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Fara J., and Urquhart J., Trends PharmacoL ScL 5(1), 21-25 (1984). Goldsworthy T.L., Morgan K.T., Popp J.A., and Butterworth B.E., Prog. CUn. Biol. Res. 369, 253-284 (1991). Hagg T., in T.R. Flanagan, D.F. Emerich, and S.R. Winn, eds., Methods in Neurosciences, Providing Pharmacological Access to the Brain: Alternate Approaches, vol. 21, Academic Press, San Diego, Calif., 1994, pp. 201-213. Lee V.H.L., Pharmacokinet. Pharmacodyn. 3, 80-92 (1991). Nau H., Trotz M., and Wegner C., in D.D. Breimer and P. Speiser, eds., Topics in Pharmaceutical Sciences, Elsevier, Amsterdam 1985, pp. 143-157. Neckers L., and Whitesell L., Am. J. Physiol. 265(9), L1-L12 (1993). Nieschlag E., Akhtar F.B., Schurmeyer T.H., and Weinbauer G., in F. Labrie and A. Belanger, eds., LHRH and Its Analogues, Basic and Clinical Aspects, Elsevier, Munster, Germany, 1984, pp. 277-286. Pilowsky P.M., Suzuki S., and Minson J.B., Clin. Exp. PharmacoL Physiol. 21, 935-944 (1994). Shaw J.E., and Theeuwes F., Aust. J. Pharm. ScL 1(2), 49-53 (1978). Sikic B.I., and Carlson R.W., in H.A.J. Struyker-Boudier, ed., Rate-Controlled Drug Administration and Action, CRC Press, Boca Raton, FIa., 1986, Chapter 8, pp. 205-218. Struyker-Boudier H.A.J., Trends PharmacoL ScL 3(4), 162-164 (1982). Theeuwes F., in A.F. Kydonieus, ed., Controlled Release Technologies: Methods, Theory, and Applications, vol. II, CRC Press, Boca Raton, FIa., 1980, Chapter 10, pp. 195-205. Theeuwes F , in L.F. Prescott and W.S. Nimmo, eds., Drug Absorption, ADIS Press, New York, 1981, Chapter 16, pp. 157176. Theeuwes F , PharmacoL Ther. 13, 149-191 (1981). Theeuwes F., and Eckenhoff B., in R. Baker, ed., Controlled Release ofBioactive Materials, Academic Press, New York, 1980, pp. 61-82. Theeuwes F., and Yum S.I., ATW. Biomed. Eng. 4(4), 343-353 (1976). Theeuwes F., Eckenhoff B., and Urquhart J., Pharm. Technol. 11(6), 96-105 (1987). Urquhart J., AAMI Technol. Assess. Rep. 5(83), 45-50 (1983). Urquhart J., in L.F. Prescott and W.S. Nimmo, eds., Rate Control in Drug Therapy, Churchill-Livingstone, New York, 1985, pp. 19-29. Urquhart J., Fara J., and Willis K.L., Annu. Rev. PharmacoL Toxicol. 24, 199-236 (1984). Waynforth H.B., and Flecknell P., Experimental and Surgical Technique in the Rat, Academic Press, New York, 1980, pp. 49-50. White J.D., and Schwartz M.W, in T.R. Flanagan, D.F. Emerich, and S.R. Winn, eds., Methods in Neurosciences, Providing Pharmacological Access to the Brain: Alternate Approaches vol. 21, Academic Press, San Diego, Calif., 1994, pp. 187200. Zaffaroni A., Drug Metab. Rev. 8(2), 191-221 (1978).

PUMPS/OSMOTICVITS VETERINARY IMPLANT

JUDY MAGRUDER

ALZA Corporation Palo Alto, California

KEY WORDS

Bovine somatotropin (BST) Intraperitoneal Porcine somatotropin (PST) Pulsatile delivery Steroids Subcutaneous Zero-order delivery
OUTLINE

Background System Design and Function Applications Conclusions Bibliography

The Veterinary Implantable Therapeutic System (VITS) is a small, implantable drug delivery system designed to provide controlled drug delivery in production animals and companion animals for periods of 1 day to 1 year. Typical VITS release is constant and zero order, but declining or pulsatile release profiles are possible by design. A wide spectrum of compounds ranging from small molecules such as steroids to larger, water-labile molecules such as peptides and proteins can be delivered. Because of the VITS pump design and its materials, VITS formulations are completely isolated from potentially damaging in vivo fluids. Because of the small pump size, dosages from//g/day to mg/day are possible, making VITS ideal for the delivery of potent molecules. VITS can be implanted subcutaneously or intraperitoneally. When used in food-production animals, the VITS is removed during slaughter. Possible candidates for VITS delivery include somatotropins, parasiticides, hormones such as estrus suppressants and growth promotion agents, ^-agonists, nutritional supplements, and antibiotics.
BACKGROUND

See also PUMPS/OSMOTICINTRODUCTION; PUMPS/

OSMOTICVITS VETERINARY IMPLANT; PUMPS/ OSMOTICDUROS OSMOTIC IMPLANT FOR HUMANS; PUMPS/OSMOTICRUMINAL OSMOTIC BOLUS.

Implants have been used commercially in animals for many years, typically for growth enhancement using steroids. For example, since the 1950s compressed tablets containing estrogenic anabolic steroids have been inserted subcutaneously in and at the base of the ears in cattle,

releasing drug through slow erosion or matrix diffusion. These growth enhancers are given for 2- to 3-month periods to improve the rate of weight gain and feed conversion, and their economic benefits have been well documented. Commercial examples of these growth promoters include Compudose (estradiol-17/?), Synovex (progesterone and others), and Ralgro (Zeranol) (1). These systems are not explanted. Similar implants have also been evaluated for delivery of parasiticides (2,3). Although these systems have been suitable for the delivery of steroids and other water-stable agents, adaptation has proved necessary for newer biotechnology products. Larger peptides and proteins are extremely water labile, degrading rapidly in an aqueous environment. They are also very potent agents, given in very small doses. To satisfy these requirements, VITS was developed as a small system in which the active drug is kept isolated from the body's aqueous environment until release. The VITS implant is much smaller than the Ruminal Therapeutic System (RUTS) ruminal bolus and can be implanted in any ruminant, nonruminant, companion, or production animal. In the VITS implant, drug is isolated from any contact with body fluids in the in vivo environment. Unlike the RUTS ruminal bolus system, in which the semipermeable membrane cup almost fully surrounds the entire system, the VITS absorbs water only at the membrane cup end; hence, the drug formulation is completely isolated from water inside the impermeable drug reservoir. Compared with repeat-injection dosing, VITS reduces animal stress resulting from restraint, handling, and dosing. With its zero-order delivery, VITS minimizes the adverse effects often associated with the elevated drug serum levels seen shortly after injection dosing. VITS is more convenient to administer than repeat-injection dosing; it eliminates the need for procedures that are often costly, difficult, and labor intensive. With VITS, the amount of drug administered is known, in contrast to the administration of drug in drinking water or food. VITS is efficient in administering therapeutic dosages of potent, expensive compounds that otherwise would have to be given frequently and in large doses because of biological clearance processes. Controlled parenteral administration of therapeutic agents by VITS increases the range of usable veterinary compounds, because many potentially useful products, such as peptides and proteins, cannot be administered by feed or bolus owing to their water lability. Controlledrelease dosage forms such as VITS can also reduce human exposure to those veterinary compounds that are unsafe for humans to handle.
SYSTEM DESIGN AND FUNCTION

Rate-controlling membrane Osmotic engines Elastomeric piston

Drug fill

Drug reservoir

Orifice

Break-off point - Break-off tab

Figure 1. Cross section of VITS.

As shown in Figure 1, the VITS system is a narrow cylinder that consists of an impermeable drug reservoir containing the drug formulation and a rate-controlling semipermeable membrane cup that contains the osmotic engine and a piston. The membrane cup subassembly is tightly coupled with the filled drug reservoir. At the time of implantation, the break-off tab is removed so that drug can be delivered. (An alternative design uses a microcrystalline

wax plug, which prevents any backflow of body fluids into the system during start-up.) VITS systems can be designed at various sizes ranging from 2 to 10 mm in diameter, depending on the dosage requirements and the size of the animal. After implantation, water from the animal's tissues moves across the membrane wall at a constant rate governed by the thickness and composition of the wall. The osmotic material swells, which pushes the piston forward into the drug reservoir. This forces drug formulation through the orifice into the surrounding tissues. The rate of drug delivery is the same as the rate of water influx into the system, based on the basic osmotic equation (equation 4) described in PUMPS/OSMOTICINTRODUCTION. System design is described in detail in the patent literature (4-20). VITS has a predictable start-up profile and a rapid shutdown profile that minimizes drug residues in tissue. At shutdown time, the piston reaches the end of the drug fill area, guaranteeing a complete cutoff of drug delivery at that point. The dosage, duration, and delivery profile of a VITS system can be adjusted by design within the ranges of 1-week to 1-year duration and //g/day to mg/day dosage. For example, by altering the permeability of the membrane, the resulting dosage and duration of the system can be changed. For a fixed system size and drug reservoir volume, a more permeable membrane results in an increased delivery rate with a shorter delivery lifetime. The inverse holds true as well: A less permeable membrane results in a decreased delivery rate over a longer delivery lifetime. Decreasing the concentration of sodium chloride in the osmotic engine produces a declining release profile (as the osmotic engine solution falls below saturation, the release slows), as shown in Figure 2 (porcine somatotropin [pST]

Release rate (mg/day)

Time (days) Figure 2. In vitro release profile of pST from a VITS system.

at 370C). Pulsatile delivery can also be achieved through system design alteration. In vivo data in finishing hogs show a good doseresponse relationship, as demonstrated in Figure 3. For more than 40 days, pST plasma concentrations were maintained for the three dosages (1.2, 3.6, and 4.8 mg/day).
APPLICATIONS

pST (ng/mL serum)

Time (days) Figure 4. Comparison of serum concentrations of pST in lean gilts as a function of dosage. Source: Adapted from Ref. 24.

One extensively studied application of VTTS technology is the administration of bovine somatotropin (bST) to cattle and pST to pigs. For example, Baile and colleagues showed that administration of a 42-day VITS bST implant (17 mg/ day) increased the growth rate by 16% for subcutaneous implantation and 25% for intraperitoneal implantation. Increases in growth rate were sustained with an 84-day VITS intraperitoneal implant when compared with two successive 42-day implants, suggesting that the formulation retains biological efficacy even when the delivery duration is extended to commercially significant time periods (21). Another study by Kasser and colleagues compared a control group with a group that received bST from two consecutive 42-day intraperitoneal VITS implants at dosages of 6, 12, and 15 mg/day. Body weight and carcass weight were significantly (P < .05) higher in treated animals than in controls. Feed conversion was significantly (P < .05) better in treated animals than in controls (22).

Armstrong and colleagues found that multiparous beef cows receiving an 84-day subcutaneous VTTS bST implant had significantly (P < .05) higher milk yields and calf weaning weights than did cows that received vehicle only (23). Subcutaneous VITS implants containing pST were compared with controls in a 6-week study in genetically lean and obese barrows and gilts (24). Administration of pST by VTTS implant significantly increased efficiency of gain and lean deposition while decreasing fat deposition. Serum pST levels, measured each week, remained significantly higher in treated pigs than in controls throughout the study (Fig. 4) (24).
CONCLUSIONS

Plasma concentration (ng/mL)

Control 1.2 mg/day 3.6 mg/day 4.8 mg/day

VITS is an osmotic implant specifically tailored for subcutaneous or intraperitoneal administration of small amounts of potent substances to animals. The drug reservoir completely isolates drug formulations from the surrounding environment, thus protecting proteins and other water-labile compounds for long periods. VITS is typically designed for zero-order release of agents, but other delivery profiles can be obtained through system design alternatives. VITS has been studied extensively in the release of bovine and porcine somatotropins. Demonstration of its feasibility for zero-order delivery of small amounts of potent molecules in animals has led to its adaptation for use in humansthe DURO S technology.
BIBLIOGRAPHY 1. RR. Klink, T.H. Ferguson, and J.L. Magruder, in G.E. Hardee and J.D. Baggot, eds., Development and Formulation of Veterinary Dosage Forms, 2nd ed., Dekker, New York, 1998, pp. 145-229. 2. C. Shih, J. Fix, and R.L. Seward, J. Controlled Release 25, 155-162 (1993). 3. S. Geerts et aL, Vet. Parasitol 50, 15-21 (1993).

Time (days) Figure 3. Comparison of plasma concentrations of VITS agent (pST) as a function of its dosage.

4. U.S. Pat. 4,959,218 (September 25, 1990), J.B. Eckenhoff et al. (to ALZA Corp.). 5. U.S. Pat. 5,034,229 (July 23, 1991), J.A. Magruder et al. (to ALZA Corp.). 6. U.S. Pat. 5,037,420 (August 6, 1991), J.A. Magruder et al. (to ALZA Corp.). 7. U.S. Pat. 5,057,318 (October 15, 1991), J.A. Magruder et al. (to ALZA Corp.). 8. U.S. Pat. 5,059,423 (October 22, 1991), J.A. Magruder et al. (to ALZA Corp.). 9. U.S. Pat. 5,110,596 (May 5, 1992), J.A. Magruder et al. (to ALZA Corp.). 10. U.S. Pat. 5,135,523 (August 4, 1992), J.A. Magruder et al. (to ALZA Corp.). 11. U.S. Pat. 5,137,727 (August 11, 1992), J.B. Eckenhoff (to ALZA Corp.). 12. U.S. Pat. 5,174,999 (December 29,1992), J.A. Magruder et al. (to ALZA Corp.). 13. U.S. Pat. 5,180,591 (January 19, 1993), J.A. Magruder, J.R. Peery, and J.B. Eckenhoff (to ALZA Corp.). 14. U.S. Pat. 5,209,746 (May 11, 1993), S.M. Balaban, J.B. Pike, J.P. Smith, and C.A. Baile (to ALZA Corp.). 15. U.S. Pat. 5,234,692 (August 10, 1993), J.A. Magruder, J.R. Peery, and J.B. Eckenhoff (to ALZA Corp.). 16. U.S. Pat. 5,234,693 (August 10, 1993), J.A. Magruder, J.R. Peery, and J.B. Eckenhoff (to ALZA Corp.). 17. U.S. Pat. 5,234,694 (August 10, 1993), J.A. Magruder, J.R. Peery, and J.B. Eckenhoff (to ALZA Corp.). 18. U.S. Pat. 5,238,687 (August 24, 1993). J.A. Magruder, J.R. Peery, and J.B. Eckenhoff (to ALZA Corp.). 19. U.S. Pat. 5,320,616 (June 14, 1994), J.A. Magruder et al. (to ALZA Corp). 20. U.S. Pat. 5,443,461 (August 22, 1995), L.E. Atkinson, J.T. Dunn, R.M. Gale, and D.L. Rivera (to ALZA Corp.). 21. C.A. Baile et al., J. Anim. ScL 71(1), 131 (1993). 22. T.R. Kasser et al., J. Anim. ScL 71(1), 131 (1993). 23. J.D. Armstrong et al., J. Anim. ScL 72(1), 182 (1994). 24. J. Klindt, RC. Buonomo, and J.T. Yen, J. Anim. ScL 70,37213733 (1992).

Recombinant technology Semipermeable membrane Site-specific delivery Sodium chloride Systemic delivery Zero-order delivery

OUTLINE

Background System Design System Performance Formulation Capabilities DUROS Leuprolide Implant Disease State Formulation Stability In Vitro Performance In Vivo Performance In Vivo-In Vitro Release Rate and Stability Correlation Implantation and Explanation Clinical Experience Conclusions Acknowledgments Bibliography

See also PUMPS/OSMOTICINTRODUCTION; PUMPS/

OSMOTICALZET SYSTEM; PUMPS/OSMOTIC D U R O S OSMOTIC IMPLANT FOR HUMANS; PUMPS/ OSMOTICRUMINAL OSMOTIC BOLUS.

The DUROS implant is a miniature, osmotically driven drug delivery system designed for the long-term, parenteral, zero-order delivery of potent therapeutic agents to humans. The DUROS implant consists of an impermeable titanium alloy cylinder capped on one end by a ratelimiting, semipermeable membrane and on the other end by a plug with an orifice for drug delivery. The interior of the DUROS implant contains a polymeric piston that separates the osmotic engine from the drug reservoir (Fig. 1). These single-use DUROS implants are sterile, nonpyrogenic, and nonbiodegradable. The DUROS implant functions according to the same osmotic principles as described for other, similar pumps in

PUMPS/OSMOTICDUROS OSMOTIC IMPLANT FOR HUMANS

JEREMY C. WRIGHT CYNTHIA L. STEVENSON GREGORY R. STEWART

Orifice

Titanium cylinder

Piston

Osmotic engine

ALZA Corporation Palo Alto, California

Drug reservoir KEY WORDS Semipermeable membrane

Biocompatibility Osmosis

Approximate dimensions-. 45 mm long x 4 mm wide Figure 1. Cross section of a DUROS Implant.

this encyclopedia. The osmotic engine, a concentrated salt mixture, establishes a very steep osmotic gradient between the interior of the DUROS implant and the surrounding interstitial fluid. In response to this osmotic gradient, water flows into the DUROS implant at a rate governed by the permeation characteristics of the semipermeable membrane. As water flows into the DUROS implant, drug is delivered from the reservoir via the orifice at the same rate and volume. A unique feature of the DUROS implant, compared with other implantable pumps, is its small size (4 mm X 45 mm), allowing implantation virtually anywhere in the body; the resultant drug reservoir volume is less than 200 //L. (DUROSSM implants with drug reservoir volumes of 50 to 500 //L have been designed.) For systemic administration, the DUROS system is implanted under the skin in an outpatient setting with local anesthesia. Explantation at the end of the delivery period is accomplished by a similar, simple surgical procedure. In addition to subcutaneous administration, intravenous, intrathecal, intratumoral, and other forms of targeted drug delivery can be accomplished with the attachment of a catheter.
BACKGROUND

tions, providing substantial dose savings. The DUROS implant therapy may offer other pharmacoeconomic advantages in today's health care environment because it requires no maintenance after implantation. The type of "silent therapy" provided by the DUROS implant is not only convenient to the patient but also ensures compliance.
SYSTEM DESIGN

As of 1997, more than 40 biotechnology drug products have been approved, and more than 270 new biotechnology drugs are currently in human clinical trials. Most of these agents are proteins produced by recombinant technology (1). Because of rapid degradation within the stomach and poor absorption from the gastrointestinal tract, proteins and other complex biomolecules cannot be given orally. Drug therapy must therefore rely on parenteral administration via acute injection or preferably through a continuous delivery system. In response to this growing need from the biotechnology sector, researchers designed the DUROS implant for the delivery of proteins and peptides. More than 15 years of research, development, and widespread industry use of osmotic pump technology in animals (the ALZET osmotic pump, the Push-Melt ruminal bolus, and the VITS veterinary implant technology) has demonstrated the potential clinical utility of an implantable osmotic pump suitable for use in humans. In particular, the ALZET pump has been used in more than 5,200 studies to deliver proteins in nonclinical studies (see PUMPS/ OSMOTICALZET SYSTEM). The widespread use of ALZET pumps further highlights the need for a human implantable osmotic pump. The use of a continuous drug delivery system such as the DUROS implant offers several pharmacokinetic, pharmacoeconomic, and quality-of-life benefits over traditional bolus dosing methods. Unlike dosing by injection, where blood levels (and clinical efficacy) of the drug vary widely with an initial peak and subsequent trough pattern, the DUROS implant delivers drug at a precisely controlled, constant rate within the therapeutic range for long periods. In some therapeutic indications or when using drugs with short half-lives, less drug may be required to achieve the desired effect than with conventional injec-

The most important design considerations for the DUROS implant were biocompatibility; delivery of stable, active drug molecules; and extended zero-order delivery. All tissue-contacting materials were chosen for their biocompatibility and history of use in human implants. Likewise, the components in contact with the drug formulation (e.g. reservoir, orifice, and piston) had to be compatible with a variety of solvents and excipients used to solubilize or suspend the drug. Additionally, the implant components could not adversely affect the drug stability. Design issues based on these considerations will now be discussed for each of the components of the DUROS implant. The rugged titanium reservoir design possesses sufficient mechanical strength to maintain the system configuration despite possible mechanical stresses, such as impact at the implant site. Additionally, the titanium reservoir is impermeable to water, ensuring drug stability and continual zero-order release. The DUROS implant has a polymeric, semipermeable membrane that is permeable to water but essentially impermeable to the osmotic solutes in the osmotic engine. The membrane may include cellulose esters, polyamides, and polyurethanes, depending on the desired characteristics of the membrane, such as system duration. Testing of polyurethane membranes has shown that the membrane material does not change permeability following implantation. Membrane function is not influenced by extracellular fluid, and the membrane remains chemically stable under physiological conditions. The osmotic engine of the DUROS implant can utilize any number of osmotically active solutes but typically contains a combination of sodium chloride (more than 50% by weight) and other excipients, including gelling polymers such as poly(vinylpyrrolidone) (PVP) or sodium carboxymethyl cellulose. The osmotic engine is produced as one or more tablets. The elastomeric piston seals the drug formulation from the osmotic engine, thus preventing leakage of osmotic solutes into the drug formulation, which could cause significant loss of drug formulation stability and deviations from zero-order delivery. In addition, the piston is compatible with the osmotic engine and moves with relatively little resistance. The orifice was designed with a small inner diameter and a suitable length to minimize diffusion of drug from the system. Otherwise, diffusion could represent a significant and uncontrolled contribution to the overall rate of delivery at low pumping rates. The drug formulation is not exposed to the surrounding tissue environment until it is released through the orifice. These features also help to prevent back-diffusion of extracellular components when

the system is implanted. Such design features are particularly important for the delivery of biotechnology drugs because proteins, peptides, and other macromolecules are easily rendered inactive by biological processes. The DUROS implant packaging maintains sterility and provides a moisture barrier to prevent premature system start-up. The assembled DUROS implant is sterile and nonpyrogenic. Because most peptides and proteins will not withstand conventional sterilization methods (e.g., irradiation or autoclaving), a sterile DUROS implant can be produced by irradiating a partially assembled system and performing the remaining filling and assembly steps under aseptic conditions.
SYSTEM PERFORMANCE

Release rate (/^L/day)

1-month system 2-month system

C V < 10% O

n= IO systems per group 3-month system 5-month system 12-month system (ongoing)

Time (days) Figure 2. Comparison of release rates in DUROS Implants as a function of system duration. variation of less than 9% among the implants (Fig. 3). A zero-order release profile was obtained from the data when assaying on a weekly basis by reversed-phase highperformance liquid chromatography (RP-HPLC). Sampling of cumulative implant output by ultraviolet (UV) spectrophotometry with a flow cell at 6-min intervals for 24 h demonstrated a continuous zero-order release rate (Fig. 4).
FORMULATION CAPABILITIES

When the system is implanted, water is osmotically drawn from the body tissue surrounding the implant (osmotic pressure, n ~7 atm) through the membrane into the sodium chloride-containing osmotic engine (n = 356 atm). The release rate of the DUROS implant is given by equation 4 in PUMPS/OSMOTICINTRODUCTION, where A is the membrane cross-sectional area for water transport, h is the membrane thickness, k is the effective permeability of the membrane, and An is the osmotic pressure difference across the membrane. dm/dt = (Alh)kAnc (1)

IfA, /i, k, and An are held constant, then a constant rate of drug delivery will result. In the DUROS implant, A and h are constant by design and manufacture, and k has been shown to remain constant over time, both in vitro and in vivo. The osmotic engine is manufactured with excess sodium chloride to maintain saturation, ensuring that An will remain constant for the intended duration of drug delivery. Hence, a continuous zero-order release profile is expected for the DUROS implant. The release rate and duration of a DUROS implant depend on the overall system size, membrane design, osmotic engine design, drug reservoir size, and concentration of the drug in the reservoir. Figure 2 shows the effect of changing the membrane permeability on release rate and duration while keeping the other parameters constant in the 4 mm X 45 mm device. For a particular reservoir size, the higher the release rate, the shorter the duration of drug delivery. In vitro studies have demonstrated constant zero-order delivery from DUROS implants. DUROS implants were placed in test tubes containing phosphate-buffered saline (PBS) and held at 370C. The implants were placed in fresh PBS weekly, and the remaining PBS was assayed for drug content. In one study with a target duration of 3 months, the delivery rate performance of five systems was measured by sampling at approximately weekly intervals. The systems exhibited zero-order delivery at 1.0//L/day for 100 days, with coefficients of variation averaging 3% for days 7 to 104 (data not shown). In another study, 30 DUROS implants maintained a target of 0.38 //L/day release of blue dye solution for 360 days with a coefficient of

DUROS implants with diameters up to 7 mm have been designed, resulting in drug formulation volumes of 50 to 500 mL. The reservoir volume of the 4 mm X 45 mm implant has a total volume of less than 200 //L. Given the limited formulation volume in a single implant, concentrated drug formulations are usually required. Formulation parameters such as saturation solubility and chemical and physical (aggregation) stability are important. For example, in a 150-mL drug reservoir, a 2-month system delivers 2.5 //L/day. Given a 400-mg/mL solution drug formulation, the implant delivers 1.0 mg/day (60 mg/ implant). Similarly, a 500-mL drug reservoir (7 mm X 45 mm) lasting 12 months delivers 1.4 mL/day. In this system, a drug formulation at 400 mg/mL delivers 560 mg/ day (200 mg/implant). Important formulation considerations for the DUROS implant include stability, solubility, and compatibility. For example, adequate drug stability and potency for a 2-year shelf life plus the implant life are desired. The formulated peptide or protein must be structurally stable and not unfold, gel, or precipitate with loss of activity or production of large particulates capable of clogging the orifice. The formulation must either chemically withstand terminal sterilization or possess sufficient physical stability for sterile filtration, if not aseptically processed. Generation of suspensions in an aseptic environment is often an important factor. The formulation must also be compatible with the pump components in terms of peptide adsorption characteristics and vehicle leachates. Biotechnology drug moieties can be formulated in aqueous (up to 400 mg/mL) or nonaqueous (up to 500 mg/mL)

Target 0.38 /LtL/day

Figure 3. In vitro release rates in the DUROS Implant as compared with the 0.38-/zL/day target.

Release rate (AcL/day)

C0V systems <9% COVtime < 1 0 % n = 30

Time (days)

UV absorbance is a measure of blue dye concentration.

UV absorbance

DUROS Implant had been pumping in vitro for several ^/ months before this ^r experiment. ^r

DUROS Leuprolide Implant is formulated as a stable nonaqueous solution. This implant is designed to provide an alternative to periodic injections of leuprolide, with the goals of long-term patient compliance and improved quality of life.
DISEASE STATE

Time (h) Figure 4. In vitro release rate in the DUROS Implant, plotted in 6-min intervals.

solutions or in aqueous or nonaqueous suspensions (up to 500 mg/mL), depending on the solubility and stability of the specific molecule. Many times nonaqueous vehicles offer enhanced stability for biomolecules, such as proteins and peptides, by minimizing hydrolytic degradation pathways (2). For drug molecules with solubility or stability limitations, nonaqueous suspensions provide an alternative. For example, stable nonaqueous protein suspensions (e.g., a interferon) in excess of 30% weight in volume (w/v) for 3 to 6 months at 37C have been reported (3).
DUROS LEUPROLIDE IMPLANT

Because of the dependence of prostate cancer on circulating androgen levels, testicular androgen ablation (i.e., lowering of circulating testosterone levels) has been the standard for primary therapy of advanced prostate cancer for more than 50 years (4). Continuous administration of Iuteinizing hormone-releasing hormone (LH-RH) agonists, such as leuprolide acetate, results in the decrease of serum testosterone levels to castrate levels. Since the 1980s, LH-RH agonist therapy has been the primary treatment strategy for androgen ablation (5-7). LH-RH therapies are associated with 80% to 90% stabilization of the disease for 10 to 18 months on average, and 2-year survival is approximately 60% (8,9). Uninterrupted drug administration is essential to the efficacy of LH-RH agonist therapy, so compliance is critical for prostate cancer patients. Unfortunately, compliance is often a problem, where 44% of patients failed to present for one or more monthly Lupron Depot injections, and 24% of patients were more than 2 weeks late in obtaining a monthly injection in the U.S. Veterans Administration system (10).
FORMULATION STABILITY

The DUROS Leuprolide Implant is designed to deliver leuprolide continuously at a nominal rate of 125 jug/day over 1 year for the palliative treatment of prostate cancer. It is implanted subcutaneously in the upper arm and explanted after 1 year. The bioactive peptide for the

Highly concentrated leuprolide solutions have demonstrated good chemical and physical stability when stored in sealed DUROS implants at 37C for the functional lifetime of the implant (2,11,12). Excipients used for the early screening of formulations included solution vehicles such

adequate for a 2-year shelf life (250C) in addition to a 1year implant life (370C).
Leuprolide (%) IN VITRO PERFORMANCE Nonaqueous Aqueous n =3

When in vitro device release rates were measured (n = 6), a zero-order release rate was seen for up to 1 year (Fig. 6). In addition, RP-HPLC analysis revealed greater than 95% in vitro drug stability on average over the test duration.
IN VIVO PERFORMANCE

Time (months) Figure 5. Comparison of the stability of aqueous and nonaqueous formulations in the DUROS Leuprolide Implant (370 mg/mL at 37O0C).

as propylene glycols, poly(ethylene glycols), ethanol, glycofurol, dimethyl sulfoxide, and water. Both aqueous and nonaqueous solution formulations demonstrated 80% to 95% leuprolide remaining after 12 months at 370C (12). For example, a 370-mg/mL aqueous leuprolide formulation was stable for up to 6 months and then dropped off to slightly below 90% stability, whereas a nonaqueous formulation showed greater than 90% stability for more than 12 months (Fig. 5). The major degradation pathways for the nonaqueous formulation were hydrolysis, racemization, oxidation, and aggregation. Similar degradation pathways were observed for the aqueous formulation. However, in the nonaqueous formulation, the proportion of leuprolide degrading to hydrolytic products decreased while aggregation products increased, resulting in a more stable formulation. In general, no aggregates larger than a trimer were observed. The final formulation used for clinical trials was a 370-mg/mL nonaqueous formulation that provided 92% stability for 2 years at 370C, which is

A 14-month canine study evaluated the DUROS Leuprolide Implant for serum testosterone concentrations. In the control group, serum testosterone levels fluctuated widely up to 600 ng/dL through the year. Conversely, for every dog that received a DUROS Leuprolide Implant, testosterone levels were suppressed to castrate levels (below 50 ng/dL) by day 25 and remained completely suppressed (Fig. 7). After 365 days, the first implant was replaced, and blood levels of testosterone remained suppressed to the end of the study (14 months). Histological evaluation of the implantation site did not reveal any unusual changes in the tissue, and neither was any systemic toxicity seen in the study. Local tissue reactions to the DUROS Leuprolide Implant were further investigated in rats and Hanford miniature swine. In rats, no unexpected local tissue reactions were observed with the implants over the 38-week study, and in general, tissue reaction scores were equal to or better than those of historical controls receiving control implant material (high-density polyethylene). In miniature swine, no infections or system expulsions occurred over the 12 weeks, and no macroscopic or microscopic evidence of untoward local tissue reactions was seen.

(RP-HPLC analysis) Leuprolide release rate (/xg/day)

(Release rate) n = 6 (SEM) Figure 6. In vitro release rate and drug stability of the DUROS Leuprolide Implant.

Time (days)

Drugstability(%)

Testosterone (ng/dL)

Removal of original DUROS implant and insertion of new implant Castrate level (<50 ng/dL)

Figure 7. Testosterone concentrations in dogs with the DUROS Leuprolide Implant.

Time (days)

IN VIVO-IN VITRO RELEASE RATE AND STABILITY CORRELATION

The in vivo performance of the DUROS Leuprolide Implant has been characterized in both dogs and rats, and the results have been compared with the performance of the same batch of implants evaluated in vitro. Cumulative drug delivery was estimated from analysis of residual drug in the reservoir (Table 1). Comparison of in vivo cumulative drug delivery with in vitro cumulative drug delivery shows agreement to within 5%. Analysis of the residual drug formulation (370 mg/mL) also permitted comparison of in vivo and in vitro stability values using RP-HPLC and SEC (Table 2). Stability was more than 96% for RP-HPLC and SEC measurements, both in vivo and in vitro, at the 6-month timepoint. At the 1-year timepoint, good stability was also observed, both in vitro and in vivo, reflecting the stability of the leuprolide formulation and the design of the orifice in preventing back

diffusion of aqueous fluids and extracellular components. Taken together, the close correlation of the in vitro and in vivo release rates and of the in vitro and in vivo stability values for the DUROS Leuprolide Implant indicates that these attributes are essentially independent of in vivo conditions and can be predicted from in vitro testing results.
IMPLANTATION AND EXPLANATION

The DUROS Leuprolide Implant is implanted subcutaneously in the upper inner aspect of the nondominant arm. The implantation is an outpatient procedure requiring local anesthesia. After normal antiseptic preparation of the site, a local anesthetic is injected along a 5-cm track. A 4to 5-mm incision is made with a scalpel through the skin at one end of the anesthesized area. The DUROS system is inserted through the incision and advanced subcutaneously along the anesthesized track. The incision site is closed with a Steristrip and a sterile bandage.

Table 1. In Vivo-In Vitro Pumping Rate Comparison (Nonaqueous Formulation) Species Rat Dog Time of explant (weeks) 24 52 In vivo cumulative delivery (mg leuprolide) 28.7 5.8 (n = 3) 60.5 3.2 (n = 6) In vitro cumulative delivery (mg leuprolide) 29.2 2.8 (n = 5) 63.5 2.3 (n = 9) Difference (%) 1.6% 4.8%

Table 2. In Vivo-In Vitro Drug Stability Comparison (Nonaqueous Formulation) Species Rat Dog Time of explant (weeks) 24 52 Method RP-HPLC SEC RP-HPLC SEC In vivo stability 97.0 97.3 96.5 93.8 0.1% (n 0.1% (n 0.1% (TZ 2.4% (n = 3) = 3) - 6) = 4) In vitro stability 96.6 97.2 96.0 97.2 0.3% (n 0.7% (n 0.4% (n 0.7% (n = 5) = 5) = 4) = 4) Difference (%) 0.4% 0.1% 0.5% 3.6%

Explanation is accomplished by external palpation and localization of the implant followed by incision and removal. After normal antiseptic preparation of the site, local anesthetic is injected at one end of the implant, and a 4- to 5-mm incision is made, perpendicular to the implant. Finger pressure is applied to the other end of the implant to elevate the removal end. A small slit is then made through any surrounding fibrotic tissue to expose the implant. The implant is then popped out by continued finger pressure on the opposite end, and the incision site is closed with a Steristrip and a sterile bandage.
CLINICAL EXPERIENCE

BIBLIOGRAPHY 1. Biotechnology Industry Organization, 1996 BIO Editors' and Reporters' Guide to Biotechnology, 2nd ed., BIO, Washington, D.C., 1996. 2. C.L. Stevenson et al., Proc. Int. Symp. Controlled Release Bioact. Mater. 23 (1996). 3. J.E. Brown, Pharm. Res. 13(9), S-79 (1996). 4. E.D. Crawford et al., J. CUn. Endocrinol. Metab. 80, 10621078 (1995). 5. A. Kaisary, C.J. Tyrell, and WB. Peeling, Br. J. Urol. 67, 502508 (1991). 6. M.S. Soloway, G. Chodak, and N.J. Vogelzang, Urology 37,4651 (1991). 7. R.P. Huben and G.P. Murphy, Cancer (Philadelphia) 62,18811887 (1988). 8. N. Bruchovsky, in J.F. Holland et al., eds., Cancer and Medicine, 3rd ed., vol. 1, Lea & Febiger, Philadelphia, 1993, pp. 885-896. 9. P. Chrisp and E.M. Sorkin, Drugs Aging 1, 487-509 (1991). 10. J.A. Shaheen, M. Amin, and J.I. Harty, Urology 42, 533-535 (1993). 11. C.L. Stevenson et al., Pharm. Res. 13(9), S-IlO (1996). 12. C.L. Stevenson et al., Program Abstr., 1997 Am. Pep. Symp. Nashville, Tenn., June 14-19, 1997. 13. J.E. Brown, Abstr. Pap. 213th Meet., Am. Chem. Soc., 1997, p. 271. 14. J.C. Wright et al., Proc. Int. Symp. Controlled Release Bioact. Mater. 24, 59-60 (1997).

A human clinical study (six male volunteers, aged 1865 years) showed that the DUROS implant and explant procedures were well tolerated (13,14). The placebo implant utilized in the study consisted of a sterile titanium alloy DUROS reservoir and membrane and orifice components; no drug formulation or internal components were used. No adverse effects were reported during the 8-week study. Additionally no "wearing" sensation was reported by the volunteers. Each implant was explanted in an outpatient surgery area in approximately 3 min. A 1-year human phase IfLl clinical study, begun in March 1997, examines the feasibility, functionality, and efficacy of one versus two DUROS Leuprolide Implants (3.75 mg/month with one implant versus 7.5 mg/month with two) in patients with advanced prostate cancer. Preliminary data show that testosterone was suppressed to castrate levels (below 50 ng/dL) by the fourth week of the trial for both the patients who received one implant and the patients who received two implants.
CONCLUSIONS

See also PUMPS/OSMOTICINTRODUCTION; PUMPS/

OSMOTICALZET SYSTEM; PUMPS/OSMOTICVITS VETERINARY IMPLANT; PUMPS/OSMOTICRUMINAL OSMOTIC BOLUS.

The DUROS implant represents an emerging application of osmotic technology for the delivery of biomolecules for human therapy. The technology reflects recent advances in biotechnology and in stabilization of peptides and proteins formulated as aqueous and nonaqueous solutions and suspensions. The DUROS implant design is adaptable for many other compounds and sites of administration. Typically the delivery is systemic, but it can be made site specific by replacing the orifice with a catheter directed to the desired locationfor example, into the intrathecal or epidural cerebrospinal fluid. The DUROS implant has demonstrated biocompatibility and functionality in animal studies. The first therapeutic application of this technology, currently in clinical trials, is the 1-year DUROS Leuprolide Implant for the treatment of prostate cancer.
ACKNOWLEDGMENTS We thank Corinne Falender, Sally Tao, Paul Johnson, Jim Brown, Joe Leonard, and Keith Dionne for their contributions. We also thank the Implant Research and Development, Biopharmaceutical Development, and Toxicology departments at ALZA Corporation.

PUMPS/OSMOTICRUMINAL OSMOTIC BOLUS

JEREMY WRIGHT

ALZA Corporation Palo Alto, California

KEY WORDS

Hydration Parasitic larvae Rumen Ruminants Selenium deficiency Semipermeable membrane

OUTLINE

Background System Design and Function Products IVOMEC SR Bolus (Ivermectin) Dura SE Bolus (selenium) Conclusions Bibliography The Ruminal Therapeutic System (RUTS) Push-Melt technology is designed to provide controlled delivery of a drug for up to 1 year in the rumen of cattle and sheep. After oral administration, each capsular system is retained in the rumen, delivering drug for an extended duration. Drug is absorbed through the ruminal or lower intestinal mucosa into the systemic circulation. For cattle, RUTS systems are generally 2 to 3 cm in diameter and up to 10 cm in length. Larger dimensions are possible, depending on the particular application. Up to 10 g of drug can be administered. The RUTS Push-Melt technology is applicable to the delivery of parasiticides, insecticides, nutritional supplements, antibiotics, growth promoters, repartitioning agents, and estrus suppressants.
BACKGROUND

the target animal's gastrointestinal transit time, but in ruminants (cattle, goats, and sheep) the transit time can be controlled by using a device with sufficient density or a geometrical configuration that keeps it in the rumen for an indefinite period. Objects are retained in the rumen if they are suitably dense (density greater than 2.0 g/cm3, preferably 2.7 to 3.0 g/cm3) or large enough to prevent passage to the lower portions of the gastrointestinal tract or upward through the esophagus in regurgitation. In addition to the RUTS system, density-based systems include a system with two semipermeable membranes attached to a stainless steel cylinder that delivers morantel tartrate (4), a system described by Conrad and Skinner that consists of a high-density cylinder containing monensin dispersed in a biodegradable matrix of polylactic acid (5), and a completely degradable corrosion-based Panacur SR bolus that releases 12 g of fenbendazole over 4 to 5 months (6). Geometry-based systems usually have a mechanism for unfolding to a larger size once in the rumen; before administration, the system is secured in a compact configuration by a degradable tape or closure. The Laby device has "wings" (polymeric strips held in place by a waterdegradable tape) that expand in the rumen (7,8); this device has been used to deliver albendazole (Captec Proftril, SmithKline Beecham) by dissolution from tablets in contact with ruminal fluids (9). Another system, consisting of a rolled trilaminate sheet, uncoils in the rumen and releases morantel tartrate (10).
SYSTEM DESIGN AND FUNCTION

In the mid-1980s, the RUTS Push-Melt technology was developed to meet the need for drug-dedicated osmotic systems for use in ruminant production animals (1,2). Ruminants such as cattle and sheep have a complex digestive system that includes a large four-chambered stomach; the chambers are the rumen, the reticulum, the omasum, and the abomasum (Fig. 1) (3). In the rumen, ingested cellulose is broken down by microorganisms into simple mono- and disaccharides suitable for digestion. Orally administered, sustained-release delivery systems are typically limited by

The RUTS Push-Melt osmotic system consists of an injection-molded semipermeable membrane that encapsulates an osmotic tablet, a partition layer, drug formulation, and an iron densifier. An exit port screen can be included (Fig. 2). Systems can vary in size from 2 to 3 cm in diameter and up to 10 cm in length, with overall drug loading capacity of up to 10 g.

1 2 3 4 5 6 7 Figure 1. Bovine digestive system. Source: Ref. 3.

Lungs Esophagus Rumen Reticulum Omasum Abomasum Descending duodenum

Osmotic tablet

Drug formulation

Density element

Exit passageway

provides the system with additional protection from ruminal debris. Although ruminal boluses are typically removed by magnets during slaughter, all system components are designed to be fragmentable and compatible with rendering equipment in the event that they are not completely removed (12). The basic mathematical expressions that describe drug release from osmotic systems are given in PUMPS/ OSMOTICINTRODUCTION. The drug delivery rate equation is dmldt = (Alh)kAnc where An is the osmotic pressure gradient between the osmotic engine and the ruminal environment. For Push-Melt systems, the membrane surface area (A) and the osmotic pressure gradient (An) change over time as the degree of hydration (H) increases (2). The effective membrane surface area increases over time as the osmotic tablet swells, but the osmotic engine itself is diluted, decreasing the osmotic pressure gradient. To reflect these time dependencies, the equation is modified as follows:
dmldt = (AH/h)kAnHc

Wax partition

Injection-molded semipermeable membrane

Exit port screen

Figure 2. Cross section of the Push-Melt Ruminal Therapeutic System (RUTS).

In the aqueous environment of the rumen, water is imbibed through the semipermeable membrane into the osmotic tablet, which swells and pushes against the partition layer. The partition layer forces the thermoresponsive drug formulation through the orifice in the densifier and through the exit port screen if it is present. The semipermeable membrane controls the rate of water imbibition and therefore the pumping rate of the system. This membrane, composed of cellulosic esters and plasticizers, must be rigid enough to ensure device integrity. The osmotic tablet consists of a swelling hydrogel (e.g., sodium carbomer) and an inorganic, osmotically active salt (e.g., sodium chloride), which provides a high osmotic gradient (more than 300 atm) across the membrane. Between the osmotic tablet and the drug formulation layer is the partition layer, which acts like a plunger in a syringe to ensure a smooth response to the swelling of the osmotic tablet. It consists of a compound with a higher melting point or a higher viscosity than the drug formulation layer. By altering the size of the partition layer, researchers can change the duration of the system while keeping the total dosage constant. A RUTS Push-Melt system can deliver one or more drugs up to 50% by volume in a solution or a suspension. In the drug formulation, drug is suspended or dissolved in a thermoresponsive vehicle that is easily stored as a solid at room temperature. The drug formulation softens to form a viscous, flowable solution or semisolid in the 4O0C ruminal environment. Microcrystalline waxes have proved useful as such vehicles (11); drugs can be suspended in these waxes at concentrations in excess of 30% by weight. Because many drugs are essentially insoluble in the wax, such formulations have minimal osmotic activity and high stability. Preparing the drug formulation as a solid improves the stability of compounds with limited solubility and increases the shelf life of the systems. Drugs can be hydrophobic or hydrophilic; if hydrophilic, they are prepared in a hydrophobic vehicle. The densifier, made of sintered iron, adds sufficient weight to the system so that it will not be regurgitated; the amount of weight required varies with the species. At the end of the exit passageway, the optional exit port screen

where the subscript H represents the dependence of A. and An on osmotic engine hydration. The osmotic pressures of the drug formulation and of the partition layer are assumed to be negligible. The mechanism of RUTS Push-Melt drug delivery is independent of in vivo environmental conditions, mainly because of the low osmotic pressures in the in vivo environment. Because of this, in vivo and in vitro system performance are closely correlated, and in vitro assessment is predictive of in vivo performance and therapeutic outcome. RUTS Push-Melt systems can be designed for a variety of drug delivery profiles such as zero-order, pulsatile, ascending, or descending. They are typically designed for zero-order drug delivery of up to 5 g/day for durations ranging from 1 day to 1 year. With zero-order drug delivery, the RUTS Push-Melt system prevents drug plasma concentrations from attaining toxic levels or declining to subtherapeutic levels. Drug can be delivered in pulses by alternating the drug and placebo layers in the formulation layer (13). Ascending and descending release profiles can be designed into the system: Creating an increase in the membrane surface area (through choice of appropriate membrane materials and osmotic agents) results in an ascending profile, whereas providing a subsaturated solution in the osmotic tablet gives a descending profile.
PRODUCTS

Two commercial products have been developed and marketed using the RUTS Push-Melt technology. Dura SE, introduced in 1989, delivers sodium selenite to seleniumdeficient cattle for up to 4 months. IVOMEC SR (ivermectin), released in 1992, delivers the parasiticide iver-

mectin to cattle for 135 days, controlling parasitic bronchitis and parasitic gastroenteritis for the entire grazing season when used at turnout. It is also effective in the treatment and control of sucking lice, mange mites, and warbles for 135 days after administration.
IVOMEC SR Bolus (Ivermectin)

Ivermectin is a unique chemical entity discovered and developed by scientists at Merck Research Laboratories. Its broad-spectrum efficacy and wide margin of safety make it an ideal anthelmintic agent (14). Ivermectin acts by paralyzing parasitic nematodes, arachnids, insects, and warbles; this result is attributed to ivermectin's effect on the central nervous system of these parasites, specifically its effect on the mediation of neurotransmission by yaminobutyric acid (GABA) (15). At therapeutic doses, ivermectin has no effect on cattle because it does not readily penetrate the bovine central nervous system. For a discussion of the pharmacokinetics of ivermectin, see Baggot and McKellar (16). Ivermectin can be given orally, parenterally, or topically. Continuous release is advantageous because animals are susceptible to reinfection when grazed on infected pastures. When ivermectin is given as a continuous-release ruminal bolus, steady-state levels of ivermectin can be ensured with minimal stress to the animal and minimal handling by the producer. When ivermectin was delivered ruminally by a weighted ALZET osmotic pump, mean plasma levels of ivermectin were predictable over a O- to 40-//g/kg/day dosage range; bioavailability was 40% (17). Using the same method of administration, Egerton and colleagues showed that ivermectin was effective in preventing the establishment of nine nematode parasite species in cattle (18). A daily dose of up to 40 //g/kg/day, delivered intraruminally, was effective in protecting grazing calves against these parasites. This work helped establish the target delivery rate for ivermectin in fully grown cattle (300 kg) at 12 mg/ day (2). The IVOMEC SR Bolus for cattle contains 1.72 g ivermectin as a 22% (w/w) suspension dispersed in a white, microcrystalline wax. The system includes an exit port screen (Fig. 2), which prevents ingress of ruminal matter into the system and increases the internal operating pressure of the system. The IVOMEC SR Bolus is 9 cm long and 2.5 cm in diameter. Delivering 12 mg/day of ivermectin for 135 days, it is effective for the treatment and seasonlong control of parasitic bronchitis (lungworm), gastrointestinal nematodes, sucking lice, mange mites, and warbles. Administration of the IVOMEC SR Bolus is accomplished by using a balling gun of appropriate size to deliver the bolus into the pharynx just beyond the back of the animal's tongue (Fig. 3) (19). Once administered, the IVOMEC SR Bolus has sufficient density to be retained in the rumen for an extended duration. Biting or regurgitation of the system occurs infrequently. In the few reported cases of biting, system integrity was not compromised, and the system could be readministered. Because of the homogeneous nature of the drug formulation (a hydrophobic suspension), ivermectin delivery

in an IVOMEC SR Bolus can be directly calculated from the weight of the pumped drug formulation (2). Hence, when systems were immersed in a fixed volume of water or phosphate-buffered saline maintained at ruminal temperature (4O0C), in vitro system performance could be determined from assayed ivermectin delivery or gravimetric measurements of the formulation delivered. For in vivo measurement, ruminants were fistulated so that the system could be removed periodically for analysis, then returned to the ruminal environment. In this case, the IVOMEC SR Bolus was placed in a metal canister with perforations on one end to permit ruminal fluid access to the osmotic tablet; the other end was not perforated, and entry of water was prevented by means of O-rings. Drug formulation was released into this latter end of the collection vessel and analyzed on periodic removal (2).
IVOMEC SR Start-up and Shutdown Delivery Profiles.

Rapid, reproducible, and predictable drug delivery startup is important with ruminal boluses for immediate prophylaxis, especially in the spring when animals are sent to fresh pastures, where an increase of parasitic larvae is typical. With prototype IVOMEC SR boluses, drug delivery was not instantaneous; a time lag was associated with water permeation into the osmotic tablet and pressurization of the drug formulation. To minimize this start-up time, the IVOMEC SR Bolus is prehydrated by adding a fixed amount of water to the packaged system, causing an increase in the internal hydrostatic pressure as water is imbibed into the osmotic tablet. Once in the 4O0C ruminal environment, the thermoresponsive drug formulation softens, with rapid onset of osmotic pumping. Zingerman and colleagues (2) have shown that the onset of drug delivery for hydrated (1.3 g of water added) IVOMEC SR boluses is rapid (2-3 days). Steady-state delivery is reached in 7 to 10 days. Anhydrous systems took 2 to 3 weeks to reach steady-state delivery (Fig. 4) (2). Reproducible and predictable delivery termination for the IVOMEC SR bolus is critical to establish the optimum withdrawal period so that drug residues are minimized to safe levels before slaughter. For the IVOMEC SR Bolus, the withdrawal period (period since last drug administration in which the animal cannot be slaughtered for human consumption) is 180 days. As shown in Figure 4 (2), termination occurred rapidly at approximately 135 days for both in vivo and in vitro systems; within 14 days, shutdown was complete (2).
IVOMEC SR In Vivo-ln Vitro Release-Rate Correlation.

Good agreement has been shown between the in vitro and in vivo release profiles for the IVOMEC SR Bolus (2). Figure 5 (2) demonstrates this agreement, which has also been verified with seven large, commercial-scale batches. The cumulative coefficient of variation at the time when all the drug formulation was expelled was 4% for in vivo systems and 4.2% for in vitro systems. IVOMEC SR Efficacy. In a study by Yazwinski and colleagues, calves treated with the IVOMEC SR Bolus had significantly fewer fecal egg counts and significantly fewer nematodes at necropsy than did the untreated calves; both

Pharynx

Epiglottis Esophagus

Tongue:

Balling gun

Figure 3. Bolus administration technique controlled-release boluses. Source: Ref. 19.

for

Mean daily ivermectin output (mg)

Hydrated in vitro (n = 10) Anhydrous in vitro (n = 10) (projected duration = 156 days) Hydrated in vivo (n = 10) Anhydrous in vivo (n - 10) (projected duration = 1 5 4 days)

Mean daily ivermectin output (mg)

In vitro (n = 6) In vivo (n = 10)

Time (days) Time (days) Figure 4. Comparison of anhydrous and hydrated (1.3 g) in vitro and in vivo ivermectin output profiles of IVOMEC SR Bolus samples. Source: Ref. 2. Figure 5. Comparison of in vitro and in vivo release profiles of ivermectin (bolus samples hydrated at 1.3 g). Source: Ref. 2.

Dura SE Bolus (selenium)

Selenium deficiency in cattle is a problem in many areas of the world, including parts of the United States. A PushMelt system, the Dura SE Bolus has been developed to deliver sodium selenite at the rate of 3 mg of selenium per day to cattle for 120 days. The system does not include the optional exit port screen; otherwise, the design is as shown in Figure 2. The drug formulation consists of sodium selenite dispersed in a microcrystalline wax. Figure 6 shows the in vitro, zero-order release profile obtained for

Release rate (mg/day)

groups were given infective larvae inoculum and grazed on an infected pasture. The ivermectin bolus prevented the establishment of not only actively developing parasitic nematodes but also arrested larvae (e.g., Ostertagia EL4). No adverse reactions were seen, and all IVOMEC SR boluses remained in the rumen throughout the study (20).

Time (days) Figure 6. In vitro release profile of selenium delivered from a Dura-SE bolus.

the Dura SE Bolus. Adair and colleagues examined the in vivo behavior of Dura SE Bolus and found that release reached a steady state within 4 weeks, continued at steady-state levels for 16 weeks, and dropped to less than 1% of steady-state levels in the final 2 weeks. Mean in vivo release was 3.1 mg/day, with a range of 2.4 to 4.1 mg/day. Excellent in vivo-in vitro correlation was obtained (21). Figure 7 shows selenium blood levels from seleniumdeficient cattle treated with the Dura SE Bolus. Selenium has a relatively long half-life, which is reflected in the slowly rising selenium levels. Nevertheless, selenium levels were in the normal range (more than 0.08 ppm) by day 35 (22). In a 220-day study, Campbell and colleagues assigned 150 selenium-deficient, pregnant beef cattle to one of four treatment groups: one Dura SE Bolus at day O, two Dura SE Boluses (one administered on day O and the second one on day 119), two selenium pellets at day O, and control. The Dura SE Bolus is designed to release 3 mg/day for 120 days; the 30-g pellets contain 10% elemental selenium and are designed to provide selenium supplementation for up to 18 months. At the end of the study, blood levels of selenium were significantly (P < .01) higher in the twoDura SE Bolus group than in any other group. Calves from cattle in the selenium-supplemented groups had significantly (P < .001) higher blood selenium levels, both before and after suckling, than did controls (23). Maas and colleagues administered the Dura SE Bolus to selenium-deficient beef heifer calves and found that mean blood selenium was maintained at more than 0.10 ug/mL for 188 days. No untoward effects were seen in the treatment group (24).
CONCLUSIONS

tions. Commercialized applications of this technology have been developed for the delivery of ivermectin, a potent parasiticide, and sodium selenite, a nutritional supplement.
BIBLIOGRAPHY 1. U.S. Pat. 4,595,583 (June 17,1986), B. Eckenhoff, R. Cortese, and RA. Landrau (to ALZA Corp). 2. J.R. Zingerman et al., J. Controlled Release 47(1), 6 (1997). 3. G.L. Zimmerman and E.R Hoberg, Parasitol. Today 4(2), 55 (1988). 4. R.M. Jones, Vet. Parasitol. 12, 223-232 (1983). 5. J.M. Conrad and D.S. Skinner, J. Controlled Release 9, 133147 (1988). 6. P. Berghen et al., Vet. Q. 16, 161-164 (1994). 7. U.S. Pat. 3,844,285 (October 29, 1974), R.H. Laby (to Commonwealth Scientific and Industrial Research Organization). 8. N. Anderson, R.H. Laby, R.K. Prichard, and D. Hennessey, Res. Vet. ScL 29, 331-341 (1980). 9. M.Y.K. Ho, D.W. Gottschall, and R. Wang, in D.H. Hutson, ed., Xenobiotics and Food-Producing Animals: Metabolism and Residues, American Chemical Society, New York, 1992, pp. 149-157. 10. W.A. Boettner et al., J. Controlled Release 8, 23-30 (1988). 11. J.B. Tuttle, in A. Standen, ed., Kirk-Othmer Encyclopedia of Chemical Technology, 2nd ed., Interscience, New York, 19631970, pp. 92-112. 12. U.S. Pat. 5,206,024 (April 27, 1993), B. Eckenhoff (to ALZA Corporation). 13. U.S. Pat. 4,723,958 (February 9, 1988), D.G. Pope and A.E. Royce (to Merck & Co. Inc.). 14. W.C. Campbell, Ivermectin and Abamectin, Springer-Verlag, New York, 1989. 15. W.C. Campbell et al., Science 221, 823-828 (1983). 16. J.D. Baggot and Q.A. McKellar, J. Vet. Pharmacol. Ther. 17, 409-419 (1994). 17. D.G. Pope, RK. Wilkinson, J.R. Egerton, and J. Conroy, J. Pharm. ScL 74(10), 1108-1110 (1985). 18. J.R. Edgerton, D. Suhayda, and C.H. Early, Vet. Parasitol. 22, 67-75 (1986). 19. R.J. Gyurik, in R TyIe ed., Drug Delivery Devices, Fundamentals and Applications, Dekker, New York, 1988, p. 569. 20. T.A. Yazwinski, H. Featherston, and C. Tucker, Am. J. Vet. Res. 56(12), 1599-1602 (1995). 21. D. Adair et al., J. Pharm. ScL 76(11), S253 (1987). 22. G.J. Sumner, Proc. Acad. Vet. Consult. Meet, August 11-12, Kansas City, Kans., 1988. 23. D.T. Campbell et al., Am. J. Vet. Res. 51(5), 813-817 (1990). 24. J. Maas, J.R. Peauroi, D.W. Weber, and RW. Adams, Am. J. Vet. Res. 55(2), 247-250 (1994).

The RUTS Push-Melt osmotic system is an innovative adaptation of osmotic technology for the delivery of agents to ruminants. It extends the delivery duration beyond the 28-day lifetime of the ALZET pump to 4 months or longer. Formulation options include suspensions as well as soluPlacebo Selenium Normal level

Selenium (ppm)

Time (days) Figure 7. Selenium blood levels in cattle administered a Dura-SE bolus. Source: Ref. 22.

See also PUMPS/OSMOTICINTRODUCTION; PUMPS/

OSMOTICALZET SYSTEM; PUMPS/OSMOTICVITS
VETERINARY IMPLANT; PUMPS/OSMOTICDUROS OSMOTIC IMPLANT FOR HUMANS.