Dose uniformity of ophthalmic suspensions

Dose uniformity of ophthalmic suspensions Michael Diestelhorst, MD, Kyoung-Ae Kwon, Richard Siiverkrup, PhD , ~C _,,~,_~"~ ~ _.,,~_.~ _ ~~,_,~

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ABSTRACT

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phthalmic suspensions are difficult to formulate because drug particles tend to sediment and interact, forming loose flocs that can be broken up by shaking or cohesive cakes that are difficult to redisperse. Effective therapy with potent drugs requires the mean dose to be adapted to the patient's needs and the

From the Department of Ophthalmology, University of Koln (Diestelhorst), and the Department of Pharmaceutical Technology, University of Bonn (Kwon, Suverkrup), Germany. Reprint requests to Michael Diestelhorst, MD, Department ofOphthalmology, University of Koln, JosefStelzmann Strafe 9, 50931 Koln, Germany. 672

variability between doses to remain within certain limits. In ophthalmic suspensions, dose precision and accuracy can be impaired by sedimentation, aggregation, and recrystallization of particles during storage, in faulty droppers, or during improper patient handling. The dose uniformity of ophthalmic suspensions depends on the number and frequency of shaking cycles and on the shaking intensity. Apt and coauthors 1 published a statistical study on the number of shaking cycles to be expected in patients. Quantitative reports are not yet available on shaking frequency and intensity or on the drug content of single drops covering the course of emptying a full container of suspension eyedrops.

J CATARACT REFRACT SURG--VOL 24, MAY 1998

UNIFORMITY OF OPHTHALMIC SUSPENSIONS

Patients and Methods Shaking Intensity Shaking intensity was studied in 31 healthy persons (mean age 27 years ± 7 [SO]) and 27 patients (mean age 64 ± 10 years). An acceleration sensor (Entran EGAX-lOD) was attached to a cylindrical test body corresponding in weight and dimensions to an eyedrop botde. Both groups were told the purpose of the study and asked to shake the dummy botde as they would usually handle medication. In each case, data were sampled for 5 seconds at a rate of 200 Hz using an industrial standard architecture portable computer with an INTEL 80286 processor and a DAP 1200 data acquisition card (Microstar Laboratories) with customized software written in Turbo PASCAL. The same specifications and conditions were used to assess the shaking intensity of a pneumatic shaker described below (Figure 1). In each instance, six shaking cycles were evaluated by Fourier analysis using the function SPECTRA of the SPSS PC Program Package (SPSS/PC+ Manual. Vol. Trends. Chicago, SPSS, Inc., 1987). The area under the periodogram within the frequency range of 0.1 to 60 Hz was taken to be a measure of the shaking intensity.

tion collector. A lid covering the dropper mouths during storage and shaking was opened, and pressure was applied to either the body of the first container or to the flexible part of its dropper. The fall of each drop was sensed using a light barrier. Under program control, the signal indicating the release of a drop caused the pressure valve of the current botde to be closed and the valve of the next botde to be opened. After samples had been taken from all specimens, the lid was closed, the bottle mount was returned to its horizontal resting position, and the test tubes in the fraction collector were advanced (Figure 1). To simulate an emptying pattern close to that prevailing in therapy, the 4 hour interval between three samples taken during daytime was followed by a nighttime interval of 12 hours. Drug content in test tubes was determined by spectrophotometry after drug particles were dissolved in an appropriate volume of methanol.

Results Examples are given for sections of the acceleration profile of an elderly patient shaking the botde slowly and with low intensity (Figure 2), of a young person shaking rapidly and vigorously (Figure 3), and of the

Dose Uniformity The content uniformity of single drops was studied in three commercially available preparations (Table 1) using four specimens from the same production batch. Before being inserted into the apparatus, the bottles were stored vertically for at least 18 hours. The botdes were mounted in a horiwntal resting position in the pneumatic shaker-dropper apparatus. They were shaken six times in a 70 degree segment of an 18 cm diameter circle. Drops were sampled successively from each botde by bringing the botdes into a vertical, head-down position over test tubes in a frac-

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Table 1. Products tested .

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93a05

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Prednisolone-21-acetate

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UNIFORMITY OF OPHTHALMIC SUSPENSIONS 150

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Figure 2. (Diestelhorst) Acceleration profile (above) and periodogram (below) of a 74-year-old female patient.

Figure 3. (Diestelhorst) Acceleration profile (above) and periodogram (below) of a healthy 27-year-old .

pneumatic shaker (Figure 4), in which the frequency is fairly low and the intensity intermediate, Corresponding periodograms are shown for comparison, In humans, the Fourier analysis displayed a pure sinusoidal acceleration profile with only one main frequency, while higher harmonics were fairly prominent in the pneumatic shaker, Nevertheless, the area under the periodogram appears to be a suitable common measure for the agitation intensity in all instances,

patient group (Figure 6). There were no indications of an association between shaking intensity and sex or between frequency of shaking and patients or healthy persons. The frequency of shaking may be of secondary importance for the redispersion of suspensions. The shaking intensity of the test apparatus corresponded to the 67th percentile of the group of patients studied and to the 18th percentile of the healthy volunteers. Its intermediate position renders it suitable for general quality control purposes.

Shaking Intensity The cumulative distributions of shaking intensity in healthy persons and in patients (Figure 5) show that the mean and variability of shaking intensities within the two populations were significantly different (analysis of variance, P < .05), As expected, patients constituted a more heterogeneous group, reflecting a certain negative correlation of shaking intensity with age in the 674

Dose Uniformity Mean drug content per drop and the range of four samples taken almost simultaneously are shown in Figure 7 for the three preparations. Horizontal lines indicate the expected content, given the nominal drug content and the average drop weight, which depends on the surface tension of the suspension and the

J CATARACf REFRACf SURG-VOL 24, MAY 1998

UNIFORMITY OF OPHTHALMIC SUSPENSIONS 150

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dropper construction, among other factors. In many cases, an upward trend was seen in the terminal phase of emptying; otherwise, the differences between products were remarkable. Best results were obtained with prednisolone acetate eyedrops, for which the mean content was close to the expected value and the variability was acceptable (Table 2, Figure 7C). The mean content of the indomethacin preparation was adequate, but the variability between drops was excessive and the increasing trend was pronounced. Superimposed on the global pattern was a daily variation: The drug content tended to increase during the day, when sampling intervals were short, and decreased after the longer night interval (Figure 7 B). This indicates that the time constant of sedimentation and aggregation processes was the same magnitude as the length of the sampling intervals.

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The mean drug content of the dexamethasone preparation amounted to only one quarter of the expected value; the missing three quarters were recovered from a semisolid residue in the containers at the

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UNIFORMITY OF OPHTHALMIC SUSPENSIONS

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end of the experiment. Even if the reduced availability at the site of administration had been planned, the between-drop variability would have disqualified this preparation (Figure 7A). Particle size appeared to be the most important formulation factor. The largest particles (mean ~7.0 JlIll) were in the indomethacin group and the smallest (mean

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676

c Figure 8. (Diestelhorst) Scanning electron micrographs of particle size: A: dexamethasone. B: indomethacin. C: prednisolone acetate.

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UNIFORMITY OF OPHTHALMIC SUSPENSIONS

Discussion The dose uniformity of suspension eyedrops depends on their homogeneity immediately before administration. Considering the labile physical state of suspensions, sufficient redispersion is possible only if particles aggregate to form loose floes that are readily broken up by agitation and if solid cakes do not form after sedimentation. An additional requirement is patient compliance: Ophthalmic suspensions must be shaken sufficiently before use. In the shaking compliance study by Apt and coauthors,l only 37 of 100 patients said they agitated their eyedrops, and most who did indicated between 6 and 15 as the preferred number of shaking motions. The shaking compliance of Out patients following cataract surgery has been discussed as a major reason for the poor performance of fluorinated steroids when compared with nonsteroidal anti-inflammatory drugs. 2-4 Our data demonstrate that in contrast to the dexamethasone suspension, prednisolone acetate eyedrops required very little shaking to redisperse the drug. The shaking intensity by patients has been quantified for the first time in this study. Results indicate shaking intensity tends to decrease in elderly patients; preparations that would be vigorously shaken by young, otherwise healthy persons may fail in older persons, whose muscle power may be reduced. In a follow-up study, the number of shaking cycles in the test device was increased to 12, 18, and 24 without significant influence on the outcome. Among the formulation factors studied, particle

size seemed to be most important. Although the suspending fluids were removed by filtration and particle interactions were probably exaggerated, the performance of the only micronized product was clearly superior. Our data explain why in some clinical studies of patients, post-cataract-surgery nonsteroidal antiphlogistics tend to have the same antiphlogistic activity on the restability of the blood-aqueous barrier as fluorinated steroidal suspensions. The prototype test apparatus could be improved in various ways but is sufficiently representative of eyedrop handling by humans to discriminate clearly between acceptable and unacceptable ophthalmic suspensions. This study might be the starting point for the development of an official test procedure.

References 1. Apt L, Hendrick A, Silverman LM. Patient compliance with use of topical ophthalmic corticosteroid suspensions. Am] Ophthalmol 1979; 87:210-214 2. Othenin-Girard P, Tritten ]-], Pittet N, Herbort CPO Dexamethasone versus diclofenac sodium eyedrops to treat inAammation after cataract surgery. ] Cataract Refract Surg 1994; 20:9-12 3. Diestelhorst M, Schmidl B, Konen W, et al. Efficacy and tolerance of diclofenac sodium 0.1 %, Aurbiprofen 0.03%, and indomethacin 1.0% in controlling postoperative inflammation. J Cataract Refract Surg 1996; 22:788793 4. Diestelhorst M, Aspacher F, Konen W, Krieglstein GK. The effect of Aurbiprofen 0.03% eye drops on the blood aqueous barrier in extracapsular cataract extraction with 10L implantation. Int Ophthalmol1991; 15:69-73

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