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Home , Estradiol diacetate, Estradiol dipropionate, Estradiol undecylate

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- and 21 Appl. No.: 277,000 progesterone, to achieve enhanced 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 , 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

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AA AOAS 4,383,993 2 and thus avoid the disadvantages inherent in the use of NASAL DOSAGE FORMS CONTAINING potentially unsafe synthetic 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 ) 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, , ointment or gel 17 A-estradiol is the most potent natural 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 , which in turn can be hydrated to . These 20 FIG. 1 is a semi-logarithmic plot of mean levels transformations take place mainly in the , 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 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 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 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 . 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 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 and estradiol By using the two tailed t-test, it can be shown that the 3-; 17-monoesters such as , 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. However, as can be seen undecanoate () and estradiol 17-val 20 from Table I, oral administration of 50 ug resulted in erate; and 3,17-diesters such as bioavailability equal to only 1.2% that of an equivalent and . dose given intravenously. Also from Table I, it can be According to the present invention, it has surpris seen that the nasal bioavailability of progesterone at the ingly been found that 17 g-estradiol and progesterone 50 pug dosage level was 85.75 times greater than the oral can be administered nasally with results considerably 25 bioavailability. superior to those obtained with oral administration. The It can also be seen from FIG. 1 that progesterone is following studies were undertaken to examine the bi very rapidly absorbed from the nasal mucosa; thus, at oavailability of progesterone and 17 g-estradiol from the 50 g dosage level, the peak plasma level was at nasal solution in comparison with the bioavailability of 30 tained in less than 7 minutes after instillation of the nose these drugs when administered orally and intrave drops. nously. FIG. 2 shows the area under the curve as a function Sprague-Dawley male rats, each weighing about 270 of dose for the intravenous and nasal routes. As can be grams, were used in the progesterone study. For nasal seen from FIG. 2, for both IV and nasal routes of ad administration, the rats were anesthetized using sodium 35 ministration the area under the curve (AUC) was di pentobarbital (50 mg/kg) and the drug was adminis rectly proportional to the dose administered. tered to the nasal cavity by means of a micropipet at The study described above indicates that progester dosage levels of 50 pug, 100 ug and 150 lug/rat of 4 one is rapidly absorbed from the nasal mucosa into the *C-progesterone (~8.5 uCi/rat) in 0.1 ml of isotonic systemic circulation without first pass metabolism. It is saline containing 1-2% Tween 80 as a solubilizing further apparent from this study that the bioavailability agent, according to the procedure described by Hirai et of progesterone when administered nasally is equivalent al, the 98th Annual Meeting of Pharmaceutical Society to the bioavailability of the drug where administered of , Okayama, April 1978, except that the end of intravenously and vastly superior to its bioavailability the tube leading from the esophagus to the nasal cavity 45 by the oral route. was closed and the drug was administered to the nostrils A study similar to that described above was under which were then closed with an adhesive agent. For taken to study the bioavailability of nasally adminis oral (intraduodenal) administration, the rats were anes tered 17 g-estradiol vis-a-vis its bioavailability via intra thetized and the abdomen of each rat was opened venous and oral routes. Sprague-Dawley male rats, through a midline incision and a 50 pg/rat dose of the 50 each weighing approximately 270 grams, were given drug (4-C-progesterone in 0.1 ml isotonic saline with dosages of 5 Jug, 10 ug and 20 g/rat of 6,7-H) 17 1-2% Tween 80) was injected directly through the p3-estradiol in 0.1 ml isotonic saline containing 1% duodenum. For intravenous administration, the rats Tween 80 via the intravenous, nasal and intraduodenal were anesthetized and the drug was injected through 55 routes, according to the procedures described above the femoral vein at dosage levels of 50 pug, 100 ug and with respect to the progesterone study. Blood samples 150 ug/rat of 4-C-progesterone in 0.1 ml of isotonic were taken periodically as described in the progester saline containing 1-2% Tween 80. Blood was sampled one study and assayed for estradiol (E2), estrone (E1) periodically from the femoral aorta after IV and nasal and total unconjugated estrogens (TUE). administration, and from the tail vein after ID adminis FIGS. 3, 4 and 5 show typical plots of the mean blood tration. Blood levels of progesterone were determined levels of TUE, E2 and E1 following intravenous, nasal by thin layer chromotography. and oral administration of 10 ug of 17 B-estradiol per FIG. 1 shows the mean blood levels of progesterone rat. These figures clearly show that 17 g-estradiol is for the study described above after intravenous, nasal 65 rapidly absorbed by the nasal mucosa. and oral administration of a dose of 50 pug?rat, while Table II below shows the area under the curve for the Table I below summarizes the area under the curve for three routes of administration at the various dosage the three routes of administration at the various doses. levels of 17 (3-estradiol. 4,383,993 5 6 TABLE II estrogen alone is to be administered for a part of th cycle. w AREA UNDER THE CURVE AND BOAVAILABILITY OF TUE, E, AND E FOR THE DIFFERENT ROUTES In another embodiment of the present invention, pro OF ADMINISTRATION AT THE WARIOUS DOSES gesterone is present in the nasal dosage form, but the DOSE ROUTE OF AUCo, NG. MIN. ML 5 estrogenic component is not. This type of composition G/RAT ADMINISTRATION TUE E2 E1 may be used in the treatment of conditions for which 5 V 555.5 290.8 53.4 natural or syntheic progestins have previously been NASAL 3370 146.8 88.5 used, e.g., in threatened or habitual abortion, endometri (0.606) (0.505) (1.657) osis and menstrual disorders such as dysmenorrhea and ORAL 119.2 1. 10.6 0. functional uterine bleeding, in inhibiting and (0.215) (0.038) (0.199) 10 IV 954.6 609.0 83.5 possibly as a "progestin only' continuously adminis NASAL 762 45.2 73.1 tered contraceptive (analogous to "minipill" type of (0.797) (0.682) (2,073) oral contraceptives). ORAL 314.2 19. 6.8 Suitable nontoxic pharmaceutically acceptable nasal (0.329) (0.031) (0.201) 15 20 V 1936.9 1062.6 64.4 carriers for use in the compositions of the present inven NASAL 777.2 891.8 354.0 tion will be apparent to those skilled in the art of nasal (0.918) (0.839) (2.153) pharmaceutical formulations. For those not skilled in ORAL 786.9 53.4 42.4 the art, reference is made to the text entitled "REM (0.406) (0.050) (0.258) INGTON'S PHARMACEUTICAL SCIENCES', 4th () RATIO WSW 20 edition, 1970. Obviously, the choice of suitable carriers will depend on the exact nature of the particular nasal As can be seen from Table II, the TUE bioavailability dosage form desired, e.g. whether the active in after nasal administration ranged from 60.6% to 91.8% gredient(s) is/are to be formulated into a nasal solution that of the corresponding doses given intravenously, (for use as drops or as a spray), a nasal suspension, a while oral administration resulted in TUE bioavailabil 25 nasal ointment or a nasal gel, as well as on the identity ity that ranged from only 21.5% to 40.6% that of the of the active ingredient(s). Preferred nasal dosage forms corresponding doses given intravenously. Thus, nasal are solutions, suspensions and gels, which contain a bioavailability of TUE was from 2.26 to 2.83 times major amount of water (preferably purified water) in greater than oral bioavailability. Even more signifi addition to the active ingredient(s). Minor amounts of cantly, Table II further shows that the E2 bioavailability other ingredients such as pH adjusters (e.g., a base such after nasal administration ranged from 50.5% to 83.9% as NaOH), emulsifiers or dispersing agents (e.g. poly that of the corresponding doses given intravenously, oxyethylene 20 sorbitan mono-oleate), buffering agents, while oral administration resulted in E2 preservatives, wetting agents and jelling agents (e.g. that ranged from only 3.1% to 5.0% that of the corre methylcellulose) may also be present. Also, a sustained sponding doses given intravenously. Thus, nasal bi 35 release composition, e.g. sustained release gel, readily oavailability of E2 was from 13.23 to 21.74 times greater can be prepared by employing 17 g-estradiol in one of than oral bioavailability. its relatively insoluble, long-acting forms, e.g. as estra The studies described above indicate that progester diol cypionate. one 17 g-estradiol are rapidly absorbed from the nasal Examples of the preparation of typical nasal composi mucosa into systemic blood without extensive intestinal tions are not set forth below. However, it is to be under or first pass metabolism. stood that these examples are given by way of illustra Progesterone and 17 f-estradiol can be conveniently tion only and are not to be construed as limiting the administered nasally to warm-blooded animals by for invention either in spirit or in scope as many modifica mulating them, singly or in combination, into a nasal tions both in materials and in methods will be apparent dosage form comprising the selected natural female sex to those skilled in the art. hormone(s) and a nontoxic pharmaceutically acceptable nasal carrier therefor. As indicated earlier, any pharma EXAMPLE 1. ceutically acceptable, estrogenically active form of 17 25 milligrams of progesterone and 5 milligrams of 17 f3-estradiol can be employed in the nasal form, e.g., the A-estradiol were combined with 10 milligrams of diol itself or one of its esters. In a preferred embodiment 50 Tween 80. That mixture was then combined with a of the invention, both progesterone and a suitable form quantity of isotonic saline sufficient to bring the total of 17 g-estradiol are present in the nasal dosage form, volume to 50 milliliters. The solution was sterilized by which can be employed in preventing conception, for being passed through a 0.2 micron Millipore filter. example, by administration in a cyclic manner anala gous to that used for the oral contraceptives. 55 EXAMPLE 2 In another embodiment, the estrogenic component, 50 milligrams of progesterone and 5 milligrams of 17 i.e., one of the suitable forms of 17 g-estradiol, is present f3-estradiol were combined with 10 milligrams of but progesterone is not; this type of composition may be Tween 80. That mixture was then combined with a used for any of a variety of conditions for which natural quantity of isotonic saline sufficient to bring the total or synthetic estrogens have previously been adminis volume of the solution to 50 milliliters. The solution was tered, e.g., to control menopausal symptoms, hot flushes sterilized by being passed through a 0.2 micron Mil and later osteoporosis; also in atropic vaginitis, and to lipore filter. relieve postpartum engorgement, dysmenorrhea, , memorrhagia, and as substitution therapy EXAMPLE 3 in ovarian dwarfism; also to control prostatic carci 65 250 milliliters of isotonic saline were heated to 80 C. noma, and possibly also as a "morning-after' contracep and 1.50 grams of Methocel were added, with stirring. tive. Also, the "estrogen only' nasal composition could The resultant mixture was allowed to stand at room be used in a sequential contraceptive regimen in which temperature for 2 hours. Then, 50 milligrams of proges 4,383,993 7 8 terone and 10 milligrams of 17 (3-estradiol were mixed 4. A composition according to claim 2, wherein the together with 10 milligrams of Tween 80. The /- pharmaceutically acceptable, estrogenically active form Tween mixture and a quantity of isotonic saline suffi of 1713-estradiol is estradiol benzoate. cient to bring the total volume to 500 milliliters were 5. A composition according to claim 2 wherein the added to the gel and thoroughly mixed. 5 pharmaceutically acceptable, estrogenically active form of 1743-estradiol is estradiol cypionate. EXAMPLE 4 6. A composition according to claim 2, wherein the Repetition of the procedure of Example 1, but omit pharmaceutically acceptable, estrogenically active form ting the 25 milligrams of progesterone, affords an "es of 17f8-estradiol is estradiol dipropionate. trogen only' nasal composition. 10 7. A composition according to claim 2, wherein the pharmaceutically acceptable, estrogenically active form EXAMPLE 5 of 1713-estradiol is estradiol enanthate. Repetition of the procedure of Example 2, but omit 8. A composition according to claim 2, wherein the ting the 5 milligrams of 1743-estradiol, affords a "proges pharmaceutically acceptable, estrogenically active form terone only ' nasal composition. 15 of 1713-estradiol is estradiol 17-valerate. 9. A composition according to claim 1, said composi EXAMPLE 6 tion comprising a nasal ointment. Substitution of an equivalent quantity of estradiol 10. A composition according to claim 1, said compo benzoate, estradiol cypionate, estradiol dipropionate, sition comprising a nasal gel. estradiol enanthate or estradiol 17-valerate for the 17(3- 20 11. A composition according to claim 10, said compo estradiol employed in Example 1, 2, 3 or 4 and repeti sition comprising a sustained release nasal gel. tion of the procedures there detailed affords other nasal 12. A composition according to claim 1, containing compositions according to the invention. from about 10 ug to 5000 ug of progesterone and from Naturally, the therapeutic dosage range for nasal about 10 ug to 500 g of a pharmaceutically acceptable, administration of the compositions of the present inven 25 estrogenically active form of 1713-estradiol. tion will vary with the size of the patient, the condition 13. A pharmaceutically acceptable nasal composition, for which the composition is administered and the par in dosage unit form, for nasal administration to elicit a ticular form of 17.6-estradiol employed (when the com systemic progestational response in a mammal, said position is an "estrogen only' or estrogen/progestin composition consisting essentially of, per nasal dosage combination). A typical dose of a combination form for 30 unit, a systemically therapeutically effective progesta use as a contraceptive would be from 10 ug to 500 ug of tional amount of progesterone and a nontoxic pharma 1713-estradiol and from 10 ug to 5000 ug of progester ceutically acceptable nasal carrier therefor, said compo one, administered nasally once daily. The quantity of sition comprising a nasal ointment or a nasal gel. nasal dosage form needed to deliver the desired dose 35 14. A composition according to claim 13, said compo will of course depend on the concentration of the active sition comprising a nasal ointment. ingredients in the composition. For example, when a 15. A composition according to claim 13, said compo composition as described in Example 2 above is used to sition comprising a nasal gel. deliver a typical dose of 0.5 mg of progesterone, the 16. A pharmaceutically acceptable nasal composition, volume of solution which would be needed would be 40 in dosage unit form, for nasal administration to elicit a approximately 0.5 ml. systemic estrogenic response in a mammal, said compo While the invention has been described in terms of sition consisting essentially of, per nasal dosage unit, a various preferred embodiments, the skilled artisan will systemically therapeutically effective estrogenic appreciate that various modifications, substitutions, amount of a pharmaceutically acceptable, estrogeni omissions and additions may be made without departing 45 cally active form of 1713-estradiol and a nontoxic phar from the spirit thereof. Accordingly, it is intended that maceutically acceptable nasal carrier therefor, said the scope of the present invention be limited solely by composition comprising a nasal ointment or a nasal gel. the scope of the following claims. 17. A composition according to claim 16, wherein the What is claimed is: pharmaceutically acceptable, estrogenically active form 1. A pharmaceutically acceptable nasal composition, 50 of 1713-estradiol is selected from the group consisting of in dosage unit form, for nasal administration to a female 176-estradiol, 3-monoesters of 1713-estradiol, 17-mono mammal for the purpose of mammalian contraception, esters of 1713-estradiol and 3,17-diesters of 178- estra said composition consisting essentially of, per nasal unit, diol. a systemically effective contraceptive amount of a com 18. A composition according to claim 17, wherein the bination of progesterone and a pharmaceutically ac 55 pharmaceutically acceptable, estrogenically active form ceptable, estrogenically active form of 1743-estradiol, of 176-estradiol is 1713-estradiol. together with a nontoxic pharmaceutically acceptable 19. A composition according to claim 17, wherein the nasal carrier therefor, said composition comprising a pharmaceutically acceptable, estrogenically active form nasal ointment or a nasal gel. of 1713-estradiol is estradiol benzoate. 2. A composition according to claim 1, wherein the 60 20. A composition according to claim 17, wherein the pharmaceutically acceptable, estrogenically active form pharmaceutically acceptable, estrogenically active form of 1743-estradiol is selected from the group consisting of of 17g-estradiol is estradiol cypionate. 1713-estradiol, 3-monoesters of 1713-estradiol, 17-mono 21. A composition according to claim 17, wherein the esters of 1713-estradiol and 3,17-diesters of 1713 pharmaceutically acceptable, estrogenically active form estradiol. 65 of 17,3-estradiol is estradiol dipropionate. 3. A composition according to claim 2, wherein the 22. A composition according to claim 17, wherein the pharmaceutically acceptable, estrogenically active form pharmaceutically acceptable, estrogenically active form of 1713-estradiol is 17(3-estradiol. of 1713-estradiol is estradiol enanthate. 4,383,993 9 10 23. A composition according to claim 17, wherein the 25. A composition according to claim 16, said compo pharmaceutically acceptable, estrogenically active form sition comprising a nasal gel. of 1713-estradiol is estradiol 17-valerate. 26. A composition according to claim 25, said compo 24. A composition according to claim 16, said compo- sition comprising a sustained release nasal gel. sition comprising a nasal ointment. 5 six

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