KR100335580B1 - Pharmaceutical oral administration - Google Patents

Abstract

The present invention relates to orally administrable pharmaceutical preparations comprising raloxifene, ethers or esters thereof, or pharmaceutically acceptable salts thereof in admixture with a hydrophilic carrier composition.

Description

Oral Administerable Pharmaceutical Formulations

Certain benzothiophenes of the general formula (I) and their pharmaceutically acceptable salts are nonsteroidal antiestrogens and antiandrogens:

Where

R and R ¹ are independently hydrogen, COR ² or R ³ ;

R ² is hydrogen, C ₁ -C ₁₄ alkyl, C ₁ -C ₃ chloroalkyl, C ₁ -C ₃ fluoroalkyl, C ₅ -C ₇ cycloalkyl, C ₁ -C ₄ alkoxy or phenyl, or C ₁ -Phenyl mono- or di-substituted with C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, nitro, chloro, fluoro or tri (chloro or fluoro) methyl;

R ³ is C ₁ -C ₄ alkyl, C ₅ -C ₇ cycloalkyl or benzyl.

These compounds are useful for the treatment of breast and prostate cancer and for the treatment of fibrocystic diseases of the breast and prostate. Compounds of formula (I) are described in US Pat. No. 4,418,068, issued November 29,1983. This patent describes methods of preparing these compounds as well as their use as antiestrogens and antiandrogen therapies. Also described are methods of preparing pharmaceutical compositions for the treatment of antiestrogens and antiandrogens.

Raloxifene, 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene, is a particularly useful compound among these benzothiophenes. . Raloxifene competitively inhibits estrogen action in many in vitro and in vivo models (Black, Jones and Falcone, Life Sci ., 32 , 1031-1036 (1983); Knecht, Tsai-Morris and Cat, Endocrinology , 116 , 1771-1777 (1985); And Simaard and Labrie, Mol. Cell. Endocrinology , 39 , 141-144 (1985). The compound also exhibits a kind of estrogen-like action in addition to its estrogen-antagonistic effect ( Endocrinology of Ortmann, Emons, Knuppen and Cat, 123 , 962-968 (1988)]. . Recent studies have shown that raloxifene is useful for treating osteoporosis in postmenopausal women (Turner, Sato and Briant's Journal of Clinical Investigation (In Press)).

The compound of formula (I) may be administered as a pharmaceutically acceptable salt. Particularly useful pharmaceutically acceptable salts of raloxifene are hydrochlorides. Such salt forms can be readily prepared by adding hydrochloric acid to a raloxifene solution in an organic solvent such as tetrahydrofuran or methanol. However, the water solubility of raloxifene hydrochloride is far below the solubility expected for organic hydrochlorides having two phenolic hydroxyl groups. Such poor solubility somewhat limits the bioavailability of these preferred salt forms. Another important limitation for optimal and consistent absorption of raloxifene hydrochloride is its hydrophobicity.

To overcome limited bioavailability, the present invention comprises oral administrable pharmaceutical formulations having increased solubility in aqueous media, including raloxifene, esters or ethers thereof, or pharmaceutically acceptable salts thereof in combination with a hydrophilic carrier composition. to provide. More specifically, the present invention provides orally administrable pharmaceutical preparations comprising raloxifene, esters or ethers thereof, or pharmaceutically acceptable salts thereof, together with surfactants, water soluble diluents and optionally hydrophilic binders. The present invention also provides a pharmaceutical formulation further comprising a lubricant and a disintegrant.

The present invention provides orally administrable pharmaceutical preparations comprising raloxifene, esters or ethers thereof, or pharmaceutically acceptable salts thereof, together with surfactants, water soluble diluents and optionally hydrophilic binders. Raloxifene, its esters and ethers are represented by the following general formula (I):

Where

R and R ¹ are independently hydrogen, COR ² or R ³ ;

R ² is hydrogen, C ₁ -C ₁₄ alkyl, C ₁ -C ₃ chloroalkyl, C ₁ -C ₃ fluoroalkyl, C ₅ -C ₇ cycloalkyl, C ₁ -C ₄ alkoxy or phenyl, or C ₁ -Phenyl mono- or di-substituted with C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, nitro, chloro, fluoro or tri (chloro or fluoro) methyl;

R ³ is C ₁ -C ₄ alkyl, C ₅ -C ₇ cycloalkyl or benzyl.

Raloxifene is a compound in which R and R ¹ are hydrogen. Methods of preparing these compounds are described in US Pat. No. 4,418,068, which is incorporated herein by reference. The pharmacologist will readily understand that the compound can be effectively administered as an ether or ester formed from one or two phenolic hydroxyl groups. Methods of making these esters and ethers are also described in US Pat. No. 4,418,068.

General chemical terms used in the above general formulas have their usual meanings. The term “C ₁ -C ₁₄ alkyl” refers to straight or branched chain alkyl having 1 to 14 carbon atoms. Representative C ₁ -C ₁₄ alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl , n-octyl, decyl, 2-methyldecyl, 2,2-dimethyldecyl, undecyl and dodecyl and the like. The term "C ₁ -C ₁₄ alkyl" includes the term "C ₁ -C ₄ alkyl". Representative C ₁ -C ₄ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl and t-butyl.

The terms “C ₁ -C ₃ chloroalkyl” and “C ₁ -C ₃ fluoroalkyl” refer to methyl, ethyl, propyl and isopropyl, one hydrogen atom to fully substituted with chlorine or fluorine atoms. Representative C ₁ -C ₃ chloroalkyl groups are chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl, 1, 1,2,2-tetrachloroethyl, 1,2,2,2-tetrachloroethyl, pentachloroethyl, 3-chloropropyl, 2-chloropropyl, 3,3-dichloropropyl, 2,3-dichloropropyl, 2,2-dichloropropyl, 3,3,3-trichloropropyl and 2,2,3,3,3-pentachloropropyl. Representative C ₁ -C ₃ fluoroalkyl groups are fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,2,2,2-tetrafluoroethyl, pentafluoroethyl, 3-fluoropropyl, 2-fluoro Propyl, 3,3-difluoropropyl, 2,3-difluoropropyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl and 2,2,3,3,3- Pentafluoropropyl.

The term "C ₅ -C ₇ cycloalkyl" denotes a cyclic hydrocarbon group having 5 to 7 carbon atoms. C ₅ -C ₇ cycloalkyl groups are cyclopentyl, cyclohexyl and cycloheptyl.

The term “C ₁ -C ₄ alkoxy” refers to groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy and the like.

The term “pharmaceutically acceptable salts” refers to salt forms of raloxifene, esters thereof or ethers thereof, which are physiologically suitable for pharmaceutical use. Pharmaceutically acceptable salts with respect to raloxifene, its esters or ethers thereof may be present as acid addition salts, primary, secondary, tertiary or quaternary ammonium salts, alkali metal salts or alkaline earth metal salts. In general, acid addition salts are prepared by reacting a compound of formula (I) with acid, wherein R, R ¹ , R ² and R ³ are as defined above. Alkali metal salts and alkaline earth metal salts are generally prepared by reacting a compound of formula (I) wherein at least one of R and R ¹ is hydrogen with a metal hydroxide of the desired metal salt.

Acids commonly used to form the above acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as toluenesulfonic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, Organic acids such as citric acid, benzoic acid and acetic acid and related inorganic and organic acids. Therefore, these pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, ammonium salts, monohydrogen phosphates, dihydrogen phosphates, meta-phosphates, pyrophosphates, chlorides, bromide, iodides, Acetates, propionates, decanates, capronates, acrylates, formates, isobutyrates, caprinates, heptanoates, propionates, oxalates, malonates, succinates, subvertates, sebacates, Fumarate, Hypurate, Maleate, Butine-1,4-Diate, Hexine-1,4-Diate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Hydroxybenzoate, Methine Oxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, α-hydroxybutyrate, glycolate, tartarate, methanesulfonate, propane It includes salts such as phones acid, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate salt, ammonium salt, magnesium salt, tetramethyl ammonium salt, potassium salt, trimethyl ammonium salt, a sodium salt, methyl ammonium salt, a calcium salt.

The term “hydrophilic binder” refers to binders commonly used in the formulation of pharmaceuticals, for example polyvinylpyrrolidone, polyethylene glycol, sucrose, dextrose, corn syrup, polysaccharides (acacia gum, tragacanth gum, Guar gum and alginate), gelatin and cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxymethylcellulose).

As used herein, the term “surfactant” refers to, for example, ethoxylated castor oil, polyglycolated glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, Commonly used in the formulation of pharmaceuticals, such as monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium laurylsulfate, cholic acid or derivatives thereof, lecithin and phospholipids, and the like Ionic and nonionic surfactants or wetting agents.

The term "water soluble diluent" refers to the formulation of a medicament, such as sugars (including lactose, sucrose and dextrose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol and sorbitol) and cyclodextrins. Typical compounds used are shown.

The term "disintegrant" refers to starch, clay, cellulose, alginate, gum, crosslinked polymer (eg crosslinked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose), sodium starch glycolate, lower -Compounds such as substituted hydroxypropyl cellulose and soy polysaccharide. Preferably, the disintegrant is a crosslinked polymer, more preferably crosslinked polyvinylpyrrolidone.

The term "lubricant" refers to talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, microcrystalline cellulose, starch, mineral oil, wax, glyceryl behenate, polyethylene glycol, Compounds often used as lubricants or glidants in the formulation of pharmaceuticals, such as sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumarate and hydrogenated vegetable oils. Preferably, the lubricant is magnesium stearate or stearic acid, more preferably magnesium stearate.

All formulations of the invention have increased solubility in aqueous media and therefore greater bioavailability is expected, with certain formulations preferred. Preferably the surfactant is an anionic or nonionic surfactant. Representative examples of these preferred surfactants are sodium laurylsulfate, sodium docusate, ethoxylated castor oil, polyglycolated glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, poly Oxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, and diglycerides or polyoxyethylene derivatives thereof. Preferably, the water soluble diluent is a sugar or polyol. If a hydrophilic binder is present, the preferred binder is sucrose, dextrose, corn syrup, gelatin, cellulose derivatives or polyvinylpyrrolidone.

More preferred are certain formulations of the invention. More preferably, the surfactant is an ethoxylated castor oil, polyglycolated glyceride, acetylated monoglyceride, sorbitan fatty acid ester, poloxamer, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene derivative, monoglyceride or ethoxylation thereof Derivatives, and nonionic surfactants such as diglycerides or polyoxyethylene derivatives thereof. More preferably, the water soluble diluent is a sugar such as lactose, sucrose and dextrose. More preferably, the hydrophilic binder is a cellulose derivative or polyvinylpyrrolidone.

Most preferred are certain formulations of the invention. Most preferably, the surfactant is a polyoxyethylene sorbitan fatty acid ester such as polysorbate 80. Most preferably, the water soluble diluent is lactose. Most preferably, the hydrophilic binder (if used) is polyvinylpyrrolidone.

Orally administrable compositions of the invention are prepared and administered according to methods known in the pharmaceutical chemistry art. Remington's Pharmaceutical Sciences, 17th ed. (A. Osol ed., 1985). For example, the compositions of the present invention can be administered in solid dosage forms such as tablets and capsules. Preferably, the composition is formulated into a tablet. These tablets are prepared by wet granulation, dry granulation or direct compression.

Tablets for the present invention are prepared using conventional tableting techniques. Common methods of preparation include blending raloxifene, its esters, ethers or salts with a water soluble diluent and optionally some disintegrant. This blend is then granulated with a solution of hydrophilic binder and surfactant in water and / or organic solvents such as methanol, ethanol, isopropanol, methylene chloride and acetone and milled as necessary. Dry the granules and reduce to a suitable size. Lubricant (eg magnesium stearate) and other optional ingredients such as additional disintegrants are added to the granules and mixed. This mixture is then compressed to a suitable size and shape using a conventional tableting machine such as a rotary tablet press. Tablets may be film coated by techniques known in the art.

Capsules for the present invention are prepared using conventional encapsulation methods. Common methods of preparation include blending raloxifene, its esters, ethers or salts with a water soluble diluent and optionally some disintegrant. This blend is then granulated with a solution of hydrophilic binder and surfactant in water and / or organic solvent and milled as necessary. Dry the granules and reduce to a suitable size. Other optional ingredients such as lubricants (eg colloidal silicon dioxide) are added to the granules and mixed. The resulting mixture is then filled into hard shell gelatin capsules of suitable size using conventional capsule-chargers.

The following formulations are merely illustrative of the invention and are not intended to limit the scope of the invention in any way. Tablets may be prepared using the ingredients and procedures described below:

A mixture of raloxifene HCl, lactose and some crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of polyvinylpyrrolidone and polysorbate 80. The granules are dried, reduced to a suitable size and mixed with stearic acid, magnesium stearate and the remaining crosslinked polyvinylpyrrolidone. This mixture is compressed into each tablet so that each tablet weighs 525 mg.

A mixture of raloxifene HCl, anhydrous lactose, dextrose and some crosslinked polyvinylpyrrolidone is granulated with an alcohol solution of polyvinylpyrrolidone and polysorbate 80. The granules are dried, reduced to a suitable size and mixed with magnesium stearate, stearic acid and the remaining crosslinked polyvinylpyrrolidone. This mixture is compressed into each tablet such that each tablet weighs 525 mg.

A mixture of raloxifene HCl, dextrose and crosslinked sodium carboxymethylcellulose is granulated with an aqueous solution of hydroxypropyl cellulose and sodium laurylsulfate. The granules are dried, reduced to a suitable size and mixed with magnesium stearate. This mixture is compressed into each tablet so that the weight of each tablet is 400 mg.

A mixture of raloxifene HCl, anhydrous lactose, spray dried hydrated lactose and some crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of polyvinylpyrrolidone and polysorbate 80. The granules are dried, reduced to a suitable size and mixed with magnesium stearate and the remaining crosslinked polyvinylpyrrolidone. This mixture is compressed into individual tablets so that the weight of the tablet is 240 mg.

A mixture of raloxifene HCl, anhydrous lactose and crosslinked sodium carboxymethylcellulose is granulated with an aqueous solution of poloxamer and hydroxypropyl cellulose. The granules are dried, reduced to a suitable size and mixed with stearic acid and magnesium stearate. This mixture is then compressed into each tablet so that the weight of each tablet is 240 mg.

A mixture of raloxifene HCl, lactose, dextrose and crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of hydroxypropyl methylcellulose and sodium laurylsulfate. The granules are dried, reduced to a suitable size and mixed with stearic acid. This mixture is then compressed into each tablet so that the weight of each tablet is 240 mg.

The mixture of raloxifene HCl, anhydrous lactose and crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of polyvinylpyrrolidone and polysorbate 80. The granules are dried, reduced to a suitable size and mixed with magnesium stearate. This mixture is then compressed into each tablet so that the weight of each tablet is 240 mg.

A mixture of raloxifene HCl, anhydrous lactose, spray dried hydrated lactose and some crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of polyvinylpyrrolidone and polysorbate 80. The granules are dried, reduced to a suitable size and mixed with magnesium stearate and the remaining crosslinked polyvinylpyrrolidone. This mixture is then compressed into each tablet so that the weight of each tablet is 240 mg.

A mixture of raloxifene HCl, mannitol, dextrose and sodium starch glycolate is granulated with an aqueous solution of polysorbate 80 and hydroxypropyl methylcellulose. The granules are dried, reduced to a suitable size and mixed with stearic acid and magnesium stearate. This mixture is then compressed into each tablet so that the weight of each tablet is 240 mg.

A mixture of raloxifene HCl, anhydrous lactose, spray dried hydrated lactose and some crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of polyvinylpyrrolidone and polysorbate 80. The granules are dried, reduced to a suitable size and mixed with magnesium stearate and the remaining crosslinked polyvinylpyrrolidone. This mixture is then compressed into each tablet such that the weight of each tablet is 230 mg.

A mixture of raloxifene HCl, spray dried hydrated lactose and some crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of polyvinylpyrrolidone and polysorbate 80. The granules are dried, reduced to a suitable size and mixed with magnesium stearate and the remaining crosslinked polyvinylpyrrolidone. This mixture is then compressed into each tablet such that the weight of each tablet is 230 mg.

The mixture of raloxifene HCl and anhydrous lactose is granulated with an aqueous solution of polyvinylpyrrolidone and polysorbate 80. The granules are dried, reduced to a suitable size and mixed with polyethylene glycol 8000. This mixture is then compressed into each tablet such that the weight of each tablet is 230 mg.

Capsules may be prepared using the ingredients and procedures described below:

The mixture of raloxifene HCl, spray dried hydrated lactose and crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of sodium laurylsulfate and hydroxypropyl methylcellulose. The granules are dried, reduced to a suitable size and mixed with colloidal silicon dioxide. This mixture is then filled into size 3 hard shell gelatin capsules using a conventional encapsulation device such that each capsule contains 230 mg of the final mixture.

A mixture of raloxifene HCl, spray dried hydrated lactose and crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of sodium laurylsulfate and hydroxypropyl methylcellulose. The granules are dried, reduced to a suitable size and mixed with colloidal silicon dioxide. This mixture is then filled into size 3 hard shell gelatin capsules using a conventional encapsulation device such that each capsule contains 230 mg of the final mixture.

A mixture of raloxifene HCl, spray dried hydrated lactose and crosslinked polyvinylpyrrolidone is granulated with an aqueous solution of sodium laurylsulfate and hydroxypropyl methylcellulose. The granules are dried, reduced to a suitable size and mixed with colloidal silicon dioxide. This mixture is then filled into size 3 hard shell gelatin capsules using a conventional encapsulation device such that each capsule contains 230 mg of the final mixture.

Claims (12)

Comprising raloxifene hydrochloride with a surfactant, polyvinylpyrrolidone, and a water soluble diluent, wherein the surfactant is a sorbitan fatty acid ester or a polyoxyethylene sorbitan fatty acid ester, and the water soluble diluent is a polyol or sugar orally administrable Pharmaceutical preparations. The formulation of claim 1 wherein said surfactant is a polyoxyethylene sorbitan fatty acid ester. The formulation of claim 1, wherein said surfactant is polysorbate 80. The formulation of claim 1 wherein said water soluble diluent is a sugar. The formulation of claim 1 wherein said water soluble diluent is lactose. The formulation of claim 1 further comprising a lubricant and a disintegrant. The formulation of claim 6 wherein the lubricant is magnesium stearate or stearic acid and the disintegrant is crosslinked polyvinylpyrrolidone. An orally administrable pharmaceutical formulation comprising raloxifene hydrochloride in combination with polysorbate 80, lactose, polyvinylpyrrolidone and magnesium stearate. The formulation of claim 8 further comprising a disintegrant. The formulation of claim 9 wherein said disintegrant is crosslinked polyvinylpyrrolidone. 8. The formulation according to any one of claims 1 to 7, further comprising a film coating. The formulation according to claim 8, further comprising a film coating.