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United States Patent (19) (11) 4,315,925 Hussain Et Al

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United States Patent (19) (11) 4,315,925 Hussain Et Al United States Patent (19) (11) 4,315,925 Hussain et al. 45 Feb. 16, 1982 54 METHOD OF ADMINISTERINGNATURAL FEMALE SEX HORMONES OTHER PUBLICATIONS Brown et al., "British Medical Journal', Mar. 4, 1972, 75) Inventors: Anwar A. Hussain; Shinichiro Hirai; pp. 585-590, Rima Bawarshi, all of Lexington, Ky. Primary Examiner-Elbert L. Roberts Attorney, Agent, or Firm-Burns, Doane, Swecker & 73 Assignee: University of Kentucky Research Mathis Foundation, Lexington, Ky. 57 ABSTRACT The invention relates to a novel method of administer 21 Appl. No.: 154,995 ing the natural femalesex hormones, 17 g- estradiol and progesterone, to achieve enhanced bioavailability 22 Filed: May 30, 1980 thereof. The invention further relates to novel dosage forms of 17 g- estradiol and/or progesterone which are 51 Int. Cl. ............................................. A01N 45/00 adapted for nasal administration, such as solutions, sus U.S. C. ................................................... 424/239 pensions, gels and ointments. The dosage forms contain 52) ing a combination of 17 (3-estradiol and progesterone 58 Field of Search ........................................ 424/239 are particularly useful as contraceptives, while the dos age forms containing only one of the hormonal compo 56 References Cited nents find utility in the treatment of conditions such as U.S. PATENT DOCUMENTS menopause, menstrual disorders, etc., which are known 3,733,407 5/1973 Segre................................... 424/239 to respond to administration of a natural or synthetic 3,942,641 3/1976 Segre ................................... 424/239 female hormone. 4,071,623 1/1978 van der Vies ....................... 424/239 4,145,416 3/1979 Lachnit-Fixson et al. ......... 424/239 20 Claims, 5 Drawing Figures - A/7F (AA/AW/SIAAF. AW O AASA Off fi - S 6.0 - RS s s - S SasS S ft - s 6 - St - SSS s # - ?t t tf t t - - t 60 #20 f I/AE, 47.0/AS U.S. Patent Feb. 16, 1982 Sheet 4 of 5 4,315,925 Af A7. 4 A 6,000 AF2. Of AS/A20 (A2) A0//(W/WA AO/W/S/AAV/0W (A 176 -ÉSIAA/04, 1947/AA/ 60 AMWA (FAMWS/A//0/. O // f0 O WASAZ O // 40 / 0. 6 0. y (/ () (6 (20% I/AA, h00AS U.S. Patent Feb. 16, 1982 Sheet 5 of 5 4,315,925 A 27. 172 -AS/A2/0/A/AA/ Z/A/A A00/5 4,315,925 2 taining 1713-estradiol or progesterone useful in the treat METHOD OF ADMINISTERING NATURAL, ment of conditions such as menopause, menstrual disor FEMALE SEX HORMONES ders, etc., which are known to respond to administration of a natural or synthetic female sex hormone. BACKGROUND OF THE INVENTION 5 The foregoing objects are achieved by nasal adminis 1. Field of the Invention tration of 17.6-estradiol (if desired, in the form of one of The present invention relates to a novel method of its estrogenically effective esters) and/or progesterone. administering the natural female sex hormones, 17(3- According to the invention, these natural female sex estradiol and progesterone, and to novel dosage forms hormones are administered via a novel nasal dosage containing those compounds, singly or in combination, 10 form, i.e., a solution, suspension, ointment or gel which are adapted for nasal administration. adapted for nasal administration. 2. Description of the Prior Art 17,3-estradiol is the most potent natural estrogen BRIEF DESCRIPTION OF THE DRAWINGS found in human beings and is the major secretory prod FIG. 1 is a semi-logarithmic plot of mean blood levels uct of the ovary. It is readily oxidized in the body to 15 of progesterone after intravenous (IV), nasal and in estrone, which in turn can be hydrated to estriol. These traduodenal/oral (ID) administration of a dose of 50 ug transformations take place mainly in the liver, where of progesterone per rat. there is free interconversion between estrone and estra FIG. 2 is a graph showing the area under the curve as diol. All three of these natural estrogens are excreted in a function of dose for the intravenous (IV) and nasal the urine as glucuronides and sulfates, along with a host 20 of related, minor products in water-soluble complexes. routes of progesterone administration (50 pug, 100' g It is widely known that, following oral administration and 150 ug dosage levels). of micronized 176-estradiol (E2), the incremental circu FIG.3 is a semi-logarithmic plot of mean blood levels lation estrogen is principally the less active species es of total unconjugated estrogens (TUE) following intra trone (E1), which reaches a peak concentration many 25 venous (IV), nasal and intraduodenal/oral (ID) admin times greater than that of E2. The conversion of E2 to istration of a dose of 10 pig of 1743-estradiol per rat. E1 and subsequently to other metabolites takes place FIG. 4 is a semi-logarithmic plot of mean blood levels during absorption from the intestine and passage of estradiol (E2) following intravenous (IV), nasal and through the liver. This extensive metabolism greatly intraduodenal/oral (ID) administration of a dose of 10 limits the oral effectiveness of the natural estrogens and 30 ug of 17g-estradiol per rat. their esters. Indeed, because of their limited oral effi FIG. 5 is a semi-logarithmic plot of mean blood levels cacy, 1713-estradiol and its esters are generally adminis of estrone (E1) following intravenous (IV), nasal and tered by intramuscular injection. intraduodenal/oral (ID) administration of a dose of 10 Progesterone is the active natural progestin whic ug of 176-estradiol per rat. occurs in the corpus luteum, placenta and adrenal cor 35 DETAILED DESCRIPTION OF THE tex. It is not effective by mouth because of its rapid INVENTION metabolism in the intestinal epithelium and in the liver, and is therefore only administered intramuscularly. The word "progesterone' as used herein means Because of their limited oral effectiveness, these natu pregn-4-ene-3,20-dione, i.e., the compound of the for ral female sex hormones have not found utility in oral mula contraceptives. Instead, only active synthetic estrogens and progestins have been prepared and are used for CH3 contraceptive purposes. The synthetic derivatives have also in many cases replaced the natural substances in the CO treatment of menopause, threatened abortion, etc. How 45 ever, the synthetic derivatives are, generally speaking, much more likely to cause toxic side effects than are the relatively safe natural hormones. SUMMARY OF THE INVENTION 50 O In view of the foregoing, it is apparent that a serious need exists for the improved delivery of the natural and is intended to include progesterone derived from female sex hormones. Thus, it is an object of the present natural sources as well as that made synthetically. invention to provide novel dosage forms and a novel The word "1713-estradiol' as used herein is intended method of administering 17(3-estradiol and progester 55 to encompass any pharmaceutically acceptable, estro one, separately or in combination, which will provide genically active form of 17g-estradiol, i.e., estra greatly enhanced bioavailability as compared to oral 1,3,5(10)-triene-3,1743-diol itself, which has the formula administration, while at the same time providing rela tive ease of administration when compared to intramus cular injection. 60 It is a further object of the present invention to pro vide a novel contraceptive method and novel composi tions for accomplishing same which utilize the natural female sex hormones, 17(3-estradiol and progesterone, and thus avoid the disadvantages inherent in the use of 65 potentially unsafe synthetic estrogens and progestins. It is yet a further object of the present invention to provide a novel method and novel dosage forms con 4,315,925 3 4 and which may be extracted from natural sources or administration at each dosage were not significantly made synthetically, or one of its 3- or 17-monoesters or 3,17-diesters. By way of illustration, suitable esters of different, even at the 0.001 level. However, as can be 17f8-estradiol for purposes of the present invention in seen from Table I, oral administration of 50 ug resulted clude 3-monoesters such as estradiol benzoate and estra- 5 in bioavailability equal to only 1.2% that of an equiva diol 3-acetate; 17-monoesters such as estradiol cypio lent dose given intravenously. Also from Table I, it can nate, estradiol 17-propionate, estradiol 17-acetate, estra be seen that the nasal bioavailability of progesterone at diol 17-heptanoate (estradiol enanthate), estradiol 17. the 50 ug dosage level was 85.75 times greater than the undecanoate (estradiol undecylate) and estradiol 17-val oral bioavailability. erate; and 3,17-diesters such as estradiol dipropionate '. It can also be seen from FIG. 1 that progesterone is and estradiol diacetate. 10 very rapidly absorbed from the nasal mucosa; thus, at According to the present invention, it has surpris the 50 ug dosage level, the peak plasma level was at ingly been found: that 17(3-estradiol and progesterone tained in less than 7 minutes after instillation of the nose can be administered nasally with results considerably drops. superior to those obtained with oral administration. The FIG. 2 shows the area under the curve as a function following studies were undertaken to examine the bi of dose for the intravenous and nasal routes. As can be oavailability of progesterone and 17g-estradiol from seen from FIG. 2, for both IV and nasal routes of ad nasal solution in comparison with the bioavailability of ministration the area under the curve (AUC) was di these drugs when administered orally and intrave rectly proportional to the dose administered. nously. - . : - Sprague-Dawley male rats, each weighing about 270 20 The study described above indicates that progester grams, were used in the progesterone study.
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