Rectal Administration of Ibuprofen: Comparison of Enema and Suppository Form

Abstract

Ibuprofen is a widely used and well-tolerated analgesic and antipyretic. It is desirable to have a formulation with a rapid rate of absorption because it is required for rapid pain relief and temperature reduction. Previous studies have described the pharmacokinetic profiles of ibuprofen suppository and the mean peak times of ibuprofen suppository were around 1.8 hours, indicating a slower rate of absorption. The aim of this study is to compare the pharmacokinetic parameters of rectal administration of ibuprofen between enema and suppository form in order to provide evidence for the faster absorption rates of ibuprofen enema. This study was a phase-1 clinical study, open-label, randomized and two-way crossover with one-week washout period comparing the absorption profile of equal dose of ibuprofen administered rectally in two treatment phases: ibuprofen suppository and enema. Blood samples were collected post dose for pharmacokinetic analyses. T_max was analyzed using a Wilcoxon matched paired test. A standard ANOVA model, appropriate for bioequivalence studies was used and ratios of 90% confidence intervals were calculated. This study showed that T_max for ibuprofen enema was less than half that of ibuprofen suppository (median 40 min vs. 90 min, respectively; p-value=0.0003). C_max and AUC_0–12 for ibuprofen enema were bioequivalent to ibuprofen suppository, as the ratio of test/reference=104.52%, 90% CI 93.41–116.95% and the ratio of test/reference=98.12%, 90%CI 93.34–103.16%, respectively, which fell within 80–125% bioequivalence limit. The overall extent of absorption was similar to the both, which were all well tolerated. In terms of T_max, Ibuprofen enema was absorbed twice as quickly as from ibuprofen suppository. Therefore it is expected that an ibuprofen enema may provide faster onset of analgesic and antipyretic benefit.

Key words

enema - fever - ibuprofen - rectal

Introduction

Fever is very common in children. Parents fear greatly about the effects of fever on their children, and the treatment of febrile illness with antipyretic drugs such as paracetamol, ibuprofen, or giving both together is widespread [1] [2]. Ibuprofen is a non-steroidal anti-inflammatory drug which serves as an analgesic, antipyretic and anti-inflammatory agent. Although the anti-inflammatory properties of ibuprofen may be weaker than other NSAIDs, it has an important analgesic and antipyretic role. Its mode of action may be related to prostaglandin synthesis inhibition. Prostaglandins have an important role in the production of pain and fever [3] [4] [5] [6].

For analgesics and antipyretics, the initial increase in plasma concentration following drug administration is a critical factor in identifying the time to onset of pain relief and temperature reduction [7]. Reckitt Benckiser Healthcare International (Hull, UK) has published their research about development of oral formulations for ibuprofen with faster absorption than standard ibuprofen. The first is a sodium ibuprofen formulation and the second is ibuprofen acid incorporating poloxamer to increase the rate of dissolution and more rapid absorption. The mean peak times of sodium ibuprofen, ibuprofen acid incorporating poloxamer, and standard ibuprofen after oral administration were 35 min, 75 min, and 90 min, respectively [8] [9].

An alternative route of ibuprofen administration other than orally may be necessary, especially among infants and children who vomit or refuse taking the drug. In such cases, rectal administration has been recommended as an alternative route. Ibuprofen suppositories for children were developed and are being marketed in Indonesia and several European countries. Previous studies have described the pharmacokinetic profiles of ibuprofen suppository and the mean peak times of ibuprofen suppository were around 1.8 hours, indicating a slower rate of absorption [10] [11] [12] [13].

For administration of ibuprofen per rectum, the enema form seems to be more suitable than suppository because of its greater contact surface, easy preparation and storage [14]. Ethical considerations prevent us from generating pharmacokinetic data in pediatric population with the assumption that the adult observations can be extrapolated to children [15]. In the present study, we performed a randomized clinical study to compare the pharmacokinetic parameters of rectal administration of ibuprofen between enema and suppository form in healthy volunteers, in order to provide supportive evidence for the faster absorption rates of ibuprofen enema formulation.

Materials and Methods

Study design

The study protocol, participant information and consent documents were reviewed and approved by the committee of the medical research ethics, faculty of medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia (Approval number: KET-62/UN2.F1/ETIK/PPM.00.02/2020) and by the National Agency of Drug and Food Control Republic of Indonesia (Number: RG.01.02.321.06.20.00062/UB). A phase-1 clinical study, open label, single dose, randomized, two-way crossover with 1-week study was conducted in accordance with Good Clinical Practice (GCP) and with the ethical principles of the Declaration of Helsinki for biomedical research involved human subjects.

Study subjects and blood sampling

Eighteen healthy volunteers were enrolled after passing a clinical screening procedure (medical history and physical examination, ECG, laboratory test: hemoglobin, hematocrit, leukocyte, platelet, leucocyte differential, erythrocyte, sGPT, sGOT, alkaline phosphatase, total bilirubin, total protein, albumin, globulin, glucose, ureum, creatinine, and urinalysis, pregnancy test, HbsAg, anti HCV, anti-HIV and drug abuse test). They were of both sexes between 18–55 years of age and with a normal BMI (18–25 kg/m²). Individual with potentially hypersensitive to ibuprofen, and those who have hemorrhoids or other diseases of the rectum and who had any gastrointestinal tract problem were excluded from the study. Based on data from previous studies, the intra-subject coefficient of variation were approximately 19.4% for AUC [12]. The sample size n=18 subjects is sufficient to ensure power of 80% for correctly concluding bioequivalence under the following assumption: α=0.05, 0.95<µ_T/µ_R<1.05 and an intra-subject coefficient of variation of 20% [16].

Subjects who met the inclusion criteria were randomly divided into two groups; group A received 125 mg ibuprofen suppository (Proris produced by Pharos, Indonesia) and group B received 125 mg ibuprofen enema (Iprox produced by Novell Pharmaceutical Laboratories, Indonesia). Before drug administration, subjects were asked to empty their rectum. At 7.00 am each single rectal dose of ibuprofen 125 mg, either as suppository or enema formulations, was administered by study nurses in prone position. After dosing, all subjects were kept in prone position for at least 1 hour. Approximately 5 mL of venous blood samples were collected in Li-Heparin blood collection tube at the following times: pre-dose, at 20, 40 min, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 hours after drug administration for pharmacokinetic analyses.

For safety measurement, subjects were monitored for the presence of adverse events. Vital sign measurements including blood pressure, heart rate, respiratory rate and body temperature measurement were performed at pre-dose, 1, 2, 3, and 12 hours after drug administration. At the time of admission, departure and return visit, subjects were asked standard probe of questions regarding the onset of new health problems.

Bioanalytical methods

Plasma concentration of ibuprofen was determined using an LC-MS/MS method with TurboIonSpray mode. The bioanalytical method had been validated according to the Guideline on Bionalytical Validation from the European Medicines Agency (EMA). Briefly, a 250 µL of plasma was added with internal standard, 50 µL of hydrochloric acid 1 N and 1 mL of tert-butyl methyl and vortex mixed for 1 min. The mixture was centrifuged at 3000 rpm for 10 min. After centrifugation, 1 mL of organic phase was removed evaporated under vacuum for 5 min. The dry residue was diluted and injected into the LC-MS/MS system.

Pharmacokinetic and statistical analysis

Peak ibuprofen plasma concentration (C_max) and time to attain this concentration (T_max) were observed directly from each plasma concentration vs. time curve. The area under the plasma concentration (AUC_0–12) was calculated by applying the linear trapezoidal rule. T_max was analyzed using a Wilcoxon matched paired test. For the AUC_0–12, and C_max data, analysis of variance, including the terms for sequence, subject nested within sequence, period and formulation, were carried out on logarithmically transformed data. Point estimates and 90% CIs for the difference between each suppository treatment and enema treatment were constructed and then back transformed to give estimates of the ratio. Equivtest version 2.0 and SAS version 9.1.3 were used for statistical calculations.

Results and Discussion

The efficacy and safety of ibuprofen has been demonstrated in children. It was found as efficacious as acetaminophen in fever reduction in children. Ibuprofen suppositories for children were used in clinical practices as an alternative route. The rapid onset of action is a desirable attribute of analgesics and antipyretics. Plasma concentrations of ibuprofen are highly correlated with the level of analgesia; therefore the more rapidly ibuprofen is absorbed to achieve therapeutic concentrations, the early onset of analgesia will occur. The rectal route of ibuprofen suppository has been proven efficacious in Indonesian children [10]. In the previous studies with the suppository form, the T_max occurred at 1.79±0.33 h and 1.85±0.34 h, indicating a slower rate of absorption [11] [12]. Rectal delivery system by enema has been developed for both systemic and local effects. Ibuprofen enema was developed as an alternative to ibuprofen suppository. Enema are mainly used for delivering drugs where rapid onset is required such as analgesic, antipyretics and management of seizure, for example paracetamol enema (Dumin) and diazepam enema (Stesolid), both manufactured by Actavis. Ibuprofen is a Nonsteroidal anti-inflammatory drugs that used primarily as analgesics and antipyretics and rapid onset are preferred. Besides that, enema formulation is easier to be transported and stored than suppository because some suppositories need to be stored in refrigerator (2–8 ^°C) to prevent melting.

The aim of this study is to compare the pharmacokinetic parameters of rectal administration of ibuprofen between enema and suppository form in order to provide evidence for the faster absorption rates of ibuprofen enema. A total of 18 healthy subjects who met the inclusion criteria were enrolled and randomized to treatment, but only 16 subjects completed the study. Two subjects withdrew from the study before period I. The mean age of subjects was 33.3 years and the mean BMI was 22.4 kg/m². This phase-1 study was conducted in healthy adult subjects since collection of the pharmacokinetic data in children is difficult due to ethical issues [15]. As described in the Pediatric Research Equity Act of 2007 “if the effects of the drug are sufficiently similar in adults and pediatric patients, it may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults [17]. However, it is expected that these results would be generalizable, as a previous study demonstrated that the pharmacokinetic ibuprofen are only minimally influenced by age [18]. Further pharmacokinetic modeling approach should be performed to predict the pharmacokinetic of ibuprofen enema in children.

[Figure 1] shows the mean plasma concentrations of the ibuprofen enema and suppository. The mean value of T_max, C_max and AUC_0–12 are presented in [Table 1]. Administration of ibuprofen enema resulted in a significantly shorter time to peak plasma concentration (T_max), compared with ibuprofen suppository (median 0.67 h vs. 1.5 h or 40 min vs. 90 min), respectively; p-value=0.0003). It is significantly faster (i.e. it was absorbed twice as fast as ibuprofen suppository). The statistical comparison of peak time (T_max) of ibuprofen in each subject is shown in [Table 2]. The enema form seemed to be absorbed more rapidly than the suppository form, which was demonstrated by earlier time to peak levels. These may be the results of greater contact surface area of enema form and issue of drug release and dissolution of enema form is circumvented.

Fig. 1 The mean plasma concentrations of the ibuprofen enema and suppository.

Table 1 Mean pharmacokinetic parameters of ibuprofen suppository vs. enema.

Parameter	Enema	Suppository
Tmax (h)	0.90±0.44	1.69±0.53
AUC0–12 (μg.h/mL)	49.79±10.10	50.28±7.40
Cmax (μg/mL)	13.77±3.03	13.00±2.11

Table 2 Statistical comparison of T_max of ibuprofen.

Subject No.	Enema (h)	Suppository (h)	Difference
S01	1.50	1.25	0.25
S02	0.33	1.50	−1.17
S03	0.67	2.00	−1.33
S04	0.67	1.50	−0.83
S05	1.25	2.50	−1.25
S06	2.00	2.50	−0.50
S07	0.67	1.25	−0.58
S08	0.67	2.50	−1.83
S10	1.00	1.50	−0.50
S11	1.00	1.25	−0.25
S12	0.33	2.50	-2.17
S13	0.67	1.50	−0.83
S14	0.67	1.50	−0.83
S15	1.00	1.00	0.00
S16	0.67	1.50	−0.83
S17	1.25	1.25	0.00
Sum	14.33	27.00	−12.67
Arithmetic mean	0.90	1.69	−0.79
SD	0.44	0.53	0.66
Minimum	0.33	1.00
Maximum	2.00	2.50
Median	0.67	1.50
Geomean	0.80	1.62
Matched Signed Rank Test
Test Value		p-value
1.5000		0.0003

The mean plasma concentrations of ibuprofen 20 min. after drug administration were 11.80 μg/mL and 2.29 μg/mL for ibuprofen enema and ibuprofen suppository, respectively. The mean plasma concentrations of ibuprofen 40 min after drug administration were 12.75 μg/mL and 6.58 μg/mL for ibuprofen enema and ibuprofen suppository, respectively. Previous studies that assessed plasma ibuprofen levels at early time points of onset suggested that a level of 5–10 μg/mL is sufficient for the onset of pain relief. [19] In previous study, the onset of antipyretic effects of ibuprofen had been evaluated. The study showed that there was an hour to 3 hour delay between peak ibuprofen plasma concentration and peak temperature decrement after an ibuprofen dose. The peak antipyresis effect was achieved at 2 hours, when the plasma concentration had decreased considerably below the peak level. [20]

The C_max results obtained for ibuprofen enema and ibuprofen suppository were 13.77±3.03 μg/mL and 13.00±2.11 μg/mL, respectively. The ratio of the enema/suppository was 104.52% with 90% CIs of 93.41–116.95%. For overall extent of absorption, both were equivalent, with enema/suppository ratios of AUC_0–12 very close to 100%. The AUC_0–12 values were 49.83 μg.h/mL and 50.31 μg.h/mL for enema and suppository, respectively. [Table 3] shows the statistical analysis of AUC_0–12 and C_max. There were no serious adverse events occurred in this study.

Table 3 Statistical analysis of AUC_0–12 and C_max.

Parameter	Enema (Geometric mean)	Suppository (Geometric mean)	Ratio enema/suppository (%)	90% CI
Cmax	13.42	12.84	104.52	93.41–116.95
AUC0–12	48.84	49.76	98.12	93.34–103.16

The confidence interval of the ratio of the enema/suppository for AUC_0–12 and C_max were within 80–125% limit specified in the EMA and FDA guidelines. The differences between the ibuprofen enema and suppository would not be expected to result in adverse clinical consequences terms of either safety or efficacy. In support of this, there was no clinically significant safety finding in this study.

Conclusion

In conclusion, the ibuprofen enema is equivalent to the ibuprofen suppository in terms of extent of absorption, but its rate of absorption, as measured by T_max is significantly faster (i. e. it was absorbed twice as fast as ibuprofen suppository). Therefore it is expected that an ibuprofen enema may provide faster onset of analgesic and antipyretic benefits.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgement

This work was supported by PT. Novell Pharmaceutical Laboratories, Indonesia.

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Publication History

Received: 24 March 2021

Accepted: 28 July 2021

Article published online:
20 August 2021