MX2008006171A - Formulations of fispemifene - Google Patents

Abstract

This invention relates to a liquid or semisolid oral drug formulation comprising a therapeutically active compound of the formula (I) or a geometric isomer, a stereoisomer, a mixture of isomers, a pharmaceutically acceptable salt, an ester thereof or a metabolite thereof, in combination with a1 pharmaceutically acceptable carrier.

Description

FORMULATIONS OF PHYSPEMIPHENE BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to a liquid or semi-solid oral drug formulation comprising fispemifen or a closely related compound as an active ingredient.

TECHNICAL BACKGROUND The publications and materials used herein to support the background of the invention and, in particular, cases to provide additional details regarding the practice are incorporated by reference. Estrogens are increasingly used for the treatment of climacteric symptoms in women. It has been shown that estrogens are also beneficial in the prevention of Alzheimer's disease (Henderson, 1997) as in the decrease of LDL cholesterol values and thereby prevent cardiovascular diseases (Grodstein &Stampfer, 1998). However, the use of estrogens increases the risk of uterine cancers and of breast (Lobo, 1995). New therapies that have the benefits of estrogens but not their carcinogenic risks are requested. Selective estrogen receptor modulators (SERM) have been developed to meet these requirements (Macgregor &Jordan, 1998). Selective modulators of the estrogen receptor have estrogen-like and anti-estrogenic properties (Kauffman &Briant, 1995). The effects can be specific to a tissue such as tamoxifen and toremifene, which have estrogen-like effects in bone, estrogen-like partial effects in the uterus and liver and a pure anti-estrogenic effect in breast cancer. Raloxifene and droloxifene are similar to tamoxifen and toremifene, except that their anti-estrogenic properties dominate. Based on the published information, many SERMs have important benefits in older women: they decrease total cholesterol and LDL, thus decreasing the risk of cardiovascular diseases and can prevent osteoporosis and inhibit the growth of breast cancer in postmenopausal women. The patents of E.U.A. US 6,576,645 and 6,875,775 describe a novel group of SERMs that are tissue-specific estrogens and that can be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer's disease and / or cardiovascular diseases without the carcinogenic risk. Certain compounds can be given to men to protect them against osteoporosis, cardiovascular diseases and Alzheimer's disease without adverse estrogenic events (gynecomastia, reduced libido etc.). Of the compounds described in said patents, the compound (Z) -2-. { 2- [4- (4-Chloro-1,2-diphenylbut-1-enyl) phenoxy] ethoxy} Ethanol (also known under the generic name Fispemifen) has shown a very interesting hormonal profile, suggesting that it will be especially valuable in treating disorders in men, in particular to prevent osteoporosis in the latter. The patent application of E.U.A. published No. 2004-0248989 suggests the use of fispemifene for the treatment or prevention of lower urinary tract symptoms such as detrusor urethral sphincter dyssynergia, abacterial prostatitis, stress prostatitis, trigonitis and orchialgia in male individuals as well as interstitial cystitis in male subjects or feminine Fispemifene is the Z-isomer of the compound of formula (I) Fispemifeno is only sparingly soluble in water.

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide an improved drug formulation containing as active ingredient a compound of formula (I) or an isomer, especially fispemifene, or a mixture of isomers, a salt, ester or metabolite thereof, in the which the dissolution and absorption of the active ingredient increases substantially. Thus, the invention involves a liquid or semi-solid oral drug formulation comprising a therapeutically active compound of formula (I) or a geometric isomer, a stereoisomer, a mixture of isomers, a pharmaceutically acceptable salt, an ester thereof or a metabolism thereof, in combination with a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1 and 2 show the individual concentration of fispemifene serum against time in two female Cynomolgus monkeys (# 05084 and # 06170, respectively) after administration of a single dose of 500 mg / kg of fispemifene in two different vehicles.

DETAILED DESCRIPTION OF THE INVENTION The term "liquid formulation" refers here particularly to a solution, a suspension with solid particles dispersed in a liquid, or a combination of both, or an emulsion with liquid drops dispersed in a liquid, or a syrup. The "liquid" may be hydrophilic or lipophilic, preferably lipophilic. The term "semi-solid formulation" refers in particular to gels and pastes. According to a preferred embodiment, the liquid drug formulation is a solution of compound 1 or its isomers, salt, ester or metabolite as a suitable carrier, which may be an individual carrier or a mixture of several carriers. The compounds of formula I have low solubility in water. Therefore, the carrier preferably will comprise one or more lipophilic ingredients. To achieve a better bioavailability it is preferred to use digestible lipids such as triglycerides, diglycerides, fatty acids, phospholipids or similar instead of digestible oils, mineral oils (Porter and Charman, 2001). A special group of carriers or useful ingredients may be derivatives of colane. The patent of E.U.A. 4.1 17.121 describes a group of derivatives of colane useful to lower the level of cholesterol and increase the flow of bile. A particularly preferred group of carriers is that of liquid fats (oils, especially vegetable oils such as corn oil, coconut oil or the like). However, the ingredients and carriers that improve bioavailability are not restricted to the foregoing. According to another preferred embodiment, the liquid drug formulation is a suspension of fine solid particles of compound I in a liquid. The liquid can be lipophilic or hydrophilic or a mixture of several liquids. Said liquids may also comprise dissolved ingredients. By decreasing the particle size of the dispersed drug compound, the surface area available for digestion and drug release improves. Preferably at least 90% of the drug substances will have a particle size of less than 150 microns and 50% of the drug substance will have a particle size of less than 25 microns. Preferably especially 90% of the drug substances will have a particle size of less than 50 microns and 50% of the drug substance will have a particle size of less than 15 microns. According to a third preferred embodiment, the liquid formulation is an emulsion. Since the aqueous solubility of compound I is very low, the emulsion preferably is a dispersion of a lipophilic phase (for example a solution and / or suspension of compound I in a lipophilic liquid) in an aqueous phase (oil in water emulsion). The emulsion may comprise additional components such as stabilizers (surfactants), emulsifiers and thickeners. According to a particularly preferred embodiment, the emulsion is a microemulsion or nanoemulsion. Micro and nanoemulsions are, in contrast to conventional emulsions, sotropic, transparent and thermodynamically stable. The particle size of the dispersed droplets in a microemulsion is typically around 0000 nm or below and in a nanoemulsion 100 nm or less. According to a fourth preferred embodiment, the liquid formulation is a syrup. Typical examples of semi-solid oral formulations are gels and pastes. The gels are created by adding a gelatinizer such as gelatin or a polysaccharide to a solution, suspension or emulsion comprising the compound I. According to a preferred embodiment, the gel is created by the addition of a gelatinizer to a microemulsion according to EP 760651 B1. Although liquid formulations such as solutions, emulsions and suspensions can be packaged in larger bottles for many doses, it may be preferable to have the drug formulation packaged in a unit dosage form, such as a capsule. Such capsule formulations are known as soft gel capsules. The capsules of Soft gelatin (or soft gel capsules) consist of a liquid or semi-solid matrix within a one-piece outer shell, like a gelatin shell. The drug component itself can be in solution, suspension or emulsion in the matrix for capsule filling. The characteristics of the filling matrix may be hydrophilic (for example polyethylene glycols) or lipophilic (such as vegetable oils of triglycerides) or a mixture of hydrophilic and lipophilic ingredients. Significant advances have been made in recent years in the formulation of filling matrices. As examples, microemulsions or nanoemulsions of the encapsulated drug can be mentioned as preconcentrated in the capsule. This means that the filling matrix is a concentrated micro or nanoemulsion, ie a combination of a lipophilic liquid containing the hydrophobic drug, a small amount of hydrophilic liquid and a surfactant. After oral administration the microemulsion will be diluted in the gastrointestinal fluid. Alternatively, the matrix may comprise only the ingredients, i.e. the drug, a lipid or a mixture of lipid and one or more surfactants. The ingredients will create, upon administration, a spontaneous microemulsion (or nanoemulsion) in the gastrointestinal fluid. The soft gel capsule consists, for example, of gelatin, water and a plasticizer. It can be transparent or opaque and can be colored and flavored if desired. No preservatives are required due to the low water activity in the finished product. The soft gel can be coated with enteric-resistant or delayed-release material. Although it can be virtually any form of soft gel, it is generally selected in ovoid or oblong forms for oral administration. The term "metabolite" will be understood as any metabolite of fispemifen. An important metabolite is ospemifene or (or deaminohydroxy) toremifene, which has the formula.

Other metabolites of fispenifeno important are the metabolites of ospemifeno 4-hydroxiospemifeno, that have the formula and the corresponding 3-hydroxiospemifene. Additional examples of metabolites are the toremifene metabolites mentioned in Kangas (1990) on page 9: 4-hydroxy (deaminohydroxy) toremifene (TORE VI), 4,4-dihydroxy (desaminohydroxy) toremifene (TORE VII), desaminocarboxy toremifene (TORE) XVIII),); 4-hydroxy (deaminocarboxy) toremifene (TORE VIII), and monophenol toremifene (TORE XIII); especially TORE VI and TORE XVIII. The compound (I) is preferably the Z-isomer, ie fispemifene. The improved drug formulation according to this invention is useful in any application of fispemifene, especially for use in the treatment or prevention of osteoporosis, cardiovascular diseases, Alzheimer's disease, symptoms of lower urinary tract treatment or for the treatment or prevention of prostate cancer in men. The required dosage of the compound (I) in the formulation according to this invention will vary with the particular condition being treated or prevented, the severity of the condition and the specific carrier employed. The optimal clinical dose of fispemifene is expected to be greater than 5 mg daily and less than 300 mg daily. A particularly preferable daily dose has been suggested in the range of 20 to 200 mg. Due to the improved bioavailability according to the method of this invention, it can be predicted that the same therapeutic effect can be achieved with doses lower than those estimated above.

The invention will be described more in detail in the following non-restrictive example.

EXAMPLE Concentration of fispemifen serum in monkeys after administration of fispemifen in two different vehicles A pilot study was conducted on the exposure of fispemifene in two female Cynomolgus monkeys (# 05084 and # 06170). Fispemifene was administered by individual oral dosage of 500 mg / kg in two different vehicles, 0.5% carboxymethyl cellulose in water (CMC), and in corn oil. Blood samples were collected 0, 1, 2, 4, 6, 8, 12, 16 and 24 hours after dosing. The concentrations of fispemifene were determined using LC-MS / MS.

Results Fispemifene was quantified in all serum samples taken after drug administration. The individual serum fispemifene concentrations against time for the two monkeys are shown in Figures 1 and 2. It can be seen that the concentration of fispemifene in serum is greater than 10 times of the corn oil vehicle from CMC in aqueous solution . This experiment shows that a liquid lipophilic as an oil can be an excellent carrier for the dissolution and / or suspension of fispemifene. It will be appreciated that the methods of the present invention can be incorporated in the form of a variety of modalities, of which only a few are described herein. It will be apparent to the person skilled in the art that other modalities exist and do not deviate from the essence of the invention. Thus, the modalities described are illustrative and should not be interpreted as restrictive.

Claims (12)

1. NOVELTY OF THE INVENTION CLAIMS 1 .- A liquid or semisolid oral drug formulation comprising a therapeutically active compound of formula (I) (i) or a geometric isomer, a stereisomer, a mixture of isomers, a pharmaceutically acceptable salt, an ester thereof or a metabolite thereof, in combination with a pharmaceutically acceptable carrier. 2. - The drug formulation according to claim 1, further characterized in that the compound (I) is fispemifen. 3. - The drug formulation according to claim 1, further characterized in that said formulation is Select from the group consisting of a solution, a suspension and a combination of a solution and a suspension. 4. - The drug formulation according to claim 1, further characterized in that said therapeutically active compound is dissolved and / or suspended in an oil. 5. - The drug formulation according to claim 1, further characterized in that said formulation is an emulsion. 6. - The drug formulation according to claim 5, further characterized in that the emulsion is a microemulsion or a nanoemulsion. 7. - The drug formulation according to claim 1, further characterized in that the formulation is a syrup. 8. - The drug formulation according to claim 1, further characterized in that the formulation is a gel. 9. - The drug formulation according to claim, further characterized in that the formulation is a paste. 10. - The drug formulation according to claim 1, further characterized in that said formulation is packaged in a unit dosage form. eleven . - The drug formulation according to claim 10, further characterized in that the dosage form is the formulation encapsulated in a soft capsule. 12. - The drug formulation according to claim 1, further characterized in that the drug comprises a bile flow promoting agent.