TITLE
Pharmaceutical composition comprising levormeloxifene in low dose.
FIELD OF THE INVENTION
This invention relates to new pharmaceutical formulations for oral administration comprising a low dose of certain 3,4-diarylchromans of formula I, or a pharmaceutically acceptable salt thereof.
The 3,4-diarylchromans of formula
(I)
wherein R is C,.6alkyl, and pharmaceutically acceptable salts thereof are known to be useful in reducing bone loss.
BACKGROUND OF THE INVENTION
Bone remodeling is the dynamic process whereby skeletal mass and architecture are renewed and maintained. This renewal and maintenance is a balance between bone resorption and bone formation, with the osteoclast and the osteoblast considered the two key participants in the remodeling process. The osteoclast initiates the remodeling cycle by resorbing a cavety in the bone which is subsequently refilled when the osteoblast synthesizes and deposits new bone matrix into the excavation. The activi-
ties of osteoclast and osteoblast are regulated by complex interactions between systemic hormones and the local production of growth factors and cytokines at active remodeling sites
Imbalances in bone remodeling are associated with such conditions as osteoporosis, Paget's disease, and hyperparathyrodism. Osteoporosis, characterized by a decrease in the skeletal mass, is one of the most common diseases of postmenopausal women and is often the cause of debilitating and painful fractures of the spine, hip and wrist.
The costs of osteoporosis, both personal and financial, are enormous. In 1984, 145,000 in-patient fracture reductions and 107,000 hip arthroplasties and replacements were performed on American women over 65 years of age. Among patients who lived alone prior to hip fracture, 15% to 20% required long-term care as a result of the fracture and one year after the fracture had still not regained their independence. The total financial cost of osteoporosis treatment, including fractures, in the United States in 1986 was 7-10 billion dollars (Peck et al.. Am.J.Med. 84:275-282. 1988).
Bone loss associated with osteoporosis has been arrested by the administration of exopeneous estrogens. To be effective, estrogen therapy must begin within a few years of the onset of menopause, and should continue for 10 to 15 years, according to Thorneycroft (Am.J.Obstet.Gvnecol. 160:1306.1310m 1989), While there are several different types of estrogens, 17-β-estradiol is the primary estrogen found natu- rally occurring in premenopausal women and is often the compound of choice for therapetic use. At the recommended dose, however, there are significant side effects, the most distrubing being the well-established correlation of estrogen therapy with endometrial and brest cancers. The incidence of carcinoma is both dose- dependent and duration-dependent.
Avoidance of the cancer risk has been achieved by the concomitant use of a pro- gestogen with estrogen. This combination, however, causes menses to return, which many women find unacceptable. A further disadvantage is that the long-term effects of the progestogen have not been fully determined. Thus, a large population of women require alternatives to hormone replacement therapies that can safely prevent the rapid bone loss that accompanies the menopause.
The formula I compounds are described in U.S. Patent No. 5,280,040. This patent describes the preparation of these compounds, as well as their use in reducing bone loss. The preparation of pharmaceutical compositions is also described.
Centchroman, which is 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1- yl)ethoxy)phenyl]-7-methoxychroman, is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et a]., U.S. Patent No. 4,447,622; Singh el al., Acta Endocrinal (Copenh) 126 (1992), 444 - 450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491 - 495; Sankaran el aL, Contraception 9 (1974), 279 - 289; Indian Patent Specification No. 129187). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra el aj., Int J Cancer 43 (1989), 781 - 783). Recently, centchroman as a racemate has been found as a potent cholesterol lowering pharmaceutical agent expressed by a significant decrease of the serum concentrations (S.D. Bain el al., J Min Bon Res 9 (1994), S 394).
Levormeloxifene, ( - ) - 3R,4R - trans- 7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2- (pyrrolidin-1-yl)ethoxy]phenyl}chromane, is a particular preferred compound from this series of 3,4-diarylchromans. Levormeloxifene may be used in human and veterinary medicine for the regulation of bone metabolism. It may be used, for example, in the treatment of patients suffering from bone loss due to osteoporosis (including post- menopausal osteoporosis and glucocorticoid-related osteoporosis), Paget's disease,
hyperparathyroidism, hypercalcemia of malignancy and other conditions characterized by excessive rates of bone resorption and/or decreased rates of bone formation.
The 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent No. 3,340,276 to Carney el a]., U.S. Patent No. 3,822,287 to Bolger, and Ray el aL, J Med Chem 19 (1976), 276 - 279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is disclosed in U.S. Patent No. 3,822,287. The optically active d- and l-enantiomers may be prepared as disclosed by Salman el aL in U.S. Patent No. 4,447,622
(incorporated herein by reference) by forming an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer. The resolvation of ( +/- ) - 3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane in its optical antipodes is described in U.S. Patent No. 4,447,622 incorporated herein by reference. Example 1 of U.S. Patent No. 4,447,622 describes the preparation of the minus enantiomer, shown by formula II :
( ID
(In this specification, the compound of formula II is referred to as levormeloxifene.) In example 2 of U.S. Patent No. 4,447,622, levormeloxifene is obtained as the free base and the hydrochloride salt.
The compounds of formula I may be administered as pharmaceutically acceptable salts. A particularly useful pharmaceutically acceptable salt of levormeloxifene is the hydrogen fumarate salt (in this specification, this compound is referred to as levormeloxifene fumarate.). This salt form is prepared by dissolving fumaric acid and (- ) -3R,4R- trans - 7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1 - yi)ethoxy]phenyl}chromane in a common solvent such as e.g. methanol, and crystallizing the resulting salt from the solution.
In WO 94/20098 the therapeutic doses of 3,4-diarylchromans for reducing bone loss, in particular, treatment of osteoporosis is mentioned to be in the range from 0.01-50 mg/kg/day, and the most preferred range being 0.1-5.0 mg/kg/day.
DESCRIPTION OF THE INVENTION
The present invention provides a pharmaceutical composition of a dosage form for oral administration comprising a compound of formula I
(I)
wherein R is C,_6alkyl; or a pharmaceutically acceptable salt thereof. The amount of compound of formula I needed is very low.
The present invention provides a pharmaceutical composition of a dosage form for oral administration comprising a compound of formula I
(l)
wherein R is Chalky!; or a pharmaceutically acceptable salt thereof, in an amount of between about 0.01 and 0.65 mg/day. Preferably the dosage form is a unit dosage form.
The compound of formula I may be used in an amount of between about 0.01 and 0.65 mg/day, in the treatment of patients suffering from bone loss due to osteoporosis (including post-menopausal osteoporosis and glucocorticoid-related osteoporosis), Paget's disease, hyperparathyroidism, hypercalcemia of malignancy and other conditions characterized by excessive rates of bone resorption and/or decreased rates of bone formation or in patients susceptible to bone loss. In one particular embodiment the pharmaceutical composition is for preventing bone loss. In another particular embodiment the pharmaceutical composition is for reducing bone loss. In a particular embodiment the bone loss is due to osteoporosis.
The present invention also relates to the use of a compound of formula I
(l)
wherein R is C^alkyl; or a pharmaceutically acceptable salt thereof, in an amount of between about 0.01 and 0.65 mg/day, for the preparation of a pharmaceutical com- position of a dosage form, preferably a in unit dose form, for oral administration for reducing bone loss. In one embodiment hereof the bone loss is due to osteoporosis.
The present invention furthermore relates to a method for reducing bone loss in a patient comprising administering to the patient suffering from bone loss a pharmaceutical composition in oral dosage form, preferably unit dose form, comprising a bone loss inhibiting amount of between about 0.01 and 0.65 mg/day of a compound of formula I
(i)
wherein R is Chalky!; or a pharmaceutically acceptable salt thereof. In one embodiment hereof the bone loss is due to osteoporosis.
In an embodiment of the present invention the composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, in an amount of between about 0.05 and 0.65 mg/day. In another embodiment the amount is between about 0.05 and 0.09 mg/day. In a still other embodiment the amount is between about 0.10 and 0.45 mg/day. In a further embodiment the amount is between about 0.45 and 0.65 mg/day. In a still further embodiment the amount is between about 0.05 and 0.45 mg/day. In a further embodiment the amount is between about 0.10 and 0.65 mg/day. In a particular embodiment the amount is about 0.25 mg/day.
In a further embodiment of the present invention R in the compound of formula I is methyl.
In a still further embodiment of the present invention the compound of formula I is in the trans configuration.
In a further embodiment of the present invention the compound of formula I is 3,4- trans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman or a salt thereof.
In a still further embodiment of the present invention the compound of formula I is an isolated l-enantiomer or a salt thereof.
In a further embodiment of the present invention the compound of formula I is ( - ) - 3R,4R - trans- 7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1 - yl)ethoxy]phenyl}chromane or a salt thereof.
In a still further embodiment of the present invention the compound of formula I is in the form of the hydrogen fumarate salt.
In a further embodiment of the present invention the compound of formula I is in the form of the hydrogen maleate salt.
In a still further embodiment of the present invention the composition further com- prises a hydrophilic binder, e.g. gelatin, cellulose derivative, cross-linked poly- vinylpyrrolidone or copolyvidone, wherein the amount of hydrophilic binder in the pharmaceutical composition is preferably from about 1% to about 25% (w/w), more preferred from about 2,5% to about 15% (w/w). More preferably, the hydrophilic binder is polyvinylpyrrolidone or copolyvidone. Most preferably, the hydrophilic binder is copolyvidone.
In a further embodiment of the present invention the composition further comprises a water-soluble diluent, wherein the amount of water-soluble diluent in the pharmacuti- cal composition is preferably from about 20% to about 98% (w/w), more preferred from about 20% to about 80% (w/w). The water-soluble diluent is preferably a sugar, a polysaccharide or cyclodextrin. More preferably, the water-soluble diluent is a sugar, such as lactose, sucrose, dextrose. Most preferably, the water-soluble diluent is lactose.
In a still further embodiment of the present invention the composition further comprises a non water-soluble diluent, wherein the amount of non water-soluble diluent in the pharmacutical composition is preferably from about 1% to about 50% (w/w), more preferred from about 5% to about 30% (w/w). The non water-soluble diluent is preferably a calcium phosphate, calcium sulphate, starches, modified starches or mi- crocrystalline cellulose. The non water-soluble diluent is more preferably microcrys- talline cellulose.
In a further embodiment of the present invention the composition further comprises an antioxidant, such as tocopherols or tocopherolesters, e.g. alpha-tocopherol succi- nate.
The composition is usually presented as a unit dose composition containing 0.01 -0.65 mg/day of a compound of formula I for oral dosing. The pharmaceutical compositions may be administered in a dosage form, preferably a unit dosage form, on a daily to weekly basis either once or divided in 2 or 3 doses, or 2 or 3 times per week or once weekly or once per 14 days.
In a still further embodiment of the present invention the composition may be on a solid dosage form, such as a tablet or capsule, or on a liquid dosage form, such as a solution, suspension or emulsion. Preferably, the composition is formulated as a tablet. For instance, such tablet may be administered on a daily basis, thus, comprising 0.01-0.65 mg of a compound of formula I, preferably levormeloxifene, more preferred levormeloxifene fumarate.
Optionally the composition further comprises a surfactant. When the surfactant is present, preferably it is an anionic or nonionic surfactant. Representative surfactants from this preferred group include sodium laurylsulfate, polyglycolyzed glycerides, polyoxyethylene sorbitan fatty acid esters, monoglycerides, diglycerides or glycerol. More preferably, the surfactant is a nonionic surfactant, such as polyoxyethylene sorbitan fatty acid esters or glycerol. Most preferably, the surfactant, when present, is glycerol.
Optionally the composition further comprises a lubricant(s) and/or a disintegrant.
In general, inhibition of bone loss is manifested as a statistically significant difference on cancellous bone volume between treatment and control groups. This can be seen as, for example, a 5-10% or more difference on spinal bone mass or bone mineral content over two years. Data from accepted animal models, such as the ovariec- tomized mouse or rat models of osteoporosis, are generally predictive of doses in humans to within one order of magnitude.
Within the present invention, the compounds of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of or- ganic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, maleic acid tar- taric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid- addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
The general chemical terms used in the above formula have their usual meanings.
As used herein, the term "Chalky!" includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like.
The term "pharmaceutically acceptable salt" represents salt forms of a compound of formula I that are physiologically suitable for pharmaceutical use. The pharmaceutically acceptable salts can exist in conjunction with a compound of formula I as acid addition primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alka- line earth metal salts. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula I, wherein R is as defined previously. The alkali metal and alkaline earth metal salts are generally prepared by the reaction of the metal hydroxide of the desired metal salt with a compound of formula I, wherein R is hydrogen.
The term "treating" or "treatment" is also intended to include prophylactic treatment.
The term "patient" is intended to include mammals, e.g. humans, such as males or females.
The term "hydrophilic binder" represents binders commonly used in the formulation of pharmaceuticals, such as polyvinylpyrrolidone, copolyvidone (cross-linked poly- vinylpyrrolidone), polyethylene glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, tragacanth, guar, and alginates), gelatin, and cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sodium car- boxymethylcellulose).
The term "water-soluble diluent" represents compounds typically used in the formulation of pharmaceuticals, such as sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), and cyclodextrins.
The term "non water-soluble diluent" represents compounds typically used in the formulation of pharmaceuticals, such as a calcium phosphate, calcium sulphate, starches, modified starches or microcrystalline cellulose.
The term "surfactant", as used herein, represents ionic and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbi- tan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium lauryl- sulfate, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids.
The term "antioxidant" represents the three groups of antioxidants, true antioxidants, reducing agents and antoxidant synergists, such as tocopherols, tocopherolesters, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, citric acid, edetic acid and its salts, lecithin and tartaric acid.
The term "disintegrant" represents compounds such as starches, clays, celluloses, alginates, gums, cross-linked polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose), sodium starch glycolate, low- substituted hydroxypropyl cellulose, and soy polysaccharides. Preferably, the disin- tegrant is a modified cellulose gum such as e.g. cross-linked sodium carboxymethylcellulose.
The term "lubricant" represents compounds frequently used as lubricants or glidants in the preparation of pharmaceuticals, such as talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumarate, and hydrogenated vegetable oils. Preferably, the lubricant is magnesium stearate or talc, more preferably magnesium stearate and talc in combi- nation.
The orally administerable formulations of the present invention are prepared and administered according to methods well known in pharmaceutical chemistry, see Remington's Pharmaceutical Sciences, 17th ed. (A. Osol ed., 1985). For example, the compositions of the present invention may be administered by means of solid dos- age forms such as tablets and capsules. Preferably, the compositions are formulated as tablets. These tablets may be prepared by wet granulation, by dry granulation, or by direct compression.
Tablets for this invention are prepared utilizing conventional tabletting techniques. A general method of manufacture involves blending of a compound of formula I, or a
salt thereof, and optionally the water-soluble diluent, the non water-soluble diluent, hydrophilic binder and optionally a portion of a disintegrant. This blend is then granulated with an aqueous solution of the hydrophilic binder or an aqueous solution of the hydrophilic binder and surfactant and milled, if necessary. The granules are dried and reduced to a suitable size. Any other ingredients, such as lubricants, (e.g. magnesium stearate) and additional disintegrants, are added to the granules and mixed. This mixture is then compressed into a suitable size and shape using conventional tabletting machines such as a rotary tablet press. The tablets may be film coated by techniques well known in the art.
Capsules for this invention are prepared utilizing conventional methods. A general method of manufacture involves blending of a compound of formula I, or a salt thereof, and optionally the water-soluble diluent, the non water-soluble diluent, a hydrophilic binder, and optionally a portion of a disintegrant. This blend is then granu- lated with an aqueous solution of the hydrophilic binder or an aqueous solution of the hydrophilic binder and surfactant in water, and milled, if necessary.
The granules are dried and reduced to a suitable size. Any other ingredients, such as a lubricant, are added to the granules and mixed. The resulting mixture is then filled into a suitable size hard-shell gelatin capsule using conventional capsule-filling machines.
The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.
EXAMPLES
Levormeloxifene fumarate and maleate was synthesized, purified and crystallized as described in the following examples.
Example 1
(-)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane, hydrogen fumarate (levormeloxifene fumarate).
To a stirred, 50 °C warm, solution of (+/-) - trans-7-methoxy-2,2-dimethyl- 3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (1.00 kg, 2.19 mol) in methanol (10 I) was added (+)-ditoluoyltartaric acid (464 g, 1.20 mol). The suspension was stirred at 50 °C until the solution was homogenous.
Formic acid (73 g, 1.59 mol) was added to the solution and the temperature was allowed to drop to 30 - 40 °C. If the crystallization has not started at this point, the solution was seeded, and the temperature was allowed to drop further down to 20 °C. The suspension was stirred for two hours at 20 °C and then cooled down to 5 - 10°C for two hours and the crystals were collected by filtration. Yield 742 g.
Recrystallization from refluxing methanol (26 I) gave after cooling to 5-10 °C and filtration pure crystals of the levormeloxifene (+)-ditoluoyltartrate salt. Yield 556 g. M.p. 136 - 138 °C (dec).
(-)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-ρhenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane, (+)-ditoluoyltartrate (500 g) was suspended in a mixture of toluene (2.5 I), water (2 I) and sodium carbonate (157 g) at ambient temperature. The mixture was stirred until the salts were dissolved. The aqueous phase was separated . The toluene phase was washed with water (2 I) and evaporated to an oil. The oil was dissolved in ethanol (1 I) at 40 - 60 °C and the solution was added to a solution of fumaric acid (69 g, 0.59 mol) in ethanol (2 I). The fumarate salt crystallized readily and
the mixture was stirred for an hour at 40 - 60 °C and then cooled down to 5 °C. The title compound was collected by filtration and dried at 50 °C to give 321 g (57 %).
M.p. 225 °C. (DSC).
H-NMR (DMSO-d6, TMS): δ (ppm): 2.90 (4H,m), 1.75 (4H, m), 3.10 (2H,t), 4.06 (2H,t), 6.69 (2H,d), 7.01 (2H,d), 4.50 (1H,d), 6.44 (1 H,m), 6.33(1 H, m), 6.38(1 H, m), 3.28(1H,d), 7.31(2H, br.s), 7.20(2H,m), 7.11(1 H, m), 1.15(3H,s), 1.27(3H,s), 3,68(3H, s), 6.53(2H,s) 10.0(2H, s).
MS: 457.2632 (M+ measured), 457.2617 (M+ calculated)
Elemental Analysis: (C30H35N O3,C4H4O4), Calculated: C:71.18 %, H: 6.85 %, N: 2.44 %, Found: C: 71.23 %, N: 7.15 %, N: 2.31 %
Optical rotation: [ α ]20 D= - 153.8 ° (c = 0.5 w/v % in ethanol).
Example 2
(-)-3R.4R-trans-7-methoxy-2.2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane. hydrogen maleate (levormeloxifene maleate)
To a stirred, 50 °C warm, solution of (+/-) - trans-7-methoxy-2,2-dimethyl- 3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (1.00 kg, 2.19 mol) in methanol (10 I) was added (+)-ditoluoyltartaric acid (464 g, 1.20 mol). The suspension was stirred at 50 °C until the solution was homogenous. Formic acid (73 g, 1.59 mol) was added to the solution and the temperature was allowed to drop to 30 - 40 °C. If the crystallization has not started at this point, the solution was seeded, and the temperature was allowed to drop further down to 20 °C. The suspension was stirred for two hours at 20 °C and then cooled down to 5 - 10°C for two hours and the crystals were collected by filtration. Yield 742 g. Recrystallization from refluxing methanol (26 I) gave after cooling to 5-10
°C and filtration pure crystals of the levormeloxifene (+)-ditoluoyltartrate salt. Yield 556 g. M.p. 136 - 138 °C (dec).
(-)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane, (+)-ditoluoyltartrate (500 g) was suspended in a mixture of toluene (2.5 I), water (2 I) and sodium carbonate (157 g) at ambient temperature. The mixture was stirred until the salts were dissolved. The aqueous phase was separated . The toluene phase was washed with water (2 I) and evaporated to an oil.
A part of the oil (3 g, 0.0066 mole) was dissolved in toluene (60 ml). Maleic acid (0.8 g, 0.0066 mole) was added. The mixture was heated until homogenous. It was stirred over night at ambient temperature. The maleinate salt crystallized readily. The title compound was collected by filtration and dried at 50 °C to give 3 g (80 %).
The compound was identified by NMR and elemental analysis.
Formulation 1
A typical tablet, which may be prepared by conventional tabletting techniques, contains:
The mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, antioxi- dant, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone. The granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium. The mixture is compressed into individual tablets yielding a tablet weight of 80 mg.