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United States Patent (19) 11) 4,383,993 Hussain Et Al

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United States Patent (19) 11) 4,383,993 Hussain Et Al United States Patent (19) 11) 4,383,993 Hussain et al. 45) May 17, 1983 (54) NASAL DOSAGE FORMS CONTAINING 4,315,925 2/1982 Hussain et al. ...................... 424/239 NATURAL FEMALE SEX HORMONES Primary Examiner-Elbert L. Roberts Attorney, Agent, or Firm-Burns, Doane, Swecker & 75 Inventors: Anwar A. Hussain; Shinichiro Hirai; Rima Bawarshi, all of Lexington, Ky. Mathis 73) Assignee: University of Kentucky Research (57) ABSTRACT Foundation, Lexington, Ky. The invention relates to a novel method of administer ing the natural female sex hormones, 17 g-estradiol and 21 Appl. No.: 277,000 progesterone, to achieve enhanced bioavailability thereof. The invention further relates to novel dosage (22) Fied: Jun. 24, 1981 forms of 17 g-estradiol and/or progesterone which are adapted for nasal administration, such as solutions, sus Related U.S. Application Data pensions, gels and ointments. The dosage forms contain (63) Continuation of Ser. No. 154,995, May 30, 1980, Pat. ing a combination of 17 g-estradiol and progesterone No. 4,315,925. are particularly useful as contraceptives, while the dos (51) Int. Cl. ............................................. AON 45/00 age forms containing only one of the hormonal compo (52) 4 - - - - - - - - - - 4 424/239 nents find utility in the treatment of conditions such as Field of Search ................................ 424/239, 238 menopause, menstrual disorders, etc., which are known (58) to respond to administration of a natural or synthetic 56) References Cited female hormone. U.S. PATENT DOCUMENTS 4, 145,416 3/1979 Lachnit-Fixson et al. ......... 424/239 26 Claims, 5 Drawing Figures a WAPS, AI WWSW of %2- Aftffff;7 fr A/FAO/WSIPt. M O W O ASA s s AE, AEIS U.S. Patent May 17, 1983 Sheet 1 of 5 4,383,993 A 27. AW (AZ (AAMAASJAAA AAJA ADWIASIAFFEW Of 50afe AASIAAOA/AI W Aff Of OWS//W. O MW O MSAA D /?) fM S. 60 SN S W S SN Ss f S S.N C N sS N f N of -r 0 - O 0.7 - M O 0. 0 20 50 IAE, A/E/IES U.S. Patent May 17, 1983 Sheet 2 of 5 4,383,993 A 27.2 AAAA/70s/A A/AAW AMSA WAAA A. A. A4000 AAA AA AAA AW/S/PAVO (A A0AAS/A0AF 007 (f AOW/AS/A/70. O /w O Wasal / 0 W 4000 S. NS J00 S 8. 2000 S s 1000 0 f // U.S. Patent May 17, 1983 Sheet 3 of 5 4,383,993 A 27. A 10 AAAI (A 101 (AWA) ASAGAS (EAA AA0AA/EAS/A2/ 0A fla -ASIAD/04, te42/PA/ AMI (AADASIAI. O / W O MSA O /?) to PW s S R S P S SN SS. S / O dy f 0 f f AAA, AWAPS U.S. Patent May 17, 1983 Sheet 4 of 5 4,383,993 Af 27.4 A. A1097 AAA Of ASIAll (A2) A0AA/ MDWSWW (A 174 -áSIM004 (247A 60 AWA (AOASI//W. O AW O MSAA O / ss 0. f M 02 IAEA, A00AS U.S. Patent May 17, 1983 Sheet 5 of 5 4,383,993 A, 27. AAA All AAA AASIA (Affy AAFE AIA/ASA.0 W 172-67A001, % Mf f/AF (AAWS//70. O // f O ASAA O /O AA AOAS 4,383,993 2 and thus avoid the disadvantages inherent in the use of NASAL DOSAGE FORMS CONTAINING potentially unsafe synthetic estrogens and progestins. NATURAL FEMALE SEX HORMONES It is yet a further object of the present invention to provide a novel method and novel dosage forms con This application is a continuation, of application Ser. 5 No.154,995, filed May 30, 1980 now U.S. Pat. No. taining 17 A-estradiol or progesterone useful in the 4,315,925. treatment of conditions such as menopause, menstrual disorders, etc. which are known to respond to adminis BACKGROUND OF THE INVENTION tration of a natural or synthetic female sex hormone. 1. Field of the Invention 10 The foregoing objects are achieved by nasal adminis The present invention relates to a novel method of tration of 17 A-estradiol (if desired, in the form of one of administering the natural female sex hormones, 17 S estradiol and progesterone, and to novel dosage forms its estrogenically effective esters) and/or progesterone. containing those compounds, singly or in combination, According to the invention, these natural female sex which are adapted for nasal administration. 5 hormones are administered via a novel nasal dosage 2. Description of the Prior Art form, i.e., a solution, suspension, ointment or gel 17 A-estradiol is the most potent natural estrogen adapted for nasal administration. found in human beings and is the major secretory prod uct of the ovary. It is readily oxidized in the body to BRIEF DESCRIPTION OF THE DRAWINGS estrone, which in turn can be hydrated to estriol. These 20 FIG. 1 is a semi-logarithmic plot of mean blood levels transformations take place mainly in the liver, where there is free interconversion between estrone and estra of progesterone after intravenous (IV), nasal and in diol. All three of these natural estrogens are excreted in traduodenal/oral (ID) administration of a dose of 50 ug the urine as glucuronides and sulfates, along with a host of progesterone per rat. of related, minor products in water-soluble complexes. 25 FIG. 2 is a graph showing the area under the curve as It is widely known that, following oral administration a function of dose for the intravenous (IV) and nasal of micronized 17 (3-estradiol (E2), the incremental cir routes of progesterone administration (50 g, 100 ug culation estrogen is principally the less active species and 150 pug dosage levels). estrone (E1), which reaches a peak concentration many FIG. 3 is a semi-logarithmic plot of mean blood levels times greater than that of E2. The conversion of E2 to 30 El and subsequently to other metabolites takes place of total unconjugated estrogens (TUE) following intra during absorption from the intestine and passage venous (IV), nasal and intraduodenal/oral (ID) admin through the liver. This extensive metabolism greatly istration of a dose of 10 ug of 17 g-estradiol per rat. limits the oral effectiveness of the natural estrogens and FIG. 4 is a semi-logarithmic plot of mean blood levels their esters. Indeed, because of their limited oral effi 35 of estradiol (E2) following intravenous (IV), nasal and cacy, 17 g-estradiol and its esters are generally adminis intraduodenal/oral (ID) administration of a dose of 10 tered by intramuscular injection. pug of 17 g-estradiol per rat. Progesterone is the active natural progestin which occurs in the corpus luteum, placenta and adrenal cor FIG. 5 is a semi-logarithmic plot of mean blood levels tex. It is not effective by mouth because of its rapid of estrone (E) following intravenous (IV), nasal and metabolism in the intestinal epithelium and in the liver, intraduodenal/oral (ID) amdinistration of a dose of 10 and is therefore only administered intramuscularly. ug of 17 g-estradiol per rat. Because of their limited oral effectiveness, these natu ral female sex hormones have not found utility in oral DETAILED DESCRIPTION OF THE contraceptives. Instead, only active synthetic estrogens 45 INVENTION and progestins have been prepared and are used for The word "progesterone" as used herein means contraceptive purposes. The synthetic derivatives have pregn-4-ene-3,20-dione, i.e., the compound of the for also in many cases replaced the natural substances in the treatment of menopause, threatened abortion, etc. How mula ever, the synthetic derivatives are, generally speaking, SO much more likely to cause toxic side effects than are the CH3 relatively safe natural hormones. CO HyC SUMMARY OF THE INVENTION In view of the foregoing, it is apparent that a serious 55 need exists for the improved delivery of the natural HyC female sex hormones. Thus, it is an object of the present invention to provide novel dosage forms and a novel method of administering 17 A-estradiol and progester o?a one, separately or in combination, which will provide greatly enhanced bioavailability as compared to oral and is intended to include progesterone derived from administration, while at the same time providing rela natural sources as well as that made synthetically. tive ease of administration when compared to intramus The word "17 g-estradiol' as used herein is intended cular injection. to encompass any pharmaceutically acceptable, estro It is a further object of the present invention to pro 65 vide a novel contraceptive method and novel composi genically active form of 17 g-estradiol, i.e., estra tions for accomplishing same which utilize the natural 1,3,5(10)-triene-3,17 g-diol itself, which has the formula female sex hormones, 17 g-estradiol and progesterone, 4,383,993 4. TABLE I AREA UNDER THE CURVE AFTER INTRAVENOUS, NASAL AND INTRADUODENAL ADMINISTRATION OF PROGESTERONE N RATS Dose AUC), ng. min/ml Nasal ID ug/rat IV Nasal D IV IV 50 1612.2 1659.0 19.0 1029 0.02 - 80.8 + 109.2 4.6 10 100 3520-0 3599.0 - 022 - and which may be extracted from natural sources or 49.0 62.4 50 4480.2 4798.9 - 07 -- made synthetically, or one of its 3- or 17-monoesters or 466.4 - 188.5 3,17-diesters. By way of illustration, suitable esters of 17 mean - SE(n = 4-6). A-estradiol for purposes of the present invention include 15 3-monoesters such as estradiol benzoate and estradiol By using the two tailed t-test, it can be shown that the 3-acetate; 17-monoesters such as estradiol cypionate, area under the curve following intravenous and nasal estradiol 17-propionate, estradiol 17-acetate, estradiol administration at each dose were not significantly dif 7-heptanoate (estradiol enanthate), estradiol 17 ferent, even at the 0.001 level.
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