USOO5720977AIIII United States Patent (19) 11 Patent Number: 5,720,977 Deghenghi 45 Date of Patent: Feb. 24, 1998

(54) ORAL WATER SOLUBLE OTHER PUBLICATIONS PHARMACEUTICAL COMPOSTIONS CONTAINING ESTRONE COMPOUND AND Ettinger B. et al., "Calcium enhances the bone-sparing CALCUM SALT effects of low-dosage estrogen in postmenopausal women', Osteoporosis Int. (United Kingdom), 1993, vol. 3, Suppl. 1, 76) Inventor: Romano Deghenghi, Cheseaux Dessus B1, St. Cergue, Switzerland pp. 157-158. Geenant H.K. et al. "Effect of estrone sulfate on postmeno (21) Appl. No.: 592377 pausal bone loss" Obstetric & Gynecology (USA) 1990, vol. 22 PCT Filed: Jul. 26, 1994 76, No. 4, pp. 579-584. 86 PCT No.: PCT/EP94/O2465 Harris E.T. et al., "The Effects of Estrone Ogen on Sprinal Bone Density of Postmenopausal Women' Arch Internal S371 Date: Feb. 1, 1996 Medicine. vol. 151. No. 10, pp. 1980-1984, Oct. 1991. S 102(e) Date: Feb. 1, 1996 87 PCT Pub. No.: WO95/07701 Primary Examiner-James M. Spear PCT Pub. Date: Mar 23, 1995 Attorney, Agent, or Firm-Pennie & Edmonds 30 Foreign Application Priority Data 57 ABSTRACT Sep. 17, 1993 IT Italy ...... M193A204 Oral water-soluble pharmaceutical compositions containing a therapeutically effective amount of a water-soluble and (51) Int. Cl...... A61K9/08: A61K 9/16; stable estrogen compound such as estropipate (piperazine A61K9/20: A61K9/46 estrone sulfate), and at least one water-soluble, pharmaceu 52 U.S. Cl...... 424/466; 424/464; 424/465; tically acceptable calcium salt in the presence of a suitable, 424/489: 514/874: 514/770; 514/784 pharmaceutically acceptable excipient. Compositions which (58) Field of Search ...... 424/464, 465, include an organic acid and a calcium carbonate or bicar 424/466,489: 514/874, 770, 784 bonate compound which reacts with the organic acid when 56) References Cited the composition is added to water to provide effervescence are preferred. U.S. PATENT DOCUMENTS 5,004,651 4/1991 Becker ...... 424/465 19 Claims, No Drawings 5,720,977 1 2 ORAL WATER SOLUBLE The estrogen component must be freely soluble in aque PHARMACEUTICAL COMPOSITIONS ous concentrated electrolyte solutions and stable, at neutral CONTAINING ESTRONE COMPOUND AND or basic pH, if the resulting pH of the liquid preparation is CALCUMI SALT acidic, the estrogen component must be stable in a conjugate form (acid sulfate) even if present as a finely dispersed This application is a 371 of PCT/EP94/02465 filed Jul. colloidal form, readily absorbed at intestinal pH. 26, 1994. The calcium preparations must be readily soluble in water giving a solution which should be clear or slightly cloudy TECHNICAL FIELD but without insoluble residues, which, if formed, will not be The present invention relates to oral water soluble phar completely absorbed. maceutical compositions containing estrone derivative, use The combination tablet or sachet must be pharmaceuti ful for the substitutive hormonal therapy (hypoestrogenic) cally stable, particularly concerning the estrogen component and in the prevention of the bone loss in the cases of senile and have an acceptable shelf-life. or post-menopausal osteoporosis. 15 The tablet or sachet must dissolve in water within a BACKGROUND ART conveniently short time, preferably within a few minutes, to avoid hydrolysis of the estrogen component or precipitation Estrone, the metabolite of estradiol, is used alone or in combination with other natural estrogens, in the form of of the calcium salts out of the saturated aqueous solution. ester (acetate, propionate) or as hydrosoluble conjugate If needed, the effervescence during dissolution of the (sodium or piperazine sulphate) in the substitutive hormonal preparation should be moderate to avoid spraying the satu therapy (hypoestrogenic) and in the prevention of the bone rated solution on the wall of the container and therefore loss in the cases of post-menopausal Osteoporosis or in depositing an insoluble rim which could take the crucial oophorectomized women. estrogen component out of solution. The administration of estrone at therapeutical doses is The ingredients of the formulation must not interfere with effected both by oral route (tablets) and parenteral or trans 25 the accuracy of the analytical determination of the estrogen dermal route. component which is present in very small amounts. In Estrogens are usually administered as oral tablets, the addition the final pH of the solution should be very close to most common preparations being conjugated (equine) 7 since higher pHs favour the precipitation of the calcium estrogens, micronized estradiol, and estrone piperazine sul ingredient as calcium hydroxide and lower pHs will fate (estropipate). 30 hydrolize the estrogen conjugate and give the less absorb The oral administration of liquid compositions containing able free estrone. estrone presents some difficulties due to the insolubility in Finally, the preparation must have an acceptable or a water of the compound, as well as of its esters. This problem pleasant taste for optimal patient compliance. can be solved by formulating the medicament in solid oral As far as the applicant is aware, there is no teaching in the forms, but the problem of the incomplete absorption of the 35 prior art on how to solve all the above problems. active ingredient at gastric level and of the possible difficulty of administering said forms to patients with poor swallowing SUMMARY OF THE INVENTION capacity still remains. After a thorough experimentation, it has now surprisingly It is well known that oral water soluble, liquid and been found that the association between a water soluble and optionally effervescent forms promote the absorption of the 40 stable estrogen derivative and a pharmaceutically acceptable active ingredient, as for example in the case of aspirin, soluble salt of calcium allows the preparation of acceptable paracetamol, potassium, and others. Moreover, the liquid liquid and, if needed, effervescent pharmaceutical compo effervescent formulations result particularly appreciated to sitions which ensure a good absorption of the active ingre patients in view of their aspect and the possibility to give 45 dient when orally administered. them good palatability. Therefore the object of the present invention are oral For the preparation of liquid forms comprising estrone it water soluble pharmaceutical compositions characterized in is necessary to provide their hydrosoluble compounds. The that they contain a combination of a water soluble and stable alkali-conjugate estrone salts (sodium-sulfates) are estrogen derivative and at least one soluble salt of calcium. hydrosoluble, but unstable in aqueous media, with the 50 Preferably, the compositions provided by the present inven resulting precipitation of insoluble products. tion are in the form of oral water soluble effervescent In the bone-loss preventive therapy it is common practice composition. to provide a calcium supplement to the patient. A large Said compositions, once added to a suitable amount of number of calcium preparations are available, including water, give complete drinkable solution within minutes. chewable tablets, ordinary oral tablets and even effervescent 55 preparations. DETALED DESCRIPTION OF THE The oral absorption of these available preparations is PREFERRED EMBODIMENTS deemed to be satisfactory, although it can be variable Advantageously, the presence of calcium ions in the depending on the nature of the calcium salt (carbonate, compositions according to the invention yields a further citrate, gluconate, lactate, phosphate, etc.). An extensive therapeutical support to the action of estrone in the treatment description of available calcium preparations can be found of senile or post-menopausal osteoporosis. A further advan in the 3 edition of Martindale. The Extra Pharmacopoeia, tage of the present invention is to provide in a single London. The Pharmaceutical Press, 1993, page 853 to 856. pharmaceutical composition a twofold therapeutic action, If the skilled technician had thought to combine an the estrogenic one and the mineral one. A still further estrogen derivative with a calcium salt in an oral, liquid 65 advantage of the present invention is to provide a drinkable composition, he would have faced some critical issues of solution, which ensures the optimal oral absorption of the pharmaceutical technology and pharmacology. active ingredients, at the same time providing a good com 5,720,977 3 4 pliance by the patient, especially by elder people having The ratios among estropipate, calcium salt and other swallowing difficulties. Lastly, the present invention pro excipients which concur in the formulation of the soluble or vides a pharmaceutical composition with a reduced cost of effervescent compositions according to the present invention medication. are not critical. In particular, estropipate and the calcium salt In a preferred embodiment of the invention calcium 5 will be contained in the form of dosage unit in a therapeu hydrogencarbonate is the calcium salt. tically effective amount, whereas the expert in the field will In a more preferred embodiment, calcium carbonate is the easily be capable of determining the ratio between the acid calcium salt. and the carbonate, or bicarbonate, as to assure a good In a even more preferred embodiment of the present effervescence and rapid dissolution of the pharmaceutical invention, calcium glycerophosphate is the calcium salt. composition. This last is preferred for its water solubility and high elemental calcium content and is also capable of providing EXAMPLES a desiderable amount of phosphorus. In a most preferred embodiment, estropipate is the estro 15 The following examples further illustrate the present gen derivative. invention. Estropipate has proved to be the most suitable estrogen Example 1 derivative because of its water solubility and stability, con trarily to the much less stable conjugate equine estrogens or For 10,000 effervescent tablets the following ingredients the insoluble non-conjugated estrogen preparations. It is were used: however clear that other stable and suitable estrogen con 17.22 kg of granular calcium carbonate jugates can be used such as the ammonium and substituted 5.20 kg of granular citric acid ammonium salts such as the tromethamine salt, the soluble 3.05 kg of granular fumaric acid succinate salts, the phosphate ester salts and similar phar 7.50 g of estropipate (estrone sulphate of piperazine 1:1) maceutically acceptable soluble derivatives well known to 25 1.00 kg of leucine hydrochloride the skilled in the art. 50 g of soluble flavours The compositions of the present invention can be in the 50 g of calcium ciclamate. form of granulate or tablets. The ingredients were put in a mixer (P-K twin-shell Said compositions are prepared according to conventional blender, or the like) and mixed for 20 minutes. The mixture techniques well known to the expert in the field, as de was tabletted, granulated and sieved (16 mesh). scribed for example in "Remington's Pharmaceutical Sci The sieved granulate was tabletted in an atmosphere with ences Handbook" XVIIEd.; Mack pub. U.S.A.. less than 30% of humidity at the temperature of 20° C. to As known, effervescence is obtained by means of a give 10,000 effervescent tablets. reaction in aqueous ambient between an acid and a carbon The above amounts can be modified according to the ate or a bicarbonate. 35 desired posology of estrone or elemental calcium, by The mostly used acids are citric, tartaric, fumaric and varying, if necessary also the amount of citric acid necessary boric acid. Citric, tartaric and fumaric acid, particularly for effervescence. citric acid, which contributes to give an agreeable taste to the Example 2 final solution, are preferred. For 10,000 effervescent tablets the following ingredients Among the carbonates usable according to the invention, were used: those of sodium, potassium, lithium and calcium can be 52.50 kg of calcium glycerophosphate cited. 22.30 kg of saccharose Calcium carbonate is more preferred, since it contempo 1.00 kg of PEG 6000 raneously yields the calcium provided in the present inven 7.50 g of estropipate (estrone sulphate of piperazine 1:1) 45 0.10 kg of silicon dioxide tion and the source of CO2 necessary for effervescence. 0.10 kg of magnesium stearate Whenever the expert in the field considered useful to use 1.50 kg of leucine suitable excipients, such as binders, lubricants, sweetenings, 1.70 kg of citric acid aromatizing, dyes, this can be done however without depart 5.00 kg of aspartame ing from the scope of the present invention. 50 5.00 kg of sodium bicarbonate. Examples of binders are sugars. glycine. The ingredients were worked according to the procedure Examples of lubricants are benzoates, polyethylene of Example 1 to give 10,000 effervescent tablets. glycols, leucine. Example 3 The process for the preparation of the compositions of the 10,000 non effervescent sachets were prepared with the present inventions provides the work up in suitable condi 55 ingredients shown in Example 2, except silicon dioxide and tions which avoids the early reaction between the acid and magnesium stearate, citric acid and sodium bicarbonate. carbonate, in particular low humidity (35% maximum) and Example 4 temperature (25° C. maximum) shall be controlled. Oral liquid pharmaceutical compositions were prepared The pharmaceutical compositions according to the inven according to conventional techniques with the following tion may be in the form of powders, granules, sachets, unitary composition: tablets, or in the form of liquid compositions, such as solutions. Calcium glycerophosphate 5.250 g Although the dosages are determined by the pathology Saccharose 2.230 g kind, the conditions of the patient (age, sex, weight) and will PEG 6000 0.100 g be established by the skilled doctor, a dose range is indicated 65 Estropipate 0.750 mg from 0.375 to 1.50 mg (corresponding to 0.3125 to 1.25 mg Leucine 0.150 g of sodium estrone sulfate). 5,720,977 5 -continued -continued Aspartame 0.050 mg leucine 0.150 g Distilled water 100 g. citric acid 1.700 g aspartame 0.050 g sodium bicarbonate O.500 g. Example 5 Oral effervescent pharmaceutical compositions were pre 10. Oral effervescent pharmaceutical compositions pared according to the above examples with the following according to claim 7 in the form of tablets having the unitary composition: following unitary composition: 10

Estropitate 0.75 mg Calcium carbonate granular 1.722 g Caglycerophosphate 5.250 g Citric acid granular 0.520 g Citric acid 0.5 g Fumaric acid gramular 0.305 g Sodium bicarbonate 0.658 mg Estropipate 0.750 mg Sucrose 4.000 g 15 Leucine hydrochloride 0.10 g Aspartame 0.04 g Soluble flavours 5.0 mg Aroma (orange) 0.05 g. Calcium ciclamate 5.0 mg. For all the above examples it is understood that flavouring 11. Oral water soluble pharmaceutical compositions agents colorants and aroma can be added according to 20 according to claim 8 in the form of granules or powder or conventional practice. sachets having the following unitary composition: The above amounts can be modified according to the desired posology of estrone or elemental calcium, by varying, if necessary also the amount of citric acid necessary Calcium glycerophosphate 5.250 g 25 Saccharose 2.230 g for effervescence. PEG 6000 0.100 g What is claimed is: Estropipate 0.375 mg 1. An oral water soluble pharmaceutical composition Leucine 0.150 g containing a therapeutically effective amount of a water Aspartame 0.050 mg soluble and stable estrogen compound and at least one water-soluble, pharmaceutically acceptable calcium salt of 12. Oral liquid pharmaceutical compositions according to calcium glycerophosphate or calcium hydrogen carbonate in claim 8 of the following unitary composition: the presence of a suitable, pharmaceutically acceptable excipient. Calcium glycerophosphate 5.250 g 2. The composition according to claim 1, characterized in Saccharose 2.230 g that the estrogen compound is estropipate (piperazine PEG 6000 0.100 g estrone sulfate). Estropipate 0.750 mg 3. The composition according to claim 1, characterized in Leucine 0.150 g that calcium glycerophosphate is the calcium salt. Aspartaine 0.050 mg 4. An oral water-soluble pharmaceutical composition con Distilled water 100 g taining a therapeutically effective amount of a water-soluble and stable estrogen compound, and first and second water 13. The composition of claim 7 wherein the water soluble soluble, pharmaceutically acceptable calcium salts in the calcium salt comprises an organic acid and a calcium presence of a suitable, pharmaceutically acceptable excipi carbonate or bicarbonate compound which reacts with the ent, organic acid when the composition is added to water. 5. The compositions according to claim 1, characterized 45 14. The composition of claim 13 where the organic acid in that calcium hydrogencarbonate is the calcium salt. is citric acid, the calcium compound is calcium carbonate 6. The composition according to claim 4, characterized in and the estrogen compound is estropipate (piperazine that the estrogen compound is estropipate (piperazine estrone sulfate). estrone sulfate). 15. The composition of claim 7 which includes an organic 7. An effervescent, oral, water-soluble pharmaceutical 50 acid and a carbonate or bicarbonate compound which reacts composition containing a therapeutically effective amount with the organic acid when the composition is added to of a water-soluble and stable estrogen compound and at least water to provide effervescence. one water-soluble calcium salt in the presence of a suitable, 16. The composition of claim 15 wherein the organic acid pharmaceutically acceptable excipient. is citric, tartaric or fumaric acid, the carbonate or bicarbon 8. The compositions according to claim 1 in the form of 55 ate compound is a sodium, potassium, lithium or calcium powders, granulates, tablets or a liquid. carbonate, and the estrogen compound is estropipate 9. Oral effervescent pharmaceutical compositions accord (piperazine estrone sulfate). ing to claim 7 in the form of tablets having the following 17. The composition according to claim 7, in the form of unitary composition: powders, granulates, tablets or a liquid. 18. The composition according to claim 4, characterized in that calcium salts include calcium glycerophosphate, calciun glycerophosphate 5.250 g saccharose 2.230 g calcium hydrogen carbonate, or the reaction product of PEG 6000 0.100 g calcium carbonate or bicarbonate with an organic acid. estropipate (estrone sulphate of piperazine 1:1) 0.750 mg 19. The composition according to claim 4, in the form of silicon dioxide 0.010 g powders, granulates, tablets or a liquid. magnesium stearate 0.010 g sk k ck ck k