DK169461B1 - Slow-release formulation, its preparation and use for increasing milk production in lactating animals - Google Patents

Description

in DK 169461 B1

The present invention relates to a slow release formulation which is characterized by the characterizing part of claim 1. The invention also relates to a process for the preparation of such a formulation, which is characterized by the characterizing part of claim 2, and the invention also relates to methods for using the formulation for increasing milk production in animals, increasing growth in animals and increasing and maintaining elevated blood levels of a biologically active protein, peptide or polypeptide, improving feed efficiency, increasing growth rate, increasing muscle size, decreasing body fat, and improving lean-fat ratio in an animal; and these methods are characterized in claims 5-10.

The formulations are suitable for parenteral administration to animals. The biologically active proteins, peptides or polypeptides include growth hormones, somatomedins, growth factors and other biologically active fragments or derivatives thereof.

Thus, the present invention relates, inter alia, to a method of increasing milk production in animals, especially dairy cows, by which method the cows are administered parenterally the compositions of the invention. The invention further relates to a method for raising and maintaining elevated levels of biologically active proteins, peptides or polypeptides in the blood of animals, wherein the method of the compositions of the invention is administered parenterally.

Waxes and fats suitable for use in the compositions of this invention generally have melting points above 40 ° C. The wax used according to the invention may be defined as set forth in Hawley's The Condensed Chemical Dictionary, II, as a low melting organic compound or high molecular weight compound, at room temperature and generally 35 having the same composition as fats and oils except that it does not contains any glycerides. Some waxes are DK 169461 B1 2 hydrocarbons, others are esters of fatty acids and alcohols. These compounds include saturated or unsaturated, long chain Cio ~ c24 fatty acids' alcohols, esters, salts, ethers or mixtures thereof. They are classified among the lipids.

5 Waxes are thermoplastic, but since they are not high polymers, they are not included in the plastic group. Common characteristics are that they are water repellent, have a smooth texture, are non-toxic and are free from unpleasant odor and color. They are flammable and have good dielectric properties. They are soluble in most 10 organic solvents and are insoluble in water. The main types are as follows: I. Natural 1. Animal (beeswax, lanolin, shellac wax, Chinese insect wax) 15 2. Vegetable (carnauba wax, candelilla wax, myrtle wax, sugarcane wax) 3. Mineral (a) Fossil or soil wax species (ozokerite, ceresin, montane (20) petroleum waxes (paraffin, microcrystalline) (wax or less refined paraffin) II. Synthetic 1. Ethylenic polymers and polyol ether esters ("Car-bowax", sorbitol) 25 2. Chlorinated naphthalenes ("Halowax") 3. Hydrocarbon type via Ficher-Tropsch synthesis.

The fat in question can be defined as set forth in Hawley's The Condensed Chemical Dictionary, ed., As a glyceryl ester of higher fatty acids such as stearic acid and palmitic acid. Such esters and mixtures thereof are solid at room temperature and have crystalline structure. Fat and tallow are examples of this. There is no chemical difference between a fat and an oil, the only difference being that the fats are solid at room temperature and the oils are liquid. The term "fat" usually refers specifically to triglycerides, while "lipid" includes all.

DK 169461 B1 3

The fat is preferably composed of mono-, di- or triglyceryl esters of long-chain cio ~ c24-fatty acids. The mono-, di- or triglycerides are predominantly composed of stearates, palmitates, laurates, linoliths, linolenates and residues or mixtures thereof. melting points above 50 ° C are the most preferred. Glyceryl tristearate is the most preferred fat. In addition, lipophilic salts of fatty acids such as magnesium stearate and the like can also be used.

The carrier medium may be an aqueous buffer system or oil system. The oil may come from animal or vegetable sources or may be synthetic. Examples of preferred oils are neutral mono-, di- or triglycerides or mixtures thereof. A neutral oil is an oil which does not contain a residual acid. Examples of carrier media suitable for use in the present invention are aqueous systems such as buffer salt solutions, organic solvents such as glycols and alcohols, and water-immiscible liquids such as oils, depending on the solubility of the active agent. ingredient to be administered.

Biologically active proteins, peptides and polypeptides suitable for administration in the present compositions are e.g. growth hormones, somatomedins, growth factors and other biologically active fragments and derivatives thereof. Examples of preferred proteins are bovine, ovine, equine, porcine, avian and human growth hormones and include those which are of natural, synthetic, recombinant or biosynthetic origin. Also suitable for admixture in the present compositions are metals or metal compounds associated with biologically active proteins, peptides and polypeptides, as well as acid salts, derivatives and complexes and anti-hydrating agents.

In the present compositions, there may be admixtures of stabilizers, preservatives, surfactants, salts, buffers or mixtures thereof. Examples of preferred stabilizers are dehydroacetic acid, salicylic anilide, sorbic acid, boric acid, benzoic acid and salts thereof, as well as sodium nitrite and sodium nitrate. For use in accordance with the invention, the substances listed above are suitably used in amounts of approx.

0.1 to 20% by weight.

Examples of preferred surfactants for use in the present compositions containing biologically active macromolecules are nonionic in nature such as polyoxyethylene sorbitan monooleate (20 moles of ethoxylation) and block copolymers of ethylene oxide and propylene oxide. For use in accordance with the invention, surfactants are suitably used in amounts of approx. 0.1 to 10.0% by weight.

Surprisingly, it has been found that increased growth hormone levels in blood can be achieved and maintained over a prolonged period, and that increased weight gain and increased milk production in lactating animals can be achieved by injecting the animals with the present compositions into a suitable carrier medium. . Elevated blood levels of biologically active proteins, peptides and polypeptides are generally considered and associated with beneficial and / or therapeutic effects. The effects 20 are e.g. weight gain, increased growth rate, increased milk production in lactating animals and associated increased availability of milk for the offspring of the treated animal, improved muscle size, improved feed efficiency, decreased body fat and improved lean meat and fat ratio. Maintaining elevated blood levels is evidence of a slow release of the active ingredient.

When elevated blood levels of the active ingredient are maintained, characteristics such as increased milk production, growth rate, improved foot-mat effect and increase in lean meat are generally observed. The present invention relates to the use of the present compositions for improving milk production, increasing growth rate, improving feed efficiency, increasing lean meat in animals, increasing and maintaining hormone levels in the blood stream of animals.

In a preferred embodiment of the invention, the biologically active protein, peptide or polypeptide is incorporated into fat or wax microspheres, which may optionally also contain some or all of the above-described extenders which are then dispersed in the carrier medium. The microspheres, preferably the fat microspheres, can have a diameter of up to 1000 μιη, with an average size of 25-300 μιη for parenteral administration. Microspheres containing up to approx. 70% of biologically active protein, peptide or polypeptide exhibit a delayed release of different duration depending on the solubility of the active ingredient and the nature of the wax or fat used, surfactant, buffer and carrier medium.

The present invention relates, as mentioned, to a slow release formulation or a depot preparation containing a mixture of a fat or wax or mixture thereof and a biologically active protein, peptide or polypeptide dispersed in a pharmaceutically and pharmacologically acceptable carrier. Microspheres and coated protein particles may be present in the depot preparation. The composition 20 may be the protein dissolved in the fat or waxed, or there may be a hydrophobic interaction or bonding of the active ingredient to the fat or wax. For hormone administration, preparations are used which contain, on a weight basis, approx. 1-30% growth hormone, somatomedin, growth factor 25 or biologically active fragment or derivative thereof preferably having an average particle size of less than 20 μιη, approx. 5-60%, preferably approx. 10-48% fat, wax or mixture thereof, and optionally containing up to approx. 15% extenders such as surfactants, stabilizers, preservatives, salts or buffers or mixtures thereof with a sufficient amount of a pharmaceutically and pharmacologically acceptable liquid carrier to a total of 100%. The carrier is again the aqueous buffer system or oil system described above.

35 For parenteral administration of growth hormones, such as bovine growth hormone, microspheres containing on a weight basis contain DK 169461 B1 6 approx. 5-40% of the solid hormone, preferably with an average particle size of less than 20 µM, containing up to about 20% of the other extensions described above for approx. 40-95% fat or wax or a mixture thereof, with an average particle size of 25-300 μη, showing sustained release of the hormone and sustained increase in milk production in lactating dairy cows for approx. 2 weeks and such preparations are preferred. These preferred compositions have shown increased milk production comparable to the 10 milk production achieved by daily injection of bovine growth hormone.

For administration of compositions containing water-soluble proteins, peptides or polypeptides such as bovine growth hormone, water-immiscible liquids are preferred, especially oils or liquid fats and water-immiscible alcohols and glycols and mixtures thereof. The carrier media is chosen to both disperse and coat the mixture or microspheres and also give the injection mixture an acceptable viscosity, using HLB (hydrophilic-lipophilic balance) and viscosity as criteria for their selection.

On this basis, fatty acid glycerides and mixtures thereof which are liquid at ambient temperature, including 25 synthetic oils, vegetable oils such as olive oil, sesame seed oil, peanut oil, sunflower seed oil, soybean oil, cottonseed oil, cotton oil, cotton oil, rapeseed oil and coconut oil, animal oils such as fish oils, fish liver oils, spermacet oils or fractions thereof and 30 mixtures thereof having HLB values in the range of 1-5 and viscosities in the range of 10 cps to 1000 cps as measured with a Brookfield viscometer RTV below use of a spindle # 1.

The present microspheres can be prepared by incorporating the active ingredient having the desired particle size and other excipients into a molten fat, wax or mixture thereof and then molding the microspheres from the resulting mixture using a series of various techniques, such as emulsifying or atomizing the mixture, or by machining the mixture of constituents and molten fat, wax or a mixture thereof mechanically and then cooling it, e.g. using a centrifugal disc as described in International Patent Application PCT / US85 / 00827. Alternatively, the mixture of active ingredients, excipients and grease, wax and mixtures thereof can be cooled to give a solid which is then processed by procedures such as rolling, grinding and the like.

The present compositions suitable for injection are readily prepared by dispersing the protein, peptide or polypeptide, excipients, fat, wax or mixtures thereof at elevated temperatures directly in the carrier medium and subsequent cooling.

The following examples serve to illustrate the invention.

Example 1

Preparation of inducible microspheres for parenteral administration of bovine growth hormone.

1. The preparation of bovine growth hormone and additives of a suitable size for incorporation into microspheres by spray drying can be accomplished by dissolving bovine growth hormone in dilute ammonium hydroxide solution and then adding the desired saline solutions such as sodium benzoate.

A nonionic surfactant such as a block copolymer of ethylene oxide and propylene oxide is added and this is allowed to dissolve under constant gentle mixing. The solution is then atomized in a Buehi mini-atomizer, model 190.

2. Preparation of injectable microspheres.

A homogeneous mixture of active ingredients and additives is prepared in the molten fat, wax or mixture thereof, and the resulting mixture is sprayed through an air / liquid spray nozzle provided with a heated jacket to hold the incoming air and the molten phase at a temperature above the melting point. The microspheres are formed as the molten droplets are cooled and collected on a 5 series of sieves in the desired size range from ca. 45 to 180 μιη and stored for later use. The microspheres which do not have the desired size are collected for recycling. Alternatively, the homogeneous mixture can be fed to a centrifugal disc and the microspheres thus formed are collected as described above, or the molten mixture can be cooled and rolled to the desired average particle size.

By using the above procedure with the materials listed in Table I, the injectable microsphere preparations listed in Table II are obtained.

DK 169461 B1 9

TABLE I

Name Designation

Glyceryl monostearate GMS

Glyceryl distearate GDS

Glyceryl tristearate GTS

Glyceryl trilaurate GTL

Soybean Soybean oil 10 Beeswax Beeswax

Karnauba wax Karnauba

Sodium laurate NaLaurate

Sodium benzoate NaBenzoate or NaBz Sodium carbonate NaCarb

Sodium Hydrogen Carbonate BiCarb

Calcium benzoate CaBenzoate

Polyoxyethylene sorbitan monooleate Overil.m. A

(20 moles ethoxylation, "Tween" 801) 20 Block copolymer of ethylene oxide and propylene oxide,

("Pluronic" F682) Surface.m. B

Glyceryl dioleate GDO

Polyoxyethylene stearate, 23 moles of POE (23) ethoxylation stearate

Polyethylene glycol distearate, PEG 1540

Average molecular weight of PEG 1540 distearate

Polyethylene glycol, average molecular weight 6000 PEG 6000

Polyoxyethylene sorbitan monostearate POE (20) sorbitan monostearate

Carbonate buffered saline 35 (pH 9.4) CBS

Polyethylene glycol PEG

Mixture of Caprylic, Caprine, Laurin and Capron Triglycerides "Miglyol" 8123 1 Hazard Description Used by ICI Americas, Inc.

2Product name used by BASF Wyandotte Corp.

45 3Product name used by Dynamit Nobel DK 169461 B1 10

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Example 2

Effectiveness of irrigable microspheres in various carrier media.

The efficacy of various injectable preparations of microspheres in different carrier media is determined using an analysis with a pituitary-grafted rat. The hypophysectomized rat does not produce its own growth hormone and is susceptible to injected bovine growth hormone. The measured response is the growth over a period of time, such as 10 days.

Each of the hypophysectomized albino rats (Taconic Farms, Sprague Dawley strain) is injected with a sufficient amount of microsphere preparation prepared as described in Example 1 to obtain a 10-day dose of 800 µg (80 µg / day). bovine growth hormone in 0.2 ml carrier medium as set forth in the following Table III.

TABLE III Carrying medium

Name Designation

Glyceryl dioleate gDO

Saline solution SAL

Caprin / Caprylic Triglycerides C / C

Soybean oil Soybean oil

Diethyl succinate DES

Aluminum Monostearate Gel Gel

"Carbowax" (thickener) THX

Test method.

Prior to the test, the animals are weighed and the animals to be used for the sample are selected on the basis of body weight. Only those animals whose body weight is a standard deviation from the mean body weight of the group are selected. The resulting group is then randomly divided into treatment groups consisting of eight rats per day. group by a randomization procedure generated by a computer. The test animals are then transferred to a clean cage and four rats are placed in each cage DK 169461 B1 16. On the first day of testing, the test animals are weighed and the animals that have too much weight gain or excessive weight loss (± 5 g) are replaced. Then the animals are used for the experiment and treated.

At the end of the 10-day experimental period, the total weight gain for each animal is recorded, and then the average weight gain per day is determined. rat for each treatment. The results of these experiments, which are summarized in the following Table IV, show the effectiveness of the injectable preparation of microspheres with different carrier media.

DK 169461 B1 17

TABLE IV

EFFECTIVENESS OF INJECTABLE MICROSPHERE IN DIFFERENT CARRIERS

5 Microsphere Preparation 10-Day According. Ex 1 Carrying medium Growth (grams) 48 GDO 19.5 32 GDO 17.9 10 18 SAL 19.4 16 GDO 18.5 12 C / C 19.8 16 GDO 15.5 12 SAL 16.6 15 27 SAL 17 , 4 16 C / C 14.0 16 GDO / DES (4: 1) 13.7 32 Soybean Oil 15.6 39 Soybean Oil 16.0 20 8 8% Gel / Soybean Oil 14.0 34 8% Gel / Soybean Oil 8.0 42 Soybean oil 12.6 43 Soybean oil 8.0 34 0.5% THX / Soybean oil 17.0 25 37 0.5% THX / Soybean oil 14.0 36 0.5% THX / Soybean oil 13.6 33 0.5% THX / Soybean oil 16.8 35 0.5% THX / Soybean oil 14.5 negative controls * 0.7 ± 3.15 30 * Average growth for 22 negative control groups (no treatment) DK 169461 B1 18

Example 3

Assessment of growth hormone microsphere preparations for dairy cows.

Lactating cows are divided into groups of 3-8 animals. During the whole test, all cows are fed with the same amount of corn silage, alfalfa hay and milk concentrate sufficient to yield 25 kg to 30 kg milk per day. day. The cows are not treated for 2 weeks, and daily milk production and bovine growth hormone levels in the blood are recorded for each group of animals.

The test or control formulations listed in the following Table V are then administered during the experimental period. The growth hormone levels in the blood of the animals are determined by conventional peri-disc RIA techniques and milk production levels are recorded daily. The results of these experiments, which are summarized in Tables VI 15 and VII, show the efficacy of the present compositions for increasing milk production and for increasing and maintaining elevated blood growth hormone levels.

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(B 1H 3 \ \ Ρ Ρ Φ ~ 0 <D Ό vo vo 1> 3 - d) P r— (Η «Ρ P <D fe -

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fe C 3 CQ CQ

10 O> 3 3 II

O fe O fe fe II

P

fe • h in S W - m> p · ι - CQ cm eg 1C- fe fe H b fe DK 169461 B1 21

TABLE VI

Average milk production increases from dairy cow trials.

5% Increase in milk production compared to non-dosed control cows_

Formulation No._ Week 1 Week 2 Week 3 Week 4 A 10.5 13.9 12.3 14.7 10 B 16.4 21.1 19.2 20.8 C 17.8 19.4 17.3 19 , 3 D 9.2 16.7 15.6 15.8 E 8.4 7.3 16.0 4.0 F 6.7 4.5 13.8 9.8 15 G 9.6 19.3 9 , 3.7 3.7 H 7.4 14.0 6.0 4.0 I 11.1 10.6 4.1 6.3 J 14.2 13.1 20.1 24.5 K 17.7 4, 9 3.6 0.1 DK 169461 B1 22

TABLE VII

Average plasma BVH concentration (ng / ml by radioimmunoassay) in dairy cows experiments.

5 Time elapsed _ Formulation no_

(Daae ^ A * B C D * E F

-24 hr 1.3 1.3 1.5 1.2 1.0 1.1 0 hr 1.4 1.2 ** 1.4 ** 1.1 1.0 ** 1.1 ** 10 3 hr 6.1 2.0 3.3 20.0 25.6 1.1 6 hr 5.2 6.9 8.5 7.2 50.1 1.2 1 day 2.6 30.8 37, 6 1.5 13.5 13.8 2 days 2.4 9.7 20.1 3.7 7.2 8.4 5 days 2.8 6.7 9.2 3.9 8.2 5.8 15 7 days 2.9 7.3 9.9 7.4 8.2 6.9 9 days 3.4 7.2 9.8 7.8 8.5 7.3 12 days 3.7 6.4 8 , 5 3.8 2.9 1.8 14 days 2.7 4.3 ** 5.6 ** 4.0 2.4 ** 1.5 ** 16 days 3.2 14.2 21.2 5.5 45.7 15.7 20 19 days 3.9 9.9 11.2 7.2 9.6 9.0 21 days 3.2 14.7 12.9 6.4 8.1 7.5 23 days 2.4 9.5 8.0 6.3 7.8 6.1 26 days 2.5 7.8 8.4 5.4 5.4 3.7 28 days 2.2 4.6 6, 1 4.9 5.0 2.8 DK 169461 Bl 23 TABLE VII (continued)

Average plasma BVH concentration (ng / ml by radioimmunoassay) in dairy cows experiments.

5 Formulation Time Formulation

Time elapsed No._ elapsed No._

(Days) J * K (Daoe ^ G * Η I

-24 hr 2.3 5.2 -24 hr 3.0 5.3 3.1 0 hr 4.1 7.3 ** 0 hr 2.9 3.8 ** 3.5 ** 10 1 hr 12 , 2 34.5 3 hr 15.0 4.6 3.8 2 hr 15.3 57.2 6 hr 10.4 3.7 4.7 4 hr 15.8 127.8 1 day 5.1 10, 2 31.5 6 hr 12.7 102.7 2 days 4.7 7.8 24.5 1 day 4.4 107.7 3 days 4.2 6.2 8.4 15 2 days 4.0 33, 3 4 days 4.8 6.7 9.2 3 days 4.1 15.3 5 days 4.3 6.5 9.7 4 days 4.7 13.1 6 days 6.1 8.0 11.2 6 days 5.7 15.8 7 days 6.2 9.6 ** 13.1 8 days 6.0 17.6 8 days 6.0 18.0 11.9 20 11 days 6.7 34.5 10 days 6.5 16.8 13.1 13 days 7.9 18.6 11.8 17 days 5.2 16.5 11.0 20 days 5.7 17.3 12.6 * Note: Blood samples are taken before daily injection 25 ** Injections are given in the morning on these days after the blood test is taken.

DK 169461 B1 24

Example 4

Slow release of compositions of the invention in sheep.

Using practically the same procedure as described in Example 3, the preparations prepared in Example 1 and listed in the following Table VIII are administered to groups of sheep (3 animals per group). The animals are dosed with 3 mg BVH microsphere equivalents per day. kg body weight. Daily blood samples are taken over a 30-day period and these are analyzed for the BVH level as described previously. The results of these 10 experiments, which are summarized in the following Table VIII, show the efficacy of the present compositions for maintaining elevated blood growth hormone levels over a prolonged period of time.

DK 169461 B1 25 t – 1 g O na in ro mo> rg n cm C cm <m cm H cm in Λ Λ α) • η ο to Ό Ό Η <D - g Λ ν (Τ 'Ό • Η C Η CM Η Μ η η Ο Ο Ο (tf Η Ο Η CM Η Η Η

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G G

-p -H -pH cm cm

tT> G O 'G H H

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I h

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Kl N H CN VO'tfHH

Λ Λ Λ Φ • Η & ιΰ Ό Ό ιΗ Φ - Ε Λ \ θ 'Ο

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ε ο ο ^ ο - 'Φ (0 to <0 h · η · η Μ · π Ν «Ο Ο Η Ο Q CQ W CO CO CQ 00 -Ρ (0 Ρ to ρ co co invor ^ n φ η · & r)> <# Ρ ft DK 169461 B1 27

Example 5

The efficacy of a mixture of bovine growth hormone of the invention in dairy cows.

A mixture of bovine growth hormone 5 containing sodium benzoate (7% w / w) and a block copolymer of ethylene oxide and propylene oxide (0.5% w / w) is prepared by the spray drying method described in Example 1.1.

The mixture thus prepared (7.28 g) is added to a stirred solution of glyceryl tristearate (19.5 g) in a mixture of 4/1 w / w mixture of a mixture of caprylic, caprin, laurine and capron triglycerides ( Miglyol 812) 3 / soybean oil (71 ml) at 75-80 ° C. The mixture is stirred at 75-80 ° C until it is homogeneous and then cooled. The resulting composition containing 6.96% bovine growth hormone by weight , 0.51% sodium benzoate, 0.03% surfactant (block copolymer) and 73.0% carrier medium are administered to lactating cows by the procedure described in Example 3. The results of these experiments, which are summarized in the following Table IX, shows the effectiveness of these compositions for increasing milk production over a longer period of time.

TABLE IX

Average milk production increases compared to non-dosed control cows.

25% Increase% Increase

Week 1_ Week 2_ 15.7 12.0

Claims (10)

A slow release formulation, characterized in that it contains growth hormone, somatomedin, growth factor or biologically active fragment or derivative thereof dispersed in fat or wax or a mixture thereof dispersed in a pharmaceutically and pharmacologically acceptable liquid carrier medium, however, when the growth hormone is bovine somatotropin and the liquid carrier is an oil, wax is not present and, when the derivative is a metal complex of a growth hormone, the liquid carrier is not an oil. Process for preparing a formulation according to claim 1, characterized in that approx. 1 to approx. 30% growth hormone, somatomedin, growth factor or biologically active fragment or derivative thereof, approx. 5 to approx. 60% fat or wax or mixture thereof, 0 to approx. 15% surfactant, preservative, stabilizer, salt, buffer or mixture thereof and oil until heated to a total of 100% to give a homogeneous mixture, and then cool the mixture to ambient temperature to form the formulation. Formulation according to claim 1, characterized in that the growth hormone is bovine, porcine or avian growth hormone. The formulation according to claim 3, characterized in that it contains, on a weight basis, approx. 5 to approx. 27% bovine growth hormone, approx. 10 to approx. 48% glyceryl tristearate, 0 to approx. 0.2% microbiological preservative and 0 to approx. 1% nonionic surfactant and a neutral mono-, di-30 or triglyceride liquid or mixtures thereof up to a total of 100%. Process for increasing milk production in lactating animals, characterized in that the animal is administered parenterally a biologically active slow-release formulation prepared by heating approx. 1 to approx. 30% growth hormone, somatomedin, growth factor or biologically active fragment or derivative thereof, approx. 5 to approx. 60% fat or wax or mixtures thereof, 0 to approx. 15% surfactant, preservative, stabilizer, salt, buffer or mixture thereof and oil until a total of 100% to obtain a homogeneous mixture and cooling the mixture to ambient temperature to form the formulation. Method for increasing milk production in animals according to claim 5, characterized in that the weight-based formulation contains approx. 5 to approx. 27% bovine 10 growth hormone, approx. 10 to approx. 48% glyceryl tristearate, 0 to approx. 0.2% microbiological preservative and 0 to approx. 1% nonionic surfactant and a neutral mono-, di-triglyceride liquid or mixtures thereof up to a total of 100%. A method for increasing weight gain in animals, characterized in that the animal is administered parenterally a biologically active slow-release formulation prepared by heating approx. 1 to approx. 30% growth hormone, somatomedin, growth factor or biologically active fragment or derivative thereof, approx. 5 to approx. 60% fat or wax or mixtures thereof, 0 to approx. 15% surfactant, preservative, stabilizer, salt, buffer or mixture thereof, and oil to a total of 100% to obtain a homogeneous mixture and cooling the mixture 25 to ambient temperature to form the formulation. Process according to claim 7, characterized in that the weight-based formulation contains approx. 5 to approx. 27% bovine growth hormone, approx. 10 to approx. 48% glyceryl tristearate, 0 to approx. 0.2% microbiological preservatives 30 and 0 to approx. 1% nonionic surfactant and a neutral mono-, di- or triglyceride liquid or mixtures thereof to a total of 100%. 9. Method for raising and maintaining elevated blood levels of a biologically active protein, peptide or polypeptide, improving feed efficiency, increasing growth rate, increasing muscle size, reducing body fat and improving lean meat ratio. fat in an animal, characterized in that the animal is administered parenterally a biologically active slow-release formulation produced by heating 5 of ca. 1 to approx. 30% growth hormone, somatomedin, growth factor or biologically active fragment or derivative thereof, approx. 5 to approx. 60% fat or wax or mixture thereof, 0 to approx. 15% surfactant, preservative, stabilizer, salt, buffer or mixture thereof, and oil to a total of 100% to obtain a homogeneous mixture and cooling the mixture to ambient temperature to form the formulation. Process according to claim 9, characterized in that the weight-based formulation contains approx. 5 to approx. 27% bovine growth hormone, approx. 10 to approx. 48% glyceryl tristearate, 0 to approx. 0.2% microbiological preservative and 0 to approx. 1% nonionic surfactant and a neutral mono-, di- or triglyceride liquid or mixtures thereof to a total of 100%.