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Nasal Dosage Forms Containing Natural Female Sex Horomones Anwar A

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Nasal Dosage Forms Containing Natural Female Sex Horomones Anwar A University of Kentucky UKnowledge Pharmaceutical Sciences Faculty Patents Pharmaceutical Sciences 5-17-1983 Nasal Dosage Forms Containing Natural Female Sex Horomones Anwar A. Hussain University of Kentucky Shinichiro Hirai University of Kentucky Rima Bawarshi University of Kentucky Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/ps_patents Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Hussain, Anwar A.; Hirai, Shinichiro; and Bawarshi, Rima, "Nasal Dosage Forms Containing Natural Female Sex Horomones" (1983). Pharmaceutical Sciences Faculty Patents. 142. https://uknowledge.uky.edu/ps_patents/142 This Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion in Pharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. UllltBdC States Patent [191 u 11 4,383,993 Hussain et al. [45] May 17, 1983 [54] NASAL DOSAGE FORMS CONTAINING 4,3l5,925 2/l982 Hussain et al. .................... .. 424/239 NATURAL FEMALE SEX HORMONES Primary Examiner-—Elbert L. Roberts [75] Inventors: Anwar A. Hussain; Shinichiro Hirai; Attorney, Agenl- 0' Firm-Bums, D0306, SWECkeT & Rima Bawarshi, all of Lexington, Ky‘ Mathls [73] Assignee: University of Kentucky Research [57] ABSTRACT Foundation’ L?xmgmn- KY‘ The invention relates to a novel method of administer [21] AppL NOJ 277,000 ing the natural female sex hormones, 17 B-estradiol and _ progesterone. to achieve enhanced bioavailability [22] Fll?di Jlln- 24, 1981 thereof. The invention further relates to novel dosage forms of 17 B-estradiol and/or progesterone which are Related US. Application Data adapted for nasal administration, such as solutions, sus [63] Continuation of sen NO’ ‘54995! May 30’ 1980’ Pam pensions, gels and ointmcnts. The dosage forms contain No' 4315925 ing a combination of l7 B-estradiol and progesterone v are particularly useful as contraceptives, while the dos Int. Cl.3 . v . r . r . A . 4 . .. age forms cgntaining only one of “13 hormonal compo. l52l U_'S- 0- - ' a ‘ 3 - - - - - - - - ~ ~ 3 ' ' ~ - r - ' - ' 3 - -- 424/239 nents ?nd utility in the treatment of conditions such as [58] Field of Search .............................. ,, 424/239, 238 menopaus?i menstrual disorders, etc" which are known [56] References Cited to respond to administration of a natural or synthetic female hormone. U.S. PATENT DOCUMENTS 26 Claims, 5 Drawing Figures 4,145,416 3/1979 Lachnit-Fixson et al. ....... .. 424/239 000” 0/ Mill/HINT!” .' III/llPINK/H01”,[17H0!"01000 5 Y I 60 30 I20 I50 mi, mum U.S. Patent May 17, 1983 Sheet 2 of5 4,383,993 Fi- q.Z/ . IV 0 mm [j /0 ma - 4on0 _ S‘ ls 3000 - I 2 a; Q 2000 - §> ‘t 1000 - m‘ LLJ I I 50 mu m lag/$1M U.S. Patent May 17, 1983 Sheet 3 of 5 4,383,993 F1527. J 000/? 0/ Mill/5mm”: . IV 0 M541 0 I! T I | Z J I f/lf , #01095 U.S. Patent May 17, 1983 Sheet 4 of5 ‘ 4,383,993 Ff quil ‘0 mm or m/mrm/oxl: 0 0/ J0 0 mm c: 10 01000lfI/[l0f(fgL,#67”! mm, mm 4,383,993 1 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.l54,995, ?led May 30, 1980 now US. Pat. No. taining 17 B-estradiol or progesterone useful in the treatment of conditions such as menopause, menstrual ‘ 4,315,925. 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 l7 B-estradiol (if desired, in the form of one of administering the natural female sex hormones, 17 B its estrogenically effective esters) and/or progesterone. estradiol and progesterone, and to novel dosage forms containing those compounds, singly or in combination, According to the invention, these natural female sex which are adapted for nasal administration. hormones are administered via a novel nasal dosage 2. Description of the Prior Art form, i.e., a solution, suspension, ointment or gel 17 B-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 of progesterone after intravenous (IV), nasal and in there is free interconversion between estrone and estra diol. All three of these natural estrogens are excreted in traduodenal/oral (ID) administration of a dose of 50 pg 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 l7 B-estradiol (E2), the incremental cir routes of progesterone administration (50 pg, 100 pg culation estrogen is principally the less active species and 150 pg 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 E1 to E1 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 pg of 17 B-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 effl of estradiol (E2) following intravenous (IV), nasal and cacy, l7 B-estradiol and its esters are generally adminis intraduodenal/oral (ID) administration of a dose of 10 tered by intramuscular injection. pg of l7 B-estradiol per rat. a Progesterone is the active natural progestin which FIG. 5 is a semi-logarithmic plot of mean blood levels occurs in the corpus luteum, placenta and adrenal cor tex. It is not effective by mouth because of its rapid 40 of estrone (E1) 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. pg of 17 B-estradiol per rat. Because of their limited oral effectiveness, these natu DETAILED DESCRIPTION OF THE ral female sex hormones have not found utility in oral 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 mula treatment of menopause, threatened abortion, etc. How 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 In view of the foregoing, it is apparent that a serious need exists for the improved delivery of the natural female sex hormones. Thus, it is an object of the present invention to provide novel dosage forms and a novel method of administering l7 B-estradiol and progester 0% 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 B-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 B-estradiol, i.e., estra tions for accomplishing same which utilize the natural l,3,5(l0)-triene-3,17 B-diol itself, which has the formula female sex hormones, l7 B-estradiol and progesterone, 4,383,993 4 TABLE I AREA UNDER THE CURVE AFTER INTRAVENOUS, NASAL AND INTRADUODENAL ADMINISTRATION OF PROGESTERONE IN RATS Dose AUQQ, ng. min/ml Nasal ID pg/rat IV Nasal ID IV IV 50 1612.2‘ 1659.0 19.0 1.029 0.012 HO t 80.8 i 109.2 i 4.6 100 3520.0 3599.0 — 1.022 -— and which may be extracted from natural sources or i 491.0 : 621.4 150 4480.2 4798.9 - 1.07] -— made synthetically, or one of its 3- or l7-monoesters or 1 466.4 1 188.5 3,17-diesters. By way of illustration, suitable esters of 17 ‘mean : SE(n = 4-6).“ B-estradiol for purposes of the present invention include 3-monoesters such as estradiol benzoate and estradiol By using the two tailed t-test, it can be shown that the 3-acetate; l7-monoesters such as estradiol cypionate, area under the curve following intravenous and nasal estradiol l7-propionate, estradiol l7-acetate, estradiol administration at each dose were not signi?cantly dif l7-heptan0ate (estradiol enanthate), estradiol 17 ferent, even at the 0.001 level.
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