Depot body on the basis of silicone rubber and process for the preparation thereof

The present invention relates to depot bodies, especially for the treatment of cattle, and a process for the preparation thereof. The depot bodies are suitable for applying active substances to the skin, for example the nasal mucous membrane, of cattle.
It is the object of the invention to provide depot bodies containing active substances which are suitable for administering these active substances over a prolonged period. The depot bodies are to be used especially for administering active substances by means of devices such as described for example in German Pat. No. 2 125 464. For this application, particularly severe requirements are to be met: The active substance(s), dosage thereof and time of administration are fixed by the prevailing medical reasons. The losses of active substance inevitably occurring on application to the mucous membrane of the nasal vestibule must be compensated for by an increased amount of active substance, which, due to the limited space at the point of administration, requires a high concentration of active ingredient in the depot body. Release of the active substance depends on its properties and those of the carrier material, and it should be dosed over a prolonged time, for example 6 weeks to 3 months, at a substantially high rate and in a carefully controlled manner. Residence times of weeks or months have to meet especially severe requirements with respect to the pharmacological tolerability and non-irritating behavior of the substances used. Because of the feed intake habits of cattle, these medicament forms must be resistant during their residence time to nasal secretion and feed components, for example milk feed in the case of calves. Resistance to mechanical strain is furthermore required, because the depot bodies are subjected to such mechanical strain during the long residence time in the nose of the animal. Taking into consideration all these requirements, this form of medicaments must furthermore be generally stable and capable of being economically manufactured.
In accordance with the invention, this object is achieved by providing a depot body on the basis of silicone rubber, which contains, in addition to the active ingredient(s) silicone rubber and optionally solid additives, from 2 to 50 weight %, relative to silicone rubber, of a release-promoting substance or mixture of such substances.
The depot bodies of the invention release the active substance in a predetermined amount per unit of time, while they themselves remain dimensionally stable during practically the full time of administration. The carrier material is based on physiologically acceptable silicone rubber, and it must for example meet defined purity requirements. The auxiliaries to be used, as well as shape and surface characteristics of the depot body are chosen in view of the anatomic conditions at the point of administration, the biopharmaceutical requirements, and the feasibility of economic manufacture.
The depot bodies are especially suitable for administering active substances by means of devices as for example described in German Pat. No. 2 125 464. Such a device is hereinafter called a nose clamp and consists preferably of a bow and two holds for one depot body each.
In addition to the application of active substances to the skin, other forms of administration of the depot bodies of the invention are possible, for example implantation. Furthermore, the composition in accordance with the invention may be injected in the form of the still liquid mass into a tissue, where cross-linking and thus formation of the depot body occurs.
Silicone rubber is distinguished by its chemical indifference, stability, high permeability and moreover easy processing. Other properties of silicone rubber such as insignificant shrinkage and a low coefficient of expansion are favorable for fastening the depot bodies to application devices.
Use of silicone rubber as a carrier for active substances and for influencing the release thereof is known in the art. The silicone rubber employed is preferably vulcanized by means of peroxides, or compounds of tin or platinum. Such forms of medicaments are intended for implantation or introduction into body cavities. The active substances are dissolved or suspended in silicone rubber. These forms of medicaments are of the matrix type or membrane/matrix type (see for example P. J. Dziuk and B. Cook, Endocrinology 78, 208 (1966) and U.S. Pat. No. 3,279,996).
A special form is a matrix of silicone rubber with emulsified hydrophilic solution systems containing the active substances optionally wrapped by a membrane, as described in German Offenlegungsschrift No. 2 547 378.
Because of the severe requirements to be met by the depot body, those on the basis of the above proposals proved to be insufficient.
Among the additives only slightly soluble in water but soluble in silicone rubber, there have been surprisingly found substances which ensure a satisfactory release of active ingredient from the depot body when present in a concentration of from 2 to 50%, relative to silicone rubber. Moreover, these substances either do not affect the mechanical properties of the silicone rubber at all or only to an insignificant extent. The addition thereof reduces the viscosity of the silicone mass and thus allows an increased concentration of active ingredient. This addition is therefore an important condition for the preparation of depot bodies which meet the above requirements in order to ensure a therapeutically active concentration of medicament in the corresponding animal.
Suitable silicone rubbers are especially those on the basis of single-component or two-component systems cross-linked by addition or condensation, for example those on the basis of dimethylpolysiloxane (such as .RTM.Silgel 601 of Wacker Chemie GmbH, Munich, an addition cross-linking two-component composition of 9 parts of component A and 1 part of component B), dimethyldiphenyl-polysiloxane, dimethylpolysiloxanol or silicone copolymers.
The release-inciting, physiologically acceptable additives soluble in silicone rubbers are preferably liposoluble, scarcely hydrosoluble alcohols, esters, ethers and ketones having from 8 to 60 carbon atoms. The depot body contains one or more (that is, a mixture) of these additives.
Release of the active ingredient(s) depends among other things on the concentration of the release-promoting substance or mixture of such substances, and increases as the amount of release-promoting substance dissolved in the silicone rubber increases. For this reason, release-promoting substances are used which have a sufficient solubility in the silicone mass. A further essential criterion resides in the requirement of non-exudation of the release-promoting substances being present in application concentration in the silicone rubber on storage. The concentration is therefore from 2 to 50, preferably 5 to 40, weight %, relative to silicone rubber.
Suitable release-promoting additives include alcohols such as 2-octyldodecanol, oleyl alcohol, phenylethanol; esters such as myristic acid isopropyl ester, caprylic/capric acid laurylstearyl ester, lauric acid hexyl ester (.RTM.Cetiol A), propionic acid myristyl ester, isostearic acid ethyl-lauryl ester, oleic acid ethyl ester, acetic acid phenyl ester, benzoic acid benzyl ester, salicylic acid methyl ester, lauric acid mono-1,1-propanediol ester, fatty acid polyethyleneglycol ester, caprylic/capric acid-1,2-propanediol diester (.RTM.Miglyol 840), caprylic/capric acid glycerol monoester, lauric acid glycerol diester, butyric acid glycerol triester, caprylic/capric/lauric acid glycerol triester (Miglyol 812), acetic/stearic/oleic acid glycerol triester, adipic acid dibutyl ester, sebacic acid dibutyl ester, phthalic acid ester, citric acid triethyl ester (.RTM.Citroflex 2): ethers such as didecyl ether, fatty alcohol polyethyleneglycol ether, alkylaryl polyethyleneglycol ether; anisol; or ketones such as methylnonylketone.
For these reasons, the addition of fatty acid esters of mean molecular weight of the myristic acid isopropyl ester, lauric acid hexyl ester or caprylic/capric acid-1,2-propanediol diester types, or of mean molecular weight ethers of the didecyl ether type is to be preferred.
The addition of such substances inciting the release of active ingredients allows for the administration of active compounds such as anabolic agents to animals in effective doses over prolonged periods by means of a nose clamp without encountering residue problems in the case where the animals are intended for human food.
The depot body may contain one or more active ingredients. The active ingredient is totally or partially wrapped by the silicone rubber, and it may be present in dissolved or disperse form, or in the form of more or less large-size particles either consisting entirely of the active substance or containing it, for example as crystals, granules, powders, with or without further additives. Homogeneous distribution in the silicone rubber is not required: on the contrary, the active substance in undissolved or undispersed form may be present in one or more chambers of the depot body. It may alternatively be present in the depot body in the form of one or more tablets which may contain in addition polyethyleneglycol(s) and further auxiliaries. However, it is recommended that the depot body contains only one tablet which is partially wrapped by the silicone rubber.
The depot bodies of the invention on the basis of silicone rubber are preferably applied to the mucosae, especially by means of a nose clamp. Because of their elasticity, they have the advantage of increasing the total elasticity of the corresponding device, and thus improving the tolerability and anti-irritating properties.
Such forms of medicaments are for example suitable for applying steroid hormones, but they may also be employed for other active substances such as antibiotics, chemotherapeutical agents, prostaglandins or vitamins.
As active substances to be applied to the mucous membrane of the nasal vestibule of cattle, anabolic agents of natural, partially synthetic or synthetic origin are especially interesting, because they aid the formation of flesh and thus improve the butchering quality. Suitable anabolic agents are for example testosterone or trenbolone, optionally in combination with estrogens such as estradiol-17.beta.. These compounds can be used in the form of alcohols or the derivatives thereof such as esters or ethers (see for example German Offenlegungsschrift No. 2 323 615).
The depot bodies are suitable for the prophylactic and therapeutic treatment of animals.
The depot bodies of the invention may have different shapes, depending on their application. They may be more or less round, cubic or square, cylindrical, oblong, oval, or have any other shape, while their surface may be smooth or structured. When applied to the nasal vestibule, they should be in close contact with the mucous membrane and not hinder respiration. The depot bodies to be applied to the nasal vestibule may be identical or different.
Preparation of the depot bodies comprises dissolving the release-promoting substance(s) in the silicone mass before vulcanization, wrapping, dissolving or dispersing the active ingredient(s), and finally cross-linking.

Composition and preparation of the depot bodies, as well as the examination and the results of the release of active ingredient in vitro are described in Examples 1 to 3. Depending on the size of the animal, that is, of its nasal vestibule, the dimensions of the depot bodies and dosage of the active ingredients may vary from the cited values, which may result furthermore in a modification of the method for determining the release of active ingredient. The examples are merely to illustrate the invention. The activity of the depot bodies of the invention in animal tests is demonstrated in Example 4.
EXAMPLE 1
Preparation of 16 depot bodies
(a) 10.712 g of dimethylpolysiloxane (addition cross-linking), component A, were mixed with 2.967 g of caprylic/capric acid-1,2-propanediol diester (corresponding to 20% of release-promoting substance). 1.192 g of dimethylpolysiloxane, component B, were added to this mixture. For aeration purposes, the batch was evacuated with agitation. After interrupting the vacuum, 3.200 g of microfine testosterone and 0.320 g of microfine estradiol-17.beta. were placed on the surface of the silicone mixture, and it was again evacuated. Subsequently, the solids in the silicone mixture were dispersed by agitation. The operations as described proceeded at room temperature and were terminated within 10 minutes. The agitation speed was 250 rpm at most. Subsequently, the mass was cast in molds. Tempering was carried out for 30 minutes at 70.degree. C., and the current was then switched off. The depot body had a cylindrical shape, a diameter of 15 mm and a height of 8 mm, a weight of 1.15 g corresponding to a content of 0.2 g of testosterone and 0.02 g of estradiol-17.beta.. The upper face of the depot body had the form of a spherical cap. The lower face was covered by a plate of plastic material having fastening devices. Further compositions of depot bodies are listed in Tables 3.1 to 3.5.
EXAMPLE 2
Preparation of 16 depot bodies
21 g of trenbolone acetate microfine, 4 g of estradiol-17.beta. (free alcohol) microfine and 26.7 g of polyethyleneglycol 4000 powder type were mixed, precompressed, granuled through a sieve of 1.5 mm and compressed to give two-face tablets having a diameter 11 mm.
10.876 g of dimethylpolysiloxane (addition cross-linking), component A, were mixed with 0.636 g of caprylic/capric/lauric acid glycerol triester (corresponding to 5% of release-inciting substance). 1.208 g of dimethylpolysiloxane, component B, were added. For aeration, the batch was evacuated with agitation for 5 minutes.
A tablet was placed on a plate of plastic material provided with a fastening device, and wrapped with the aerated silicone mixture in a suitable mold. Tempering was carried out for 60 minutes at 40.degree. C., and the current was then switched off. The thickness of the silicone rubber layer was 2 mm. The depot body had a cylindrical shape, a diameter of 15 mm and a height of 8 mm, a weight of 1.0535 g corresponding to a content of 0.125 g of trenbolone acetate and 0.02 g of estradiol-17.beta.. The upper face had the form of a spherical cap. The lower face was covered by a plate of plastic material having fastening devices. Further compositions are listed in Table 3.6.
EXAMPLE 3
Method for testing in vitro the release of active ingredient from depot bodies containing from 210 to 280 mg of acetate or from 200 to 469 mg of testosterone, optionally in combination with from 40 to 60 mg of estradiol-17.beta. and estradiol diacetate, respectively.
250 ml of water were charged each to Erlenmeyer flasks having a nominal volume of 300 ml. They were closed by means of ground glass stoppers provided with a fastening device for the holds of the depot bodies at the part facing the interior of the flasks. The fastening device had a length which ensured that the depot bodies were immersed in the water and that their distance from the bottom of the flask was 1 cm. The flasks were agitated at +38.5.degree. C. in an incubation shaking machine (for example air bath of Messrs. Braun or water bath of Messrs. Infors) at a frequency of 200/min.
The water used for elution was replaced daily. The content of testosterone and trenbolone acetate, respectively, was determined by spectrophotometry directly in the extract, optionally after dilution with water. After having united the extracts of one week and concentrated them on an ion exchanger column, the content of estradiol-17.beta. was determined by colorimetry with dansyl chloride.
The results with respect to release of active substance from depot bodies of the invention having a different composition are listed in the following Tables. For a comparison, there is furthermore indicated in these Tables the release from a depot body without addition of a release-promoting substance.
Table 3.1
Comparison of testosterone release in vitro from silicone rubber type Silgel 601 containing dissolved, scarcely hydrosoluble substances. The data are relative to two depot bodies each of identical volume and identical surface (see Example 1)
TABLE 3.1.1______________________________________Composition mg mg mg mg______________________________________Testosterone (free alcohol) 200 200 300 300microfineEstradiol-17.beta. (free alcohol) 40 40 60 40microfine2-Octyl-dodecanol -- 115 -- --Caprylic/capric/lauric acid -- -- -- 63glycerol esterSilgel 601 1950 1945 1240 1197Total weight 2190 2300 1600 1600______________________________________Testosterone releasein vitro mg mg mg mg______________________________________within 1 day 4 9 10 12within 4 days 10 19 20 29within 11 days 19 36 34 51within 14 days -- -- 40 57within 15 days -- -- 41 59______________________________________
TABLE 3.1.2__________________________________________________________________________Composition mg mg mg mg mg mg mg mg mg.sup.(+) mg mg mg mg mg__________________________________________________________________________Testosterone (free alcohol) 400 400 400 400 400 400 400 400 400 400 400 400 400 469microfineEstradiol-17.beta. (free alcohol) 40 40 40 80 40 40 40 40 40 80 40 40 80 38microfineMyristic acid isopropyl -- 93 372 -- -- -- -- -- -- 182 -- -- -- --esterLauric acid hexyl ester -- -- -- 364 -- -- -- -- -- -- -- -- -- --Caprylic/capric acid -- -- -- -- 93 372 -- -- -- -- -- -- -- --laurylstearyl esterCaprylic/capric acid-1,2- -- -- -- -- -- -- 186 279 332 182 -- -- -- --propanediol esterAdipic acid dibutyl -- -- -- -- -- -- -- -- -- -- 93 -- -- --esterSebacic acid dibutyl ester -- -- -- -- -- -- -- -- -- -- -- 93 -- --Phthalic acid dioctyl ester -- -- -- -- -- -- -- -- -- -- -- -- 91 --Didecyl ether -- -- -- -- -- -- -- -- -- -- -- -- -- 436Silgel 601 1860 1767 1488 1456 1767 1488 1674 1581 1328 1456 1767 1767 1729 1307Total weight 2300 2300 2300 2300 2300 2300 2300 2300 2100 2300 2300 2300 2300 2250__________________________________________________________________________Testosterone releasein vitro mg mg mg mg mg mg mg mg mg mg mg mg mg mg__________________________________________________________________________within 1 day 13 16 32 21 14 28 24 21 20 20 19 16 14 28within 4 days 28 35 79 58 29 70 52 48 74 62 45 41 28 69within 11 days 48 56 137 101 47 112 79 83 135 109 69 73 50 118within 14 days 52 61 152 114 52 124 87 92 151 123 76 83 53 133within 15 days 54 63 157 -- 55 129 90 102 168 -- 78 86 55 138within 21 days 65 68 184 -- 60 152 106 120 187 -- 89 102 67 164__________________________________________________________________________ (+)"G
Table 3.2
Comparison of testosterone release in vitro from silicone rubber on the basis of an addition cross-linking two-component system on the basis of dimethyl-diphenylpolysiloxane (hereinafter called Silicone SLM 71260) containing dissolved, scarcely hydrosoluble substances. The data are relative to two depot bodies each having identical volume and identical surfaces (see Example 1).
TABLE 3.2.1.______________________________________Composition mg mg mg mg______________________________________Testosterone (free alcohol) 300 300 300 300microfineCaprylic/capric acid -- 260 -- --glycerol esterCaprylic/capric/lauric acid -- -- 260 --glycerol esterCaprylic/capric acid-1,2- -- -- -- 260propanediol esterSilicone SLM 71260 1300 1040 1040 1040Total weight 1600 1600 1600 1600______________________________________Release of active sub-stance in vitro mg mg mg mg______________________________________within 1 day 20 22 20 22within 4 days 45 76 71 81within 14 days 81 158 145 154______________________________________
TABLE 3.2.2.______________________________________Composition mg mg______________________________________Testosterone (free alcohol) 300 400microfineCaprylic/capric acid-1,2-propanediol esterSilicone SLM 71260 1040 960Total weight 1600 1600______________________________________Release of active substancein vitro mg mg______________________________________within 1 day 22 31within 4 days 81 93within 14 days 154 178within 21 days 180 207______________________________________
TABLE 3.2.3.__________________________________________________________________________Composition mg mg mg mg mg mg mg.sup.+ mg__________________________________________________________________________Testosterone (free al- 400 400 400 400 400 400 400 400cohol)microfineEstradiol-17.beta.-(free al- -- 40 -- 40 -- -- 40 80cohol)microfineEstradiol-17.beta.-diacetate 52 -- 52 -- 52 52 -- --microfineCaprylic/capric acid -- -- 369 372 554 739 664 --1,2-propanediol esterLauric acid-hexyl -- -- -- -- -- -- -- 364esterSilicone SLM 71260 1848 1860 1479 1488 1294 1109 996 1456Total weight 2300 2300 2300 2300 2300 2300 2100 2300__________________________________________________________________________Testosterone releasein vitro mg mg mg mg mg mg mg mg__________________________________________________________________________within 1 day 15 15 22 22 21 21 23 21within 4 days 36 41 76 80 79 83 80 70within 14 days 68 75 142 142 146 173 177 138within 16 days 74 81 152 153 159 191 202 150within 28 days -- 117 -- -- 207 257 285 --within 43 days -- 141 -- -- 254 315 357 --__________________________________________________________________________ .sup.+ = "F
TABLE 3.3______________________________________Comparison of trenbolone acetate release in vitro from si-licone rubber type Silgel 601 containing dissolved, scar-cely water-soluble substances. The data are relative totwo depot bodies each having identical volume and identi-cal surfaces (see Example 1).______________________________________Composition mg mg mg mg mg mg mg______________________________________Trenbolone acetate 210 210 210 210 210 210 210microfineEstradiol-17.beta. 40 40 40 40 40 40 40(free alcohol)microfineMyristic acid iso- -- 103 410 -- -- -- --propyl esterCaprylic/capric acid -- -- -- 103 -- -- --laurylstearyl esterCaprylic/capric/ -- -- -- -- 103 -- --lauric acid glycerolesterCaprylic/capricacid-1,2-propanediol -- -- -- -- -- 410 --esterAdipic acid dibutyl -- -- -- -- -- -- 103esterSilgel 601 2050 1947 1640 1947 1947 1640 1947Total weight 2300 2300 2300 2300 2300 2300 2300______________________________________Trenbolone acetaterelease in vitro mg mg mg mg mg mg mg______________________________________within 1 day 15 10 13 11 20 20 17within 4 days 48 50 63 47 60 70 59within 14 days 109 115 153 113 123 158 126within 21 days 139 137 184 133 -- 174 --within 28 days 158 -- -- -- -- -- --within 42 days 189 -- -- -- -- -- --______________________________________
TABLE 3.4.1__________________________________________________________________________Comparison of estradiol-17.beta. release in vitro from si-licone rubber type Silgel 601 containing dissolved, scarce-ly hydrosoluble substances. The date are relative to twodepot bodies each having identical volume and identical sur-faces (see Example 1).__________________________________________________________________________Composition mg mg mg mg mg.sup.+ mg mg mg__________________________________________________________________________Testosterone (free alco- 400 400 400 400 400 400 400 469hol) microfineEstradiol-17.beta. (free 40 40 80 40 40 40 40 38alcohol) microfineMyristic acid isopropyl -- 372 -- -- -- -- -- --esterLauric acid hexyl ester -- -- 364 -- -- -- -- --Caprylic/capric acid -- -- -- 372 -- -- -- --laurylstearyl esterCaprylic/capric acid-1,2- -- -- -- -- 332 -- -- --propanediol esterAdipic acid dibutyl -- -- -- -- -- 93 -- --esterSebacic acid dibutyl -- -- -- -- -- -- 93 --esterDidecyl ether -- -- -- -- -- -- -- 436Silgel 601 1860 1488 1456 1488 1328 1767 1767 1307Total weight 2300 2300 2300 2300 2100 2300 2300 2250__________________________________________________________________________Estradiol 17.beta. releasein vitro mg mg mg mg mg mg mg mg__________________________________________________________________________within 1 week 1.10 4.62 5.72 4.26 5.64 2.62 2.50 3.72within 2 weeks 1.72 8.16 -- 7.88 10.30 3.56 3.78 5.74within 3 weeks 2.26 10.34 -- 10.82 13.80 4.18 4.96 7.82within 4 weeks 3.02 12.64 -- -- 16.56 -- -- 9.62within 5 weeks 3.36 -- -- -- 19.04 -- -- 10.96within 6 weeks 4.34 -- -- -- 20.94 -- -- 12.46__________________________________________________________________________ .sup.+ = "G
TABLE 3.4.2______________________________________Comparison of estradiol-17.beta. release in vitro from si-licone rubber type SLM 71 260 containing dissolved, scar-cely hydrosoluble substances. The data are relative to twodepot bodies each having identical volume and identical sur-faces (see Example 1).______________________________________Composition mg mg mg mg mg mg.sup.+______________________________________Testosterone (free al- 400 400 400 400 400 400cohol) microfineEstradiol-17.beta. 40 80 40 40 40 40microfineLauric acid hexyl ester -- 364 -- -- -- --Acetic/stearic/oleic -- -- -- 93 -- --acid glycerol esterCaprylic/capric acid- -- -- 93 -- 372 6641,2-propanediol esterSilicon SLM 71260 1860 1456 1767 1767 1488 996Total weight 2300 2300 2300 2300 2300 2100______________________________________Estradiol-170-release in vitro mg mg mg mg mg mg______________________________________within 1 week 3.10 6.52 3.96 4.68 6.26 6.48within 2 weeks 4.12 11.68 6.24 7.96 11.28 13.76within 3 weeks 5.58 15.86 8.34 9.84 -- 19.54within 4 weeks 7.74 -- -- -- -- 24.56within 5 weeks 8.62 -- -- -- -- 29.08within 6 weeks 10.16 -- -- -- -- 32.84______________________________________ .sup.+ ="F
TABLE 3.5______________________________________Comparison of estradiol-17.beta. release in vitro from si-licone rubber type Silgel 601 containing dissolved, scar-cely hydrosoluble substances. The data are relative totwo depot bodies each having identical volume and identi-cal surfaces (see Example 1).______________________________________Composition mg mg mg mg mg mg______________________________________Trenbolone acetate 210 210 210 210 210 210microfineEstradiol-17.beta. 40 40 40 40 -- --microfineEstradiol-17.beta. diacetate -- -- -- -- 52 52microfineCaprylic/capric/lauric -- 103 -- -- -- 102acid glycerol esterCaprylic/capric acid-1,2- -- -- 410 -- -- --propanediol esterMyristic acid-1,2-propyl -- -- -- 410 -- --esterSilgel 601 2050 1947 1640 1640 2038 1936Total weight 2300 2300 2300 2300 2300 2300______________________________________Release of activesubstance in vitro mg mg mg mg mg mg______________________________________within 1 week 0.44 1.96 2.18 2.44 1.36 1.90within 2 weeks 1.08 3.32 4.42 4.32 2.66 3.26within 3 weeks 1.76 -- 6.30 6.0 4.28 --within 4 weeks 2.30 -- -- -- 5.76 --within 5 weeks 2.70 -- -- -- 7.18 --within 6 weeks 3.08 -- -- -- 8.68 --______________________________________
TABLE 3.6______________________________________Comparison of trenbolone acetate release in vitrothrough a layer of 2 mm of silicone rubber type Silgel 601and Silicone SLM 71 260, respectively, containing dissolv-ed, scarcely hydrosoluble substances. The data of the Tableare relative to two depot bodies of the same kind (see Ex-ample 2).______________________________________Composition mg mg mg mg______________________________________TabletTrenbolone acetate 210 210 210 210microfineEstradiol-17.beta. (free alcohol) 40 40 40 --microfineEstradiol-17.beta. diacetate -- -- -- 52microfinePolyethyleneglycol 4000 267 267 -- --Polyethyleneglycol 6000 -- -- 267 255Silicone layerCaprylic/capric/lauric acid -- 79 -- --glycerol esterCaprylic/capric acid-1,2- -- -- -- 636propanediol esterSilgel 601 1590 1511 -- --Silicone SLM 71260 -- -- 1590 954______________________________________Trenbolone acetaterelease in vitro mg mg mg mg______________________________________within 1 day 4 4 4 13within 4 days 12 14 17 57within 14 days 42 49 51 138within 21 days 59 77 75 193within 28 days 84 103 107 236within 35 days 105 125 -- --within 42 days 130 152 -- --______________________________________
EXAMPLE 4
Activity test on milk-fattened store calves using depot bodies as indicated in Tables 3.1.2 "G" and 3.2.3 "F", respectively, for testosterone, and 3.4.1 "G" and 3.4.2 "F", respectively, for estradiol-17.beta..
Test operation
Nose clamps according to German Pat. No. 2 125 464 containing depot bodies were applied to 2 groups of 7 milk-fattened store calves each having an average weight of 75.4 and 74.8 kg, respectively, and left at their place for 6 weeks. A third group of 6 calves having an average weight of 76.5 kg remained untreated and served as control. For observing the weight development, the calves were weighed 3 times in intervals of 14 days, and the daily weight increase and the feed utilization (feed consumption:weight increase) per group during the time of treatment was calculated.
Results
The results of daily weight increase, feed utilization and cumulative weight development of groups 1-3 (3=control group) are listed in the following Tables.
______________________________________Average values of daily weight alteration in g and % TimeGroup 1. and 2. week 3. and 4. week 5. and 6. week______________________________________1 n = 7corr. to "G" 1377 126% 1337 153% 1133 129%2 n = 7corr. to "F" 1367 125% 1327 152% 1255 143%3 n =6Control 1095 100% 869 100% 881 100%______________________________________Average feed utilization pergroup during the 6 weeks' test periodsGroup 1 n = 7 Group 2 n = 7 Group 3 n = 6corr. to "G" corr. to "F" Control______________________________________1.45 1.44 1.81+ 19.9% +20.6% .+-. 0______________________________________Cumulative weight development in kg and %Averageweight in- Group 1 n = 7 Group 2 n = 7 Group 3 n = 6crease in time corr. to "G" corr. to "F" Control______________________________________up to 2. week 19.3 126.1% 19.1 124.8% 15.3 100%up to 4. week 38.0 138.2% 37.7 137.1% 27.5 100%up to 6. week 53.9 135.4% 55.3 138.9% 39.8 100%______________________________________
The results demonstrate that using depot bodies corresponding to "G" and "F", administered by means of the nose clamp, a weight increase superior to that of a control group (group 3) by 14.1 and 15.5 kg/calf, respectively, is obtained, and furthermore a feed utilization increase of about 20% as compared to the control.
The individual results of cumulative weight development were statistically obtained by comparison in pairs in the T test according to Student (P smaller than 0.01).

Number	Date	Country
2149699	Apr 1972	DEX
1991M	Sep 1963	FRX

Depot body on the basis of silicone rubber and process for the preparation thereof

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