Use of a cross-linked polycarboxylic polymer and progesterone for manufacture of medicinal preparations

The invention relates to the field of pharmaceutical production, namely to the use of a cross-linked polycarboxylic polymer and progesterone in the manufacture of a medicament.

Progesterone is a naturally occurring steroid that is the main steroid secreted by women of childbearing potential. This steroid has been extensively studied and has been found to be important for the biosynthesis of many other steroids, including glucocorticoids, androgens and estrogens. Progesterone also promotes uterine development and many other specific changes in the lining of the uterus and uterine muscle tissue, which is crucial for the development of decidual tissue and for differentiation of the multilayer squamous epithelium and glandular epithelial tissue. Progesterone also acts in various ways during pregnancy, namely, breast enlargement, suppression of uterine contractions, pregnancy support, immunological protection of the embryo, and inhibition of prostaglandin synthesis. Progesterone has been used pharmaceutically for the treatment of many clinical conditions such as luteinization phase failure, dysfunctional uterine bleeding, endometriosis, uterine cancer, benign breast disease, preeclampsia and is involved in in vitro fertilization, preventing premature miscarriage and suppressing uterine mucosa. therapy (ERT).

The most widely used substance is a synthetic progesterone replacement that has undesirable effects such as depression and water retention in tissues. In addition, most progestins derived from 19-nor2 testosterone result in a positive effect of estrogens on lipoprotein levels (HDL). On the other hand, natural progesterone does not cause water retention in tissues, is rarely associated with depression and does not adversely affect lipid levels.

Hormone replacement therapy (HRT) with progesterone in menopausal women carries the risk of breast cancer, which can lead to the same level of blame for both estrogen and progesterone. The proliferation of the dorsal lobe of the duct, which is the major cause of breast cancer, is relatively low during the follicular phase of the menstrual cycle (estrogen only). It is subsequently elevated by one of two factors in the mid-late lutein phase (estrogen and progesterone). Thus, the combination of estrogen and progesterone demonstrates that there is a greater effect of stimulating cell division than estrogen alone compared to progesterone in the uterine lining as an antimitotic agent. These observations have led to the development of the estrogen hypothesis of progesterone in breast etiology. This hypothesis is based on the fact that the risk of breast cancer increases with estrogen alone, but continues to increase without the simultaneous protection of breast epithelium by estrogen and progesterone. Based on data received in Sweden, it was assumed that the risk associated with the combination HRT is greater than that based on ERT alone, as demonstrated by the rate of breast mitosis.

Another problem with progesterone is central nervous system (CNS) depression. Too much progesterone can cause fatigue and in some cases progesterone can be used as an analgesic.

There have been many difficulties in administering natural progesterone to patients in order to have adequate levels of serum and tissue. When progesterone is administered during the boom, it is rapidly degraded. See, e.g., Adlecruz, H. and Martin, FJ Steroid Biochem., 13: 231-244 (1980) and Maxson, WS, and Hargrove, JT, Fertil. Steril, 44: 622-626 (1985). Some studies have shown that tissue progesterone levels can be achieved at a dose of 200 mg progesterone, serum progesterone levels recorded for six hours, but with a wide range of variations among patients. See Maxson, WS and Hargrove, JT, Fertil. Steril., 44: 622-626 (1985); Whitehead, MI, et al., Br. Med. J., 180: 825-827 (1980); Sitruk-Ware, R, et al., Contraception 36: 373-402 (1987).

Progesterone administration to the rectum has also been tested at progesterone doses of 25 mg and 100 mg, reaching peak plasma progesterone levels between 4 and 8 hours after administration, followed by a gradual decrease, but thus maintaining stable plasma progesterone levels was difficult. . See Maxson, WS Clinical Obset. Gynecol, 30: 465-477 (1987); Nillius, SJ and Johansson, EDB Am. J. Obstet. Gynecol, 110: 470-479 (1971). Subcutaneous administration produced a rapid result: progesterone rapidly appeared in the serum, reaching a maximum of 10 times the baseline but returning to v

of the basic amount within 24 hours. See Villanueva, B, et al., Fertil. Steril, 35: 433-437 (1981). Nasal administration at doses of 20 mg and 30 mg resulted in mean peak concentrations of 2.1 and 4.1 ng / ml at approximately 30 and 240 minutes, respectively.

Intramuscular administration of progesteroma has been performed. A dose of 100 mg progesterone was achieved with a serum progesterone concentration of 40 to 50 ng / ml for 2 to 8 hours v

after the appointment. See Nillius, SJ and Johansson, EDB, Am. J. Obstet. Gynecol., 110: 470-479 (1971). This appointment indicated that such injections should be given daily or every other day to produce results. See Whitehead, M. and Godfree, V. in Hormone Replacement Therapy, Churchill Livingston Edinburgh 1992, pp 91. Subcutaneous administration has also been studied with six 100 mg progesterone capsules implanted in women who have given birth. Watch Croxatto,

HB et al., Act. Endocrinol, 100: 630 (1982). Progesterone levels peak at 4.4 ng / ml during the first week after implantation and reach a peak average of 1.9 ng / ml at 6 months. after implantation. Progesterone implantation is not convenient for cyclin therapy and furthermore physiological amounts of progesterone are not achieved in this way.

Topical application of radioactive progesterone has been shown to be absorbed through the skin. See Mauvais-Jarvis, Progesterone., Et al., J. Clin. Endocrinol. Metab., 29: 1580-1587 (1969). Labeled metabolites were found in the urine 48 hours after administration. Nevertheless, absorption was only 10% of the administered dose. The good fat solubility of progesterone guarantees long-term survival of these steroids but extensive local metabolism reduces the overall effect of steroids. Topical application of progesterone in breast therapy appeared to have no effect on

histology or bleeding if ruptures have occurred. See Sitruk-Ware, R., et al., J. Clin. Endocrin. Metab., 44: 771-774 (1977).

Progesterone has also been introduced into the vagina during postmenopausal women receiving ERT. See Villanueva, B., et al., Fertik Sterik, 35: 433437 (1981). Administration of a 50 mg / ml suspension of progesterone containing carboxylmethyl cellulose and methyl cellulose in the vagina showed rapid absorption of progesterone through the vaginal mucosa. In the peripheral circulation, hormones appeared directly after 15 minutes. increased 10 times the basal serum level (0.34 ng / ml). Maximum progesterone levels were reached 1 or 2 hours after dosing and were 30-40 fold higher than baseline (12.25 ng / ml). Serum progesterone levels remained at this level for more than 7 hours, gradually decreasing over the next ten hours to 3.68 ng / ml. See Villanueva, B., et al., Fertil. Steril., 35: 433437 (1981). These studies showed that progesterone absorption was increased in women also receiving ERT.

The vaginal prescription of progesterone is frustrating due to the diversity of patients. Side effects included vaginal irritation and discharge, vaginal inflammation, itching and sporadic onset of menstruation. See Maxson, WS Clinical Obstet. Gynecol., 30: 465-477 (1987). However, no other undesirable effects were observed.

The present invention encompasses the manufacture of a medicament based on the use of a cross-linked polycarboxylic acid polymer, wherein the medicament is used for topical administration of progesterone to the vagina. This route of administration produces serum progesterone levels ranging from 1 ng / ml to 6 ng / ml, although complete reversal of endometrial secretion is still shown. In this way, low levels of progesterone in the bloodstream reduce the risk of side effects while protecting against endometrial cancer.

FIG. 1 is a graphical representation of serum progesterone concentration versus time of treatment, according to the present invention, when a dose of 45 mg progesterone was administered to the vagina every other day in women with ovarian failure.

FIG. Figure 2 is a graph depicting serum progesterone levels versus time of treatment, according to the invention, with a dose of 90 mg progesterone administered every other day to women with ovarian failure.

Fig. 3 is a graph depicting the serum progesterone content versus time of treatment, when a 180 mg progesterone dose according to the invention was administered to the vagina every other day in women with ovarian failure.

The present invention also relates to an improved vaginal delivery of progesterone to a female. Progesterone, which is used to prevent endometrial cancer, needs to be present in the blood circulation and breast at the lowest concentration needed and for the minimum number of days to achieve a growth inhibiting effect on the endometrium while keeping the risk of developing breast cancer with progesterone. In addition, low levels of serum progesterone do not cause possible CNS depression and other possible side effects. The use of a slow release bioadhesive polymer with relatively low levels of progesterone for vaginal delivery of progesterone has shown the surprising result that complete secretion of uterine mucosa occurs at very low serum progesterone levels, which reduce the risk of breast cancer and other progesterone related side effects. As a result, this method allows for the practical use of progesterone.

Changes in the secretory phase of the lining of the uterus following progesterone administration were used as an indicator when the therapeutic effect of progesterone was achieved in the lining of the uterus. The present invention provides, in particular, this change in secretion of the uterine lining by administration of progesterone to the vagina at low serum circulating progesterone concentrations of about 1 ng / ml to about 6 ng / ml, and preferably about 1 ng / ml to 4 ng / ml, and more preferably from about 1 ng / ml to 2 ng / ml. In the prior art, including vaginal suppositories, the amount of circulating progesterone required was much higher, from about 10 ng / ml to 12 ng / ml, yielding the same changes. During normal physiological luteinization, progesterone levels in the blood should reach at least 7 ng / ml to produce a change in endometrial secretion, which is the necessary physiological concentration required for a change in endometrial secretion.

These results of uterine mucosal biopsy following the use of progesterone according to the invention show a change in the secretory phase beyond that expected for such amount of progesterone, speak of uterine selectivity for drug delivery through the vagina. In addition, part of the progesterone administered through the vagina is known to pass through the uterus before entering the mainstream circulation. The exact effect of the mechanism's primary passage through the uterus is not fully understood. Three hypotheses can be explained by data demonstrating the effect of a primary intrauterine passage: (1) vaginal progesterone may pass into the uterus via the local vascular system, (2) direct progesterone release into the uterus, or (3) progesterone may reach the uterus via the lymphatic system. . In support of this latter hypothesis, vaginal cancer reaches up to 1/3 of the uterus and continues to spread through the lymphatic vessels of the uterus. According to the second hypothesis, progesterone can be dispersed passively between cells and close to the uterus. The results obtained with the present invention can be applied to the lining of the uterus and thereby minimize the loss of progesterone, the amount of progesterone in the circulation and the concomitant side effects.

This invention has minimized the risk of cancer associated with HRT. The concentration of progesterone injected into the body according to the present invention is insufficient to increase the duration of mitosis in the terminal lobe duct, although it has a beneficial effect on the lining of the uterus.

Another advantage of the present invention is that when a dose of 10 mg to 200 mg of progesterone is administered to menopausal women undergoing HRT to prevent endometrial cancer, the coronary vasodilator effect of foleculin is not eliminated.

Additionally, the present invention addresses the lack of utility of estrogen / progesterone ligaments and HRT application of contraceptive measures during the boom. These regimens would affect the breasts on a daily basis with a combination of high levels of estrogen and progesterone.

In order to achieve the desired serum progesterone levels of 1-6 ng / ml over a continuous period of approximately 48 hours when a change in endometrial secretion is achieved, 10 to 200 mg of progesterone is administered according to the present invention every other day for 12 days. doses (6 doses) into the vagina, each administered 10 to 12% by weight of progesterone. When drugs are introduced into the vagina to achieve the desired serum progesterone levels, the amount of progesterone required in the drug delivery system will vary depending on the patient's physiological properties and the release rate of the polymer used in the drug delivery system. Additionally, if daily or more frequent dosing of progesterone is required, the amount of progesterone administered at each dose may be reduced.

In the present invention, serum progesterone levels are maintained within a relatively narrow range of 1-6 ng / ml and remain unchanged after each dose as previously believed. In addition, although progesterone levels in the lining of the uterus are not easy to measure quickly, the presence of a constant effect on the lining of the uterus indicates that the change in the secretory phase continues throughout the treatment period.

Administration of mg progesterone to the vagina every other day according to the present invention, while reversing the secretion, results in a serum concentration of 1 to 3 ng / ml which is difficult to measure. Clinical studies have shown that such a progesterone assignment for more than 12 days will inhibit the growing effect of estrogen on the lining of the uterus. A dose of 90 or 180 mg of progesterone given every other day according to the invention produces a serum concentration of approximately 4 to 6 ng / ml, on the other hand, nevertheless causing antimitosis of the uterine lining and effect of secretion. Such high doses may be necessary for women undergoing in vitro fertilization (IVF). The use of IVF may make the lining of the uterus susceptible to a growing egg, solely due to exogenous hormones that may be due to alterations in estradiol (E2) and progesterone regimens. This high level of progesterone in the blood contributes to avoiding the side effects of progesterone, which is the risk of CNS depression and breast cancer during IVF.

A system for administering a medicament according to the present invention is described in U.S. Pat. 4,615,697 in description, by Robinson. This bio-adhesive polymeric system is superior in that it is inserted into the vagina for a relatively long period of time, from 48 to 72 hours, whereas most drug delivery systems fall off the vaginal wall in less than four hours. The polymer holds progesterone and releases it slowly over time. The drug delivery system allows immediate contact with the vaginal epithelium, which allows direct delivery of the drug as described above. Unexpectedly, the delivery system delivers enough progesterone to the uterine lining at a level as low as the progesterone delivery route.

Pat. The polymers used in 4,615,697 are cross-linked polymers having at least 80 percent of the monomers comprising the polymer having at least one functionally active carboxyl group. A more preferred polymer is the Polycarbophil described in the US Patent and known in the market as BFGoodrich Specialty Polymers of Clevlend, OH under the trademark NOVEON - AA1. These polymers cannot be used in the form of their salts as this would reduce their bio-adhesive properties. The crosslinked agent comprises from 0.1 to 6.0% by weight of the polymer, preferably from 1.0 to 2.0% by weight. Suitable crosslinked agents include divinylbenzene, N, N-diallyl acrylamide, 3,4-dihydroxy-1,5-hexadiene, 2,5-dimethyl-1,5-hexadiene and the like. In addition, U.S. Pat. 4,615,697 further states that the maximum drug delivery efficiency can be obtained by using it with a cross-linked polymer while being patient-friendly. Excipients may include lubricants, plasticizers, binders, coloring agents, flavoring and / or odor control agents and the like.

Polymers described in U.S. Pat. No. 4,615,697, may be adapted to control the rate of progesterone uptake, i.e., by altering the amount of agent cross-linked. Typically, the release rate of the amount of drug in the polymer is the most important factor, so this release rate can be adjusted by supplying an appropriate amount of progesterone, knowing that the polymer remains in place for about 48 hours. It has been estimated that approximately 10% to 12% of the amount of progesterone present in the drug delivery system is released from the polymer in which it is present within 24 hours.

The drug delivery system with the drug can be inserted into the vagina, as it is known in the art, by various means, such as buoyancy, showering, and manual. Preference is given to the mode of administration using the devices described in U.S. Designs Nos. 07/863 879 and no. 07/862 282. These devices are elongated hollow containers with one end that can be opened and the other end where the medication is administered can be inserted. Such a device makes it possible to measure in advance the quantities of polymer and drug contained in a hermetically sealed container, which is relatively easy for women to use. Such containers also retain the drug and polymer in a sterile environment until it is used. Before use, the container is opened and the open end is inserted into the vagina, while the other end is compressed to expel the contents of the container into the vagina.

EXAMPLE

Eighteen young women with pre-suppressed ovarian function agreed to be candidates for in vitro fertilization and volunteered to participate in the study. The high rate of pregnancies, which has been fully accounted for by egg fertilization, has led to the use of estradiol and progesterone replacement cycles as a research system for analyzing the ability of the endometrium to absorb hormones. Previous work has shown that significant increases or decreases in estradiol levels during luteinisation do not affect uterine mucosal morphology at embryo implantation (day 20) or late luteinization (day 24), and therefore progesterone is probably a highly variable hormone. For all patients tested, this was documented that ovarian suppression was complete as demonstrated by ultrasound baseline and hormone contour (low E2 (estradiol) and high ovarian follicle hormone induction (FSH levels)). Following detailed notification of the planned studies, a list of patients was compiled and administered E2 at doses of 0.1 to 0.4 mg each, using one or more transdermal systems (Estraderm ™ TTS 100, Ciba Pharmeceuticals, Paris, France), delivering 0, 1 mg E2 per day. On day 15, patients who received E2 for 14 days were examined in a clinical trial center. On the morning of day 15, the patients were randomized into 3 groups and given one of three doses of progesterone. Progesterone was administered to the vagina using its gradual release system of the present invention comprising 12.9% by weight glycerol, 4.2% by weight mineral oil, 1% by weight hydrogenated palm oil glycerol, 0.08% by weight sorbic acid, 0 , 18% by weight of methylparaben, 1% by weight of CARBOPOL 934P (obtained from BF Goodrich), 2 wt% polycarbophil or 4 or 8 wt% progesterone and the remainder of the water. The doses of 45, 90 and 180 mg of progesterone contained: The 45 mg dose used a 4 wt% progesterone formulation, and the 90 mg and 180 mg doses used a 8 wt% progesterone formulation. For example, a 1.125 gram composition containing 4% w / w progesterone was used to administer 45 mg of progesterone. Patients were randomized to 3 groups of 6 patients and each group had v

given to each patient in one of these three doses. Patients received these doses at 11 o'clock on the 15th day and were repeated every other day until the 25th day (total of 6 treatments). During the 6 days spent in the hospital, patients were subjected to serial blood tests (E2, estrone, LH (luteinisation hormone) FSH and progesterone) every 6 hours for hormone measurements. They were also subjected to daily vaginal ultrasound examination using a high resolution probe (ALT-HDI, 5-9 MHZ). A 15-minute ultrasound scan of the lining of the uterus was recorded by the S-VHS system for further autonomous image analysis using an appropriate computer system.

Eighteen patients in the study underwent a biopsy of the lining of the uterus on day 24 (6 patients in each progesterone dose group). Separately, from all serial blood tests over time of 6 days spent in the clinic during treatment, all patients also had blood samples taken twice weekly.

Uterine mucosal biopsy taken from 18 patients on day 24 showed complete alteration of uterine mucosal stromal secretion except in 2 patients who showed a symptom usually seen during menstruation.

(mucous membrane of the uterus). In these two patients, some alterations in secretion were observed in the endometrial stroma. These two patients were treated with progesterone 180 mg and 90 mg, respectively. Alterations in endometrial stromal secretion were also observed in another 16 patients who had a complete decidual reaction. Echoscopy data confirmed the characteristic E2 filling showing individual values ​​of intrauterine thickness between 5 and 12 mm. Plasma progesterone levels observed during progesterone therapy in women for the first 6 days are shown in FIG. 1, FIG. 2 and FIG. 3, each depicting testimony at doses of 45 mg, 90 mg and 180 mg of progesterone, respectively. In summary, mean progesterone serum ng / ml is plotted, with the area plotted representing the 95% accuracy of the range over the days of progesterone therapy. As can be seen, the progesterone levels obtained at the two higher doses (90 mg and 180 mg) appeared similar and ranged from 2 to 8 ng / ml. In contrast, plasma progesterone levels achieved with a 45 mg dose every other day were lower, ie between 1 and 3 ng / ml. These data indicate that complete reversal of secretion occurred in all patients receiving the 45 mg dose. Data from the literature, as well as from the results obtained by the experimenter, indicate that such low levels of progesterone in plasma may result in markedly abnormal biopsy of the lining of the uterus on day 24 of the study.