GB2191397A - Subcutaneous implant - Google Patents

Subcutaneous implant Download PDF

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Publication number
GB2191397A
GB2191397A GB08615367A GB8615367A GB2191397A GB 2191397 A GB2191397 A GB 2191397A GB 08615367 A GB08615367 A GB 08615367A GB 8615367 A GB8615367 A GB 8615367A GB 2191397 A GB2191397 A GB 2191397A
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oestradiol
growth
implant according
subcutaneous implant
implant
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GB2191397B (en
GB8615367D0 (en
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James Francis Roche
John Mary Clancy
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Drug Systems Res & Dev
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Drug Systems Res & Dev
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

A subcutaneous implant for promoting growth in livestock comprises a solid cylindrical component of a self-curing silicone rubber which has a diameter in the range of 3.0-3.5 mm and a length in the range of 10-40 mm impregnated with a growth-promoting amount of oestradiol or a pharmaceutically acceptable salt thereof and which is sufficient to maintain a sustained and substantially constant plasma level of oestradiol of between 10-20 pg/ml over the growth-promoting period. The dimensions of the implant are such that it is possible to achieve up to 100% retention thereof following implantation and throughout the growth-promoting period.

Description

SPECIFICATION Subcutaneous implant This invention relates to subcutaneous implants and, in particular, to an oestradiol subcutaneous implant for use in promoting growth in livestock.
Subcutaneous oestradiol implants for the promotion of growth in ruminants are known. Our Patent Application No. 341/84 (U.K. Patent Publication No. 2,154,138A) describes and claims a subcutaneous implant comprising a substantially hollow cylindrical component of silicone rubber impregnated with oestradiol and having a core consisting of an active ingredient dispersed in a biocompatible, biosoluble polymeric material which dissolves within days of implantation.
U.K. Patent Publication No. 2 030 044A describes a solid, cylindrical subcutaneous implant for ruminants which has a bio-compatible inert core and a bio-compatible coating of oestradiol embedded in a dimethyl-polysiloxane rubber. Problems have been encountered in practice with the implant of U.K. Patent Publication No. 2 030 044A which is sold under the Trade Mark COMPUDOSE and is described by J.C. Parrott et al in Journal of Animal Science, Vol. 61 No. 4, 1985. Implants sold under the Trade Mark COMPUDOSE have a diameter of 5 mm and suffer loss rates from implanted cattle of 3-30%. As described by J.C. Parrott et al supra by coating the implant with oxytetracycline hydrochloride, the loss rate can be reduced but not eliminated.
It is also known that one can achieve a constant release of a steroid from silicone rubber such as dimethylpolysiloxane (DPS) since the rubbers are readily permeable to steroids. Silicone rubbers such as DPS are found to be useful in implants because they do not cause foreign body reactions even after prolonged periods. After the implant has been exhausted, an empty hull of foreign material is left embedded in the tissue which can be removed and replaced by a fresh implant.
The administration of oestradiol to animals is considered to have two major effects. Firstly it stimulates the release of growth hormone and secondly recent work has indicated the presence of specific oestradiol receptors in muscle, which results in oestradiol acting locally on muscle to stimulate growth. Furthemore, the administration of oestradiol to bulls suppresses testicular development resulting in a reduced aggressiveness and easier farm management. Oestradiol administration effectively achieves a hormonal "castration" of male animals.
It is an object of the present invention to provide an improved subcutaneous implant for the sustained release of oestradioi so as to achieve an optimum plasma concentration over the period of growth promotion and which implant can be retained in situ over a predetermined period of time.
Accordingly, the invention provides a subcutaneous implant for promoting growth in livestock, which comprises a solid cylindrical component of a self-curing silicone rubber impregnated with a growth-promoting amount of oestradiol or a pharmaceutically acceptable salt thereof and sufficient to maintain a sustained and substantially constant plasma level of oestradiol of between 10-20 pg/ml over the growth promoting period, said component having a diameter in the range 3.0-3.5 mm and a length in the range 10-40 mm and permitting up to 100% retention of the implant following implantation and throughout the growth promoting period.
After implantation with the implant according to the invention initially plasma levels of oestradiol will frequently go above 20 pg/ml. However the plasma levels soon stabilise such that the above specified concentration range is maintained throughout the effective growth promoting period.
Preferably, the oestradiol or pharmaceutically accpetable salt thereof is present in the silicone rubber component at a concentration of from 10-30% by weight, especially 20% by weight. A preferred form of oestradiol is oestradiol-17ss. A preferred salt of oestradiol is the benzoate salt thereof.
An especially preferred implant according to the invention has a diameter of 3.2 mm, a length of 25 mm and contains oestradiol-17ss at a concentration of 20% by weight.
Preferably, the livestock is represented by poultry or a ruminant animal, most especially cattle.
The silicone rubber is preferably a dimethylpolysiloxane (DPS) rubber. Especially preferred dimethylpolysiloxanes are those known generically as SILASTIC such as SILCOSET (SILCOSET is a Trade Mark) sold by I.C.l. PLC or SILASTIC 382 and MDX-4-4210 sold by the Dow Corning Corporation. Such silicone rubbers consist of two components-a first component consisting of liquid, uncured rubber and a second component including a curing agent. The first and second components are mixed and allowed to cure.
The invention also provides a method of promoting growth in livestock, which comprises implanting in an animal an implant as hereinabove defined.
When the animal is a ruminant animal, the implant is preferably implanted in the ear. It will be appreciated that the implant is desirably implanted in a portion of the body which is not destined for human consumption.
Experimental trails carried out by us have shown that the principal reason for loss of implants from livestock is one of size, as hereinafter described. Our studies have shown if the implant of U.K. Patent Publication No. 2 030 044A with its inert core is reduced in diameter, then the loss rate will be reduced, but as the amount of active ingredient is also reduced, the efficacy of the implant is correspondingly reduced so that it no longer serves as an effective growth promoting agent. As one will appreciate the release of oestradiol from the implant is determined by the surface area of the implant.
In the course of carrying out our studies and trials we have examined the blood levels of oestradiol and have been able to determine an optimum blood level of oestradiol for growth promotion, as hereinafter described.
The implant of the present invention improves weight gain and feed conversion in fattening cattle for periods of 200 days.
The invention will be further illustrated by the following Example.
EXAMPLE An implant consisting of a solid cylinder 3.2 mm in diameter and 25 mm long and containing 47 mg oestradiol 17ss and 188 mg silastic rubber was formed in the following way. Oestradi ol-17ss (1 g) (supplied by Sigma limited, UK) was mixed with component 1 of medical grade silastic 382 (4 g) under vacuum for 30-60 minutes. Component 2 of silastic 382 (curing agent in the form of a catalyst consisting of 1-stannous octoate) (0.05g) was added to the mixture of component 1 and oestradiol and the materials were remixed and injection moulded into a mould roughly 50 cm in length and 3.2 mm in diameter. The oestradiol/silastic mixture was allowed to harden and then cut into the desired lengths of 25 mm. The implants so formed are optionally sterilised in plastics packets.
Implants of varying lengths may, of course, be prepared by cutting the hardened oestradiol/silastic cylinder to the desired length. The concentration of oestradiol will, of course, be correspondingly altered.
FIELD TRIALS Field trials were carried out as follows: a group of animals (bulls, calves, or steers) was selected and randomised into two groups. One group of animals served as controls and the other group were implanted with subcutaneous implants prepared as in Example 1. The implant was administered by subcutaneous implantation in the ear. Normal aseptic precautions were observed. The animals were weighed prior to implantation and at regular intervals (2-4 weeks) thereafter. The control aminals were similarly weighed.
EFFICACY AND RETENTION RATE STEERSEXPERIMENT 1 An experiment was carried out to determine the effect of different implants of silastic rubber based formulations of oestradioi-17ss on carcass data of steers and retention data of said implants. The results are given in Table 1.
TABLE 1 Type of No.of Days to Carcass Wt. Conformation Fat Recovery Implant Animals Saughter (kg) (g) (g) % (g) Cortrol (No Imp lant 16 258 321 3.23 3.75 - Solid 5 x 30 18 237 341 3.26 3.72 80% 12/16 Hollows 5 x 30 18 238 346 3.26 3.89 66% 12/18 Solid 4.2 x 50 17 237 340 3.26 3.67 75% 12/16 Solid 3.2 x 50 16 231 349 3.23 3.74 75% 12/16 F Test * ** N.S. N.S.
RSD + 25 18 0.58 0.44 (a) Adjusted for differences in initial weight (g) Adjusted for differences in initial weight and days to slaughter.
+ RSD = Root square deviation.
In Table 1 conformation refers to the shape of a cut of an animal carcass. Conformation is given a particular score with very lean cuts having a higher score than fatty cuts. Fat is scored on a conventional fat scale.
STEERSEXPERIMENT 2 An experiment was carried out in steers to determine the effect of different lengths of solid implants according to the invention of 3.2 mm diameter and as prepared according to Example 1 on carcass data and retention rate. The results are shown in Table 2 which shows the effect of different lengths on carcass weight, conformation and fat scores of steers.
TABLE 2 No. of Carcass Confor animals Wt. (Kg) mation Fat Recovery CONTROL (No Implant) 8 307 2.25 3.00 12.5 mm 8 317 2.25 3.13 100% 25 mm 9 332 2.67 3.44 100% 50 mm 7 331 2.57 3.43 86% LSD 20 0.48 0.35 It will be observed from Table 2 that 100% retention of the implant was obtained in the case of the implants of 12.5 mm or 25 mm in length. Only 86% recovery was obtained with the implant of 50 mm length. Indeed, when such implants were administered subcutaneously, implants were found within 1 hour in the animal locus. Accordingly, it will be appreciated that the length of the implant dictates the duration of effectivess.
STEERS-EXPERIMENT 3 An experiment was carried out to determine the optimum dose of oestradiol-17ss for growth promotion in steers. The results are shown in Table 3.
TABLE 3 Dose Titration of silastic rubber based oestadiol implants according to the invention in steers Wt. Wt. Wt. Wt. Wt. ADG++ No. (kg) (kg) (kg) (kg) (kg) 1-399 days 98 day 206 days 303 days 399 days Control 13 255 296 365 442 515 0.638 (No (molant) 12.5 x 3.2 (24mg08+) 14 248 285 368 446 520 0.681 25 x 3.2 (47mg08) 15 249 287 375 471 531 0.778 50 x 3.2 (94mg08) 15 247 294 371 463 531 0.757 F Test N.S. N.S. N.S. * N.S. ** 29 31 36 40 43 0.078 + OB = Oestradiol - 17B- benzoate.
++ ADG average daily gain.
The following conclusions can be drawn from Experiments 1, 2 and 3: 1. Implantation with the solid implant according to the invention significantly increases livestock gain of steers over a 200 to 400 day period 2. Implantation with the solid implant according to the invention significantly increases carcass gain 3. The dimensions of the solid implant according to the invention reduce the loss rate after implantation observed with larger silastic implants. In fact, no loss of the solid implant according to the invention (12.5 mm or 25 mm in length) was seen during all the trails 4. The solid implant according to the invention provides the optimum growth rate.
BULLS EXPERIET 4 An experiment was carried out to determine the optimum implant formulation for use in bulls over a 200 day period. The results are shown in Table 4.
Dose Titration of silastic rubber based oestradiol implants according to the invention in bulls Init. Wt. ADG* Wt. ADG ADG No. Wt. 96 1-96 200 96-200 1-200 (kg) (kg) (kg) (kg) (kg) (kg) Control 22 169 250 0.849 319 0.663 0.752 (No Implant) 12.5 mm 23 162 244 0.855 316 0.690 0.767 25 mm 24 164 250 0.893 322 0.695 0.790 50 mm 20 166 255 0.930 329 0.717 0.820 L.S.D. 29 24 0.085 27 0.062 0.075 * ADG = Average daily gain CALVES-EXPERIMENT 5 An experiment was carried out to compare the effect of the solid implant according to the invention on calves over a 150 day period compared with two implantations of an implant sold under the Trade Mark Synovex S. The results are given in Table 5. All weights are expressed in kilograms.
TABLE 5 The effect of different formulations of oestradiol implants on livestock gain of calves Init. Wt. Wt. ADG* Wt. ADG No. Wt. 49 98 1-98 150 1-150 Control 15 138 174 202 0.653 233 0.633 (No Implant) Synovex S x98 days 15 142 181 213 0.724 244 0.680 Implant of Example 1 3.2mmx25mm (47mgOB) 15 143 184 217 0.755 250 0.713 * ADG = Average daily gain The results of Experiment 5 show that a single implant according to the invention increases carcass weight and shows a more beneficial effect than two Synovex S implants at 98 day intervals. Synovex S is a compressed tablet implant consisting of 8 tablets containing in total oestradiol-17ss benzoate (20 mg) and progesterone (200 mg).
BLOOD SERUM LEVELS Blood serum levels of oestradiol-17ss were determined in steers implanted with 12.5 mm, 25 mm and 50 mm implants having a diameter of 3.2 mm and as prepared in Example 1. The results are shown in Fig. 1. In Fig. 1 curve a corresponds to the control, curve b corresponds to the 12.5 mm implant, curve c corresponds to the 25 mm implant and curve d corresponds to the 50 mm implant. Optimum results were obtained for the 25 mm implants in the efficacy studies reported above. Such 25 mm implants maintain a level of oestradiol-17ss of just over 10 pg/ml serum.
Fig. 2 is a summary of an investigation of serum oestradiol levels in steers implanted with implants sold under the Trade Mark Synovex S and implants sold under the Trade Mark Torevex S (oestradiol-17ss benzoate (20 mg), progesterone (200 mg)) Torevex S is also a compressed tablet implant consisting of 8 tablets and is identical in composition and form to Synovex S. The graphs of Fig. 2 represent oestradiol levels of steers implanted with Synovex S (curve b) and Torevex S (curve c) implants and of control steers (curve a) versus days post implantation after deletion of significantly outlying values.
From the results indicated in Fig. 1 with the implant according to the invention it can be concluded that the serum blood levels of oestradiol obtained with said implant according to the invention are below that obtained with either Synovex S implants or Torevex S implants. It is not unreasonable, therefore, to assume that tissue levels with the implant according to the invention will not be greater than that observed with Synovex S or Torevex S implants.
SLAUGHTER DATA Hot carcass weight was determined in steers implanted with implants as prepared in Example 1 (3.2 mm in diameter) and of variable lengths. The results are given in Table 6.
TABLE 6 Hot Carcass No. (Kg.) Wt.
Control 14 321.3 (SD 25.2) (No implant) 50 mm 14 333.3 (SD 22.1) 25 mm 14 337.6 (SD 19.3) 12.5 mm 14 334.1 (SD 28.2) Eye muscle area and dorsal fat thickness were determined in slaughtered steers previously implanted with implants as prepared in Example 1 (3.2 mm in diameter) and of variable lengths.
The results are given in Table 7.
TABLE 7 Eye Muscle Fat No. Area (cm) Thickness (mm) Control 14 76.2 (SD 9.7) 9.4 (SD 4.4) (No Implant) 50 mm 14 82.2 (SD 5.8) 9.7 (SD 1.7) 25 mm 14 82.1 (SD 10.3) 9.9 (SD 1.6) 12.5 mm 14 82.5 (SD 10.1) 9.1 (SD 3.3) If one considers the musculature of a species of animal, any particular muscle will vary considerably from one animal to another. However, it is found that the area of muscle which varies least and is most consistent in animals is the eye muscle area. A similar consistency is found in the dorsal fat area of the eye which is chosen as a measure of fat thickness in postslaughtered animals.
Table 8 gives results for conformation and fat in the slaughtered steers the subject of Tables 6 and 7. As stated above conformation is a measure of the shape of a cut of an animal carcass which is given a particular score. The higher the score the leaner the cut. In Table 8, the letters E and P refer to the EUROP scale for conformation which is a European carcass classification scheme. On the EUROP scale E corresponds to very good conformation, conformation progressively descreasing with values of U through P. For ease of computerisation and statistical analysis in the present experiments E has been assigned a value of and P and a value of 5. The conventional fat scale has values ranging from 1 through 5, 1 corresponding to a low fat content and 5 corresponding to a high fat content.
TABLE 8 No. Conformation Fat Control 14 3.5 (0.13) 3.4 (0.14) (No Implant) 50 mm 14 3.42 (0.15) 3.33 (0.17) 25 mm 14 3.3 (0.12) 3.4 (0.1) 12.5 14 3.8 (0.15) 3.52 (0.11) (E=1; (1=leo; P=5) (5=Hl) GROWTH PERFORMANCE Growth performance over 103 days was measured in the case of steers implanted with implants as prepared in Example 1 (3.2 mm in diameter) and of variable lengths. The results are given in Table 9.
TABLE 9 Growth Performance over 103 days A.D.G.
No. (KgJ Control 14 0.75 (SD 0.2) (No Implant) 50 mm 14 0.95 (SD 0.19) 25 mm 14 0.96 (SD 0.19) 12.5 mm 14 0.88 (SD 0.19) FEED EFFICIENCY Feed efficiency was determined in a group of steers implanted with implants as prepared in Example 1 (3.2 mm in diameter) and of variable lengths. The results are given in Table 10.
TABLE 10 No. Feed efficiency Control 14 0.0799 (SD 0.0197) (No Implant) 50 mm 14 0.0976 (SD 0.021) 25 mm 14 0.0979 (SD 0.024) 12.5 mm 14 0.0914 (SD 0.019) A side effect observed with the use of oestradiol implants is a temporary change in sexual behaviour and this applies to the implant according to the invention. For example, one observes a transitory increase in sexual activity in some of the implanted animals. However, this heightened sexual activity is generally only observed in about 2% of the animals implanted.
It has been found that the small diameter (3.0-3.5 mm) used in the implants according to the invention results in a reduced loss rate as indicated above. With the implants of the invention one can use a small diameter needle which results in less damage at the site of implantation and consequently less risk of infection. With implants of length greater than 40 mm, it is difficult to correctly align the implant at the site of implantation. Silastic being a rubber has considerable resilience. Accordingly, one possible explanation for the significant loss of implants of lengths greater than 40 mm is that the implant actually springs out of the hole through which it has been implanted after implantation.

Claims (19)

1. A subcutaneous implant for promoting growth in livestock, which comprises a solid cylindrical component of a self-curing silicone rubber impregnated with a growth-promoting amount of oestradiol or a pharmaceutically acceptable salt thereof and sufficient to maintain a sustained and substantially constant plasma level of oestradiol of between 10-20 pg/ml over the growth promoting period, said component having a diameter in the range 3.0-3.5 mm and a length in the range 10-40 mm and permitting up to 100% retention of the implant following implantation and throughout the growth promoting period.
2. A subcutaneous implant according to Claim 1, wherein the oestradiol or pharmeceutically acceptable salt thereof is present in the silicone rubber component at a concentration of from 10-30% by weight.
3. A subcutaneous implant according to Claim 1 or 2, wherein the oestradiol or pharmaceutically acceptable salt thereof is present in the silicone rubber component at a concentration of 20% by weight.
4. A subcutaneous implant according to any one of Claims 1 to 3, wherein the silicone rubber is a dimethylpolysiloxane.
5. A subcutaneous implant according to any preceding claim, which is 15-30 mm in length.
6. A subcutaneous implant according to Claim 5 which is 25 mm in length.
7. A subcutaneous implant according to any preceding claim, wherein the diameter of the implant is 3.2 mm.
8. A subcutaneous implant according to any preceding claim, wherein the oestradiol is in the form of oestradioi-17ss.
9. A subcutaneous implant according to any one of Claims 1 to 8, wherein the oestradiol is in the form of oestradoil-17ss benzoate.
10. A method of promoting growth in livestock, which comprises implanting in an animal an implant as claimed any one of Claims 1 to 9.
11. A method according to Claim 10, wherein the livestock is poultry.
12. A method according to Claim 10, wherein the livestock is a ruminant animal.
13. A method according to Claim 10, wherein the livestock is cattle.
14. A subcutaneous implant according to any one of Claims 1 to 9, for use in promoting growth in livestock.
15. A subcutaneous implant according to any one of Claims 1 to 9, for use in promoting growth in cattle.
16. Use of a subcataneous implant according to any one of Claims 1 to 9, for promoting growth in livestock.
17. Use of a subcutaneous implant according to any one of Claims 1 to 9, for promoting growth in cattle.
18. A subcutaneous implant according to Claim 1, substantially as hereinbefore described with particular reference to the accompanying Example.
19. A method according to Claim 10 for promoting growth in livestock, substantially as hereinbefore described with particular reference to the accompanying field trials.
GB8615367A 1986-06-09 1986-06-24 Subcutaneous implant Expired - Fee Related GB2191397B (en)

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IE153586A IE58536B1 (en) 1986-06-09 1986-06-09 Subcutaneous implant

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GB2191397A true GB2191397A (en) 1987-12-16
GB2191397B GB2191397B (en) 1990-05-16

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326278A1 (en) * 1988-01-21 1989-08-02 Dow Corning Kabushiki Kaisha Method for the manufacture of drug permeable materials
WO2000047232A1 (en) * 1999-02-14 2000-08-17 Jianjian Xu Sustained release implant, methods for preparation thereof and for treating cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB998794A (en) * 1962-08-28 1965-07-21 Dow Corning Carrier for controlled release of drugs
GB2030044A (en) * 1978-09-22 1980-04-02 Lilly Co Eli Subcutaneous prolonged release estradiol implant pellet

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB998794A (en) * 1962-08-28 1965-07-21 Dow Corning Carrier for controlled release of drugs
GB2030044A (en) * 1978-09-22 1980-04-02 Lilly Co Eli Subcutaneous prolonged release estradiol implant pellet

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326278A1 (en) * 1988-01-21 1989-08-02 Dow Corning Kabushiki Kaisha Method for the manufacture of drug permeable materials
WO2000047232A1 (en) * 1999-02-14 2000-08-17 Jianjian Xu Sustained release implant, methods for preparation thereof and for treating cancer

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Publication number Publication date
GB2191397B (en) 1990-05-16
GB8615367D0 (en) 1986-07-30
IE58536B1 (en) 1993-10-06

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Effective date: 19920624