Note: Descriptions are shown in the official language in which they were submitted.
~73~57
This invention relates to a two-componen-t pharmaceu-
tical preparation which is characterized by the property of
providing a prolonged release of the medicament component due
to gradual and essantially uniform digestion of exposed surfaces
of the supporting matrix component.,~The medicament composition
is made up of originally essen-tially undenatured native milk
solids which are first reacted with ~an aldehydic insolubilizing
agent in the presence of the drug~ granulated,~and final~ly com-
prsssed into solid ddsage form. More particularly, it is con-
cerned w~th such preparations and methods of their productionwhich provide extremely efficient prolonged release of drugs in
ruminant animals such as cattle and sheep.
In the treatment of illnesses indigenous to ruminants,
it is often extremely desirable to provide a medicament compo-
sition which has the property of slowly and steadily releasing
the drug into the bloodstream of the host. For example, when
cattle become ill from diseases such as that oommonly referred
to as "shipping fever", it is generally necessary to treat them
daily with one of the sulfonamide or antibiotic drugs for a ;
period of several days in order to overcome infectious processes,
lower their body temperatures and alleviate other debilitating
symptoms. In the past this has normally been accomplished by
repeated doses of the appropriate drug in order to maintain a
therapeutically active amount thereof in the bloodstream of the
affected animal. As can be appre~ia~ed, this daily procedure
increases costs and is a time-consuming procedure, especially
when there are a large number of sick animals which mu~ be
treated as often as once every twenty-four hours. Therefore,
-1- ;
1~3357
there is a great need for a method of ~reatmen~ which allows
administration o~ a dosage form containing a therapeutic drug
agent which is o such lasting duration that the necessity ~or
repeatedly a~ministering drug doses to the ruminant animal over
an extended period is avoided.
The prolonged release medicamen~ co~nposi~ions of ~e
prior art can be grouped into four general classes. First~ some
compositions depend upon retarded dissolution to provide their
prolonged release capabilities. An example would be c~psules
.
which contain mixtures of beadlets coated with varying numbers
or thicknesses of coatings of slowly soluble substances which
must be dissolved at varying rates, depending primarily upon the
. various thiclcnesses o~ the coat~ngs.
Another ~ype of prior ar~ composition attempts to
produce the desirable prolonged lelease qualities by coating
2x~remely sm~1 granules or WnOle tablets of medicament with
~anned gelatin or collagenic films which are poorly soluble, but
slowly digestible or leachable.
Yet another type of prolonged release medicament
emp~oys a physical wicking action through pores in a matrix
which surrounds the medicinal dru~. Examples of this type of
prolonged release formulation include those characterized by
porous plastic or other insoluble or water repellant carriers
whose pores contain and slowly release medicament by an aqueo~s
leaching process.
Finally, a number of formulations have achieved a
limited prolonged release capability ~y attaching medicament
molecules to an ion exchange resin so that the medicament will
be released when exposed to speci~ic pH environments in certain
~egions of the gastrointestinal trac~.
-- 2 --
10733S~
These pr:Lor attempts at producing a satisfactory
prolonged release composition have met wi~h only limi.ted success.
A primary problem has been the necessity ~or repeated dosing of
the animal because of the rela~ively rapid release rate of the
medicament making them effective ~or only comparatively short
periods of time. More significantly, however, the rate of
medicam~.nt release from these compositions is heavily de~)endant
upon a generous water content or the presence of relatively
specific narrow pH ranges in certain regions of the gastroin-
testinal tract at certain critical time intervals after treatmento the mammal. Hence, the release patterns can be seriously
affected by varying peristaltic activi.ty, pH aberrations or water
content in the gastrointestinal tract. Since these factors
characteListlcally vary consider~bly and cannot be depended upon
in si.ck animals, most o~ these prolonged release compositions
tend to be unpredictable and therefore undesirable in performance. -
~~oreo~er, these prior art prolonged reiease dosage forms are
characterized by an unpredictability in performance and ineffi-
ciency in medicament release, which detracts from their usefulness
in practice. In addition, the methods necessary to produce these
compositions are o~ten very expensive and dificult to consistently ,
duplicate.
Therefore, there is a decided need in the art for a
prolonged release medicament composition which has significantly
enhanced prolonged release properties and is also characterized
by a uniform and predictable release of the medicament under
widely varying conditions of pH anG water content in the gastro-
intestinal tract of the host ruminants. Furthermore, the present
invention when used in ruminant animals, has the very unique
property of a direct relationship between the de~ree of fever and
duration of the prolonged release period. For example, the
~733~i7
higher the fever, the more prolonged -the release. Other slow
release boluses of the present art designed for use in ruminants
do not have -this desirable characteristic. In fact, most of them
exhibit a shorter release period in feverish animals.
Accordingly, it has been discovered that the above-
outlined problems and deficiencies can be overcome by providing a
prolonged release composition for the traatment of ruminant
animals which comprises a first matrix component of insolubilized
originally essentially native milk solids that have been inti-
mately admixed with and support a second drug component which ispresent in therapeutically significent amounts.
In general, a compressed, self~sustaining dosage form
according to the invention is made up of a therapeutically
significant amount of a drug intim~bely entrapped within and
uniformly distributed throughaut an essentially water-insoluble
but slowly digestible matrix made from milk solids which were
originally essentially undenatured. As used herein, the phrases
"native milk" and !~essentially undenatured" refer to milk solids~
whether derived from whole, condensed or skim milk in either dry
or liquid form.
In practice, the compressed dosage form is produced by
first admixing the native milk solids with -the drug. Then a
predetermined amount of an insolubilizing aldehyde agent such as
an aqueous solution of formaldehyde is added that serves to form
a cross-linked, lattice-type matrix with the milk pro-tein which
renders the milk solids essentially water-insoluble but slowly
digestible. The mixture is next granulated, dried and then
subjected to sufficient compression to form a rela-tively dense,
self-sustaining oral dosage form. As an alterna-tive to granula-
tion, spray drying of the reacted milk solids and drug may becarried out. It is preferable that the compressed dosage form be
_ L~--
33~t~
capable of re~i~t~g slgniflcant di~integratlorl when tumbled in
water a~ a te~pe~a~ure oiE abou~ 37 C. for a~c lea~t tw~n~y~four
hours .
In the developmen~ of ~he pre~ent intrent~ a number
of s~gnificarlt and ~urprislrAg discoveria~ re made. Orle i~portant
finding was that only native mille (l.e., es~ent~ally undenatured)
wa~ operable as ~he proteln mEItrix. t~ile eiLther whole or no~fat
natiye- milk i8 usable, the conssituent protein~ extxæcted there-
fro~ do no~ yield the desired propereles when used as the olatri~
10 component. For e~ple, caseill or cafieislates, which are th~
chief comp3nents of mllk, do not ~erv~ as an adequate protein
ma~crix when employed alo~e. ~oreover, a recomblnation of ~che
componen~s o milk (e~g., lac~co~e added to calcium ancl sodium
caseinstes) also iEalls to exhibit the requi~ite properties.
Other unrelated ~ubstances such as gelati~s~ col~agen, keratln,
80y flour, whea~ genm ~Qal~ whey9 hemog10b~p p~n~o bea~ meal9
cotton~eed meal~ soy 10ur and soybea~ ~eal have bee~ te~ted in
the development of the present ~nven~ion, bu~ all have fa~1ed ~o
pass 80m2 criteria ~ece~ar~ for the product~o~ of satisfactory
prolonged release compres~ed drug compo~itions. Therefore~ it i8
believed that thc ~pecific morpholo w of native mllk i8 an e~en-
~ial ~eature which allows the milk to act as a prolonged release
matrix ~fter tre~t~ent wi~h a~ appropria~e aldehyde in~olubilizin~
agent and coDlpres~ nto a 8elf-8U8tai~ rlg body.
Aldehydic ~n~olubiliz~g agents for use in the pres~nt
inv~ntlon ~ust of eourse be capable of reac~i~g with native ~llk
to give the n~ce~sary degree of chemical modific~tion i~ the
re~ul~ing supp~rt ~atri~ in order to produce the de~lxed xelea~e
patternæ in ~he ~in~l co~po~ition. F~rth~r, any exce3s al~unts
o~ lnsolubilizing ag~nt mu8t be ra~ovable rom or rendered e~sen-
tlally nontoxic in the final product, and incapa~ble of reactin~
10'~335'~
to any significant degree with the drug component. In prefe~red
foxms, aqueous solutions of insolubilizing agents which have an
aldehydic functioning group thereon have been ound to be especi-
ally advantageous. This classification includes solutions o~
formaldehyde as the preferred agent. Ho~eYer, aqueous solutions
of such wa~er-soluble, volatile, aliphatic aldehyde compounds as
~lutaraldehyde, acetaldehyde, butyraldehyde, propi~naldehyde
having from l to 5 carbon atoms are also useful.
Drugs which have utility in the present invention
include, but are not limited to, sulfamethazine, sulfathiazole,
~uladimethoxine and similar sulfonami.des. However, other medica-
ments such as common aspirin, organo~phosphates and the tetra-
cyclines are ~ully operable and ~ave excellent prolonged release
characteristics.
In the proferred preparation technique, the two phases~
of the composition (i.e., native milk and drug~ are first thoroughly
a~mixed and the aldehyde insolubilizing agent added to effect
cross-linking or other chemical modifications of the milk to fol~m
a matrix which upon subsequent granulation and drying of the
~0 composition entraps and supports the drug in the ~atrix. The
final step involves compression of the granules into a shape
which provides an efective drug dosage for administration to
sick ruminants. For example, in preparing boluses for administra-
tion to cattle, the resultant self-sustaining bodies should
preferably resist significant disintegration when tumbled in
water at about 37~ C. for at least twenty-four hours. In this
way, the bodies retain their integrity in water, but are slowly
digestible by ~roteolytic digesti~e enzymes or bacterial floral
enzymes found in ~he stomach and gastrointestinal tract of cattle
s~^e
J ~ v ~;; P .
While the physical and chemlcal actions responsible for
the prolonged release effects in such compositions are not wholly
- 6 -
1~)73~57 `~
`:
understood, it is believed that the digestive enzymes and/or
bacterial floral enzymes present in the digestive -tract of the
host ruminant ac-t to slowly digest the insolubilized milk suppor-t
matrix, thus re~easing the entrapped dru~. These enzymes and/or
microorganisms apparently attack -the exposed surface of the
tablet or bolus and thus slowly and progressively digest the
matrix component; therefore, new surfaces are continually being
exposed and the rate at which drug is released can be assumed to
be approximately proportional to the total surface area exposed
1~ at a given time. Hence, the release rate is initially high and
thereafter slowly and s-teadily decreases over time as the self-
sustaining body diminishes in size due to diges-tion.
Figure 1 is a graphical representation showing com-
parative prolonged release tests with~sick cattle between a
single administration of boluses produced according to the
present invention as opposed to an equivalent to-tal dosage of a
conventional bolus of the prior art, the latter requiring four
intermittent administrations spaced twenty-four hours apart;
Fig. 2 is a graphical representation showing the effect
of initial body temperature of sick cattle upon the prolonged
release characteristics of boluses made in accordance with the
ins~ant invention;
Fig. 3 is a graphical representation o~ the comparative
prolonged release results obtained from the administration to
both sick and healthy cattle of equivalent doses of boluses made
according to the-~inventiQn;
Fig. 4 is a graphical representation of the comparative
prolonged release rate results obtained from the administration
to two groups of sick cattle of equivalent doses of boluses made
according to the invention, one group being given boluses made
~73357
from water-treated granules, while the other was given boluses
made from formaldehyde-treated granules;
Fig. 5 is a side ele~ational view showing one typical
form of a-~compressed bolus produced according to the invention,
in actual size;
Fig. 6 is a front elevational view of the bolus shown
in Fig. 5;
Fig. 7 is a rear elevational view of the bolus shown in
Fig. 5; and
Fig. 8 is an end elevational view of the bolus shown in
Fig. 5.
By way of example, a bolus 10, shown for illustrative
purposes only as being suitable for administration to sick
cattlelj preferably comprises a compressed, solid, rela-tively
dense self-sustaining body of the size depicted in Figs.~5-8.
~h~hough~1the~iprec-ise~shape andiphysical dimensions of the bolus
are not critical, it is contemplated that it be sized and con-
figured so that it is usable in universally emp~oyed bolus guns
familiar to those skilled in the art. Therefore, as shown in
those drawings, the bolus 10 includes an arcuate top face 12 and
a similarly configured bottom face 14. Connecting the two opposed
faces is a substantially vertical, peripherally extending contin-
uous sidewall 16. For convenience, an indentation 18 is fashioned
in the approximate center of top face 12 so that the bolus can be
easily broken into approximate half portions. The bolus illustrated
full size in Fig~. 5-8 is especially adapted for administration
to cattle. Sheep bo~luses would be correspondingly smaller.
I~ is!--to be understood, however, that other types of
compressed oral dosage forms of varying shapes and densities can
be produced as desired in accordance with this invention. All
-8-
~Q~3357
th~t is required is ~hat the dri.ed insolubilized milk and drug
compositicn be comprcssed to form a sel~-sustaining body that can
~e orally a~ninistered in conventional manner to the intended
ruminant host.
In order to facilitate an understanding o the methods
, . . .
of the present invention, the ~ollowing Examples detail the
critical steps as well as the ~:ique properties of the medicament
compositions ultimately produced. It is to be understood, however,
that the Eæamples are for the purposes of illustration only, and
are not in any way to be taken as speci~ic limitations upon the
o~erall scope of the invention.
EX~MPLE I
-
In order to produce boluses especially useful for
administration to ruminants, the following processing technique
has proved to be use~ul in production scale runs.
55~ lA~ gra~s ~g.~ U.S.P. grade sul~e~h~zille is
thoroughly Inixed in a large ribbon b]ender with 255 kg. of
instant essentially undenatured nonfat dry milk ~ntil the two
components are initimately and thoroughly admLxed. A 1.5% by
weight aqueous solution of formaldehyde is then prepared in the
ra~io of ~lO.S cc o~ 37% by weight formaldehyde sol~tion diluted
with tap water to make a total volume of 1,000 cc. A total of
approximately 26~ liters of such solution is mixed with the
native dried milk and sulfamethazine admixture in a conventional
pharmaceutical "pony" blender.
A~ter complete ~ixing of these ingredients, the ~esulting
product is granulated with an oscillatin~ granulator using a
No. 4 mesh screen. These granules are then spread onto large
trays and allowed to dry overnight at approximately 140~ F.
3u r ollowirl~ drying, 1 hg. ol pharmaceu~ical grade Carbo
po~ 934P ~acrylic acid cross-linked with polyallyl sucrose, sold
* Trademark
_ 9 _
~ 335~
by the B. F. Goodrich Company) is dissolved in 270 liters slightly
warmed 99% aqueous solution of isopropyl alcohol, and the resulting
solu~ion is slowly added to the dried granules in a pony mixer.
A calcium hydro~ide suspension produced by suspending 12 kg.-of
Ca(OH)2 in 30 liters of isopropyl alcohol is then sl~wly added to
the foregoing while mixing continues until all of the ingredients
a~e thoroughly mixed. The resulting product is again pu~ on
trays and allowed to dry overnight at approximately 140 F.
followed by granulation through a No. 5 screen. (The Carbopol
934P, calcium hydroxide and isopropyl alcohol do not afect the
proionged released capabilities of the boluses produced by this
.*
method. Carbopol 934P is added merely to facilitate compression
of the granules and to enhance the appearance and handling charac-
teristics of the final product, while Ca(OH)2 is added to precipi-
tate and hence facilitate drying of the Carbopol 934P.)
Following the second drying and granulation steps, the
granulat2d mlxture ic pl~c~d ~n a large ribb^n blen~r and 135
kg. of U.S.P. grade sulfamethazine and 9 kg. of magnesium stearate
are added thereto. This added drug substar.tially "fills" any
interstices remaining in the milk matrix granules, while the
stearate serves merely as a conventional lubricant to aid in
compression of the sel-sustaining bodies.
Standard sized boluses for administration to cattle as
depicted in Figs. 5-8 can be produced, or dosage forms suitable
for sheep, fbr example, can be formed. This is accomplished in a
bolus press capable of a compression of approximately 16 tons per
square inch. The resulting bolus ~as a density greater than 1
and preferably about 1.23 grams/cubic centimeter. The chemical
composition of each bolus as described in the example is:
sulfamethazine 22.50 grams
nonfat dry milk 8.50 " "
- fo~maldehyde trace
* T~^ademark
~ 10 -
~Oq33S~
Car~opol 934P ~.06 " "
calcium h~dro~ide 0.40 " "
isopropyl alcohol trace
magnesium stearate 0.32 " "
The following experiments demonstrate the unexpected
specificity and criticality of employing native ci.e., essen-
tially undenatured~ mil~ which has ~een insolubilized wlth an
aldehydic agen~ as the drug carrier in the prolonged release
medicament compositions of the present invention. These for-
~0 mulations exhibit required resistance to disinteg~ation as wellas p~olonged release properties.
EXAMPLE II
(a~ A quantity o non~at dried milk was dissolved in
water and denatured by steam autoclaving at 121~ C. for 45 mlnutes,
then dried at 40 C. 9 ground to a fine powder and used to make
boluses as described in Example I (except for omission of the
Garbopol 934Pl. These boluses appeared firm and hard but they
disintegrated in 3 minutes when tumbled in tap water at 37 C.
(U.S.P. disintegration test~. O~viously, with such a short
disintegration time, it would not be possible to obtain prolonged
release e~fects; there~ore, the autoelaved formulation was not
tested in ViYo. ~y contrast, boluses made in accordance with
Example I Cagain omitting Carbopo~ 934P~ and thtls containing
essentiaily undenatured dried milk reacted with formaldehyde,
resisted disintegration ~or 168 hours.
~) 350 gms. of nonfat dried milk was den~tured by
boiling ~ th 10 gms. of calcium chloride Cthe latter was added to
facilitate denaturation since it is known to disrupt hydrogen
bonding). A granulation incLuding sulfamethazine was made as
~n described in ~xample I hereo and the granules were di~ested in
1% papain solution.
~ Tradem~rk
- 11
~335~
~ c~ ~n identlcal granulation was made as described in
section Ca) of this Example, excep~ undencltured milk was used in
the formulation, and the granules were digested in lV/~ papain
solution.
The digestion results for the papain tests of paragraphs
Cb) and Cc~ are as follows:
TABLE 1
.
% of Dru~ Released by Di~estion
1 ~r. 3 Hrs. 5 Hrs.
Undenatured Milk [Ex.II(c)] 3.2% ~6.2% 27.6%
.
Denatured Milk ~Ex.II(b)]98.65% Q.69% 0.66%
Small C9/16"2 tablets were also made from the granu-
lations of the preceding table and disintegration rates ~U.S.P.
method - tumbled in water~ were compared:
TABLE 2
Undenatured Milk lEx.II(c)~ 4+ hours
Denatured Milk [Ex.II(b2~ 20 minutes
From the above experiments it is obvious that denatured
milk is non-functional in the process of this invention.
':
EX~MPLE III
20 - - - -
(a~ Native condensed whole milk - 384 ml. of commer-
. .
cial essentially undenatured condensed milk was added to 215 gms.
o~ sulfamethazine to produce a slurry of fairly liquid consis-
tency. 4.2 cc . of formaldehyde (0.04287 cc. of 37% aqueous
formaldehyde per gm. protein) was added to the slurry and the
resulLing mix,ufe was dried to a consis~ency suitable for granu-
lation. The material was then granulated through a No. 4 scr~en
- 12 -
~073~7 :
and dried for about 24 hours. Magnesium stearate lubricant was
next added and 20 gm. boluses formed thereErom. When tumbled in
water at 37C., the boluses remained substantially intact in
excess of six days.
(b) In a manner similar to that outlined in section
(a) of this Example, a number of other substances were tested in
order to determine their prolonged release capabilities. In each
instance a number of threshold criteria were employed to screen
those compounds totally unfit for use in a compressed oral dosage
form. For example, if a given compound did not produce good
discrete granules or if the granules were incapable of forming a
self-sustaining body upon compression, they were not subjected to
further tests. Table 3 hereunder tabulates the results obtained
when the specified matrix substance was Eirst admixed with U.S.P.
grade sulfamethazine and a 1.5% aqueous solution of formaldehyde,
then granulated~ dried, and finally compressed into a solid
dosage form (if possib~e to do so). The compressed forms as
applicable were tumbled in water at 37 C. to determine relative
disintegration times.
In those instances where the initial criteria were met, !:;
water disintegration and optionally in vivo durational effect
tests were performed to determine the desirability of a particular
compound for use in the present invention (Tables 4 an~ 5).
In each instance in Tables 4 and 5, 29% of the named
compound was used in conjunction with 71% sulfamethazine. The
matrix component was treated with an amount of aqueous formalde~
hyde such that the formaldehyde-protein ratio was about 1:23.
The produc-tion and experimental protocols used were identical
with those outlined in Example I, omitting Carbopol 934P. All
*Trademark
-13-
~0733S'~
,
percentages are by ~Ieight. As can be appreciated ~rom a study of
Tables 4 and 5, only the formulas of Experimen~s Nos. 3, 4, 7, 8,
17, 18 and 19 mee~- the requirements or use in a compressed oral
dosage fo~n.
Image
- 15 -
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- 17
3357
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_ 79 .- .
'~0'733S~
,
Additional studies were made as recorded in Exarnple IV
hereunder to determine if formaldehyde treatment o~ a mLxture
containing liquid skim milk and a medicament (i.e., sodium sulfa
thiazole) would extend the duration of observed plasma levels
when compared to an untreated control mixture.
EXAMPLE IV
Eight mixed breed feeder pigs were divided into two
groups of four each. Animals in one group were designated as
principals while animals in the other group were designated as
positive controls. Each group consisted of two males and two
females. The a~erage weight of the principals was 120 lbs.,
while the controls averaged 117 lbs.
All animals were conditioned ~o the skim milk by
removal o their water and feed source each afternoon, with skim
milk given the following morning. Feed and water were given
~fLe~ the ~ilk was consume~. une quart ~46 ml.~ o~ sklm
milk/,pig/day was fed for two days, followed ~y 1-1/2 quarts
(1,'419 mI.~/pig/day for two days and then 2 quarts (1,892 ml.~/
pig/day for two days.
The mixtures administered to each principal consisted
. of sodi~ sulfathiazole ~.F., Granular, Merck Lot No. F221990)
stirred and dissolved into 2 quarts (1,892 ml.), of,skim milk so
that it contained 97.2 mg. (i.5 grains) sodium sulfathiazole/lb.
body weight. Formalin containing 37% formaldehyde was then
added to this mixture to equal 0.5% by ~olume ~9.47 ml./2qt~.
The mixtures were allowed to stanc at room temperature for 48
hours before administration.
The mLx~ures administered to each positi~e control
were prepared in the same mam~er except ~he formalin was omitted.
These mixtures were also allowed to stand at room temperature
for 48 hours.
- ~0 -
~C~73~57
All solids and liquids were wi-thdrawn from the pigs at
4:00 p.,m. one afternoon and replaced af-ter trea-tment at approxi-
mately 6:50 p.~m. (principals) and 7;30 p.m. (controls) the
following day. Preadministration~blood samples were collected
and mixed with potassium oxalate, as were samples collected at
1~ 3, 5, 7, 12, 18 and 24 hours post-administration.
Blood plasma samples from the pigs were assayed for
sulfathlazole by a spectrophotometric adaptation of teh Bratton-
Marshall Reaction with results expressed as mg. % ~ree sulfa-
thiazole. The values listed in Tables 6 and 7 have been correctedfor the preadministration levels observed.
Results::
Vomitus was observed from 3 of L~ pigs receiving the
formaldehyde-treated mixtures. Volume es-timates are included in
Table 6. The vomiting occurred within 4 to 11 minutes post-
administration. No vomitting was observed in any of the positive
control animals. All animals appeared ~o be in good health
prior to, during and after the study,
The sulfathiazole plasma levels for the two groups
(Tables 6 and 7) showed that pigs given the formaldehyde-treated
mixture exhibited effective therapeutic plasma levels (5 mg. %)
at nono o~ the sampling intervals~ while -the positive con-trol
group had such levels until the fifth hour post-administra~ion.
_21-
~l335
TABL~ 6
.
Principal Group
Formula: Sodium Sulfathi~zole in 2 quarts (1,892 ml.)
skim milk containing formalin (37%) O.S% by
volume. Stored at room temperature for 48
hours before administration.
Dosage: 97.2 ml. (1-1/2 grains) ~odium Sulfathiazole/
lb. body weight.
. .
Pig Time (Hrs Post-Administra~ion)
~0 No. 1 3 5 7 12 18 24
.
432 1-31 ~ 32.4 2.1 0.1 0.0 0.0 _
44 3 . 5 6 . 2 3 . 8 2 . 7 r 4 _
.
493 1 3 1 7 0 7 1 2 0 3 ~.0 0.0
504 0.3 0.7 0.7 1.4 0.2 0.2 ~.0 _
_ _
Avera~e 1.6 3.2 1.9 1.9 0.3 0.05 0.0
1 Values in mg. ~ ree sulfathiazole in plasma
2 Vomitus observed - Total approximately 1 cup (236 ml.)
3 Vomitus observed - Total approximate 4-1/2 cups ~1,062 ml.
Vomitus o~served - Total 1~ cup C236+ ml.)
TABLE 7
Control Group
Formula: Sodium Sulfathiazole in 2 quarts (1,892 ~1.)
skim milk. Stored 48 hours at room temperature
be~ore administration.
Dosage: 97.2 mg. (1-1/2 grains) sodium sulfathiazole/
lb. body weight.
P g 1 Time (Hrs Post-Adm nis~rat on) 24
9.51 8.9 6.8 3.6 1.5 1.~ 0.1
_ _ .
46 - 9.5 8.4 2.7 2.4 2~0 0.3 0.0
.
47 -9.6 8 0 5 5 3.0 0.5 0.0 0.0
48 10.0 1~.2 6.4 4.7 1.6 1.0 0.0
AveraF,e 9. 7 _8.9 S.4 _ 3.4 1.4 0.6 0.03
1 Yalues in mg. % ree sul~athiazole i.n ~lasma
- 22 -
~73~5~
It is therefore apparant that addition of ~ormaldehyde
to a solution o skim milk and sodium sulfa~hiazole was not
unctional in providing prolonged efective (above 5 mg. %)
blood levels. In fact, it did not provide effective blood
levels at any time interval. Vomition is a known side effect of
orally administered formaldehyde. But even if one s~ould decide
to exclllde the three principals that vomited, the one remaining
pig only had an effective therapeutic plasma level at the three
hour sampling interval, compared to effective levels at the one,
thr e and five hour intervals for the positive controls.
The desirability of employing an insolubilizing agent
in order to render the native milk protein matrix inso:Luble is
~urther demonstrated by the graphical representation of Figure
4. Graph A ~hereof shows the prolonged release capabilities of l.
boluses made in the manner outlined wherein native milk was
insolv.bilized with 1.5% aqueous formaldehyde (except that no ;
~arh~pol ~3~P ~r.der was employed~, wi~ile ~raph ~ shows the
results of an ad~inistration of boluses made from non-reacted
milk granulated only with ~ater. In each instance an equivalent
in bolus form of 2~.5 grams of sulfamethazine per 100 polmds
body weight was given to four cattle sick with "shipping ~ever".
As can be seen in Fig. 4, aldehydic insolubili~ation of the
granules beore granulation and compression materially in~reases
the prolonged release properties o~ the ultLmate product.
In contrast-to the subs~ances usable in the present
invention as the matrix component, it has been found that a much
broader class of insolubilizing aldehyde agents can be used. In
general, the only limitations upon the aldehydic insolubilizin~
agent are that it produce the requisite degree of insclubiliza~ion
in the native milk protein to render the latter (when suffi-
ciently compressed with a medicament~ significantly resistant to
* Trademark
- ~3
~q335'~
disintegratlon in water, and that it be essentia'lly removable or
relatively nontoxic to the host ruminant man~al in use and
nonreactive with the medicament employed in the finished dosage
form. In particular, it has been found t'hat aqueous solutions
o aliphatic, relatively volatile aldehydic insolubilizing
agents contai.ning from l to 5 carbon a~oms are particularly
useful in this context. While aqueous formaldehyde is the
preferred insolubilizing agent, a number of other aldehydes have
been tested and all find utility to a greater or lesser degree.
Formalde~lyde is es~ecial'y pre~erred, however, because it is
highly ~olatile; that is, after the formaldehyde is added to
modify the milk protein matrix, any residual amo~ts can rapidly
~e substantially entirely removed by evaporation from the gran-
ules, there~y preventing any significant toxicity to the host
ruminant mammal. For example, in tests r~n on the boluses
produced according to Example I, less than 0.03% by wei~ht of
residual formaldehyde was ~ound therein.
~ le ~ollowing additional E~ample establishes that
various types of aldehydic insolubilizing ag~nts are ~unctional
in insolubi'lizing native ~ilk protein and impar~ prolonged
release characteristics to the drug compositions prepared there-
from.
EXAMPLE V
~ oluses w~re prepared in accordance with the protocol
of E~ample I except Carbopol 934P was omitted and different
aldehydes as identified were substituted for formaldehyde as the
milk protein insolubilizing agent. Enzymic dissolution tests
were conducted on the granules prior to compression as well as
after forming thereof into boluses.
~0, * Trademark
. . ;
~- 2~ -
33~';'
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- 2~ -
~733S~
In view of the foregoing, it is apparent that aqueous
solutions of a wide variety of aldehydes are operable to modi~y
the native milk protein matrix in order to provide desira~le
prolonged release characteristics.
An ln ~ivo blood study was co~ducted using cattle
~2 to 4 cows per group) to determine the effects of varying
amounts of formaldehyde (the preferred aldehyde? on a slightly
modified standard bolus formula described in Exa~ple I (i.e.,
71% by weight sulfamethazine, 29r/o native dried milk, but without
Carbopol 934P). The following Table 9 shows the various for-
maldehyde-milk protein ratios employed and levels of sulfametha-
zine maintained in the test cattle over time. Each cow was
given a bolus equivalent 22.5 grams sulfamethazine per 100
pounds body weight.
.. . . . ... . ............ ... . ....... :
.
~ULr~l~T~ h LEV~-(m~/iOO ml whole ~.LOQd~
Forma~dehyde-Milk Protein Weight Ra~ios
0 ~ No
Time (Hrs~Formaldehyde 1:34.5 _ 1:231:6.9 1:2.3
0 1.4 ~.8 a.o 1.3 2.0
8 15.5 16.4 ~.8 5.0 3.3
24 23.2 23.7 20.9 1~.2 8.8
3~ 20.~ 24.~ 22.1 17.8 11.4
~8 11.9 7.6 18.1 14.~ 13.2
56 ~.1 4.8 16.5 9.g 11.5
72 3.7 2.0 7.4 ~.8 8.0
~0 2.7 1.3 6.3 3.1 6.1
~6 1.8 ~ .6 1.3 5.2
_
: From ~he above Table it can be verified that the
~n release rate can be prolonged by increasin~ the amount of for-
maldehyde used, and that for tlle particular insolubilizing
- 26 -
~ 3~57
agent, a fo~aldehyde-mllk protein ratio of 1:23 gives the bes~
results.
Xn the use of such aldehydes~ it has generally been
found necessary to conduct the insolubilizing reaction in the
presence of water ~as by employing aqueous solutions of ~he
aldehyde in question~. This is believed necessary because o
two empirically discovered facts. First, when aldehydes are
employed in conjunction with anhydrous solvents, good granules
cannot be ormed. Apparently, it is necessary to have some
retained wa~er as water of hydration after drying in order to
give ~he granules the necessary cohesive and elastic properties
which facilitate interlocking and binding upon compression.
Ad~itionally, the amount of water present in some
man~er seems to affect the degree and efficiency of the aldehyde-
milk insolubilizing reaction; if too little water is present,
insu~ficient insolubilization occurs, and if an excess is present,
t~e ~su;tallt granuies can become so nard and dense that they
fail to adhere-upon compression. Therefore, in the use of
aldehydic insolubiliæing agents, optimum amounts of water are
20 necessary. For the broad category of such agents, a water to
total dry content ratio o~ rom about 1:2.5 to 1:10 by weight
has advantageously been employed. In the most preferred form,
~his ratio is about 1:3.
It is also desirable in the production of drug formu- ;
lations according to the invention to minimize as much as possible
the total amount of insolubilizing agent employed. ~or example,
if excess amounts o aldehydic insolubilizing agents are used,
incompatible side reactions may occur between the agent and the
medicament. Therefore, in general the insolubilizing agent
30 should be used in amounts sufficient to give adequate modi~ication
of the milk protein matrix while nevertheless minimizing undeslrable
- 27 -
~C~733~7
side reactions. In the case of formaldehyde as shown by Table
9, a formaldehyde to milk-pro-tein ratio of from about 1:50 -to
1:2 by weight has been found effective, w;th a preferred ratio
of about 1:23.
EXAMPLE VI
A bolus formulation was made as follows:
Sulfamethazine 2~250 gms
Non-fat dried milk 1,000 gms
Formaldehyde 1% solu-tion771 cc ;~
Granulate
Carbopol*934 40 gms
Isopropyl alcohol 1,400 cc
Calcium hydroxide 40 gms
Isopropyl alcohol 200 cc.
Dry
Compress into 34 gm. boluses
Disintegation time 5 days
These boluses were administered to two sheep at a
dosage oE 22.5 gms per 100 lbs. body weigh-t and blood levels
~ere maintained above 5 mg. ~ from the 10th to 86th hour. The
formaldehyde-protein ratio in this case was 1:47.4.
Since the aldehyde functional group is the essential
insolubilizing factor, slightly different aldehyde-protein ratio
ranges are advantageously used when C2 to C5 aldehydes are
employed as the protein insolubilization agent in lieu o~ the~ ~
preferred formaldehyde reactant agent. Exemplary ranges are set
forth herein with the best ratios being referenced inside of
respective parentheses:
2 carbon atoms - e.g. acetaldehyde 1:1 to 1:35 tl:10)
3 carbon atoms - e.g. propionaldehyde 1:1 to 1:25 (1:10)
4 carbon atoms - e.g. n-butyraldehyde 1:1 -to 1:20 (1:10) .
5 carbon atoms - e.g. glutaraldehyde 1:1 to 1:30 (1:10
As discussed previously, virtually all medicaments are
operable herein, especially if they are in a powdered or fine
granular state and do not substantially react with the insolu-
bilizing aldehyde agent during the formulation of the prolonged
release compositions. In the use of particular drugs according
*Trademark
-28-
iLC)t~ ~35~
.
to the invention, it may sometimes be necessary to modify the
production parameters in order to main~ain the chemical integrity
of the medica~ent. For example, drying temperatures of about
140 F. have proven successful when sulfamethazine is employed
as the medicament. However, o-ther drugs may undergo deleterious
reactir.ns at such temperatures and, therefore, ~he dryillg step
should be performed at lower temperatures or even at low tempera-
tures and under a vacuum. As a consequence freeze-drying or
spray-drying processes may be substituted for the granula~ion
and drying steps detailed in Example I. Any such modifications
o the processes discloaed herein will be wel]. within the know-
ledge of one skilled in the art, however.
Exemplary formulations contailling different types of
drugs are as follows:
EXAMPLE VII
A bolus was made as ioïiows:
Sulfadimethoxine 2,250 gms.
Non-fa~ dry milk 1,000 gms.
Formaldehyde 1% solution 771 cc.
Granulate .
Carbopo~X934 -40 gms.
Ethyl alcohol 99~/O 1,407 cc.
Calcium hydroxi.de 40 gms.
Ethyl alcohol 1,005 cc.
Granulate
Magnesium stearate 32 gms.
Sul~adimethoxine 450 gms.
Compress into 34 gm. boluses
Disintegration time 5-1/2 days
These boluses were ad~inistere~ to two sheep at a
dosage of 22.5 gm. per 100 lb. body weight and effec~ive blood
levels above 5 mg. % were maintained from the 10th to 106th
hours post administration.
* Trademark
- 29 -
.
~335~
EX~MPLE VIII
A bolus formulation was made as follows:
Tetracycline base 1,000 gms.
Non-fat dry milk 1,000 gms.
Formalin 43 cc.
Watcr 1,200 cc.
Granulate
~agnesi~ stearate 18.2 gms .
Stearic acid 36.4 gms.
Compress into 30.9 gm. boluses
Disintegration time 3-1/2 days
~X~MPLE IX A
,
A ormulation was made accordin~ to the following
formula, granulated and compressed into oral dosage foL~ns:
Coumaphos 109 gms.
Instant non-fat dry milk891 gms.
Formalin 382 cc.
Water G50 cc.
Granulate, dry, then add:
Magnesi~m stearate 10 gms.
- Compress
Tablet Size ~ ,ation Time
. .
2 gm. ~ days
5 gm. 5 days
EXAMPLE IX B
A formulation was also made as follows:
Coumaphos~ 436 gms.
Xnstant non-fat dry milk 554 ~ns.
Formalin 237.5 cc.
Water . 530 cc.
Cranulate, dry, then add:
Magnesium stearate 10 gms.
Compress
Resu~ts:
Tabl t Size Disintegration Time
3Q grains 8 days
--
~733~
EXAM~LE IX C
formulation was made as follows:
Coumaphos 109 gms.
Instant non-fat dry milk~91 gms.
Formalin 382 cc.
Water 500 cc.
Granulate, dry, then add:
Magnesium sulfate 10 gms.
Compress
Results:
Ta~le~ Siæe Disintegration Time
30 grains 5 to 6 days
EXAMPLE X
table~ formulation was made as follows:
Chloramphenicol 100 gms.
Non-fat dry milk 45 gms.
Formaldehyde 1% solution35 gms.
Granulate
Compress into 7.32 gm. tablets ;^~
2û nisinteg~ati^n t~.c -1/2 days
The ratio of drug to milk solids can be varied over a r
wide range as long as suficient dried milk is present to form a
continuous support matrix for the medicament. For example, the
resultant tablet, pellet or bolus can contain rom 0.5% to 80%
by weight medicament and rom 20% to 99.5% by weight native
milk. The preerred percentage is from about 40% to 50~/O drug
and from 50% to 60% dried milk.
Compressed compositions made according to this inven-
tion are intended to con~ain medically significant amounts of
drugs; however, the percentage composi~ion of the drug will
vary dependin~ on relative potencies. For example, atropine
is ex~remely potent in contrast to sulfonamide drugs. Exem-
pl~r-~ ~ormu1a~ions in ~his ~esp~c~ are.
`` .' l: .
~73357
EXAMPLE XI A
l. Atropine lO0 gms.
Dried m;lk20,000 gms.
Formaldehyde Trace
Total 20,100 gms.
Makes l,000 boluses weighing 20 gms. each.
EXAMPLE XI B
2. Sulfame-thazlne8,000 gms.
Dried milk 2,000 gms.
Formaldehyde Trace
Total 10,000 gms.
Makes 500 boluses weighing 20 gms. each.
The size of granules employed in the final compression
to ~orm table-ts or boluses in accordance with the invention can
also be varied. In general, the granules must only be of a size
which permits their compression into a self-sustaining body. In
practice, it has been found that granules of a mesh size from 4
to 50, or preferably from 4 to 14, can advantageously be employed
for this purpose.
In order to further establish the effect of particle
siae on the release pattern, several boluses made according to
the formula described in Example I (minus Carbopol*) were pul~ver-
ized to a very fine powder by means of a hammer mill, then
lrecompressed by direct compression into boluses of the same size
and hardness as previous~y.
The original boluses required 5 to 8 days to disinte-
grate in water while the recompressed boluses disintegrated in 3
days.
From this it can be concluded that although larger
particle sizes seem to favor a more prolonged release pattern,
nevertheless fairly prolonged disintegration rates can be ob-
tained when the granules are completely destroyed, then re~om-
pressed without regranulating.
*Trademark
_32-
1~73~S7
The compressed dosage forms aecording to the invention
for administration to ruminants are produced under donditions
causing the body to have a density of above about 1 gram per
cubic centimeter of water~ and pre~erably from 1.1 to 1.6 gm/cc.
This prevents the oral dosage form in use from floating upon the
surface of the rumen contents or other liquid in the rumen-
reticulum of the host mammal, and causing it to sink so that the
compressed body is not carried out of the rumen too rapidly by
the passage of liquids therefrom.
Having described in detail the components, processes
and parameters required for the production of prolonged release
medicament compositions, the desirable properties of the latter
will now be discusse.d. ;`
When a self-sustàining oral dosage body produced in
accordance with the invention is administered to a ruminant, the
following process is theorized to occur. Since the dosage form
is extremely resistant to disintegration or disso~lution in
water, the amount of water in the animal's stomach or tract
probably has l~ttle effect thereon. However, because the dosage
form is not immune to digestion by digestive and bacterial
floral enzymes, it is likely that the eventual disintegration and
dissolution of the bolus can be primarily attributed to break-
down by the proteolytic enzymes present in the digestive tract.
Hence, as such enzymes act on the exposed surface of the body
by digesting -the insolubillzed protein matrix, medicament is
simultaneously released; this concurrently and progressively
exposes new surfaces of -the body to be digested in like manner
until the entire support ma~rix is consumed and all o~ the
entrapped drug released. Thus, the release rate appears to be
related to the total surface areas exposed at any given time,
and it therefore steadily declines as -the compressed body erodes
-33-
~33S7
and diminishes in size.
The prolonged release capabilities of oral dosage
forms produced in accordance with the i~vention can best be
s~o~n with reference to Fig. 1, showing the comparative prolonged
release properties o~ boluses o the present invention compared
with a typical fast-release medicament composition of the prior
art. The experimental methods used in ga~hering such data is
explained in the following Example.
EXAMPLE XII
Three groups o cattle sick with "shipping fever" were
chosen in order to test in vivo the prolonged release capabilities
of ~he present boluses and those of the prior art. The three
groups consisted of the followi~g:
TAB~E 10
.
Total Number AYerage Initial
Group of Cows _Temperature
- C 143 10~.00
D 133 104.10
E 143 104.15
Group C was orally given an amount of the present
prolonged release composition as described in Example I in bolus
form equal to approximately 22.5 grams of sulfamethazine per 100
pounds of body weight. This was given at time "0" shown on
corresponding Graph C of Fig. 1.
~roup D was dosed with a standard rapi.dly disintegrating
sulfamethazine composition being marketed by another pharmaceuti-
,cal manufacturer, according to the following schedule (total
dosage being equal to group C, e.g., 22.5 gmsllO0 lbs body
ht~.
- 34
~0~335
TABLE 11
Time ~Hrs~ Dosage
01~1/2 grains/pound body wt.
~4 3/4 " "
4~ 31~ " "
72 1/2 " "
. TOTAL 3-1/2 " "
(Three and one-half grains per pound is approximately equal to
22.5 grams per 100 pounds.~
~0 Group E was dosed initially at time "0" with a sulfa-
methazine bolus in accordance with the invention in an amount
equal to ap?roximately 11.25 ~rams sulfamethazine pe:r 100 pounds
body weight. As can be appreciated, this is a "half-dose" of
the composition given to Groups C and D.
Turning now to the graphs of Fig. 1, the average pro-
longed release results obtained for each of the Groups is depicted.
This data was collected by intermittently taking blood samples
of each animal to determine the sulfamethazine content thereof
and averaging all of the results in order to p~ovide the graphs
shown in Fig. 1. The average data used to construct the graphs
is shown in the following Tablc:
. .
.
3:~S~ .
,~ .,
~ . ~ ~
.' ~.~ . ~
p~ o ~1
C~ ~ u~
O~,D ~ p~
F~ ~: ~ ~ o~ o~ o ~ ~ oo ~ ' o r~
o ~ . ~ ~ ~ r~ ~ o ~ o u~ ~
P~ .~ o ~ . . . .. . . . . o
~ ~oo ~ ~; ~ ~' ~ ~ o ~o ~ ~ ~, ~
~ ~, ~ o
c~ a)~.~ . ~C .
~o h ~1:
~,~i . . ~
.'' . . . . ,S~,
U~' ' . _ . ~: .,
. . ~ '
o P:~ N o . . ~q
~ . : ~'
R U -X -X -X
. ~ . oo ~ . o U~ ~ ' .
~ N E3 ~ u~ C~ O ~ r--I 00 c~
P~ ~ d 13 . . . . . , . . . a
~ r~ lr-l ~~D 1~ ~D ~ 1~ ~ C~l U~
O o ~ 1 0 ~ al
P; ~ ~ ~0 . . . ~.
~¦ ~ ~ -
A~ ~, . , bO
.' ~3 . . ~'
~ ~ rf ~
~ ~0 ,R~ o . . ~o
.- ~ N O . 0
~ ~ . , . r-l,
::~ E~ -i O ~ 00 C~
O h ~ ~ `J o .~ o co
~ ~ .~ ~ . . . . . . . . . u~
U .~ o ~ ~J o ,~ ~d
a) ~ ~ o~ . ~ ~ 4~
O b~ . . ~1
, . O
... ~ . ' . . W
b~) P .
h ~ t~l
~-~ . r~
¢ ~::1 O ~ ~ 0~ ~ ~D O ~ co O
C~ ~ O ~ ~ r~
.~ IJ _~ r l r~ ~n
, E~ . ~:
~ .
- 3~ -
:
3LI:1733S7
A level of 5 milligrams sulfamethazine per 100 milli-
liters of blood is commonly accepted as a "therapeutically
active" level. As shown in the groups of ~ig. 1, Graph C (all
graphs are denoted with letters corresponding t:o the groups they
represent) shows that at the3dosage level~defined, the prolonged
release composition of the present invention prolongs a thera-
peutically active amount oE sulfamethazine in the cow's blood-
stream for a period of almost 140 hours, minus a 1~ to 18 hour
lag time in onset, while the "half-dose" (Graph E) remains
therapeutically active for approximately 105 hours (including
the 14 to 18 hours onset lag time). While the fast release
standard bolus compositions also maintain a therapeutic level
for approximately 135 hours, it is important to note that this
can be accomplished only through the use of four successive
administrations of the drug over a period of three days. As can
be appreciated, these numerous administrations can be accos~ly
and time-consuming procedure, especially if a grea* number of
animals are affected by the disease in question. Moreover, the
extra handling and restraint on the animals often causes con-
siderable stress to the latter and can affect their recoveryrate. Hence, it is generally much more desirable -to provide a
therapeutically significant prolonged release of medicament
through a single dosing operation. This has been impossible to
achieve to any comparable degree with the medicament compositions
of the prior art.
During the development of the present invention, It
was also unexpectedly discovered that the rate of prolonged
release in rumlnants is poàitively affected by the degree of
sickness of -the animal, as indicated by its initial temperature
upon dosing. That is, with a sicker animal having a rela-tively
higher temperature, the compositions of the present invention
sustain a therapeutically active amount of drug within i-ts
-37-
1073357
bloodstream for a ~&~ period than would be a~ttainable with an
animal less severely ill and showing a relatively lower tem~
perature. This surprising result may be explainable as follows.
Because the present compositions are ac~ecl on by the enzymes o
the bacteria flora present in the ruminant animal's stomach, the
rate of dissolution is somewhat depend~nt upon the concentration
o bacteria and protozoa present in the rumen. Additionally, it
is known that with increasing body temperature, the bacterial
and protozoal population of the r~minant's digestive system is
~0 altered so that lesser amounts of them and their associated
proteolytic enzymes are present. Therefore, ln sicker animals
there is a smaller concentration of the required enzymes for
digestion of prolonged release compositions, and consequently
these formulations remain acti~e for a longer period of time.
This property will be more clearly illustrated in the following i ~
Example. ;
FXAMPLE XIII
A number of cattle suffering from "shipping fever"
we~e initially dosed with specified amounts of sul~amethazine
boluses produced in accordance with the invention, and their
body temperatures ~ere taken Group F (Fig. 2) was given an
amount of bolus equal to approximately 22.5 grams sulfamethazine
per 100 pounds body weight, and a second Group G was given a
"half-dose" equaling approximately 11 25 grams sulfamethazine
per 100 poun-ds body weight. The total time in which each dosage
sustained a therapeutically active amount of sulfamethazine in
the blood of each cow was then determined and Graphs F and G of
Fig. 2 were prepared from the following data:
,
3~ -
:l~';t335~
. .
.~J~ ~ ~ .
h ~' ~D O O
r~ o o o ~
~1 . ..
C~ . - . .,
~ .
~ ~ o~ o
O )~ . .
. . . .,
~ . .
~1 ,,, ~Jp~ 0 0 c~ J O 1::
~4 ~ o c~
. ~ 'P~' ~ .
. ~ U~ ' .~
~'
. ~ U~ C~l ~ ~1 oO
,1 r~
. . . ,.~. . O
. . . O O O C7 0 0 rd
. rd ~ a) O O O O O :1
~ h ~ O ~ r l ,1 ~ r-l
H E~ ~ D
E~ ~ o o ~ o o .
- 3g -
3357
As shown in the ~diately preceding Table ~nd eorre-
spond~ng Graph~ F and G, there is a positi~e correlation between
initial body ~ce~p~rature of the ~ick cow and the amount o~ ti
in whieh a ~herapeutically active amount o~ dic~m~nt re~alns
isl its bloods~ream. As the temp~rature in¢rlease~ from about
102.0 F. to about 107 F. the th~rapeutlcally activ2 duration
iT~crease~ from about 100 hours to about 180 he>urs in the Group
given the "full-dose'l.
Therefore, it i~ evident tha~c the total prolo~ged
10 release duratio~ can be estimated from the ~itial temperature
of the anim~l being dosed. For e~cample, lf such ar anil h~s a
temperature of from 103.1 - 104.0 F. and a dosage of approxi-
mately 22.5 gram~ ~ulfamethazine per 100 pound~ body waight i8
administered, the total time in which a therapeutically active
amount of sulfamethazine remains ln the ruminant anlmal ' 5 blood-
stream i8 approximately 132 hour~. 0 eourse, for a~other glven
type of an~mal ant disease, othe~ predictive data would need to
be consulted in order ~o determ~ne ~he approximate duration of
medicam~nt release~
It should also be noted ~hat ~che for2going release
charac~eristic of the msdicame~t compo~itions of ~he present
invention in sick animal~ is extrem~ly ~urprising il~ viaw of the
prior ar~. In the prolonged xelea~e compo8itions here~co~ore
aYailable, ~here wa~ no way to predict ~ot~l durational effects
or ~he u~liformity of their operation. In fact, in many cases
the prolonged release period i~ ~horter in feverlsh rumin~lt
as&imal~. Thls is pr~arily due ~co the fact tha~c they operate on
an e~tirely dif~erent principle th n the compo~ition~ of the
present inventi~n, depending for their operatio~ uporl water
content or speciflc pH range~ in cer~ain xegions of ~he gas-
troi~testinal tr~ct of the host ruminant ~a~l. A~ shown
~ 40 -
~LO~7335~7 r
above, the compositions of the present invention are substan-
tially insoluble in water and are relatively resistant to disin-
tegration at pH 1 to 14. Hence, neither water nor pH variations
found in vivo significantly affect their per~ormance.
These effects are further demonstrated by reference to
Fig. 3. In that case, a bolus equivalen~ of 22.5 grams sulfa
methazîne per 100 pounds body weight was given to two groups, H
and I, of cattle. Group H consisted of 143 cows sick and fever-
ish with shipping fever, while Group I consisted o~ 27 nonfeverish
cows. As can be seen from a study o Fig. 3, the identical
bolus dosage forms maintained a therapeutically active level of
sulfamethazine in sick cows or a subs~antially longer period
than in their nonfeverish counterparts.
However, the prolonged release capabilities of the
oral dosage forms cf this invention are nevertheless substantiai
(about ~0 hours, Graph I, Fig. 4) even in healthy cattle.
Therefore, these medicament compositions are also quite useful
in treating diseases such as "~oot rot" which do not elevate the
temperature of the afflicted animal. Moreover, because of this
substantial prolonged release in nonEeverish animals, it could
sometimes be advantageous to prophylactically administer the
oral dosage forms of the invention to healthy animals in order
to prevent or lessen the effects of common debilitating diseases.
- 41 -
