- Email: [email protected]
Omeprazole Absorption from a Compounded Transdermal Formulation in Healthy Volunteers
RESEARCH
Omeprazole Absorption from a Compounded Transdermal Formulation in Healthy Volunteers Curtis E. Haas, Lydia Lin, Denise Cloen, Thomas Kufel, Richard Moon, and Valerie Frerichs Received September 22, 2004, and in revised form December 26, 2004. Accepted for publication January 31, 2005.
ABSTRACT Objective: To evaluate the plasma concentration versus time profile of omeprazole following the administration of a compounded transdermal gel formulation in healthy volunteers. Design: Single-dose transdermal pharmacokinetic (PK) study including a comparison with historical data from an oral PK study. Setting: Academic clinical research center. Participants: Eight healthy volunteers between 18 and 50 years of age. Interventions: Omeprazole gel 40 mg (0.8 mL) was applied to the ventral surface of the forearm covering an area of 7 × 15 cm without an occlusive dressing. Blood samples were collected just before application and then at 1, 2, 3, 4, 6, and 8 hours. Plasma concentrations of omeprazole were determined using a validated liquid chromatography tandem mass spectrometry method. Main Outcome Measures: PK parameters (maximal plasma concentration [Cmax], the time of Cmax [Tmax], the area under the omeprazole concentration versus time curve from 0 to 8 hours, the elimination rate constant, and the halflife of the elimination phase) following transdermal administration, compared with historical controls who had received an oral omeprazole 40 mg dose during a previous study. Results: Of the eight volunteers, five had undetectable plasma omeprazole concentrations throughout the 8-hour study, precluding a complete PK analysis. For the three volunteers with detectable plasma omeprazole concentrations, the values ranged from 0.204 to 0.552 ng/mL. Including values of 0 for the patients with undetectable levels, the mean (± SD) Cmax was 0.153 ± 0.241 ng/mL, and the Tmax in patients with detectable levels occurred at approximately 6 hours. The plasma concentrations following transdermal administration were approximately 1,000-fold lower than those observed with oral dosing. Conclusion: Transdermal absorption from a single dose of the omeprazole gel formulation used in this study was poor. This transdermal gel formulation is clearly not bioequivalent to the oral capsule. Keywords: Transdermal drug administration, omeprazole, pharmacokinetics, compounding. J Am Pharm Assoc. 2005;45:473–478.
Vol. 45, No. 4
July/August 2005
www.japha.org
Curtis E. Haas, PharmD, is Assistant Professor, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo; and Director, Clinical Research Center, U.S. Department of Veterans Affairs (VA) Western New York Healthcare System, Buffalo. At the time this study was conducted, Lydia Lin, PharmD, was Student Pharmacist, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, N.Y. Denise Cloen, BSN, was Nurse Manager and Research Coordinator, Clinical Research Center, VA Western New York Healthcare System, Buffalo. Thomas Kufel, MD, is Attending Physician, Department of Medicine, VA Western New York Healthcare System, Buffalo. Richard Moon, PharmD, is Owner, Pharmacy Innovations, Jamestown, N.Y., and Adjunct Clinical Faculty, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, N.Y. Valerie Frerichs, PhD, is Scientific Manager, Core Analytical Laboratory, and Research Assistant Professor, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, N.Y. Correspondence: Curtis E. Haas, PharmD, University at Buffalo, 311 Hochstetter Hall, Buffalo, NY 14260-1200. Fax: 716-645-2886. E-mail: [email protected] Disclosure: Dr. Moon owns a pharmacy that prepared and dispensed the transdermal omeprazole product tested in this study. The authors declare no other conflicts of interest or financial interests in any products or services mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria. Funding: Supported by a grant from Pharmacy Innovations, Jamestown, N.Y. The mass spectrometer was obtained by Shared Instrumentation Grant #S10RR14572 from the National Center for Research Resources, National Institutes of Health. At the time of this study, Dr. Haas and Ms. Cloen were partially supported by the VISN-2 Research Development Fund, U.S. Department of Veterans Affairs.
Journal of the American Pharmacists Association
473
RESEARCH
Transdermal Omeprazole Absorption
O
meprazole is a widely prescribed proton pump inhibitor for the treatment of acid-peptic disorders including peptic ulcer disease, gastroesophageal reflux disease, gastric acid hypersecretory conditions, and dyspepsia. Currently, omeprazole is commercially available in an oral dosage form composed of encapsulated, enteric-coated beads. Since no alternative formulations are available, omeprazole is difficult to administer to patients who have difficulty swallowing or require a pediatric dose. An extemporaneously prepared suspension of omeprazole using a sodium bicarbonate solution has been described for use in patients with nasogastric or nasoenteral feeding tubes.1 The sodium bicarbonate solution is intended to neutralize stomach acid and reduce the amount of drug degradation that occurs before absorption.2 The high sodium content of this formulation is undesirable for fluid-restricted patients or those with significant heart disease. In addition, the bicarbonate-containing suspension has poor palatability, which may lead to nonadherence with this formulation, especially with children. An extemporaneously prepared transdermal gel formulation of omeprazole has been prescribed for use in pediatric patients in some communities with anecdotal reports of good clinical
AT A GLANCE Synopsis: A compounded transdermal gel formulation of omeprazole was clearly not bioequivalent to the oral dosage form approved by the Food and Drug Administration, according to this pharmacokinetic analysis. Using a product that was commonly compounded in their geographic area at the time of this study, the investigators found poor transdermal absorption of omeprazole over 8 hours following a single 40 mg application of drug in eight healthy volunteers. Serum omeprazole concentrations were undetectable in five participants, and levels in the three volunteers with detectable levels were 1,000-fold lower than in a prior study of oral omeprazole 40 mg doses conducted in this laboratory. Analysis: The results of this study highlight the importance of evaluating the bioequivalence of extemporaneously compounded pharmaceuticals before their clinical use, especially when nonsystemic routes of administration or previously unproven dosage forms are being prescribed. The expertise to prepare correctly formulated and chemically stable products is a very important aspect of professional compounding, but it is only the first step in assuring the dispensing of a safe and effective pharmaceutical product. There must be adequate and properly designed research to define the bioavailability, bioequivalence, clinical safety, and efficacy of these compounded products before they are dispensed for use in the community.
474
Journal of the American Pharmacists Association
response, and this product was being compounded by pharmacies in our area at the time this study was conducted, prompting an interest in further evaluating the product. Transdermal delivery of omeprazole, if effective, may offer the advantages of easy administration and avoidance of first-pass metabolism, which may improve the bioavailability of the drug.3 Although the transdermal formulation used in this study has been shown to be chemically stable for at least 3 months (data on file, R. Moon), no plasma concentration or bioequivalence data are available to support the potential clinical utility and routine prescribing of transdermal omeprazole.
Objective The objective of this study was to evaluate the plasma concentration versus time profile of omeprazole following topical administration of a stable gel formulation in healthy adult volunteers. In addition, the data for topical administration was compared with omeprazole plasma concentrations observed following oral administration of the drug to healthy volunteers during a study conducted at the same research center.4
Methods This study was completed at the Clinical Research Center, U.S. Department of Veterans Affairs Western New York Healthcare System (VAWNYHS), and was approved by the VAWNYHS Institutional Review Board. Eight healthy adult volunteers between 18 and 50 years of age, of both genders, and any race were enrolled in the study. Subjects had no history or evidence of chronic or acute medical diseases as documented by medical history, physical examination, and routine laboratory tests. Volunteers were excluded if they met any of the following criteria: a skin condition that might have affected transdermal drug absorption; regular consumption of any prescription or nonprescription medications known to inhibit or induce cytochrome P450 2C19 or 3A4 enzymes; women who were pregnant (a negative urine pregnancy test was required) or lactating; seropositive for human immunodeficiency virus; known hypersensitivity to omeprazole or any component of the transdermal formulation; or a history of alcohol or substance abuse. Alcohol abuse was defined as regular consumption of more than two alcoholic beverages on 5 or more days per week during the past 6 months. Substance abuse was defined as a history of consuming illicit drugs anytime in the past 6 months. All subjects provided written informed consent before any study-related procedures or tests.
Omeprazole Formulation The transdermal omeprazole formulation was a pH-balanced pleuronic lecithin organogel (PLO) prepared by Pharmacy www.japha.org
July/August 2005
Vol. 45, No. 4
Transdermal Omeprazole Absorption
Innovations (Jamestown, N.Y.), which contained a final omeprazole concentration of 50 mg/mL. This product is stable for at least 3 months under refrigeration (data on file, R. Moon).
Study Protocol Each of the participants underwent a physical examination, medical history, comprehensive metabolic panel, and complete blood cell count within 10 days before the study day. The volunteers were instructed to consume a low-fat breakfast and to avoid caffeine-containing beverages and foods on the morning of admission to the Clinical Research Center. Each subject had a 20-gauge intravenous catheter placed in a forearm vein, and then 40 mg (0.8 mL) of omeprazole PLO was applied to the contralateral forearm. The research nurse, using a gloved finger, evenly spread the gel over the ventral surface of the forearm covering a premarked area of 7 × 15 cm. Participants were informed to avoid touching or rubbing the area. Blood samples of 5 mL each were collected in K3EDTA-containing tubes (Becton Dickinson #366452, Franklin Lanes, N.J.) just before the application of the omeprazole PLO and at 1, 2, 3, 4, 6, and 8 hours after the application. Within 30 minutes of collection, the samples were centrifuged at 1,200 g for 15 minutes. The plasma was harvested, divided into 2 aliquots, and then frozen at –80° C until the time of assay.
Historical Controls During a prior study involving 12 healthy volunteers meeting essentially the same inclusion and exclusion criteria used in this study, participants received an intravenous dose of midazolam 0.025 mg/kg, and oral doses of omeprazole 40 mg, caffeine 100 mg, and debrisoquine 10 mg on two separate occasions—before and after 7 days of treatment with rifampin. This study was conducted by the authors at the same research center. The plasma omeprazole concentrations versus time profile and pharmacokinetic parameters for the baseline period before exposure to rifampin were used as historical control data for this study.4 In brief, subjects fasted overnight and then received an oral dose of omeprazole 40 mg (AstraZeneca, Lot 63438) at 8:00 am, along with the other medications listed above. Blood samples were collected just before the medications and 5, 30, and 60 minutes, then 2, 4, 6, and 8 hours after the dose. The blood samples of 10 mL each were collected using an EDTA-containing tube, centrifuged at 1,200 g for 15 minutes, and the plasma harvested and frozen at –80o C until the time of assay.
Assay Methods Plasma omeprazole concentrations were determined using a method developed for the simultaneous quantification of midazolam, omeprazole, and their primary hydroxy metabolites in plasma using high-performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). In brief, 50 microliters of Vol. 45, No. 4
July/August 2005
www.japha.org
RESEARCH
80% methanol:20% ammonium hydroxide adjusted to pH 8.2 with formic acid (v:v) was added to 250 microliters of each of the control and unknown samples. We used 300 microliters of each calibration standard for analysis. After 50 microliters of the internal standard (flurazepam 2 mcg/mL) was added to all samples, controls and standards, 3 mL of ethylacetate:hexane (75:25, [v:v]) was added for extraction. Samples were shaken on high speed (Eberbach Instrument Apparatus, Ann Arbor, Mich.) for approximately 25 minutes and then centrifuged for 10 minutes at 3,000 g. The supernatant was removed, placed into a clean test tube and evaporated to dryness with air using a Zymark Turbo Vap LV (Hopkinton, Mass.) set at 50° C for 30 minutes. Samples were reconstituted in 100 microliters of the mobile phase mix and injected into the LC/MS/MS system for analysis. The LC/MS/MS system consisted of an Agilent 1100 series autosampler (Foster City, Calif.), an Agilent 1100 series pump, an Agilent 1100 series degasser, and an Applied Biosystems PE/Sciex, API 3000 mass spectrometer (Foster City, Calif.) equipped with a Turbo-ionspray source. The system was controlled through Analyst Software, version 1.1 (Applied Biosystems, Foster City, Calif.). Analytes were separated on a Waters Symmetry Shield RP8 (Milford, Mass.), which was 3.0 mm inner diameter by 150 mm in length and packed with 5 micrometer-sized particles. The injection volume was 20 microliters. Isocratic elution using a mobile phase mix of 35% 5 mM ammonium hydroxide/formic acid pH 8.2 and 65% methanol, delivered at a rate of 400 microliters/minute, was used for separation. Before entering the electrospray source housing, the flow was split 1:1 using a PEEK tubing splitter (Upchurch Scientific, Oak Harbor, Wash.), with one split line directed to waste and the other to the Turbo-ionspray source. Optimal parameters for MS/MS detection of the analytes were determined, with positive ionization providing the greatest detectability for all four analytes. The working calibration range used for this method was 0.4 to 100 ng/mL, with limits of detection of ≤50 pg/mL, for each of the analytes. The intraday and interday coefficients of variation were between 1.6% and 11% for all four analytes.
Data Analysis When adequate data were available, a standard noncompartmental pharmacokinetic (PK) analysis of the serum concentration versus time data was conducted for both the transdermal gel and oral protocols. The following PK parameters were estimated when possible: maximal plasma concentration (Cmax), the time of Cmax (Tmax), the area under the omeprazole concentration versus time curve from 0 to 8 hours (AUC0–8h), the elimination rate constant (ke), and the half-life of the elimination phase (t1/2) using WinNonlin software (version 4.0, Pharsight, Inc., Cary, N.C.). The demographic characteristics of the two study groups were compared using Mann–Whitney rank sum test or Fishers exact test as appropriate for the data. All pharmacokinetic and demographic parameters are presented using descriptive statistics. Journal of the American Pharmacists Association
475
RESEARCH
Transdermal Omeprazole Absorption
Results Eight healthy adult volunteers were enrolled, and they completed the study on a single day. The demographic characteristics of participants and historical controls are shown in Table 1. Six of the eight participants in the current study took part in the previous oral study. Five of the eight participants receiving topical gel had no detectable omeprazole plasma concentrations throughout the 8hour study, while the other three had very low concentrations detectable at only a few time points. Therefore, the intended noncompartmental pharmacokinetic analysis for the transdermal data was not possible. In the three patients with detectable levels, plasma omeprazole concentrations ranged from 0.204 to 0.552 ng/mL, with a mean (± SD) Cmax for these three participants of 0.525 ± 0.032 ng/mL. Assuming a Cmax of 0 for the patients with undetectable plasma concentrations, the mean (± SD) Cmax for the group was 0.153 ± 0.241 ng/mL. For the three subjects with measurable plasma concentrations, the Tmax was approximately 6 hours after the application of the omeprazole gel. Following oral administration, the mean Cmax was 391 ± 260 ng/mL at a mean Tmax of 3.1 ± 2.1 hours. This represents approximately a 1,000-fold difference in the achievable plasma concentrations following the same dose by the two routes of administration (Figure 1).
Discussion Pharmaceutical compounding remains an essential but specialized practice within the profession of pharmacy that meets many unmet needs for the delivery of drug therapy to select patient Table 1. Demographics of Study Participants
Variables
Transdermal Group (n = 8)
Oral Groupc ( n = 12)
Age, in years, mean ± SDa
34.3 ± 9.2
35.8 ± 5.1
Genderb
7 men, 1 woman
11 men, 1 woman
7 white, 1 African
9 white, 3 African
Race/ethnicityb
American
American
Weight, in kg, mean ± SDa
79.3 ± 7.0
78.1 ± 16.3
Height, in cm,
175.6 ± 7.6
174.2 ± 8.9
mean ± SDa aNo
significant differences between the two groups (Mann–Whitney rank sum test).
bNo
significant differences between the two groups (Fishers exact test).
cOral
476
data are from Reference 4.
Journal of the American Pharmacists Association
Figure 1. Serum Omeprazole Concentrations Versus Time Following Oral and Transdermal Administration Log–linear plot of the average serum concentration versus time data following topical ( , n = 8) and oral ( , n = 12) administration of omeprazole to healthy volunteers. Each curve starts at the point of the first detectable plasma concentrations. The error bars represent the standard deviation.
•
•
groups. Isolated reports relative to the quality of extemporaneously compounded pharmaceutical preparations has raised several concerns in recent years because of reports of contamination of sterile products leading to patient harm, subpotent or inconsistent preparations, and limited stability data for many compounded products.5–7 These concerns have led to calls for improvement in quality control and the establishment of a uniform set of standards for pharmaceutical compounding.7,8 In addition to the physicochemical and microbiologic quality issues that are essential to compounding quality pharmaceutical products, the pharmacist or physician preparing extemporaneously compounded products must be certain these are safe and efficacious for their intended uses. Topical administration of drugs with the intent of transdermal absorption to the systemic circulation is an attractive, noninvasive route of administration. However, the skin presents a formidable barrier to drug absorption. Factors that may influence the successful use of transdermal drug delivery include the physicochemical and pharmacokinetic properties of the drug, the formulation of the preparation, and the health and physicochemical properties of the stratum corneum at the drug administration site.9 Sastry and Diwan10 compared the gastric ulcer protective effects afforded by transdermal omeprazole with oral administration in Wistar rats using three different gastric ulcer experimental models. The transdermal formulation resulted in superior antiulcer activity and a more rapid onset compared with oral administration of the same dose. The oral and transdermal dose (5 mg) administered to these rats weighing 120–180 grams was huge relative to the www.japha.org
July/August 2005
Vol. 45, No. 4
Transdermal Omeprazole Absorption
dose administered in our study, the topical dose was administered over a large relative surface area (2.5 cm2) on the depilatory-treated dorsal surface of the rat, and a cellophane tape occlusive dressing was applied. In addition, these investigators used a polyethylene glycol (PEG) 400: PEG 4000 (1:1) ointment formulation that is much more lipophilic and occlusive than the PLO gel used in our study. Plasma concentrations of omeprazole were not measured, so whether the results of the study were due to greater drug bioavailability following transdermal absorption is not known. The results of this animal study suggests that transdermal absorption of omeprazole may be a viable route of administration; however, the dose and surface area requirements if comparable in humans would make it impracticable and expensive. Although several different models of varying complexity have been proposed to explain or predict drug penetration through the skin, the two physicochemical properties of the drug most consistently demonstrated to be important predictors of transdermal absorption are molecular weight and lipid solubility, defined by the log octanol-water partition coefficient (log P).11–14 Omeprazole has a molecular weight (MW) of 345.4, indicating a molecular size that should not prevent transdermal absorption, and is comparable with other drugs with acceptable permeability coefficients using an in vitro skin preparation (e.g., indomethacin, MW = 357.8; triamcinolone, MW = 394.4; fentanyl, MW = 336.5; scopolamine, MW = 303.4).13–15 Optimal skin permeability is associated with drugs that are moderately lipophilic (log P ≅ 2–3).9,16 The log P for omeprazole is 2.23.17 Recently described quantitative structure–permeability relationship models estimate a log permeability coefficient (log Kp) in a range of –3.9 to –4.2 for omeprazole.13,14 Using the same methods, drugs that have been successfully developed for topical administration have similar log Kp values (scopolamine, log Kp = –4.30; fentanyl, log Kp = –2.25; nicotine, log Kp = –2.48).14 Therefore, based upon its physicochemical properties, omeprazole is a potential candidate for transdermal drug delivery. Because of limited absorption of drugs across the skin (< 10–15 mcg • cm–2 • hour–1), most successfully developed transdermal drugs are active at blood concentrations of a few ng/mL or less (e.g., nicotine, estradiol, fentanyl).9 Following oral doses of omeprazole 20 mg daily, the maximum plasma concentration on days 1 and 7 were 342 ± 124 ng/mL and 632 ± 138 ng/mL, respectively.18 The elimination half-life of omeprazole in healthy adults is approximately 1 hour.18,19 Based upon the pharmacokinetic properties of omeprazole and the estimated maximal rates of drug delivery across the skin as shown in our study, a transdermal formulation of omeprazole applied to a practical surface area of skin is unlikely to be successful in achieving plasma concentrations of drug comparable to those obtained after oral or intravenous administration. In our study, plasma concentrations of omeprazole following the administration of the gel formulation were only detectable in three of eight subjects. The overall concentrations ranged from below the detectable level of 0.05 ng/mL to 0.552 ng/mL. This Vol. 45, No. 4
July/August 2005
www.japha.org
RESEARCH
represents plasma concentrations approximately 1,000-fold less than what we and others have observed following an equivalent oral dose.4,18 Although the data were inadequate to perform a formal bioequivalence analysis, the transdermal formulation was clearly not bioequivalent to the oral dosage form in this singledose study and this formulation cannot be recommended for clinical use pending further study. The results of this study highlight the importance of evaluating the bioequivalence of extemporaneously compounded pharmaceuticals before their clinical use, especially when nonsystemic routes of administration or previously unproven dosage forms are being prescribed. The expertise to prepare correctly formulated and chemically stable products is a very important aspect of professional compounding, but it is only the first step in assuring the dispensing of a safe and effective pharmaceutical product. There must be adequate and properly designed research to define the bioavailability, bioequivalence, clinical safety, and efficacy of these compounded products before they are dispensed for use in the community.
Limitations Potential limitations of this pilot study were the use of an arbitrarily chosen dose and concentration of omeprazole in the formulation. Since there were no previous studies exploring the transdermal absorption of omeprazole in humans, we elected to study a dose and formulation of omeprazole equivalent to what was being dispensed for clinical use in our community. In addition, transdermal drug absorption may be associated with a long lag time.16 The 8-hour sampling period and single-dose design may have been inadequate to characterize the transdermal absorption of omeprazole from this formulation under steady-state conditions. In the current study, the omeprazole PLO was applied without the use of an occlusive dressing, consistent with how patients were being instructed on its use in our community. The use of an occlusive dressing may have increased the transdermal absorption of omeprazole. The relatively large surface area used for drug administration without an occlusive dressing may have resulted in evaporation of the aqueous portion of the gel vehicle, contributing to the poor transdermal absorption observed. However, in the mathematical model of drug penetration proposed by Okamoto et al.,11 the smaller the volume of solution applied to the surface of the skin (donor solution), the shorter the mean transit time across the interface of the donor solution and the stratum corneum. Therefore, in theory a smaller donor volume secondary to evaporation should facilitate drug penetration. Several modifications, such as increasing the application surface area, increasing the dose or drug concentration, modifying the pH or lipophilicity of the formulation, including a chemical enhancer in the formulation, incorporation of an occlusive dressing, or the use of iontophoresis, electroporation, or Journal of the American Pharmacists Association
477
RESEARCH
Transdermal Omeprazole Absorption
phonophoresis, may improve the absorption of omeprazole across the skin. If an effective topical dosage form is to be developed, considerable additional research will be required to define the optimal formulation, dose, and conditions for administration.
Conclusion The data from this study suggest poor transdermal absorption over 8 hours after the application of a single 40 mg dose of an omeprazole PLO formulation that was used in our community at the time this study was conducted. Although formal bioequivalence analysis was not conducted, this formulation of omeprazole is clearly not bioequivalent to an oral dosage form approved by the Food and Drug Administration.
References 1. Quercia RA, Fan C, Liu X, Chow MS. Stability of omeprazole in an extemporaneously prepared oral liquid. Am J Health Syst Pharm. 1997;54:1833–6. 2. Pilbrant A, Cederberg C. Development of an oral formulation of omeprazole. Scand J Gastroenterol. 1985;108(suppl):113–20. 3. Berner B, John VA. Pharmacokinetic characterization of transdermal delivery systems. Clin Pharmacokinet. 1994;26:121–34. 4. Haas CE, Brazeau D, Cloen D, et al. Cytochrome P-450 mRNA expression in peripheral blood lymphocytes as a predictor of enzyme induction. Eur J Clin Pharmacol. In press. 5. FDA/Center for Drug Evaluation and Research. Report: limited FDA survey of compounded drug products. Accessed at www.fda.gov/cder/ pharmcomp/survey.htm, July 12, 2004.
6. Al-Achi, A, Greenwood R, Koo J. Need for quality-control testing of extemporaneously prepared oral solids. Am J Health Syst Pharm. 1996;53:1194–5. 7. Trissel LA. Compounding our problems—again. Am J Health Syst Pharm. 2003;60:432. 8. Allen LV. Contemporary pharmaceutical compounding. Ann Pharmacother. 2003;37:1526–8. 9. Kalia YN, Merino V, Guy RH. Transdermal drug delivery. Clinical aspects. Dermatol Clin. 1998;16:289–99. 10. Sastry MSP, Diwan PV. Comparative evaluation of orally and transdermally administered omeprazole against experimentally induced gastric ulcers in rats. Indian J Pharmacol. 1993;25:234–6. 11. Okamoto H, Yamashita F, Saito K, Hashida M. Analysis of drug penetration through the skin by the two-layer skin model. Pharm Res. 1989;6:931–7. 12. Potts RO, Guy RH. Predicting skin permeability. Pharm Res. 1992;9:663–9. 13. Cronin MTD, Dearden JC, Moss GP, Murray-Dickson G. Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships. Eur J Pharm Sci. 1999;7:325–30. 14. Moss GP, Cronin MTD. Quantitative structure-permeability relationships for percutaneous absorption: re-analysis of steroid data. Int J Pharm. 2002;238:105–9. 15. Li CJ, Obata Y, Higashiyama K, et al. Effect of 1-O-ethyl-3-butylcyclohexanol on the skin permeation of drugs with different physiochemical characteristics. Int J Pharm. 2003;259:193–8. 16. Lee CK, Uchida T, Kitagawa K, et al. Skin permeability of various drugs with different lipophilicity. J Pharm Sci. 1994;83:562–5. 17. Omeprazole Monograph. The Physical Properties Database (PHYSPROP). North Syracuse, N.Y.: Syracuse Research Corporation. Accessed at http://esc.syrres.com/interkow/webprop.exe?CAS=7359058-6), August 20, 2004. 18. Song JC, Quercia RA, Fan C, et al. Pharmacokinetic comparison of omeprazole capsules and a simplified omeprazole suspension. Am J Health Syst Pharm. 2001;58:689–94. 19. Marier J-F, Dubuc M-C, Drouin E, et al. Pharmacokinetics of omeprazole in healthy adults and in children with gastroesophageal reflux disease. Ther Drug Monit. 2004;26:3–8.
“Iceberg During 2 pm Sunset” • Off the coast of Barrow, Alaska • November 2003 • Carmen “Skip” Clelland
478
Journal of the American Pharmacists Association
www.japha.org
July/August 2005
Vol. 45, No. 4
Omeprazole Absorption from a Compounded Transdermal Formulation in Healthy Volunteers Curtis E. Haas, Lydia Lin, Denise Cloen, Thomas Kufel, Richard Moon, and Valerie Frerichs Received September 22, 2004, and in revised form December 26, 2004. Accepted for publication January 31, 2005.
ABSTRACT Objective: To evaluate the plasma concentration versus time profile of omeprazole following the administration of a compounded transdermal gel formulation in healthy volunteers. Design: Single-dose transdermal pharmacokinetic (PK) study including a comparison with historical data from an oral PK study. Setting: Academic clinical research center. Participants: Eight healthy volunteers between 18 and 50 years of age. Interventions: Omeprazole gel 40 mg (0.8 mL) was applied to the ventral surface of the forearm covering an area of 7 × 15 cm without an occlusive dressing. Blood samples were collected just before application and then at 1, 2, 3, 4, 6, and 8 hours. Plasma concentrations of omeprazole were determined using a validated liquid chromatography tandem mass spectrometry method. Main Outcome Measures: PK parameters (maximal plasma concentration [Cmax], the time of Cmax [Tmax], the area under the omeprazole concentration versus time curve from 0 to 8 hours, the elimination rate constant, and the halflife of the elimination phase) following transdermal administration, compared with historical controls who had received an oral omeprazole 40 mg dose during a previous study. Results: Of the eight volunteers, five had undetectable plasma omeprazole concentrations throughout the 8-hour study, precluding a complete PK analysis. For the three volunteers with detectable plasma omeprazole concentrations, the values ranged from 0.204 to 0.552 ng/mL. Including values of 0 for the patients with undetectable levels, the mean (± SD) Cmax was 0.153 ± 0.241 ng/mL, and the Tmax in patients with detectable levels occurred at approximately 6 hours. The plasma concentrations following transdermal administration were approximately 1,000-fold lower than those observed with oral dosing. Conclusion: Transdermal absorption from a single dose of the omeprazole gel formulation used in this study was poor. This transdermal gel formulation is clearly not bioequivalent to the oral capsule. Keywords: Transdermal drug administration, omeprazole, pharmacokinetics, compounding. J Am Pharm Assoc. 2005;45:473–478.
Vol. 45, No. 4
July/August 2005
www.japha.org
Curtis E. Haas, PharmD, is Assistant Professor, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo; and Director, Clinical Research Center, U.S. Department of Veterans Affairs (VA) Western New York Healthcare System, Buffalo. At the time this study was conducted, Lydia Lin, PharmD, was Student Pharmacist, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, N.Y. Denise Cloen, BSN, was Nurse Manager and Research Coordinator, Clinical Research Center, VA Western New York Healthcare System, Buffalo. Thomas Kufel, MD, is Attending Physician, Department of Medicine, VA Western New York Healthcare System, Buffalo. Richard Moon, PharmD, is Owner, Pharmacy Innovations, Jamestown, N.Y., and Adjunct Clinical Faculty, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, N.Y. Valerie Frerichs, PhD, is Scientific Manager, Core Analytical Laboratory, and Research Assistant Professor, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, N.Y. Correspondence: Curtis E. Haas, PharmD, University at Buffalo, 311 Hochstetter Hall, Buffalo, NY 14260-1200. Fax: 716-645-2886. E-mail: [email protected] Disclosure: Dr. Moon owns a pharmacy that prepared and dispensed the transdermal omeprazole product tested in this study. The authors declare no other conflicts of interest or financial interests in any products or services mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria. Funding: Supported by a grant from Pharmacy Innovations, Jamestown, N.Y. The mass spectrometer was obtained by Shared Instrumentation Grant #S10RR14572 from the National Center for Research Resources, National Institutes of Health. At the time of this study, Dr. Haas and Ms. Cloen were partially supported by the VISN-2 Research Development Fund, U.S. Department of Veterans Affairs.
Journal of the American Pharmacists Association
473
RESEARCH
Transdermal Omeprazole Absorption
O
meprazole is a widely prescribed proton pump inhibitor for the treatment of acid-peptic disorders including peptic ulcer disease, gastroesophageal reflux disease, gastric acid hypersecretory conditions, and dyspepsia. Currently, omeprazole is commercially available in an oral dosage form composed of encapsulated, enteric-coated beads. Since no alternative formulations are available, omeprazole is difficult to administer to patients who have difficulty swallowing or require a pediatric dose. An extemporaneously prepared suspension of omeprazole using a sodium bicarbonate solution has been described for use in patients with nasogastric or nasoenteral feeding tubes.1 The sodium bicarbonate solution is intended to neutralize stomach acid and reduce the amount of drug degradation that occurs before absorption.2 The high sodium content of this formulation is undesirable for fluid-restricted patients or those with significant heart disease. In addition, the bicarbonate-containing suspension has poor palatability, which may lead to nonadherence with this formulation, especially with children. An extemporaneously prepared transdermal gel formulation of omeprazole has been prescribed for use in pediatric patients in some communities with anecdotal reports of good clinical
AT A GLANCE Synopsis: A compounded transdermal gel formulation of omeprazole was clearly not bioequivalent to the oral dosage form approved by the Food and Drug Administration, according to this pharmacokinetic analysis. Using a product that was commonly compounded in their geographic area at the time of this study, the investigators found poor transdermal absorption of omeprazole over 8 hours following a single 40 mg application of drug in eight healthy volunteers. Serum omeprazole concentrations were undetectable in five participants, and levels in the three volunteers with detectable levels were 1,000-fold lower than in a prior study of oral omeprazole 40 mg doses conducted in this laboratory. Analysis: The results of this study highlight the importance of evaluating the bioequivalence of extemporaneously compounded pharmaceuticals before their clinical use, especially when nonsystemic routes of administration or previously unproven dosage forms are being prescribed. The expertise to prepare correctly formulated and chemically stable products is a very important aspect of professional compounding, but it is only the first step in assuring the dispensing of a safe and effective pharmaceutical product. There must be adequate and properly designed research to define the bioavailability, bioequivalence, clinical safety, and efficacy of these compounded products before they are dispensed for use in the community.
474
Journal of the American Pharmacists Association
response, and this product was being compounded by pharmacies in our area at the time this study was conducted, prompting an interest in further evaluating the product. Transdermal delivery of omeprazole, if effective, may offer the advantages of easy administration and avoidance of first-pass metabolism, which may improve the bioavailability of the drug.3 Although the transdermal formulation used in this study has been shown to be chemically stable for at least 3 months (data on file, R. Moon), no plasma concentration or bioequivalence data are available to support the potential clinical utility and routine prescribing of transdermal omeprazole.
Objective The objective of this study was to evaluate the plasma concentration versus time profile of omeprazole following topical administration of a stable gel formulation in healthy adult volunteers. In addition, the data for topical administration was compared with omeprazole plasma concentrations observed following oral administration of the drug to healthy volunteers during a study conducted at the same research center.4
Methods This study was completed at the Clinical Research Center, U.S. Department of Veterans Affairs Western New York Healthcare System (VAWNYHS), and was approved by the VAWNYHS Institutional Review Board. Eight healthy adult volunteers between 18 and 50 years of age, of both genders, and any race were enrolled in the study. Subjects had no history or evidence of chronic or acute medical diseases as documented by medical history, physical examination, and routine laboratory tests. Volunteers were excluded if they met any of the following criteria: a skin condition that might have affected transdermal drug absorption; regular consumption of any prescription or nonprescription medications known to inhibit or induce cytochrome P450 2C19 or 3A4 enzymes; women who were pregnant (a negative urine pregnancy test was required) or lactating; seropositive for human immunodeficiency virus; known hypersensitivity to omeprazole or any component of the transdermal formulation; or a history of alcohol or substance abuse. Alcohol abuse was defined as regular consumption of more than two alcoholic beverages on 5 or more days per week during the past 6 months. Substance abuse was defined as a history of consuming illicit drugs anytime in the past 6 months. All subjects provided written informed consent before any study-related procedures or tests.
Omeprazole Formulation The transdermal omeprazole formulation was a pH-balanced pleuronic lecithin organogel (PLO) prepared by Pharmacy www.japha.org
July/August 2005
Vol. 45, No. 4
Transdermal Omeprazole Absorption
Innovations (Jamestown, N.Y.), which contained a final omeprazole concentration of 50 mg/mL. This product is stable for at least 3 months under refrigeration (data on file, R. Moon).
Study Protocol Each of the participants underwent a physical examination, medical history, comprehensive metabolic panel, and complete blood cell count within 10 days before the study day. The volunteers were instructed to consume a low-fat breakfast and to avoid caffeine-containing beverages and foods on the morning of admission to the Clinical Research Center. Each subject had a 20-gauge intravenous catheter placed in a forearm vein, and then 40 mg (0.8 mL) of omeprazole PLO was applied to the contralateral forearm. The research nurse, using a gloved finger, evenly spread the gel over the ventral surface of the forearm covering a premarked area of 7 × 15 cm. Participants were informed to avoid touching or rubbing the area. Blood samples of 5 mL each were collected in K3EDTA-containing tubes (Becton Dickinson #366452, Franklin Lanes, N.J.) just before the application of the omeprazole PLO and at 1, 2, 3, 4, 6, and 8 hours after the application. Within 30 minutes of collection, the samples were centrifuged at 1,200 g for 15 minutes. The plasma was harvested, divided into 2 aliquots, and then frozen at –80° C until the time of assay.
Historical Controls During a prior study involving 12 healthy volunteers meeting essentially the same inclusion and exclusion criteria used in this study, participants received an intravenous dose of midazolam 0.025 mg/kg, and oral doses of omeprazole 40 mg, caffeine 100 mg, and debrisoquine 10 mg on two separate occasions—before and after 7 days of treatment with rifampin. This study was conducted by the authors at the same research center. The plasma omeprazole concentrations versus time profile and pharmacokinetic parameters for the baseline period before exposure to rifampin were used as historical control data for this study.4 In brief, subjects fasted overnight and then received an oral dose of omeprazole 40 mg (AstraZeneca, Lot 63438) at 8:00 am, along with the other medications listed above. Blood samples were collected just before the medications and 5, 30, and 60 minutes, then 2, 4, 6, and 8 hours after the dose. The blood samples of 10 mL each were collected using an EDTA-containing tube, centrifuged at 1,200 g for 15 minutes, and the plasma harvested and frozen at –80o C until the time of assay.
Assay Methods Plasma omeprazole concentrations were determined using a method developed for the simultaneous quantification of midazolam, omeprazole, and their primary hydroxy metabolites in plasma using high-performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). In brief, 50 microliters of Vol. 45, No. 4
July/August 2005
www.japha.org
RESEARCH
80% methanol:20% ammonium hydroxide adjusted to pH 8.2 with formic acid (v:v) was added to 250 microliters of each of the control and unknown samples. We used 300 microliters of each calibration standard for analysis. After 50 microliters of the internal standard (flurazepam 2 mcg/mL) was added to all samples, controls and standards, 3 mL of ethylacetate:hexane (75:25, [v:v]) was added for extraction. Samples were shaken on high speed (Eberbach Instrument Apparatus, Ann Arbor, Mich.) for approximately 25 minutes and then centrifuged for 10 minutes at 3,000 g. The supernatant was removed, placed into a clean test tube and evaporated to dryness with air using a Zymark Turbo Vap LV (Hopkinton, Mass.) set at 50° C for 30 minutes. Samples were reconstituted in 100 microliters of the mobile phase mix and injected into the LC/MS/MS system for analysis. The LC/MS/MS system consisted of an Agilent 1100 series autosampler (Foster City, Calif.), an Agilent 1100 series pump, an Agilent 1100 series degasser, and an Applied Biosystems PE/Sciex, API 3000 mass spectrometer (Foster City, Calif.) equipped with a Turbo-ionspray source. The system was controlled through Analyst Software, version 1.1 (Applied Biosystems, Foster City, Calif.). Analytes were separated on a Waters Symmetry Shield RP8 (Milford, Mass.), which was 3.0 mm inner diameter by 150 mm in length and packed with 5 micrometer-sized particles. The injection volume was 20 microliters. Isocratic elution using a mobile phase mix of 35% 5 mM ammonium hydroxide/formic acid pH 8.2 and 65% methanol, delivered at a rate of 400 microliters/minute, was used for separation. Before entering the electrospray source housing, the flow was split 1:1 using a PEEK tubing splitter (Upchurch Scientific, Oak Harbor, Wash.), with one split line directed to waste and the other to the Turbo-ionspray source. Optimal parameters for MS/MS detection of the analytes were determined, with positive ionization providing the greatest detectability for all four analytes. The working calibration range used for this method was 0.4 to 100 ng/mL, with limits of detection of ≤50 pg/mL, for each of the analytes. The intraday and interday coefficients of variation were between 1.6% and 11% for all four analytes.
Data Analysis When adequate data were available, a standard noncompartmental pharmacokinetic (PK) analysis of the serum concentration versus time data was conducted for both the transdermal gel and oral protocols. The following PK parameters were estimated when possible: maximal plasma concentration (Cmax), the time of Cmax (Tmax), the area under the omeprazole concentration versus time curve from 0 to 8 hours (AUC0–8h), the elimination rate constant (ke), and the half-life of the elimination phase (t1/2) using WinNonlin software (version 4.0, Pharsight, Inc., Cary, N.C.). The demographic characteristics of the two study groups were compared using Mann–Whitney rank sum test or Fishers exact test as appropriate for the data. All pharmacokinetic and demographic parameters are presented using descriptive statistics. Journal of the American Pharmacists Association
475
RESEARCH
Transdermal Omeprazole Absorption
Results Eight healthy adult volunteers were enrolled, and they completed the study on a single day. The demographic characteristics of participants and historical controls are shown in Table 1. Six of the eight participants in the current study took part in the previous oral study. Five of the eight participants receiving topical gel had no detectable omeprazole plasma concentrations throughout the 8hour study, while the other three had very low concentrations detectable at only a few time points. Therefore, the intended noncompartmental pharmacokinetic analysis for the transdermal data was not possible. In the three patients with detectable levels, plasma omeprazole concentrations ranged from 0.204 to 0.552 ng/mL, with a mean (± SD) Cmax for these three participants of 0.525 ± 0.032 ng/mL. Assuming a Cmax of 0 for the patients with undetectable plasma concentrations, the mean (± SD) Cmax for the group was 0.153 ± 0.241 ng/mL. For the three subjects with measurable plasma concentrations, the Tmax was approximately 6 hours after the application of the omeprazole gel. Following oral administration, the mean Cmax was 391 ± 260 ng/mL at a mean Tmax of 3.1 ± 2.1 hours. This represents approximately a 1,000-fold difference in the achievable plasma concentrations following the same dose by the two routes of administration (Figure 1).
Discussion Pharmaceutical compounding remains an essential but specialized practice within the profession of pharmacy that meets many unmet needs for the delivery of drug therapy to select patient Table 1. Demographics of Study Participants
Variables
Transdermal Group (n = 8)
Oral Groupc ( n = 12)
Age, in years, mean ± SDa
34.3 ± 9.2
35.8 ± 5.1
Genderb
7 men, 1 woman
11 men, 1 woman
7 white, 1 African
9 white, 3 African
Race/ethnicityb
American
American
Weight, in kg, mean ± SDa
79.3 ± 7.0
78.1 ± 16.3
Height, in cm,
175.6 ± 7.6
174.2 ± 8.9
mean ± SDa aNo
significant differences between the two groups (Mann–Whitney rank sum test).
bNo
significant differences between the two groups (Fishers exact test).
cOral
476
data are from Reference 4.
Journal of the American Pharmacists Association
Figure 1. Serum Omeprazole Concentrations Versus Time Following Oral and Transdermal Administration Log–linear plot of the average serum concentration versus time data following topical ( , n = 8) and oral ( , n = 12) administration of omeprazole to healthy volunteers. Each curve starts at the point of the first detectable plasma concentrations. The error bars represent the standard deviation.
•
•
groups. Isolated reports relative to the quality of extemporaneously compounded pharmaceutical preparations has raised several concerns in recent years because of reports of contamination of sterile products leading to patient harm, subpotent or inconsistent preparations, and limited stability data for many compounded products.5–7 These concerns have led to calls for improvement in quality control and the establishment of a uniform set of standards for pharmaceutical compounding.7,8 In addition to the physicochemical and microbiologic quality issues that are essential to compounding quality pharmaceutical products, the pharmacist or physician preparing extemporaneously compounded products must be certain these are safe and efficacious for their intended uses. Topical administration of drugs with the intent of transdermal absorption to the systemic circulation is an attractive, noninvasive route of administration. However, the skin presents a formidable barrier to drug absorption. Factors that may influence the successful use of transdermal drug delivery include the physicochemical and pharmacokinetic properties of the drug, the formulation of the preparation, and the health and physicochemical properties of the stratum corneum at the drug administration site.9 Sastry and Diwan10 compared the gastric ulcer protective effects afforded by transdermal omeprazole with oral administration in Wistar rats using three different gastric ulcer experimental models. The transdermal formulation resulted in superior antiulcer activity and a more rapid onset compared with oral administration of the same dose. The oral and transdermal dose (5 mg) administered to these rats weighing 120–180 grams was huge relative to the www.japha.org
July/August 2005
Vol. 45, No. 4
Transdermal Omeprazole Absorption
dose administered in our study, the topical dose was administered over a large relative surface area (2.5 cm2) on the depilatory-treated dorsal surface of the rat, and a cellophane tape occlusive dressing was applied. In addition, these investigators used a polyethylene glycol (PEG) 400: PEG 4000 (1:1) ointment formulation that is much more lipophilic and occlusive than the PLO gel used in our study. Plasma concentrations of omeprazole were not measured, so whether the results of the study were due to greater drug bioavailability following transdermal absorption is not known. The results of this animal study suggests that transdermal absorption of omeprazole may be a viable route of administration; however, the dose and surface area requirements if comparable in humans would make it impracticable and expensive. Although several different models of varying complexity have been proposed to explain or predict drug penetration through the skin, the two physicochemical properties of the drug most consistently demonstrated to be important predictors of transdermal absorption are molecular weight and lipid solubility, defined by the log octanol-water partition coefficient (log P).11–14 Omeprazole has a molecular weight (MW) of 345.4, indicating a molecular size that should not prevent transdermal absorption, and is comparable with other drugs with acceptable permeability coefficients using an in vitro skin preparation (e.g., indomethacin, MW = 357.8; triamcinolone, MW = 394.4; fentanyl, MW = 336.5; scopolamine, MW = 303.4).13–15 Optimal skin permeability is associated with drugs that are moderately lipophilic (log P ≅ 2–3).9,16 The log P for omeprazole is 2.23.17 Recently described quantitative structure–permeability relationship models estimate a log permeability coefficient (log Kp) in a range of –3.9 to –4.2 for omeprazole.13,14 Using the same methods, drugs that have been successfully developed for topical administration have similar log Kp values (scopolamine, log Kp = –4.30; fentanyl, log Kp = –2.25; nicotine, log Kp = –2.48).14 Therefore, based upon its physicochemical properties, omeprazole is a potential candidate for transdermal drug delivery. Because of limited absorption of drugs across the skin (< 10–15 mcg • cm–2 • hour–1), most successfully developed transdermal drugs are active at blood concentrations of a few ng/mL or less (e.g., nicotine, estradiol, fentanyl).9 Following oral doses of omeprazole 20 mg daily, the maximum plasma concentration on days 1 and 7 were 342 ± 124 ng/mL and 632 ± 138 ng/mL, respectively.18 The elimination half-life of omeprazole in healthy adults is approximately 1 hour.18,19 Based upon the pharmacokinetic properties of omeprazole and the estimated maximal rates of drug delivery across the skin as shown in our study, a transdermal formulation of omeprazole applied to a practical surface area of skin is unlikely to be successful in achieving plasma concentrations of drug comparable to those obtained after oral or intravenous administration. In our study, plasma concentrations of omeprazole following the administration of the gel formulation were only detectable in three of eight subjects. The overall concentrations ranged from below the detectable level of 0.05 ng/mL to 0.552 ng/mL. This Vol. 45, No. 4
July/August 2005
www.japha.org
RESEARCH
represents plasma concentrations approximately 1,000-fold less than what we and others have observed following an equivalent oral dose.4,18 Although the data were inadequate to perform a formal bioequivalence analysis, the transdermal formulation was clearly not bioequivalent to the oral dosage form in this singledose study and this formulation cannot be recommended for clinical use pending further study. The results of this study highlight the importance of evaluating the bioequivalence of extemporaneously compounded pharmaceuticals before their clinical use, especially when nonsystemic routes of administration or previously unproven dosage forms are being prescribed. The expertise to prepare correctly formulated and chemically stable products is a very important aspect of professional compounding, but it is only the first step in assuring the dispensing of a safe and effective pharmaceutical product. There must be adequate and properly designed research to define the bioavailability, bioequivalence, clinical safety, and efficacy of these compounded products before they are dispensed for use in the community.
Limitations Potential limitations of this pilot study were the use of an arbitrarily chosen dose and concentration of omeprazole in the formulation. Since there were no previous studies exploring the transdermal absorption of omeprazole in humans, we elected to study a dose and formulation of omeprazole equivalent to what was being dispensed for clinical use in our community. In addition, transdermal drug absorption may be associated with a long lag time.16 The 8-hour sampling period and single-dose design may have been inadequate to characterize the transdermal absorption of omeprazole from this formulation under steady-state conditions. In the current study, the omeprazole PLO was applied without the use of an occlusive dressing, consistent with how patients were being instructed on its use in our community. The use of an occlusive dressing may have increased the transdermal absorption of omeprazole. The relatively large surface area used for drug administration without an occlusive dressing may have resulted in evaporation of the aqueous portion of the gel vehicle, contributing to the poor transdermal absorption observed. However, in the mathematical model of drug penetration proposed by Okamoto et al.,11 the smaller the volume of solution applied to the surface of the skin (donor solution), the shorter the mean transit time across the interface of the donor solution and the stratum corneum. Therefore, in theory a smaller donor volume secondary to evaporation should facilitate drug penetration. Several modifications, such as increasing the application surface area, increasing the dose or drug concentration, modifying the pH or lipophilicity of the formulation, including a chemical enhancer in the formulation, incorporation of an occlusive dressing, or the use of iontophoresis, electroporation, or Journal of the American Pharmacists Association
477
RESEARCH
Transdermal Omeprazole Absorption
phonophoresis, may improve the absorption of omeprazole across the skin. If an effective topical dosage form is to be developed, considerable additional research will be required to define the optimal formulation, dose, and conditions for administration.
Conclusion The data from this study suggest poor transdermal absorption over 8 hours after the application of a single 40 mg dose of an omeprazole PLO formulation that was used in our community at the time this study was conducted. Although formal bioequivalence analysis was not conducted, this formulation of omeprazole is clearly not bioequivalent to an oral dosage form approved by the Food and Drug Administration.
References 1. Quercia RA, Fan C, Liu X, Chow MS. Stability of omeprazole in an extemporaneously prepared oral liquid. Am J Health Syst Pharm. 1997;54:1833–6. 2. Pilbrant A, Cederberg C. Development of an oral formulation of omeprazole. Scand J Gastroenterol. 1985;108(suppl):113–20. 3. Berner B, John VA. Pharmacokinetic characterization of transdermal delivery systems. Clin Pharmacokinet. 1994;26:121–34. 4. Haas CE, Brazeau D, Cloen D, et al. Cytochrome P-450 mRNA expression in peripheral blood lymphocytes as a predictor of enzyme induction. Eur J Clin Pharmacol. In press. 5. FDA/Center for Drug Evaluation and Research. Report: limited FDA survey of compounded drug products. Accessed at www.fda.gov/cder/ pharmcomp/survey.htm, July 12, 2004.
6. Al-Achi, A, Greenwood R, Koo J. Need for quality-control testing of extemporaneously prepared oral solids. Am J Health Syst Pharm. 1996;53:1194–5. 7. Trissel LA. Compounding our problems—again. Am J Health Syst Pharm. 2003;60:432. 8. Allen LV. Contemporary pharmaceutical compounding. Ann Pharmacother. 2003;37:1526–8. 9. Kalia YN, Merino V, Guy RH. Transdermal drug delivery. Clinical aspects. Dermatol Clin. 1998;16:289–99. 10. Sastry MSP, Diwan PV. Comparative evaluation of orally and transdermally administered omeprazole against experimentally induced gastric ulcers in rats. Indian J Pharmacol. 1993;25:234–6. 11. Okamoto H, Yamashita F, Saito K, Hashida M. Analysis of drug penetration through the skin by the two-layer skin model. Pharm Res. 1989;6:931–7. 12. Potts RO, Guy RH. Predicting skin permeability. Pharm Res. 1992;9:663–9. 13. Cronin MTD, Dearden JC, Moss GP, Murray-Dickson G. Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships. Eur J Pharm Sci. 1999;7:325–30. 14. Moss GP, Cronin MTD. Quantitative structure-permeability relationships for percutaneous absorption: re-analysis of steroid data. Int J Pharm. 2002;238:105–9. 15. Li CJ, Obata Y, Higashiyama K, et al. Effect of 1-O-ethyl-3-butylcyclohexanol on the skin permeation of drugs with different physiochemical characteristics. Int J Pharm. 2003;259:193–8. 16. Lee CK, Uchida T, Kitagawa K, et al. Skin permeability of various drugs with different lipophilicity. J Pharm Sci. 1994;83:562–5. 17. Omeprazole Monograph. The Physical Properties Database (PHYSPROP). North Syracuse, N.Y.: Syracuse Research Corporation. Accessed at http://esc.syrres.com/interkow/webprop.exe?CAS=7359058-6), August 20, 2004. 18. Song JC, Quercia RA, Fan C, et al. Pharmacokinetic comparison of omeprazole capsules and a simplified omeprazole suspension. Am J Health Syst Pharm. 2001;58:689–94. 19. Marier J-F, Dubuc M-C, Drouin E, et al. Pharmacokinetics of omeprazole in healthy adults and in children with gastroesophageal reflux disease. Ther Drug Monit. 2004;26:3–8.
“Iceberg During 2 pm Sunset” • Off the coast of Barrow, Alaska • November 2003 • Carmen “Skip” Clelland
478
Journal of the American Pharmacists Association
www.japha.org
July/August 2005
Vol. 45, No. 4