TWI250027B - Improved growth stimulant compositions - Google Patents

Abstract

An improved weight and growth stimulant for domesticated animals such as cattle, pigs and sheep is comprised of an anabolic agent that is subcutaneously administered in the form of a dual release implant formulation. Increased gains are particularly improved when zeranol is administered in an immediate-release and controlled-release formulation which allows for a one-time dosage injection.

Description

1250027 Field of the Invention The present invention relates generally to veterinary medicinal compositions and & amps which control the release of active compounds to animals. More particularly, the present invention discloses a dual formulation; a sputum that stimulates growth and weight gain σ of livestock. BACKGROUND OF THE INVENTION Recent advances in veterinary science and veterinary § pharmacology have resulted in the growth and development of larger, healthier and heavier cattle, pigs, sheep and horses. In particular, with regard to cattle, sheep and herds, the need to feed the world's population through the production of meat provides the impetus to raise livestock as quickly and as large as possible.

Anabolic agents are widely used to promote the growth of cattle and other livestock, and stimulated growth promotion is desirable for cattle farmers because it increases the rate of weight gain and the average amount of weight gain of the average amount of food consumed (called Feeding efficiency is the biggest. Typically, the steroid is supplied to the animal as a biodegradable or non-biodegradable, transplantable tablet over time, which is injected into the skin using a graft device. It has proven to be successful; however, animals may have to be transplanted 2-4 times during their growth.

The grafting device for subcutaneous delivery of these steroid pellets includes a handle-shaped outer casing having a handle, a hollow needle on the front side of the outer casing for injecting the pill into the animal, and a pusher. The push rod can be slid into the needle and supported in the housing for longitudinal discharge. A chamber is provided in the housing and the needle is connected. The pill-containing kit is inserted and can be discharged therein. The longitudinally retractable back pressure device (needle retractor) is placed in the outer casing in parallel with the push rod and the hollow needle in the outer casing. The push rod and the back pressure device are moved by a drive mechanism, which is similarly provided in the housing and which is operated by a lever fastened to the handle (board machine)

Page 5. 1250027 V. Inventions and actions. Thus, the arcuate gear segment of the coupling lever and the gear returning device and the gear of the push rod are coupled to the driving mechanism and the back pressure device. This device is described, for example, in U.S. Patent 5,5 1 4,1 0 1 . Protein anabolic hormone (Formula I, C A S registration number: 2 6 5 3 8 - 4 4 - 3 ) is a synthetic generation that shows significant results in the promotion of bovine weight gain and growth.

Formula I herbicide. Protein anabolic hormone, a resorcinol lactone derivative, has been shown to have a positive effect on dynamic protein metabolism. However, in the growth and development of cattle, for the most appropriate results, the formulation of protein-containing anabolic hormones or other such anabolic agents must be administered at least twice during the growth and development period of 170 days. Obviously, this necessity brings the cattle back from the grasslands, injects the grafts and delivers them again, which is a laborious and time consuming procedure. It has been determined that protein anabolic hormones and other anabolic enzymes provide optimal growth and weight gain results in early and throughout the growth cycle of the animal. It requires an immediate release/sustained release dual formulation that is still not possible to date.

US Patent 5, 643, 595 to Lew is disclosed and filed for use in livestock

Il

I

III * 1250027 V. INSTRUCTIONS (3) The long-term degrading agent for the degradation of the polymerized anabolic hormone, the continuous degradable polymeric polyanhydride of the polymer, and also the method of the Lewi, which is reported to be the following during the delivery of the system. Lewis ^ 3 applies for a useful activity in promoting steroids containing biodegradable microparticles. The vitamin deficiency of the class and animal is the use of a new packaged hormone to make a transplanted Hudson system, including steroids. Bio-matrix and antibiotics for growth promoters. The steroid growth promoter may comprise a protein which is formulated in a homopolymer or co-release microparticle comprising lactic acid and/or acetic acid. Other organisms used in this sustained release formulation include polycaprolactone, polydiethylenediazine di-, poly-orthoester, cocoon and mixtures thereof. U.S. Patent No. 5,4 2,7,9,6, discloses a growth-enhancing steroid comprising a biodegradable microbe, such as a protein anabolic hormone, which is released in a variety of ways. The drug holds ‘up to 200 days. The same polymer is used for L e ~ other patents. <<>> Patent 5, 419, 910 and 5, 2 88, 49 6 also discloses a sustained release delivery system for microparticles of animal growth. Material '1 and depolymerization matrix, such as poly-d, 1-lactic acid, polyglycolate. The package contains a steroid growth promoter and an antibiotic. Its / protein anabolic hormones are revealed to increase the total weight and: /, : National Patent 4, 874, 6 1 2 reveals a multi-component JIANG ant 2 for continuous release, long-term delivery: agent pair, hormone replacement therapy, cancer treatment, salty: nine #, to biodegradable Polymers such as =: Metabolism steroids and their conjugated animal growth promoting ΐ: substrates comprising lactic acid and/or hexanoic acid copolymers, disclosed in U.S. Patent 4,191,74, the disclosure of which is incorporated herein by reference.

1250027 V. INSTRUCTIONS (4) Metabolic agents can be revealed individually or in groups as in fact, the length of the actives is as 'see US 4, 542, 0 2 5; unfortunately, the primes are assimilated in the egg day. Apply two to four. The present invention is larger than other types of weight gain. S own party's provide for the purpose of applying drugs. plant. The stimulating, alcohol and its known 4, 6 75, , 33 0 〇 proteinogenic growth period is the long-term sustained release of the most advanced animal transfer drug, one of which is estradiol. The protein is one of these reagents. The use of biodegradable granules in the metabolic solidification period is continuously used in this technique. National patents 4, 683, 288; 4, 677, 191; '4, 530, 840; 4, 489, 055 and 4, 389 are not all the growth of the prior art delivery system. The most probable weight gain and other anabolic agents in one of the animals, providing a one-time application only to provide an anabolic metabolic formulation, 乂: alcohol treatment of the animal and no increase A further object of the invention is to provide a synthetic #, which is only given once in the growth period of the material, and is still applied to the immediate growth and weight increase of the drug in the whole period of time, and the purpose of the invention is State treatment, the larger of the beans, the metabolic transfer formula to transplant the increased stimulation of cattle: 丄 and larger feeding efficiency. The present invention immediately releases g = material (or commonly referred to as a graft), which is formulated to contain an anabolic agent, and (a) a steroid - not a particular pharmacy. Example 189; Assimilation of the drug. It must be used for the long-term growth of the long-term growth and the growth of the X-ray, a long-term rate, containing the opposite of the [i) system 1250027 V. Inventive Note (5) formula containing anabolic agents and controlled release agents, complex Heart and Controlled Release Formulations Synergize Growth and Weight Increase 2 Immediate Release Formulations Release Formulations and Controlled Release Formulations provide the same irritation to the animal. Apply the drug quickly and continuously after the other, regardless of whether it is applied or not. Applicants have found that the double formulation is much higher than the growth and weight gain port when the formulation is only transplanted (1) or (1). The present invention further discloses a method of preparing a dual formulation, a anabolic graft composition comprising a dual formulation, and a method of using the composition to stimulate growth and weight gain in an animal. Detailed Description of the Month February In a specific embodiment, the present invention discloses a growth rate, a large growth amount, and a large silver food efficiency for an animal, sometimes referred to as a cow in the present case. The method. The method comprises administering an anabolic composition, which is a dual formulation comprising: (i) an immediate release formulation comprising an anabolic agent, and (丨丨) a controlled release formulation comprising an anabolic agent With a controlled release agent. Immediate release formulation and controlled release formulation pair = synergistic growth and weight gain required stimulation. Even if the double formula can be applied as a single composition by applying two or more (1) and (丨丨) at the same time as a single administration (injection) device, or applying a formula one time at a time, regardless of the applicator Pseudo-la-la-a----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- The present invention relates to a method for stimulating an increased growth rate of a food animal, a larger growth amount and a larger feeding rate, which comprises

Page 9.

1250027 V. INSTRUCTIONS (6) For the treatment of ingots. The biodegradable and non-biodegradable compressed medicaments of the present invention are as advantageous as the advantages of the methods known in the art, particularly for transplant systems, mixed: 'no" with $: degradable and non-living The ability to degrade the system's release rate (multiple enthalpy. The ability of the table for the ingot (pill)), and the ability to design the noon (the phasic release). In a preferred embodiment, the application of the animal is by Growth promotion; = the side of the agent ... the way to synthesize the activity in the synthesis: and:: the weight of the desired compression shape (for example, the activity of the drug controlled release agent synthesis synthesis generation 4: shot: the next: other medicine ingot t There are two upper ones, as described in the following examples. Therefore, the others are used as immediate release formulations and the latter as control (four) release formulations. The anabolic agents used in the two formulations may be the same or different. Suitable for growth in the present invention. Descriptive anabolic agents for enhancers include protein anabolic hormones, estradiol and its derivatives, such as, for example, estradiol benzoic acid vinegar, norazandolone acetate (All, CAS registration number: 1016b 34 —9, which is from Pharmacia & Upjohn Company, Kalamaz〇〇, Michigan), growth hormone and its derivatives, testosterone and its derivatives, for example, such as testosterone propionate, norepinephrine, progesterone, derivatives thereof and combinations thereof.

1250027 V. Description of invention (7) Η

〇 Immediately prepare a small amount of the agent, which is shaped as a diluent, such as commercially available, such as starch. In the control of the normal control release compatibility. The polymer is accumulated in the body. The anabolic agent may be used alone or, as appropriate, in the formulation for the release of the matrix substance, for example, a diluent, a tableting agent or the like suitable for insertion into the skin. Some examples of such materials include lactose, stearic acid as a lubricant, Shi Xishi as a slip agent, and the like. Example Ra 1 gro® is available in lactose. Other diluents, mannitol, glucose alcohol, sucrose, dextrin, starch, hydrolyzed release formulations (also referred to herein as sustained release formulations), are polymeric matrices. The polymer matrix material must be defined as bio-noun biocompatibility as non-toxic to animals and not carcinogenic. Since the matrix material is biodegradable, the polymer matrix degrades into a product that is easily disposed of by the body, and should not remain in the animal as a biocompatible and indefinitely in the case where the matrix is non-biodegradable. Inside. Suitable examples of the polymerization used in the present invention include poly(D,L-lactide-co-glycolide) copolymerization.

Page 11 1250027 V. Description of invention (8) Methylcellulose... 2: C = nanocellulose. As with immediate release; moderate: base and polymer matrix materials can be considered as appropriate. - the substance of this substance, the excipient, the tableting agent as a moisturizing agent; the agent: sugar as a diluent, magnesium stearate, ethyl cellulose, a private plant is usually in the shape of a cylindrical tablet. The tablet usually has a diameter of about 2. 笔 pen to 6 · 〇 mm and a length of about 丨·〇 mm to about 4 · 〇 mm.

The grafting agent for controlled release is usually prepared by a step in which the active anabolic agent is mixed with other selected materials to form a poly(D,L-lactide-co-bf) copolymer or ethylcellulose, and then It is known in the art to compress in the mold of a tablet press. Suitable descriptive steps for making such biodegradable polymers and implants with non-biodegradable polymers are described below in this case.

The release rate of the anabolic agent in the controlled release formulation can be controlled in a number of ways. With regard to the poly(D,L-lactide-co-glycolide) eupolymer, the degradation rate of the carrier matrix can be increased by reducing the size of the polymer chain and the molecular weight inevitably. Increasing the amount of active anabolic agent, which inevitably reduces the weight ratio of the active copolymer, increases the rate of release. The addition of additional plasticizers and other excipients can even accelerate degradation and release. Such modifications are readily apparent to those skilled in the art. The preparation of a graft comprising a biodegradable polymer (e.g., a poly(D,L-lactide-co-glycolide) copolymer) can utilize any method known in the art.

Page 12 1250027 丨5, invention description (9) ! I is completed. A descriptive step is as follows. Preferably, the anabolic active compound I is first dissolved in a suitable solvent which also dissolves, emulsifies or disperses the poly(D,L-lactide-co-glycolide) copolymer. Suitable dissolutions include organic solvents such as acetone, oxime, dioxins, other aromatic hydrocarbons, cyclic ethers, esters, alcohols, and the like, and mixtures thereof. The polymeric matrix material is also dissolved or dispersed in the solvent, and the resulting emulsion or solution can be mixed into a continuous phase. Surfactants can be added to the solution to prevent cohesion. The solvent is then removed, which is usually applied by heat, low pressure applications or both. The temperature used is not critical, but should not be too high to produce degradation of the active compound or the transplanted biodegradable matrix material. Once the solvent is removed, the solid dose graft can then be prepared using a standard ingot molding machine known in the art. Preferably, the anabolic agent used in the formulation of the present invention is a protein assimilating i. A commercially available formula for protein anabolic hormones is Ralgro® (from |

Schering-Plough, Terre Haute, Indiana, another | contains some lactose. The protein anabolic hormone content in the present formulation is from about 50% by weight to 95% by weight, preferably about 55% by weight, based on the total weight of the transplanted composition (including the immediate release portion and the controlled release portion). About 85% by weight and most preferably 丨 is in an amount of from about 60% by weight to about 80% by weight. : I poly(D,L-lactide-co-glycolide) copolymer in an amount ranging from about 1.0% by weight; from 1 to about 10% by weight and preferably from 1.0% by weight to about 5:0% by weight Add 丨 to continuously release the formula. 0重量重量至至0. 0重量百分比和更更优选。 If the use of ethyl cellulose instead of poly (D, L-lactide-co-glycolide) copolymer as a reagent, a larger amount can be used, such as about 1.0% by weight to 8. 0% by weight and 0重量%。 Preferably, it is about 2.0% by weight to about 7. 0% by weight.

Page 13 1250027 V. INSTRUCTIONS (10) Other optional substances may be added depending on the length of drug delivery required, but most of them are added in standard amounts known in the art. For example, the diluent or excipient may be present in an amount of from about 20% to about 40% by weight, preferably from about 25% to about 40% by weight, and typically from about 25% to about 3% by weight. Measure your mouth. The food 'drug and make-up (|, FD & C)) may be added to the formulation in an amount of from 1% by weight to 2.0% by weight, such as a coloring pigment, and is known in the art. Containing a non-biodegradable polymer (for example, Grafts such as ethylcellulose can be prepared by procedures known in the art. A descriptive step is as follows: an anabolic agent such as a protein anabolic hormone is mixed with a diluent in a revolving mixer, such as, for example, lactose, as appropriate And suitable dyes. In separate mixers =, commercially available from Aquacoat ECD-30® (available from FMC, Philadelphia, Pennsylvania), an aqueous dispersion of ethylcellulose suitable for plastics, such as human ^ ^ ^ or dibutyl phthalate, etc. Plasticized ethyl cellulose and then blending degree y jin ° 丨 丨 1 / sugar mixed and granulated. The granules in the temperature of about 5 〇 ° C to 70 ° 〇 6 weight The mineral-to-recipe formulation is characterized by a total weight of from about 0. 2% by weight to about the total weight of the formulation. The dried granules are then sieved through a sieve, for example, magnesium oleate, &::3, etc. Lubricant, such as hard and then compressed into; ♦:; for example, such as dioxane矽,Lubrication; granules are not sputum, pounds and the size and hardness of the pill. Distributed in:: cis limit, it is believed that the pseudo-latex ethyl cellulose is evenly metabolized with the agent: Ϊ. The matrix particles are finely blended together to form a toughness. The compression in the tablet mold further fuses the component to a heating or curing step as a weight because it appears to melt or coalesce the ethyl 1250027 I. Cellulose particles form a true matrix structure around the active. This causes the active anabolic/excipient blend to be completely captured by the ethylcellulose chain: catch. For immediate release formulations, use as commercially available A composition of the protein anabolic hormone product, for example, Ralgro®, is compressed and compressed into a suitable size ingot. Any optional ingredient, such as, for example, a dye, can be mixed before being compressed into a tablet.

The dual formulation of the present invention is prepared by placing a specific amount in an injection device; a tablet containing a controlled release formulation and a specific amount of the immediate release formulation (including Ralgro®, which is a protein anabolic hormone plus) Preparation of lactose ingots! The amount of each type is determined based on the amount of protein assimilating the protein that is desired to be injected into the animal. For comparison purposes, dual-injection injections can be compared and controlled! Formulation tablets alone or protein anabolic hormone tablets are injected separately, so that the total amount of protein 1 anabolic hormone remains to be combined with the total protein assimilation factor of the dual formulation of the present invention. Growth-enhancing graft pills are usually injected subcutaneously into the ear or other livestock. After application, the water diffuses from the tissue of the animal into the drug bond and is driven by the hydration of the lactose i and the low degree of hydration by the anabolic agent. The dissolved activity is then diffused from the matrix structure into the systemic circulation of the animal. As evidenced by the examples, Applicants have found that the dual-prepared tablet of the present invention surprisingly produces a higher growth and weight gain in the test animals than in the controlled release tablet alone or in the protein anabolic hormone tablet alone. Another specific embodiment of the present invention reveals an anabolic metabolic composition and formulation for increasing the rate of growth of bovine stimuli, greater growth, and greater foraging efficiency. The composition of the present invention is a double release formulation, which is packaged

Page 15 1250027 i V. INSTRUCTIONS (12) Contains: (i) an immediate release formulation containing an anabolic agent, and (11) a controlled release formulation containing an anabolic agent and a controlled release agent Neutral

I! The release formulation and the controlled release formulation work together to grow and gain weight. The types and examples of (i) or (li) are described above.

A further embodiment of the present invention discloses a method for increasing growth rate, larger growth, and greater feeding efficiency for cattle that require improved growth, weight gain and feeding efficiency, by means of the cattle An anabolic transfer composition is applied as a dual release formulation comprising: (i) an immediate release formulation comprising an anabolic agent, and (ii) a controlled release formulation comprising an anabolic agent and controlled release Agents, wherein the immediate release formulation and the controlled release formulation synergistically perform the desired stimulation for growth and weight gain. The types and examples of (i) and (i i ) are described above. A further embodiment of the invention relates to a method for stimulating increased growth rate, greater growth, and greater feeding efficiency in an animal, the method comprising: preparing an immediate release formulation comprising an anabolic agent, for example | For example, a reagent as described above, which is a shaped object suitable for being loaded in a device,

For example, such as pills, tablets, etc., the device is suitable for applying the shaped object to an animal (for example, as described above); preparing a controlled release formulation containing anabolic agents and controlling a release agent which is a shaped object similar to the above and suitable for loading in a device in step (a), wherein the I anabolic agent of step (a) and the anabolic agent of step (b) may be the same or The shaped object of step (a) and the shaped object of step (b) are such that the total synthetic guanidine metabolizing agent is based on the combined weight of the two formulations (ie, the formulation of step (a) and the formulation of step (b)) Loaded in a ratio of 50 to 9.5 weight percent

Page 16 1250027 V. INSTRUCTION DESCRIPTION (13); and applying the shaped body to the animal, wherein the immediate release formulation and the controlled release formulation cooperate to effect the desired stimulation. Suitable controlled release agents and methods of making the formulations are described above. The following examples are provided to more fully describe how to make and use the grafts of the present invention, and to demonstrate superior results. However, it should be noted that the examples are for illustrative purposes only, and that minor variations or variations in amounts and/or methods are not contemplated. It should also be noted that the extent of any such change or variation that does not substantially alter the effect of the composition or the final product is considered to be within the spirit and scope of the invention as set forth in the appended claims. EXAMPLES Example 1: Comparison of weight gain of protein-containing anabolic hormones as controlled release formulations with protein anabolic hormones as immediate release formulations: The following protein anabolic hormone matrix-based formulations were prepared to compare controlled release formulations containing protein anabolic hormones with R a 1 gr ο® and placebo (an ineffective control). As mentioned previously, Ralgrd® is a commercially available product of protein anabolic hormones and lactose. § 卞 Composition A controlled release formulation: protein anabolic hormone / poly (D, L-lactide-co-glycolide) copolymer; 50: 50% by weight) (all protein anabolic hormone 1 800 mg) B control Release formula: protein anabolic hormone / ethyl cellulose (50 · · 50% by weight) (all protein anabolic hormone 180 mg) C Ralgrc@ (all protein anabolic hormone 36 mg) D placebo: no protein anabolic hormone .

Page 17 1250027 V. INSTRUCTIONS (14) Grafts were prepared as follows. For Formulation A, poly(D,L-lactide-co-b-6g曰5〇·5ϋ 3·991 g) was placed in an Erlenmeyer flask and dissolved in gram of acetic acid B vinegar Lactose (26.06 g) was dried and mixed in a mortar, and FD&C coloring dye (〇·44 g) was added thereto. It contained L-milk parent 9 S-co-glycolide and The solvent of ethyl acetate is then added to the protein, the wood/lactose mixture, and the composition is then heated to 4 Torr - it is dried and granulated and sieved through a 25 mesh screen. Add Cab - 〇 - Si ι@矽= 'Shift J (〇· 6 6 5g) and magnesium stearate (U 3 , added as a lubricant, and then compressed in the ingot mold to have 12-20 Strong Co= Early = solid graft (26. 6 〇 6 mg of each graft). Formula 6 was prepared by using similar ethyl cellulose as the polymer matrix and "Uac〇at migration with this technique." For Formulation C, Ralgro® will be prepared as a drug ingot without a protein anabolic hormone. For a dozen (2 〇) head yak, and 卞 + ground is lighter; π α dry under the ear subcutaneous In order to be appropriate = = = : with the skill of the cockroach, formula c is applied twice, in the first. 素. Each small steer cattle in their developmental dose: 36 mg of protein assimilation of the various stages of the calculation of the specific allocation: 1 Weighed during the time period, and the average weights of each group from 10,000 A to D are as follows:

1250027 V. INSTRUCTIONS (15) Table 1 Days of treatment Days Days Days Days Days Days Days Days Days 28 28 56 70 84 112 140 168 182 A 339 423 483 544 562 616 693 765 803 B 337 426 492 558 568 631 701 780 806 C 339 431 506 562 578 644 716 812 838 D 342 420 473 531 536 593 645 709 742 The results show that the weight gain increase using the controlled release formulation (A or B) is slightly lower, or the extraction is statistically equal to the R of Formula C a 1 gr 9 re-transplant design 〇 Example 2 • The double-formulation of the present invention increases the weight gain relative to the immediate formulation alone, or controls the individual weight gain of the formula: Studying the double immediate release/controlled release pellet of the present invention, And compare the effects of protein anabolic hormones (such as Ralgro®) alone, controlled release formulations alone and ineffective placebo controls on body weight and growth. This can be accomplished by replacing the specific controlled release pellet of Example 1 with a Ralgrc^δ tablet. The dosage of the application is as follows. 0 The total weight of the application is shown in brackets 〇

Formulation Composition E Placebo: no protein anabolic hormone. F Ralgro® (protein anabolic hormone 36 mg; 3 12 mg each).

Page 19 I-1250027 V. INSTRUCTIONS (16) G protein anabolic hormone immediate release (1 18 mg protein peptide) + protein anabolic hormone controlled release - poly (〇2 lacto-co-glycolide) ) (protein anabolic hormone 8 〇 milli'· ^ 20 mg each pill) [all protein anabolic hormone 98 true Η protein anabolic hormone immediate release (丨 丨 8 mg protein peptide) + protein anabolic hormone controlled release / poly (D 2 lactolacide _ co-glycolide) (protein anabolic hormone 160 milligrams · a 0 203⁄4 grams of protein anabolic hormone pills) [all hormones 178 mg]. Protein is immediately released from the protein anabolic hormone (丨8丨 protein,

J 素 丸) + protein anabolic hormone controlled release / B = stimulating hormone (protein anabolic hormone 16 〇 mg; 8 each 2 〇 body, quasi-assimilating hormone) [all protein anabolic hormone 丨 7 8 mg]. Immediate release of albumin anabolic hormone (one 丨8 mg protein peptide) + protein anabolic hormone controlled release / meimei 2 (protein anabolic hormone 80 mg; 4 each 2 〇 mg ^, white, bucket of hormone pills) ) [All protein anabolic hormone 9 8 mg] δ ί ::- In order to prepare the double formula 本 of the present invention and 1, a protein assimilation in the pill; 8 protein anabolic hormone controlled release pills are placed in the clothing ΐ 二阳 J Controlled release of the formula half of the amount of a protein anabolic hormone immediately deleted control pills placed in the device. Prepare the immediate release of the pill as in Example 1.

Page 20 1250027 V. INSTRUCTIONS (17) — --- Controlling the release of the pill and applying the same method to the 6 groups of cattle, ie, in the ear skin:: "Fitting the sixty two in order to compare the improved formula with the current veterinarian The technique follows: 2:: Le twice 'on day 0 (36 mg) and on the 70th again in gram 2. Each calf is weighed at different intervals during its development, sub- and average The results of the formula and average body weight increase of each group of the specific formulas given to each group on each date are as follows: I average body weight (public _^ treatment days formula (-1) days 0 days 28 days 56 days 84 days 1 12 days 140 E 309 303 352 389 425 461 491 F 309 300 356 398 435 477 511 G 308 301 354 401 444 485 525 Η 309 302 358 404 445 485 525 I 309 302 357 408 451 494 533 J 309 302 356 402 443 481 518 As evidenced by the results shown by G-J, excellent growth and weight gain were observed with the dual release formulation of the present invention. Therefore, one of the prescription pills was replaced by an immediate release pill: (one of nine) Time (formulation Η and I), weight increase Far higher than the above standard re-transplant design (formulation F)

Page 21

1250027 V. Description of invention (18)

The result was observed. Even if the controlled release fraction is reduced by half (from 160 to 80 mg or from 8 to 4 pills), this improvement is significant, as shown by Formulations G and J.

Claims (1)

1250027 ^ 砸ΓΓ90Ι4 丨补尤一修:Ε·6. Application for patents ^·' 1. One type is only given during one period; one preparation-year-stimulus increases growth rate, larger growth amount and larger A silver food efficiency anabolic graft composition comprising: (i) an immediate release formulation comprising a protein anabolic hormone, and (ii) a controlled release formulation comprising a protein anabolic hormone and a controlled release agent, wherein The release formulation and the controlled release formulation are each present in the composition in a weight ratio range of 1:2 to 1:25 and synergistically produce the stimulus. 2. The graft composition of claim 1, wherein the immediate release formulation and the controlled release formulation are each present in the composition in a weight ratio ranging from 1:2 to 1:10. 3. The graft composition of claim 1, wherein the immediate release formulation and the controlled release formulation are each present in the composition in a weight ratio range of 1:3 to 1:8. 4. The graft composition of claim 1, wherein the composition is injected under the cowhide. 5. The graft composition of claim 1, wherein the protein anabolic hormone comprises from about 50% by weight to about 9% by weight of the composition based on the total weight percent. 6. The graft composition of claim 1, wherein the protein anabolic hormone comprises from about 60% to about 80% by weight of the composition. 7. The graft composition of claim 1, wherein the immediate release formulation additionally comprises a diluent. 8. The graft composition according to claim 7, wherein the diluent is selected from the group consisting of lactose, mannitol, glucose alcohol, sucrose, dextrin, and lake. O:\61\61004-941228.ptc Page 24 1250027 _ Case No. η 88119044_年/〆月 曰 Amendment _ 6. Patent application range Powder, hydrolyzed starch, and combinations thereof. 9. The graft composition of claim 8 wherein the diluent is lactose. 10. The graft composition according to claim 1, wherein the controlled release agent is selected from the group consisting of poly(D,L-lactide-co-glycolide), ethyl cellulose, methyl acrylate-methacrylic acid An oxime ester copolymer, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and combinations thereof. 11. The graft composition according to claim 10, wherein the controlled release agent is poly(D,L-lactide-co-glycolide). 12. The graft composition of claim 10, wherein the controlled release agent is ethylcellulose. The weight of the grafting composition comprises from about 1.0% by weight to about 8.0% by weight, based on the total weight of the grafting composition. 14. The graft composition of claim 1 further comprising a filler, a binder, an excipient, a formulation, a colorant, and combinations thereof. 15. A method of increasing the growth rate, greater growth, and greater feeding efficiency of a bovine stimulation during a growing period of a bovine, comprising administering to the bovine an anabolically transplanted composition, The composition comprises: (i) an immediate release formulation comprising a protein anabolic hormone, and (ii) a controlled release formulation comprising a protein anabolic hormone and a controlled release agent, wherein the immediate release formulation and the controlled release formulation each Weight ratio range 1: 2 to O:\61\61004-941228.ptc Page 25 1250027 _ Case No. Π88Π9044_年f〆月日_iMz_ VI. Patent Application Range 1: 2 5 is present in the composition and synergistically produces the stimulus. 16. The method of claim 15, wherein the immediate release formulation and the controlled release formulation are present in the composition in a weight ratio of 1:25. 17. According to the method of claim 15, Wherein the administering comprises subcutaneous injection of the composition into the bovine. 18. The method of claim 15, wherein the protein anabolic hormone comprises from about 50% to about 9% by weight of the composition. 19. The method of claim 15, wherein the protein anabolic hormone comprises from about 60% by weight to about 80% by weight of the composition. 20. The method of claim 15, wherein the immediate release formulation additionally comprises a diluent. 2 1. The method according to claim 20, wherein the diluent is selected from the group consisting of lactose, mannitol, glucose alcohol, sucrose, dextrin, starch, hydrolyzed starch, and combinations thereof. 22. The method of claim 21, wherein the diluent is lactose. 23. The method of claim 15, wherein the controlled release agent is selected from the group consisting of poly(D,L-lactide-co-glycolide), ethylcellulose, decyl acrylate-mercaptoacrylate Ester copolymers, mercapto cellulose, hydroxyethyl cellulose, hydroxypropyl decyl cellulose, sodium carboxy decyl cellulose, and combinations thereof. 24. The method of claim 23, wherein the controlled release reagent is poly(D,L-lactide-co-glycolide). O:\61\61004-941228.ptc Page 26 1250027 _ Case number £788119044_ Amendment by year/〆月曰_6. Patent application scope 25. According to the method of claim 23, the control release The reagent is ethyl cellulose. 26. The method of claim 15, wherein the composition further comprises a filler, a binder, a tableting agent, an excipient, a colorant, and combinations thereof. 2 7. A method for increasing the growth rate, larger growth, and greater silver efficiency of cattle during the growing period of the cattle, the method comprising: (a) preparing a protein-containing protein An immediate release formulation of an anabolic hormone, which is suitable for being loaded into a first tablet or pill in an injection device, the injection device being suitable for applying the tablet or pill to an animal; (b) preparing a a controlled release formulation of a protein anabolic hormone and a controlled release agent, which is contained in a second tablet or pill suitable for loading in the injection device of step (a); (c) the first tablet or pill and the first a second tablet or pill is loaded in the injection device in a ratio such that the total protein anabolic hormone is in a ratio ranging from 50 to 95% by weight based on the combined weight of the formulation of the step (a) and the formulation of the step (b); (d) applying the medicinal tablet or pill to the animal, wherein the immediate release formulation and the controlled release formulation are each present in a ratio ranging from 1:2 to 1:25 based on their combined weight, and synergistically produce irritation. 28. The method of claim 27, wherein the controlled release reagent of step (b) is poly(D,L-lactide-co-glycolide), ethylcellulose, decyl acrylate-methyl Methyl methacrylate copolymer, methyl cellulose, O:\61\61004-941228.ptc Page 27 1250027 a_Amendment_Case No. 88119044 VI. Patent application scope hydroxyethyl cellulose, hydroxypropyl fluorenyl cellulose, carboxy decyl sodium cellulose, and combination. 29. The method according to claim 27, wherein the formulation of step (a), step (b) or both comprises lactose. O:\61\61004-941228.ptc第28页