MXPA98009888A - Pharmaceutical compositions of droloxif - Google Patents

Abstract

Compositions of matter comprising droloxifene or a pharmaceutically acceptable salt thereof and a cyclodextrin, the preferred cyclodextrins are SBECD and HPBCD the composition may comprise a dry mixture, a dry inclusion complex or an aqueous solution, the citrate salt is aqueous; citrate is the preferred

Description

DROLOXYPHENE PHARMACEUTICAL COMPOSITIONS BACKGROUND OF THE INVENTION This invention relates to pharmaceutical compositions of droloxifene. In U.S. Patent 5,047,431 (the disclosure of which is incorporated herein by reference) droloxifene is described as an antitumor agent, particularly it is also useful for the relief of bone diseases caused by deficiency of estrogens or similar substances which is observed at often in women after menopause or in those to whom the ovaries have been removed (U.S. Patent No. 5,254,594, the disclosure of which is incorporated herein by reference). reference). The formulation of pharmaceutical dosage forms is often hampered by poor solubility and / or > aqueous stability of the drug of interest which, in turn, severely limits its therapeutic application. Conversely, By increasing the solubility and stability of the drug by an appropriate formulation, an increased therapeutic efficiency of the drug can be brought about. Various methods have been used to increase the solubility and stability of a drug, such as the use of organic solvents, emulsions, liposomes and micelles, chemical modifications and complexation of the drug with appropriate complexing agents, such as the cyclodextrins. Cyclodextrins, sometimes called Schardinger dextrins, were first isolated by Villiers in 1891 as a digest of Bacillus amylobacter in potato starch. The fundamentals of the chemistry of cyclodextrins were established by Schardinger in the period 1903-1911. However, until 1970, only small amounts of cyclodextrins could be produced in the laboratory and the high production cost prevented the use of cyclodextrins in the industry. In recent years, extraordinary improvements in the production and purification of cyclodextrins have been achieved and these have become less expensive, thus making possible the industrial application of cyclodextrins. Cyclodextrins can form inclusion complexes with a large variety of hydrophobic molecules by absorbing a complete molecule ("host molecule") or part of it in the hollow cavity. The stability of the resulting complex depends on how the host molecule fits into the cyclodextrin cavity. The following published patents disclose the use of cyclodextrins to stabilize pharmaceutical compounds: WO 9311757, WO 9002141, WO 9416733 and EP 658348.

The following articles describe the use of cyclodextrins to stabilize compounds undergoing an isomerization reaction: F. Hirayama et al., J. Pharm. Sci., 81, 817 (1992), G. Duveneck et al., Phys. Chem., 93, 7,166 (1989) and P. Bortolus et al., J. Phys. Chem., 91, 5,046 (1987). The following are general articles on solubilization and stabilization of pharmaceutical compounds using cyclodextrins! T. Loftsson and -others, J. Pharm. Sci., 85, 1017 (1996), H. Helm et al., Eur. J. Pharm. Sci., 3, 195 (1995), B.W. Muller et al., In: Proc. 4th Int. Symp. Cvclodextrins. 369-382 (1988), E. Pop et al., Pharm. Res. , 8, 1044 (1991), B. Gorecka et al., Int. J. Phar. , 125, 55 (1995) and M. Brewster et al., Pharm. Res. , 8, 792 (1991). The following book discusses the preparation procedures of compound-cyclodextrin complexes! F. Hirayama et al., Cyclodextrins and their Industrial Uses, D. Duchene edition, Editions de Sante, Paris, 1987, chap. 4, p. 131-172. Although cyclodextrins have been used to increase the solubility, dissolution rate and stability of a large number of compounds, it is also known that there are many compounds in which the formation of complexes with cyclodextrins is not possible or does not provide advantages (J.

Szejtli, Cyclodextrins in Drua Formulations: Part II, Pharmaceutical Technology, 24-38, August 1991).

BRIEF DESCRIPTION OF THE INVENTION This invention relates to compositions of matter comprising a cyclodextrin and a compound of formula I (droloxifene) or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutically acceptable salt 20 is the citrate salt. Preferably, the composition is a dry mixture. Preferably, the composition is a dry inclusion complex. Preferably, the composition is an aqueous solution of an inclusion complex. Preferably, the cyclodextrin in any of the above compositions is a β-cyclodextrin and it is especially preferred that the cyclodextrin is β-cyclodextrin (non-derivatized), hydroxypropyl-β-cyclodextrin (HPBCD) or sulfobutyl ether-β-cyclodextrin (SBECD). The compositions can be administered orally, for example, in the form of a tablet, capsule or solution, or parenterally, for example, in the form of an injectable, or by inhalation, to a mammal (e.g., a man or a woman) that need The term "composition (s) of matter", as used herein, including the appended claims, encompasses inter alia compositions of droloxifene and a cyclodextrin which are dry physical mixtures, dry inclusion complexes or aqueous solutions of dissolved inclusion complexes. For example, a composition may comprise a dry mixture of droloxifene physically mixed with a dried cyclodextrin, for reconstitution for use as a liquid formulation intended for oral administration. A composition, in a preferred embodiment, may also comprise an aqueous solution or other solution that has been lyophilized or otherwise dried (for example, in a vacuum oven or in another suitable device), so that the composition comprises a pre-formed complex complexed cyclodextrin-droloxifene dry inclusion complex, which can then be reconstituted prior to oral or parenteral administration), or that can be administered orally in a capsule or compressed. A composition may also comprise the aqueous solution itself, that is, droloxifene plus cyclodextrin plus water. The inclusion complexes are, therefore, within the scope of the term "composition of matter", whether they are preformed, formed in situ or formed in vivo. The term "mgA" indicates the (in milligrams) of droloxifene, calculated as free base (molecular weight of droloxifene = 387.52).

DETAILED DESCRIPTION OF THE INVENTION The preparation of droloxifene, l- [4 '- (2-dimethylaminoethoxyphenyl] -1- (3'-hydroxyphenyl)' 2 'phenylbut-1-ene, and salts are described in United States Patent No. 5,047,431. pharmaceutically acceptable thereof The pharmaceutically acceptable acid addition salts of droloxifene are non-toxic salts, such as salts formed with organic acids (eg, formic, acetic, trifluoroacetic, citric, maleic, tartaric, methanesulfonic, benzenesulfonic or toluenesulfonic acids) citrate salt, with inorganic acids (eg, hydrochloric, hydrobromic, sulfuric or phosphoric acids) or with amino acids (eg, aspartic or glutamic acids) .The pharmaceutically acceptable acid addition salts of droloxifene can be used. prepare in the technique by a conventional methodology treating a solution or suspension of droloxifene, in free base form, with approximately one chemical equivalent or with a slight excess of a pharmaceutically acceptable acid. The salt can be isolated by conventional methods, such as filtration when the salt precipitates spontaneously, for example, in the form of crystalline material, or can be isolated by concentration and / or addition of a non-solvent, particularly if the salt is amorphous. The use of droloxifene has been described for the treatment of a variety of diseases / ailments, including breast cancer, and of bone diseases, such as osteoporosis. Any cyclodextrin can be used in this invention. The following descriptions of cyclodextrin are given as examples and not as limitation. Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on the outer surface and a hollow cavity in the center. Its outer surface is hydrophilic and, therefore, they are normally soluble in water, but the cavity has lipophilic character. The most common cyclodextrins are the o-cyclodextrin, β-cyclodextrin and p-cyclodextrin which consist, respectively, of 6, 7 and 8 units of glucose units in the positions O-1,4- The number of these units determines the size of The cavity. Useful cyclodextrins include O-, β-, and p- cyclodextrins, methylated cyclodextrins, hydroxypropyl-β-cyclodextrin (HPBCD), hydroxyethyl-β-cyclodextrin (HEBCD), branched cyclodextrins in which one or two glucose or maltose radicals are enzymatically linked to the ring of cyclodextrin, ethyl- and ethyl- carboxymethylcyclodextrins, dihydroxypropylcyclodextrins and sulfoalkyl ether cyclodextrins. The degree of substitution is not considered critical and the aforementioned cyclodextrins can have essentially any degree of substitution (per whole molecule of cyclodextrin), as is known in the art. The hydroxyl groups of β-cyclodextrin are sometimes chemically modified to increase the solubility of the cyclodextrin as well as the complex formed with the host molecule. Mixtures of cyclodextrins, as well as individual species, are feasible to make dosage forms according to the invention. For use in this invention, two highly soluble commercial cyclodextrins (500 mg / ml), sulfobutyl ether-β-cyclodextrin (SBECD) and hydroxypropyl-β-cyclodextrin (HPBCD) are preferred. HPBCD and SBECD are preferred for both oral and parenteral administration. HPBCD is well known in the art; see, for example, publication R 81 216 entitled "Encapsin HPB", by Jansen Biotech N.V. SBECD is also known and has been described in U.S. Patent Nos. 5,376,645 and 5,134,127, both to Stella et al., And incorporated herein by reference.

Typically, cyclodextrin derivatives are formed by alkylation (e.g., methyl- and ethyl-β-cyclodextrin) or by hydroxyalkylation of the hydroxyethyl derivatives of O-, β- and p-cyclodextrin or by replacing the primary hydroxyl groups with saccharides (e.g. glucosyl- or maltosyl-β-cyclodextrin). Hydroxypropyl-β-cyclodextrin and its preparation by the addition of propylene oxide to β-cyclodextrin, and hydroxyethyl-β-cyclodextrin and its preparation by the addition of ethylene oxide to β-cyclodextrin are described in United States Patent No. 3,459,731, the disclosure of which is incorporated herein by reference. An amount of droloxifene is used such that the composition provides the desired therapeutic effect. Droloxifene can be administered one to four times a day with a unit dosage of 0.25 mg to 100 mg, to human patients, both in oral and parenteral administration, but the above dosage can appropriately be avoided depending on the age, body weight and disorder patient's doctor and the type of administration. One dose per day is preferred. The solid formulations may include tablets, capsules or oral powders ideal for reconstitution with water before dosing. Typically a mixture of a cyclodextrin and droloxifene, as a dry inclusion complex, can be used as a capsule filling or can be compressed to form a tablet for administration oral. By exposing it to an aqueous medium of use, such as the luminal fluid of the gastrointestinal tract or the salivary fluid of the oral cavity, this inclusion complex helps to increase the bioavailability with respect to the non-complexed drug. These formulations typically contain other components known to those skilled in the art, such as fillers, disintegrants, binders, lubricants, dispersing agents and thickening agents, as well as other excipients such as colorants and flavors. Examples of said components are provided in the examples. In liquid formulations, cyclodextrins serve the dual purpose of increasing the stability as well as the solubility of droloxifene. Liquid formulations include, for example, oral solutions, oral suspensions, parenteral solutions and parenteral lyophilisates. The effect of cyclodextrins in increasing solubility facilitates obtaining a dosage form in solution having the desired dosage. Oral liquid formulations may contain other excipients known to those skilled in the art, such as thickening agents, dispersing agents, colorants and flavors. The liquid formulations may also contain buffers, antioxidants, preservatives and tonicity adjusters. Typical buffers include phosphates, acetates, citrates and glycine. Examples of antioxidants include ascorbic acid, sodium bisulfite, sodium metabisulfite, monotiglycerol, thiourea, hydroxytoluene butylated, butylated hydroxyanisole and salts of ethylenediaminetetraacetic acid. Preservatives useful in liquid formulations include benzoic acid and its salts, sorbic acid and its salts, alkyl esters of para-hydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol, thimerosal, benzalkonium chloride and cetylpyridinium chloride. To adjust the tonicity, if necessary, the aforementioned buffers can be used as well as dextrose, glycerin and sodium chloride. A solid inclusion complex can be formed by conventional procedures. That is, an excess amount of droloxifene is added to an aqueous solution of cyclodextrin until the equilibrium solubility is obtained. The water is then removed by evaporation techniques and the remaining solid is dried to give the drug-cyclodextrin complex. Alternatively, the complex can be precipitated from an aqueous solution by adding a solvent in which the complex is insoluble or soluble in minimal amounts. The molar ratio of the droloxifene inclusion complex may vary depending on the initial concentrations of each component in the solution. In general, the amount of cyclodextrin in a formulation is such that the molar ratio of cyclodextrin to droloxifene is from 0.1: 1 to 20: 1, preferably from 0.5: 1 to 10: 1, more preferably from 1: 1 to 4: 1 . In a solid formulation, the ratio of cyclodextrin to droloxifene is generally from 120: 1 to 1: 2, preferably from 40: 1 to 1: 1, more preferably from 20: 1 to 1: 1 (w / w). If the formulation is an aqueous solution, it may contain cyclodextrin in a wide range of concentrations. The preferred concentration of cyclodextrin in a liquid formulation will depend on the dose of droloxifene and the pH of the solution. However, generally, the preferred range of cyclodextrin in said aqueous solutions is 0.2-50% (weight / volume). Cyclodextrin may be present in an amount greater than that necessary to completely complex droloxifene. An inclusion complex can be formed for a liquid formulation of droloxifene by conventional methods. That is, a desired inclusion complex of droloxifene can be formed in it by adding droloxifene in an amount greater than the amount corresponding to the equilibrium solubility (or lower, depending on the desired concentration of the product solution), directly to a solution previously made of cyclodextrin dissolved in water (or in another suitable aqueous medium pharmaceutically acceptable). A combination comprising sterile water (or another aqueous pharmaceutically acceptable medium, such as a buffer), cyclodextrin and dissolved droloxifene is sufficient to form a solution of the product that can be administered directly parenterally to human patients. This product solution, after a filtration sterile, it can be used for immediate administration to patients, no tonicity adjustment is required, or it can be stored at 5 ° C for periods of up to two years or more. In a liquid formulation, the concentration of droloxifene is generally 0.2 mgA / ml to 150 mgA / ml, preferably 1 mgA / ml to 125 mgA / ml, more preferably 5 mgA / ml to 100 mgA / ml. Alternatively, the inclusion complex of droloxifene in cyclodextrin can first be isolated by drying, usually by lyophilization. The isolated dry inclusion complex can be stored at room temperature for periods of up to two years or more, and can be reconstituted to form a product solution when needed. When a solution of the product is required, it can be done by dissolving in water (or in another aqueous medium) the isolated inclusion complex, in an amount sufficient to generate a solution of the concentration required for oral or parenteral administration to patients. If parenteral administration is the chosen route of administration, intramuscular injections are preferred. For more examples of excipients and examples of methods of preparing pharmaceutical compositions, see Pharmaceutical Sciences, by Remington, Mack Publishing Company, Easter, PA, 15th edition (1975). Blends of cyclodextrin / droloxifene were examined and shown to have increased solubility and stability as follows: The solubility of droloxifene citrate in an aqueous pH 3 phosphate buffer, with and without various levels of cyclodextrins, was determined. The solubility test of droloxifene citrate in 'solutions of cyclodextrin (SBECD and 'HPBCD) was performed using an equilibrium solubility procedure. The following protocol was used for the determination of solubility. The HPBCD was purchased commercially from Janssen Biotech N.V. (Belgium). The SBECD employed had a degree of substitution with sulfobutyl groups of 6.5, average value per molecule of β-cyclodextrin, and was made by a procedure analogous to that described in Example 3 of US Patent 5,376,645. Aqueous solutions of 0.02M phosphoric acid buffer (H3PO4) and 0.02M dibasic sodium phosphate (Na2HP04.) Were prepared separately, dissolving, respectively, 2.25 g and 2.84 g in portions other than one liter of deionized water and shaking with a magnetic stirring rod until dissolution is achieved. To obtain a buffer of pH 3, the two previous buffers were combined in an approximate ratio of 2: 1 (buffer H3PO4: buffer Na2HP ?.). The final volume of the resulting pH 3 buffer is not critical. To 25-ml volumetric flasks were added weights of HPBCD or SBECD to produce the final concentrations of each cyclodextrin indicated in Table 1. For example, to prepare a 2% (w / v) solution of HPBCD in phosphate buffer At pH 3, exactly 0.5 g of HPBCD was added to a 25 ml graduated flask. Approximately 90% of the total volume was filled with buffer and the flask was stirred until the dissolution of the cyclodextrin was completed, usually in 15 minutes. Then sufficient buffer was added to complete the solution and the flask was inverted several times to achieve a homogeneous solution. To 5 ml glass vials with screw cap 3 ml of the desired cyclodextrin solution was added. An excess of solid droloxifene citrate was added to each vial. The contents of the vials were mixed for three days at room temperature to give sufficient time to establish equilibrium. After three days, the vials contained undissolved solids, which indicates a saturated solution under the conditions used. The content was filtered to a clean vial of screw cap, through a Millex-HV 0.45 μm filter (Millipore, Bedford, MA) and the drug concentration was determined by a high performance liquid chromatography (HPLC) method. As an example of an HPLC assay used to determine the solubility of droloxifene, the amount of dissolved droloxifene was determined using an Ultrasphere C18 column (registered trademark of Beckman, Fullerton, CA) with an isocratic mobile phase formed by 45% water, 31% methanol, 24% acetonitrile and 0.15% trifluoroacetic acid. The pH of the mixture was adjusted to 3 with ammonium hydroxide. The detection was by ultraviolet (UV) absorption at a wavelength of 230 nm. Quantification was easily performed by comparing the area of the HPLC peak with the peak area taken from a standard concentration plot versus the peak area for patterns of known concentration. As is conventional, droloxifene standard concentrations falling within a linear range of concentration versus absorbance were selected for the UV detector employed. The saturated equilibrium solution obtained after filtering the solutions from the test vials was serially diluted to reach the linear range of the standard graph. The dilution was carried out by adding isocratic mobile phase. The results detailed in the following Table 1 below demonstrate an increase in the solubility of droloxifene citrate with cyclodextrin.

TABLE 1 The stability of droloxifene citrate at pH 3 was determined with various concentrations of SBECD and HPBCD. In this protocol, 0.02M sodium phosphate pH 3 buffer solution and cyclodextrin solutions were prepared as in the determination of the cyclodextrin solution at a level of 18 ml clear glass with screw cap containing a pre-weighed amount of droloxifene citrate. The vials were shaken until the dissolution of droloxifene citrate was completed. The concentration of droloxifene citrate ranged from 0.05 to 0.1 mgA / ml. The concentrations of HPBCD included 0.2, 2, 4, 7 and 10% w / v. The concentrations of SBECD included 0.33 and 3.3% p / v. The vials were stored in a fluorescent lighting box of 256 cd.m. The solutions were briefly removed from time to time to determine the drug concentration using the HPLC method described for the determination of solubility. The results of the following table 2 show an increase in the stability of droloxifene with the inclusion of cyclodextrins. The concentrations of cyclodextrin that cause the greatest stabilizing effect depends on the efficiency of formation of the inclusion complex of droloxifene-cyclodextrin, that is, the stability constant, as well as the initial concentration of droloxifene present. This test, which is performed in the presence of an intense light source, demonstrates an increase of 1.3-4X in stability, which is very useful to ensure the stability of droloxifene after reconstitution to form a solution, for example, in a hospital. This increase in stability is also useful for preconstituted aqueous solutions that must have a life useful long, for example, 2 years, even if they are packaged in a container partially protected from light. Droloxifene is significantly more stable outside of light; however, an increased stability in solution protected from light is also observed when β-cyclodextrins are present. Although it is not desired to be bound by any theory, it is believed that the incorporation of droloxifene into the cavity of the cyclodextrins minimizes a cis-trans isomerization reaction, thereby reducing the formation of the isomer product of decomposition and causing an overall increase in stability .

TABLE 2 The following examples are possible formulations EXAMPLE 1 Formulation of a 40 mg tablet of droloxifene (*) Present as droloxifene-cyclodextrin inclusion complex (**) Based on 66.9% droloxifene in droloxifene citrate salt EXAMPLE 2 Formulation of a 40 mg oral solution of droloxifene (40 mg droloxifene / tablespoon) (*) Based on 66.9% droloxifene in salt droloxifene citrate EXAMPLE 3 Formulation of a parenteral solution of 60 mg of droloxifene (60 mg of droloxifene / 2 ml) (*) Based on 66.9% droloxifene in salt droloxifene citrate

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - A composition of matter comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a cyclodextrin.

2. - A composition according to the claim 1, wherein the compound of formula I is the citrate salt.

3. - A composition according to the claim 2, wherein said composition is a dry mixture.

4. A composition according to claim 2, wherein said composition is a dry inclusion complex of said compound with said cyclodextrin.

5. A composition according to claim 2, wherein said composition is an aqueous solution of an inclusion complex of said compound with said cyclodextrin.

6. A composition according to the claim 1, wherein said cyclodextrin is a β-cyclodextrin.

7. A composition according to claim 6, wherein said β-cyclodextrin is β-cyclodextrin, HPBCD or SBECD.

8. - A composition of matter comprising an inclusion complex of a pharmaceutically acceptable salt of a compound of formula I in a cyclodextrin.

9. An inclusion complex according to claim 8, wherein the salt of the compound of formula I is the citrate salt.

10. A composition according to claim 9, wherein said cyclodextrin is a β-cyclodextrin.

11. A composition according to claim 10, wherein said β-cyclodextrin is HPBCD or SBECD.