Administration of steroid hormones

Crystalline complexes of steroid hormones with gamma-cyclodextrin are prepared by mixing the components together. Tablets can be formed from the complexes, which can be administered by contact with the mucosa to provide effective transfer of the hormones into the systemic circulation, gradually eliminating the hormones therefrom.

FIELD OF THE INVENTION 
The present invention relates to a pharmaceutical form for sublingual 
administration of hormones. 
BACKGROUND OF THE INVENTION 
Therapeutic use of steroidal hormones is required in the treatment of a 
number of diseases, including lack of natural hormones, osteoporosis, and 
premenstrual syndrome. However, effective treatment is difficult, since 
these steroids are absorbed only slowly from the gastrointestinal tract, 
and are rapidly cleared from circulating blood by the liver. 
Numerous attempts have been made to circumvent these problems, including 
the administration of huge doses of natural hormones orally or 
preparations of oil solutions of hormones which are injected 
intramuscularly, and synthesis of analogs of natural hormones. The latter 
approach provides active preparations which may have significant side 
effects. Administration of these hormones transdermally or by nasal sprays 
has also been suggested, but these methods have not met with great 
acceptance. The optimal method for the administration of steroidal 
hormones would use noninvasive entry of physiological amounts of 
chemically unmodified hormones, and would lead to normal levels of 
hormones in the circulation. Furthermore, such a method should be 
adaptable for mass use. 
Deficiency of steroidal hormones in the elderly is a problem of 
particularly serious consequences. In postmenopausal women, unless 
corrected, this deficiency leads to osteoporosis, which, in the United 
States, is blamed for over one million bone fractures annually. In men, 
the production of testosterone does not dramatically decrease with age, 
but the amount of testosterone binding globulin increases and thus, in 
some men, hormonal supplementation is needed. 
Steroidal hormones are readily available, and supplementation by natural 
compounds can be used. However, oral administration of these steroids is 
complicated by their lack of solubility, which delays their absorption 
until they reach the lower gastrointestinal tract, where metabolism by the 
portal vein-liver system, i.e., first-pass effect, and degradation by 
microbial flora are problems. 
The use of hydrophilic cyclodextrin derivatives in pharmaceutical 
preparations of steroid hormones has been disclosed in Pitha, U.S. Pat. 
No. 4,596,795. Amorphous hydrophilic derivatives of beta- and 
gamma-cyclodextrins seemed to give better results than any of the parent 
cyclodextrins for the solubilization of steroid hormones, a step which 
appears to be crucial for their absorption by tissues. In a human trial, 
amorphous derivatives of beta-cyclodextrins enabled effective 
administration of testosterone, estradiol, or progesterone under 
conditions when improvements obtainable with beta-cyclodextrin alone were 
marginal. 
Hayashi et al., in British application No. 2,104,907A, disclose 
cyclodextrin inclusion compounds wherein at least one guest compound 
selected from the group consisting of eicosapentaenoic acid and 
docosahexaenoic acid is included. The guest compound reduces cholesterol 
levels in human serum, and the inclusion compound can be incorporated for 
this purpose in pharmaceutical compositions. 
Jones, in U.S. Pat. No. 4,555,504, disclose inclusion compounds of 
cyclodextrins and cardiac glycosides which have high aqueous solubility 
and can be used for preparing pharmaceutical formulations containing 
cardiac glycosides for use in therapy. The preferred cyclodextrin is 
beta-cyclodextrin. 
Szejtli et al., in U.S. Pat. No. 4,524,068, disclose a cyclodextrin 
inclusion complex of piperonyl butoxide. In this case, the complex is 
prepared by reacting cyclodextrin or an aqueous or non-aqueous solution 
thereof with piperonyl butoxide. The cyclodextrin complexes are said to 
synergize the pesticidal effect of known insecticides and fungicides to a 
greater extent than piperonyl butoxide. 
Szejtli et al., in U.S. Pat. No. 4,380,626, disclose inclusion compounds of 
2-chloro ethyl phosphonic acid formed with an alpha-, beta-, or 
gamma-cyclodextrin or mixtures thereof. These complexes can be used for 
preparing plant growth regulating compositions. 
Pitha et al., in J. Pharm. Sci. 75, No. 2, February, 1986, 165-167, 
disclose that condensation products of beta-cyclodextrin with propylene 
oxide or epichlorohydrin, which are amorphous and thus very soluble in 
water, can be used to form complexes with testosterone, progesterone, and 
estradiol. 
Cyclodextrins are products of the enzymatic degradation of starch, and 
contain six to eight glucose units joined in a ring by alpha-1.fwdarw.4 
glycosidic bonds. They are known to solubilize nonpolar compounds and 
improve the absorption of drugs from the gastrointestinal tract. 
Nevertheless, beta-cyclodextrin itself has proven unsuitable for improving 
the absorption of drugs. 
The lack of toxicity of the cyclodextrins has already been documented using 
animals. 
It has been observed that steroidal hormones are present in the serum only 
when the drug is absorbed into the bloodstream in such a means that the 
portal vein is bypassed. This is in accordance with the fast metabolism of 
steroidal hormones in the liver. The half-lives of these hormones in the 
circulatory system are estimated to be in minutes. The direct route into 
the bloodstream bypassing the portal vein is known to be less immediately 
affected by liver metabolism than entry from the gastrointestinal tract. 
Furthermore, metabolism of the drug by intestinal tissue is avoided. 
SUMMARY OF THE INVENTION 
It is an object of the present invention to avoid the above-described 
deficiencies in the prior art. 
It is another object of the present invention to provide a composition for 
direct administration of steroid hormones across the mucosa. 
It is yet a further object of the present invention to provide compositions 
for effective administration of steroid hormones. 
It has been found that the rapid dissolution and rapid reversibility of 
formation found in some inclusion complexes of steroids permits efficient 
absorption of hormones directly into the bloodstream while bypassing the 
portal vein system, including sublingually, buccally, rectally, or 
ocularly. This direct absorption of hormones is highly desirable, since 
then the hormone is less subject to rapid metabolism by the portal 
vein-liver system, and relatively long periods of hormone levels in 
circulation may be obtained in this manner. The only other known way to 
avoid first pass effects in oral administration is by administering a 
prodrug of hormone together with lipids into the lymphatic system. 
Previously, effective absorption of steroid hormones from the oral cavity 
was obtained only by using amorphous, rather than crystalline, complexes 
with cyclodextrin derivatives. However, the present invention has 
demonstrated that even dissolution of some crystalline complexes may be 
sufficient for reasonable absorption to occur. 
According to the present invention, a solid complex is formed from a 
steroid hormone and gamma-cyclodextrin by mixing appropriate amounts of 
the steroid hormone and gamma-cyclodextrin in water. The appropriate 
proportions in the mixture can be determined by examining the descending 
curvature of the Bs-type phase solubility of FIG. 1. 
For example, 1 gram of testosterone and 57 grams of gamma-cyclodextrin were 
added to 500 ml of water, and the mixture was stirred at 25.degree. C. for 
seven days. The complex, which precipitated as a microcrystalline powder, 
was removed by filtration and dried under vacuum at room temperature for 
24 hours. This powder corresponded to a 1:2 
testosterone:gamma-cyclodextrin complex, which had a molecular weight of 
2882. 
The complexes of the present invention are transported into the bloodstream 
directly by direct administration across the mucous membranes or the 
conjunctiva in the body for immediate absorption into the bloodstream. For 
the purposes of the present invention, direct administration against the 
mucous membranes, or mucosa, means that the active ingredient with 
optional fillers or excipients is administered by direct contact with the 
mucosa. This, of course, would exclude oral administration by swallowing, 
as the active ingredient there would not necessarily be indirect contact 
with the mucosa, and the active ingredient is transported directly to the 
portal vein. These complexes thus are preferentially administered 
buccally, sublingually, rectally, or ocularly.

DETAILED DESCRIPTION OF THE INVENTION 
Complexes of steroidal hormones with gamma-cyclodextrin are prepared by 
stirring the components for several days in aqueous suspension. The 
resulting complexes contain about 10% steroid. Tablets were made from 
pulverized complexes, and these tablets, when administered sublingually, 
resulted in a markedly elevated hormonal level in the human subject. 
Dissolution of the tablet under the tongue occurred within 10 to 15 
minutes. When the complex was dissolved in water and administered by 
stomach tube, elevation of the hormones in the serum was minimal. 
The solid complex of testosterone and gamma-cyclodextrin was prepared by 
mixing the appropriate amounts of testosterone and gamma-cyclodextrin in 
water. The appropriate mixture was determined by examining the descending 
curvature of the Bs-type phase solubility diagram, as shown in FIG. 1. By 
way of example, one gram of testosterone and 57 grams of 
gamma-cyclodextrin were added to 500 ml of water, and the mixture was 
stirred at 25.degree. C. for seven days. The complex, which precipitated 
as a microcrystalline powder, was removed by filtration and dried under 
vacuum at room temperature for 24 hours. This powder corresponded to a 1:2 
testosterone-gamma-cyclodextrin complex, which had a molecular weight of 
2882. 
The composition of the present invention was administered to a 53-year-old 
male with hypopituitarism which had been diagnosed when he was 47. The 
subject had used a daily supplement of thyroxine, and the experiments were 
performed just before the subject was supplemented with the depo form of 
testosterone, when his testosterone levels were subnormal. The subject 
swallowed a stomach tube, size 18Fr, total length 50 inches, to simulate 
fasting conditions for the administration of liquids into the subject. The 
position of the tube was ascertained by the subject's reaction to the 
rapid introduction of 50 ml. of air into the tube, and measuring the 
acidity of liquid aspirated therefrom to identify stomach juice. 
The phase-solubility diagram of the testosterone-gamma-cyclodextrin system 
in water, FIG. 1, is of the B.sub.s -type, i.e., a complex of limited 
solubility is formed. A complex containing both components began to 
crystallize out from the solution when the concentration of 
gamma-cyclodextrin reached about 13 mM, a concentration which is lower 
than the solubility of gamma-cyclodextrin itself, 168 mM. The 
concentration of testosterone in the solution varied from that in water 
(0.13 mM, 37 micrograms/ml) through a maximal solubilization of 8.7 mM 
(2.5 mg/ml) to that of limit value (1.21 mM, 350 micrograms/ml). The 
isolated complex contained 10% testosterone by weight, i.e., one molecule 
of testosterone for two molecules of gamma-cyclodextrin. 
When the crystalline complex was equilibrated with water, a full 
dissolution occurred up to about 4 mg/ml (i.e., 0.4 mg/ml of 
testosterone), and at that point the concentration of dissolved 
testosterone was close to the limit value above. When further amounts of 
crystalline complex were added, incomplete dissolution occurred. The 
phase-solubility diagram of FIG. 2 is somewhat rounded, thus suggesting 
the possibility of several components in the system. Thus, for example, 
both 1:1 and 1:2 complexes may be formed, the latter with a lower 
solubility, as seen in FIG. 1. When that complex is again dissolved in 
water, it partially reverts to a 1:1 complex. Incomplete dissolution may 
be due to the formation of equilibria involving less soluble components. 
The maximal concentrations of testosterone obtainable with the crystalline 
complex were about 4.5 mM (1.3 mg/ml). That solubilization is considerably 
lower than those obtained with amorphous cyclodextrin derivatives, namely, 
2-hydroxypropyl-beta-cyclodextrin or poly-beta-cyclodextrin. 
The crystalline complex of the present invention can be directly processed 
into tablet form in a manner similar to other complexes. The tablets may 
contain any pharmaceutically acceptable fillers or excipients which are 
appropriate for the intended use of the tablets. These tablets dissolved 
completely in an appropriate volume of water, with a rate of testosterone 
release which was orders of magnitude higher than the dissolution of 
testosterone from a tablet containing cellulose as the excipient, cf. FIG. 
3. Nevertheless, the release of testosterone from tablets of 
gamma-cyclodextrin complex was at about a ten times lower rate than 
tablets of a testosterone-hydroxypropyl-beta-cyclodextrin complex. 
When tablets of testosterone-gamma-cyclodextrin complex were administered 
sublingually, their full dissolution was rather slow (10-15 minutes) when 
compared to previously evaluated preparations. However, these tablets 
provided an efficient transfer of the hormone into the circulation, as 
shown in FIG. 4. The half-life of testosterone thus introduced into the 
circulation was about one hour, which was comparable to that observed with 
the testosterone-hydroxypropyl-beta-cyclodextrin complex administered in 
the same way. When solutions of testosterone and gamma-cyclodextrin 
complex were introduced in similar amounts by a gastric tube directly into 
the stomach, serum levels of hormone were much lower, as can be seen in 
FIG. 4. Similarly, when the complex was administered into the stomach in a 
dry form using hard gelatin capsules, transfer into the circulating blood 
was much lower than after sublingual administration, as shown in FIG. 4. 
Corresponding complexes of 1 mg estradiol with gamma-cyclodextrin and 20 mg 
progesterone with gamma-cyclodextrin, prepared as above, were tested on a 
male volunteer. One hour after administration, the serum level of 
estradiol was 40.4 ng/dL, and progesterone level was 940 ng/dL. 
The rapid dissolution and rapid reversibility of formation which is found 
in some inclusion complexes of steroids enables efficient absorption of 
hormones from the oral cavity. Absorption of hormones through the mucosa 
or conjunctiva is highly desirable, since the hormone is not as much the 
subject of rapid metabolism by the portal vein-liver system, and 
relatively long periods of hormone levels in circulation may be obtained 
in this manner. The only other way to avoid first pass effects in per os 
administration is by administering a prodrug of the hormone together with 
lipids into the lymphatic system. Previously, effective absorption of 
steroid hormones from the oral cavity was obtained only by using 
amorphous, but not crystalline, complexes with cyclodextrin derivatives. 
The present results demonstrate that even dissolution of some crystalline 
complexes is sufficient for reasonable absorption to occur. 
The dissolution rates of testosterone alone or its release from complexes 
of interest were measured and compared with published data. These 
dissolution rates can be arranged in a scale with the relative order: 
testosterone 1&lt;testosterone:beta-cyclodextrin complex 
3&lt;testosterone:gamma-cyclodextrin complex 
33&lt;testosterone:poly-beta-cyclodextrin complex 
330.congruent.testosterone:2-hydroxypropyl-beta-cyclodextrin complex 330. 
The effects of complexation on testosterone solubility can be compared on 
an absolute scale:testosterone, 37 
micrograms/ml&lt;testosterone:beta-cyclodextrin comples, 23 
micrograms/ml&lt;testosterone:gamma-cyclodextrin complex, 350 
micrograms/ml&lt;testosterone:poly-beta-cyclodextrin complex or 
testosterone:2-hydroxypropyl-beta-cyclodextrin complexes, which can be 
dissolved to 30,000 micrograms/ml. Previous evaluations of absorption from 
the oral cavity and the present data indicate that the demarkation line 
for effectiveness is close to, but includes, the 
testosterone-gamma-cyclodextrin complex. Solubilization to about 1 mM and 
a dissolution rate of about 5 micromoles/min may be satisfactory for the 
drug form to be administered sublingually. 
In contrast to beta-cyclodextrin and to chemically modified cyclodextrin 
complexes, the presently used gamma-cyclodextrin is susceptible to the 
amylases of human saliva. The hydrolysis yields products which do not 
complex or solubilize testosterone. The data presented here and their 
comparison with published data show that this hydrolysis does not preclude 
the successful use of this hydrolyzable carbohydrate in sublingual 
tablets. 
The crystalline complexes of steroid hormone with gamma-cyclodextrin can be 
used to treat a variety of conditions, including testosterone replacement 
in hypogonadism, progesterone replacement and therapy, testosterone 
supplementation of male contraception, and estradiol replacement and 
therapy. 
The foregoing description of the specific embodiments will so fully reveal 
the general nature of the invention that others can, by applying current 
knowledge, readily modify and/or adapt for various applications such 
specific embodiments without departing from the generic concept, and 
therefore such adaptations and modifications are intended to be 
comprehended within the meaning and range of equivalents of the disclosed 
embodiments. It is to be understood that the phraseology or terminology 
employed herein is for the purpose of description and not of limitation.