MX2010011296A - Method and pharmaceutical composition for obtaining the plasmatic progesterone levels required for different therapeutic indications. - Google Patents

Abstract

The invention relates to the development of a method and pharmaceutical compositions for obtaining plasmatic progesterone levels in humans and for maintaining a plasmatic progesterone concentration between 42 and 3.5 ng/mL for eight days as well as maximum plasmatic concentrations (Cmax) between 12 and 42 ng/mL, sufficient for use in different therapeutic options that require said progesterone concentrations.

Description

M ETHOD AND PHARMACEUTICAL COMPOSITION TO ACHIEVE PROGESTERONE PLASMA LEVELS REQUIRED FOR DIFFERENT THERAPEUTIC INDICATIONS.

Field of the Invention The present invention relates to the design of a method and pharmaceutical compositions to achieve and maintain plasma levels of progesterone in humans between 42 and 3.5 ng / mL for 8 days as well as maximum plasma concentrations (Cmax) between 12 and 42 ng / mL, sufficient for its application in different therapeutic indications that require such concentrations of progesterone. TECHNICAL FIELD Background of the Invention In the state of the art there are numerous pharmaceutical compositions for administering drugs in a controlled manner and more particularly for providing hormones, however, in each case there are very important drawbacks for example, it is reported that when progesterone is administered orally it has the disadvantage of suffer an extensive hepatic metabolism due to the effect of the first step in which the metabolites can have side effects, in addition to this way progesterone has a limited bioavailability. That is why therapies administered orally, require higher doses of progesterone and therefore, are more likely adverse events to greater exposure.

The present invention constitutes an alternative to achieve more precise, reproducible plasma concentrations and with less variation throughout a treatment from a lower number and frequency of injections, facts that can not be achieved with the therapies and products containing progesterone, available To the date. The method object of the present invention can be applied within the medical practice for various therapeutic indications that require progesterone such as treatment of secondary amenorrhea, dysfunctional uterine bleeding, premenstrual syndrome when higher concentrations of progesterone are required in women with oofercetomy, supplementation of progesterone for luteal phase support in assisted reproduction procedures, threat of abortion and prevention of recurrent abortion due to luteal insufficiency, premature birth, endometrosiosis, endometrial hyperplasia, hirsutism, among others.

The method of the present invention allows a greater permanence of progesterone in plasma within the therapeutic levels required for the indications described in the previous paragraph for up to 8 days, without the risk observed with conventional therapies and without repeated administration of the Progesterone may lead to variations in plasma concentration observed in techniques known to date.

The present invention is applied to progesterone supplied in the form of an injectable suspension, which allows obtaining the plasma concentration ranges required for therapeutic indications requiring progesterone, described on page 2. It also applies to any regardless of the geometric shape of the progesterone. particles of active principle that is to say, it applies to suspensions of particles with a well-defined geometric shape such as spherical microparticles or crystals without a defined geometrical shape.

In view of the foregoing the state of the art closest to the invention are the patents US 5,360,616 ('61 6) and U.S. 5,643,604 ('604) both in the name of de Aplicaciones Pharmaceuticals, S.A. of C.V.

The patent ('616) relates to injectable pharmaceutical compositions of modified release medicinal products consisting of solid, non-porous microspheres of 1 to 300 microns of spheroids manufactured by the spray and freeze process. However, this patent refers only to a modified release microsphere formulation and its manufacturing process but does not describe the possible applications of its modified in-vivo release, which allows reaching human plasma levels useful for various therapeutic options with progesterone particularly , those described on page 2.

The patent ('604) relating to a parenteral dosage form in which the active ingredient is contained in microspheres ie in spherical structures determined by one or more pharmacologically inactive carrier substances but does not describe the possible applications of its modified release in -live, which allows reaching plasma levels in humans useful for various therapeutic options with progesterone particularly to support the luteal phase.

To date known medicinal compositions have not achieved with a single administration, maintain for more than a day progesterone plasma concentrations appropriate for therapy requiring progesterone, particularly those described on page 2.

However, the present invention includes a method to achieve and maintain more precise, reproducible plasma concentrations and with greater variation throughout the aforementioned treatment, a fact that can not be achieved with the therapies and pharmaceutical products available to date.

In another embodiment of the present invention it is possible to administer progesterone in a single injection or in multiple injections since from the first injection it is possible to achieve the permanence of progesterone in plasma within the range required for the indications described on page 2.

In yet another embodiment of the invention, the pharmaceutical composition is provided in the form of an injectable suspension of spherical microparticles or microcrystals without a defined geometrical shape.

Objects of the Invention It is an object of the present invention to provide a therapeutic option of weekly administration of progesterone to avoid daily administration, even two or three times a day in order to maintain plasma progesterone levels for 8 days between 13 and 3.5 ng / mL with a single injection of 1,00 mg of progesterone.

It is another object of the invention, in an alternative embodiment, to maintain plasma progesterone levels for 8 days between 20 and 7 ng / mL with a single injection of 200 mg of progesterone.

It is another object of the present invention, in an alternative embodiment, to maintain plasma levels of progesterone between 26 and 8 ng / mL with four weekly injections of 200 mg of progesterone.

It is another object of the invention, in an alternative embodiment, to maintain plasma progesterone levels between 42 and 1 3 ng / mL with four weekly injections of 300 mg of progesterone.

It is another object of the invention to decrease the amount and frequency of administration of progesterone required by the oral route in order to decrease the likelihood of adverse events caused by frequent and prolonged exposure to progesterone.

It is another object of the invention, to avoid maximum peaks of plasma concentration observed after the administration of oil solutions of progesterone and the possible adverse events associated with high plasma concentrations of progesterone caused by said maximum peaks.

It is another object of the invention, to diminish the events traumatic and local irritability observed with injectable oil solutions containing progesterone, which need to be injected daily.

It is another object of the invention to avoid the discomfort and inconsistency of doses observed in the intravaginal administration, the lack of reproducibility of the amount of progesterone absorbed and the fact that the plasma concentrations rapidly decrease in such a way that it is not possible to maintain the therapeutic levels beyond 24 hours.

It is still another object of the invention to provide a drug according to the invention, in a scheme of single injections or repeated injections.

It is still another object of the invention to provide progesterone in the form of mircroespheres or microcrystals in injectable suspension.

Brief Description of Figures.

Figure 1 is a graph of plasma progesterone concentration as a function of time, after a single injection or of an injectable suspension of 1000 mg of progesterone microspheres.

Figure 2 is a graph of plasma progesterone concentration as a function of time, after a single injection of an injectable suspension of 200 mg of progesterone microspheres.

Figure 3 is a graph of plasma progesterone concentration as a function of time, after four injections of an injectable suspension of 200 mg of progesterone microspheres.

Figure 4 is a graph of plasma progesterone concentration as a function of time, after four injections of an injectable suspension of 300 mg of progesterone microspheres.

Figure 5 is a graph of plasma progesterone concentration as a function of time, after four injections of an injectable suspension of 300 mg of progesterone microcrystalline particles that do not have a defined geometric shape.

Detailed description of the invention The present invention provides a method and pharmaceutical compositions for weekly administration preferably, during which the plasma concentration of progesterone is maintained at therapeutic levels required for certain treatments with this hormone.

Progesterone plasma levels for 8 days are between 13 and 3.5 ng / mL with a single injection of 100 mg, between 20 and 7 ng / mL with a single injection of 200 mg, between 26 and 8 ng / mL after four injections of 200 mg of progesterone, and between 42 and 13 ng / mL after four injections of 300 mg progesterone, all in the form of an injectable suspension of d progesterone.

The release of progesterone in the human body is such that its permanence is favored in the concentration intervals required for various therapeutic options that require progesterone. In an ideal situation, the dissolution of the drug including progesterone is directly proportional to the rate of erosion of the microspheres or microcrystalline particles at the injection site and is not dependent on the geometry thereof.

Examples The following examples illustrate some preferred embodiments of the invention where plasma levels are achieved accurately and for 8 days.

Example 1 UNIQUE INJECTION OF 100mg OF SPHERICAL MICROPARTICLES OF PROGESTERONE, IN INJECTABLE SUSPENSION.

It was administered to 12 postmenopausal women a 100 mg single injection of spherical progesterone microparticles, in the form of an injectable aqueous suspension. The plasma levels obtained are illustrated in Figure 1, in which it is observed that plasma concentrations of progesterone are maintained for up to 7 days at appropriate levels for various therapies that require such progesterone concentrations.

Example 2 UNIQUE INJECTION OF 200 mg OF PROGESTERONE SPHERICAL MICROPARTICLES IN INJECTABLE SUSPENSION.

A single injection of 200 mg of spherical progesterone microparticles in the form of an injectable aqueous suspension was administered to 12 postmenopausal women. The plasma levels obtained are illustrated in Figure 2, in which it is observed that progesterone plasma concentrations are maintained for up to 7 days at appropriate levels for various therapies that require such progesterone concentrations and are described on page 2.

Example 3 REPEATED INJECTIONS OF 200 mg PROPHESTERONE SPHERICAL MICROPARTICLES, IN INJECTABLE SUSPENSION.

Four repeated injections of 200 mg of spherical progesterone microparticles in the form of an injectable aqueous suspension were administered to 15 postmenopausal women. The plasma levels obtained are illustrated in Figure 3, in which it is observed that plasma concentrations of progesterone are maintained for up to 7 days at appropriate levels for various therapies that they require these concentrations of progesterone and they are described on page 2.

Example 4 REPETI DAS INJECTIONS OF 300 mg PROPHESTERONE SPHERICAL MICROPARTICLES IN SUSPENSION I NYECTABLE.

Four repeated injections of 300 mg of spherical progesterone microparticles in the form of an injectable aqueous suspension were administered to 13 postmenopausal women. The plasma levels obtained are illustrated in Figure 4, in which it is observed that progesterone plasma concentrations are maintained for up to 7 days at appropriate levels for various therapies that require such progesterone concentrations and are described on page 2.

Example 5 REPETI DAS INJECTIONS OF 300 mg MICROPARTÍCU LAS CRYSTALS OF PROGESTERONE, WITHOUT GEOMETRIC FORM DEFI N I DA IN SUSPENSION I NYECTABLE.

Fourteen postmenopausal women were given four repeated injections of 300 mg of progesterone microcrystals without a defined geometrical shape in an injectable aqueous suspension. The plasma levels obtained are illustrated in Figure 5, in which it is observed that progesterone plasma concentrations are maintained until or for 7 days at appropriate levels for various therapies that require such progesterone concentrations and are described on page 2.

Claims (21)

1. CLAIMS 1. A method to maintain in humans, sustained plasma progesterone concentrations between 42 and 3.5 ng / mL for 8 days and maximum plasma concentrations (Cmax) between 12 and 42 ng / mL sufficient for its application in different therapeutic options that require progesterone. 2. The method described in claim 1, which is sufficient to maintain plasma concentrations of progesterone between 13 and 3.5 ng / mL from the administration of a 100 mg progesterone injection in the form of an injectable suspension. 3. The method described in claim 2, wherein the application is secondary amenorrhea, dysfunctional uterine hemorrhage, premenstrual syndrome, progesterone replacement in women with oophorectomy. 4. The method described in claim 1, wherein the plasma concentrations of progesterone are maintained between 20 and 7 ng / mL from the administration of a 200 mg injection of progesterone in the form of an injectable suspension. 5. The method described in claim 1, wherein the plasma concentrations of progesterone are maintained between 26 and 8 ng / mL from multiple injections of 200 mg of progesterone in the form of an injectable suspension. 6. The method described in claim 4, wherein the application is in supplementation of the luteal phase in assisted reproduction procedures, threatened abortion and prevention of recurrent abortion due to luteal insufficiency, premature birth, endometriosis, endometrial hyperplasia and hirsutism, in secondary amenorrhea , dysfunctional uterine hemorrhage and premenstrual syndrome when higher levels of progesterone are required. 7. The method described in claim 1 for maintaining progesterone plasma concentrations of 42 and 13 ng / mL from the administration of multiple injections of 300 mg of progesterone in the form of an injectable suspension. 8. The method described in claim 7, wherein the application is in supplementation of the luteal phase in assisted reproduction procedures, threatened abortion and prevention of recurrent abortion due to luteal insufficiency, premature birth, endometriosis, endometrial hyperplasia and hirsutism, in secondary amenorrhea. , dysfunctional uterine hemorrhage and premenstrual syndrome when higher levels of progesterone are required. 9. The method described in claim 1, obtained from an injectable aqueous suspension of progesterone particles. 10. The method described in claim 8, obtained from a single injection or single dose of an injectable aqueous suspension of progesterone particles with spherical shape. eleven . The method described in claim 9, obtained from multiple or multi-dose injections of an injectable aqueous suspension of progesterone particles with spherical shape. 12. The method described in claim 9, obtained from an injectable aqueous suspension of progesterone particles without defined geometric shape. 13. The method described in claim 12, obtained from a single injection or unit dose of an injectable aqueous suspension of progesterone particles without defined geometric shape. 14. The method described in claim 12, obtained from repeated injections of an injectable aqueous suspension of progesterone particles without defined geometric shape. 15. The method described in claim 1, obtained from an injectable suspension. 16. Injectable pharmaceutical composition for single injection of progesterone particles with spherical shape. 17. Pharmaceutical composition according to claim 16, wherein the shape of the pogesterone particles lack a defined shape. 18. Pharmaceutical composition according to claim 16, wherein the progesterone particles that do not have a defined geometrical shape are crystals that can be injected in the form of an injectable aqueous suspension. 1 9. Use of a pharmaceutical composition according to claims 16 to 18, to treat secondary amenorrhea, dysfunctional uterine hemorrhage, premenstrual syndrome (when higher progesterone concentrations are required), progesterone substitution in women with ooferctomy, phase supplementation Lute in procedures of assisted reproduction, threatened abortion, and prevention of recurrent abortion due to luteal insufficiency, premature birth, endometriosis, endometrial hyperplasia, hirsutism, among others. 20. Aqueous injectable suspension of progesterone particles with spherical shape. twenty-one . Aqueous injectable suspension of progesterone crystals without defined geometric shape. SUMMARY The present invention relates to the design of a method and pharmaceutical compositions to achieve plasma levels of progesterone in humans and maintain a progesterone plasma concentration between 42 and 3.5 ng / ml for 8 days as well as maximum plasma concentrations (Cmax). between 1 2 and 42 ng / m L, sufficient for its application in different therapeutic options that require such progesterone concentrations.