Extended release growth promoting two component composition
Patent References 2232438 2236574 2314185 2379832 3239345 3248294 3773919 Novel zootechnical compositions Processes for preparation of microspheres Novel zootechnical compositions InventorsAssigneeApplicationNo. 11023337 filed on 12/22/2004US Classes:514/170, Plural Compounds containing cyclopentanohydrophenanthrene ring systems514/171, With additional active ingredient514/178, Oxygen single bonded to a ring carbon of the cyclopentanohydrophenanthrene ring system514/182, Oxygen single bonded to a ring carbon of the cyclopentanohydrophenanthrene ring system514/450, The hetero ring has at least seven members552/625, The A ring is a benzene ring (e.g., estrones, estradiols, etc.)552/646, Unsaturation between the 4- and 5-positions (e.g., 19-nortestosterones, 13 beta-alkyl-4-gonene-3,17-diones etc.)552/650, Oxygen bonded directly at the 16- or 17-position of the cyclopentanohydrophenanthrene ring system549/269Bicyclo ring system having the lactone ring as one of the cyclosExaminersPrimary: Badio, Barbara P.Attorney, Agent or FirmForeign Patent References
International ClassesA61K 31/56A61K 31/335 C07J 1/00 C07D 313/08 DescriptionSustained release pharmaceutical compositioncontaining growth promoters for use in food animals are described in U.S. Pat. No. 3,939,265 issued to J. A. Grandadam on Feb. 17, 1976 and U.S. Pat. No. 5,288,496 issued to D. H. Lewis on Feb. 22, 1994. The rate of release of the growth promotersof these compositions, however, generally does not comport with the growth periods of food animals in feedlots, the rate of release of the promoters declining over the growth period and becoming markedly reduced before the expiration of the period. Toovercome this deficiency in feedlot growth promotion, it would be desirable to provide an extended release composition, from which the growth promoters are uniformly released over the growth period of the food animal in the feedlot, thereby enhancing theweight gain of the animal and improving the feed efficiency of the formulation. It has now been found that a composition comprising a first composition comprising growth promoters and a second composition comprising growth promoters and a biodegradablepolymer releases the promoters over an extended period of time corresponding to the growth period of feedlot animals. The present invention relates to an extended release composition comprising a first composition comprising growth promoters and a second composition comprising growth promoters and a biodegradable polymer. More specifically, the presentinvention relates to a composition comprising a first composition comprising a compound of formula 1 ##STR00001## wherein R is loweralkyl; the ester derivatives, geometric isomers, stereoisomers, or optical isomers thereof, a compound of formula 2##STR00002## wherein R1, and R2 are loweralkyl; the ester derivatives, geometric isomers, stereoisomers, or optical isomers thereof, a compound of formula 3 ##STR00003## wherein R3 and R4 are loweralkyl; the geometric isomers,stereoisomers, or optical isomers thereof, a compound of formula 4 ##STR00004## wherein R5 is loweralkyl; the ester derivatives, geometric isomers, stereoisomers, or optical isomers thereof; or a compound of formula 5 ##STR00005## wherein R6 isloweralkyl; the ester derivatives, geometric isomers, stereoisomers, or optical isomers thereof; and a second composition comprising a compound of formula 1 ##STR00006## wherein R is loweralky; the ester derivatives, geometric isomers, stereoisomers, oroptical isomers thereof, a compound of formula 2 ##STR00007## wherein R1 and R2 are loweralkyl; the ester derivatives, geometric isomers, stereoisomers, or optical isomers thereof, a compound of formula 3 ##STR00008## wherein R5 isloweralkyl; the ester derivatives, geometric isomers, stereoisomers, or optical isomer thereof, a compound of formula 4 ##STR00009## wherein R3 and R4 are loweralkyl; the geometric isomers, stereoisomers, or optical isomers thereof, and acompound of formula 5 ##STR00010## wherein R6 is loweralkyl; the ester derivatives, geometric isomers, stereoisomers, or optical isomers thereof; and a biodegradable polymer selected from the group consisting of homopolymers and copolymers ofγ-butyrolactone, δ-valerolactone, ε-caprolactone, glycolide, DL-lactide, L-lactide, glycolic acid, DL-lactic acid, L-lactic acid, and combinations thereof, polydioxanones, polyorthesters, polyanhydrides, polycarbonates,polyesteramides, and polyphosphazines, useful for the promotion of weight gain in food animals. The present invention also relates to a pharmaceutical dosage form containing the composition, a method of preparing the dosage form utilizing thecomposition, as well as pellets of the composition for implantation in food animals. Preferred compositions of growth promoters are those wherein R, R1, R2, R3, and R4, R5 and R6 are methyl and the aroyl or alkanoyl ester derivatives thereof, where applicable. More preferred compositions are those wherein the growth promoters are; (a) 17β-acetoxyestra-4,9,11-trien-3-one; (b) 17β-benzoyloxyestra-4,9,11-trien-3-one; (c) 17β-propionyloxy-4-androsten-3-one; (d) pregn-4-en-3,20-dione; (e)estra-1,3,5(10)-trien-3,17β-diol; (f) 17β-benzoyloxyestra-1,3,5(10)-trien-3-ol; (g) 3,4,5,6,9,10,11,12-decahydro-7,14,16-trihydroxy-3-methyl-1H(2)-benzoxacyc- lotetradecin 1-one. Preferred biodegradable polymers are homopolymers and copolymers of glycolide, DL-lactide, L-lactide, glycolic acid, DL-lactic acid and L-lactic acid and combinations thereof. More preferred biodegradable polymers are copolymers of DL-lactide and glycolide, copolymers of L-lactide and glycolide, polymers of L-lactide and polymers of DL-lactide, designated polylactides. As used throughout the specification and appended claims, the term "alkyl" refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 5 carbon atoms. Examples of alkyl groups are methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-butyl, 1-pentyl, 3-pentyl, and the like; the term "alkanoic acid" refers to a compound formed by combination of a carboxyl group and a hydrogen atom or alkyl group. Examples of alkanoic acid are formic acid, acetic acid,propanoic acid, 1-methylpropanoic acid, 2,2-dimethylacetic acid, pentanoic acid, and the like; the term "alkanoyl" refers to the radical formed by removal of the hydroxyl group from an alkanoic acid. Examples of alkanoyl groups are formyl, acetyl,propanoyl, 2-methylpropanoyl, 2,2-dimethylacetyl, pentanoyl, and the like. The term "aryl" refers to an unsubstituted or a substituted phenyl group. Examples of aryl groups are benzene, 2-methylbenzene, 3-chlorobenzene, 4-hydroxybenzene,3-methoxybenzene, methoxybenzene, 3-nitrobenzene, 2-trifluorobenzene, and the like. The term "aroic acid" refers to a compound formed by combination of an carboxyl group with an aryl group. Examples of aroic acids are benzoic acid, 2-methylbenzoicacid, 3-chlorobenzoic acid, 4-hydroxybenzoic acid, 3-methoxybenzoic acid, 3-nitrobenzoic acid, 2-trifluorobenzoic acid, and the like. The term "aroyl" refers to the radical formed by removal of the hydroxyl group from an aroic acid. Examples of aroylare benzoyl, 2-methylbenzoyl, 3-chlorobenzoyl, 4-hydroxybenzoyl, 3-methoxybenzyol, 2-nitrobenzoyl, 2-trifluoromethylbenzoyl, and the like. The term "lower" as applied to any of the aforementioned groups or compounds refers to a group or compound havinga carbon skeleton containing up to and including 5 carbon atoms. The expression "ester derivatives" refers to esters of the hydroxy group or groups of compounds of the present invention and an alkanoyl or aroyl group. Examples of ester derivatives areesters of formic acid, acetic acid, propanoic acid, 1-methylpropanoic acid, 2,2-dimethylacetic acid, pentanoic acid, benzoic acid, 2-methylbenzoic acid, 3-chlorobenzoic acid, 4-hydroxybenzoic acid, 3-methoxybenzoic acid, 2-nitrobenzoic acid and2-trifluoromethylbenzoic acid and the like. The compounds of the compositions of the present invention which lack an element of symmetry exist as optical antipodes and as the racemic forms thereof. The optical antipodes may be prepared from the corresponding racemic forms by standardoptical resolution techniques or by synthesis from optically active precursors. The present invention comprehends all optical isomers and racemic forms thereof and all stereoisomers of the compounds of the compositions disclosed and claimed herein. The formulas of the compounds shown herein are intended to encompass allpossible optical and stereoisomers of the compounds so depicted. The expression "food animal" refers to an animal raised for the purpose of providing a source of protein in the diet of humans or other animals. Examples of food animals are bovine animals, such as cows, cattle, steers, calves, and the like,ovine animals such as sheep; porcine animals such as pigs, and the like and avians such as chickens, turkeys and the like. The expression "conventional drug delivery" refers to the temporally uncontrolled release of a drug into the blood of an animal resulting in a short duration of action, the blood levels of the drug being either initially high (intravenousadministration) and falling off rapidly, or initially low (extramuscular administration), rapidly rising and falling off rapidly. The expression "sustained release" refers to the slow release of a drug into the blood of an animal over a prolonged period of time wherein the blood levels of the drug decline rapidly over time, but not as rapidly as in conventional release. The expression "controlled release" refers to sustained release wherein constant blood levels of the drug are maintained over a period of time. The expression "delayed release" refers to the release of a drug into the blood of an animal after an induction period subsequent to the administration of the drug, without an initial burst release of the drug. The expression "extended release" refers to the controlled release of a drug into the blood of an animal over a long period of time. The expression "steroid" refers to a compound characterized by the presence of a perhydrocyclopentenophenanthrene ring system. The term "biodegradable polymer" refers to those synthetic and naturally occurring water-insoluble polymers that degrade by hydrolysis or enzymatic processes. Examples of useful biodegradable polymers include, but are not limited to thealiphatic polyesters of hydroxy acids (i.e. the "polylactides") such as the homopolymers and copolymers prepared by ring-opening polymerization of glycolide, DL-lactide, L-lactide, γ-butyrolactone, δ-valerolactone, ε-caprolactone, aswell as blends of these polymers. Other examples include homopolymers and copolymers prepared by directed condensation of glycolic acide, DL-lactic acid, L-lactic acid, and various other classes of polymers including the polydioxanones, polyorthoesters,polyanhydrides, polycarbonates, polyesteramides, polyamides and polyphosphazines. The growth promoters of the compositions of the present invention are described in the art. For example, the steroids of the formulas 1 and 3 are described in U.S. Pat. No. 3,939,265 issued to J. A. Grandadam on Feb. 17, 1996; the steroids informula 2 are described in U.S. Pat. No. 2,236,574 issued to H. Koester, et al., on Apr. 11, 1941; the steroid of formula 3 is described in U.S. Pat. No. 2,232,438 issued to A. Butendant on Feb. 18, 1941; and the macrocycles of formula 5 aredescribed in U.S. Pat. No. 3,239,345 issued to E. B. Hodge, et al., on Mar. 8, 1966. The ester derivatives of the growth promoters are also described in the art, or may be prepared by conventional esterification techniques, e.g. treating compoundscontaining a hydroxyl group with an alkanoyl or an aroyl halide in the presence of an acid acceptor. The "polylactides" as defined herein are described in U.S. Pat. No. 5,366,734 issued Nov. 22, 1994 to F. G. Hutchinson and are prepared by polymerization of lactic acid or glycolic acid, alone, or the corresponding lactides or glycolides, orcopolymerization of lactic acid and glycolic acid, or the corresponding lactides and glycolides, as described therein, or are available from commercial sources, for example, Birmingham Polymers, Inc., Birmingham, Ala. The biodegradable polymers of the compositions of the present invention, i.e. the polydioxanones, polyorthoesters, polyanhydrides, polycarbonates, polyesteramides, polyamides and polyphosphazines, are described in, for example, U.S. Pat. No.5,508,730 issued to R. C. Fuissz on May 21, 1996, among others. The extended release composition of the present invention comprises a first and second composition formulated as a pharmaceutical dosage form for administration to a food animal for weight gain in the feedlot. The first composition of theformulation comprises growth promoters of formulas 1 to 5 wherein R, R1, R2, R3, R4, R5, and R6 are as defined herein, and the ester derivatives thereof, preferably those growth promoters wherein R, R1, R2,R3, R4, R5, and R6 are methyl and the aroyl or alkanoyl ester derivatives thereof, where applicable, more preferably, growth promoters selected from the group consisting of: (a) 17β-acetoxyestra-4,9,11-trien-3-one; (b)17β-benzoyloxyestra-4,9,11-trien-3-one; (c) 17β-propionyloxy-4-androsten-3-one; (d) pregn-4-en-3,20-dione; (e) estra-1,3,5(10)-trien-3,17β-diol; (f) 17β-benzoyloxyestra-1,3,5(10)-trien-3-ol; and (g)3,4,5,6,9,10,11,12-decahydro-7,14,16-trihydroxy-3-methyl-1H(2)-benzoxacyc- lotetradecin-1-one. The second composition of the formulation comprises growth promoters of formulas 1 to 5 wherein R, R1, R2, R3, R4, R5, and R6 are as defined herein and the ester derivatives thereof, preferably, those growthpromoters wherein R, R1, R2, R3, R4, R5, and R6 are methyl and the aroyl or alkanoyl derivatives thereof, where applicable, more preferably, growth promoters selected from the group consisting of: (a)17β-acetoxyestra-4,9,11-trien-3-one; (b) 17β-benzoyloxyestra-4,9,11-trien-3-one; (c) 17β-propionyloxy-4-androsten-3-one; (d) pregn-4-en-3,20-dione; (e) estra-1,3,5,(10)-trien-3,17β-diol; (f)17β-benzoyloxyestra-1,3,5(10)-trien-3-ol; (g) 3,4,5,6,9,10,11,12-decahydro-7,14,16-trihydroxy-3-methyl-1H(2)-benzoxacyc- lotetradecin-1-one, and a biodegradable polymer, preferably, homopolymers and copolymers of glycolide, DL-lactide, L-lactide,glycolic acid, DL-lactic acid and L-lactic acid, and combinations thereof, more preferably copolymers of DL-lactide and glycolide and copolymers of L-lactide and glycolide. The formulation may contain, in addition to the growth promoters, the activeingredients, excipients, e.g., pharmaceutical binders and fillers, such as starch, ethylcellulose, cellulose acetate, sucrose, and polyvinylpyrrolidone. Ethylcellulose is preferred. The formulation may also contain an adhesive, for example,cholesterol, and a lubricant, for example, magnesium stearate. The homopolymers and copolymers of glycolide, DL-lactide and L-lactide, glycolic acid, DL-lactic acid and L-lactic acid, and combinations thereof, are characterized by their composition and molecular weight. Composition can be convenientlydetermined by nuclear magnetic resonance spectrometry. For polymers prepared by ring-opening polymerization, the composition is described as the molar composition based on the cyclic monomers from which the polymer was prepared. For those prepared bydirect condensation, the composition is described as the molar composition of the hydroxyacid residues present. The compositions of the polylactides that are useful in preparing the formulations described herein include all homopolymers and copolymersthat exhibit glass transition or crystalline melting transition temperatures greater than about 40° C. The preferred compositions are those copolymers of DL-lactide and glycolide with monomer ratios in the range from about 50:50 to about 90:10and the most preferred compositions are those with monomer ratios in the range from about 60:40 to about 75:25. All monomer ratios are expressed as the ratio of DL-lactide to glycolide Molecular weight can be monitored by dilute-solution viscosity measurements. As described herein, dilute-solution viscosities are measured in either chloroform (≥65% lactide) or hexafluroisopropanol (<65% lactide) at 30° C. anda concentration of about 0.5 g/dL (IV<1.5 dL/g) or 0.2 g/dL (IV=1.5-3.5 dL/g). The inherent viscosities of the polylactides may fall within the range of about 0.1 dL/g to about 3.5 dL/g; that of the preferred polymers being in the range of about 0.3dL/g to about 1.5 dL/g. The biodegradable polymer, preferably, a polylactide, of the second composition of the formulation serves as a coating of a core of the formulation and may be present as a minor component of the core in an amount within the range of from about 0to about 10%. The timing of the initial release of the growth promoters from the second composition formulation, the coated composition, is determined by the relative amounts of the promoters to the biodegradable polymeric coating, as well as thecharacteristics of the coating. Generally, the greater the proportion of biodegradable polymer to the growth promoters, the greater the retardation of the initial release of the growth promoters, i.e., the longer delayed release period. For example, intable 1, the uncoated pellet began releasing immediately while the 10.8 wt. % coasted pellet did not begin to release until approximately 45 days and the 19.8 wt. % of coated pellet did not begin to release until approximately 55 days. The timing of release of the growth promoters from the coated formulation is also dependent on the relative proportions of the DL-lactide to glycolide units in the copolymers and the molecular weight thereof. Generally, the greater theproportion of DL-lactide units to glycolide units in the copolymer, the greater the delay of the release of the growth promoters from the formulation. For example, the delay of release of the growth promoters, 17β,-acetoxyestra-4,9,11-trien-3-oneand estra-1,3,5(10)-trien-3,17β-diol, from the coated formulation decreased by increasing the amount of DL-lactide units in the copolymer in a formulation having a coating of DL-lactide-glycolide copolymer. Generally, the greater the molecular weight of the biodegradable polymer, the greater the delay of the release of the growth promoters. The in vitro rates of release of the growth promoters of the present invention are determined by conventional methods known in the art, for example, by the methods described by J. W. Gibson in Intrauterine Contraception: Advances and FutureProspects, G. I. Zatuchni, et al. Editors, Harper and Row, Philadelphia, Pa., 1984, pages 218 and 219. In one such in vitro method, for example, the second composition formulation containing growth promoters of formula 1 and 4, in the form of a coatedpellet was added to an aqueous solution of a dissolution medium of sodium dodecyl sulfate (5 wt. %) and incubated at 37° C. Samples of the dissolution medium were removed periodically and analyzed by high performance liquid chromatography for thepresence of the growth promoters. The first composition of the present extended release composition is formulated by processes comprising operations conventional in the pharmaceutical arts. In a typical process, a mixture of growth promoters and excipients if any, namely, abinder and an adhesive, are combined in a high shear mixer, and the mixture is wetted with a granulated solution. The granulation is then screened, dried, a lubricant is added, and tableted into pellets. The second composition of the extended release composition is formulated by mixing the growth promoters, excipients, if any, such as a binder and an adhesive, and a solution of a biodegradable polymer, evaporating the solution, screening anddrying the granulate, adding a lubricant, and tableting the granulate. The tablets, so obtained, containing the biodegradable polymer in the core, are then coated with a solution of a biodegradable polymer to provide the coated delayed release pellets. In practice, as detailed in the examples, a solution of a biodegradable polymer e.g. a polylactide, preferably a copolymer of DL-lactide and glycolide, characterized by its inherent viscosity, and having a ratio of lactide units to glycolideunits, preferably in the range of from about 50:50 to 90:10, most preferably in the range from about 60:40 to about 75:25, is added to a granulation of growth promoters, such as, for example, 17β-acetoxyestra-4,9,11-trien-3-one, andestra-1,3,5(10)-trien-3,17β-diol, an adhesive, preferably, cholesterol, a binder, preferably, ethylcellulose, in a planetary mixer, and the solvent is evaporated. The dried granules are mixed with a lubricant, preferably magnesium stearate, thentableted with a press optimally equipped with tools having a beveled edge, the fill weight being from about 25 mg to about 50 mg, a fill weight of about 33 mg being preferred, to provide core tablets. A solution of a biodegradable polymer, preferably acopolymer having a ratio of DL-lactide to glycolide units of about 50:50 to about 90:10, most preferably in the range of from about 60:40 to about 75:25 in an organic solvent such as acetone is sprayed onto the core tablets in an air suspensioncoater-drier to provide delayed release pellets having the desired release rate properties. The pellets of the first composition granulation, the uncoated sustained release pellets containing growth promoters and excipients, if any, and the second composition granulation, the delayed release pellets, containing growth promoters, abiodegradable polymer, preferably a polylactide and excipients, if any, coated with a biodegradable polymer, preferably a polylactide, are administered to food animals in the feedlot to afford extended release of the growth promoters over the feedlotperiod. The extended release of the growth promoters is a composite of the sustained release and delayed release characteristics of the uncoated first and coated second compositions, respectively. The rate of release of the sustained release firstcomposition initially increases, reaches a maximum and then rapidly decreases. The release of the growth promoters from the coated delayed release formulation is initially delayed over the period that the sustained release formulation releases thegrowth promoters and until the release reaches the maximum and begins to decline. At about that point in time, the coated formulation, without a burst release of promoters, releases the promoters to provide a composite release of the promoters over theextended period the food animal is in the feedlot. The composite rate of release of the growth promoters of the composition of the present invention is determined by the release rates of the first, the sustained, and the second, the delayedformulations. The sustained, first composition releases the growth promoters upon administration into the food animal. The rate of release of promoters increases sharply, reaches a maximum and then declines. The release of the growth promoters of thesecond composition is delayed from the time of administration. By adjusting the time at which the second composition release the growth promoters, the composite release is extended over time, the time the food animal is in the feedlot. For example, byadjusting the initial release of the growth promoters of the first composition so that it is sustained over from about 1 day to about 70 days after administration, and the initial release of the second composition so that it is delayed for about 60 daysto about 70 days after administration, a composite release extended over about 1 day to about 180 days after administration may be obtained. An extended release of about 200 days after administering the feedlot period for bovines, is attainable byappropriate adjustment of the release characteristics of the sustained and delayed compositions, the uncoated and coated compositions of the growth promoters. The growth promoting compositions of the present invention are administered to food animals by one of various methods known in the art. Generally, the growth promoting compositions are administered parenterally, typically, subcutaneously aspellets to an inedible member of the animal, by means of a syringe (of sufficient size to accommodate the pellets) or a conventional implant gun, the cartridge thereof being loaded with the pellets containing the sustained and delayed compositions. Administration of the pellets of the growth promoting first and second compositions by simultaneous implantation from the cartridge gun is preferred. The pellets of the first and second growth promoting compositions may be prepared in various shapes. For implantation by means of an implantation gun, a cylindrical shape is preferred. The length of the cylindrical pellet may vary from about 3mm to about 6 mm, a length of about 4 mm to about 5 mm being more preferred, a length of about 4.3 mm being most preferred. The diameter of the pellet may vary from about 2 mm to about 4 mm, a diameter of about 2.5 mm to about 3.5 mm also being morepreferred. Optionally, the cylindrical pellets may have a beveled edge. The pellets, preferably cylindrical in shape, as defined above, may contain various amounts of growth promoters and coating levels. For example, the pellets may contain about 16 mg to 24 mg of 17β-acetoxyestra-4,9,11-trien-3-one, preferablyabout 19 to 21 mg of 17β-acetoxyestra-4,9,11-trien-3-one, more preferably about 20 mg of 17β-acetoxyestra-4,9,11-trien-3-one, and about 2.0 mg to about 6.0 mg of estra-1,3,5(10)-trien-3,17β-diol, preferably about 3.0 mg to about 5.0 mg ofestra-1,3,5(10)-trien-3,17β-diol, more preferably either about 2.0 or 4.0 mg of estra-1,3,5(10)-trien-3,17β-diol. Suitable coating levels of DL-lactide-glycolide include on a weight basis about 13 weight percent to about 25 weight percent ofthe level of 17β-acetoxyestra-4,9,11-trien-3-one and about 11.5 weight percent to about 23.0 weight percent of the level of estra-1,3,5(10)-trien-3,17β-diol. The pellets, preferably cylindrical in shape, as defined above, may contain various amounts of growth promoters and coating levels. Typically, for example, the pellets may contain about 13 to about 25 weight percent of17β-acetoxyestra-4,9,11-trien-3-one and about 11.5 to 23.0 weight percent of estra-1,3,5(10)-trien-3,17β-diol. The desired growth promotion is achieved when the present composition comprising an uncoated composition of growth promoters, the first composition, and a coated composition of growth promoters, the second composition, are administeredsimultaneously to a food animal at a dose of about 0.75 mg/day/animal to about 1.2 mg/day/animal, a dose of about 0.95 mg/day/animal being preferred to attain the desired weight gain for the period the animal is in the feedlot. These doses are attainedwhen about 8 to about 10 pellets of each composition are administered to the food animal. The dose level defined above is for the administration of the growth promoters of the composition comprising the first and second compositions of growth promoters to bovines, namely, cows, steers, heifers and calves. For administration to otherfarm animals, the doses are adjusted accordingly. While the first and second compositions may comprise different growth promoters, i.e. different combinations of the hereinbefore defined compounds and dose levels, it is preferred to administer pelletsof the first and second composition comprising the same growth promoters and the same dose levels as determined by the amount of promoters in each pellet and the number of pellets to be administered. As hereinbefore described the release rates of the growth promoters from the first (uncoated) and second (coated) compositions of the present invention are determined by methods known in the art. In one such determination of release rates(dissolution rates), in vitro, individual pellets of growth promoters 17β-acetoxyestra-4,9,11-trien-3-one and estra-1,3,5(10)-trien-3,17β-diol, uncoated and coated with 75:25-DL-lactide-glycolide copolymer were added to 50 ml of aqueous sodiumdodecyl sulfate (5 wt. %) and incubated at 37° C., without agitation. Periodically, samples of the dissolution medium were collected, and the concentration of the growth promoters in the dissolution medium was determined by high performanceliquid chromatography. The cummulative release rates of pellets of uncoated 17β-acetoxyestra-4,9,11-trien-3-one and 17β-acetoxyestra-4,9,11-trien-3-one coated with 10.8 wt. % of 75:25 DL-lactide-glycolide polymer (DL-PLG) is shown in Table 1. TABLE-US-00001 TABLE 1 % Released Cores Coated % Released Cores Coated Elapsed % Released with 75:25 with 75:25 Time Uncoated DL-PLG DL-PLG days Core 10.8 wt. % Coating 19.8 wt. % Coating 1 11.58 0.00 0.00 3 28.20 0.00 0.00 4 36.64 0.00 0.00 855.45 0.00 0.00 9 58.70 0.01 0.00 14 72.72 0.04 0.00 21 87.35 0.04 ND 28 96.73 ND 0.00 35 99.80 0.12 0.00 43 0.85 0.04 50 5.04 0.94 57 25.41 3.42 64 42.01 10.84 71 53.07 ND ND--Not determined DL-PLG refers to the copolymer of DL-lactide-glycolide The following examples are for illustrative purposes only and are not to be construed as limiting the inventor. EXAMPLE 1 Granulation of a Composition of 17β-acetoxyestra-4,9,11-trien-3-one and Estra-1,3,5(10)-trien-3,17β-diol with 75:25-DL-lactide-glycolide Copolymer A solution of 52.6 g of 75:25 DL-lactide-glycolide copolymer (Inherent viscosity of 0.67 dL/g in chloroform at 30° C.) in 5210.5 g of acetone was slowly added to a granulation of 1000 g of a mixture of 17β-acetoxy-4,9,11-trien-3-oneand estra-1,3,5(10)-trien-3,17β-diol, also containing chloesterol, ehethytylcellulose and magnesium stearate, and was granulated in a 4-L planetary mixer at a slow speed, until the acetone had evaporated. The granulate was ground in a Thomas-WileyIntermediate Laboratory Mill equipped with a 20 mesh screen and then passed through a sieve to afford a dry granulation of about 60 mesh. The composition of the dry, sieved granulation is shown below, the amounts are in wt. %. TABLE-US-00002 17β-acetoxy-4,9,11-trien-3-one 59.3 1,3,5(10)-estra-3,17β-diol 11.9 Cholesterol 18.6 Ethyl cellulose 3.7 Magnesium Stearate 1.5 75:25 DL-lactide-glycolide copolymer 5.0 EXAMPLE 2 Tableting of 17β-acetoxyestra-4,9,11-trien-3-one, Estra-1,3,5(10)-trien-3,17β-diol, and 65:25-DL-lactide-glycolide Copolymer Granulation The dried, sieved granulation of Example 1 was tableted on a Stokes-Merrill 900-512-001 Rotary Tablet Press equipped with 3-mm diameter flat-face tooling having a 30°×0.2 mm beveled edge. Fill weight was adjusted to provide pelletswith an average weight of about 33 mg, and the compression force was adjusted to provide pellets with an average hardness of about 70 N. After tableting, the length, diameter, and hardness of the tablets were determined on a Vankel VK-200 Tablet HardnessTester. The amounts of 17β-acetoxyestra-4,9,11-trien-3-one and estra-1,3,5(10)-trien-3,17β-diol of the tablets were determined by extracting individual pellets with ethanol and analyzing the extracts by high performance liquid chromatography. The data are shown in Table 2. EXAMPLE 3 Coating of the Tablets of 17β-acetoxyestra-4,9,11-trien-3-one and Estra-1,3,5(10)-trien-3,17β-diol with 65:25-DL-lactide-glycolide Copolymer Tablets (40 g as prepared in example 2) and placebo tablets prepared from Avicel PH-101 were charged into the coating chamber of 4/6-in. fluid bed coater (Coating Place, Inc., Verona, Wis.) equipped with a Wurster insert. The tablets were coatedwith 1.0 wt. % of DL-Lactide-glycolide acid copolymer in acetone solution using the following coating conditions: fluidization air--25-35 SCFM; atomization air--14 psig, 35 SCFH; liquid feed--0.8 mL/min; inlet air temperature--100-107° F.; outletair temperature--90° F. Coating level was monitored by periodically interrupting the coating process, removing a sample, and measuring weight gain. Samples of coated pellets were removed for testing when the coating level reached approximately10 wt. % and 20 wt. % of the copolymer. The harness, 17β-acetoxyestra-4,9,11-trien-3-one content and estra-1,3,5(10)-trien-3,17β-diol content of the coated pellets was measured as described above. Coating level was calculated from the changein the percent content of the growth promoters and pellet weight. The data are shown in Table 2. EXAMPLE 4 Coating of the Tablets of 17β-acetoxyestra-4,9,11-trien-3-one and 1,3,5(10)-trien-3,17β-diol, with 75:25-DL-lacticide-glycolide Acid Copolymer Tablets (40 g prepared in example 2 and 70 g of placebo tablets prepared from Avicel PH-101) were charged into the coating chamber of 4/6-in. fluid bed coater (Coating Place, Inc., Verona, Wis.) equipped with a Wurster insert. The tablets werecoated with a 1.0 wt. % 75:25 DL-lactide-glycolide copolymer in acetone solution using the same coating conditions as described in Example 3. Coating level was monitored by periodically interrupting the coating process, removing a sample, and measuringweight gain. Samples of the coated pellets were removed for testing when the coating level has reached approximately 10 wt. % and 20 wt. %. The hardness, 17β-acetoxyestra-4,9,11-trien-3-one content and 1,3,5(10)-estratrien-3,17β-diol contentof the coated pellets was measured as described above. Coating level was calculated from the change in the percent content of the actives and pellet weight. The data are shown in Table 2. TABLE-US-00003 TABLE 2 Properties of TBA and E2 Uncoated Pellets and Pellets Coated with Lactide-Glycolide 65:35 65:35 75:25 75:25 Uncoated DL-lactide-glycolide DL-lactide-glycolide DL-lactide-glycolide D- L-lactide-glycolide Property Pelletscopolymer coating copolymer coating copolymer coating copolymer coating Nominal Coating wt. 10% 20% 10% 20% Pellet Wt, mg 31.2 35.3 40.2 35.5 39.9 Pellet Length, mm 3.96 4.22 4.35 4.17 4.26 Pellet Diameter, mm 2.97 3.09 3.24 3.12 3.23 Harness, N 69.0120.3 163.4 116.6 156.1 TBA Content, mg 17.2 16.9 17.4 16.7 16.8 TBA Content, wt % 56.0 48.3 43.2 48.8 42.5 E2 Content, mg 3.54 3.54 3.63 3.46 3.51 E2 Content, wt % 11.5 10.1 9.0 10.1 8.9 TBA/E Ratio 4.86 4.77 4.79 4.83 4.79 Coating Level (TBA NA 13.722.8 12.8 24.3 basis), wt % Coating Level (E2 NA 12.2 21.7 12.2 22.6 basis), wt % Coating Level (Wt NA 11.6 22.4 12.1 21.8 basis) wt % Pellet weight, n = 50; Length, diameter, and hardness, n = 10; TBA and E2 contents, n = 5. Weight percentage of TBAand E2 were calculated from the individual pellet weights used in the content assay. TBA refers to 17β-acetoxyestra-4,9,11-trien-3-one E2 refers to estra-1,3,5(10)-trien-3,17β-diol * * * * * Other References
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