HK1179531B - Parenteral pharmaceutical form which releases aromatase inhibitor and gestagens, for the treatment of endometriosis - Google Patents

Description

Parenteral dosage form for delivery of aromatase inhibitor and progestin for treatment of endometriosis

The present invention is for the treatment of endometriosis (endometris) and involves the provision of an parenteral dosage form (delivery system) for the controlled release of Aromatase Inhibitor (AI) at a rate which does not induce stimulation of the ovary (without increasing the secretion of gonadotropins which would induce follicle growth) by negative feedback of the pituitary-ovarian-axis (pituitary-ovarian-axis) and of progestogens (progesterone/progestogen) at a rate which provides contraceptive efficacy based on known local effects (e.g. reduction and thickening of cervical mucus impairing sperm rise; affecting endometrial and tubal peristalsis disrupting implantation and ovum transport). AI in combination with an ovulation-inhibiting amount of a progestin can lead to estrogen deficiency (e.g., hot flashes, decreased bone density) due to a strong inhibition of endogenous estrogen synthesis. Due to the low dose (no counter-regulated AI and no reliable ovulation-inhibiting progestogen) used in the present invention, the risk of estrogen deficiency is effectively minimized by the combination. The dosage form described herein is preferably a polymer-based dosage form comprising at least one compartment, the or each compartment comprising a core or a core surrounded by a membrane, the core and the membrane consisting essentially of the same or different polymer composition, wherein at least one compartment comprises an AI and at least one compartment, which may be the same or different from the compartment comprising the AI, comprises a progestin. The parenteral dosage form may be any dosage form suitable for delivering the therapeutically active agent at a controlled release rate over a prolonged period of time, such as a vaginal ring (IVR; the terms vaginal ring and intravaginal ring are synonymous in use), which period of time may be from 1 week to 3 months, preferably from 4 to 6 weeks, and for an intrauterine device (IUD), the terms intrauterine device and intrauterine system (intrauterine system) are synonymous in use, which period of time may be from 3 months to 1 year or more. Preferred dosage forms are either IVR, as described above, or IUD, which offers the additional advantage of achieving additional local action at the endometriotic foci near the site of action.

Endometriosis is a chronic disease that is suffered by about 10% of women of childbearing age. The disease is characterized by the presence of endometrioid tissue outside the uterine cavity. There are various theories as to the pathogenesis of endometriosis. It is likely that in most cases it is initiated by retrograde menstruation (retrogradememturation) in which endometrial tissue enters the abdominal cavity through the fallopian tubes and endometrial cells adhere to the surface of abdominal tissue and organs to form an abnormal endometrial implant, i.e. a focal of endometriosis. This endometrioid tissue can respond to changes in the hormonal environment during the menstrual cycle in the same way as normal endometrium, so that when estrogen and progesterone concentrations are changed, the tissue reacts in the same way as the endometrium itself. However, during the diseased period, these endometriotic foci can become disjointed from the normal menstrual cycle. The presence of endometrial implants on the abdominal surface (endometrial nodules) can induce an inflammatory response that, together with nerve fiber growth, can manifest as a pathophysiological/anatomical relationship leading to symptoms commonly associated with endometriosis, such as pelvic pain, dysmenorrhea, and dyspareunia.

The treatments currently necessary for endometriosis are based on the inhibition of the production of ovarian estrogens (e.g. gonadotropin releasing hormone analogues (GnRH analogues), danazol (danazol), medroxyprogesterone acetate (medroxyprogesterone acetate), dienogest (dienogest), Combined Oral Contraceptives (COC)) by central inhibition of the pituitary-ovarian-axis. However, inhibition of ovarian estrogen production during treatment with GnRH analogs, if not treated with additional estrogen, results in side effects associated with estrogen deficiency, such as hot flashes and bone loss being the most relevant side effects. Other side effects may include: transient vaginal bleeding, vaginal dryness, decreased libido, breast distending pain, insomnia, depression, irritability and fatigue, headache and decreased skin elasticity. Therefore, in order to reduce these side effects during the treatment of GnRH analogues, so-called back-adjunctive therapies (add-back peptides) have been established, in which (conjugated) estrogens or norethindrone acetate (NETA, partly metabolized to estradiol) are added to the treatment of GnRH analogues. Both treatments (GnRH analogue + estrogen or GnRH analogue + NETA) are used at their full effective dose, which also means that a full spectrum of the corresponding expected side effects of these drugs may occur. COC is also effective in treating endometriosis on its own and does not require any back-up therapy.

However, as in the case of the counter-additive therapy, exogenous estrogen is applied to the patient by COC therapy, in this case the strong estrogen ethinylestradiol (ethinylestrodiol). In this case, the use of exogenous estrogens could theoretically impair the therapeutic effect of progestogens or GnRH analogues on endometriosis, an antiestrogen-dependent disease.

On the other hand, inhibition of the pituitary-ovarian-axis has no effect on extraovarian estrogen production sites, which may be critical for new therapies for endometriosis. Previous studies have shown that aromatase, which catalyzes the conversion of testosterone and other androgen precursors to estrogen, is expressed in endometriotic foci (Urabe M et al, Acta Endocrinol (Copenh) 1989,121(2):259-64, Noble LS et al, J Clin Endocrinol Metab.1996,81(1): 174-9). This may therefore explain why the treatment of the above mentioned therapies fails, only inhibiting the production of oestrogens by the ovaries, whereas endometriotic foci can produce large amounts of oestradiol at their locus. In addition, the inflammatory mediator prostaglandin E2 has been shown to be a strong stimulator of aromatase expression, which further enhances the production of estrogen at the locus in the inflammatory milieu of the endometriotic foci (Noble LSet et al, J Clin Endocrinol metab.1997,82(2): 600-6).

Typical doses of AI (e.g., 1 mg/day anastrozole) reduced systemic estrogen levels in postmenopausal women by more than 85% (Geisler J et al, J Clin Oncol 2002,20(3): 751-757). In premenopausal women, this effect is reduced by countermodulation of the pituitary-ovarian-axis (i.e., pituitary induction of reduced systemic estrogen levels results in sustained secretion of gonadotropins which stimulate estrogen synthesis in the ovary and partially suppress AI action), which results in stimulation of ovarian follicular growth (in fact, this effect is used in patients with low ovarian fertility to stimulate follicular growth). For this reason, AI is used in endometriosis patients at the doses normally used for the treatment of breast cancer in postmenopausal women, in combination with drugs which inhibit counter-regulation in various clinical trials, for example with NETA (Ailawaddi RK et al, Fertility & Sterility 2004,81(2): 290-. In addition to inhibiting counter-regulation, a reduction in side effects associated with estrogen deficiency is also considered to be an advantage of these combinations. However, administration of exogenous estrogen or NETA in these combinations reduces the efficacy of AI for the treatment of symptoms of endometriosis (see above).

WO 03/15872 describes a method for treating or preventing uterine fibroids (uterine fibroids) or endometriosis by intravaginal administration of AI to a patient. Said invention discloses the advantage of local effect using AI monotherapy claiming to reduce systemic side effects by local administration. Said application does not disclose the binding of AI in parenteral dosage form to a progestogen and in particular does not disclose the binding of AI to a progestogen in IVR or IUD. In contrast to the present invention, WO 03/15872 does not disclose any way of achieving a contraceptive effect, which is essential in the present invention, since avoidance of pregnancy is crucial for a meaningful product regimen as long as the woman of childbearing age is treated with AI. The technical solution described in the present invention is to combine the contraceptive activity of AI and progestin in an parenteral dosage form to avoid physical separation of the two and thus to exclude the possibility of using AI for the treatment of endometriosis without contraceptive protection. This possibility is not excluded when two physically separable dosage forms are used.

The oral use of AI-conjugated progestogens (AI + NETA, Ailawadi RK et al 2004) or COCs (Amsterdam LL et al 2005; WO 04/69260) has also been proposed. Both combinations are intended to prevent estrogen deficiency by exogenously administered estrogenic activity (NETA estrogen metabolism; ethinyl estradiol in COC). The disadvantage of these treatment modalities and the difference from the invention described in this application is that in both cases the administration of exogenous estrogenic activity (conversion of the NETA moiety to estrogen; COC containing the strong estrogen ethinylestradiol) is necessary to avoid side effects. But this impairs the pharmacodynamic effect of the AI on endometriotic tissue. Furthermore, these disclosures do not describe the advantage of local application of AI, which inhibits locally expressed aromatase of endometriotic foci near the dosage form, thereby reducing the dose required to achieve the required full pharmacological effect.

Probably most closely related to the invention described in this application is patent application WO 03/17973, which discloses the vaginal application of AI, alone or in combination with other compounds affecting estrogen metabolism, such as cyclooxygenase-2 inhibitors (COX-2 inhibitors) and 17-beta-hydroxy-steroid-dehydrogenase-1 inhibitors (17 beta HSD-1 inhibitors). In addition, the invention claims a method of not inhibiting ovarian estrogen synthesis. Said invention discloses the advantage of combining AI with other drugs that influence estrogen metabolism by topical application. Said application does not disclose the binding of AI and estrogen in parenteral dosage form and in particular does not disclose the binding of AI and progestin in IVR in the doses reported. In contrast to the present invention, WO 03/17973 does not disclose any way of achieving a contraceptive effect. Again, it is important to recognize that only a physically inseparable combination of AI activity and contraceptive effectiveness will produce a meaningful product.

US 2011/0033519A 1 (published: 2011, 2/10) describes dosage forms for the local delivery of aromatase inhibitors, optionally in combination with contraceptive substances, to uterine tissue. Therefore, it should be able to treat or prevent diseases such as hysteromyoma, adenomyosis and endometriosis. Since progestogens may stimulate the growth of uterine fibroids, the use of progestogens is not recommended and instead copper and other precious metals are preferred as the basic ingredient of contraception. Suitable doses of IUD aromatase inhibitor, e.g. for anastrozole, are reported to be 1 μ g to 10mg per day. However, said patent suggests using a period of 5-10 years, which appears not to be feasible from a technical point of view.

When using IVR/IUD, one aspect of the invention described in this application is based on the following concept: local application of AI at a dose that does not induce a countermodulation of the pituitary-ovarian-axis but shows aromatase inhibition at endometriotic foci. Since AI administration does not result in a counter-regulatory effect, there is no need to use progestogen or COC to suppress the pituitary-ovarian-axis, which allows the progestogen dose to be reduced by local mechanisms to the dose necessary to achieve a contraceptive effect. This approach will avoid estrogen deficiency symptoms and will not require the administration of exogenous estrogen. In addition, since endometriosis is an estrogen-dependent disease, the therapeutic effect of AI is not impaired without the administration of exogenous estrogen. Since the progestogen also has an inhibitory effect on the expression of aromatase, the progestogen in the present invention can increase the effect of AI.

In order to avoid, on the one hand, the adverse pituitary-ovarian-axis regulation effect caused by the use of the highest possible AI dose and, on the other hand, the optimal contraceptive effect of progestogen-only based contraception using the highest possible progestogen dose below the ovulation-inhibiting dose, it is necessary to administer the active ingredient in a controlled-release formulation which avoids high fluctuations in the serum level which can trigger an adverse pituitary-ovarian axis regulation. This will be achieved by parenteral dosage forms, preferably IVR or IUD.

The invention described in this application combines in this way an effective treatment of endometriosis with a reliable contraceptive method (no AI intake without contraceptive protection and therefore no undesired embryo exposure to AI) by an parenteral dosage form in an application manner that supports high compliance. In contrast to the methods described in the prior art, in the present invention, the combination will reduce the drug exposure of both the AI and the progestin to the amount necessary to produce an effect, which will also minimize the risk of adverse side effects associated with reduced estrogen levels (e.g., hot flashes, bone loss, etc.).

In order to minimize the risk of side effects associated with estrogen deficiency, the progestogen exposure sought in the present invention will be lower than the exposure achieved by administering a given progestogen at an ovulation-inhibiting dose (independent of the route of administration), but high enough to provide contraceptive efficacy by local action, as measured, for example, by the uterine mucus score (Insler V et al, Int J Gynecolobstet 1972,10: 223-. Oral ovulation-inhibiting doses of the various progestogens which result in specific progestogen-specific plasma or serum concentrations after oral administration are described in the literature, for example, in Neumann F et al, reproduktionmedizin 1998,14:257-264 or Taubert H D, Kuhl, H, Kontrazepton mit Hormonen,2. Aufl.1995. More specifically: the AI dose in the conjugate will not significantly stimulate ovarian activity beyond the effect of a typical progestin alone as contemplated by the present invention in the progestin dose to be administered. The experimental settings for determining progestin and AI dosages are described in the experimental section.

The dosage forms of the invention comprising a combination of an AI and a progestin are particularly suitable for treating endometriosis, which provides a therapeutic effect against symptoms associated with endometriosis; the risk of side effects associated with estrogen deficiency (e.g. bone loss, hot flashes) is minimized. At the same time the present invention will provide a physically inseparable daily exposure of progestogen to ensure a reliable contraceptive effect and thus avoid any risk of pregnancy due to subsequent undesired exposure of the embryo to AI. This is a major aspect of the present invention as it significantly increases the safety of the desired product (see for comparison WO 03/15872 and WO 03/17973). Furthermore, the parenteral/topical administration in a dosage form with a controlled release rate, for example by means of an optimized regimen (IVR/IUD), allows the achievement of a dose suitable for achieving the desired therapeutic effect and reduces as far as possible the main side effects associated with a fluctuating exposure of the active ingredient (amplitude between, for example, the maximum serum level after ingestion of the oral formulation and the minimum serum level before the next ingestion), compared to oral administration. Furthermore, the topical administration may be particularly advantageous for treating endometriosis foci in the vicinity of an parenteral dosage form (e.g., in the case of vaginal endometriosis, deep infiltrating endometriosis, adenomyosis, or posterior fornix endometriosis).

Aromatase inhibitor (Aromatase inhibitor)Compounds that inhibit the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. The AI reduces or blocks estrogen synthesis through the action of aromatase inhibitors. An optional AI is, for example, anastrozole (anastrozole)Exemestane (exemestane)Fadrozole (fadrozole)Formestane (formestane)Letrozole (letrozole)Pentrozole, Volvazole (vorozole)Or AI BGS649 from Novartis, which may be in clinical development to date (clinicalrials. gov identifier: NCT01116440; NCT 01190475) and pharmaceutically acceptable salts thereof.

Parenteral dosage form (intestinal dosage form)Is a dosage form in which absorption of the drug proceeds while avoiding passage through the gastrointestinal tract. It may be any dosage form suitable for delivering the therapeutically active agent at a controlled release rate over an extended period of time. The dosage form may thus be formulated for a wide range of applications including, for example, transdermal patches (transdermal patches), implants (implants), depot injections (including microparticles, in situ depot forming dosage forms, etc.), intravaginal, intracervical and intrauterine dosage forms. According to a preferred embodiment, the dosage form is IVR or IUD. IVR is a substantially ring-shaped polymeric dosage form that provides controlled release of the active ingredient to the vagina over an extended period of time. IUDs are any polymeric dosage form that provides for the controlled release of an intrauterine active ingredient to the uterus over a prolonged period of time. Subcutaneous implants are a substantially rod-shaped polymeric dosage form that include one or more rods that provide systemic controlled release of an active ingredient to the body over an extended period of time.

Release rateRefers to the average amount of active agent released from the dosage form over a 24 hour period that can be absorbed through surrounding tissues. It is known to those skilled in the art that the mean release rate of parenteral dosage forms decreases over the time of application.

Long term controlled release dosage form (controlled long-term release dosage form)Refers to any dosage form suitable for administration over an extended period of time and which avoids the fluctuations in drug levels typically induced by immediate release formulations (e.g., tablets, injections, etc.).

Progestogen (getagen)Is a synthetic progestogen with a progestational effect similar to progesterone. Progestogens other than progesteroneAlso for example allylestrenol (allesterone), chlormadinone acetate (chlormadinone acetate), cyproterone acetate (cyproterone acetate), desogestrel (desogestrel), dienogest (dienogest), drospirenone (drospirenone), dydrogesterone (dydrogesterone), etonogestrel (etonogestrel), norethisterone (ethynodiol), gestodene (gestodene), levonorgestrel (levonorgestrel), lineestrol (lynestrenol), medroxyprogesterone (medroxestone), medroxyprogesterone acetate (medroxystrel), nomegestrol (nomegestrol), norethindrone (norethindrone), and pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof. These progestagens may also be provided as esters or any other suitable chemical variant.

Daily release rate below ovulation inhibitory dose but high enough to provide reliable contraceptive protection Progestogen of noteIt is meant that the known effects (e.g., cervical mucus decreases and thickens to disrupt sperm elevation; affecting endometrial and tubal motility to disrupt implantation and egg transport) prevent fertilization of the egg. The progestogen dose normally used for this effect can be found in the formulationHas a tablet dosage of 30 μ g levonorgestrel.

Typical oral ovulation-inhibiting doses are (Neumann F et al, Reproduktionmedizin, 1998,14: 257-) -264; Taubert H D, Kuhl, H, Kontrazepton mit Hormonen,2. Aufl.1995)

Note: it is known to those skilled in the art that the ovulation-inhibiting dosage value of a progestogen varies to some extent for methodological and statistical reasons. The progestogen dose/exposure used in the present invention will be lower than that which would produce reliable ovulation inhibition in the case of parenteral or oral application. For oral use, the ovulation-inhibiting doses are given in the literature and listed as examples in the above table.

If the ovulation-inhibiting dose is unknown for a given progestogen, the release rate to be used in parenteral dosage forms will be determined in pharmacokinetic/pharmacodynamic studies in which the effect of different doses of progestogen to be used on the ovaries, cervix and hormones (ovarian activity by vaginal ultrasound, hormone levels in the blood, cervical mucus by uterine mucus scoring) will be measured. As an example of an indeterminate but locally effective ovarian suppressive dose, the systemic exposure of Levonorgestrel (LNG) following release from IVR is equivalent to the exposure of levonorgestrel following oral administration at a daily dose above 10 μ g but below 50 μ g.

The potential release of the active ingredient, i.e. the so-called burst effect, is known to the person skilled in the art to be substantially increased shortly after insertion in IVR, IUD or polymer-based implants. IVR, IUD and polymer-based implants that exhibit this burst effect shortly after insertion are considered to be claimed even though the release rate increases during the duration of the burst effect.

Not inducing daily release rate of stimulus to the ovary by negative feedback of pituitary-ovary-axis Aromatase Inhibitor (AI)(no increase in secretion of gonadotropins inducing follicle growth) refers to the highest dose that does not induce additional follicle growth compared to the progestin treatment cycle as measured by blood hormone levels (follicle stimulating hormone = FSH, luteinizing hormone = LH, estradiol, progesterone) and as measured by vaginal ultrasound.

The release rate to be used for the parenteral dosage form if unknown for a given AI will be determined according to example 2 of the present application that the systemic exposure achieved by the dosage form is on average less than the exposure produced by 1mg (or 0.1mg to 0.9 mg) per day/oral for anastrozole. For letrozole, the systemic exposure achieved by the dosage form is less than that produced by 2.5mg (or 0.1mg to 2.4 mg) per day/oral. Pharmacokinetic accumulation should be considered here.

The potential release of the active ingredient, i.e. a substantial increase (the so-called burst effect) shortly after insertion, of IVR, IUD or polymer-based implants is known to the person skilled in the art. IVR, IUD and polymer-based implants that exhibit this burst effect shortly after insertion are considered to be claimed even though the release rate increases during the duration of the burst effect.

The use in IVR provides a convenient formulation with low variability of drug serum levels, which avoids hepatic first pass metabolism of the drug and improves therapeutic compliance (treatment compliance) as daily memory drug intake is not required. In particular, the contraceptive principle of progestogen pills (POP, "single progestogen pills") at doses lower than the ovulation-inhibiting dose requires an accurate dosage schedule to ensure a reliable contraceptive effect. In this regard, continuous administration using IVR is highly advantageous. Topical application allows for dosages suitable to achieve the desired therapeutic effect and may result in reduced major side effects associated with systemic exposure of the active ingredient. It is known to those skilled in the art that the use of IVR (or alternative depot formulations, and more particularly in the case of polymer-based dosage forms) results in a change (decrease) in the daily release rate over the administration period. Dosage forms exhibiting such modifications are considered to be claimed. Preferred dosage forms are those for topical application, more particularly IVRs and IUDs. Particularly, IVR is preferable.

Preferred IVRs and IUDs include anastrozole as an aromatase inhibitor. Particularly preferred is an IVR containing anastrozole. Also particularly preferred are such anastrozole-containing IVRs, wherein the systemic exposure of anastrozole achieved after release from the IVR corresponds to the exposure of anastrozole after oral administration at a dose of less than 1mg (or 0.1 to 0.9 mg) anastrozole per day. Likewise, it is particularly preferred for the IVR to contain levonorgestrel as the progestin.

Preferred IVRs and IUDs contain levonorgestrel, dienogest or gestodene as progestin. IVR with levonorgestrel as progestin is particularly preferred. Also particularly preferred are IVRs of this type, wherein the systemic exposure to levonorgestrel achieved after release from the IVR is equivalent to levonorgestrel exposure after oral administration at a dose of greater than 10 μ g but less than 50 μ g per day. Similarly, it is particularly preferred for the IVR to contain anastrozole as an aromatase inhibitor.

Very particular preference is given to IVRs of the type having anastrozole as aromatase inhibitor and levonorgestrel as progestin. Likewise, particular preference is given to IVRs containing anastrozole as aromatase inhibitor and having levonorgestrel as progestin, and wherein the systemic exposure to anastrozole achieved after release from the IVR corresponds to the systemic exposure to anastrozole after oral administration at a dose of less than 1mg (or 0.1 to 0.9 mg) of anastrozole per day, and wherein the systemic exposure to levonorgestrel achieved after release from the IVR corresponds to the systemic exposure to levonorgestrel after oral administration at a dose of greater than 10 μ g but less than 50 μ g per day.

For a particularly preferred IVR, the duration of the long-term release is from 1 week to 3 months, particularly preferably from 4 to 6 weeks. For an IUD that is also preferred, the long-term release is at least 3 months, preferably one year or more.

Due to the burst effect, the dosage form according to the invention can achieve the release rate required according to the invention only after one, two or three days after the start of the treatment, in special cases only after one week. Where initiation of treatment refers to the point in time at which the dosage form is used.

All preferred embodiments mentioned in this specification can be used for the treatment of endometriosis. Simultaneous contraception in the treatment of endometriosis is particularly preferred. Also particularly preferred is a method for simultaneous treatment of endometriosis and contraception, optionally using one of the preferred dosage forms mentioned above.

Detailed description of parenteral dosage forms

Parenteral dosage forms capable of providing controlled release of an active ingredient over an extended period of time, including, for example, implants, intrauterine devices and vaginal rings, are generally formed from biocompatible polymers and contain one or more drugs that are released by diffusion through the polymer matrix. A number of different configurations of the dosage form are known from the literature. Some dosage forms may include a polymer matrix but no membrane or wall encasing the matrix (monolithic dosage forms), while some other dosage forms include a polymer matrix, a core, and are encased by a membrane. The simultaneous administration of two or more therapeutically active substances has been widely used and a number of different configurations of the dosage form are known from the literature.

According to one embodiment of the invention, the dosage form comprises at least one compartment comprising a core, or a core surrounded by a membrane, said core and membrane comprising the same or different polymer composition, wherein at least one of said compartments comprises AI, and optionally at least one compartment, which may be the same or different from said compartment comprising AI, may comprise a progestogen or a compound having progestogenic activity.

The compartment thus essentially comprises one polymer composition, wherein the polymer composition of the core, the membrane or both may comprise one or more therapeutically active substances. The polymer composition may be suitably selected such that the release of the therapeutically active agent is modulated by the core, the membrane, or both.

According to embodiments in which the dosage form comprises more than two compartments, the compartments may be placed adjacent to each other, side by side, one on top of the other or at least partially overlapping each other and may be further separated from each other by a separation membrane or by an inert placebo compartment. The compartments may be solid or hollow.

The film, if present, may cover the entire dosage form or only a portion of the dosage form, and thus its degree of extensibility may vary depending on a variety of factors, such as the choice of materials and the choice of active agents. The membrane may consist of more than one layer. The thickness of the membrane depends on the materials and active agents used and also on the release profile desired, but typically the thickness is less than the thickness of the core unit.

The polymer compositions of the core, the membrane and the possible separation membrane or the inert placebo compartment may be the same or different and may be one single polymer or a mixture of polymers or may consist of polymers mixed with each other.

In principle any polymer can be used, biodegradable or non-biodegradable, as long as it is biocompatible. Examples of commonly used polymeric materials include, but are not limited to, polysiloxanes, polyurethanes, thermoplastic polyurethanes, copolymers of ethylene/vinyl acetate copolymer (EVA) with dimethyl siloxane and methyl vinyl siloxane; biodegradable polymers such as poly (hydroxyalkanoic acid), poly (lactic acid), poly (glycolic acid), poly (diglycolic acid), poly (L-lactide), poly (lactide-co-diglycolic acid), and mixtures of at least two thereof.

The structural integrity of the material may be enhanced by the addition of particulate materials such as silica or diatomaceous earth. The polymer composition may also include additional materials to, for example, adjust hydrophilicity or hydrophobicity to achieve a desired release rate of one or more of the therapeutic substances, while taking into account that all additives need to be biodegradable and not harmful to the patient. The core or membrane may also include, for example, a complex-forming agent such as a cyclodextrin derivative to modulate the initial burst of the substance to an acceptable or desired level. Auxiliary substances, such as surfactants, antifoaming agents, stabilizers, solubilizers or absorption delaying agents, or mixtures of any two or more of these, may also be added to impart desired physical characteristics to the body of the dosage form. Additives such as pigments, gloss agents, matting agents, colorants, mica, or the like may also be added to the body of the dosage form or the film or both to provide the desired visual appearance to the dosage form.

Preparation of parenteral dosage forms

According to the present invention, the parenteral dosage form can be prepared according to standard techniques known in the art, and the shape and size of the dosage form can be freely selected by those skilled in the art.

A sufficient amount of at least one therapeutically active agent may be incorporated into the polymer composition of the core or the membrane by using different methods depending on the stability of the substance. For example, the substance may be homogeneously mixed in the polymer matrix, or the polymeric material and the substance may be dissolved in a suitable solvent or solvent mixture (dichloromethane, tetrahydrofuran, etc.) and most of the solvent removed under reduced pressure, the viscous solution crystallized and the drug-polymer composition subsequently further dried and granulated. The therapeutically active substance can also be mixed into the molten polymer, especially when a thermoplastic elastomer is used, followed by cooling of the mixture. The drug-polymer composition is then processed into a desired shape using known methods, such as, for example, molding, injection molding, rotational/injection molding, casting, extrusion (e.g., co-extrusion, coating extrusion, and/or blend extrusion), and other suitable methods.

The materials for the membrane, with or without therapeutically active substance, can be prepared according to the above-described method. The film may be assembled onto the core, for example by moulding, spraying or dipping, or by using a coating extrusion or coextrusion process, or by mechanically stretching or expanding a preformed tubular shaped film by a pressurised gas such as air, or by swelling in a suitable solvent (for example propanol, isopropanol, cyclohexane, diglyme, etc.).

The polymer rod thus obtained can be cut into sections of desired length to form a compartment comprising a core or a core surrounded by a membrane. The compartment, or two or more compartments connected together, may be used as a subcutaneous implant, or connected to the body of an intrauterine device, or assembled in any way suitable for the purpose, for example in a substantially annular dosage form. The term "substantially annular" should be understood to include, in addition to annular dosage forms, any other substantially annular structure suitable for intrauterine or vaginal administration, such as helically wound coils and ring systems having a helical surface. The intrauterine device may have other shapes than a substantially annular shape and may for example be T-shaped, S-shaped, 7-shaped or omega-shaped. The compartment to be connected to the intrauterine device may be hollow so that it can be easily placed on the intrauterine device body. Or the core may be applied first to the body and in a next step wrapped by a film. The implant typically has a rod-like form.

The compartments or the ends to which the compartments are joined may be joined by using coupling means which may be any method, mechanism, device or material known in the art for bonding or joining materials or structures together. Such coupling may include, for example, solvent bonding, adhesive bonding, thermal welding, thermal bonding, pressure, and the like. The tubular compartments may also be connected by using plugs or plugs made of any inert biodegradable material, for example one that does not allow the transport of active materials. Alternatively, the substantially annular dosage form may be prepared by: a compartment or combination of compartments is placed in a mould at elevated temperature and molten high density polyethylene is injected between the ends thereof, followed by cooling of the resulting ring or joining the ends together by welding.

Example 1: determination of progestin dosage in accordance with the invention by ovulation inhibition studies

In ovulation inhibition studies, different dosages of a set progestogen will be tested using vaginal ultrasonography and blood hormone level (estradiol, progesterone) measurement to determine the maturation of ovarian follicles by the progestogenAnd the effects of ovulation. Furthermore, the cervical mucus will be studied according to the uterine mucus scoring method for the expected changes in the typical cervical mucus characteristics of progestagen-only contraceptive methods (Insler V et al, Int J Gynecol Obstet 1972,10(6): 223-228). An Insler-scored dosage that inhibits ovulation by less than 95%, and preferably in the range of about 40-80%, and produces cervical mucus of < 9, will be selected as the progestin dosage of the invention. This dosage is specific to each progestogen. It is known to the expert in the field and can therefore be expected that some follicular growth will occur with this contraceptive method (e.g. generation of persistent ovarian follicles is a progestin bolusA known effect of (a); see: fachinformation Microlut date 7 months 2007, page 2 [4.4.2 Warnhinweise; Persistilende Ovarialfollikel]). Pharmacokinetic accumulation should be taken into account when determining the dose.

Example 2: effect of aromatase inhibitors on Pituitary-ovarian-axis and follicular development

In another pharmacodynamic study, the effect of the parenteral dosage form, preferably IVR, AI alone and/or in combination with progestin on pituitary-ovarian-axis and follicular development will be studied by blood hormone level determination (follicle stimulating hormone = FSH, luteinizing hormone = LH, estradiol, progesterone) and vaginal ultrasound measurements. The minimum exposure of AI and progestin to induce additional follicular growth compared to the untreated or progestin treated cycle can be used as a dosage threshold for AI in combination with progestin. This dose is a unique value for each AI. Stimulation of the follicles by AI has been described in the literature as occurring, for example, at doses of 2.5mg of levonorgestrel or 1mg of anastrozole orally (Mitwall MF & Casper RF, Fertil Steril.2001,75(2): 305-9; Fisher SA et al, Fertil Steril2002, 8 months, 78(2): 280-5; Badawy A et al, Fertil Steril 2008,89(5): 1209) 1212; Wu HH et al, Gynecol Endocrinol 2007,23(2): 76-81). The targeted average daily exposure, for example for anastrozole administered via the preferred parenteral dosage form (which as described above for the present invention is IVR or IUD), is less than 1mg (or 0.1mg to 0.9 mg). It is less than 2.5mg (or 0.1mg to 2.4 mg) for levonorgestrel.

The highest possible amount of AI in combination with a progestogen in the dosages described above, which does not result in additional follicle growth stimulation compared to the progestogen alone as defined above, will be determined by the human pharmacodynamic studies described above. The effect of the progestogen on cervical mucus is maintained in combination with AIs.

The experimental setup was valid for any parenteral application. For IVR, the experiments described above for the single component and for the conjugates will be performed by using IVRs.

Example 3: manufacture of vaginal rings for in vivo studies

For in vivo studies using cynomolgus monkeys (cynomolgus monkey), anastrozole-releasing vaginal rings were made that fit the size of the cynomolgus monkeys. The outer diameter of the ring is 14mm and the cross-section is 2.3 mm.

The ring contains a core of anastrozole and elastomer, wherein the core is coated by a controlled release membrane. The target drug dose is achieved by appropriate selection of the materials of the core and the membrane, and by adjustment of the drug concentration and the surface of the anastrozole-containing core and the membrane thickness. These parameters are suitably selected so that controlled release of anastrozole is possible over a period of more than 30 days.

Three formulations (A, B, C; referred to in figure 1 as high, medium and low doses) of the anastrozole-releasing ring were prepared, each releasing anastrozole for at least 30 days. The starting dose of anastrozole was 390 micrograms/day (a), 85 micrograms/day (B), or 27 micrograms/day (C). Placebo rings were also made.

a) Manufacture of anastrozole-releasing rings

Core

Two core compositions were prepared, one containing anastrozole in a matrix made of silicone elastomer (polydimethylsiloxane); the other contained silicone elastomer (polydimethylsiloxane) alone. The anastrozole-containing core is prepared by mixing (micronising) anastrozole and the silicone elastomer in a mixer. The anastrozole content of the mixture was 35% by weight. The mixture was shaped in a die to give a small elastic rod with a thickness of 2mm and cured (which can also be achieved by extrusion through a nozzle). Extrusion of the silicone elastomer core gives a small elastic rod with a thickness of 2mm (this can also be achieved by being in a die).

Film

The drug controlled release membrane tube is made of silicone elastomer (polydimethylsiloxane) by tube extrusion. The tube wall thickness (film thickness) was about 1.5 mm.

Ring assembly

The anastrozole core was cut into three lengths: 38mm (A), 6mm (B) and 1.5mm (C). The silicone elastomer core was cut into two lengths to achieve a total core length of 38 mm. The membrane tube was cut to a length of 38mm and swollen in cyclohexane.

The rings are assembled by pushing the core segments into the swollen membrane tubes. The tube is formed into a loop by overlapping. After evaporation of the solvent, the tube shrinks and the parts are compacted.

Anastrozole release

Method of producing a composite material

The release of anastrozole from the ring was analysed in vitro at 37 ℃ in a 1% aqueous solution of 2-HP-beta-CD (2-hydroxypropyl-beta-cyclodextrin) under a shaking bath (100 rpm). The solution was changed daily except on weekends. The sample solution was analyzed by HPLC using an Inertsil ODS-3,150X4mm 5 μm column and methanol/water (1/1) as eluent at a flow rate of 1.0 ml/min. The detection wavelength for anastrozole was 215 mm. Three loops were tested in parallel.

Rate of in vitro release

The loop was tested in vitro for up to 40 days. The in vitro release rate was continuous and controlled, but in the test showed a total decrease of about 30% in the initial value after 30 days. The initial release rate was 390. mu.g/day (A), 85. mu.g/day (B) and 27. mu.g/day (C), and the average release rate over a 30-day period was 305. mu.g/day (A), 64. mu.g/day (B) and 16. mu.g/day (C).

The in vitro release rate of anastrozole is plotted in figure 1.

In vitro study of primate Ring

The ring (5) used for each dose (A, B and C) was recovered separately and analyzed for residual anastrozole content. The anastrozole content was determined by extraction of the ring using (THF) and subsequent analysis by HPLC.

The in vivo release of anastrozole is obtained by calculating the amount of anastrozole in the ring that is reduced during use, e.g. the initial amount minus the amount remaining in vitro, and dividing this by the number of days (variable) in which the ring is usedEstimated value. Table 1 lists the average (5 rings) in vitro anastrozole content for each dose as well as the anastrozole content in the control ring (unused ring) and the calculated average daily anastrozole release rate.

TABLE 1 in vivo Anastrozole Release estimates daily for doses A, B and C, calculated from the mean in vivo test time and mean analysis of the in vitro and unused control rings

Example 4: feasibility demonstration in crab eating macaque

The cynomolgus macaques are suitable as animal models for studying human endocrine conditions as their reproductive system is comparable to the human reproductive system (Weinbauer, n., Niehaus, Srivastav, Fuch, Esch, and j. mark Cline (2008), "Physiology and Endocrinology of the innovative Cycle in macaques." oxidative Pathology 36(7): 7S-23S). This includes, inter alia, cycle length, hormone receptors, morphology, endocrine system and pituitary-Ovarian axis regulation (Borghi, M.R., R.Niesvisky, et al (1983). "Administration of inflammatory and anti inflammatory assays of LH-RH index and expression in Macaca fascularis." manipulation 27(6): 619-626. SaturOne, T.I., Katsumi Hamana (1996) "innovative Response to exogenous genes in endogenous genes monogenes monkey keys". International Journal of biology, 15(3): 194: 204). The pharmacodynamic and pharmacokinetic effects of the vaginally administered dose of the aromatase inhibitor anastrozole were studied during one menstrual cycle by inserting a vaginal ring (IVR) with three different release rates. In particular, the influence on the pituitary-ovarian axis was investigated by measuring the hormones estradiol, FSH, progesterone (blood collection required for this was carried out over the entire experimental period; day 1, four times [ 0 hour, 1 hour, 3 hours, 6 hours after insertion of IVR ]; day 2 and day 3, each 1 time; after this time point, collection was again carried out every 3 days) and by ultrasonography (2X weekly) of the ovary. Hormone assays (estradiol [ Siemens/DPC ], progesterone Beckmann-Culter/DSL ], FSH [ SHG ]) were performed according to the instructions provided by the supplier. One to three days after the last day of the menstrual cycle, IVRs with initial in vivo release rates of 0 micrograms/day (placebo, no anastrozole), 390 micrograms/day, 85 micrograms/day, or 27 micrograms/day were inserted into each group of 5 animals. Animals with irregular cycles were excluded from the experiment.

A decrease in estradiol levels throughout the cycle and a significant decrease in follicular phase was observed in the group with an initial release rate of 390 μ g/day, which is important for estrogen-dependent proliferation of endometriotic and endometriotic foci (table 2, line 5 and fig. 2). As shown in table 2, lines 1, 2 and 3, countermodulation by the pituitary-ovarian axis did not occur at the doses used (no difference compared to placebo control). Comparable FSH levels between groups showed no stimulatory effect on the pituitary-ovarian axis at the doses used. Consistent with this, no ovarian cyst formation was observed (see row 7 of table 2). This experiment shows that aromatase inhibitors (e.g. anastrozole) can be used to reduce endogenous estrogen levels in animal models without triggering counter-regulation.

The following table contains a summary of the in vivo and in vitro release rates of anastrozole from the IVR [ table 1], estradiol (E2), progesterone and FSH levels and information on the formation of ovarian cysts using different doses of anastrozole during the menstrual cycle (days 1-26) [ table 2 ].

Table 1: in vivo and in vitro release Rate summaries

Table 2: estradiol (E2), progesterone and FSH levels, and ovarian cyst formation during the menstrual cycle (days 1-26)

FIG. 2 shows estradiol levels (pmol/l) during follicular phase. Compared to the placebo group, 390 μ g anastrozole per day significantly reduced estradiol levels (P value < 0.0478).

The anastrozole concentration in plasma samples was quantitatively determined by using liquid chromatography liquid-liquid extraction in conjunction with tandem mass spectrometry (LC/ESI-MS/MS). The analysis was performed in Agilent 1200 and AB Sciex triple quadrupole 5500 in positive ionization mode. For this purpose, first 100. mu.l of each plasma sample are taken, mixed with 300. mu.l of an aqueous solution containing any non-structurally related compound as internal standard and extracted with 1.3ml of methyl tert-butyl ether in a Perkin Elmer Mass Spectrometry Prep Station (Perkin Elmer Mass Prep Station). After phase separation, the organic phase was blown off and the residue was taken up in 30. mu.l of LC eluent (50% methanol/50% water, v/v). Of these, 5 μ l was injected into LC/MS/MS, the M/z change 294 ([ M + H ] +) → 225 was recorded, and the signal was integrated using AB Sciex software analyst 1.5. The concentration of the plasma samples was determined from the resulting area by means of a standard curve present in the same order (0, 0.0500 to 1000nM in plasma, n = 2). The lower limit determined by this method is about 1.2. mu.g/l (quadratic standard curve, weighted 1/x). The time course of the serum concentration of anastrozole can be seen in figure 3. Plasma protein binding of anastrozole in human and cynomolgus monkey plasma (free fragment [ fu ]) was determined by the following method: dialysis was performed in a 96-Well microdialysis apparatus (HT-Dialysis LLC) at 37 ℃ for 7 hours using a Dialysis membrane made of regenerated cellulose (MWCO 3.5K) (see Bank, M.J. Bank et al (2003), "Development and differentiation of a 96-Well Equilibrium Dialysis apparatus for Measuring Plasma Protein Binding" J.Pharma. Sci.92(5): 967-974) and the dialysate was subsequently measured by means of LC/ESI-MS/MS. The free fragment (fu) was calculated to be 34% in humans and 52% in cynomolgus macaques.

Figure 3 shows the time course of plasma concentrations of anastrozole after IVR administration in cynomolgus macaques.

The mean plasma concentration (Css) of the anastrozole was calculated as the mean of all concentrations measured from the first day of IVR insertion through to the end of the experiment per dose group.

To calculate the in vivo release rate of anastrozole from the vaginal ring, the in vivo plasma Clearance (CL) of cynomolgus macaque was determined in a separate experiment. For this experiment, anastrozole was administered intravenously to cynomolgus macaques at a dose of 0.2mg/kg in 50% PEG400 in each case, blood samples were taken at different times, and plasma concentrations were determined by LC/ESI-MS/MS. The plasma clearance to anastrozole thus calculated was 0.58 l/h/kg.

Then according to the equation: rin = Css CL (see table X) the average in vivo release rate (Rin) from the IVR was calculated. It is evident that the mean release rate calculated in this way matches very well the in vitro release rate in buffer (in vitro/in vivo correction factor of 1.1). Furthermore, they are consistent with the mean in vivo release rate calculated from the in vitro residual volume of the ring used at the end of the study.

Subsequently, the in vitro IVR release rate of IVR in human applications was estimated, which was necessary to reach serum levels that reduce estradiol in cynomolgus monkeys. In cynomolgus macaques, this was achieved in the highest dose group with a mean serum concentration (Css) of 5.9 μ g/l. The corresponding effective serum concentration in humans was estimated to be 9. mu.g/l, taking into account species-specific plasma protein binding, according to equation (1) below.

Equation 1:

the mean in vivo release rate of IVR necessary to achieve a plasma concentration in the human of 9 μ g/l was calculated according to equation 2. For this equation, the plasma clearance rate of anastrozole in humans is required. It is known only for oral administration (CL/F) (clin. pharmacol. and biopharmac. review, NDA020541(September 28,1995)) and can be used as CL for calculation since the oral bioavailability (F) is about 1.

Equation 2: rin_{Human being}=Css_{Human being}·CL_{Human being}

An in vivo release rate of 246 ug/d was obtained which had to be kept constant to achieve reduced levels of estradiol in humans in monkeys. Assuming that anastrozole permeates comparably in the vagina of primates and humans, the in vitro/in vivo correction factor of 1.1, calculated from the primate experiments, gave a constant in vitro release rate of 270 micrograms anastrozole/day in buffer for humans. If there is a comparable decrease in release rate over time for IVR in humans as for monkeys, the corresponding initial in vitro release rate will need to be higher; calculated as about 350 mug per day (table 1).

Graph list

FIG. 1: in vitro release rates (micrograms/day) of anastrozole for formulation a (high dose =390 micrograms/day), B (medium dose =85 micrograms/day), and C (low dose =27 micrograms/day)

FIG. 2: estradiol levels during the follicular phase (pmol/l). 350 μ g anastrozole per day significantly reduced estradiol levels compared to placebo (P value < 0.0478)

FIG. 3: time course of plasma concentration of anastrozole after IVR administration in cynomolgus macaques

Claims (4)

1. A vaginal ring for use in the treatment of endometriosis comprising anastrozole and levonorgestrel, wherein the systemic anastrozole exposure achieved after release from the vaginal ring is equivalent to the anastrozole exposure following oral administration at a dose of 0.1 to 0.9mg anastrozole per day, and wherein the systemic levonorgestrel exposure achieved after release from the vaginal ring is equivalent to the levonorgestrel exposure following oral administration at a dose of greater than 10 μ g but less than 50 μ g per day, wherein the vaginal ring is free of estrogen.

2.A vaginal ring for use in the treatment of endometriosis according to claim 1 wherein said desired release rate is achieved by a burst effect for only one, two or three days after commencement of treatment.

3. The vaginal ring for use in the treatment of endometriosis according to claim 1 wherein the vaginal ring has a long-term release period lasting from 1 week to 3 months.

4. The vaginal ring for use in the treatment of endometriosis according to claim 1 wherein the vaginal ring has an extended release period lasting from 4 to 6 weeks.