CA1198371A - Nasal composition for administering to a female mammal, in dosage form, for mammalian contraception - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to a novel pharmaceu-tically acceptable nasal composition, in dosage unit form, for nasal administration to a female mammal for the purpose of mammalian contraception. The composi-tion consists essentially of, per nasal dosage unit, a systemically effective contraceptive amount of a combination of progesterone and a pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol, together with a nontoxic pharmaceutically acceptable nasal carrier therefor. The composition comprises a nasal ointment or a nasal gel.

Description

BACKGROU~D OF THE INVENTION

Field of the Invention:
I'he present invention relates to a novel pharmaceutically acceptable nasal composition, in dosage unit form, for nasal administration to a fem~le mammal with the com~osition comprising progesterone and a pharmaceutically acceptable estrogenically active form of 17~-estradiol, together with a nontoxic pharmaceutically acceptable nasal carrier.
Description of the Prior Art:
17~-estradiol is the most potent natural estrogen found in human beings and is the major secretory product of the ovary. It is readily oxidized in the body to estrone, which in turn can be hydrated to estriol. These transfor-mations take place mainly in the liver, where there is free interconversion between estrone and estradiol. All three of these na-tural estrogens are excreted in the urine as glucuronides and sulfates, along with a host of related, minor products in water-soluble complexes. It is widely known that, following oral administration of micronized 17~-estradiol (E2), the incremental circulation estrogen is principally the less active species estrone (El), which reaches a peak concentration many times greater than that of E2. The conversion of E2 to El and subsequently to other metabolites takes place during absorption from the intestine and passage through the liver~ This extensive metabolism greatly limits the oral effectiveness of the natural estrogens and their esters. Indeed, beca-use of their limited oral efficacy, 17~-es-tradiol and its esters are generally administered by intramuscular injection.

Progesterone is the active natuxal progestin which occurs in the corpus luteum, placenta and adrenal cortex. It is not effective by mouth because of its rapid metabolism in the intestinal epithelium and in the liver, and ls therefore only administered intramuscularly.
Beeause of their limited oral effeetiveness, these natural female sex hormones have not found utility in oral contraceptives. Instead, only active synthetic estrogens and progestins have been prepared and are used for contraceptive purposes. The synthetic derivatives have also in many cases replaced the natural substances in the treatment of menopause, threatened abortion, etc.
However, the synthetic derivatives are, generally speaking, much more likely to cause toxic side effec-ts than are the relatively saEe natural hormones.

SUMMARY OF THE I~VE~TIOM

In view of the foregoing, from a broad aspect, the present invention provides a novel pharmaceutically aceeptable nasal composition, in dosage unit form, for nasal adminis-tration to a female mammal for the purpose of mammalian contracep-tion. The cornposition consists essentially of, per nasal dosage unit, a systemically effective contraceptive amount of a combination of progesterone and a pharmaceutically acceptable, estrogen-ieally aetive -form of 17~-estradiol, together with a nontoxic pharmaeeutically acceptable nasal carrier therefor. The eomposition comprises a nasal ointment or a nasal gel.

33~7~

BRIEF DESCRIPTIO~ OF THE DR~WINGS

FIG. 1 is a semi-logarithmic plot of mean blood levels of progesterone after intravenous (IV), nasal and intraduodenal~oral (ID) administration o~ a dose of 50 ,ug of progesterone per rat.
FIG. 2 is a graph s'nowing the area under the curve as a function of dose for the intravenous (IV) and nasal routes of progesterone administration (50 ~ug, 100 ~g and 150 ~g dosage levels).

) FIG. 3 is a semi~logarithmic plot of mean blood levels of total unconjugated estrogens (TUE) following intraYenous ~IV), nasal and intraduodenal/~ral ~ID) adminis-tration of a dose of 10 ~g o 17 ~-estradiol per rat.
FIG. 4 is a ~emi-logarithmic plo~ of mean blood levels of estradiol (E2~ following intravenous (IV3~ na~al and intraduodenal~oral 5ID1 administration of a dose of 10 ~g of 17 ~-estradiol per rat.
FIG. 5 is a semi-logarithmic plot of mean blood levels of estrone (El) followiny intravenous ~IV)~ nasal and intraduodenal/oral (ID) administration of a dose of 10 ~g of 17 ~-estradiol per rat.

DETAILED DESCRIPTION OF ~HE INVENTION

me word Npro~esterone" as used herein means pregn-4-ene 3,20-dione, i.e., the compound of the ~ormula ~3C CO

H C l I

and is in~ended to include progesterone deriv~d from natural sources as well as that made synthetically.

~5-i I

3~

m e word "17 ~-estradiol" as used her~in is intended to encompass any pharmaceutically acceptable, e~trogenicall~ active form o 17 ~-estradiol, iOe., estra-1,3,5(103-triene-3, 17 ~-diol itselft which has the formula 0~

~3C

~ .

HO

and which may be extracted from na~ural sources or made synthetically, or one of its 3- or 17-monoesters or 3,17-dies~ers. By way of illustration, sui~able esters of 17 ~-estr~diol for purposes of the present invention include 3 mono2s~ers such as estradiol ~enzoate and es~radiol 3-~cetate; 17-monoesters such as estradiol cypionate~ estradiol - 17-propionate, estradiol 17-acetate, estradiol 17-heptanoate ~estradiol enanthate)~ e~tradiol 17-undecanoate (estradiol ~ndecylate) and estxadiol 17~valerate; and 3,17-diesters such as estradiol dipropionate and estradiol diacetateO
According to the present inven~ion, it has surpris-ingly been found that 17 ~-estradiol and progesterone can be administ~red nasally with results considerably superior to those obtained with oral administration. The following studies were undertaken to examine the bioavailability of progesterone and 17 ~-estradiol from nasal solution in 37~

comparison with the bioavailability of these drugs when administered orally and int:xavenously.
Spr~gue-Dawley male rats, each weighing about 270 grams, were used in the proge~teron~ study. For nasal administration~ the rats were anesthetized using sodium pentobarbital ~50 mg/kg) and he drug was administerea ~o the nasal ca~ity by means of a micropipet at dosage levels of 50 Jl~, 100 ~Ig and 150 lJg/rat of [4-14C]-proges~erone (~8.5 ~lCi/rat) ln 0.1 ml of isotonic saline containing 1-2%
Tween 80 as a ~olubilizing agent, according ~o the procedure described by Hirai et al, the 98~h Annual Mee~ing of Pharma-ceutical Socie~y of Japan, Okayama, April 1978, except that the end of the tube leading from the esophagus to the nasal cavity was closed and the drug was administered to ~he nostrils which were then closed with an adhesive agent. For oral ~intraduodenal) administra~ion, the rats were anesthe~
tized and the abdomen of each rat was opened through a midline incision and a 50 ~g/rat dose of the drug ([4-14C]-~rogesterone in 0.1 ml isotonlc saline with 1-2% Tw~en 80) was injected directly through the duodenum. For intravenous administrationt the rats were anesthetized and the drug was injected through the femoral vein at dosage levels of 50 ~g, 100 ~g and 150 ~g/rat of ~4-14C~-pxogesterone in 0.1 ml of isotonic saline containing 1-2~ Tween 80. Blood was sampled periodically from the femoral aorta after IV and nasal adminis~ration, and from the tail vein after ID administration.
Blood levels of progesterone were determined by thin layer chromotography.

337~

FIG. 1 shows the mean blood levels of progesterone for he study described above after intravenous, nasal and orAl admini~tration of a dose o 50 ~g/rat, while Table I
below summarizes the area under the curve for the three routes Q~ administration at the various doses.

TABLE I

AREA UNDER THE CURVE AFTER INTRAVENOUS, NASAL AND INTRADUO~
DENAL ADMINISTRATION OF PROGESTERONE IN RATS

AUC~ , ng.min/ml Dose u Nasal ID
~g/rat IV Nasal ID IV IV

1612.2* 1659.~ 19.~ 1.029 ~.012 ~0.8 ~109.2 ~4.6 100 3520.0 3599.0 - 1.022 ~491.0 +621.4 150 ~480.2 4798.9 ~4~6.~ 8.5 * means ~ SE(n-4-6).

- By using the two tailed ~-test, it can be shown that the area under the curve following intravenous and nasal administration at each dosage were not significantly different, even at the 0.001 level. However, as can be seen ~rom Table I, oral administration of 50 ~g resulted in bioavailability equal o only 1.2% that of an equivalent dose given intravenously. Also from Ta~le I, it can be seen that the nasal bioavailability of progesterone at the 50 ~g lS dosage level was 85.75 times greater than the oral bioavail-ability.

i, 37~

It can al~o be seen from FIG. 1 that progesterone is very rapidly absorbed from the nasal mucosa; thus, at the 50 ~g dosage level, the peak plasma level was attai~ed in less than 7 minutes after instillation o~ ~he nose drops.
FIG. 2 shows the area under the cunre as a function of dose for ~he intravenous and nasal routes~ As can be seen from FIG. 2" Eor both IV and nasal routes of adminis-tration the area u~der the curve lA~C) was directly propor-~iGnal to the dose administered.
The study described above indicates that proges-terone is rapidly absorbed from the ~asal mucosa into the systemic circulation without first pass metabolism. It is further apparent from this study *hat the bioavailability of progesterone when admini~tered nasally i equivalent to the bioavailability of the drug where administered intravenously and vastly ~uperior to its bioavailability by the oral route.
~ study similar ~o hat described above was under-taken to study the bioavailability of nasally administered 17 ~-estradiol vis-a-vis its bio~vailability via intravenous and oral routes. Sprague-Dawley male rats, each weighing approximat~ly ~70 grams, were given dosages of 5 ~g, 10 ~g and 20 ~g/rat of [6~7-3H] 17 B-estradiol in 0.1 ml isotonic saline containing 1% Tween 80 via the intravenous, nasal and intraduodenal routes, according to the procedures described above with respect to the proges~erone study. Blood samples were taken periodically as described in the progesterone study and assayed ~or estradiol (E2), es~rone ~El) and total unconjugated estrogens (TUE).

_g_ ~ !33~7~

FIGS~ 3, 4 and 5 ~how typical plots of the mean blood levels of ~UE, E2 and ~1 followiny intravenous, nasal and oral administratil~n of 10 ~Ig of 17 ~ estradiol per rat.
These figu~es clearly show that 17 ,B-~3stradiol is rapidly absorbed by th~ ~asal mucosa.
Table II below shows th~ area under the curve for the three routes of administration at the various dosage leve 1 s of 17 ~ -e st rad iol .

TABLE II

AREA UNDER THE C~RVE AND BIOAVAILABILITY OF TUE, E2 ~ND El FOR
THE DIFFERENT ROUTES OF RDIMINISTRATION AT T~E VARIOUS DOSE5 DOSE ROUTE OF A~C~o t NG. MIN. ML 1 ~G/RAT ADMINISTRATION TUE E2 El IV 555.5 290.8 53.4 NASAL 337.0 146.8 88.5 (0.606) (0.505) (1.657) ORAL 119.2 11.1 10.6 (0.215) (0.038) (0.1g9) IV 954.6 609.0 B3.5 NASAL 761.2 415.2 173.1 S0.797) (0.682) (2.073) ORAL 314.2 19.1 16.8 (0.329) (00031) (0.201) IV 1936.9 1O6~D6 164.4 NASAL 1777.2 ~1.8 354~0 (0~918) (0.~39) (2.1~3) CRAL 786~9 53.4 42.4 (0.406) lO.~50) to.258) ) RATIO VS. IV

17~

As can be seen ~rom Table II, the TUE bioavail-ability after nasal administration ranged from 60.6~ to 91.8~ that of the corresponding doses given intravenously, while oral administration re 5U lted in T~E bioavailability that ranged from only 21 5~ to 40.6% that of the corres-ponding doses given intravenously. Thus, nasal bioavail ability of TUE was from 2.26 to 2.83 times greater than oral bioavailability. Even more signiicantlyl Ta~le II further shows that the E2 bioavailability after nasal administration ranged from 50.5% to 83.9~ that of the corresponding do6es given intravenously, while oral administration resul~ed in E2 bioavailabilities that ranged from only 3 .1% to 5 . 0% that of the corre~ponding doses given intravenously. Thus, nasal bioavailability of ~2 was from 13.23 to 21.74 times greater than oral bioavailability.
The studies described above indicate ~hat proges terone and 17 ~-estradiol are rapidly absorbed from the nasal mucosa into systemic blood without extensivP intestinal or first pass metabolism.

2-0 Progesterone and 17 ~-estradiol can be conveniently administered nasally to warm~blooded animals by formulating them, singly or in combination, into a nasal dosage form comprising the selected natural female sex hormone(s) and a nontoxic pharmaceutically acceptable nasal carrier thereforO
~5 As indicated earlier, any pharmaceutically acceptable, estrogenioally active form of 17 ~-estradiol can be employed in the nasal form9 e.g., the diol itself or one of i~5 esters. In a preferred embodiment of the inventlon, both progesterone and a suitable form of 17 ~-estradiol are ,, il3~

present in the nasal dosage form, which can be employed in preventing conception~ for example, by administration in a cyclic manner analagous to that used for the oral conceptives.
In another embodiment, the estrogenic component, i.e., one of the ~uitable forms of 17 ~-e~tradiol, is present but progesterone is not; this type of composition may be used for any of a variety of conditions for which natural or synthetic e~rogens have previously been administered, e~g., to control menopausal symptomsl hot flushes and later osteoporosis; also in atropic vaginiti~, and to relieve postpartum breast engorgement, dysmenorrhea, amenorrhea, menorrhagia, and as suhstit~ion therapy in ovarian dwarf-ism; also to control prostatic carcinomat and possibly also as a "morning-after" contraceptive. Also, ~he "estrogen only" nasal composition could be used in a sequential contraceptive regimen in which estrogen alone is to be administered for a part of the cycle.
In another embodiment of the present inYention~
progesteron~ is present in the nasal dosage form, bu~ ~he estrogenic component is not. This type of composition may ~e used in the treatment of conditions for which natural or synthetic progestins have previously been used, e~g., in threatened or habitual abortion, endometriosis and menstrual disorders such as dysmenorrhea and functional u~erine bleeding, in inhibiting ovulation and possibly as a "pro-gestin only" continuously administered contraceptive (analo-gous to "minipill" type of oral contraceptives).
Suitable nontoxic pharmaceutically acceptable nasal carriers for use in the eomposi~ions of the present 1~-I

~ai3~a invention will be apparent to those skilled in the art of nasal pharmaceu~ical formulations~ For those not ~killed in the art, refer nce is made to the text entitled "REMINGTON'S
PHARMACEUTICAL SCIENCES", 4th edition, 1970. Obviously, the choice of ~uitable carriers will depend on the exa~t nature of the particular nasal dosage form desired, e~g. whether the active ingredient(s) is/are to be formulated into a nasal solution (for use as drops or as a spray)g a nasal I suspension, a nasal ointment or a nasal gel, as well as on the idPntity of the active ingredient~s~ Preferred nasal dosage forms are solutions, suspensions and gelst which contain a major amount of water (preferably purified water) in addition to the active ingredient(s3. Minor amounts of other ingredients such as pH adjusters ~e.g., a base such as NaOH), emulsifiers or disper~ing agents (e.g. ~olyoxyethylene 20 sorbitan mono-oleate~, buffering agents, preservatives, wetting agents and jelling agents ~e.g. methylcellulose) may also be present. Also, a sustained release compo~ition, ~.g. sustained release gel, readily can be prepared by employing 17 ~-estradiol in one of its relatively insoluble, long-acting forms, e.g. as estradiol cypionate~
Examples of the preparation of typical nasal compositions are set forth below~ However, it is to be understood that these examples are given by way of illustra-tion only and are not to ~e construed as limiting the invention either in spirit or in scope as many modifications both in materials and in methods will be apparent to those skilled in the art.

$~7~

25 milligrams of progesterone and 5 milligrams of 17 ~-estradiol were combined with 10 milligrams of Tween* 80. That mixture was then combined with a quantity of isotonic saline sufficient to bring the total volume to 50 milliliters. The solution was sterilized by being passed through a 0.2 micron Millipore filter.

50 milligrams of progesterone and 5 milligrams of 17 ~-estradiol were combined with 10 milligrams of Tween* 80. That mixture was then combined with a quan-tity of isotonic saline sufficient to bring the total volume of the solution to 50 milliliters. The solution was sterilized by being passed through a 0.2 micron Millipore filter.

250 milliliters of isotonic saline were heated to ~30C and 1.50 grams of Methocel* were added, with stirring. The resultant mixture was allowed to stand at room temperature for 2 hours. Then, 50 milligrams of progesterone and 10 milligrams of 17 ~-estradiol were mixed together with 10 milligrams of Tween* 80. The steroid/Tween* mixture and a quantity of isotonic saline sufficient to bring the total volume to 500 milliliters were added to the gel and thoroughly mixed.

* Registered trademark -- 1~ --`~s ~513'7~L

Repetition of the procedure of Example 1, but omitting the 25 milligrams of progesterone, affords an ~estrogen only~ nasal composition.

Repetition of the procedure of ~xample 2, but omitting the 5 milligrams of 17g-estradiol, affords a ~pro-gesterone only~ nasal composition.

Substitution of an equivalent quantity of es~radiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate or estradlol 17-valerate for the 17B-estradiol employed in Example 1, 2, 3 or 4 and repeti~ion of the procedures there detailed affords o~her nasal compositions 1~ according to the inventionO

Naturally, the therapeutic dosage range for nasal administration of the compositions of the present invention will vary with the size of the patient, the condition for which the composition is administered and the particular iorm of 17 g-estradiol employed (when the composition is an ~estrogen only" or estrogen/progestin combination~O A
typical dose of a combination iorm ~or use as a contraceptive would be from 10 ~g to 500 ~g of 17 g es~radiol and from 10 I

~g to 5000 yg of progesterone, adminiætered nasally once daily. The quantity of nasal dosage form needed to deliver the desired d~se will of ~ourse depend on the concentration of the active ingredients in the compositionO For example, , when a composition as described in Example 2 above i~ used to deliver a typical dose of 0.5 mg of progesteroneg the volume of ~olution which would be needed would be approx-imately 0.5 ml.
While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions and additions may be made without departing from the spirit $hereof. Accordingly, it is in~ended that the scope of the present inv~ntion be limited solely by the scope of the following claims~

~16

Claims (26)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A pharmaceutically acceptable nasal composition, in dosage unit form, for nasal administration to a female mammal for the purpose of mammalian contraception, said composition consisting essentially of, per nasal dosage unit, a systemically effective contraceptive amount of a combination of progesterone and a pharmaceutically accept-able, estrogenically active form of 17.beta.-estradiol, together with a nontoxic pharmaceutically acceptable nasal carrier therefor, said composition comprising a nasal ointment or a nasal gel.

2. A composition according to claim 1, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is selected from the group consisting of 17.beta.-estradiol, 3-monoesters of 17.beta.-estradiol, 17-monoesters of 17.beta.-estradiol and 3,17-diesters of 17.beta.-estradiol.

3. A composition according to claim 2 wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is 17.beta.-estradiol.

4. A composition according to claim 2, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is estradiol benzoate.

5. A composition according to claim 2 wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is estradiol cypionate.

6. A composition according to claim 2, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is estradiol dipropionate.

7. A composition according to claim 2, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is estradiol enanthate.

8. A composition according to claim 2, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is estradiol 17-valerate.

9. A composition according to claim 1, said composition comprising a nasal ointment.

10. A composition according to claim 1, said composition comprising a nasal gel.

11. A composition according to claim 10, said composition comprising a sustained release nasal gel.

12. A composition according to claim 1, containing from about 10 µg to 5000 µg of progesterone and from about 10 µg to 500 µg of a pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol.

13. A pharmaceutically acceptable nasal composition, in dosage unit form, for nasal administration to elicit a systemic progestational response in a mammal, said composition consisting essentially of, per nasal dosage unit, a systemically therapeutically effective progesta-tional amount of progesterone and a nontoxic pharmaceuti-cally acceptable nasal carrier therefor, said composition comprising a nasal ointment or a nasal gel.

14. A composition according to claim 13, said composition comprising a nasal ointment.

15. A composition according to claim 13, said composition comprising a nasal gel.

16. A pharmaceutically acceptable nasal composition, in dosage unit form, for nasal administration to elicit a systemic estrogenic response in a mammal, said composition consisting essentially of, per nasal dosage unit, a systemically therapeutically effective estrogenic amount of a pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol and a nontoxic pharmaceuti-cally acceptable nasal carrier therefor, said composition comprising a nasal ointment or a nasal gel.

17. A composition according to claim 16, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is selected from the group consist-ing of 17.beta.-estradiol, 3-monoesters of 17.beta.-estradiol, 17-monoesters of 17.beta.-estradiol and 3,17-diesters of 17.beta.-estradiol.

18. A composition according to claim 17, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is 17.beta.-estradiol.

19. A composition according to claim 17, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is estradiol benzoate.

20. A composition according to claim 17, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is estradiol cypionate.

21. A composition according to claim 17, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is estradiol dipropionate.

22. A composition according to claim 17, wherein the pharmaceutically acceptable, estrogenically active form of 17.beta.-estradiol is estradiol enanthate.

23. A composition according to claim 17, wherein the pharmaceutically acceptable, estrogenically active form or 17.beta.-estradiol is estradiol 17-valerate.

24. A composition according to claim 16, said composition comprising a nasal ointment.

25. A composition according to claim 16, said composition comprising a nasal gel.

26. A composition according to claim 25, said composition comprising a sustained release nasal gel.