HUT64848A - Medical preparatives for preventing and treating osteoporises after menopausa - Google Patents

Description

Osteoporosis is one of the major health problems in the Western world, both in terms of high social costs and the damage it causes to patients, particularly through fractures of the forearm, femur, and vertebra.

In fact, osteoporosis is characterized by a decrease in bone volume, which means that bone tissue is of normal but inadequate quantity, which causes an increase in bone fragility.

Osteoporosis is particularly common in postmenopausal (postmenopausal) women and is associated with decreased ovarian function and estrogen deficiency.

As a result, estrogens have been and continue to be a good therapeutic protection for post-menopausal osteoporosis by slowing bone loss and reducing fracture rates.

The use of estrogens in the treatment of post-menopausal symptoms is particularly advantageous in that it not only offsets and compensates for bone mineral loss, but also regulates menopausal disorders (vasomotor, neuropsychiatric and urinary tract disorders).

There are several types of estrogens, including natural and synthetic estrogens.

In the post-menopause substitution therapy, natural estrogens are preferred and have fewer side effects. Of the natural estrogens, conjugated estrogens are mainly used, with a minimum effective daily dose of 0.625 mg, and there are literature reports that 0.300 mg is sufficient for treatment to prevent bone loss when combined with adequate calcium supplementation.

Doses lower than the above are by no means considered effective.

However, the use of estrogens in therapy requires careful risk assessment as their use can have serious side effects. The use of estrogens is totally contraindicated in acute and chronic liver disease, pathological cerebral vasculature and thromboembolic disease, hypertension, breast and endometrial cancer, and in some cases it is relatively contraindicated, such as gallbladder disease, rheumatoid diabetes, obesity, lipid metabolism disorders, cardiovascular failure and epilepsy.

In order to limit the risk associated with chronic estrogen administration, and primarily to reduce the risk of carcinogenicity at the endometrial level, estrogens are usually combined with a progesterone-containing formulation which exerts a protective effect at the endometrial level. However, progesterone formulations have important cardiovascular side effects and alter serum lipid levels.

Recently, ipriflavone has been shown to be an active agent in the prevention and treatment of post-menopausal and senile osteoporosis, which has a complex mechanism of action and in any case appears to be a direct inhibitor of bone resorption.

Unlike other isoflavones, ipriflavone does not exhibit estrogenic activity.

Yamazi I. et al., Life Science, 38, 757-764, have demonstrated that ipriflavone can enhance the uterotrophic effect of low-dose estrone in ovariectomized rats without exerting direct estrogenic effects.

Lack of estrogen effects has also been reported in studies of 10 women who received ipriflavone 600 or 1000 mg orally and evaluated for LH (luteinising hormone) and FSH (follicle stimulating hormone) over a 24 hour period. LH secretion was also evaluated during naloxone (NAL) infusion before and 20 days after ipriflavone treatment.

Naloxone is commonly used to evaluate the stimulatory effects of estrogens on the endogenous opioid system of women beyond the menopause.

It is known that in postmenopausal women, NAL does not induce LH response and this response can be reversed by estrogen administration.

The administration of ipriflavone did not affect basal LH and FSH levels, unlike the control group in which EC-treated women had an LH response to NAL; thus, it was demonstrated that ipriflavone does not induce estrogen activity at the hypothalamus and pituitary level.

Furthermore, 20 days after treatment with ipriflavone, there was no detectable cytological change in the vagina in subjects in this group.

Yamazi, I. et al., Life Sci., 38, 1535-1541, also determined the effect of increasing doses of ipriflavone on calcitonin secretion in ovariectomized rats, a study conducted in the presence and absence of estrogens, demonstrating that estrogen is secreted in the presence of ipriflav.

Ipriflavone was administered orally, estrogen subcutaneously.

Based on the data obtained, the authors concluded that ipriflavone, at least in part, has a mechanism to inhibit bone loss by increasing the excretion of calcitonin in the presence of estrogens.

However, the effect and potential interaction of the combination of ipriflavone with estrogens has never been studied in animals or humans.

On the other hand, this therapeutic approach cannot neglect the fundamental role that hormone replacement therapy plays in the control of menopausal symptoms and the resulting direct dose-response relationship (Jensen, J., Christiansen, C., Maturitas, 5, 125 (1983)). ].

It has now been discovered that this is the basis of the present invention that ipriflavone in combination with estrogens can be advantageously administered in free, conjugated or esterified form, providing a more effective and safer therapy for complex menopausal symptoms.

We have assured that ipriflavone, which alone is effective for bone metabolism and capable of halting mineral bone loss, not only interacts with estrogen at its normal therapeutic dose, but in combination with estrogens, its effectiveness remains.

This result is particularly surprising because it demonstrates an unpredictable functional synergism between the two active ingredients and allows for the full treatment of post-menopausal conditions (prevention of osteoporosis and treatment of menopausal disorders) with obvious benefits.

It is a fact that

a) ipriflavone maintains its efficacy in reducing bone mineral at the normal therapeutic dose (600 mg / day),

b) estrogen is effective at controlling very low doses (0.300 mg / day or 0.150 mg / day) to control menopausal symptoms, about half or about a quarter of the usual daily dose (0.625 mg / day),

c) the extreme reduction in the daily dose of estrogen reduces the risk of serious side effects,

d) consequently, the dose and frequency of progesterone therapy can be significantly reduced.

The effects of combined administration of ipriflavone and estrogens were investigated in a 1-year study in an appropriate group of patients who were physiologically menopausal between 12 and 24 months and were confirmed by laboratory tests and had not received any prior treatment.

The study groups were treated according to the following different therapeutic regimens:

- Group 1: natural conjugated estrogens (CE)

0.3 mg / day + placebo

- Group 2: CE 0.3 mg / day + ipriflavone 600 mg / day

- Group 3: CE 0.15 mg / day + placebo

- Group 4: CE 0.15 mg / day + ipriflavone 600 mg / day.

There was also a control group in the study to which only placebo was given.

For ethical reasons in the control group and in order to ensure adequate exogenous calcium intake, each patient in the study was also given 1 g of calcium daily.

Ipriflavone and placebo were indistinguishable and double-blind conditions were used to compare them.

The first clinical follow-up was performed 3 months after the start of treatment, including assessment of typical menopausal symptoms. Six months after the start of treatment, in addition to clinical examination, mineralometry was also performed by fixed-point dual-photon absorption.

Table 1 shows the results of the determination of bone mineral content of 76 women measured on the spinal bone one month after the start of treatment.

1 «Table

Bone mineral content in mg / cm ² (+ SE), measured in the distal portion of the spinal bone of postmenopausal women 6 months after initiation of ipriflavone + conjugated estrogen treatment

P (n = 13) P + CE 0.15 (= 16) P + CE 0.30 (n = 17) Ip + CE 0.15 (n = 13) Ip + CE 0.30 (n = 17) basis 377.54 397.25 396.58 403.85 382.24 value 17.60 20.27 17.46 17,24 16.49 6 X X X X X month 372.00 -1.44 394.31 -0.23 401.12 + 1.47 414.85 +3.08 393.35 + 3.16 ° * 17.55 18.95 17.03 16.96 15.72

P = placebo

P + CE 0.15 - placebo + conjugated estrogens 0.15 mg / day

P + CE 0.30 - placebo + conjugated estrogens 0.30 mg / day

Ip + CE 0.15 - ipriflavone 600 mg / day + conjugated estrogens

0.15 mg / day

Ip + CE 0.30 - ipriflavone 600 mg / day + conjugated estrogens

0.30 mg / day n - number of patients in each group% difference from baseline * - Wilcoxon test treatments p <0.001 versus placebo ° Within Student test treatments p <0.002 versus baseline.

The results presented in Table 1 demonstrate that the combined use of estrogens at the subactive dose not only maintains the effect of ipriflavone on bone mineral loss, but also enhances this effect.

In fact, even in the group of patients, effective bone mass control occurs after 6 months of treatment with Ip + CE 0.15, unexpectedly in the group of patients who received Ip + CE 0.30 in bone mineral content. unexpectedly, statistically significant growth occurred.

This result is all the more surprising since no results have been reported so far for active substances that affect bone metabolism that enhance their effect in combination with estrogens.

The results obtained for each characteristic menopause symptom are shown in Table 2. For the evaluation of symptoms, the evaluation numbers have the following meaning:

- heat waves: 0 = none; 1 = less than 5 daily;

= 5-10 daily; 3 = more than 10 daily.

- other symptoms: 0 - none; 1 = slight; 2 = medium;

= severe.

In Table 2, the mean scores and the associated standard error are reported for each time point and for each treatment. Symptoms were analyzed by Wilcoxon Signed-Rank significance test using differences in t3 and t6 times.

• ··· «* *« ♦ ··

Table 2

Evaluation of some vasomotor symptoms in postmenopausal women before, 3 and 6 months after treatment with ipriflavone + conjugated estrogen

Symptoms P P + CE 0.15 P + CE 0.30 Ip + CE 0.15 Ip + CE 0.30 n to t3 12 l, 42 (± 0.19) l, 17 (± 0.17) N. S. 15 1.80 (± 0.17) 0.87 (± 0.26) p <0.01 14 1.93 (+0.22) 0.79 (+0.24) p <0.01 11 1.73 (+0.30) 0.18 (+0.18) p <0.01 13 2.08 (± 0.26) 0.69 (± 0.21) p <0.01

heat waves

t6 0.83 (± 0.21) p <0.05 0.60 (+0.21) p <0.01 0.64 (± 0.23) p <0.01 0.09 (± 0.09) p <0.01 0.69 (+0.21) p <0.01 n 12 12 14 13 14 lake l, 42 (± 0.23) 1.83 (+0.21) l, 79 (± 0.21) l, 77 (± 0.20) l, 86 (± 0.25)

joint pain / muscle pain

t3 1.00 (+0.25) 1.00 (± 0.28) 1.14 (+0.29) 0.77 (± 0.26) l, 07 (± 0.30) N. S. p <0.05 p <0.01 p <0.01 p <0.05 t6 1.00 (+0.28) 0.75 (+0.28) l, 00 (± 0.26) 0.38 (+0.18) 1.00 (+0.26) N. S. p <0.05 p <0.05 p <0.01 p <0.05 n 10 11 12 7 13 lake 1.00 (+0.30) 1.36 (+0.15) l, 33 (± 0.14) 1.14 (+0.14) 1.46 (+0.24)

palpitations

t3 l, 10 (± 0.23) 0.64 (+0.20) 0.58 (± 0.19) 0.57 (± 0.20) 0.69 (± 0.21) N. S. p <0.01 p <0.01 N. S. p <0.01 t6 0.80 (+0.20) 0.64 (± 0.20) 0.33 (+0.22) 0.29 (+0.18) 0.69 (+0.17) N. S. p <0.01 p <0.01 p <0.05 p <0.05

P = placebo

P + CE 0.15 P + CE 0.30 - placebo + conjugated estrogens 0.15 mg / day - placebo + conjugated estrogens 0.30 mg / day

Ip + CE 0.15 - ipriflavone 600 mg / day + conjugated estrogens · * ·· ·· ♦ 4 • · »• · · ·

0.15 mg / day

Ip + CE 0.30 - ipriflavone 600 mg / day + conjugated estrogens

0.30 mg / day n - number of patients in each group.

The results in Table 2 demonstrate that very low doses of estrogen, such as 0.15 mg / day, can provide effective control of menopausal symptoms.

However, such low dose estrogens alone are not capable of controlling bone mineral loss, as clearly shown in Table 1. Combination therapy with ipriflavone, an active ingredient in bone mineral metabolism, allows for very low doses of estrogen to be achieved:

- prevention and control of bone mineral loss;

- prevention and control of menopausal disorders; and besides, the side effects of using estrogens are extremely reduced.

The combination of the two active ingredients can be carried out simultaneously, by administering the two active ingredients separately, simultaneously or sequentially, or by using a single pharmaceutical composition comprising the two active ingredients combined.

In the first case, which allows for a more adaptable, more flexible treatment regimen, appropriate dosage units should be prepared in the form of a kit consisting of dosage units of each active ingredient in an amount sufficient to provide a unit duration of treatment.

In the second case, new pharmaceutical compositions are used which contain the two active compounds in a single dosage unit.

For the sake of example, some compositions are shown below. In the compositions, 0.15 mg or 0.30 mg estrogen dosage unit and 600 mg ipriflavone dosage unit are shown for simplicity, any other dose (higher, medium or lower) of estrogen or ipriflavone may be used as long as effective and non-toxic, these doses are within the scope of the invention.

Example 1

Soft gelatine capsule unit dose formulation containing 300 mg ipriflavone and 0.15 mg conjugated estrogen in combination.

ipriflavone 300.00 mg Natural conjugated estrogens 0.15 mg Soy lecithin 50.00 mg Medium chain triglycerides 259.85 mg Hydrogenated vegetable oils 70.00 mg

Example 2

Soft gelatine capsule is a unit dose preparation which

Contains 300 mg ipriflavone and 0.30 mg conjugated estrogen in combination.

Ipriflavon 300.00 mg

Natural Conjugated Estrogens 0.30mg «« 4 «* ··· ·» 4 4 * 4 · * * 444 φ »* · 4» 4 »» · 4 • · · 4 · 4

- 13 Soybean lecithin

50.00 mg

Medium chain triglycerides

259.70 mg

Hydrogenated vegetable oils

70.00 mg

Example 3

Compressible capsule unit dose composition which

Contains 600 mg ipriflavone and 0.30 mg conjugated estrogen in combination.

ipriflavone

600.00 mg

Natural conjugated estrogens

0.30 mg

Soy lecithin

27.00 mg

Medium chain triglycerides

870.70 mg

It is a mixture of palmitic acid and stearic acid mono-, di56.00 mg and triglycerides

White chocolate

600.00 mg

Sodium saccharinate

1.00 mg

sorbitol

300.00 mg

Orange flavoring

25.00 mg

1-3. The pharmaceutical compositions of Examples 1 to 8 are prepared by the process described in PCT Patent Publication No. WO 91/14429.

When available to the physician, the two active ingredients in discrete units, as well as one or more compositions containing the two active ingredients in defined doses, will allow the physician to select the most appropriate treatment type and regimen.

Various dosage regimens may be used, for example 200-600 mg ipriflavone and 0.15-0.30 mg estrogen.

Ipriflavone is given as 200 mg capsules three times a day with food.

More recently, two new pharmaceutical compositions containing ipriflavone are being prepared.

One is a soft gelatin capsule containing 300 mg ipriflavone given twice daily and the other is a compressible capsule containing 600 mg ipriflavone taken once daily with an evening meal.

The present invention also encompasses pharmaceutical compositions comprising the two active ingredients in a single dose, namely:

Unit dosage formulations containing 300 mg ipriflavone in combination with 0.15-0.30 mg conjugated estrogen; and

Unit dose formulations containing 600 mg ipriflavone and 0.15-0.30 mg conjugated estrogen.

Accordingly, the possible daily therapeutic regimen is as follows:

A. 200 mg ipriflavone tablets: 300 tablets / day with meals + 0.15-0.30 mg estrogen to be taken after an evening meal.

B. 300 mg ipriflavone capsules: 2 capsules daily taken with two main meals + 0.15-0.30 mg estrogen taken after an evening meal.

C. 300 mg capsule ipriflavone: 1 capsule / day to be taken at noon + 1 capsule combination of 300 mg ipriflavone and 0.15-0.30 mg estrogen prepared according to the example of the present invention, which after an evening meal need to be taken.

D. 300 mg ipriflavone capsules: 2 capsules / day in a kit containing 0.15 mg estrogen to be taken with the two main meals.

E. 600 mg compressible ipriflavone capsule: 1 capsule / day in a combination of 0.15-0.30 mg estrogen, to be taken with an evening meal.

From the above, the preferred treatment regimen is at the discretion of the physician.

Because one of the most important aspects of the present invention is a combination product containing a very low dose of estrogen, a dose which is not effective in preventing bone loss but active in the control of menopausal symptoms, such a product can be prepared in many ways; they can be used in possible dosage forms, including transdermal patches.

In order to facilitate the therapeutic cycle, suitable formulations may be prepared for each product of the invention and provided with information on the regimen.

Claims (7)

PATENT CLAIMS An oral pharmaceutical composition for the treatment of menopausal syndrome, in particular for the prevention and treatment of post-menopausal osteoporosis, and for the treatment of menopausal disorders comprising 200-600 mg ipriflavone in combination with 0.15-0.30 mg estrogen per dosage unit. 2. The pharmaceutical composition of claim 1, wherein said estrogen is conjugated estrogen or esterified estrogen. The pharmaceutical composition of claim 1 in the form of a kit of parts comprising ipriflavone and estrogen as a combined preparation for simultaneous, separate or sequential use. The pharmaceutical composition according to claim 1 or 2, in the form of soft capsules, each containing 300 mg of ipriflavone active ingredient in combination with about 0.15-0.30 mg of estrogen. The pharmaceutical composition according to claim 1 or 2, comprising 600 mg ipriflavone per dosage unit in combination with about 0.15-0.30 mg estrogen. 6. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains estrogen as estrogen. 7. The combined use of estrogens and ipriflavone for the preparation of an oral pharmaceutical composition for the prevention and treatment of post-menopausal osteoporosis and for the treatment of menopausal disorders.