Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol

Definitions

• Osteoporosis is one of the major health problems in Western world, both for its high social cost and for the damages it brings about in patients, causing fractures in particular in forearm bones, in femur and in vertebrae.
• osteoporosis is characterized by a quantitative decrease in the amount of the bone, which means that the quality of bone tissue is normal, but it is insufficient; hence the increase of bone fragility.
• Osteoporosis is especially frequent in postmenopausal women, in relation with a decrease on ovaric function, and it is related to a deficit of estrogens. Therefore, estrogens have represented, and they still represent, a good therapeutic protection in the prevention of postmenopausal osteoporosis, since they slow down the bone loss and decrease the fracture rate.
• the use of estrogens in the treatment of postmenopausal symptoms is especially preferred, since it is useful not only to contrast and balance the loss of bone mineral content, but also to control climacteric disorders (vasomotor, neuropsychic , genitourinary disorders).
• climacteric disorders vasomotor, neuropsychic , genitourinary disorders.
• conjugated estrogens ar mainly used, whose minimal effective daily dose i known to be 0.625 mg, even though literature report that a dose of 0.300 mg can be sufficient for th control of bone mass loss, if combined to an adequat calcium supply.
• estrogens such as acute and chronic hepatopathies, cerebral vascular pathology and thromboembolic pathology, hypertension, mammary and endometrium neoplastic disease, and several relative contra- indications, such as cholecystopathies, endometriosis, fibrocystic mastopathy, uterine fibromyomatosis, diabetes, obesity, dyslipidemias, cardiocirculatory insufficiency, epilepsy.
• estrogens are usually combined with a progestinic preparation that would exert a protecting action at endometrium level.
• Progestinic preparations cause important side-effects on cardiovascular system, as well as changes of the serum lipid concentrations.
• a drug that recently turned out to be effective in prevention and treatment of postmenopausal and senile osteoporosis is ipriflavone, a compound having a complex mechanism of action that, anyhow, seems to exert a direct inhibition on bone reabsorption. Unlike other isoflavones, ipriflavone does not exert estrogen activity.
• Naloxone is commonly used to evaluate the stimulation of endogenous opioid system exerted by estrogens in postmenopausal women.
• Ipriflavone did not affect LH and FSH basal levels, nor, unlike what happened in a control group of
• Yamazi et al. (Life Sci. vol. 38, pages 1535-1541) also determined the effects of ipriflavone increasin doses on calcitonin secretion in ovariectomized rats, in the presence and in the absence of estrogens, showing that ipriflavone, in the presence of the estrogen, stimulates calcitonin secretion.
• Ipriflavone was administered orally, the estrogen subcutaneously.
• ipriflavone at least partially, had mechanism inhibiting bone mass loss mediated by an increase in calcitonin secretion in the presence of estrogens.
• the effects and possible interferences of ipriflavone and estrogens combination were never investigated in animals, nor in man.
• ipriflavone can favourably be administered in combination with estrogens, either in the free or conjugated or esterified form, for a more effective and safer therapy of the complex postmenopausal symptoms.
• the Applicant could evidence that ipriflavone, which is per se active on bone metabolism and able to stop mineral bone loss, when administered at normal therapeutic dosages in combination with estrogens not only does not interfere with the estrogen actions, but it dramatically reduces the required dosage of the latter, while keeping the effectiveness thereof in the control of climacteric symptoms.
• Each group was treated according to a different therapeutic scheme: - group 1: natural conjugated estrogens (CE) 0.3 mg/day + placebo
• a control group was administered with placebo only.
• Ipriflavone and placebo were not distinguishable and were compared in double-blind conditions.
• the combination of the two active ingredients can be carried out either extemporarily, by administering the two drugs separately, simultaneously or sequentially, or using unitary pharmaceutical compositions containing the two combined drugs.
• suitable packages will be prepared in form of kit-of-parts containing separate administration units for each drug, which units being sufficient to a given treatment time.
• novel pharmaceutical compositions will be used containing the two active ingredients in a single unit-dose.
• compositions are reported hereinbelow.
• the estrogen unit dose is indicated in 0.15 mg or 0.30 mg for sake of simplicity and that of ipriflavone in 600 mg, any other estrogen or ipriflavone dosage (higher, intermediate or lower), as far as it is effective and non-toxic, being comprised within the scope of the invention.
• EXAMPLE 1 Unitary composition of soft-gelatin capsules containing as the active ingredient 300 mg of ipriflavone in combination with 0.15 mg of conjugated estrogens.
• Hydrogenated vegetable oils 70.00 mg EXAMPLE 3.
• Ipriflavone is provided in the form of 200 mg capsules, to be administered 3 times a day, at meals. Recently, two novel pharmaceutical compositions containing ipriflavone have been prepared.
• the first one consists of soft-gelatin capsules, each containing 300 mg of ipriflavone, to be administered twice a day; the other one consists of squeezable capsules containing 600 mg of ipriflavone, to be administered only once a day, during the evening meal.
• the present invention also relates to pharmaceutical compositions containing the two active ingredients at set dosages, namely:
• Ipriflavone 300 mg capsules: 2 capsules/day, t be taken at the two main meals + 0.15-0.30 mg o estrogens to be taken after the evening meal.
• Ipriflavone 300 mg capsule: 1 capsule/day, to b taken at the noon meal + 1 capsule prepare according to the examples of the invention, containing 300 mg of ipriflavone in a se combination with 0.15-0.30 mg of estrogens, to b taken after the evening meal.
• a combination product of ipriflavone with very low doses of estrogens which doses are per se ineffective in preventing bone mass loss but active in controlling climacteric symptoms
• a product can be prepared in a variety of ways using the estrogens in all of the possibl administration forms, including transdermic patches.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=11358374

Family Applications (1)

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• 1991
  • 1991-02-01 IT ITMI910253A patent/IT1244697B/it active IP Right Grant
• 1992
  • 1992-01-24 IE IE021992A patent/IE920219A1/en unknown
  • 1992-01-27 NZ NZ241418A patent/NZ241418A/xx unknown
  • 1992-01-28 AU AU11884/92A patent/AU1188492A/en not_active Abandoned
  • 1992-01-28 CA CA002101547A patent/CA2101547A1/en not_active Abandoned
  • 1992-01-28 WO PCT/EP1992/000174 patent/WO1992013538A1/en not_active Application Discontinuation
  • 1992-01-28 HU HU9302183A patent/HUT64848A/hu unknown
  • 1992-01-28 EP EP92903484A patent/EP0569415A1/en not_active Ceased
  • 1992-01-30 ZA ZA92661A patent/ZA92661B/xx unknown

Non-Patent Citations (1)

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