Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1995-09-11
1999-09-21
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514178, 514182, A61K 3156
Patent
active
059554541
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates to a nasal pharmaceutical preparation having a composition and a form suitable for nasal administration, such as nasal drops and nasal spray, suspensions, gels, ointments, creams and powders, containing a progestogen, for example norethisterone (acetate).
PRIOR ART
Progestogens are used in the treatment of menstrual disorders, alone or in combination with estrogens. Progestogens are also used in the case of endometriosis and of certain cancers. In hormone replacement therapy in (post)menopausal women, progestogens are added to estrogen treatment in order to prevent carcinoma of the endometrium. Similarly, as a contraceptive, progestogens are used, alone or in combination preparations, in oral treatment or as injectable retard preparations. Important examples of progestogens are progesterone, which is a natural hormone, and synthetic progestogens such as norethisterone (acetate), levonorgestrel, norgestrel, desogestrel, gestodene, lynestrenol, ethynodiol diacetate, norgestimate, 3.beta.-hydroxydesogestrel, 19-norprogesterone, medroxyprogesterone (acetate), dydrogesterone, (no)megestrol (acetate), cyproterone (acetate) or medrogestone.
Norethisterone (17.alpha.-ethinyl-17.beta.-hydroxyestr-4-en-3-one, norethindrone, NET) is a synthetic progestogen which is used in many countries in steroid preparations used in oral contraceptives, and also as a progestogen administered alone. In addition, norethisterone acetate (NETA) is used in some formulations. After absorption, it is hydrolyzed to norethisterone.
After oral administration, blood NET levels are obtained which are only approximately 60% of those obtained after intravenous administration (D. J. Black et al., Clin. Pharm. Therap. 1978; 24:439-447). This demonstrates that NET is metabolized in the intestinal wall and the liver after absorption via the oral route ("first-pass" effect). As a result, the oral administration of NET is not very effective and leads to a needless loading of the body with drug. With the aim of decreasing this effect, an NET nasal spray has recently been developed and studied in 8 volunteers (T. C. Anand Kumar et al., Contraception 1991; 44:245-267). The authors show that the application of NET via the nasal route in women is of great interest for use in contraceptive preparations. In previous publications, good results have also been described with the same nasal NET formulation in monkeys (V. Puri et al., J. Reprod. Fert. 1986; 76:215-220) and women (R. S. Shah et al., Contraception 1985; 32:135-147). The nasal formulation employed in these studies was prepared as follows. The norethisterone was dissolved in a propylene glycol/ethanol/water (3:3:4 by volume) solution. The dose of NET administered via the nasal route in the study published in 1991 was 300 .mu.g of NET daily in each woman. The nebulizer used delivered 150 .mu.g of NET in each nasal spraying of 100 .mu.l. The requisite dose of 300 .mu.g of NET was delivered by spraying 100 .mu.l once daily in each nostril.
The medicinal products and the additives employed in nasal formulations of medicinal products should not be detrimental to the nasal epithelium and nasal mucociliary clearance. The influence of medicinal products and of additives on the functioning of the cilia in the nose is a crucial parameter (W. A. J. J. Hermens and F. W. H. M. Merkus, Pharm. Res. 1987; 4:445-449, and F. W. H. M. Merkus et al., J. Controlled Release 1993; 24:201-208).
In experiments conducted by the Applicant, the nasal NET formulation dissolved in a propylene glycol/ethanol/water (3:3:4 by volume) mixture was seen to be very toxic with respect to the ciliary movement of ciliary tissue (as shown in the attached FIGURE). The ciliary movement of human nasal tissue is stopped rapidly in a few minutes by this formulation. Nasal mucociliary clearance, in which the ciliary movement is the most important parameter, must not be disturbed by medicinal product formulations, since it constitutes the most important defence mechanism for protecting the respiratory tra
Adir et Compagnie
Jordan Kimberly
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