Note: Descriptions are shown in the official language in which they were submitted.
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IMPROVED GROWTH STI T1 A~ yn~tpncrrrnwre
i i lVllL
FIELD OF THF 1NVF~r~rrn~r
5 The invention relates generally to veterinary pharmaceutical
'compositions and formulations that control the release of the active
compound therein to the animal. More specifically, the present
invention discloses actives in a dual formulation that stimulates growth
and weight gain in domestic animals.
10
BACKGROUND OF THE INVENTION
There have been many recent advances in the veterinary sciences
and veterinary pharmacology that have resulted in the growth and
development of larger, healthier and heartier, bovine, porcine, ovine
15 and equine species. Particularly with respect to the bovine, ovine and
porcine groups, the need to feed the world's population through the
production of meat provides the impetus to raise domestic animals that
grow as quickly and as large as possible.
Anabolic agents; are widely used to promote the growth of cattle
20 and other domestic animals and stimulated growth promotion is
desirable among the cattle farmers because it maximizes both rate of
weight gain and the absolute amount of weight gain per average
amount of food consumed, which is termed feed efficiency. Generally,
steroids are supplied to the animal in the form of a bio-degradable or
25 non-biodegradable, implantable, time release pellets) which is injected
under the skin using an implant device. These have been proven to be
successful; however, the animals may have to be implanted 2~_ times
during their growth period.
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The implant devices used for the subcutaneous delivery of these
steroid pellets consist of a housing in the shape of a pistol with a handle,
a hollow needle for injecting the pellet into the body of the animal
located at the front side of the housing, and a push-rod. The push-rod
:can be slid into this hollow needle and is supported in the housing so as
to be displaceable longitudinally. A chamber is provided in the housing
and is attached to the needle. A magazine containing the pellets is
inserted and displaceable therein. A longitudinally displaceable press-
back device (spring ejector) is arranged in the housing parallel to the
push-rod and hollow needle in the housing. The push-rod and press-
back device are moved by a driving mechanism which is similarly
provided in the housing and which can be set in motion by the
operating lever (trigger) fastened to the handle. This engages the
driving mechanism and press-back device via a toothed segment
coupled with the operating lever and a toothed wheel engaging the
press-back device and push-rod. Such a device design is described, for
example, in U.S. patent 5,514,101.
Zeranol , ormula I_ CAS Registry Number: 26538-44-3) is an
anabolic agent which has shown impressive results in the promotion
HO
vn
of weight gain and growth in cattle. Zeranol, a resorcylic acid lac~tone
derivative, has shown to be a positive influence on dynamic protein
metabolism. However, during the growth and development of the
cattle, current formulations containing zeranol or other such anabolic
agent must be administered at least twice over the 170 day growth and
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development period for optimal results. Obviously, this necessitates
bringing cattle in from the fields, reinjecting the implant and
transporting them out again which is a laborious and time-consuming
process.
5 It has been determined that zeranol and other anabolic agents
provide the best growth and weight gain results when administered
early on and throughout the. animal's growth cycle. This would require
a dual immediate-release/sustained-release formulation which has been
hereinbefore not possible.
10 United States Patent No. 5,643,595 to Lewis discloses and claims a
delivery system for veterinary growth promotants consisting of a
biodegradable polymeric matrix that contains a steroid growth
promotant and an antibiotic. The steroid growth promotant may consist
of zeranol which is formulated within sustained-release microparticles
15 consisting of homopolymers or copolymers of lactic and/or glycolic acid.
Other biodegradable polymers used in the sustained-release
formulations include polycaprolactone, polydioxonene, polyorthoesters,
polyanhydrides, waxes, casein and mixtures thereof.
United States Patent No. 5,427,796 also to Lewis discloses a
20 method for increasing animal growth comprising the administration of
an anabolic steroid such as zeranol in a biodegradable microparticle
delivery system that releases the drug in a multiphasic manner. Drug
delivery duration allegedly lasts up to 200 days. The same polymers are
used in Lewis's other patents noted above and below.
25 United States Patent Nos. 5,419,910 and 5,288,496 to Lewis also
disclose and claim a microparticulate sustained-release delivery system
for promoting growth in animals. The microparticles are comprised of a
biodegradable polymeric matrix such as poly-d,l-lactic acid, polyglycolic
acid and the like. The microparticles separately encapsulate a steroid
30 growth promotant and an antibiotic. Zeranol, among other anabolic
steroids, is disclosed as one of the useful actives that result in increased
bulls weight and growth.
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United States Patent No. 4,874,612 to Deasy discloses a multi-
component implant for the sustained-release, long-term delivery of
pharmaceutical agents to humans and animals for the treatment of
vitamin deficiencies, hormone replacement therapy, cancer therapy,
5 infection and the like. Preferably, the biodegradable polymers -
comprising the implants are used to deliver animal growth promotants
which contain anabolic steroids such as zeranol as well as their
combinations. The matrix used to make the implants consists of-lactic
acid/glycolic acid copolymers.
10 United States Patent No. 4,191,741 to Hudson et al discloses and
claims polymeric implants for the long-term sustained-release of
anabolic agents to ruminant animals. The steroids can be administered
alone or in combination, one of which is estradiol. Zeranol is not
specifically disclosed as one of these agents.
15 In fact, the use of biodegradable particles for the long-term,
sustained-release of anabolic steroids and other pharmaceutical actives
is known in the art. See for example, United States Patent Nos.
4,683,288; 4,677,191; 4,675,189; 4,542,025; 4,530,840; 4,489,055 and
4,389,330.
Unfortunately, not all of the prior art delivery systems enable
20 zeranol to be administered in a way that maximizes the growth and
weight gain potential that exists. Whereas zeranol and other anabolic
agents must be administered two to four times during the growth phase
. of the animal, it would be most advantageous to provide a formulation
that need only be administered once.
25 It is an object of the present invention to provide an anabolic
implant formulation for increased growth and weight gain significantly
greater than that achieved by animals given other steroid therapies and
those given none at all. It is a further object of the present invention to
provide an anabolic implant formulation that is given only once during
30 the growth phase of the animal yet provides both immediate and
sustained, long-term administration of the drug throughout the growth
period for optimal growth and weight gain.
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SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a method and an
anabolic implant formulation for stimulating increased rate of growth, greater
amount of growth and greater feed efficiency in cattle.
Thus, in one aspect, there is provided a method for stimulating increased
rate of growth, increased amount of growth and increased feed efficiency in
cattle,
comprising the administration of an anabolic implant dual formulation
composition to said cattle which composition comprises: (i) an immediate-
release
first formulation comprising an anabolic agent, and (ii) a controlled-release
second
to formulation comprising an anabolic agent and a controlled-release agent,
wherein
said immediate-release formulation and said controlled-release formulation
cooperate to effect said stimulation, and said composition produces a growth
and
weight gain in cattle higher than that of said first formulation (i) or second
formulation (ii) alone.
15 In another aspect of the invention, there is provided an anabolic implant
dual formulation composition for stimulating increased rate of growth;
increased
amount of growth and increased feed efficiency in cattle, said composition
comprising: (i) an immediate-release first formulation comprising an anabolic
agent, and (ii) a controlled-release second formulation comprising an anabolic
a o agent and a controlled-release agent, wherein said immediate-release
formulation
and said controlled-release formulation cooperate to effect said stimulation;
and
said composition produces a growth and weight gain in cattle higher than that
of
said first formulation (i) or second formulation (ii) alone.
In still another aspect of the invention, there is provided a method for
a 5 stimulating increased rate of growth, greater amount of growth and greater
feed
efficiency in an animal, said process comprising:
(a) preparing an immediate-release first formulation comprising an
anabolic agent, in a first shaped object suitable for loading into a device
which
device is suitable for administration of said shaped object into the animal;
3 0 (b) preparing a controlled-release second formulation comprising an
anabolic agent and a controlled-release agent, in a second shaped object
suitable
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- 5a -
for loading into said device in step (a), wherein said anabolic agent in step
(a) and
said anabolic agent in step (b) may be the same or different,
(c) loading said device with said first shaped object and said second
shaped object in a ratio such that the total anabolic agent is in the 50-95
weight
percent range based on the combined weight of said first and second
formulations;
and
(d) administering said shaped objects into the animal as a dual
formulation, wherein said immediate-release formulation and said controlled-
release formulation cooperate to effect the stimulation, and said dual
formulation
io produces a growth and weight gain in cattle higher than that of said first
formulation or second formulation alone.
The immediate-release formulation and the controlled-release formulation
may be simultaneously administered, or one immediately followed by the other
in
quick succession in whichever order the administrator chooses, to the animal.
15 Applicants have found that the inventive method of administering a dual
formulation surprisingly results in growth and weight gain in the animal much
higher than when either formulation (i) or (ii) is implanted without the
other.
The present invention further discloses a method of preparing the above-
noted dual formulation, an anabolic implant composition comprising a dual
a o formulation, as well as a method for stimulating growth and weight gain in
animals using such compositions.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, this invention discloses a method for stimulating
increased rate of growth, greater amount of growth and greater feed efficiency
in
a s animals, sometimes generally referred to as cattle in this application.
The method
comprises administering an anabolic implant composition which is a dual
formulation comprising (i) an immediate-release formulation containing an
anabolic agent, and
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(ii) a controlled-release formulation containing an anabolic agent and a
controlled-release agent. The immediate-release formulation and the
controlled-release formulation cooperate in the cattle to effect the
desired stimulation of growth and weight gain. Even though the dual
formulation may be administered as one composition by simultaneous
administration of both (i) and (ii) above in one administrating
(injecting) device, or administered one formulation followed by the
other in quick succession in whichever order the administrator prefers,
the following description, for simplicity sake, describes the invention as
a single step simultaneous administration method.
The present invention concerns a method of stimulating
increased rate of growth, greater amount of growth and greater feed
efficiency in food animals which comprises providing to such animals
biodegradable and non-biodegradable compressed tablets loaded with an
anabolic agent. The method of the present invention provides
advantages over methods known in the art such as, inter alia, increased
weight gain, a biodegradable or nonbiodegradable system, an implant
system, the ability to mix tablets (pellets) containing different drugs and
the ability to program the release rate (multiphasic release patterns).
In a preferred embodiment, administration of the growth
promotant to food animals by the method of the invention is achieved
by a single administration of the growth promotant loaded into
compressed shapes such as, for example, tablets which release the active
anabolic agent into the animal in a constant or pulsed manner and
eliminates the need for repetitive injections. Some of the tablets contain
the active anabolic agent with no controlled-release agent, while the
other tablets contain the active anabolic agent with a controlled-release
agent, as described later in the Examples. Thus, the former acts as the
immediate-release formulation while the latter acts as the controlled
formulation.
The anabolic agent used in the two formulations may be the same
or different. Illustrative anabolic agents suitable for and useful as
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_7_
growth promotants in the present invention include zeranol, estradiol
and its derivatives such as, for example, estradiol benzoate, trenbolone
acetate (Form.ula II CAS Registry Number: 10161-34-9, available from
Pharmacia & Upjohn Company, Kalamazoo, Michigan), somatotrophin
~-and its derivatives, testosterone and its derivatives such as, for example,
testosterone propionate, salbutamol, progesterone, its derivatives and
combinations thereof.
H
CH3 O CH3
O
H
O
In the immediate-release formulation, the anabolic agent may be
used as it is or optionally formulated with minor amounts of other
materials such as, for example, diluents, excipients, tabletting agents and
the like that are suitable for insertion under the skin. Examples of some
of these materials include lactose as a diluent, magnesium stearate as a
lubricant, silica as a glidant and the like. For example, the commercially
available Ralgro~ is formulated with lactose. Other diluent materials
include, for example, mannitol, sorbitol, sucrose, dextrose, starches,
hydrolyzed starches, and the like.
In the controlled-release formulation (also referred to as
sustained-release formulation in this application), generally the
controlled-release agent is a polymer matrix. The polymeric matrix
material must be biocompatible. The term biocompatible is defined as a
polymeric material which is not toxic to an animal and is not
carcinogenic. Whereas the matrix material is biodegradable, the
polymeric material should degrade by bodily processes to products
readily disposable by the body and should not accumulate therein.
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_g-
When the matrix is non-biodegradable, it is still biocompatible and may
remain within the animal at the site of implantation indefinitely.
Suitable examples of polymeric matrix materials useful in the present
inventiow include poly(D,L-lactide-co-glycolide) copolymer, ethyl
_ cellulose, methyl acrylate-methyl methacrylate copolymer,
methylcellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose,
sodium carboxymethyl cellulose, and the like. As in the immediate-
release formulation, the anabolic agent and the polymer matrix material
in the controlled-release formulation may be optionally formulated
with minor amounts of other materials such as, for example, diluents,
excipients, tabletting agents and the like, that are suitable for insertion
under the skin. Examples of some of these materials include lactose as a
diluent, magnesium stearate as a lubricant, silica as a glidant and the
like.
The implant is generally in the shape of a cylindrical tablet. The
tablet will generally have a diameter of from about 2.0 mm to 6.0 mm
and a length of from about 1.0 mm to about 4.0 mm. The implants for
the controlled-release are generally prepared by a procedure wherein the
active anabolic agent is mixed with the poly(D,L-lactide-co-glycolide)
copolymer or the ethyl cellulose together with the other optional
materials and this is then compressed in the die of a tabletting press as is
known in the art. Suitable illustrative procedures to make such
implants with biodegradable polymer and with non-biodegradable
polymer are described later in this application.
The rate of release of the anabolic agent in the controlled-release
formulation can be controlled by a variety of measures. With respect to
the poiy(D,L-lactide-co-glycolide) copolymer, the rate of degradation of
the carrier matrix can be increased by decreasing the size and
consequently the molecular weight of the polymer chains. Increasing
the amount of the active anabolic agent and consequently reducing the
active copolymer weight ratio will increase rate of release. The
incorporation of additional plasticizers and other excipients may even
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-9-
speed up the degradation and release. Such modifications will be
obvious to those skilled in the art.
The preparation of the implants containing a biodegradable
polymer such as, for example, the poly(D,L-lactide-co-glycolide)
'copolymer, may be achieved utilizing any number of methods known
in the art. An illustrative procedure is as follows. Preferably the anabolic
active is first dissolved in a suitable solvent that will also solubilize,
emulsify or disperse the poly(D,L-lactide-co-glycolide) copolymer:
Suitable solvents include organic solvents such as acetone, chloroform,
methylene chloride, other aromatic hydrocarbons, cyclic ethers, esters,
alcohols and the like and mixtures thereof. The polymer matrix
material is also dissolved or dispersed in the solvent and the emulsion
or solution formed thereby may be mixed into a continuous phase. A
surfactant may be added to the solution to prevent agglomeration.
The solvent is then removed, generally by the application of heat,
the application of reduced pressure or both. The temperature employed
is not critical but it should not be so high as to result in a degradation of
either the active compound or the implant biodegradable matrix
material. Once the solvent is removed, the solid dose implants may
then be prepared using a standard tabletting die press as is known in the
art.
Preferably, the anabolic agent useful in the formulation of the
present invention is zeranol. A commercially available formulation of
zeranol is Ralgro~ {from Schering-Plough Corporation, Terre Haute,
Indiana) which additionally contains some lactose. The zeranol content
in the present formulation is in an amount of from about 50 w#.% to 95
wt.% preferably from about 55 wt.% to about 85 wt.% and most
preferably from about 60 wt.% to about 80 wt.°!°, based on the
total
weight of the implant composition (including both the immediate-
release part and the controlled-release part).
The poly {D,L; lactide-co-glycolide) copolymer is incorporated in
the sustained-release formulation in amounts ranging from about 1.0
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wt.% to about 10 wt.% and preferably from about 1.0 wt.% to about 5.0
wt.%. If ethyl cellulose is used as the agent in place of the poly(D,L-
lactide-co-glycolide) copolymer, greater amounts may be used such as
from about 1.0 wt.% to 8.0 wt.% and preferably from about 2.0 wt.% to
about 7.0 wt.%.
The other optional materials may be added to the formulation
according to the length of drug delivery desired, but for the most part
these will be added in standard amounts as is known in the art. For
example, a diluent or excipient may be added in amounts of from about
20wt.% to 40 wt.%, preferably in an amount of from about 25wt.% to 40
wt.%, and typically in amounts of from about 25 wt.% to 30 wt.%.
Coloring dyes for foods, drugs & cosmetics ("FD & C"), and the like may
be incorporated into the formulations in amounts of from 0.1 wt.% to
2.0 wt.% as is known in the art.
Implants containing non-biodegradable polymer such as, for
example, ethyl cellulose, may be prepared by procedures known in the
art. An illustrative procedure is as follows: The anabolic agent such as
zeranol is mixed with a diluent such as, for example, lactose, and
optionally a suitable dye in a planetary mixer. In a separate mixer, an
aqueous dispersion of ethylcellulose commercially available as Aquacoat
ECD-30~ (available from FMC Corporation, Philadelphia, Pennsylvania}
is mixed with a suitable plasticizer such as triacetin, or dibutyl sebacate,
etc. The plasticized ethyl cellulose is then blended with the anabolic
agent/lactose mixture and granulated. The granules are dried at a
temperature of from about 50° c to 70° C until the formulation
is
characterized by a moisture level of from about 0.2 wt.% - 0.6 wt.% based
on the total weight of the formulation. The dried granules are then
sized through a sieve, such as, for example, the Fitzmill sieve or its
equivalent, and then lubricated with an appropriate lubricant such as
magnesium stearate and a glidant such as, for example, silicon dioxide.
The granules are then compressed into pellets of the desired size and
hardness.
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Without being bound to any theory, it is believed that ethyl
cellulose which is a pseudolatex matrix is distributed evenly throughout
the wet mass. Upon drying, the matrix particles become finely blended
with the active anabolic agent and the excipients. Compression in the
tablet die further condenses the ingredients together.
A heating or curing step is important as this seems to fuse or
coalesce the ethyl cellulose particles forming a true matrix structure
about the active. This results in the active anabolic agent/excipient
blend being fully entrapped by the ethyl cellulose chains.
For the immediate-release formulation, compositions such as the
commercially available zeranol product, such as, for example, Ralgro~,
may be used and compressed into suitable size tablets. Any optional
ingredients such as, for example, dye and the Iike, may be mixed in
before compressing into tablets.
The inventive dual formulation is prepared by taking a certain
number of thus-prepared tablets containing the controlled-release
formulation and a certain number of thus-prepared immediate-release
formulation (including Ralgro~ which is zeranol plus lactose) tablets in
the injection device. The number of each kind is determined based on
the total amount of zeranol one desires to inject into the animal. For
comparison purposes, the dual formulation injection may be compared
with injection of either the controlled formulation tablets alone or the
zeranol tablets alone such that the total amount of zeranol would still
match with the total zeranol in the inventive dual formulation. The
growth enhancement implant pellets are generally subcutaneously
injected into the cattle, or other domesticated animal under the ear.
After administration, water diffuses into the tablet from the tissue of the
animal and is driven by hydration of the lactose and to a small extent by
hydration of the anabolic agent. The dissolved active then diffuses out
of the matrix structure and into the animal's systemic circulation. As the
EXAMPLES demonstrate, Applicants found that the inventive dual
formulation tablets surprisingly resulted in a higher increase of growth
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and weight gain in the test animals than either the controlled-release
tablets alone or the zeranol tablets alone.
Another embodiment of the present invention discloses anabolic
implant compositions and formulations for stimulating increased rate
'flf growth, greater amount of growth and greater feed efficiency in cattle.
The inventive composition is a dual release formulation which
comprises: (i) an immediate-release formulation containing an anabolic
agent, and (ii) a controlled-release formulation containing an anabolic
agent and a controlled-release agent, wherein the immediate-release
formulation and the controlled-release formulation cooperate to effect
the desired stimulation of growth and weight gain. The types and
examples of (i) and (ii) are described above.
A further embodiment of the present invention discloses a
method of stimulating increased rate of growth, greater amount of
growth and greater feed efficiency in cattle, whose growth, weight gain
and feed efficiency need to be improved, by administering to said cattle
an anabolic implant composition which is a dual release formulation
which comprises: (i) an immediate-release formulation containing an
anabolic agent, and (ii) a controlled-release formulation containing an
anabolic agent and a controlled-release agent, wherein the immediate-
release formulation and the controlled-release formulation cooperate to
effect the desired stimulation of growth and weight gain. The types and
examples of (i) and (ii) are described above.
A still further embodiment of the present invention concerns a
method for stimulating increased rate of growth, greater amount of
growth and greater feed efficiency in an animal. The method comprises:
preparing an immediate-release formulation comprising an anabolic
agent such as, for example, the agents described above, in a shaped object
suitable for loading into a device such as, for example, pellets, tablets
and the like, which device is suitable for administration of said shaped
object into the animal (such as, for example, the pistol described earlier);
preparing a controlled-release formulation containing an anabolic agent
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and a controlled-release agent, in a shaped object similar to above and
suitable for loading into the device in step (a), wherein said anabolic
agent in step (a) and said anabolic agent in step (b) may be the same or
different; loading the device with the shapely object in step (a) and the
5 -shapely object in step (b) in a ratio such that the total anabolic agent is
in
the 50-95 weight percent range based on the combined weight of the two
formulations (i.e. the formulation in step (a) and the formulation in
step (b)); and administering the shaped objects into the animal, wherein
said immediate-release formulation and said controlled-release
10 formulation cooperate to effect the desired stimulation. Suitable
controlled agents and methods for making the formulations are
described above.
The following EXAMPLES are provided to more fully describe
how to make and use the implants of the present invention, as well as
15 to demonstrate the superior results attained thereby. It should be noted
however that the examples are for illustrative purposes only and that _
minor changes or variations may be made in the amounts and/or
methods that are not covered therein. It should also be noted that to the
extent any such changes or variations that do not materially alter the
20 composition or effects of the final product are deemed as falling within
the spirit and scope of the present invention as later recited in the
claims.
EXAMPLES
~114PLE 1~ Comnari~nn of Weight Gain with Zeranol arc
m dia - el a F 1 io o la ~ n onta~ i ' 1.
_as Controlled-release F~~,xlation~ The following zeranol matrix
base formulations were prepared to compare controlled-release
30 formulations containing zeranol with Ralgro~ and a placebo (an
ineffective control). As stated earlier, Ralgro° is a commercially
available product of zeranol and lactose.
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Formulation Comuos, ition
A Controlled-release Formulation: zeranol/poly(D,L-
lactide-co-glycolide copolymer; 50:50 wt%) (180 mg
total zeranol)
5 B Controlled-release Formulation: zeranol/ethyl
cellulose (50:50 wt%, 180 mg total zeranol)
C Ralgro~ (36 mg zeranol)
D Placebo: no Zeranol
10 The implants were prepared as follows. For formulation A, the
poly (D,L-lactide-co-glycolide 50:50, 3.991 g) was placed in an Erlenmeyer
flask and dissolved in 50 grams of ethyl acetate. Separately, the zeranol
and lactose (26.606 g) were mixed together dry in a mortar to which the
FD & C coloring dyes (0.44 g) were added. The solvent comprising D,L-
15 lactide-co-glycolide and ethyl acetate was then added to the
zeranol/dye/lactose mixture. The composition was then heated to 40-
45°C. to complete dryness and granulated and sized through a 25 mesh
screen. A Cab-O-Sil~ silica glidant (0.665 g) was added along with
magnesium stearate (1.33 g) which was added as a lubricant. The
20 compositions were then compressed in a tabletting die to obtain solid
implants {26.606 mg each implant) with a hardness of 12-20 Strong Cobb
units. Formulation B was prepared in a similar manner using ethyl
cellulose as the polymer matrix and Aquacoat ECD-30 instead of ethyl
acetate. For formulation C, Ralgro~ was made into similar size tablets
25 using procedures known in the art. And formulation D, the control
with no zeranol was made into tablets similar to in formulation C.
The implants were administered to twenty (20) steers
subcutaneously under the ear. l:n order to properly compare the.
formulations of the present invention with those of the prior art,
30 formulation C was administered twice, once at day 0 and again at day 70,
each dose containing 36 mg of zeranol. Each steer was weighed at
selected time periods during its development and the average body
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weight for each group given a particular formulation A to D was
calculated for each date and are as follows:
Table 1
Treatment Day Day Day Day Day Day Day Day Day
0 28 56 70 84 112 140 168 1'82
A 339 423 483 544 562 616 693 765 803
B 337 426 492 558 568 631 701 780 $06
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 with either controlled-
release formulation (A or B) is slightly lower than or, at best; statistically
equivalent to that of the Ralgro~ re-implant program of formulation C.
15 x 2:C a's o i i v i eD
Formulation versus Weieht Gain with Immpd;ate Formulation al ne
Qr with Controlled Formulation aloruP The effects of implanting the
dual immediate-release/controlled-release pellets of the present
invention on weight and growth gain were studied and compared with
20 zeranol (as Ralgro~) alone, with controlled-release formulation alone
and with a non-effective placebo control. That could be done by
replacing certain controlled-release tablets of Example 1 with Ralgro~
tablet(s). The administered dosages were as follows. The total weight
administered is shown in brackets.
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Formulation tom o ition
E Placebo control; no zeranol
F Ralgro~ (36 mg zeranol; 3 pellets 12 mg each)
5 G Zeranol immediate-release (1 pellet of 18 mg zeranol) + Zeranol
controlled-release-poly (D,L; lactide-co-glycoside) (80 mg zeranol;
4 pellets of 20 mg each) [98 mg total zeranolj
H Zeranol immediate-release (1 pellet of 18 mg zeranol) + Zeranol
controlled-release /poly (D,L-lactide-co-glycolide) (160 mg zeranol;
0 8 pellets of 20 mg zeranol each) [178 mg total zeranol]
I Zeranol immediate-release (1 pellet of 18 mg zeranol) + Zeranol
controlled-release /ethyl cellulose (160 mg zeranol; 8 pellets of 20
mg zeranol each) [178 mg total zeranol]
J Zeranol immediate-release (1 pellet of 18 mg zeranol) + Zeranol
~ 5 controlled-release /ethyl cellulose (80 mg zeranol; 4 pellets of 20
mg zeranol each) [98 mg zeranol total]
As can be seen, to prepare the inventive dual formulations H and
I, one zeranol immediate-release pellet and 8 zeranol controlled-release
20 pellets were taken in the device. Similarly, to prepare the inventive
dual formulations G and J containing just half the amount of the
controlled-release formulation, one zeranol immediate-release pellet
and 4 controlled-release pellets were taken in the device. The
immediate-release pellets and control release pellets were formulated as
25 in Example 1 and administered to six groups of cattle in a similar
fashion, i.e., subcutaneously under the ear. Again, in order to compare
the improved formulations with the prescriptions currently followed in
the veterinary art, formulation F was administered twice, once (36 mg)
at day 0 and again (36 mg) at day 70. Each steer was weighed at different
30 intervals during its development and the average weight for each group
given a particular formulation was averaged for each date. The
formulations and average weight gain results for each are as follows:
CA 02348841 2001-04-30
WO 00/25743 PCT/US99l23993
-17-
T e2
~~el~ht fin lr;l.~..raii~ i
Treatment Day Day Day Day Day Day Day
=Formulation (-1) 0 28 56 84 112 140
309 303 352 389 425' 461 491
F 309 300 356 398 435 477 511
G 308 301 354 401 444 485 525
H 309 302 358 404 445 485 525
1 309 302 357 408 451 494 533
309 302 356 402 443 481 518
As is evidenced by the results shown for formulations GJ,
superior growth and weight gains were observed with the inventive
dual release formulations. Thus, when one (out of nine) of the
controlled-release formulation pellets was replaced with one
immediate-release pellet (formulations H and n, the weight gain became
significantly higher than the results observed following the standard
immediate re-implant program (formulation F) above. Such
improvement was also noticed even when the controlled-release
fraction was reduced by half (from 160 to 80 mg or 8 to 4 pellets) as
shown in formulations G and J.
