III III III US005595759A United States Patent (19) 11 Patent Number: 5,595,759 Wright et al. (45) Date of Patent: Jan. 21, 1997 (54) PROCESS FOR PROVIDING THERAPEUTIC 4,309,996 l/1982 Theeuwes ............................... 128/260 COMPOSITION 4,320,759 3/1982. Theeuwes ..... ... 128/260 4,449,983 5/1983 Cortese et al. ..... 604/892 (75. Inventors: Jeri D. Wright, Dublin; Brian L. 2. Esthet al. 3. V at aal Cal. .... o E. styleEa. f Calif 4,948,593 8/1990 Wright et al...... 424/473 son, Porto ey, all of Calli. 5,032,406 7/1991 Dansereau et al. 424/472 73) Assignee:rena Ms Alza Corporation,o Palo Alto, Calif. 5,200,1975,098,714 3/19924/1993 Wright et al.......al. ........................... 424/473 (21 Appl. No.: 337,701 OTHER PUBLICATIONS 22 Filed: Nov. 10, 1994 Wurster,(1960) pp. Dale 82-84. E. J. Am. Pharm. Assn., Sci. Ed., vo. 49, (51) Int. Cl. ... A61K 9/20 Wurster, Dale E., J. Am. Pharm. Assn., Sci. Ed., vol. 48 52 U.S. Cl. .......................... 424/464; 424/465; 424/474; (1959) pp. 451-454. 424/480 The Pharmacological Basis of Therapeutics, by Goodman & (58) Field of Search ..................................... 424/464, 465, Gilman, 7th Ed. (1985) pp. 1430-1439. 424/473, 474, 479, 484, 486, 426 Pharmaceutical Sciences, by Remington, 14th Ed., (1970) I Wr ws pp. 1626-1680. 56) References Cited Primary Examiner-Thurman K. Page U.S. PATENT DOCUMENTS Assistant Examiner Sharon Howard Attorney, Agent, or Firm-Paul L. Sabatine; Mary Ann 2,799,241 7/1957 Wurster ..................................... 18/24 Dillahunty; Felissa H. Cagan 3,133,132 5/1964 Loeb et al. ................................ 264/49 3,845,770 1 1/1974 Theeuwes et al....................... 128/130 (57) ABSTRACT 3,916,899 11/1975 Theeuwes et al...... 4,063,064 12/1977 Saunders et al. ...... As A process is disclosed and claimed for preparing a thera 4.088,864 5/1978 Theeuwes et al. ou 219/260 peutic composition comprising asteroid or a dosage form 4,160,020 7/1979 Ayer et al. ............. - - - - - - 424/15 comprising the composition, which therapeutic composition 4,177.256 12/1979 Michaels et al. ......................... 424/22 or dosage form is indicated for human administration. 4,200,098 4/1980 Ayer et al. .............................. 128/260 4,285,987 8/1981. Ayer et al. .................................. 427/3 7 Claims, No Drawings 5,595,759 1. 2 PROCESS FOR PROVIDING THERAPEUTIC gon-4-en-3-one oxime, d-133-ethyl-17o-ethinyl-17B-hy COMPOSITION roxygon-4-en-3-one, 133-ethyl-173-hydroxygon-4-en-3- One, 133,17B-diethyl-17B-hydroxygon-4-en-3-one, FIELD OF THE INVENTION ethylnodiol diacetate, medroxyprogesterone, chlormadione acetate, 17o-ethinyl-173-acetoxy-17-norandrost-4-en-3- This invention pertains to a therapeutic composition, to a one, 3-ketodesogestrel, desogestrel, gestodene, gestodene dosage form, and to a process for preparing the therapeutic acetate, levonorgestrel-2-methylbutanoate, levonorgestrel composition, and the dosage form. The therapeutic compo acetate, levonorgestrel butanoate, levonorgestrel butyrate, sition and the dosage form comprise a drug, for example, a levonorgestrel cyanoacetate, levonorgestrel cyclobutane car pharmaceutically acceptable steroid selected from an estro boxylate, levonorgestrel cyclopropylcarboxylate, norgestrel gen, or a progestin, or both an estrogen and a progestin. 10 decanoate, norgestrel pentanoate, norgestrel-2-methyl-2- enoate, norgestrel formate, norgestrel glycidol, norgestrel BACKGROUND OF THE INVENTION keptanoate, norgestrel hexanoate, northisterone methoxyac The direction of much medical and scientific research in etate, northisterone nonanoate, northisterone pentanoate, recent prior art endeavors has been to provide a therapeutic 15 desogestrel propanoate, desogestrel valerate, desogestrel-2- composition comprising a drug, or to provide a dosage form ethylbutanoate, desogestrel cyclobutylheptanoate, and d, comprising a drug indicated in both instances for therapy, or I-norgestrel. The dosage of progestin or progestin deriva for contraception. In the latter, the therapeutic composition, tives in a composition is 10 ng to 500 mg. and the dosage form are a means for administering a In providing the process for producing the composition, therapeutically acceptable progestin to a human. The prior 20 and the dosage form containing the composition the process art, in recent patents, U.S. Pat. Nos. 4,948,593; 5,098,714; provides also a combination of an estrogen and a progestin and 5,200,197 all issued to Wright et al, there are disclosed selected from the combination consisting of ethinyl estradiol compositions comprising an estrogen and a progestin that and cyproterone acetate, ethinyl estradiol and desogestrel, are administered for contraceptive purposes. While these ethinyl estradiol and dimethisterone, ethinyl estradiol and compositions operate successfully for their intended pur 25 ethylnodiol diacetate, ethinyl estradiol and ethynodiol diac pose, it has now been discovered a process can be provided etate, ethinyl estradiol and gestodene, ethinyl estradiol and that improves the manufacture of the composition and gestodene, ethinyl estradiol and levonorgestrel, ethinyl correspondingly a dosage form containing the composition. estradiol and lynestrenol, ethinyl estradiol and norethin The present invention has an object to provide a process for drone acetate, ethinyl estradiol and norethindrone propi preparing a therapeutic composition comprising a member 30 onate, ethinyl estradiol and norethindrone, ethinyl estradiol selected from the group consisting of an estrogen, a proges and norethindrone butyrate, ethinyl estradiol and norethin tin, or a combination of an estrogen and a progestin, which drone palmitate, ethinyl estradiol and norethisterone, ethinyl can be administered as a composition, or administered from estradiol and norgestrel, ethinyl estradiol and norgestimate, a dosage form. The invention further has an object to provide ethinyl estradiol and norethynodrel, ethinyl estradiol and a method for administering a composition for contraception 35 progesterone, ethinyl estradiol and hydroxyprogesterone, which composition is produced by the process of the inven estrone and progesterone, estrogen and progesterone, estro tion. gen and levonorgestrel, estrogen and norgestrel, estrogen and norethindrone, estrogen and norgestimate, estrogen and DESCRIPTION FOR PROVIDING THE norethisterone, estrogen and norethynodrel, estrogen and INVENTION hydroxyprogesterone, estrogen and desogestrel, estrogen and gestodene, estriol and desogestrel, estriol and gestodene, In providing the process to produce the composition, and estriol and desogestrel, estriol and gestodene, estriol and the dosage form, the estrogen contraceptively acceptable for levonorgestrel, estriol and norethindrone, estriol and norg these purposes comprise a member selected from the group estrel, estriol and norgestimate, estriol and progesterone, consisting of estrogen, estradiol, estradiol valerate, estradiol 45 estriol and hydroxyprogesterone, estriol and desogestrel, benzoate, estradiol cypionate, estradiol ether, estradiol ester, estriol and dimethisterone, and estriol and norethisterone. estradiol propionate, estradiol dipropionate, estradiol The composition consisting of a contraceptive pair of an acetate, ethinyl estradiol esters, 17o-ethinyl estradiol estrogen and progestin comprises 11 ng to 1750 mg of the acetate, 17o-ethinyl estradiol benzoate, 17o-ethinyl estra steroid pair. diol ethers, 17o-ethinyl estradiol ethers, estrone, estrone 50 A process for providing a composition consisting of acetate, estrone sulfate, estriol, estriol succinate, 178-estra levonorgestrel (LNG) and ethinyl estradiol (EE) comprises diol, ethinyl estradiol 17-methyl ether, ethinyl estradiol the following process steps: 3.835 g of micronized ethinyl 3-anthranilate hydrochloride, ethinyl estradiol 3-methyl estradiol is dissolved in an organic solvent, ethyl alcohol, ether, ethinyl estradiol 3, 17-dimethyl ether, ethinyl estra 1777.5g with constant stirring to produce a wet granulation. diol-17-ethyl ether, and estrone phosphate. The dosage 55 Next, separately, 18.335 g of levonorgestrel is mixed in a amount of estrogen or estrogen derivative in a composition blender with 250 g of a hydroxyalkylcellulose, hydroxypro is 1 ng to 1000 mg. pylmethylcellulose possessing a 11,200 molecular weight to In providing the process for producing the therapeutic yield a drug levonorgestrelhydroxypropylmethyl-cellulose composition and the dosage form, the progestin for these homogenous blend. Then, an osmopolymer, poly(alkylene purposes comprise a member selected from the group con 60 oxide), 4702.83 g of poly(ethylene oxide) possessing a sisting of progesterone, d-norgestrel, norethindrone, 200,000 molecular weight, is added to the blend comprising levonorgestrel, norgestimate, norethisterone, norethisterone the levonorgestrel and the hydroxypropyl-methylcellulose acetate, norethynodrel, norethindrone acetate, 17-hydrox and the three ingredients, the poly(ethylene oxide), hydrox yprogesterone, 17-hydroxyprotesterone ester, 17-hydrox ypropylmethylcellulose and the levonorgestrel blended into yprogesterone ether, 19-nor-17-hydroxyprogesterone, 65 a homogenous blend for 10 minutes. Next, the ethinyl 19-nor-17-hydroxyprogesterone ester, 19-nor-17-hydrox estradiol granulation is added slowly to the dry three yprogesterone ether, 17B-acetoxy-133-ethyl-17o-ethinyl ingredient blend and the blending continued for 7 to 9 5,595,759 3 4 minutes. Next, the just prepared wet