CA1158553A - Controlled release formulations and method of treatment - Google Patents

Abstract

Abstract of the Disclosure Controlled release formulations useful in the prolonged treatment and control of microbial in-fections in animals are comprised of a microbial agent intimately dispersed throughout a copolymer derived from lactic acid and glycolic acid. A method for providing protection to animals for extended periods of time following a single administration is provided.

Description

~S8S53 CO~TROLLED RELEASE FORMULATION5 AND METHOD OF TREATMENT
This in~-ention concerns formulations capable of supplying an effective dose of an antimicrobial agent to an animal over a prolonged period of time, and a method of preventing and treating diseases.
The concept of administering a drug to an animal in a form which is capable of supplying an effective dose of the drug to the animal over a pro-longed period of time is known in the art. Yolles, forexample, in U.S. Patent No. 3,887,699, describes a formulation comprised of drug intimately dispersed throughout a biodegradable polymeric material which is in the form of a solid film which is implanted suh-cutaneously into the animal. Schmitt et al., in U.S.Patent Nos. 3,736,646 and 3,875,937, describe polymers and copolymers which are useful as surgical devices and delivery systems. Boswell et al., in U.S. Patent No.
3,773,919, disclose formulations which include a lactide polymer and which allegedly permit prolonged release of drugs for a controlled period of time.
The use of polymeric formulations for the slow release of drugs in the treatment of various diseases in animals has suffered in a numbel of re-spects. The polymers currently available generally areprepared in such a way that removal of ~he polymer-ization catalys~ from the polymer is impossible or impracticable. As a result, when the poiymer is placed in an animal and degrades over a perlod of time, undesirable quantities of polymerization catalysts such as metal o~ides or strong acids remain in the animal l~S8553 tissues. This is particularly undesirable when the animals so treated are used for meat or other food production. Additionally, most of the polymers known in the art have physical characteristics which neces-sitate their administration by implantation; seeYolles, U.S. Patent No. 3,887,699. Such implantation requires the services of one skilled in surgical methods. Moreover, as pointed out by Siegrist et al., in U.S. Patent No. 3,535,419, the slow release polymeric formulations currently available lack a suf~iciently controlled rate of release to be predictable over a useful period of time. This aspect is particularly critical when the active agent being administered can become lethal at elevated doses, and ineffective at insufficient doses.
This invention provides formulations com-prising a pharmacological agent which is effective prophylactically or therapeutically in combination with a copolymer capable of uniformly releasing the active agent in effective amounts over a predetermined period of time. Also provided are copolymeric formulations capable of complete biodegradation into readily metab-olized substances. Formulations which can be admin-istered by injection and which, when biodegraded, leave no undesirab'e residues in animal tissues, are also included. Still further provided is a method for effectively preventing the formation of infectious diseases in animals and treating animals suffering from infectious diseases.

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X-4822 _3_ The present invention provides novel formu-lations which permit the controlled delivery of pharma-ceuticals to animal systems, and a method of prophylactic and therapeutic treatment of infectious diseasas. More particularly, the invention provides a controlled release formulation capable of delivering an effective dose of an antimicrobial agent over a prolonged period of time and biodegradable into readily metabolized substances and normal active ingredient metabolic products, which formulation is useful in the prophyla-ic and therapeutic treatment of diseases caused by micro-organisms in animals, which comprises about 5 to about 85 weight percent of an antimicrobial agent intimately dispersed throughout a copolymer derived from about 60 to about 95 weight percent lactic acid and about 40 to about 5 weight percent glycolic acid, said copolymer having an .~nherent viscosity of about 0.08 to about 0.30 when measured in chloroform, a weight average ; molecular weight of about 6000 to about 35000, and said formulation being in combination with suitable excipients and carriers therefor.
A preferred formulation according to this invention comprises a prophylactically or therapeu-tically effective amount of a pharmaceutical agent intimately dispersed throughout a copolymer derived from about 60 to about 90 weight percent lactic acid and about 40 to about lO weight percent glycolic acid having a viscosity in chloroform of about 0.10 to about 0.25 and a weight average molecular weight of about 15,000 to about 30,000.

~58553 A more preferred formulation is one wherein the copolymer contains from about 70 to about 80 weight percent lactic units and about 30 to about 20 weight percent glycolic units having an inherent viscosity of about 0.13 to about 0.23.
Particularly preferred pharmaceutical agents used in the formulations are antimicrobial agents, such as the tetracyclines, penicillins, cephalosporins, macrolide antibiotics, sulfa drugs, aminoglycosides and other agents specifically useful in the treatment and prevention of microbial infections.
This invention additionally provides a method for treating animals suffering from a microbial disease or suspected of developing a microbial infection com-prising administering to the animal a copolymericformulation capable of releasing an effective amount of an antimicrobial agent over a prolonged period of time.
The method is preferably carried out by subcutaneously or intramuscularly administering a copolymer derived from about 60 to about 95 weight percent lactic acid and about 40 to about 5 weight percent glycolic acid, said copolymer having an inherent viscosity in chloro-form of about 0.08 to about 0.30, said copolymer having uniformly dispersed therethrough an effective amount of an antimicrobial agent and other suitable diluents and excipients, said formulation being uniformly dispersed through a suitable carrier or diluent to facilitate parenteral administration.
A preferred method of treatment according to this invention comprises subcutaneously administering ~S8553 ( X-4822 ~5_ to an animal suffering from or susceptible to .~icrobial infection and in need of treatment an effective amount of a controlled release copolymeric formulation con-taining a compatible antimicrobial agent.
A copolymeric material ideally suited to the controlled release of an effective amount of a pharma-ceutical agent to an animal such that the animal can be effectively treated with a minimum of administrations has been discovered. Such copolymeric material is prepared by a process which permits the substantially complete removal of polymerization catalyst, thereby permitting the total degradation of the copolymeric matrix in a biological system without the concomitant accumulation of toxic residues in animal tissues. This aspect of the invention is of particular significance in the treatment of animals utilized in the production of meat for human consumption.
The copolymers required for the formulations of this invention are prepared by condensation of lactic acid and glycolic acid in the presence of a readily removable polymerization catalyst. Such catalysts include strong acid ion-exchange resins in the form of beads or similarly hard structures which are easily removed by filtration or similar techniques.
Particularly preferred polymerization catalysts include commercially avai~able strong aci ~ ion-exchange resins such as Amberlit I~R-118(H), Dowe.. ~CR-W (formerly Dowex S~W), Duolite~C-~0, Amberlys ~15, Dowe ~MSC-l, Duolit -25D, Duolit ~S-26 and related strong acid ion-exchange resins. The catalyst is added to a mixture -r ~
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l~S8553 of about 60 to about 95 weight percent of lactic acid and about ~0 to about 5 weight percent of glycolic acid. The amount of catalyst utiliæed is not critical to the polymerization, but typically is from about 0.01 to about 20.0 parts by weight relative to the total weight of combined lactic acid and glycolic acid. The polymerization generally is carried out in the absence of solvents; however, organic solvents such as dimethyl-sulfoxide or N,N-dimethylformamide can be utilized if desired. The polymerization reaction routinely is carried out in a reaction system equipped with a condensing system, thereby permitting the collection and removal of water that is formed, as well as facil-itating the removal of any lactide and glycolide byproducts that are formed. The polymerization re-action generally is conducted at an elevated temper-ature of about 100 to about 250C., and at such tem-perature is usually substantially complete within about 48 to about 96 hours. Ideally, the reaction can be carried out under a reduced pressure, thereby further facilitating removal of water and byproducts.
The copolymer thus formed is readily re-covered by simply filtering the molten reaction mixture to remove substantially all of the strong acid ion-exchange polymerization catalyst. Alternatively, thereaction mlxture can be cooled to room temperature and then dissolved in a suitable organic solvent such as dichloromethane or acetone and then filtered by normal means so as to remove the solvent~insoluble strong acid ion-exchange resin. The copolymer then is isolated by .
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~S8553 removal of the soivent from the filtrate, for instance by evaporation under reduced pressure. Further purifi-cation of the copolymer can be accomplished if desired by re-dissolving it in a suitable organic solvent and further filtration, including the use of standard filter aids if desired.
The copolymer thus formed is required in the formulations and method of treatment provided by this invention. Such copolymers, while not amenable to exact structure elucidation, are characterized as having a weight average molecular weight of about 6000 to about 35000, and preferably from about 15000 to about 300G0. The copolyme~s are unique in that they are classified as high molecular weight substances having an inherent viscosity from about 0.08 to about 0.30 when measured by standard techniques utilizing an Ubbelohde viscometer in which chloroform has an efflux time of about 51 seconds at 25C. The inherent viscosity of the copolymers is determined by the following equations nr = t/to ninh = ln ~r wherein: nr is relative viscosi~y;
to is efflux time of solvent;
t is efflux time of the soiution;
ninh is inherent viscosity;
C is concentration in grams per 100 ml. of solvent; and ln is logarithm.

~58553 i X-4822 ~8-The copolymers utilized in the formulations of this lnvention are additionally unique in that they are capable of providing a controlled release of pharmaceutical agents heretofore unavailable, in addition to being of such physical makeup which permits their suspension in a suitable vehicle, thus allowing convenient administration, for example via subcutaneous injection. The formulations alternatively can be administered orally or by implantation.
The formulations comprehended by this in-vention comprise an effective amount of an antimicrobial agent uniformly admixed and dispersed throughout the copolymeric matrix hereinabove described. The formu-lations contain from about 5 to about 85 weight per-cent of active ingredient, ideally about 20 to about 75 weight percent, and more preferably about 30 to about 60 weight percent. The pharmacologically anti-microbial agents which can be utilized in the formu-lations include those agents commonly employed in the treatment of the particular disease sought to be prevented or treated with the formulation of the invention. Commonly used active agents include anti-biotics such as the t:etracyclines, particularly chlor-tetracycline, oxytetracycline, doxycycline and tetra-cycline; penicillirs such as ampicillin, benzylpeni-cillin, penicillin V; cephalosporanic acids such as the cephalosporin oximes; cephalosporin salts; oxycephalo-sporins, the cloxacillins and the like. Additional antibiotics routinely used in the formulations of the invention include streptomycin, novabiocin, neomycin, ~158553 X-4822 _9_ sulfonamides, erythromycin, colistin, lincomycin, nalidixic acid, apramycin, salinomycin, nigericin, kanamycin, kitsamycin, tylosin, furaltadone, vancomycin, thiostrepton, gentamycin, tobramycin, spiramycin, ristocetin, soimycin and the like. Preferred formu-lations contain as an antimicrobial agent selected from erythromycin, spiramycin, tylosin, 5-O-mycaminosyl tylonolide~the tetracyclines, oxytetracycline, doxycycline, neomycin, lincomycin and cephalosporins, particularly cephalosporin oximes. A particularly preferred formu-lation of the invention is one comprised of the copolymer and about 30 to about 60 weight percent of the macrolide antibiotic tylosin, in addition to commonly used pharma-ceutical diluents, excipients and carriers.
The formulations provided by this invention can be prepared in any of a number of ways. A pre-ferred method of preparation comprises dissolving a suitable amount of the aforementioned copolymer in an organic solvent that is readily removed by evaporation, and then adding the desired amount of pharmacologically active agent. For example, about 50 grams of a co-polymer derived from about 80 weight percent of lactic acid and about 20 weight percent of glycolic acid, said copolymer having an inherent viscosity of about 0.23, can be dissolved in about 200 to about 400 ml. of a suitable organic solvent such as dichloromethane, acetone, diethyl ether, tetrahydrofuran, chloroform, or the like. A pharmacological agent such as tylosin, in the amount of about 30 grams, can be added to the dissolved copolymer. The solution thus formed can be ~585S3 ~

spray driecl by conventional methods so as to obtain a formulated solid product having uniform mixing of copolymer and active agent and being of substantially uniform particle size. Such formulation can be utilized ; 5 in the creatment of microbial diseases in animals. For instance, the formulation can be utilized in the treat-ment of pneumonia in young calves. If desired, a suitable amount of the formulation can be suspended in a suitable vehicle such as sesame oil, glycerol tri-acetate or triacetin and injected subcutaneously. Such treatment provides the slow release of active ingredient ; to the animal, such that the effective dose of active drug is rom about 4 to about lO mg. per pound per day for a period of about ~ to lO days.
The formulations of the invention can alter-natively be prepared by dissolving the copolymer and antimicrobial agent in a suitable organic solvent, followed by removal of the solvent by evaporation. The copolymer-antimicrobial agent formulation next can be melted and the melt can be extruded into rods having a diameter of about 2.0 to about 7.0 millimeters in diameter. The extruded rods can be cut to desired lengths so as to provide a specific amount of active agent. For example, a formulation which includes about 50 grams of the antibiotic tylosin and about lO0 grams of a copolymer derived from about 70 to about 80 weight percent of lactic acid and about 30 to about 20 weight percent glycolic acid, said copolymer having an inherent viscosit:y of about 0.13 to about 0.23, can be melt extruded into rods having a diameter of about 5.0 ', ' .
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millimeters. Such rods of formulated tylosin a~e, whencooled to room temperature, quite hard and are trans-lucent, and accordingly give the apparence of a amber colored glass. Such glass can be cut into desired lengths so as to obtain the desired dose of tylosin antibiotic. The glass rod of about 40 to 80 mm. can be implanted under the skin of the animal to be treated, or alternatively the glass can be ground into small particles and passed through an appropriate wire sieve, for example from about 60 to about 160 mesh, so as to obtain formulated copolymer-tylosin that is easily suspended in an oil such as sesame oil or the like.
The oil can then be injected subcutaneously to an animal such as a calf to provide therapeutic or pro-phylactic treatment against microbial infection such as pneumonia.
~ he formulations provided by this invention can contain, in addition to the copolymer matrix and the antimicrobial ingredient, other substances commonly utilized in medicinal formulations. Diluents, carriers, binders, excipients and adjuvants routinely incorporated in such ~ormulations include gum tragacanthe, acacia, corn starch, gelatin, alginic acid, magnesium stearate, aluminum monostearate, beeswax, sucrose, lactose, methylparaben, propylparaben, mannitol, propylene glycol, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, cocoa butter, polyoxyethylene sorbitan monolaurate, ethyl lactate, sorbitan trioleate, calcium stearate, talc and the like. Carriers commonly utilized in , ~585S3 ~

administering the formulations by injection include mineral oil, peanut oil, sesame oil, as well as aquecus solutions such as normal sodium chloride solution or sodium carboxymethyl cellulose in water, as well as aqueous polyvinylpyrrolidone.
The formulations contemplated herein can, if desired, include more than one pharmacologically active ingredient. Certain antibacterial agents, for example, have an immediate onset of action, while others may not be completely effective until normal treatment has been carried out repeatedly. According to this invention, a fast acting pharmacological agent can be combined with the aforementioned copolymer matrix, together with a slower acting active agent. Administration of such lS formulation is then effective to treat and protect the host animal against a particular disease for several days, weeks, or even months.
An additional aspect of this invention is a method of treatment utilizing the novel formulations hereinabove described. The method of treatment provided herein comprises administering to an animal suffering from an infectious microbial disease and in need of treatment, or to an animal suspected of developing a disease and in need of prophylactic treatment, a suit-2r~ able amount of a copolymer derived from about 60 to about 95 weiyht percent of lactic acid and about 40 to about 5 weight percent of glycolic acid, said copolymer having an inherent viscosity in chloroform of about 0.08 to about 0.30, having a weight average molecular 30 ~eiyht of about 6000 to about 35000, and said copolymer ~5~3553 ~
X-482~ -13-having admixed uniformly therethrough an effective amount of antimicrobial agent, said amount of admin-istered copolymer-antimicrobial agent being such that the animal receives an effective amount of antimicrobial agent over a prolonged and predetermined period of time.
A number of animals, particularly food producing animals such as swine, ruminants, poultry and the like, are inflicted with a variety cf diseases at birth and during early stages of development. Many such diseases are transmitted through the parent directly to the offspring. One such disease commonly suffered by young pigs is mycoplasmal pneumonia.
Similarly, numerous young calves suffer and die each year from pneumonia contacted as a result of exposure to severe weather conditions.
There is substantial economic loss suffered each year due to deaths caused by these various diseases.
While therapeutic agents are known which are effective against such diseases, no practical and effective means has been heretofore developed for the administration of such agents to young animals. For example, the owner of a herd of several hundred young calves simply is unable to treat such herd with a therapeutic agent

2~ which requires miltiple daily administrations. While some therapeutic agents are orally effPctive and can be added to feed or to water, very young animals such as newborn pigs and calves simply do not consume suf-ficient quantities of these substances to obtain a dose of active agent sufficiently large to effectively treat the disease. Moreover, substantial losses can be i: , ~S85S3 Gbviated if newborn animals could be protected fromdiseases by prophylactic treatment until such time that the animals have a sufficiently developed auto-immune system to effectively combat diseases to which they are exposed.
According to the method of this invention, a controlled release formulation as described hereinabove is administered to an animal so that the animal receives, with a single administration, an effective dose of antimicrobial agent continuously for a period of several days. For example, a controlled release formu-lation comprised of about 2.0 to about 12.0 grams of an antibiotic such as tylosin o- oxytetracycline and about 1.0 to about 12.0 grams of a çopolymer derived from about 80 weight percent of lactic acid and about 20 weight percent glycolic acid can be extruded into a glass rod, ground, screened to uniformity through an 80 140 mesh screen, and suspended in sesame oillglycerol triacetate or triacetin containing about 1 to about 2 percent of aluminum monostearate and about 1 to about 2 percent of beeswax, for convenient subcutaneous admin-istration to a young calf weighing about 100 to about 200 pounds. Such treatment is effective for releasing to the animal the active ingredient at the rate of 25 about 1.0 to about 15.0 mg. per pound each day for about eight days. Such treatMent is particularly effective for the therapeutic and prophylactic therapy of pneumonia in calves.
While the controlled release formulations are preferahly adrninistered by subcutaneous or intramuscular injection according to this invention, treatment via .

~58SS3; , X-48~2 -15-alternative routes is also contemplated. For example, the antimicrobial agent can be formulated with the copolymer and additional binders and carriers and molded into a suitable bolus for convenient oral administration. Alternatively, the controlled release formulations can be extruded into rods or the like and implanted under the animals skin according to standard techniques. Additionally, ~he formulations can be enclosed or encapsulated in a device suitable for administration as a suppository or as an intrauterine or intramammary device. Such formulations are thus effective for prolonged treatment of mastitis and similar diseases.
The particular amount of controlled release formulation required for a particular treatment will vary, dependiny upon the species, age and weight of the host animal being treated, the particular dlsease to be guarded against, or treated, as well as the specific antimicrobial agent selected for the treatment, the route of administration and the frequency. Generally, an amount of formulated controlled release drug will be administered so that the daily payout of antimicrobial ingredient is comparable to or somewhat less than the recommended daily dosage of that particular active drug. For example, tylosin is known to be effective in the trea~ment of contagious calf pneumonia, diphtheria, foot rot, metritis and pneumonia in cattle, and erysipelas, pneumonia, dysentery and arthritis due to mycoplasma in swine. The effective dose of tylosin in the treatment of such diseases is from about l.G to about 20.0 mg.
per pound of animal body weight, when administered ~1~855~

intramuscularlv. According to the method of this invention, a controlled release formulation of co-polymer and tylosin is administered so that the daily dose of tylosin is from about 0.5 to about 15 mg. per pound of animal body weight. The formulation is such that total payout of the antimicrobial ingredient is accomplished within about 5 to about 10 days, generally in about 7 or 8 days. It is contemplated that in one aspect of this invention, young calves (from 2 to about 25 days old) czn be effectively protected from and treated for a disease such as pneumonia by the sub-cutaneous administration of a formulation of this invention containing about 2.0 to about 10.0 grams of tylosin once every 7 to 10 days, the total number of such treatments being from 1 to about 4, or as needed by the severity of the condition being treated or guarded against.
The formulations and method of treatment pro-vided by this invention have been evaluated in several tests designed to show their utility and efficacy. One such test consisted of treating calves injected with varying dosages of tylosin in controlled release formu-lations. Tylcsin was formulated with a copolymer derived from about 80 weight percent lactic acid and about 20 weigh. percent glycolic acid, having a viscosity of about 0.20. The formulations were extruded into glass rods. The glass rods were ground, passed through a 60 onto a 140 mesh screen (about 100 to 200 micron particle si~e) and then suspended in 5 ml. of sesame oil. Three tormulations were prepared such that the effective dc4es of tylosin were 2.5 mg./lb./day, , ~L~585S3 S.0 mg./lb./day and 7.5 mg./lb./day respectively. The formulations also contained about 1 to 2 percent by weight of beeswax and about 1.5 to about 2.5 percent by weight of aluminum monostearate, which ingredients aided syringability. The formulations thus prepared were administered subcutaneously in the neck of young calves suffering from naturally occuring bacterial pneumonia. Fifteen calves were held as controls and received no medication. Three groups of fifteen calves each were treated on day zero and again on day 7 with the three respective formulations. Mortality was determined after fourteen days. The results of the test are presented in Table I.
Table I
Dose of Tylosin from controlled release formulations Mortality mg./lb./daydeaths out of fifteen Control 10 2.5 4 5.0 6 7.5 3 In a similar study, twenty young calves suffering from naturally occuring pneumonia were treated sub cutaneously on day zero and again on day seven with a t~losin formulation designed to release about 4.0 mg.
per pound per day for about seven days. Ten infected calves were held as controls and not treated. During the course of the experiment, clinical observations were made, including nasal discharge, ocular discharge ~,~

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and diarrhea. Rectal temperatures and mortality were recorded. Of the control group receiving no medication, six of the ten infected animals died by the twenty-first day (60 percent mortality). Of the treated group, only five of the twenty infected animals had died (25 percent mortality). Table II below lists the average daily rectal temperatures of the control group and the treated group. The data demonstrates that the treated group had uniformly lower temperatures than the control group, thus indicating that the treated group suffered a less severe infection than the control group.

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~585S3 A particularly preferred prophylactic treat-ment according to this invention comprises the admin-istration to young pigs an effective amount of a formulation of this invention for the prevention of mycoplasmal pneumonia caused by Mycoplasma hypopneu-moniae. This particular disease has been estimated to occur in over half of the pigs in the world and to cause an average economic loss of about one dollar per head. This particular disease is transmitted from the sow to one or more newborn pigs in a litter within a few days after birth of the litter. Because of its contagious nature, the disease can be rapidly trans-; mitted to most of the other newborn pigs in the litter.
While no drug is known which is effective against this disease after the animal has been infected, certain drugs,including tylosin and chlortetracycline, are effect ve prophylactically when administered to the animal prior to contact with the disease. While daily injections of such active agents would probably control the disease, such treatment is impracticable due to the labor required, the cost, the injection site irritation and related factors. Moreover, feed additives and the addition of the therapeutic agent to a watering trough is ineffective simply because the newborn animals do not consume sufficient quantities of these substances in order to injest an ef~ective dose of the therapeutic agent.
The method of the present invention affords a means whereby newborn and young animals can be effectively protected against infection by mycoplasmal pneumonia.

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-~S85S3 Such metho~ accordingly contemplates treatment of young animals with an antimycoplasmal agent-copolymer formu-lation such as those hereinabove described. Such formulation can be administered at birth and period-ically thereafter as required up to weaning, thusproviding effective prophylactic treatment against the disease. Typical formulations utilized for the treat-ment of mycoplasmal pneumonia in young animals according to the method of this invention are comprised of the aforementioned copolymer, derived from about 60 to about 95 weight percent lactic acid and about 40 to about 5 weight percent glycolic acid, and a suitable antimycoplasmal agent such as tylosin and chlortetra-cycline. A particularly preferred method of prophylactic treatment according to the invention comprises admin-istering a controlled release formulation of the aforementioned copolymer and the antibiotic tylosin.
While tylosin is reported to be ineffective as a treat-ment for mycoplasmal pneumonia, it s surprisingly and significantly effective prophylactically against such disease when administered according to the method of this invention. For instance, formulations comprised of about 100 to about 1500 mg. o~ tylosin intimately dispersed throughout from about lO0 to about 1500 mg.
of a copolymer derived from about 70 to about 80 weight percent lactic acid and about 30 to about 20 weight percent glycolic acid, having a viscosity of about 0.13 to about 0.23, can be administered to a newborn pig at the rate of about lO to about 50 mg/kg about once every 7 to 14 days. Such treatment is effective in uniformly and continuously protecting the young animal from contactin~ mycoplasmal pneumonia.

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~!~5~3SS3 As previously pointed out, the formulationscan be administered by any of several ways. For the treatment of young pigs, the formulations ideally are extruded into rods, and the rods are cut into appro-priate length, for example about 20 mm., to give thedesired dosage of active ingredient. Such rod can be implanted subcutaneously in the an mal. Alternatively, the formulated rods can be ground to uniformity and suspended in a suitable carrier for convenient sub-cutaneous or intramuscular injection.
The following detailed examples are presentedby way of illustration of certain specific embodiments of the invention.
Example l To a 3-neck round bottom flask equipped with a condenser and thermometer were added 864.0 g. of lactic acid, 201.0 g. of glycolic acid and 12.0 g. of Dowex HCR-W2-H ion exchange resin. The mixture was stirred and heated to 130C. for three hours, during which time 400 ml. of water were distilled and collected.
After discarding the water thus produced, stirring and heating were continued and the pressure was gradually reduced by vacuum over three hours, after which time the temperature of the reaction mixture had incre~sed to 150C. at a final pressure of 5 torr. An additional 12.0 g. of Dowex HCR-W2-H catalyst was added to the reaction mixture, and the mixture then was heated to 170C. at 5.0 torr for twenty-four hours, and then at 185C. at 5.0 torr for an additional 48 hours. The molten reaction mixture next was filtered to remove ' ~L~5~5S3 most of the ion exchange polymeriæation catalyst, and the filtrate was allowed to cool to room temperature to give 700 g. of 80 percent lactic--20 percent glycolic copolymer. The copolymer was analyzed by proton nuclear magnetic resonance spectrometry and shown to be comprised of 76 percent by weight of lactic units.
The viscosity of the copolymer was determined in a Ubbelohde viscometer in which chloroform had an efflux time of 51 seconds at 25C. The copoli~mer was dissolved in chloroform at a concentration of 0.50 g.
per 100 ml. of solvent. Inherent viscosity of the copolymer was then determined according to the formulas:
nrel = - ninh = lcnnrel wherein:
nrel = relative viscosity to = efflux time of solvent (CHC13) t = efflux time of solution inh = inherent viscosity C = conc. in grams/100 ml.
The inherent viscosity of the copolymer thus prepared ~as determined to be 0.19 dl/g.
Example 2 Following the general procedure set forth in ~xample 1, 432 g. of lactic acid and 101 g. of glycolic acid were condensed in the presence of a total of 12.0 g. of Amberlyst 15 ion exchange polymerization catalyst to afford 350 g. of a copolymer comprised of about 80 percent lactic units and about 20 percent glycolic units. The copolymer had the following inherent viscosity: 0.18 dl/g.

i~S8SS3 Example 3 Following the general procedure of Example 1, 422.0 g. of laetic acid were condensed with 14~.0 g. of glyeolic acid in the presence of a total of 12.0 g. of Dowex HCR-W2-H ion exchange polymerization catalyst.
After removing the catalyst by filtration of the molten reaction mixture, there was provided 350 g. of a eopolymer derived from about 75 pereent by weight of laetie aeid and about 25 percent by weight of glycolic aeid. The eopolymer exhibited the following inherent viseosity: 0.19 dl/g.
Example 4 Following the general procedure of Example 1, 15 1080 g. of lactie aeid were eondensed with 252 g. of glyeolie aeid in the presence of a total of 30.0 g. of Dowex HCR-W2-H ion exehange polymerization catalyst to give, after removal of the eatalyst, 750 g. of a eopolymer whieh was shown by proton NMR to contain about 79 pereent of laetie units and about 21 pereent of glyeolie units. The eopolymer exhibited the following inherent viscosity: 0.20 dl/g.
Example 5 Following the procedure of Example 1, 1080 g.
of laetie aeid were eondensed with 120 g. of glyeolie aeid in the presence of a total of 15.0 g. of Dowex HCR-W2-H ion exehange polymerization eatalyst to provide, af~er work-up, 530 g. of a eopolymer derived P~58SS3 from about 90 weight percent of lactic acid and about 10 weight percent of glycolic acid. The copolymer had an inherent viscosity of 0.20 dl/g.
Example h Following the procedure of Example 1, 710 g.
of lactic acid were condensed with 190 g. of glycolic acid in the presence of a total of 12.0 g. of ~owex HCR-W2-H ion exchange polymerization catalyst to provide 500 g. of a copolymer comprised of about 70 percent lactic units and about 3G percent glycolic units. The copolymer had an inherent viscosity of: 0.12 after 2~ hours at 175C.
Example 7 The procedure of Example 1 was followed to condense 1080 g. of lactic acid with 120 g. of glycolic acid in the presence of a total of 30.0 g. of Dowex HCR-W2-H ion exchange polymerization catalyst. After workup, there was recovered 750 g. of a copolymer derived of about 89 weight percent of lactic acid and about 11 weight percent of glycolic acid having an inherent viscosity of 0.20 dl/g.
The copolymers provided by this invention additionally have been characterized by gel permeation chromatography (high pressure liquid chromatography) and subsequent determination of molecular weight. Gel permeation chromatography separates sample molecules by differences in effective molecular size in solution.
Separation is accomplished as a result of the pore size distribution in the packing material. This analytical - ~58S53 technique allows determinations o~ weight-average molecular weight, number average molecular welght, molecular weight distribution, and dispersity for polymeric materials.
Several such experiments have been carried out on the copolymers of this invention. Standard gel permeation chromatographic coiumns were used, and the support in each case was commercial uStyragel. All samples and standards were dissolved in a solution of 80 parts tetrahydrofuran and 20 parts dichloromethane.
The indirect method (i.e. the "Q-Factor Method") of calibrating the gel permeation chromatographic columns was used to obtain molecular weight averages for the copolymers of the invention. Commercial polystyrene, with a Q Factor of 41.3, was used in the calibrations.
The following Table presents several determinations of molecular weight by standard gel permeation chromato-graphic techniques as outlined above. A more detailed discussion of the technique utilized is presented by Slade in Polymer Molecular Weights, Marcel Deckker, ; Inc., 1975.
In the Table, column I presents the relative proportions of lactic units and glycolic units making up the copolymer analyzed. Column II gives the inherent viscosity of each copolymer analyzed. Column III
reports the strong acid ion exchange resin utilized to prepare the copolymer being analyzed. Column IV presents the ~leight average angstrom size as determined from the gel pe~meation chrornatographic retention time for the particular copolymer. Column V presents the weight ~.585S3 average molecular weights for the various copolymers prepared by the process of this invention. The weight average molecular weights are determined by multiplying the Q-Factor for polystyrene (41.3) times the weight average angstrom size for the particular copolymer being analyzed. Column VI is the relevant Example number.
As demonstrated in the Table, the preferred copolymers of this invention have a molecular weight from about 15,000 to about 35,000, and ideally -,-rom about 15,000 to about 30,000.

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- Example 8 Preparation of Spray Dried Formulation Containing Tylosin A solution of 50.0 g. of tyiosin (free base) in 150 ml. of dichloromethane was added in one portion to a stirred solution of 50.0 g. of a copolymer made up of about 75:25 weight percent lactic acid:glycolic acid, inherent viscosity of 0.18 dl/g. in 200 ml. of dichloromethane. Fresh dichloromethane was a~ded to the mixture until the solution volume was 400 ml. The solution was stirred at room temperature and then spray dried in a conventional spray drier having a pressure tank head pressure of 0.688 x 106 dynes/cm2 and an atomization pressure of 0.07 x 106 dynes/cm2. The inlet temperature of the spray drier was about 54 to about 57C., and the spray rate was 8 ml. per minute.
The spray-dried product was ground to uniformity and passed through a No. 60 U.S. Standard Mesh Screen. l'he formulated product so formed can be suspended in a sesame oil carrier for convenient subcutaneous in-jection into an animal suffering from microbial in-fection or in need of prophylactlc treatment against such infection.
Example 9 Preparation of Spray Dried Formulation Containing Apramycin To a stirred solution of 15.0 g. of a copoly-mer made up of about 65:35 weight percent lactic acid:
glycolic acid, inherent viscosity of 0.19 dl/g. in ' ' ~158553 40 m]. of dichloromethane was added in one portion 5~0 g. of apramycin free base. The solution was - diluted to 80 ml. with additional dichloromethane. The , solution then was spray dried at the rate of 10 ml. per ; 5 minute in a spray drier with inlet temperature from about 48 to about 51C. and atomization pressure of 0.07 x 106 dynes/cm2. The spray dried formulation was - ground and passed through a No. 60 mesh screen to ,afford a uniformly sized controlled release formulation of apramycin. The formulation can be suspended in a suitable vehicle and injected subcutaneously into an animal suffering from bacterial pneumonia.
Example 10 To a solution of 5.0 g. of a copolymer made up of a~out 80:20 weight percent lactic acid:glycolic ' acid, inherent viscosity of 0.20 dl/g. in 50 ml. of , chloroform was added in one portion 5.0 g. of tylosin as the free base. The solution was stirred for several minutes and then the solvent was removed b~ evaporation under reduced pressure. The product 50 formed was extruded into rods of about 5.0 millimeters diameter, such rods resembling an amber glass. The glass rods were ground to uniformity and passed through a screen 25 having mesh of about 60 to about 140. The screened formulation so formed can be suspended in a suitable carrier such as sesame oil or 10 percent a~ueous polyvlnylpyrrolidone.

~S8S53 Example 11 The controlled release tylosin glass-like formulation of Example 10 was evaluated in mice for its ability to uniformly release an effective amount of active agent over a prolonged period of tlme. The method utilized was similar to that reported by Ose et al. in J. Vet. Res., 29, 1863-1866 (1968). Mice weighing about 20.0 grams were administered, by sub-cutaneous injection, 25 mg. of the formulat.iGn (active ingredient 12.5 mg. per animal) and then challenged with logl0 dilutions of a tryptose broth culture of Erysipelothrix rhusiopathiae at various time periods.
Control groups of non-medlcated mice also were chal-lenged at the same rate as the test groups. The LD50 of the treated animals and the control animals was calculated at various time intervals. The numerical difference represents logl0 protection units attrib-utable to the treatment, thus indicating the degree oE
protection over a prolonged period. The results of such ~xperiment are presented belo~-Treatment Loyl0 units of prot_c~ion Day 7 Day 10 Day 14 Day 18 Day 21 Controlled release 25of tylosin 12.5 mg./animal 5.5 4.8 1.3 1.0 0.2 Measurable amounts of tylosin were determlned in theurine of the treated animals for 18 days following adrninistration.

~585S3 Example 12 A formulation comprised of 50 weight percent of tylosin in a copolymer made up of about 80 weight percent lactic acid and about 20 weight percent glycolic acid was extruded into the form of a glass rod. The rod was cut into portions weighing 25 mg., such that - the dose of tylosin was 12.5 mg. per glass rod. The rods so prepared were implanted into mice, and the degree of release of active agent was indicated by measuring Log10 units of protection at various intervals following treatment, according to the method described in Example 11. The results are presented in the following table:
15 Treatment Log units of Protection Day 1 7 11 1~ 17 21 28 Implanted Tylosin 12.5 mg. ~6.0 >5.3 4.2 6.0 5.7 3.3 1.2 The tests described in Examples 11 and 12 demonstrate that various controlled release tylosin formulations are effective in providing protection from disease by the slow release of antibiotic for periods up to 28 days following administration.

Example 13 A formulation of this invention was prepared by mixing a solution of 5 g. of erythromycin in dichloro-methane with a dichloromethane solution of 5.0 g. of a copolymer derived from about 79 weight percent lactic acid and about 21 weight percent glycolic acid (viscosity about 0.20). The solution was spray dried by following ~L~585S3 the general procedure set forth in Fxample 8. Theproduct thus formed was a dry powder of uniform consistency. I'he powder was passed through a wire seive of 60 to 140 mesh. The formulation so for~led was separated into 25 mg. portions (each containing l2.5 mg.
of erythromycin) and suspended in 0.2 ml. of 10% poly-vinylpyrro1idone. The formulations thus prepared were injected (12.5 mg/mouse) subcutaneously into mice ; infected with Erysip _othri,Y rhusiopathiae. A con-trol group of infected mice received one dose of aqueous erythromycin at the rate of 12.5 mg/mouse. The Log10 units of protection agalnst an Erysipelothrix rhusiopathiae challenge was determined at various time intervals following dGsing. The results are presented below.
Treatment Log units of protection day 1 day 2 day 3 day 5 Group 'reated with controlled 20 release formulation 4.l 3.4 1.9 0 Group treated with aqueous erythromycin l.3 0 0 0 The data demonstrates that a single dose of controlled release formu:lation provides continuous protection for several days, whereas a single dose of conventional active agent affords only minimal protection for a short period of time.

~L~585S3 Example 14 A formulation comprised o~ 50 weight percentof tetracycline and 50 weight percent of a copolymer derived from about 80 weight percent lactic acid and about 20 weight percent glycolic acid (viscosity about 0.23) was prepared and spray dried according to the method of Example 8. The formulation thus prepared was suspended in a sesame oil vehicle. On day 1, 12.5 ~g.
of the formulation (6.25 mg/mouse of active ingredient), was administered by subcutaneous injection to a test group of mice. The mice were then challenged with _asteurella multocida. A control yroup of mice similarily challenged were treated on day 1 with aqueous tetracycline at the rate of 6.25 mg/mouse. As described hereinabove, the logl0 units of protection for the two groups were deter~ined at various intervals followiny treatment.
The results are presented in the following table:
TreatmentLog units of Portection Day 1 Day 2 Day 3 Da~ 5 Controlled release tetracycline>4.8 >7.6 >5.0 >4.9 aqueous tetra-cycline3.9 3.2 0.8 --The controlled release formulation afforded protection against several log10 challenge dilutions at each challenge interval over a prolonged period of time, whereas the aqueous tetracycline failed to afford significant protection beyond the second day.

~S8553 X-4~22 -35-':

Example 15 The tylosin controlled release formulation prepared according to Example 10 was analyzed in young chickens for its effect on Mycoplasma gallisepticum, S the causative agent of chronic respiratory disease in poultry. Groups of young chickens were challenged by injection into the thoracic air sac with 0.1 ml. of 2.
broth culture of ycoplasma gallisepticum at 5 or 10 days following a sinsle subcutaneous administration oF
the tylosin formulation of the invention (25 mg/chicken of formulation, 12.5 mg/chicken of active ingredient).
A control group of chickens were infected at the same intervals as the treated group, but the control group received no medication. Various animals from the two groups were sacrificed at various time intervals and ; analyzed for the presence or absence of air sac lesions.
At day 5 following the initial challenge with Mycoplasma gallisepti.cum, twelve animals from each group were analyzed. Of the treated group, none had evidence of air sac lesions. In contrast, nine out of the twelve nonmedicated animals had air sac lesions. At day 10 following the initial infection, only four out of twelve treated animals had air sac lesions, whereas nine out of eleven nonmedicated animals showed sisnif-icant air sac lesions.
Example 16 A controlled release formulation containing 50 weight percent of the aminoglycoside antibiotic neomycin and 50 weight percent of a copolymer derived from about 80 weight percent of lactic acid and abou~

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20 weight percent of glycolic acid was prepared by the spray drying process described in E~ample 8. The formulation was suspended in sesame oil and subcu-- taneously injected into a group of 1-day old chicks at the rate of 10 mg per chick (active ingredient at the rate of 5 mg per chick). Another group of animals were held as controls and received no antibacterial agent, while still another group of animals received a single injection of aqueous neomycin at the rate of 5 mg per chick. Selected groups of the treated animals were challenged at day 1, day 3 and day 5, respectively, with Escherichia coli. The following table shows the -number of animals that died out of each of the three groups receiving challenge.

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~L~L585S3 The data demonstrates that a formulation of this in-vention provides continuous protection over a prolonged period of time, whereas conventional treatment provides only slight protection for a relatively short period or time (one day).
Example 17 .
As pointed out hereinabove, a particularly preferred method of treatment according to this in-vention comprises administering a controlled releaseformulation provided herein to a new-born animal, such as a pig, thereby protecting the animal from developin~
a microbial disease during the time that such animal is nursing.
The following experiment was carried out to illustrate the ef~ectiveness of the tylosin controlled release formulation of this inven-tion in protecting pigs from developing mycoplasmal pneumonia during the time they are nursing. Sixteen pigs less than one week of age were inoculated intranasally with a suspension of mycoplasmal pneumonia infected lung tissue. They were placed in one-half of a Horsfal-Bauer isolation unit which had been divided with an open mesh grid into two equal-sized compartments. These pigs were con-sidered seeder pigs and served to provide exposure totreated and nonmedicated control pigs equivalent to the ex~posure provided to a litter by the sow.
Two weeks later, sixteen neonatal plgs were placed in the unoccupied sides o L the isolation units as representative o~ new-born pigs. Eleven of tne new pigs were treated with a 50 percent tylosin-copolymer ~58SS3 controlled release formulation (prepared as describedin Example 10). The formulation was suspended in - sesame oil containing 1.5 percent by weight of beeswax and 1.5 percent by weight of alurninum monostearate.
The animals received an intramuscular injection on day zero of sufficient quantity that each pig recelved 250 mg. of tylosin (i.e. 500 mg of the controlled release formulation). On the tenth day of the experi-ment, the treated pigs received a second injection o such size that each pig received 375 mg. of tylosin, and again on the twentieth day the treated animals were administered 500 mg of active ingredient (1000 mg of the formulation). Five pigs were not medicated and were included as controls to demonstrate that trans-mission of mycoplasmal pneumonia from the seeders wouldoccur. All pigs were killed on the 34th day following placement of the second group of pigs in the units.
Lungs were isolated and examined for gross lesions, (an indication of infection), and cultures from lung tissue were made for Mycoplasma hyopneurroniae. As shown in the accompanying summary table, out of ni.ne tylosin controlled release treated piqs, none were ir.fected, as determined b~ gross lung lesions or reisolation of M.
hyopneumoniae from the luny. In contrast, mycoplasmal pneumonia ~as transmitted to three of the five non-medicated controls. The two deaths that occurred in the treated group and the one seeder pig that died during the study were due to causes other than myco-plasrnal pneumonia.

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~L51~553 The results of the study demonstrate thatnew-born animals exposed to mycoplasmal pneumonia can be effective]y protected against contacting such disease by treatment according to this invention. A single parenteral administration of a controlled release formulation of this invention provides protection to such animals for periods of about seven to about twelve days. Longer perioc.s of protection, for instance from about fourteen to about twenty-one days, can be achieved by administering the formulations by implantation and the like.
Example 18 A formulation comprised of fifty percent doxycycline ancl fifty percent of a copolymer derived from about 80 weight percent lactic acid and about 20 weight percent glycolic acid was prepared by the method of Example 8. The formulation so prepared was admin-istered by a single subcutaneous injection (in sesame oil) to a group of mice at the ra-ce of 25 mg/mouse (effective dose of do~ycycline therefore was 12.5 mg/mouse).
Another group of mice received a single dose of aqueous doxycycline at the rate of 12.5 mg/mouse. Following medication, all of the animals were challenged at various time int(-rvals with Pasteurella multocida. The followiny table presents the log10 protectioll units at various time intervals following treatment and sub-sequent challenge.

~58SS3 ~-4822 -42-Treatment Log10 protection post treatment Day 0 Day 3 Day 5 aqueous doxycycl~ne3.3 0 1.2 controlled release doxycycline>5.8 >5.3 >6.7 The results demonstrate that controlled release doxycycline of this invention provides pro-tection against ~5.3 log Pasteurella multocida challenge units at each challenge period. In contrast, aqueous doxycycline provides little protection beyond the initial treatment and challenge.
Exarmp].e 19 . As already pointed out, a preferred formu-lation of this invention comprises a cephalosporin antibacterial agent intimately dispersed throughout a copolymer as hereinabove defined. Especially preferred cephalosporin antibiotics to be uti.lized include the 7-a-methoxyimino-a-(2-aminothjazol-4-yl)acetamido-3-substituted-3-cephem-4-carboxylic acids or salts, ~herein the 3-substituent is, _ t er alia, methyl, 5-methyl-(1,3,4-thiadiazol-2-yl) thiomethyl, (l-methyl-5,6-dioxo-1,3,4-triazin-2-yl)thiomethyl, (l-carboxy-methyl-1,2,3,~-tetrazol-5-yl)thiomethyl and (1,2,3,4-tetrazole-5-yl)thiomethyl.
A typical cephalosporin commonly utilized in the forrnulations of the invention is 3-methyl-7-a-methoxyimino-a-(2-aminothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid. Such compound was dissolved l~S8553 in an organic solvent such as dichloromethane at the rate of about 100 mg in 100 ml. of solvent. About 100 mg of a copolymer derived from about 80 weight percent lactic acid and about 20 weight percent glycolic acid, with a viscosity of about 0.20, was added to the solution. The solution was then spray dried by the method of Example 8 to give a uniform mi~ture of active agent and copolymer. The formulation thus formed was suspended in 20 ml. of sesame oil.
In a test designecl to demonstrate the con-trolled release of active ingredient from the above formulation, one group of mice were given a single subcutaneous injection of 12.5 mg. of 3-rnethyl-7-a-methoxyimino-a-(2-aminothiazol-4-yl)acetamido-3-cephem-4~carboxylic acid (cephalosporin acid). Another group of mice were given a single subcutaneous in-jection of 25 mg of the controlled release formulation (controlled release cephalosporin acid), so that the dose of active ingredient was 12.5 mg. per mouse. The animals were then challenged at various time intervals with Pasteu ella multocida. The following table shows the results of the treatments in units of log10 pro-tection at various days post~treatment for the two treated groups.
25 TreatmentLog10 protection at various days post-treatment Day 0Day 1 Day 3 Day 5 cephalosporin acid >5.2 0.7 0 0.4 controlled release cephalosporin acid >5.2~4.4 >4.5 >4.7 : , ~

~ :

~158SS3 x-4822 -44-The data makes clear the fact that a singletreatment with a controlled release formulation OL
this invention protects the host animal for several days, whereas a correspondinc3 single dose of the active ingredient alone affords protection for no more than one day.
Example 20 One of the following cephalosporin compounds was dissolved in an organic solvent such as dichloro-methane at the rate of about 90 mg. in 100 ml. of solvent. About 250 mg. of a copolymer derived from about 80 weight percent lactic acid and about 20 weiyht percent glycolic acid, with a viscosity of about 0.20, was added tQ the solution. The solution was then spray dried by the method of Example ~ to give a uniform mixture of active agent and copolymer.
The formulation tnus formed was suspended in about 20 ml. of triacetin.
In a test designed to demonstrate the con-irolled release of active ingrediellt from the above formulation, a group of mice were given a single subcutaneous injection of 4.6 mg. of one of the following cephalosporin compounds in the contrclled release formulation. The animals were then challenged at various time intervals with Pasteurella m ltocida.
The follo~1ing table shows the results of the treatments in units of loal0 protection at various days post-treatment for the various groups.

x-4822 -45-Tr_atmentLog10 protection at various days post-treatment Day 1 Day 2 Day 3 A 6.6 5.1 4.5 B 4.4 2.4 1.0 A -- sodium 7-a-methoxyimino-a-(2-aminothiazol-4-yl)-acetamido-3-(1-me-thyl-5,6-dioxo-1,3,4-triazin 2-yl)thiomethyl-3-cephem-4-carboxyla-te.
0 B = sodium 7-a-methoxylmino-a-(2-aminothiazol-4-yl)acetamido-3-methyl-3-cephem-4-carboxylate.
The data indicate that both compounds pro-tected for several days.

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Claims (22)

The embodiments of the invention in which an exclusive property or previledge is claimed are defined as follows:

1. A controlled release formulation capable of delivering an effective dose of an antimicrobial agent over a prolonged period of time and biodegradable into readily metabolized substances and normal active ingredient metabolic products, which formulation is useful in the prophylactic and therapeutic treatment of diseases caused by microorganisms in animals, which comprises about 5 to about 85 weight percent of an antimicrobial agent intimately dispersed throughout a copolymer derived from about 60 to about 95 weight percent lactic acid and about 40 to about 5 weight percent glycolic acid, said copolymer having an inherent viscosity of about 0.08 to about 0.30 when measured in chloroform, a weight average molecular weight of about 6000 to about 35000, and said formulation being in combination with suitable excipients and carriers therefor.

2. The formulation of claim 1, wherein the copolymer is derived from about 60 to about 90 percent lactic acid and about 40 to about 10 percent glycolic acid, said copolymer having a viscosity of about 0.10 to about 0.25 and a weight average molecular weight of about 15,000 to about 30,000.

3. The formulation of claim 2 wherein the antimicrobial agent is a penicillin, cephalosporin, tetracycline, sulfa drug, macrolide antibiotic, or aminoglycoside.

4. The formulation of claim 3 wherein the antimicrobial agent is chlortetracycline, tetracycline, oxytetracycline, doxycycline, ampicillin, benzylpeni-cillin, penicillin V, cephalosporins, cloxicillin, streptomycin, lincomycin, novobiocin, neomycin, spira-mycin, erythromycin, colistin, nalidixic acid, salino-mycin, nigericin, kanamycin, kitsamycin, gentamycin, tobramycin, apramycin, furaltadone, vancomycin, thio-strepton, ristocetin, soimycin, tylosin, 5-O-mycaminosyl tylonolide or sulfonamides.

5. The formulation of claim 1 wherein the copolymer is derived from about 70 to about 80 weight percent lactic acid and about 30 to about 20 weight percent glycolic acid, having an inherent viscosity of about 0.13 to about 0.23.

6. The formulation of claim 5 wherein the antimicrobial agent is tetracycline, oxytetracycline, doxycycline, lincomycin, spiramycin, neomycin, erythro-mycin, tylosin, 3-methyl-7-.alpha.-methoxyimino-.alpha.-(2-amino-thiazol-4-yl)acetamido-3-cephem-4-carboxylic acid, or 3-(1-methyl-5,6-dioxo-1,3,4-triazin-2-yl)thiomethyl-7-.alpha.-methoxyimino-a-(2-aminothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid.

7. The formulation of claim 1 comprising about 20 to about 75 weight percent of antimicrobial agent uniformly admixed with a copolymer derived from about 70 to about 80 weight percent lactic acid and about 30 to about 20 weight percent glycolic acid, said copolymer having a viscosity of about 0.13 to about 0.23.

8. The formulation of claim 7 wherein the antimicrobial agent is present in about 30 to about 60 weight percent.

9. The formulation of claim 6 or 8 wherein the antimicrobial agent is doxycycline.

10. The formulation of claim 6 or 8 wherein the antimicrobial agent is oxytetracycline.

11. The formulation of claim 6 or 8 wherein the antimicrobial agent is 3-methyl-7-a-methoxyimino-a-(2-aminothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid, or 3-(1-methyl-5,6-dioxo-1,3,4-triazin-2-yl)thio-methyl-7-a-methoxyimino-.alpha.-(2-aminothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid or their salts.

12. The formulation of claim 6 or 8 wherein the antimicrobial agent is lincomycin.

13. The formulation of claim 6 or 8 wherein the antimicrobial agent is spiramycin.

14. The formulation of claim 6 or 8 wherein the antimicrobial agent is erythromycin.

15. The formulation of claim 6 or 8 wherein the antimicrobial agent is neomycin.

16. The formulation of claim 6 or 8 wherein the antimicrobial agent is tylosin or 5-O-mycaminosyl tylonolide.

17. The formulation of claim 1, said formu-lation comprising about 30 to about 60 weight percent of tylosin admixed with from about 70 to about 40 weight percent of a copolymer derived from about 70 to about 80 weight percent of lactic acid and about 30 to about 20 weight percent of glycolic acid.

18. The formulation of claim 1 or 17, said formulation comprising about 40 weight percent tylosin admixed with a copolymer derived from about 80 weight percent lactic acid and about 20 weight percent glycolic acid, said copolymer having a viscosity of about 0.18 to about 0.23.

19. The formulation of claim 1 or 17, said formulation comprising about 50 weight percent of tylosin admixed with a copolymer derived from about 80 weight percent lactic acid and about 20 weight percent glycolic acid, said copolymer having a viscosity of about 0.18 to about 0.23.

20. The formulation of claim 1 or 17, said formulation comprising of about 55 weight percent of tylosin admixed with a copolymer derived from about 80 weight percent lactic acid and about 20 weight percent glycolic acid, said copolymer having a viscosity of about 0.18 to about 0.23.

21. The formulation of claim 1 or 17 in the form of extruded glass-like rods having a diameter of about 2 to about 7 mm.

22. The formulation of claim 1 or 17 in the form of extruded glass-like rods being ground to uni-formity and passed through a seive having mesh of about 60 to about 140.