Journal of Controlled Release 85 (2002) 73–81www.elsevier.com/ locate/ jconrel

D evelopment and in-vitro evaluation of sustained releasePoloxamer 407 (P407) gel formulations of ceftiofur

b c d a ,*Lin Zhang , Daniel L. Parsons , Christine Navarre , Uday B. KompellaaDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center 986025,Omaha, NE 68198-6025,USA

bHoffman-La Roche, Nutley, NJ, USAcDepartment of Pharmacal Sciences, Auburn University, Auburn, AL 36849,USA

dLarge Animal Clinic, Auburn University, Auburn, AL 36849,USA

Abstract

The objective of this study was to develop sustained release Poloxamer 407 (P407) gel formulations of ceftiofur fortreating foot infections in cattle. The formulations contained 25–35% (w/v) P407 alone or with polyvinyl pyrrolidone(PVP), carboxy methylcellulose (CMC), or hydroxylpropyl methylcellulose (HPMC) as an additive. The in-vitro releaseprofiles of ceftiofur from the P407 formulations and the gel dissolution profiles were obtained simultaneously. Ceftiofurrelease followed zero order kinetics and correlated well with the weight percentage of P407 dissolved, indicating that theoverall rate of release of ceftiofur is controlled by dissolution of the P407. An increase in P407 content from 25 to 35%resulted in a decrease in the rate of ceftiofur release. However, it appears that other factors may have also affected the drugrelease rate. Inclusion of PVP, CMC, and HPMC in the gel decreased the rate of release of ceftiofur to some extent. Adecrease in the temperatures of the release medium decreased the release rate of ceftiofur, but not the rate of gel dissolution.The pH of the release medium showed a very slight effect on the release of ceftiofur and did not affect gel dissolution due tothe non-ionic nature of P407. 2002 Elsevier Science B.V. All rights reserved.

Keywords: Sustained release; Poloxamer 407; Ceftiofur; In-vitro release

1 . Introduction systemic administration of antimicrobial agents,which is expensive and labor intensive [1]. In

Local delivery of antibiotics is desired in con- addition, when drug is administered systemically, itditions such as osteomyelitis, soft-tissue infection is distributed throughout the body to various organsand for prevention of post-surgical infections. In the and tissues. Only a relatively small amount reachescurrent treatment for deep infections of the bovine its target site. Local delivery can increase therapeuticfoot, such as arthritis and osteomyelitis, surgical effectiveness and reduce harmful systemic effects.salvage techniques must be used in combination with For these reasons, techniques of local antimicrobial

therapy have been developed. These include intra-articular injection, and locally implanted antimicro-*Corresponding author. Tel.:11-402-559-5320; fax:11-402-bial impregnated beads, sponges, and osmotic pumps559-9543.

E-mail address: ukompell@unmc.edu(U.B. Kompella). [2–4]. Compared with these, a local sustained-re-

0168-3659/02/$ – see front matter 2002 Elsevier Science B.V. All rights reserved.PI I : S0168-3659( 02 )00273-0

74 L. Zhang et al. / Journal of Controlled Release 85 (2002) 73–81

lease single-dose gel injection in cattle foot joint can 2 .2. Instruments and equipmentprovide a reliable local antibiotic concentration anddoes not require surgical expertise to implant or The following instruments and equipment wereremove the dosage form. used in the study: analytical balance (Model A-

P407, one of the commercially available polyoxy- 200DS, Denver Instrument, Arvada, CO) and pHethylene:polyoxypropylene block copolymers, con- meter (Model 320, Corning, Corning, NJ). Thetains|70% polyoxyethylene units and 30% polyox- vacuum pump used to filter distilled water wasypropylene blocks. This polymer has low toxicity, obtained from GAST Manufacturing (Benton Har-excellent compatibility with other chemicals, and a bor, MI). The HPLC system, which was obtainedhigh solubilizing capacity for different drugs. P407 from Shimadzu (Kyoto, Japan), consisted of a sol-at concentrations of 20% or higher in aqueous vent delivery pump (LC-6A), an autoinjector (SIL-solution exhibits the unique property of reversible 6B), a data processor (Chromatopac CR-501), and athermal gelation. These preparations transform from UV detector (SPD-6A). A 25-cm long Microsorb C18

low-viscosity solutions to semisolid gels upon heat- column (Rainin Instruments, Emeryville, CA) with a˚ing from 48C to body temperature (378C). Such gels particle diameter of 5mm and a pore size of 100 A

can be localized near the injection site and wide was utilized.spread distribution of the drug can be minimized.These properties make P407 an attractive vehicle for 2 .3. HPLC assay of ceftiofurcontrolled release.

Ceftiofur is a broad-spectrum third-generation The HPLC mobile phase consisted of 75% (v/v)cephalosporin with activity against many of the water, 25% (v/v) acetonitrile, and 90 mg of heptaneorganisms commonly cultured from bone infections sulfonic acid per liter. The pH was adjusted to 4.0 by[5]. It is approved for intramuscular use in food the addition of glacial acetic acid [6]. The mobileanimals for interdigital dermatitis. Its solution was phase was delivered at a constant flow rate of 1also successfully used in local limb injection in cattle ml /min. The detection wavelength was 290 nm and[1]. The present study was conducted to develop a the injection volume was 30ml for all samples.poloxamer-based gel formulation for joint injectionin cattle to treat foot infections. The effects of 2 .4. Preparation of P407 gel formulations offormulation variables on in-vitro drug release were ceftiofurinvestigated.

The poloxamer gel was prepared by a modificationof the cold method [7]. Aqueous solutions of cef-tiofur were prepared using 0.1 M phosphate buffered

2 . Materials and methods saline (pH 7.4). The required amount of the selectedadditive for each formulation was weighed anddissolved in 10 ml of a cold (48C) aqueous solution

2 .1. Materials of ceftiofur (200 mg/ml). Then 1 ml of the coldaqueous solution of ceftiofur and the additive was

Poloxamer 407 was obtained from BASF (Parsip- added slowly to a vial containing an appropriatepany, NJ). Naxcel (ceftiofur sodium) was obtained amount of P407. The dispersion was stored in afrom Pharmacia and Upjohn (Kalamazoo, MI). refrigerator and vortexed periodically until the P407HPLC grade acetonitrile was purchased from Fisher dissolved completely.Scientific (Fairlawn, NJ). Hydroxypropyl methycel-lulose was obtained from Sigma (St. Louis, MO), 2 .5. In-vitro studiessodium carboxy methylcellulose was from AmendDrug and Chemical (New York, NY) and polyvinyl In-vitro studies were performed in an incubationpyrrolidone was from ISP Technologies (Wayne, room (258C) and at 378C using a membrane-lessNJ). All other chemicals and solvents were reagent dissolution model. This model has the advantage ofgrade. discerning formulation factors while allowing the

L. Zhang et al. / Journal of Controlled Release 85 (2002) 73–81 75

release medium to contact the gels directly [8]. After temperature (258C) and 378C using a gel containingthe formulations formed a gel at ambient tempera- 25% (w/v) P407 without any additive.ture, an isotonic phosphate buffer, pre-equilibrated atthe experimental temperature, was used as the re-2 .5.3.3. Effect of pH on drug release from the gellease medium. First, 1 ml of the release medium was formulation. The effect of pH on gel dissolution andcarefully layered over the surface of the gel formula- drug release was studied at 378C using 25% (w/v)tions to avoid mixing, and then at predetermined P407 without any additive. Isotonic phosphate buf-time intervals, the entire release medium was re- fers (0.1 M) of pH 5.5, 6.5 and 7.4 were used as themoved. The vial was weighed at each time point release media.after complete removal of the medium, and thenfresh release medium was layered over the gel 2 .5.3.4. Effect of additives on drug release from theformulation. Each experiment was performed in gel formulations. The effect of additives was studiedtriplicate. at 378C using 25% poloxamer formulations of

ceftiofur with one of the following additives: 2%(w/v) sodium carboxymethylcellulose (CMC), 2%2 .5.1. In-vitro erosion profiles of P407 gelshydroxypropyl methylcellulose (HPMC), and 2%The vials were weighed after each removal of thepolyvinyl pyrrolidone (PVP). The concentration ofrelease medium. The differences in weight of thethe additives was kept low to ensure completevials between points yielded the amount of the P407dissolution of polymers and formation of a homoge-gel formulation dissolved during that time period.neous gel. The P407 gel formulation with no additiveThe erosion profile was then obtained by plotting thewas used as a control.cumulative weight of each P407 gel formulation

dissolved versus time.

3 . Results2 .5.2. In-vitro release of ceftiofur from P407 gelformulations

3 .1. Preparation of P407 gel based formulationsThe in-vitro release profile of ceftiofur from the

of ceftiofurP407 gel was investigated simultaneously with theerosion profiles. The release of ceftiofur from the

In preliminary studies, P407 gel formulationsP407 gels was obtained by analyzing aliquots of the

containing ceftiofur were optimal at polymer con-release medium using the HPLC method described

centrations between 20 and 35% (w/w). At P407above.

concentrations,20% (w/w), the gel remained liquidbeyond the normal gelling temperature (|20 8C).

2 .5.3. Effect of formulation factors on in-vitro When the polymer concentration was.35% (w/w),release of ceftiofur from P407 gel the polymer did not completely dissolve in the

medium. In subsequent studies, w/v rather than w/w2 .5.3.1. Effect of Poloxamer 407 concentration on concentrations were employed. All gels were free-drug release. The effect of varying the P407 con- flowing viscous liquids at the storage temperaturecentration was studied. Aqueous formulations con- (48C), formed a semi-solid gel at both experimentaltaining ceftiofur and either 25, 30, or 35% (w/v) temperatures (i.e. 25 and 378C), and returned to theP407 without any additive were prepared as de- liquid state upon cooling to 48C. The initial con-scribed above. The in-vitro dissolution of these gel centration of ceftiofur in the gel was kept constant atformulations and the release of ceftiofur from them 200mg/ml. At this concentration, ceftiofur waswere studied at 378C using the membrane-less completely dissolved.system.

3 .2. In-vitro studies2 .5.3.2. Effect of temperature on drug release fromthe gel formulation. The effect of temperature on gel 3 .2.1. In-vitro erosion profiles of P407 gelsdissolution and drug release was studied at room The erosion profiles were obtained by plotting the

76 L. Zhang et al. / Journal of Controlled Release 85 (2002) 73–81

cumulative percent of each P407 gel formulation of gel dissolution decreased as the concentration ofdissolved versus time (Fig. 1a). Least-squares regres- gel increased.

2sion analysis showed linearity (r .0.99) for all threeconcentrations of gel at 378C. As expected, the rate

3 .2.2. In-vitro release of ceftiofur from P407 gelformulations

The percentage of ceftiofur released in vitro wasregressed against time, also using least-squares re-gression analysis (Fig. 1b). The amount of ceftiofur

2released increased linearly (r .0.99) with time forall three formulations. This indicated that the in-vitrorelease of ceftiofur from these P407 gel formulationsfollowed zero-order kinetics at 378C. Zero orderrelease rate constants (k ) were calculated for the0

formulations and are listed in Table 1. As expected,the rate of ceftiofur release decreased with anincrease in gel concentration.

3 .2.3. Correlation of gel dissolution and ceftiofurrelease

The percent drug release was plotted as a functionof the percent gel dissolved at 378C (Fig. 1c).Though the plots appeared to have a very slightcurvature, they were analyzed using least-square

2regression. Excellent fits (r .0.99) were obtainedfor each concentration of gel. Thus, the rate of drugrelease correlated well with the rate of gel dissolu-tion. The correlation is essentially perfect at a gelconcentration of 25% where the slope of this plot is1.0. As the gel concentration increased, the slope ofthis plot increased to 1.158 at 30% and to 1.317 at35%. This implied that the contribution of drug

Table 1Release constantk (mg/min) of different gel formulations0

Gel concentration (w/v)

25% 30% 35%

37 8C, pH 7.4 0.50 0.42 0.3025 8C, pH 7.4 0.42 – –

Fig. 1. Influence of P407 concentration (♦ 25% (w/v), j 30%37 8C, pH6.5 0.48 – –

(w/v), andm 35% (w/v)) on gel dissolution and ceftiofur release37 8C, pH 5.5 0.42 – –

at 378C. (a) Cumulative percent of P407 dissolved versus time,37 8C, pH 7.4 with CMC 0.42 0.32 0.24

(b) cumulative percent ceftiofur released versus time, and (c)37 8C, pH 7.4 with HPMC 0.48 0.36 0.28

correlation of cumulative percent gel dissolved and cumulative37 8C, pH 7.4 with PVP 0.40 0.30 0.26

percent ceftiofur released. Data are expressed as means6S.D. forn53. –, Not determined

L. Zhang et al. / Journal of Controlled Release 85 (2002) 73–81 77

release by diffusion through the gel increased as thegel concentration increased.

3 .2.4. The effect of various factors on the in-vitrorelease of ceftiofur from P407 gel formulations

3 .2.4.1. Effect of Poloxamer 407 concentration ondrug release. The effect of P407 concentration onpercent gel dissolved from the gel formulation wasinvestigated at 378C (Fig. 1). The data showed thatincreasing the concentration of P407 from 25% (w/v) to 35% (w/v) decreased the cumulative percentgel dissolved after 6 h from|96 to 40%. The percentdrug released profile (Fig. 1b) also indicated thatincreasing the concentration of P407 decreased thepercent drug released at 378C. Increasing the con-centration of P407 from 25% (w/v) to 35% (w/v)decreased the cumulative percent drug released after6 h from|98 to 56%. But, if gel dissolution was theonly mechanism affecting the overall release ofceftiofur, then the observed slopes in Fig. 1c wouldbe approximately unity. It was observed that 25%(w/v) P407 without any additives provided a slopevery close to unity, but increasing the gel con-centration increased the slope of the percent drugrelease–percent gel dissolved curve (Fig. 1c). Thisindicated that factors other than gel dissolution suchas drug diffusion also affected ceftiofur release at thehigher gel concentration. The effect of these factorswas also dependent on gel concentration.

3 .2.4.2. Effect of temperature on drug release fromthe gel formulation. The effect of temperature on gel

Fig. 2. Influence of temperature (j 37 8C andh 25 8C) on geldissolution and ceftiofur release at room temperaturedissolution and ceftiofur release. (a) Cumulative percent of P407(25 8C) and 378C using 25% (w/v) P407 gel formu-dissolved versus time, (b) cumulative percent ceftiofur released

lation without any additive is shown in Fig. 2. These versus time, and (c) correlation of cumulative percent gel dis-comparisons indicated that there was no major solved and cumulative percent ceftiofur released. Data are ex-difference (P,0.05) in the gel dissolution profile. pressed as means6S.D. for n53.

However, at room temperature the cumulative per-centage of ceftiofur released after 6 h decreased to79.78 from 96.36% at 378C. The slope of the plotdecreased from 0.0025 at 378C to 0.0021 at room temperature increased drug release through factorstemperature. Fig. 2c also shows that at room tem- other than gel dissolution such as drug diffusion.perature, the slope of the percent drug release–percent gel dissolved curve (0.9148) was lower than 3 .2.4.3. Effect of pH on drug release from the gelat 378C (1.0056). This indicated that an increase in formulation. The effect of pH on gel dissolution and

78 L. Zhang et al. / Journal of Controlled Release 85 (2002) 73–81

ceftiofur release was studied at release medium pH 0.05) due to pH in the dissolution profiles of the gelsvalues of 5.50, 6.50, and 7.40 using 25% P407 and or, consequently, in the release profiles of ceftiofurphosphate buffer solutions (Fig. 3). The results from the gels between pH 5.50 and 6.50, or betweenshowed that there was no significant difference (P, pH 6.50 and 7.40. Only pH 5.50 and 7.40 showed a

slight difference in the slopes of the percent drugreleased. At pH 5.50 the drug release versus geldissolution profile has a lower slope than at pH 6.50and 7.40 (Fig. 3c). This indicated that when the pHof the release medium decreased, diffusion of cef-tiofur from the gel matrices slightly decreased.

3 .2.4.4. Effect of different additives on drug releasefrom the gel formulations. The effect of additiveswas studied at different P407 concentration gelformulations (Fig. 4). Statistical analysis showed thatin 30% (w/v) P407 gel formulations (Fig. 4b), everyformulation with an additive released drug at asignificantly slower rate (P,0.05). In 25% (Fig. 4a),and 35% (Fig. 4c) P407 formulations, only 2%HPMC containing formulations did not show asignificantly slower release (P,0.05). Statisticalanalyses were performed using one-way analysis ofvariance (SAS). Fig. 5 shows the correlation of drugrelease with gel dissolution for 25–35% P407 formu-lations with or without additives.

4 . Discussion

4 .1. In-vitro erosion profiles of P407 gels

The drug release kinetics correlated well with thedissolution rate of the P407 gel. For a simple slab ofarea A containing a uniformly dispersed drug (C ),0

the amount of drug released at any timet is dM /t

dt 5BC A, whereB is the surface degradation rate0

(cm/s) [9]. For an ideal heterogeneous eroding(surface erosion) system, the release kinetics willequal the degradation rate of the polymer. In thesystem we studied,C and A were kept constant0

throughout the release study. The release was pri-marily controlled by the surface degradation rate and

Fig. 3. Influence of pH (♦ pH 5.5,j pH 6.5, andm pH 7.4) on was zero order during the course of the study.gel dissolution and ceftiofur release at 378C. (a) Cumulative Poloxamer degradation involves the hydration ofpercent of P407 dissolved in vitro versus time, (b) cumulative

water-insoluble side groups that are converted topercent ceftiofur released in vitro versus time, and (c) correlationwater-soluble polymers as a result of ionization,of cumulative percent gel dissolved and cumulative percent

ceftiofur released. Data are expressed as means6S.D. for n53. protonation, or hydrolysis of the groups [10]. The

L. Zhang et al. / Journal of Controlled Release 85 (2002) 73–81 79

Fig. 4. Influence of various formulation additives (♦ control, j2% CMC,m 2% HPMC, andX 2% PVP) on ceftiofur release at37 8C. Cumulative percent ceftiofur released in vitro versus time

Fig. 5. Influence of various formulation additives (♦ control, jfor (a) 25% (w/v) P407, (b) 30% (w/v) P407, and (c) 35% (w/v)2% CMC, m 2% HPMC, andX 2% PVP) on gel dissolution atP407.37 8C. Correlation of cumulative percent gel dissolved andcumulative percent ceftiofur released for (a) 25% (w/v) P407, (b)

release is actually controlled by the surface hydration 30% (w/v) P407, and (c) 35% (w/v) P407.rate.

4 .2. In-vitro release of ceftiofur from P407 gel vitro release of ceftiofur from P407 gel formulationsformulations followed zero order kinetics at room temperature

(25 8C) and at 378C. The Poloxamer system is oneThe ceftiofur release profile showed that the in- of the swelling-controlled systems that function by a

80 L. Zhang et al. / Journal of Controlled Release 85 (2002) 73–81

process of continuous swelling of the polymer carrier due to an increase in drug diffusion in aqueousthat is associated with simultaneous or subsequent channels at higher temperature.dissolution of the polymer carrier. Relatively simplesteps have described the process of drug release from4 .3.3. Effect of pH on drug release from the gelswelling-controlled release systems that exhibit dis- formulationsolution. Recently, there has been a new understand- Water-based plain Poloxamer gel is a non-ionicing of the molecular interpretation of polymer disso- system, and is expected to be quite stable withlution [11]. According to this theory, by choosing respect to pH. Indeed, pH did not affect dissolutionsolvent–polymer–drug systems, drug release can be of the gel. However, when pH decreased, the releasediffusion-controlled or dissolution-controlled. In our of ceftiofur decreased slightly, possibly due to acase, the zero-order ceftiofur release from the P407 decrease in drug solubility and diffusion.gel formulations can be explained by the mechanismof dissolution-controlled release. 4 .3.4. Effect of different additives on drug release

from the gel formulations4 .3. Effect of several factors on in-vitro release of Drug diffusion from a Poloxamer gel is throughceftiofur from P407 gel formulations extramicellar aqueous channels. The microviscosity

of the water channels controls drug diffusion and4 .3.1. Effect of Poloxamer 407 concentration on release by this mechanism. Another inert, hydro-drug release philic polymer would decrease the amount of free

The P407 gels are viewed as consisting of large water in the water channels, and affect molecularpopulations of micelles and aqueous channels in orientation of the gel matrix. The length and size ofwhich the incorporated solute may be released by its the diffusional channels also controls drug release.passage through the aqueous channels and due to gel Therefore, additives will change drug release kineticsdissolution. The decrease in the rate of release with [13]. CMC forms a cross-linked network gel [14].an increase in the P407 concentration could be Because of the ionic nature of CMC, hydrogen bondsattributed to the increase in the number and size of and van der Waals forces between molecules ofthe micelles formed at the higher polymer con- different polymers become extensive. HPMC swellscentration. This could cause a greater tortuosity in in water forming disordered three-dimensional phys-the aqueous phase of the gel structure [12] and a ical networks. In general, the molecule entanglementslower rate of dissolution. In addition, higher Polox- and the extensive hydrogen bonds will form tightlyamer concentrations results in a shorter inter-micellar orientated gel structures. Polyvinyl pyrrolidone is adistance, leading to greater number of cross-links common additive in parenteral products, which canbetween neighboring micelles and a greater number increase the viscosity of the solvents, thereby reduc-of micelles per unit volume [8]. ing the diffusion coefficient of the drug. Also, if a

water-soluble drug undergoes complexation with an4 .3.2. Effect of temperature on drug release from additive, a delay in drug release occurs. Thus, asthe gel formulation expected, the additives decreased the rate of release

The P407 gels are considered to consist of mi- of ceftiofur, except for 2% HPMC in the 25 and 35%celles and aqueous channels. The latter is the region P407 formulations by delaying both gel dissolutionfrom which the incorporated solute is directly avail- and drug diffusion.able for release. The more lipophilic the drug, themore it will partition into the micelles and less willexist in the aqueous channels. Ceftiofur is a highly 5 . Conclusionssoluble drug, so its diffusion will not be hinderedsignificantly. An increase in temperature increased Drug delivery in the veterinary field is differentthe release rate of drug despite an increase in bulk from that in the human field. A number of importantviscosity and no change in the dissolution rate of the issues must be considered. First and foremost is thegel. This increase in the release rate of drug is likely overall product cost, which includes administration

L. Zhang et al. / Journal of Controlled Release 85 (2002) 73–81 81

Kompella, Ceftiofur distribution in plasma and joint fluidexpense. For a novel drug delivery system, one offollowing regional limb injection in cattle, J. Vet. Pharmacol.the major advantages is extending product lifeTher. 22 (1) (1999) 13–19.

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pump, Clin. Orthop. 192 (1985) 284–290.tiofur were developed and evaluated in vitro. The gel[5] S.A. Brown Jr., R.J. Yancey, J. Steffan, Ceftiofur sodium:formulation released drug primarily through gel

antimicrobial activity of parent ceftiofur and metabolites,dissolution and the release followed a zero-order Acta Vet. Scand. Suppl. 87 (1991) 95–97.mechanism, similar to previous reports with polox- [6] F. Courtin, A.L. Craigmill, S.E. Wetzlich, C.R. Gustafson,amer gels [15]. The release mechanisms can be T.S. Arndt, Pharmacokinetics of ceftiofur and metabolites

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from Pluronic F-127 gels, Int. J. Pharm. 32 (1986) 223–228.A cknowledgements [13] P.C. Chen-Chow, S.G. Frank, In vitro release of lidocaine

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Kavitha Koushik for her editorial assistance in the gel dissolution: drug release in stirred systems, J. Controlledpreparation of the manuscript. Release 67 (2000) 191–202.

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