Journal of Pharmaceutical Research International

30(1): 1-10, 2019; Article no.JPRI.51675

ISSN: 2456-9119
(Past name: British Journal of Pharmaceutical Research, Past ISSN: 2231-2919,
NLM ID: 101631759)

Formulation, in vitro and Bioavailability

Assessments of Ranitidine Rectal Suppositories
Khaled Shalaby1,2, Ahmed M. Samy2, Alaa Kassem2, Mohamed F. Ibrahim2,
Nabil K. Alruwaili1, Hazim M. Ali3 and Mohammed Elmowafy1,2*
1
Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, P.O. Box 2014,
Saudi Arabia.
2
Department of Pharmaceutics and Ind. Pharmacy, Faculty of Pharmacy (Boys), Al-Azhar University,
Nasr City, Cairo, Egypt.
3
Department of Chemistry, College of Science, Jouf University, Sakaka, Saudi Arabia.

Authors’ contributions

This work was carried out in collaboration among all authors. Authors KS, AMS and AK designed the
studies and performed the statistical analysis. Authors MFI, NKA and ME wrote the protocol and wrote
the first draft of the manuscript. Author HMA managed the analyses of HPLC. Author ME managed
the literature searches. All authors read and approved the final manuscript.

Article Information

DOI: 10.9734/JPRI/2019/v30i130262
Editor(s):
(1) Dr. R. Deveswaran, Associate Professor and Head, Drug Design and Development Centre, Faculty of Pharmacy,
M. S. Ramaiah University of Applied Sciences, India.
Reviewers:
(1) Md. Anwarul Haque, University of Tsukuba, Japan.
(2) Camilo Torres-Serna, Universidad Santiago de Cali, Colombia.
(3) Michael Bordonaro, Geisinger Commonwealth School of Medicine, USA.
(4) Syed Umer Jan, University of Balochistan, Pakistan.
Complete Peer review History: https://sdiarticle4.com/review-history/51675

Received 13 July 2019

Accepted 30 September 2019
Original Research Article
Published 10 October 2019

ABSTRACT

The objective of the current work was to develop and evaluate suppository dosage form in order to
improve ranitidine bioavailability as a substitute to the oral administration. Suppocire (different
grades), Witepsol W25 and polyethylene glycol (PEG) were used as suppository bases and
prepared by molding method. The prepared formulations were examined for hardness,
disintegration time, melting point, content uniformity, drug release, stability and bioavailability. The
hardness ranged from 3.82 to 12.53 kg and disintegration time from 13.32 to 28.22 min. The
melting points of fatty bases had values from 33.94 to 36.82±0.36ºC while PEG based
suppositories melting points were directly proportional chain length. Higher content uniformity was
_____________________________________________________________________________________________________

*Corresponding author: E-mail: [email protected];

 Shalaby et al.; JPRI, 30(1): 1-10, 2019; Article no.JPRI.51675

observed in PEG based suppositories due to easy incorporation of RT into water soluble base.
Release was affected by hydroxyl value and molecular weight (in cases of fatty and PEG bases
respectively). All formulations were relatively stable after 12 months. In vivo studies of all
formulations exhibited double peak phenomena. PEG based formula (S8) showed significant higher
Cmax (10.05±1 μg/ml) and AUC0-12 (58.313±3.9 µg.h/mL) than fatty bases and oral solution. In
conclusion, rectal administration of S8 could be prepared as an alternative to the oral dosage form
to improve bioavailability and overcome the first-pass metabolism.

Keywords: Ranitidine; rectal suppositories; bioavailability.

1. INTRODUCTION either dissolve in the rectal fluid (in case of water

soluble base as polyethylene glycol; PEG) or
Ranitidine hydrochloride (RT) is as a reversible melt on the mucous layer (in case of oleaginous
histamine H2-receptors blocker with a limited base). The lipid–water partition coefficient of a
effect on H1-receptors [1,2]. RT is indicated in drug can particularly determine the choice of the
peptic ulcer, gastroesophageal reflux disease suppository base and in turn influence drug
(GERD) and pathological hypersecretory release from that base. Lipophilic drug which has
conditions (e.g., Zollinger–Ellison syndrome) [3]. high affinity to fatty suppository base escapes
According to Biopharmaceutical classification slower than hydrophilic substance from fatty
scheme (BCS), RT is categorized as class III bases. On the other hand, water soluble bases
drug of high solubility (aqueous solubility is dissolve in the anorectal fluids and release both
nearly 660 mg/ml) and low permeability through water-soluble and oil-soluble drugs [11].
biological membranes (log P ~ 0.2) meaning that
it is permeation rate limited drug. As the So, the aim of the present work was to formulate
molecular weight of RT is relatively small (350 RT in different suppository bases. The prepared
gm/mol) [4,5], paracellular route represents the formulations were examined for physicochemical
majority of the percentage absorbed. However, characteristics and in vitro RT release. Selected
the biological half life is relatively short (2.5-3.5 formulations were subjected to accelerated and
h) and relative bioavailability is nearly 50% of shelf stability studies. Depending upon the
administered dose [6] due to extensive first pass obtained results, selected formulations were
metabolism [3]. tested for in vivo bioavailability and compared
with RT oral solution.
Oral route of administration is considered as the
most common and preferable route owing to 2. MATERIALS AND METHODS
ease of administration, patient compliance and
flexibility in formulation [7]. However, oral route 2.1 Materials
becomes unsuitable in some cases such as
nausea, vomiting or convulsion. In such cases, RT was kindly gifted by Egyptian Pharmaceutical
the rectal route may offer a suitable alternate. Industries Company (EPICO). Witepsol W25was
Rectal route is also preferred if the drug is supplied by Nobel Dynamitte, West Germany.
extensively metabolized or deactivated by liver Suppocire A, Suppocire AI, Suppocire AM,
enzymes [8]. The superior hemorrhoidal veins Suppocire AP and Suppocire BM, were supplied
were reported to drain the absorbed drugs into by Gattefossé, France. Polyethylene glycol
the portal vein and subsequently into the liver. (PEG) 400, PEG 1000, PEG 1540, PEG 4000
On the other hand, the middle and inferior and PEG 6000 were supplied by Sigma Aldrich
hemorrhoidal veins drain the lower part of the (Germany). All other chemicals are of analytical
rectum and venous blood is returned to the grade.
inferior vena cava. Therefore, drug absorbed in
the latter system will initiate its circulation 2.2 Formulation of RT Suppositories
throughout the body, bypassing the liver [9].
Lymphatic circulation also assists in the Molding from a melt technique was used to
absorption of rectally administered drugs [10]. prepare all formulations of medicated and non-
Rate and extent of drug absorption following medicated suppositories. We used 1-gm capacity
rectal administration are governed by several molds. Briefly, the base was molten at suitable
factors. Depending on the physicochemical temperature then the drug was added using
properties of the base used, a suppository will magnetic stirrer until a homogenous mixture was

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obtained. The mixture was then poured into using hardness tester (Erweka Apparatus
molds and left for cooling and solidification. The GMBH, Germany).
suppositories were removed from the molds and
kept in opaque containers in a refrigerator for 24 2.3.4 Disintegration test
h before testing. For PEG based suppositories,
blend of different molecular weight PEG bases This test was carried out to determine the time
was used to attain the most suitable consistency necessary for the suppository to disintegrate
and best characteristics. The composition of completely inside the rectum to release its drug
different formulations is outlined in Table 1. to the absorption medium. Five suppositories
from each formula were placed in water bath at
2.3 Physicochemical Evaluation of RT 37± 0.5ºC. The time from the beginning of
Suppositories deformation of the tested suppository until
complete melting or dissolving was recorded.
2.3.1 Determination of displacement value
2.3.5 Melting point
For preparing a convenient suppositories
containing RT with the suggested bases, the The melting point range was tested for both fatty
displacement values (DV) for each base must be bases water soluble base of RT suppositories.
determined firstly. The DV of RT was determined The test was carried out using melting point
by comparing the weight of plain suppository apparatus (Galen Kamp, Germany) and capillary
bases with that of the medicated suppositories. tube. Five suppositories from each formula were
Suppositories were of one gram size and allowed to melt at the lower possible
containing 150 mg of RT. To determine DV, the temperature. The capillary tubes were dipped in
prepared suppositories were left at room the melted samples in a manner so as to fill 1 cm
temperature for 24 hours before testing. Each length of each tube. The samples inside the
experiment for both non-medicated and tubes were allowed to solidify till the ends of the
medicated suppositories containing 150 mg RT tubes were sealed. The tubes were stored in a
was investigated in triplicates. refrigerator till using. To carry out the test, the
temperature of the tester was elevated to 5ºC
The displacement values were calculated by below the expected melting point of the base,
using the following equation [12]: and then the capillary tubes were inserted into
their place in the apparatus. The temperature
DV= (100 x (N – M)/ (M x A) +1 was raised at a rate of 0.5 ºC/min. The
temperatures at which the suppositories started
Where, to melt (start of capillary tube dipping) and the
temperatures at which complete melting took
N = Weight of non-medicated (plain) place (complete dipping of capillary tube) were
suppositories recorded.
M= Weight of medicated suppositories
M= Medicament (RT) percentage 2.3.6 Content uniformity
2.3.2 Accuracy of the formulated RT Five suppositories were randomly chosen and
suppositories each suppository was weighed and allowed to
Accuracy of RT suppositories was done to melt or dissolve in 200 ml distilled water in a
calculate the production yield of the prepared suitable beaker with the aid of magnetic stirrer,
suppositories and to compare the actual drug and heated to about 50ºC on hot plate.
content with the theoretical drug content in each Sample of 2 ml was withdrawn, filtered,
suppository. Production yield was calculated by diluted to a suitable volume and assayed
dividing the actual suppository weight by the spectrophotometerically at 313 nm (Jenway 6305
theoretical suppository weight and then UV/VIS spectrophotometer, England).
transferred to a percent. This step was done to
show the efficacy of the formulation technique. 2.4 In vitro RT Release

2.3.3 Hardness test or fracture point The release of RT from different formulations
was carried out using rotating basket method
The force necessary to break the suppository (Erweka DT6R, Heusenstamm, Germany). The
was measured to determine the brittleness and dissolution medium was 900 ml of distilled water
fragility of suppositories. The test was performed maintained at 37ºC. Suppositories were held in a

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rotating basket at speed of 50 rpm. A sample of 3 2.6.2 Pharmacokinetic study

ml of the dissolution medium was removed at
predetermined time intervals (0.25, 0.5, 1, 1.5, 2, The experiment was carried out with 24 rabbits
2.5 and 3h) and replaced with an equal volume (n=6) divided randomly into four groups with six
of distilled water. The withdrawn samples were rats each. Group I, II and III were rectally
assayed spectrophotometerically at 313 nm. administered S3, S6 and S10 respectively.
Group IV administered a single oral dose of RT
2.5 Shelf- Storage Stability Testing solution. At predetermined time intervals (pre-
dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10
The formulated suppositories were packed in and 12), blood sample (0.75 milliliter) was taken
glass container, protected from light and stored from the retro-orbital plexus and put into
for 12 months at refrigerator temperature (4ºC). heparinized tube. Samples were directly
Enough samples were evaluated at the centrifuged at 5000 rpm for 15 min to separate
beginning of the storage and at time intervals of plasma and stored at −40°C until analysis.
1, 2, 3, 6, 9 and 12 months.
2.6.3 Chromatography
2.6 Pharmacokinetic Study
The plasma concentrations of RT were
This study was performed in order to investigate determined by a HPLC (LC10 Analytical System,
the bioavailability selected formulations (S3, S6 Shimadzu, Japan). The stationary phase
and S10 basing upon acceptable physical consisted of Nova-Pack C18 (60Ǻ, 3.9×150 mm,
characteristics and stability) when compared with 4 μm, Waters, USA). The mobile phase
RT oral administration in rats. consisted of 45:1:54 methanol: 0.05 M
phosphate buffer pH 9.3: water. The mobile
2.6.1 Animals
phase was delivered into HPLC apparatus at a
White male albino rabbits (weighing ~2 kg), flow rate of 1.5 ml/min, using maximum
provided from the animal house of the faculty of wavelength of 313 nm at pH 9.3. Measurement
pharmacy, were used in this study. They were of samples was carried out after construction of
housed under conventional laboratory conditions calibration curve. Calibration curve was
throughout the period of experimentation. The constructed by spiking one ml blank (drug free)
animal handling procedure was performed in plasma with different concentrations of RT
accordance by the Animal Care and Use to provide concentrations from (0.05-10
Committee of Jouf University, College of µg/ml). One ml of plasma, 50 µl of internal
Pharmacy. The animals were fed a standard rat standard (procainamide in methanol; 50mg/L)
pellet diet and allowed free access to water. and 15 µl of 6N sodium hydroxide were added.

Table 1. Compositions of different formulations of rectal RT suppositories

Code Added Base Water

RT Suppocire Witepsol PEG % %
(mg) PEG PEG PEG PEG PEG
400 1000 1540 4000 6000
S1 150 Suppocire AP ------- ------- ------- ------- ------- ------- -------
S2 150 Suppocire BM ------- ------- ------- ------- ------- ------- -------
S3 150 Suppocire A ------- ------- ------- ------- ------- ------- -------
S4 150 Suppocire AM ------- ------- ------- ------- ------- ------- -------
S5 150 Suppocire AT ------- ------- ------- ------- ------- ------- -------
S6 150 ------- Witepsol ------- ------- ------- ------- ------- -------
W25
S7 150 ------- ------- 75 ------- 25 ------- ------- -------
S8 150 ------- ------- 90 ------- 10 ------- ------- -------
S9 150 ------- ------- ------- 33 ------- 57 ------- 10
S10 150 ------- ------- 20 ------- 30 ------- 50 -------
S11 150 ------- ------- ------- ------- 40 ------- 40 20
S12 150 ------- ------- ------- ------- 50 ------- 50 -------

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Then 2 ml of 4% v/v isopropanol in ethylacetate results were observed in production yield where
were added. Tube was mechanically shaken for higher values were in PEG based suppositories
20 mints and then centrifuged at 3000 rpm for 10 and lower values were in Suppocire based
mints. The organic layer was evaporated under suppositories. This behavior might be attributed
stream of nitrogen to dryness at 40ºC. The to difference in specific gravity between water
residue was reconstituted in 250µl methanol and soluble bases (as PEG) and semi-synthetic fatty
20µl of the sample was injected into the column. bases (as Suppocire). The hardness ranged from
3.82 to 12.53 kg. According to B.P., proper
2.6.4 Calculation of pharmacokinetic hardness of suppositories is considered for
parameters values above 5.4 kg [13]. So, all formulations
complied with standard specification except S2
The main pharmacokinetic parameters were and S10. Regarding disintegration time, prepared
obtained with the help of a pharmacokinetic formulations ranged from 13.32 to 28.22 min.
program Kinetica™ v.4 software. The time of This wide range was expected to directly affect
maximum concentration (Tmax) and values of dissolution pattern. The melting points of fatty
maximum concentration (Cmax) were directly bases had values from 33.94 to 36.82±0.36ºC. In
obtained from the plasma concentration–time case of PEG based suppositories melting point
curve where the area under the concentration– ranged from 39.94 to 43.83ºC. It was reported
time curve (AUC) was calculated by linear that melting point of PEG is directly proportional
trapezoidal method. The relative bioavailability of chain length [14] which was also revealed by our
formulations was determined using the following results. Generally, PEG based suppositories do
equation: not melt in colon but they dissolve or disintegrate
colonic aqueous media. So the temperature
( )%
required for complete disintegration was
determined. Considering RT content uniformity,
=
the difference between the average of each
formula and the theoretical loading was less than
±9% with standard deviations of less than 5%.
2.7 Statistical Analysis Higher content uniformity was shown in PEG
Results in this work are expressed as a mean ± based suppositories which might be ascribed to
standard deviation (SD). The statistical analysis the direct and easy incorporation of RT (water
was carried out by one-way ANOVA and means soluble drug) into water soluble base or rather
were compared by Tukey's multiple comparison than dispersion of the drug particles in fatty
testing using GraphPad Prism v.5. Software. bases (differ in natures).
Difference at P < 0.05 was considered to be
significant. 3.2 In vitro RT Release

3. RESULTS AND DISCUSSION In vitro release profile of different formulations

was assessed by rotating basket method.
3.1 Physicochemical Evaluation of RT
Suppositories Fig. 1 (A and B) depicts the dissolution properties
of suppositories. It is obvious that different
In this work we used two types of suppository suppository bases influence the in vitro release
bases to prepare RT suppository semisynthetic pattern of drugs [15]. Generally, chemical
oleaginous bases (Suppocire and Witepsol) and composition and nature of the base and solubility
water-soluble bases (PEG). Visual inspection of RT in the base affect drug release. Even the
verified good surface appearance, absence of bases belonging to the same category, variation
fissuring, fat blooming and migration of active in drug release was observed. The higher
ingredients. hydroxyl value, the higher hydrophilic
characteristic of the base. This can influence
Physicochemical evaluations were performed on both the release and the absorption rates of the
all prepared batches. The obtained results are drug. The melting point influences the rate of
outlined in Table 2. Displacement values with bringing the drug free in the dissolution medium.
respect to drug were found to be in range 1 to S1 (Suppocire AP containing formulation) is
2.1. Higher values were recorded in Suppocire composed of saturated polyglycolyzed glycerides
based suppositories while lower values were with high hydroxyl value (30-50) and relatively
found in PEG based suppositories. Contradictory suitable melting range (30-35ºC). So, it can

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improve RT release by increasing the hydrophilic Average plasma concentrations (n꞊6) were
environment around the drug and getting it free plotted with time to obtain the figure shown in
in the dissolution medium [16]. These Fig. 3. However, all investigated formulations
characteristics could interpret high RT release exhibited two or more distinct peaks in all the
(nearly 92%). Nearly similar release percentage curves of the animals and distinct double peaks
was observed in S6 (Witepsol W25 containing in the mean plasma concentration-time plot. This
formulation; 89.3%). The release of drugs will be double peak phenomenon of RT was reported by
enhanced by incorporation in vehicles of low many literatures [18,19,20]. The appearance of
affinity for the drug or in which the drug is less the second peak might be ascribed to bile flow
soluble. It was reported that the release of drug [21], enterohapatic recycling [22] or sustained
from oleaginous bases is directly proportional to release behavior of formulation which in turn
the solubility of drug in water [17]. Even the resulted in parallel absorption of RT from the
bases are classified in the same category, lower proximal and more distal parts of the intestine
release percentages were recorded for S2, S3, [20]. It is obvious that there was great variation
S4 and S5 (Suppocire BM, Suppocire A, in the plasma concentration-time profile
Suppocire AM and Suppocire AT containing between Suppocire AP based formulation and
formulations respectively). This behavior may be other investigated formulations. The main
ascribed to higher melting points of these pharmacokinetic parameters of RT from different
formulations (see Table 2). S2, S3, S4 and S5 investigated formulations are listed in Table 3.
showed 73.6%, 78%, 72.3% and 75.3% The experimental results showed that S8 was of
respectively (Fig. 2A). Concerning PEG bases the highest (P <.05) rate and extent of RT
formulations (Fig. 2B), RT release relies upon absorption where Cmax of S1, S6, S8 and RT
PEG molecular weight; the higher percentage of solution were 3.23±0.12, 3.90±0.05, 10.05±1 and
high molecular weight PEG, the slower RT 3.82±0.66 µg/mL respectively. Regarding first
release. S8 contained 90% of PEG 400 (liquid in peak, results also showed faster RT absorption
nature) and exhibited the highest amount of drug from S6 than other investigated formulations (1h
released (61.3%) among PEG based required for appearance of first peak) while RT
formulations. S12 contained 50% of PEG 6000 solution required 2.5h. This confirmed faster
(solid in nature) and exhibited the lowest amount absorption from rectal route than oral route.
of drug released (22.2%) among PEG based Although fatty bases (S1 and S6) were expected
formulations. The release of RT from PEG bases to enhance colonic drug release and hence
took the following descending order: S8 > S7 > absorption as they had low affinity to RT
S9 > S10 > S11 > S12. This might be ascribed to (hydrophilic drug), the PEG (hydrophilic) based
high melting point of high molecular weight PEG formula (S8) showed significant higher AUC0-12
[16]. (58.313±3.9 µg.h/mL) than fatty bases
(Suppocire AP and Witepsol W25; 29.122±2.3
3.3 Stability Studies µg.h/mL and 27.314±1.9 µg.h/mL respectively).
This behavior may be explained colonic
Stability studies of different formulations were metabolism of RT. It was reported that RT is
investigated by storage at 4ºC for 12 months. RT metabolized by colonic bacteria [23]. Authors
concentration was determined at different time used batch culture fermentation system to
points as shown in Fig. 2 (A and B). All simulate colonic conditions and concluded that
formulations were relatively stable regarding RT RT was degraded by cleavage of an N–oxide
concentration as the percentages remaining after bond using UV and mass spectrometry analysis.
12 months were more than 90%. In our case, we suggest that RT could promptly
3.4 Bioavailability Studies release from fatty bases and then extensively
degraded in colonic environment before efficient
Based on aforementioned results, it was found absorption. Regarding PEG based batch (S8),
that three RT suppository formulations S1 RT was partitioned between two favorable
(Suppocire AP based), S6 (Witepsol W25 based) media; aqueous media of colon and PEG matrix
and S8 (PEG based) had higher in vitro drug of suppository and slowly releases. This could
release than many other corresponding minimize colonic degradation of RT. This
formulations and demonstrated good self-life suggestion could be partly explained lower
stability for 1 year. So, they were selected for in absorption rate constant (0.397±0.02h-1) and
vivo studies. For more convenient work, study higher absorption half life (1.745±0.03h) when
was designed to carry out relative bioavailability compared to other investigated formulations.
studies in comparison with oral RT solution. Moreover, PEG can improve permeability of

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drugs by both disorganization of intercellular from PEG based suppositories. In addition,

spaces and hence paracelluar absorption (major relative bioavailability of the investigated
route of RT absorption) and interaction with formulations were 109.57, 102.76 and 219.39 for
membrane transporters [24] (RT is a substrate S1, S6 and S8, respectively confirming the
for efflux and influx membrane transporters). By superiority of S8 formulation over other
this way we could interpret higher bioavailability investigated formulations in improving RT
of RT as class III drug (permeability rate limited) bioavailability.

Table 2. Physicochemical characteristics of different batches of RT suppositories (n=3, S±D)

Code DV Production Hardness Disintegration Melting Content

yield (%) (kg) time (min) point (ºC) uniformity (%)
S1 2.1±0.3 99.4.±2.6 5.77±0.12 16.20±0.62 33.94±0.72 99.4.±2.6
S2 1.7±0.2 98.9±3.5 3.82±0.16 28.22±0.73 36.82±0.36 98.9±3.5
S3 2.1±0.4 98.7±4.3 7.56±0.60 14.38±0.45 35.70±0.54 98.7±4.3
S4 1.7±0.1 101.2±3.7 5.75±1.2 23.01±0.25 35.80±0.61 101.2±3.7
S5 1.8±0.2 99.3±4.4 8.95±0.94 25.26±0.95 35.89±0.93 99.3±4.4
S6 1.5±0.1 98.5±3.4 7.63±1.10 13.32±0.74 34.42±0.48 98.5±3.4
S7 1.1±0.1 100.6±4.8 5.95±1.10 23.25±0.38 39.94±0.18 100.6±4.8
S8 1.0±0.1 108.7±3.2 12.49±0.63 21.48±0.65 41.00±0.67 108.7±3.2
S9 1.3±0.3 106±2.5 10.88±1.30 18.94±0.94 41.82±0.27 106±2.5
S10 1.08±0.07 108.5±4.1 4.87±0.21 16.29±0.15 42.00±0.90 108.5±4.1
S11 1.2±0.09 103.9±1.7 6.31±2.00 20.30±0.35 41.82±0.44 103.9±1.7
S12 1.4±0.1 108.8±2.9 12.53±0.57 24.30±0.83 43.83±0.75 108.8±2.9

Fig. 1. In vitro release of RT from different suppository formulations; (A) Fatty bases and (B)
PEG base

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Fig. 2. Shelf stability study of RT loaded suppository formulations; (A) Fatty bases and (B) PEG
base

Fig. 3. Plasma level-time curve of S1, S6, S8 and RT oral solution

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Table 3. Pharmacokinetic parameters of RT suppository formulations (n=5, S±D)

Pharmacokinetic Formulation
parameter S1 S6 S8 RT oral solution
Tmax1 (h) 1.5 1 1.5 2.5
Tmax2 (h) 4 4 4 4
Cmax1 (µg/mL) 2.63±0.02 2.56±0.13 3.55±0.43 3.40±0.47
Cmax2 (µg/mL) 3.23±0.12 3.90±0.05 10.05±1 3.82±0.66
AUC0-12 (µg.h/mL) 29.122±2.3 27.314±1.9 58.313±3.9 26.580±4.1
-1
K ab (h ) 0.7351±0.04 0.701±0.05 0.397±0.02 0.762±0.03
T1/2ab (h) 0.9426±0.07 0.987±0.07 1.745±0.03 0.908±0.04
-1
K el (h ) 0.0807±0.001 0.162±0.002 0.319±0.01 0.186±0.004
RB 109.57 102.76 219.39 ------

4. CONCLUSION delivery system: A newer formulation

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