927) a modest increase in the solubility of the taxoid was observed by using unsubstituted cyclodexins and the so-called β-cyc 1 or xtri na s-r ami fi dates that are modified enzymaticallyA considerable increase was observed when an aqueous solution of methylated β-cyclodextrins was used as the effective solubilizer of paclitaxel (PCT WO 94/26728), using a combination of methylated β-cyclodextrin and ethanol to prepare solutions of paclitaxel from 1 to 4 mg / ml (European patent No. 788373). These concentrates of the taxoid do not precipitate if diluted to a certain limit they avoid the use of toxic detergents. It was also suggested to use 2, 6 - di - o - me ti 1 - ß - cic 1 or xtri na as a more effective ubiquity of paclitaxel (EPA 0639380) and detailed results of its potency were published. so 1 ub 11 iz an te (J. Pharm.Sci.84.10, pages 1223-1230, 1995). However, there are certain reservations regarding the use of methylated ß-cyclodextrins in injectable because of their surfactant properties, their affinity for cholesterol and other lipid components of the cell membrane even at low concentrations and doses. The use of branched cyclodextrins in a thio function to solubilize anti-cancer taxcides has been described (for example, docetaxel and paclitaxel, see PCT WO 95/19994), but without giving details regarding an increase in solubility. , to stability and toxicity. Such formulations provide a significant increase in the water solubility of paclitaxel. However, the drug can precipitate when the necessary dilution is performed for parenteral application (0.3 to 1.2 mg / ml). The present invention aimed to further improve both the solubility of the taxoids in injectable formulations and the stability of the systems whose drug is a taxoid and which are intended for parenteral administration, decreasing as much as possible the toxicity of the auxiliary materials that are used for formulation purposes. The present invention is based on the discovery that acetylated γ-cyclodextrin and hydroxy-or op 11-ß-cyc 1 or xtri na exert a positive effect on the prolongation of the supersaturation state of paclitaxel and docetaxel dissolved, thus avoiding premature precipitation without the need to use ethanol as a co-option 1 ve nte. This discovery was a surprising fact because the γ-cyclodextrin and its hydroxyriphenyl derivatives, known to possess the largest cavities among the CDs, were considered the least adequate to solubilize and complex the paclitaxel (Ins. J. Pharm. 133, 191-201, 1996). This was confirmed by us in studies in which the equilibrium solubility of paclitaxel was recorded as a function of the concentration of the aqueous solutions of chemically modified β-cycloses or xtri na s, and in which practically no effect was detected. 1 ub 111 useful, even at high concentrations of cyclo 1 or xtri na. See table 1: solubility of paclitaxel as a function of the concentration of acetyl-β-cyclodextrin.

Table 1 The solubility in water of paclitaxel at room temperature is approximately 0.5 ug / ml, whereby a concentration of dissolved paclitaxel of 170 ug / ml as achieved in 40% solution of? -cyt 1 or xtrine acetylated represents an increase in solubility of approximately 340 times. However, the data indicated above are poor when compared to those obtained in a 40% w / v aqueous solution of DIMEβ in which approximately 800-1000 ug / ml of paclitaxel is dissolved. Similar poor results are obtained by using HPβCD as s or 1 ub i 1 i z an t e. This value is far from the desired value and corresponds to that of a therapeutic dose of paclitaxel, and the use of such dosage would require the administration of more than 70 grams of c i c 1 or of x t r i n a with the paclitaxel dosage unit of 30 mg. The object of the present invention is a process for preparing pharmaceutical compositions for parenteral use in the solid state and instantly soluble in water, and also solutions thereof in aqueous solvents containing ace 111 -? - cic 1 or xtri na or hi dr ox i - pr op 11 - ß-cic 1 or xtri na (hereinafter referred to as "cic 1 ode xtrinas") procedure comprising a) dissolving the taxoid, preferably paclitaxel or docetaxel, or its salts or hydrates in ethanol and then carrying out one of the following steps: i) adding the solid "cyclodextrm" and optionally other water-soluble auxiliary substances usually used in medicines for parenteral use, dissolving the mixture in an aqueous solvent and lyophilizing to obtain a solid or II) adding the solid, surface-active, amorphous and preferably freeze-dried "cyclodextrin" and optionally other water-soluble auxiliary substances usually used in medicines for parenteral use, evaporate the solvent and dry to obtain a solid or III) mix the solution with the solid, high surface area, amorphous and preferably lyophilized "cyclodextrin" (and possibly other auxiliary substances soluble in water and usually used in medicines for parenteral use ) and then dissolve with an aqueous solvent eventually in the presence of an effective amount a of an isotonizing additive to obtain a solution containing A) said taxoid as active ingredient and B) said "cyclodextrm" and C) and also other auxiliary substances soluble in water and usually used in medicines for parenteral use being the ratio weight between the taxoid and the "ciclo-dextpna" from 1:25 to 1: 250; and optionally, b) when step i) or ??) is carried out, dissolving the solid in an aqueous solvent to obtain a parenteral solution with a desired and suitable concentration and ready to be used directly for medical treatment. According to the invention, paclitaxel is used in its hydrolyzed polymorph form or in its solvated form as, for example, that of the solvate formed with ethanol. In a preferred embodiment of the invention, paclitaxel is used as the active ingredient together with a 1 to 100 weight ratio of 1: 100 to 1: 150. In another embodiment of the invention, the use of docetaxel with HPβCD in a weight ratio between 1:25 and 1: 100 is preferred.

In carrying out the process of the invention, any of the following compounds can be used as a solvent or aqueous diluent: water of injectable quality, an aqueous solution of an isotonizing additive such as sodium chloride, glucose, mannitol, dextrose. The latter solutions must contain said ingredients in an amount such that it is effective to isotonize the aqueous solution under the given conditions. Therefore, the concentrations that are usually adequate for the systems that are used in pharmaceutical solutions should be modified a bit due to the presence of the employee and the taxoid employed. Consequently, concentrations of approximately 0.9% w / v sodium chloride, or approximately 5% w / v glucose should be optimized for the specific composition, depending on the taxoid used and the quantity and quality of the CD employee. Other objects of the present invention are pharmaceutical compositions which, as active ingredients, contain any of the products prepared according to the process of the invention.

Another object of the present invention are the solid and water-soluble pharmaceutical compositions and their solutions in aqueous solvents, compositions which A) as the active ingredient contain a finely dispersed taxaid with a large surface area such as paclitaxel and docetaxel, optionally in the form of its salts or its polymorph hydrates or solvates such as, for example, solvates formed with ethanol; and B) contain a finely dispersed and high surface area α-α-C ti-C 1-1 or X-thia or hydroxypropyl-β-cyclodextrin ("cyclodextrin") - the weight ratio between the aforesaid taxoid and the aforementioned "cyclodextrin" being from 1:25 to 1:50; C) and that eventually contain other auxiliary materials soluble in water and usually used in medicines intended for parenteral administration. The preferred compositions of the invention contain paclitaxel as the active ingredient and a cyclodextrin in a weight ratio between 1: 100 and 1: 150. Other preferred compositions of the invention are the combinations of docetaxel and h i d r ox i -op r op 11 - ß - c i c 1 ode x t r i na in a weight ratio between 1:25 and 1: 100. Other objects of the present invention are methods for preventing self-aggregation and premature precipitation of a taxoid such as paclitaxel and docetaxel and their solvate and hydrate salts in aqueous solutions, and to prolong the dissolution state of the drug by the use of taxoids in the form of pharmaceutical compositions according to the present invention and detailed above. Another object of the present invention is the method for the treatment of undesired cell proliferation which employs effective amounts of the pharmaceutical compositions according to the invention and described above in more detail. Paclitaxel solutions of immediate employment remain physically unchanged for a reasonable period of time. For intravenous treatment it is generally necessary that the solutions employed be physically stable for at least 6 hours. When the compounds according to the present invention are dissolved in aqueous solutions, reconstituted solutions are obtained which are stable for at least 6 to 8 hours. In the case of the solutions of the com pations of pa c 1 i t a xe 1 / Ac? CD and docetaxel / Ac? CD or HPßCD physical stabilities have been measured for more than 24 hours of time. According to this method a parenteral dosage form is provided which contains the pharmaceutical composition and which is administered to a patient in need of such treatment. The dosage units of 100 mg of taxoid can be prepared in lyophilized form. These are diluted to obtain ready-to-use solutions that can be used, for example, for intravenous treatment. According to the necessary and applicable treatment, the specific needs of the patient can be administered several units of 100 mg in order to reach 1 effective dose corresponding to the desired amount, generally expressed in mg / m2 of body surface area. Thus, for example, the recommended dose of paclitaxel between 135 and 250 mg / m2 of body surface area can be achieved. The drug can be used effectively by intravenous administration, intravenous 11 on ea 1, intramuscular or subcutaneous depending on the type of cancer to be treated and the taxoid and cyclodextrin that has been selected for employment. Treatment results that can be obtained are better than those of the known therapies because the dosage form has a considerably lower toxicity than the vehicles contained in the compositions; known and used to date. It is also not necessary to subject the patient to a p um e d i c a on with spheroids at n t i h i s t and H2 receptor antagonists before the administration of paclitaxel or docetaxel to prevent severe reactions of h i p e r s i n i i i d i. In the examples described below, details of the invention are illustrated without the intention of limiting the scope of protection.

I. Preparation instructions Example 1: Preparation of solid combinations and r e c on s 111 u ib 1 s of pa 111 a 1 / ce 111 -? - c i c 1 ode x t r i n a by drying. 3 mg of paclitaxel (dissolved in 0.3 ml of ethanol) to 500 mg of acetyl -? - c i c 1 or x t r i n a powder (lyophilized from the aqueous solution). This mixture is kept under vacuum for 18 hours and on phosphorus pentoxide to remove the ethanol. Portions of this ethanol-free powder blend are dissolved in 5, 4, 3 and 2 ml respectively, of 5% aqueous solutions of glucose. Table 2 shows the physical stability of these reconstituted solutions.

Table 2 my aggregates of glucose solution at 5 5 mi 4 mi 3 mi 2ml Paclitaxel final 0.6 0.75 1.0 1.5 mg / ml Ac? Final CD mg / ml 100 125 167 250 Stability evaluated > 120 > 48 > 48 > 48 after 72 hours visually in the precipitation occurred hours paclitaxel 0.576 mg / ml (HPLC) This experiment is repeated with smaller quantities of a c e t i 1 -? - c i c 1 ode x t r i n a. 3 mg of paclitaxel (dissolved in 0.3 ml of ethanol) are added to 450 mg, 400 mg or 350 mg of freeze-dried samples of α 1? -cyc 1 or xtriα, then the mixture is kept under vacuum during 18 hours and phosphorus pentoxide to remove the ethanol. Each of these combinations is dissolved in 5, 4, 3 and 2 ml of a 5% aqueous solution of glucose. Tables 3, 4, and 5 summarize the compositions and physical stabilities of these reconstituted solutions of paclitaxel that have been prepared according to Example 1 and employing different amounts of acetylcholine.

Table 3 Table 4 Table 5 Example 2: Preparation of a paclitaxel formulation with a nominal concentration of 0.6 mg / ml paclitaxel. 6.5 g of a c e t i 1 -? - c i c 1 o de x t r i n a amorphized with 3 ml of a solution of paclitaxel with a concentration of paclitaxel of 10 mg / ml (corre sponding to 30 m paclitaxel). Immediately 50 ml of a 5% dextrose solution is added to the moistened mixture and the composition is stirred until a clear solution is obtained. After filtering the solution through a 0.2 um filter membrane, the solution concentration of dissolved paclitaxel was determined by HPLC, obtaining a value of 0.55 ± 0.05 mg / ml. The solution can be stored at room temperature, under normal light conditions and in glass containers for at least 6 hours without noticeable opalescence and / or particle formation. A new HPLC analysis of paclitaxel dissolved after 6 hours of storage shows that the concentration of dissolved paclitaxel has not decreased. Example 3: preparation of a paclitaxel formulation with a nominal concentration of paclitaxel of approximately 0.3 mg / ml 6.5 g of acetyl 1-γ-cyclodexid previously amorphized with 3 ml of a paclitaxel solution are moistened with a paclitaxel concentration of 10 mg / ml (corresponding to 30 mg of paclitaxel). Immediately add 100 ml of a 5% dextrose solution to the moistened mixture and stir until a clear solution is obtained. After filtering the solution through a 0.2 um filter membrane, the concentration in this solution of the paclitaxel dissolved by HPLC is determined, obtaining a value of 0.27 ± 0.03 mg / ml. The solution can be stored at room temperature, under normal light conditions and in glass containers for at least 12 hours without noticeable opalescence and / or particle formation. A new HPLC analysis of paclitaxel dissolved after 12 hours of storage shows that the concentration of dissolved paclitaxel has not decreased over 12 hours. Example 4: Preparation of a docetaxel formulation with a nominal concentration of docetaxel of 0.5 and 1 mg / ml. 100 mg of a ce t i 1 -? - c i c 1 ode x t r i na amorphized with 0, 1 ml of a docetaxel solution with a concentration of docetaxel of 20 mg / ml (corresponding to 2 mg of docetaxel). To the samples of this moistened solid mixture immediately add 1 or 2 ml of a 5% w / v aqueous dextrose solution and stir the mixture until a clear solution is obtained. The concentrations of docetaxel dissolved in the solution according to example 4 are 1 and 0.5 mg / ml, respectively. The solutions can be stored at room temperature, under normal light conditions and in glass containers for at least 24 hours without noticeable opalescence and / or particle formation. The composition of both solutions referred to a dosage unit of 20 mg of docetaxel is as follows: 1000 mg of Ac? CD 20 mg of docetaxel 1 ml of ethanol 20 ml or 40 ml of 5% dextrose Example 5 : preparation of a docetaxel formulation with a nominal concentration of docetaxel of 0.75 mg / ml using hydroxypropyl-β-cyclodextrin (HPβCD) 200 mg of HPβCD is wetted with 0.15 ml of a stored solution of docetaxel with a concentration of docetaxel of 20 mg / ml (corresponding to 1.5 mg of docetaxel). To this moistened mixture 2 ml of a 5% aqueous dextrose solution are immediately added and the mixture is stirred until a clear solution is obtained. The concentration of docetaxel dissolved in the solution according to example 5 is 0.75 mg / ml. The solutions can be stored at room temperature, under normal light conditions and in glass containers for at least 24 hours without noticeable opalescence and / or particle formation. The composition of the solutions referred to a dosage unit of 20 mg of docetaxel is the following: - 2670 mg of HPβCD - 20 mg of docetaxel 1 ml of ethanol - 27 ml of 5% dextrose Example 6: preparation of a product - 11 of 111 binary passage of pac 111 ax 1 / ace 111 -? - cic 1 or of xtrin To 5.0 g of ace 111 -? - cic 1 or of amorphized xtrine are added 30 mg of paclitaxel dissolved in 3 ml of ethanol. To this wet powder is added 2 ml of ethanol and then it is dissolved in 50 ml of distilled water to obtain a clear solution with a nominal concentration of paclitaxel of 0.6 mg / ml. This solution is rapidly frozen in dry ice and lyophilized to obtain a white lyophilized product with a content of 0.6 + 0.05% by weight of paclitaxel. This lyophilized product can be easily reconstituted to its original volume in solution if 50 ml of a 5% aqueous solution of glucose is added. A clear solution is obtained with a paclitaxel concentration of 0.6 mg / ml. The concentration is measured by HPLC after filtering the test solution through a 0.2 μm membrane. The content of paclitaxel after preparation is: 0.513 ± 0.07 mg / ml * after 25 hours of storage is: 0.556 + _ 0.01 mg / ml (* the difference between the nominal concentration and the measured concentration of paclitaxel is due to the volume expansion of the lyophilized product). Example 7: preparation of a product c o-11 e f 111 binary b c o d t a xe 1 / a ce 111 -? - c i c 1 odex t r i n a. To 400 mg of a-111-? - c i c 1 ode x t r i n amorphisada add 10 mg of docetaxel dissolved in 0.5 ml of ethanol. This wet powder is dissolved in 8 ml of distilled water to obtain a clear solution with a nominal concentration of docetaxel of 1.25 mg / ml. This solution is rapidly frozen in dry ice and lyophilized to obtain a white lyophilized product with a content of 2.25 ± 0.1% docetaxel. 50 mg of this solid lyophilized product can be easily dissolved in 1 ml of a 5% aqueous solution of glucose to obtain a clear solution with a content of docetaxel of 1.13 mg / ml (determined by HPLC). The reconstituted solution can be stored at room temperature, under normal conditions and in a glass container. When measuring the concentration by HPLC after 21 hours of storage, a value of 1 is obtained, 15 ± 0.02 mg / ml. Even after 72 hours of storage, no opalescence or the formation of solid particles in the solution is observed. Example 8: preparation of a co-freeze-dried product of pa 111 ax 1 / a 111 -? - c i c 1 ode x t r i n a / glucose. Dissolve 30 mg of paclitaxel in 3 ml of ethanol. This solution is added to 5.0 g of acetyl -? - c i c 1 or d e x t r i n a amorphisade. To this wet powder, add 2 ml of ethanol and then dissolve it in 50 ml of a 5% aqueous solution of glucose. A clear solution is obtained with a nominal concentration of paclitaxel of 0.6 mg / ml. This solution is frozen on dry ice and lyophilized to obtain a white lyophilized product with a content of 0.42 ± 0.01% paclitaxel. This lyophilized product can be easily reconstituted to its original volume if 50 ml of distilled water is added. A clear solution with a nominal concentration of paclitaxel of 0.6 mg / ml is obtained. The reconstituted solutions are stored at room temperature, under normal conditions and in closed glass containers. The concentration of paclitaxel during storage is measured by HPLC after filtering the test solutions. The content of paclitaxel immediately after preparation is: 0.530 ± 0.08 mg / ml * after 25 hours of storage is: 0.541 ± 0.05 mg / ml (* the difference between the nominal concentration and the measured concentration of paclitaxel is due to the volume expansion of the lyophilized product).

Example 9: Preparation of a co-lyophilized product of do c e t ax 1 / a c e 111 -? - c i c 1 ode x t r i n a / glucose. To 400 mg of a-111-? - c i c 1 o of x t r i n amorphisada add 8 mg of docetaxel dissolved in 0.4 ml of ethanol This wetted powder is dissolved in 8 ml of an aqueous solution of glucose at 5% w / v. A clear solution with a nominal concentration of docetaxel of 1 mg / ml is obtained. This solution is frozen in dry ice and lyophilized to obtain a white lyophilized product with a docetaxel content of 1%. 100 mg of this freeze-dried solid product free of ethanol can be easily reconstituted in 1, 2 or 4 ml of distilled water to obtain clear solutions with nominal concentrations of docetaxel of 1, 0.5 or 0.25 mg / ml, respectively. Table 6 shows the physical stability of the docetaxel solutions during a 21-hour storage at room temperature and in a closed glass container, which stability is determined by measuring the concentration of docetaxel dissolved at different nominal concentrations by HPLC.

Table 6 EXAMPLE 10 Preparation of a binary co-lyophilized product of do cetaxe 1 / hi dr ox ipr op i 1 - ß - ci clodext quina (HPβCD) To 300 mg of HPβCD there is added 6 mg of docetaxel dissolved in 0.3 ml of ethanol. This wet powder is dissolved in 6 ml of distilled water to obtain a clear solution with a nominal concentration of docetaxel of 1 mg / ml. This solution is rapidly frozen in dry ice and lyophilized to obtain a white lyophilized product with a content of 2% w / w docetaxel. 50 mg of this solid lyophilized product can be easily dissolved in 1 or 2 ml of a 5% w / v glucose aqueous solution to obtain clear solutions with docetaxel contents of 0.97 and 0.59 mg / ml, respectively ( determined by HPLC).

The reconstituted solutions are stored at room temperature, under normal conditions and in a glass container. When measuring docetaxel concentrations by HPLC after 21 hours of storage, values of 0.95 ± 0.05 and 0.49 ± 0.05 mg / ml are obtained. Example 11: prolongation of the dissolved state and s ta r e s t u r o 'of the paclitaxel by co-evaporation. 30 mg of paclitaxel are dissolved in 6 ml of ethanol and the solution is intensively mixed with 5 g of α-111-γ-c-odextrone. 3 ml of ethanol are added and the mixture is stirred for 5 minutes at room temperature. The ethanol content is then removed in a stream of nitrogen using a rotary evaporator fitted with a vacuum. The resulting white solid is then dissolved in 5 ml of deionized water to form a slightly opalescent solution that is immediately frozen with dry ice and lyophilized. The resulting lyophilized product is an amorphous and instantly soluble powder, which is conveniently reconstituted to a clear solution by the addition of water for injection or a 5% aqueous solution of glucose. The reconstituted solution has a concentration of dissolved paclitaxel of 0.3-0.6 mg / ml and remains stable for at least 24 hours at room temperature. Example 12: parenteral composition for intravenous application. To 5.0 g of amorphized and large surface area, 100 mg of paclitaxel dissolved in 10 ml of ethanol are added. To this wet powder is added 10 ml of ethanol and then it is dissolved in 80 ml of distilled water to obtain a clear solution with a nominal concentration of paclitaxel of 1.25 mg / ml. This solution is quickly frozen in dry ice and lyophilized to obtain a white lyophilized product with a content of 0.7 ± 0.05% by weight of paclitaxel. This lyophilized product can be easily reconstituted to a volume of 100 ml using an aqueous solution at 5% w / v dextrose. A clear solution is obtained, with a paclitaxel concentration of 1.0 mg / ml and ready to be applied intravenously.

Claims (12)

1. Process for the preparation of instantly soluble solids for pharmaceutical use and their solutions in aqueous solvents, characterized by a) dissolving in ethanol a taxoid, preferably paclitaxel or docetaxel, or a salt or hydrate or solvent thereof and subsequently performing any of the following steps: i) add a solid 1-cyclodextrin derivative ie ace 111 -? - cic 1 odextrin or hydroxy-p r or i-1-ß-cic 1 odextrin (and optionally other common soluble auxiliary materials) in pharmaceutical products for parenteral purposes), dissolve the mixture in an aqueous solvent and lyophilize to obtain a solid; or 11) adding a lyophilized solid or cyclic derivative, i.e., ace 111 -? - cyc 1 or xtri na ohydroxy-pr op 11-ß-cyc 1 or xtrin (and op cit ion other usual soluble auxiliary materials in pharmaceutical products for parenteral purposes), evaporate the solvent and dry to obtain a solid; or III) mixing the solution with a large surface area preferably cyclo 1 or freeze-dried xtrine solids ie ace 111 -? - cic 1 or xtrinaohi dr ox i - pr op i 1 - ß - cic 1 odex trinay op ci on a lme other auxiliary materials soluble in pharmaceuticals for parenteral purposes and subsequently dissolving with an aqueous solvent op citionately in the presence of an isotonized additive to obtain a solution; containing: A. as an active ingredient the taxoid and B. the derivative of cic 1 ode xtri na and C. opc i ona lmen te other soluble auxiliary materials usual in pharmaceutical products for parenteral purposes, by means of which a ratio in taxoid weight: cic 1 odex tri na ranges from 1:25 to 1: 400; -with the restriction that when the hydrotext i -pr op 11 - ß- cic 1 or xtri na is used the taxoid can be only docetaxel in a weight ratio of 1:25 to 1: 100 taxoi of: cic 1 or - of xtri na and op ci ona lmen teb) when the steps) or 11) were used to dissolve the solid in an aqueous solvent, in this way obtain a solution for direct medical treatment.

2. Process according to claim 1, characterized by using as the aqueous solvent or diluent any of the following: water of injectable quality, an aqueous solution of isotonized additive such as sodium chloride, glucose or dextrose comprising these ingredients in an effective amount to isotonize the aqueous solution

3. Process according to any of claims 1 and 2 characterized by using as the component of ci c 1 or xtri na any of the following: a ce 111 -? - cic 1 ode xtri na having a degree of acetylation between approximately 2 a Approximately 12 acetyl groups per ring of cyc 1 or xtrine, ace 111 - β-cyc 1 or xtri na having an acylation degree of about 8 acetyl groups per cyc 1 or xtrine ring.

4. Process according to any of claims 1 to 3 characterized by using paclitaxel in its hydrolyzed polymorphic form or in its solvent form such as ethanol solvate.

5. Process according to any of the rei indications 1 and 2 characterized to be used as the component of cyc 1 or of xtri na hi dr ox i -pr op 11 -ß-cic 1 or xtrin, preferably any of the following: hi dr ox i -pr opox i - ß - cic 1 ode xtri na having a degree of substitution between approximately 2 to approximately 10 groups hi dr ox ipr op 11 or per ring of cic 1 ode xtri na, hi dr ox i - pr op 11 - β-cyc 1 odextrin having a degree of substitution between about 4 to about 6 hydroxypr or 11 groups or per cyc 1 or xtrin ring.

6. Instantly soluble solids products for pharmaceutical products and their solutions in aqueous solvents, the compositions c omp a) as an active ingredient a finely dispersed large surface area amorphous, preferably lyophilized taxoid, preferably paclitaxel or docetaxel, its salts or its polymorphic hydrates or solvents such as solvates formed with ethanol and b) a solid amorphous of large finely dispersed surface area preferably derived from freeze-dried xtrin cyc 1, ie acetyl-β-cyclodextrm or hydroxy-propyl-β-cyclodextrin, by means of which the weight ratio of the taxoid: cyc 1 or xtrin ranges between 1:25 and 1: 400 with the restriction that when the hydroxy-pr op 11-ß-cic 1 or xtrin is used the taxoid can be only docetaxel in a weight ratio of taxoid: cic 1 or xtrin of 1 : 25 to 1: 100; c) and optionally other soluble auxiliary materials used in pharmaceutical products for parenteral purposes.

7. Product according to claim 6, characterized in that it comprises paclitaxel and a c and 111 -? - c i c 1 or d e x t r i n a in a weight ratio of 1: 100 to 1: 250.

8. Instantly soluble solids for pharmaceutical use and their solutions in aqueous solvents, the compositions comprise any of the products prepared according to the processes according to claims 1 to 5.

9. Method for the prevention of self-aggregation and premature precipitation of a taxoid of the group of placitaxel and docetaxel and its salts, solvates and hydrates in aqueous solutions and prolong the dissolved state s or resaturation of the drug when using the taxoids in the form of products of according to any of claims 6 to 8.

10. Method of treatment of proliferation of unwanted cells by using effective amounts of pharmaceutical compositions according to any of claims 6 to 8, characterized by administering to a patient in need of such treatment a dosage form containing the pharmaceutical composition according to any of claims 6 to 9 containing an effective amount of a taxoid preferably from the group paclitaxel and docetaxel and their salts and solvates and hydrates.

11. Method according to rei indication 10, characterized by administering to a patient in need of such treatment a dosage form comprising paclitaxel, its salts, solvates or hydrates and acetyl 1-γ-cyclodextrin in a weight ratio of 1: 100 to 1: 250.

12. Method according to claim 10, characterized by administering to a patient in need of such treatment a dosage form comprising docetaxel, its salts, solvates, or hydrates and hydroxy-propyl-β-cyclodextrin in a weight ratio of 1: 25 to 1: 100