Patent Application: US-16270802-A

Abstract:
this invention relates to a method for inhibition of skin atrophy , or epithelial or mucosal atrophy in women , or to a method for treatment or prevention of symptoms related to said atrophy , said method comprising administering to the woman an effective amount of the compound of formula or a geometric isomer , a stereoisomer , a pharmaceutically acceptable salt , an ester thereof or a metabolite thereof .

Description:
the methods according to this invention are particularly useful for women during or after the menopause . however , the methods according to this invention is not restricted to women in this age group . this invention relates particularly to the use of the estrogen receptor modulator ospemifene in women during or after the menopause . ospemifene is the z - isomer of the compound of formula ( i ) and it is one of the main metabolites of toremifene , is known to be an estrogen agonist and antagonist ( kangas , 1990 ; international patent publications wo 96 / 07402 and wo 97 / 32574 ). the term “ metabolite ” shall be understood to cover any ( deaminohydroxy ) toremifene metabolite already discovered or to be discovered . as examples of such metabolites can be mentioned the oxidation metabolites mentioned in kangas ( 1990 ) on page 9 ( tore vi , tore vii , tore xviii , tore viii , tore xiii ), especially tore vi and tore xviii , and other metabolites of the compound . the use of mixtures of isomers of compound ( i ) shall also be included in this invention . a particular form of atrophy to be inhibited is urogenital atrophy . symptoms related to urogenital atrophy can be divided in two subgroups : urinary symptoms and vaginal symptoms . as examples of urinary symptoms can be mentioned micturation disorders , dysuria , hematuria , urinary frequency , sensation of urgency , urinary tract infections , urinary tract inflammation , nocturia , urinary incontinence , urge incontinence and involuntary urinary leakage . as examples of vaginal symptoms can be mentioned irritation , itching , burning , maladorous discharge , infection , dyspareunia , leukorrhea , vulvar pruritus , feeling of pressure , postcoital bleeding , vaginal dryness and difficulty in sexual arousal . the effect of atrophy of the skin is cosmetic , but can also be associated with pathological conditions such as decreased ability of the skin to undergo wound healing . atrophy or aging of skin appears as change of smoothness and texture causing roughness in look and feel on the outer surface of the skin , change of elasticity of the skin effecting the mechanical properties of the skin , and changes in skin pigmentation . skin aging in postmenopausal women can also be measured as decrease in the mitotic rate of keratinocytes , changes in dermal thickness and decrease in glucosaminoglucans and soluble collagen which are linked to the moisture content of the skin . the new and surprising effect of ospemifene was found in a clinical study . in this study , raloxifene ( 60 mg / day ) or ospemifene at different doses were given to elderly female volunteers for a period of 3 months . at the dose levels of 30 , 60 and 90 mg of ospemifene daily , a significant decrease in vaginal atrophy was observed . an improved sexual activity was also reported . these properties are new and unique among the known selective estrogen receptor modulators ( serms ) and indicate that ospemifene at the doses from 25 mg to slightly lower than 100 mg daily , particularly 30 to 90 mg daily , can be successfully used to alleviate symptoms derived from atrophy , especially urogenital atrophy in women during or after the menopause . furthermore , ospemifene has a superior profile of estrogenic and antiestrogenic effects when compared to any known antiestrogen or serm compound . ospemifene has been found to alleviate many symptoms related to urogenital atrophy , both urinary symptoms and vaginal symptoms . ospemifene has also been found to alleviate sexual dysfunction and to increase the sexual activity . types and causes of female sexual dysfunction are particularly desire disorders , arousal disorders , orgasmic disorders and painful intercourse ( dyspareunia ). most of these are due to hormonal reasons , especially to reduced estrogen and testosterone concentrations . vaginal atrophy is one of the main causes of female sexual dysfunction and will typically develop after the menopause when the estrogen concentrations decrease . typically this leads to painful intercourse , which indirectly may influence on any type of sexual dysfunction , including psychological causes . in elderly women vaginal atrophy is often the main reason for decreased sexual activity . ( spector and carey , 1990 ). estrogens and testosterone are useful pharmaceutical treatments of vaginal dryness and it is not surprising that pure antiestrogens like raloxifene cause vaginal dryness . subsequently , the patients are not satisfied with the treatment which causes painful intercourse and will stop the therapy . the compound ( i ) can according to this invention be administered by various routes such as oral , topical , transdermal , intravaginal or subcutaneous routes , of which oral or transdermal administration routes are the most preferable . suitable preparation forms include for example tablets , capsules , granules , powders , suspensions , syrups and transdermal formulations , ointments , creams , or gels . also subcutaneous implants may be useful for prolonged use . for vaginal local delivery vaginal creams , gels , vagitories , vaginal tablets , pessaries or vaginal rings are preferred . a clinical phase i – ii study was carried out to study the effects of ospemifene on endometrial thickness , endometrial pathology , ( biopsy taken by curettage as described by vuopala et al , 1982 ) and cervical smear in healthy postmenopausal female volunteers in the age range 55 to 69 years . tolerability and pharmacokinetics were also assessed . raloxifene ( 60 mg daily ) was used as reference . ospemifene was given perorally at the doses of 30 , 60 and 90 mg daily . there were 29 volunteers at each dose level , as well as in the raloxifene group . ospemifene was administered in gelatine capsules containing either 30 , 60 or 90 mg of ospemifene . the thickness of the endometrium was evaluated by ultrasonography using a hitachi eub - 405 instrument . the vaginal epithelium was assessed by karyopyknosis index which is a well known assessment method among the skilled persons . in this method , the vaginal fraction of the cervical smears is estimated as the percentage of the number of cells from different layers : the parabasal cell layer ; the intermediate cell layer ; and the superficial cell layer . estrogenicity is seen by a shift towards superficial cell fraction . in postmenopausal women this fraction usually is close to zero and estradiol treatment increases the fraction close to 100 . samples were taken before and after the treatment ( at 3 months ). the vaginal dryness symptoms were also assessed by using a visual analogue scale where the volunteers themselves recorded their subjective estimates . the scale is based on a 100 - mm line on paper . the left end represents no symptom and the right end the worst possible symptom . the change from pre - treatment to 3 months estimates was assessed and considered to be indicative of the treatment efficacy . there were no differences in the demographic data between the treatment groups in any of the pre - treatment measurements . table 1 below shows the change in maturity index for parabasal cells ( mi 1 ) and maturity index for superficial cells ( mi 3 ), after 3 months &# 39 ; administration of varying doses of ospemifene or raloxifene . in fig1 a to 1d there are shown changes ( from start to 12 weeks &# 39 ; treatment ) in the karyopyknosis index for superficial cells of the vaginal epithelium for the individuals treated daily with 30 mg ospemifene ( 1 a ), 60 mg ospemifene ( 1 b ), 90 mg ospemifene ( 1 c ), and 60 mg raloxifene ( 1 d ). in the figures , the code fc - 1271a is used instead of the generic name ospemifene . cervical smear assessments indicate that no one in the raloxifene group ( fig1 d ) had a significant change from baseline to post - treatment in the karyopyknosis index for superficial cells . most of the individuals in the ospemifene groups had slight increases in the index , but in rest of the subjects the estrogenic effect was very weak , if measurable at all . in all cases the increase was small (& lt ; 40 except for one case which was 45 in the 90 mg group ) when compared to estradiol which is known to increase the index virtually by 100 . a weak but statistically significant estrogenic effect in the cervical smear was therefore documented . no pathological changes were seen in any sample . fig2 shows that raloxifene caused only a minor decrease on vaginal dryness , assessed by the individuals &# 39 ; subjective estimate , while all the ospemifene dosage levels indicated a clear decreasing effect . the dose level 60 mg ospemifene daily gave the best result . ospemifene had a weak estrogenic effect on endometrial histology . this effect is clearly weaker than that seen with estrogen replacement therapy . there were no malignant findings in the endometrium . the thickness of the endometrium as assessed by ultrasonography showed only a minor , statistically not significant , increase in the thickness ( average 0 . 2 mm , 0 . 5 mm and 0 . 5 mm ) at the dose levels of 30 , 60 and 90 mg , respectively . the measured values were always smaller than 8 mm , which is considered to be a thickness which is indicative for a physiologically significant estrogenicity of serms like tamoxifen ( hann et al , 1997 ; lahti et al , 1993 ). in the clinical phase i and ii studies , 241 posmenopausal women have been treated with ospemifene . 77 were treated with 25 – 30 mg , 78 with 50 – 60 mg , 78 with 90 – 100 and 8 with 200 mg daily dose of ospemifene . in the control groups , 47 were treated with placebo and 29 with raloxifene . some of the subjects reported spontaneously alleviation of the symptoms associated with urogenital atrophy . the symptoms include both vaginal and urinary symptoms such as vaginal discomfort with irritation , itching , burning , smarting , dyspareunia , postcoital bleeding , vulvar itching and / or malodorous discharge and leukorrhea . the urinary symptoms alleviated in individual cases include urinary incontinence , recurrent urinary tract infections , micturition disorders , urinary frequency , nocturia , sensation of urgency , urge incontinence and involuntary urinary leakage . also , the clinicians reported cases where signs of urogenital atrophy , such as vaginal pallor , petechiae , friability , vaginal dryness , vaginal mucosa atrophy and ulceration were alleviated by ospemifene . in the clinical study , where the effects of ospemifene on quality of life and cardiovascular parameters were studied , the patients were asked for sexual activity . the questionnaire included “ worsening ” or “ no effect ” on sexual activity . improvement on sexual activity was not asked . when 70 patients had been followed up for 6 weeks , 27 of them had spontaneously reported to the investigators increased sexual activity . similar reports were independently obtained from different centers of the study . this strongly suggests that ospemifene has a positive effect on the sexual activity and quality of life . the results indicate that ospemifene has a unique pharmacological profile with regard to estrogen - like effects on vaginal atrophy and insignificant endometrial effects . in these tissues the estrogenicity is markedly lower than that of the known serms tamoxifen and toremifene , but higher than that of raloxifene . in contrast to other serms , it does not cause menopausal symptoms . actually ospemifene at the doses of 25 mg or more , and especially 30 – 90 mg daily , alleviated such symptoms . ospemifene has an especially beneficial effect in that it decreases vaginal dryness and sexual dysfunction . based on the present data , the optimal clinical dose is expected to be higher than 25 mg daily and lower than 100 mg daily . a particularly preferable daily dose is found in the range 30 to 90 mg . at the higher doses ( 100 and 200 mg daily ), ospemifene shows properties more similar to those of tamoxifen and toremifene . ospemifene is an especially valuable drug because it has an excellent tolerability . in addition , ospemifene decreases total and ldl cholesterol , increases hdl cholesterol , and prevents osteoporosis and early stage breast cancer . the present invention suggests that ospemifene and other compounds of formula ( i ) can be also used during menopause as hormone replacement therapy instead of estrogens , which are known to increase the risk of breast and endometrium cancers . it will be appreciated that the methods of the present invention can be incorporated in the form of a variety of embodiments , only a few of which are disclosed herein . it will be apparent for the expert skilled in the field that other embodiments exist and do not depart from the spirit of the invention . thus , the described embodiments are illustrative and should not be construed as restrictive . delmas p d , bjarnason n h , mitlak b h , ravoux a c , shah a s , huster w j , draper m , christiansen c : effects of raloxifene on bone mineral density , serum cholesterol concentrations , and uterine endometrium in postmenopausal women . n engl j med 337 : 1641 – 1647 , 1997 ettinger b , genant h k , cann c e : long - 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