CA1073357A - Controlled release ruminant medicinal composition - Google Patents
Controlled release ruminant medicinal compositionInfo
- Publication number
- CA1073357A CA1073357A CA264,952A CA264952A CA1073357A CA 1073357 A CA1073357 A CA 1073357A CA 264952 A CA264952 A CA 264952A CA 1073357 A CA1073357 A CA 1073357A
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Abstract
CONTROLLED RELEASE RUMINANT
MEDICINAL COMPOSITION
Abstract A slow release oral dosage medicinal composition for ruminant animals which is a compressed dosage form of a dry, essentially water-insoluble, slowly digestible matrix is prepared by first treating an admixture of originally essentially undenatured native milk solids and the drug with a sufficient quantity of an aldehydic agent to insolubilize the milk protein solids This treated composition is then preferably granulated and the granules compressed under sufficient pressure to form a densified body which is not only resistant to disintegration for over twenty-four hours when tumbled in water, but also has a specific gravity at least greater than about 1 to cause the dosage form upon administration to a ruminant animal to have a tendency to sink in the rumino-recticular fluids and become entrapped in the rumino-recticular compartments.
MEDICINAL COMPOSITION
Abstract A slow release oral dosage medicinal composition for ruminant animals which is a compressed dosage form of a dry, essentially water-insoluble, slowly digestible matrix is prepared by first treating an admixture of originally essentially undenatured native milk solids and the drug with a sufficient quantity of an aldehydic agent to insolubilize the milk protein solids This treated composition is then preferably granulated and the granules compressed under sufficient pressure to form a densified body which is not only resistant to disintegration for over twenty-four hours when tumbled in water, but also has a specific gravity at least greater than about 1 to cause the dosage form upon administration to a ruminant animal to have a tendency to sink in the rumino-recticular fluids and become entrapped in the rumino-recticular compartments.
Description
~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~.
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 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 ~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 ~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:
.
% 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:
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
(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 ~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 ~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.
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'~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
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~.
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 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 ~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 ~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:
.
% 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:
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
(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 ~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 ~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.
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'~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.) 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 ~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
Vomitus o~served - Total 1~ cup C236+ ml.) 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 ~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.
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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 ~ 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 ~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) .
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.
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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 ~ 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 ~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 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 .
~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 ~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~.
~0~335 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 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 -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.
.
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 .
~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 ~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~.
~0~335 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:
. .
.
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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 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:
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- 3g -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.
Claims (30)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A composition providing prolonged release of a medicament upon oral administration to ruminants comprising a compressed self sustaining body of slowly digestible matrix within which said medicament is distributed, said matrix com-prising the reaction product of originally undenatured native milk solids and at least one water soluble volative aliphatic aldehyde of from 1 to 5 carbon atoms, said composition having a density greater than 1, containing no more than minor and nontoxic residual amounts of any unreacted aldehyde and being resistant to total disintegration when tumbled in water and about 37°C for at least 24 hours.
2. A composition as defined in claim 1 wherein said body is composed of compressed granules of said re-action product and said medicament.
3. A composition as defined in claim 1 wherein said aldehyde is formaldehyde.
4. A composition as defined in claim 3 wherein the weight ratio of formaldehyde to said milk solids is from 1:2 to 1:50.
5. A composition as defined in claim 4 wherein the ratio is 1:23.
6. A composition as defined in claim 1 wherein said aldehyde is acetaldehyde.
7. A composition as defined in claim 6 wherein the weight ratio of acetaldehyde to said milk solids is from 1:1 to 1:35.
8. A composition as defined in claim 7 wherein the ratio is 1:10.
9. A composition as defined in claim 1 wherein said aldehyde is n-butyraldehyde.
10. A composition as defined in claim 9 wherein the weight ratio of n-butyraldehyde to said milk solids is from 1:1 to 1:20.
11. A composition as defined in claim 10 wherein the ratio is 1:10.
12. A composition as defined in claim 1 wherein said aldehyde is glutaraldehyde.
13. A composition as defined in claim 12 wherein the weight ratio of glutaraldehyde to said milk solids is from 1:1 to 1:30.
14. A composition as defined in claim 13 wherein the ratio is 1:10.
15. A composition as defined in claim 2 wherein the granules have a mesh size of from about 4 to about 50.
16. A composition as defined in claim 1 having a density from about 1.1 to about 1.6.
17. A composition as defined in claim 16 wherein the density is about 1.23.
18. A composition as defined in claim 1 wherein said medicament is sulfamethazine.
19. A composition as defined in claim 1 wherein said medicament is sulfathiazole.
20. A composition as defined in claim 1 wherein said medicament is sulfadimethoxine.
21. A composition as defined in claim 1 wherein said medicament is tetracycline.
22. A composition as defined in claim 1 wherein said medicament is an organophosphate.
23. A composition as defined in claim 1 wherein said medicament is coumaphos.
24. A process for the preparation on of a composition which provides prolonged release of a medicament upon oral administration to a ruminant which comprises treating a mix-ture of undenatured native milk solids and said medicament with at least one water soluble volatile aliphatic aldehyde of from 1 to 5 carbon atoms and in the presence of an amount of water wherein the weight of water to weight of dry in-gredients is in the range of about 1:2.5 to about 1:10, the aldehyde being in an amount sufficient to render the milk solids essentially water-insoluble but slowly digestible, granulating the resultant water-insoluble reaction product, and compressing the resultant granules into a composition having a density greater than 1 and which resists total disintegration when tumbled in water at about 37°C for a time period exceeding about 24 hours.
25. The process as defined in claim 24 wherein said aldehyde is in the form of an aqueous solution.
26. The process as defined in claim 24 wherein said granules are sized to a mesh size of from about 4 to about 50.
27. The process as defined in claim 24 wherein said granules are compressed under sufficient pressure that the resulting composition has a density from about 1.1 to about 1.6.
28. The process as defined in claim 27 wherein the composition is compressed to a density of about 1.23.
29. The process as defined in claim 24 wherein the aldehyde is formaldehyde.
30. The process as defined in claim 29 wherein the weight ratio of formaldehyde to milk solids during insolubilization is from about 1:2 to about 1:50.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/631,885 US4044119A (en) | 1973-05-03 | 1975-11-14 | Method of controlling release of medicament and bolus therefor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1073357A true CA1073357A (en) | 1980-03-11 |
Family
ID=24533176
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA264,952A Expired CA1073357A (en) | 1975-11-14 | 1976-11-05 | Controlled release ruminant medicinal composition |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1073357A (en) |
-
1976
- 1976-11-05 CA CA264,952A patent/CA1073357A/en not_active Expired
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