Meloxicam (MLX) is a highly potent non-steroidal anti-inflammatory drug (NSAID) of the enolic class that is more selective in inhibiting cyclooxygenase COX-2 than COX-1; therefore, it possesses superior gastrointestinal safety profile than regular NSAIDS.[1–4] Although used mainly as an antirheumatic in rheumatoid arthritis, osteoarthritis, and other joint diseases, the drug is also an effective analgesic for various conditions.[1,5] While, MLX is well absorbed after oral administration, with an absolute bioavailability of 89%,[6] previous pharma-cokinetic studies proved that MLX has t
max longer than
5 h, indicating the slow absorption of MLX after an oral administration.[7] Consequently, parenteral formula-tion of MLX is used to obtain a faster analgesic response in the treatment of syndromes involving acute pain.[6,7] It is therefore reasonable to investigate the approaches
that may facilitate oral absorption of MLX for treating acute pain.
Although tablets are the most widely used dosage form because of their convenience in terms of self- administration, compactness, and ease in manufactur-ing, yet, pediatric and geriatric patients usually suffer difficulties in swallowing conventional tablets. This is often responsible for poor patient compliance with the dosage regimen, or even stopping the treatment and therefore resulting in an ineffective therapy. To overcome this drawback, the need for a patient-friendly dosage form was satisfied by innovating oral fast-disintegrating tablets, also known as ‘fast-melt’, ‘fast-disintegrating’, ‘orodispersible (ODT)’ or ‘fast-dissolving’ tablets. These tablets begin to disintegrate immediately after coming into contact with saliva, with complete disintegration normally occurring within 30–50 s after administration,
Address for Correspondence: Dr Ahmed Abdelfattah Aboelwafa, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt. Tel: +2 0108 756746. E-mail: [email protected]
RESEARCH ARTICLE
A pilot human pharmacokinetic study and influence of formulation factors on orodispersible tablet incorporating meloxicam solid dispersion using factorial design
Ahmed A. Aboelwafa and Rania H. Fahmy
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
AbstractMeloxicam (MLX) suffers from poor aqueous solubility leading to slow absorption following oral administration; hence, immediate release MLX tablet is unsuitable in the treatment of acute pain. This study aims to overcome such a drawback by increasing MLX solubility and dissolution using PEG solid dispersion (SD), then, to investigate the feasibility of incorporating the SD into orodispersible tablets (ODTs). A 23 full factorial design was employed to investigate the influence of three formulation variables on MLX ODTs. The selected factors: camphor (X
1) as pore-
forming material, and croscarmellose sodium (X2) as superdisintegrant, showed significant positive influence, while
PEG content (X3) was proved to negatively affect both disintegration and wetting times. In addition, isomalt increased
disintegration and wetting times when compared to mannitol as diluents. The pharmacokinetic assessment of the optimum ODT formulation in healthy human subjects proved that the faster MLX dissolution by using PEG solid dispersion at pH 6.8 resulted in more rapid absorption of MLX. The rate of absorption of MLX from ODT was significantly faster (p = 0.030) with a significantly higher peak plasma concentration (P = 0.037) when compared to the marketed immediate release MLX tablet with a mean oral disintegration time of 17 ± 3 s.
and can be taken any time or place disregarding the availability of water, or the need to swallow a large mass of material as a unit.[8–10]
ODTs have been investigated for their potential in increasing the bioavailability and rate of absorption of poorly water soluble drugs through enhancing their dissolution profile. Some studies revealed that bio-availability and rate of absorption were improved;[11,12] on the other hand, in other studies, the bioavailabil-ity and rate of absorption of many drugs remained unaltered[13–15] on formulating a drug in ODT and com-paring it to immediate release tablet. Ali et al.[1] stud-ied the pharmacokinetics of MLX administered as fast dissolving tablet and immediate release tablet in rats and found that they have similar properties in normal untreated rats but not in the vagally suppressed rats. Formulation of MLX in ODT was performed by some research groups, but pharmacokinetics studies were not carried out.[16,17]
MLX is practically insoluble in water[5] and in the stomach (pH 1.0).[1] MLX can be classified as a Class II compound having a low solubility and high perme-ability according to the Biopharmaceutics Classification System.[18] The pharmacokinetic profiles of these drugs can generally be changed by formulation techniques that increase their aqueous solubility.[7] To achieve adequate pharmacodynamic properties such as rapid onset of the drug effect, fast dissolution is important for this type of drug.[19]
Solid dispersions of many poorly water soluble drugs including MLX have been proved as an effective method for improving dissolution rates of drugs and their satura-tion solubility by incorporating them into a water-soluble polymer matrix as polyethylene glycol (PEG).[20–22] In the preparation of a solid dispersion, the drug can be mixed with the melted excipients. After solidification, the prod-uct is suitable for further processing. This melt technol-ogy is up-to-date ‘green’ technology as it does not use any organic solvents.[23] PEG is applicable for this pur-pose, because of its low melting point, low toxicity and it is inexpensive.[24]
However, the use of PEG in ODTs is limited probably because it is known that PEG drastically prolongs the disintegration time. Therefore, the aim of this study is to investigate the feasibility of preparation of MLX ODT with fast onset of action using simple and inexpensive direct compression method utilizing PEG as a disso-lution enhancer. In addition a comparison between isomalt and mannitol as diluents in ODTs was carried out.
A 23 full factorial design was employed to evaluate the individual and combined effects of the formula-tion variables on the performance of these tablets. The optimum MLX ODT selected based on statistical analysis of the results obtained was further subjected to in vivo pharmacokinetic evaluation in human vol-unteers and compared with the marketed immediate release MLX tablet.
Materials and methods
MaterialsMeloxicam (MLX) was purchased from Sigma (St Louis, MO, USA), Polyethylene glycol 4000 (PEG) was pur-chased from Fluka BioChemika (Switzerland). Camphor was purchased from Elgomhoria Co. (Cairo, Egypt). The diluents used were 160 µm granulated mannitol (Pearlitol® 160C) that was kindly gifted by Roquette-Pharma (France), and Agglomerated isomalt (gale-nIQ™ 721) that was kindly gifted from BENEO-Palatinit, Mannheim, Germany. Cross-linked sodium carboxym-ethylcellulose (Crosscarmellose sodium; Ac-di-sol) was purchased from FMC Corporation (Philadelphia, USA). Colloidal silicone dioxide (Aerosil® 200) was pur-chased from Degussa-Röhm GmbH & Co. (Germany). Magnesium stearate was obtained from Prolabo (France). High-performance liquid chromatography (HPLC) grade methanol and acetonitrile were obtained from Merck (Darmstadt, Germany). All other reagents and chemicals were of analytical grade.
MethodsPreparation of MLX solid dispersion and physical mixtureSolid dispersions of MLX in PEG were prepared by the fusion process[21,25,26] containing four different drug:polymer weight ratios (1:1 [SD1], 1:2 [SD2], 1:3 [SD3], and 1:5 [SD4]). Table 1 gives an overview of the formulations’ compositions evaluated during this study and their corresponding PEG concentrations. Accurately weighed amounts of MLX with the corresponding weights of PEG were mixed together over a heating water bath at 70 ± 5°C for 15 min (Melting point of PEG 4000 is 50–58°C).[27] The fused samples were cooled at room temperature and solidified by placing them for 1–4 days in desiccators over silica gel before pulverizing them in a glass mortar and pestle. Afterwards, all the powdered samples were sieved (40 mesh) and stored in closed containers away from the light and humidity until use. The physical mixtures (PM) were prepared by blending together the accurately weighed amounts of MLX and PEG in a mortar for 5 min. The resulting PMs were sieved (40 mesh), collected, and stored in a closed container away from the light and humidity.[21,26,28]
Solid state characterization of MLX:PEG 4000 solid dispersions and PMX-ray diffraction (XRD). In order to determine the powders’ crystalline state, X-ray powder diffraction was performed using X-ray diffractometer (Scintag XGEN-4000, Advanced Diffraction systems, Scintag Inc., USA). The X-ray diffraction (XRD) patterns were determined for MLX, PEG 4000, PM (1:1) and solid dispersions. The samples were exposed to nickel-filtered Cu-Kα radia-tion at a scan rate of 8°/min over the 2θ range of 4° and 60° (voltage of 45 kV and a current of 40 mA) and the results were then obtained as peak height (intensity) versus 2θ.
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Table 1. Composition of MLX solid dispersions formulations and their PEG 4000 concentrations, the relative degrees of crystallinity, and the dissolution parameters in phosphate buffer (pH 6.8)*.
FormulaPEG 4000
concentration
Relative degree of crystallinity Dissolution parametersRDC at
*RDC indicates relative degree of crystallinity; SD, standard deviation from the mean; IDR, initial dissolution rate; PD, percentage of drug dissolved; PM, physical mixture.
Table 2. Composition of MLX orodispersible tablets (250 mg).Ingredient Quantity
MLX* 15 mg
PEG 4000* 15 mg or 75 mg
Camphor 5% or 10%Croscarmellose sodium 10% or 20%Magnesium stearate 1%Aerosil 1%Isomalt or mannitol to 250 mg
*used in the form of solid dispersion with MLX:PEG ratio of 1: 1 or 1:3.
Incorporating MLX solid dispersion: Pilot pharmacokinetic study 3
given in Table 2. Prior to mixing, the raw materials were separately passed through a screen (40 mesh). Accurately weighed powdered 1:1 or 1:3 solid disper-sion, containing amount equivalent to 15 mg MLX, was mixed with the other excipients using mortar and pestle and compressed using a single-punch tablet machine (Royal artist, Bombay, India) equipped with flat faced 13 mm punches. The tablet weight before sublimation was adjusted to 250 mg and the hard-ness was set to 5 kg using Monsanto hardness tester (Sheetal Scientific Industries, Mumbai, India). The prepared tablets were subjected to sublimation at 50°C for 24 h in a vacuum oven (to ensure complete sublimation of camphor).
For each diluent, isomalt or mannitol, a 23 random-ized full factorial design was employed to evaluate the individual and combined effects of three formula-tion variables. In this design, three factors were evalu-ated, each at two levels, and experimental trials were performed at all eight possible combinations with replication. The percentage of camphor (X
1), the per-
centage of croscarmellose sodium (X2), and amount
of PEG (X3) were selected as independent variables
and the disintegration time (DT) and the wetting time (WT) were selected as dependent variables (Table 3). The levels of the independent variables were cho-sen based on preliminary experiments. A significant level of 5% was used as the criterion to reject the null hypothesis. All analyses were performed using the MINITAB Software (Release 14, Minitab Inc., State College, PA, USA).
Thermal analysis. Differential scanning calorimetry (DSC) analysis was performed using Differential Scanning Calorimeter (Shimadzu, DSC-50, Kyoto, Japan) to assess the thermal behaviors of MLX, PEG 4000, PM (1:1) and solid dispersions in the temperature range of 30–350°C, and to determine the degree of crystallinity of MLX in both the PM and solid dispersions. Samples of 2–5 mg of the pure MLX or the above mentioned samples were sealed in 50-µL aluminum pans and subjected to a constant heat-ing rate of 10°C/min with an empty pan used as reference standard. The instrument was calibrated with indium for melting point and the heats of fusion and the whole ther-mal behaviors were studied under a nitrogen purge.
Evaluation of the dissolution behavior of MLX:PEG 4000 solid dispersions and PMIn vitro dissolution studies of MLX alone, from the solid dispersions and PM were performed in triplicate using USP Dissolution Test Apparatus II (Pharma Test, Germany). The paddle method was utilized at a rotation speed of 50 rpm in 1000 mL phosphate buffer (pH 6.8) at 37 ± 0.5°C. Accurate weight of each powdered sample equivalent to 15 mg MLX was added to the dissolution medium. At predetermined time intervals, 3-mL aliquots were withdrawn from the dissolution medium and filtered through 0.45 µm Millipore® membrane filter (Versapor, German Sciences, Germany). The initial dissolution medium volume was maintained constant by replac-ing the aliquots with equal volumes of fresh buffer. The removed aliquots were adequately diluted and analyzed spectrophotometrically (Shimadzu, model UV-1601 PC, Kyoto, Japan) for their MLX content at 362 nm against a blank of phosphate buffer (pH 6.8). Certain criteria were used to evaluate the dissolution profiles; including the initial dissolution rate (IDR) that was calculated as per-centage of the drug dissolved/min over the first 10 min, the percentage of the drug dissolved after 15 min (PD
15),
and after 60 min (PD60
).[28,29]
Preparation of MLX ODTs utilizing combined sublimation and high superdisintegrant concentration techniques using 23 full factorial designDifferent MLX ODT formulations were prepared by direct compression according to the composition
The codes in the table symbolize: Level usedFactor −1 1X
1: % of Camphor 5% 10%
X2: % of croscarmellose sodium 10% 20%
X3: Amount of PEG (mg) 15 mg 75 mg
4 A.A. Aboelwafa and R.H. Fahmy
Pharmaceutical Development and Technology
Characterization of the formulated MLX ODTIn order to ensure the uniformity of tablets weights, and the extent of camphor sublimation, 20 tablets were ran-domly selected from each formula and weighed before and after camphor sublimation. Then, for each formula, the mean tablet weight and percentage weight loss due to camphor sublimation with the corresponding standard deviations were calculated.
The friability of a sample of 20 tablets was measured using a digital tablet friability tester (Model DFI-1, Veego, Bombay, India), which complies with USP testing standards. Twenty preweighed tablets were rotated at 25 rpm for 4 min. The tablets were then reweighed after removal of fines and the percentage of weight loss was calculated and taken as a measure of friability.
For the determination of hardness, the mean hardness was determined for each formula from the hardness of 10 randomly chosen tablets using hardness tester (VK 200, Vankel Industries Inc., Cary, NC, USA).
The wetting time test and water absorption ratio (WAR) were used to illustrate the porosity and capillarity of the ODT. They were measured by a simple procedure; five circular tissue papers, each 10 cm in diameter, were placed in a Petri dish containing 10 mL of methylene blue-containing water. The tablet was carefully placed on the top of the tissue paper and the time required for the water to reach the upper surface of the tablet is recorded as the wetting time. Each tablet was weighed
before and after it is completely wetted in the Petri dish, then the water absorption ratio was calculated from the equation:
WAR 100 W W W= − /a b b( )
(1)
as Wa and W
b are the tablet weights after and before water
absorption, respectively. To check for reproducibility, the measurements were carried out six times and the mean value was calculated.[10,30]
The in vitro disintegration time was determined using a USP disintegration test apparatus (VTD-3, Veego, Bombay, India). In this experiment, 900 mL of distilled water kept at 37 ± 0.5°C was used as the disintegration medium and the test results presented were the average of six determinations. The time of total disintegration was the point at which all visible parts of the tablets have been eliminated.
In vitro dissolution of MLX ODTIn vitro dissolution of MLX ODT was performed on selected formulations using USP Dissolution Test Apparatus II (Pharma Test, Germany) containing 1000 mL phosphate buffer (pH 6.8). This was performed by placing a tablet of each formula, containing an equivalent of 15 mg MLX in the dissolution apparatus beaker and the paddle was then rotated at 50 rpm at 37 ± 0.5°C. 3 mL aliquots were withdrawn from the dissolution medium every 5 min for 20 min and then after 30, 45, 60, 90, and 120 min. After each sample withdrawal, the medium was replenished with the same volume of fresh buffer. The removed ali-quots were filtered through 0.45 µm Millipore® mem-brane filter (Versapor, German Sciences, Germany), adequately diluted and analyzed spectrophotometrically (UV-1601 PC, Shimadzu, Kyoto, Japan) for their MLX content at 362 nm against a blank of Phosphate buffer (pH 6.8).
In vivo pharmacokinetic studiesStudy designThe study was carried out to compare the pharmacokinet-ics of MLX from the selected optimum ODT formulation (F12) with conventional commercially available imme-diate release tablet (IR) following the administration of single doses of 15 mg of MLX each. Two-treatment, two-period, randomized, crossover design was used. Four healthy male human volunteers participated in the study (weight 70–85 kg, aged between 28 and 34 years and height from 170–185 cm) and all were non-smokers. The biochemical examination of the volunteers revealed nor-mal kidney and liver functions. None of the volunteers were on drug treatment one week before the participa-tion in the study. The nature and the purpose of the study were fully explained to them, and informed written con-sent was obtained from every volunteer. The study was approved by the Cairo University Protection of Human Subjects Committee and the protocol complies with the declarations of Helsinki and Tokyo for humans. The study
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0 10 20 30o 2- Theta
SD4 (1:5)
SD3 (1:3)
SD2 (1:2)
SD1 (1:1)
PM (1:1)
PEG 4000
Meloxicam
40 50 60
Figure 1. X-ray diffraction patterns of pure meloxicam, PEG 4000, physical mixture, and the solid dispersions. The curves have been displaced vertically for better visualization.
Incorporating MLX solid dispersion: Pilot pharmacokinetic study 5
was performed over two periods. In period I, half the number of volunteers (group 1) received the marketed IR tablet (treatment A) which is considered as a reference standard and the other half (group 2) received the ODT tablet F12 (treatment B).
The ODT tablet was administered orally without water. Each subject was instructed to keep the ODT in the mouth for few minutes until completely dissolved in the saliva and the oral disintegration time was recorded as the time until the volunteer felt that the tablet had disappeared in his mouth. The IR tablet was ingested with 150 mL of water. For both treatment groups, food was withheld for at least 2 h after dosing and water was allowed after 30 min. A washout period of one week separated the peri-ods. In period II, group 1 received treatment B and group 2 received treatment A.
Blood samples (5 mL) were collected from the volun-teers’ forearm cubital vein using a hypodermic syringe through an indwelling cannula over a period of 48 h at the following sampling times: 0 min (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24 and 48 h after administration of each treatment. Plasma was separated by immediate centrifugation of the blood samples at 5000 rpm for 10 min. The plasma was pipetted into glass tubes and then frozen at −20°C until analysis by HPLC. The quantitative determination of MLX in human plasma was performed by a reverse-phase high-performance liq-uid chromatography (HPLC) procedure as described by Bae et al.[31].
Pharmacokinetic analysisPharmacokinetic parameters for MLX, following oral administration of the two treatments, were determined from the plasma concentration time data by means of a model-independent method using a computer program, Kinetica® (version 5, Thermo Fischer Scientific). The ter-minal elimination rate constant K (h−1) was obtained from the slope of the linear regression of the log-transformed plasma concentration-time data in the terminal phase. The t
1/2 (h) was calculated as 0.693/K. The maximum
drug concentration (Cmax
, µg/mL) and the time to reach C
max (t
max, h) were obtained from the individual plasma
concentration-time curves. The area under the curve AUC
0–24 (µg.h/mL) was determined as the area under the
plasma concentration-time curve up to the last measured sampling time and calculated by the trapezoidal rule. The area under the curve from zero to infinity AUC
0-∞ (µg.h/
mL), was calculated as AUC0-∞
= AUC0–24
+ Ct/k where C
t is
the last measured concentration at the time t.
Statistical analysisAll the results were expressed as mean ± standard devia-tion (SD). The pharmacokinetic parameters, C
max, t
max,
AUC0–24
and AUC0-∞
were compared between treatments A and B with the ANOVA test for the untransformed data and calculating 90% confidence interval of the ratio of test/reference using log-transformed data. The inclusion of the confidence interval within 0.8–1.25 was taken as
a demonstration of bioequivalence. The non-parametric Signed Rank Test (Mann-Whitney test) was used to com-pare the medians of t
max for treatments A and B using the
software Minitab®. The untransformed values for t1/2
were compared using ANOVA test. The level of significance was α = 0.05. A P-value of ≤ 0.05 was considered statisti-cally significant.
Results and discussion
Preparation and characterization of MLX solid dispersions and physical mixturesThe selection of PEG 4000 as suitable carrier for the prep-aration of MLX solid dispersion by the fusion method was based on the fact that it has lower melting point than MLX to avoid drug decomposition resulting from excessive heat during the preparation of the solid dispersions (m.p. of PEG 4000 ≈ 50–58°C while that of MLX is 261°C).[27] In addition, it has rapid solidification rate, favorable solu-tion properties, low toxicity and low cost.[24,32]
X-ray diffractograms of MLX, PEG 4000, PM (1:1), and the solid dispersions at 1:1, 1:2, 1:3, and 1:5 drug:polymer ratio are shown in Figure 1. The XRD peaks of MLX revealed that the drug was in a highly crystalline state, as indicated by its numerous sharp distinctive peaks; the most characteristic MLX peaks were at 2θ diffraction angles of 13.06° and 25.84°. PEG 4000 alone exhibited two clear characteristic peaks at 19.15° and 23.15°. The characteristic peaks of both MLX and PEG were clearly observed at the same 2θ values in the physical mixture indicating that the crystallinity of MLX was not changed in the physical mixture. Additionally, the heights of these characteristic peaks were similar in both physical mixture
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0 50 100 150
Temperature (°C)
Hea
t flo
w (m
W)
SD4
SD3
SD2
SD1
PM (1:1)
PEG 4000
Meloxicam
200 300250 350
Figure 2. DSC thermograms of pure meloxicam, PEG 4000, physical mixture, and the solid dispersions. The curves have been displaced vertically for better visualization.
0 15 30 45
SD4
SD3SD2SD1
PMMLX
0102030405060708090
100
60Time (min)
Mel
oxic
am re
leas
ed (%
)
75 90 105 120
Figure 3. Dissolution profiles of MLX alone, from 1:1 PM and from solid dispersions of different MLX:PEG 4000 ratios. *In the Figure SD1 denotes MLX: PEG 4000 ratio of 1:1, SD2; 1:2, SD3; 1:3, and SD4; PM indicating (1:1) physical mixture.
6 A.A. Aboelwafa and R.H. Fahmy
Pharmaceutical Development and Technology
(1:1) and the solid dispersion containing the same ratio (SD1), suggesting that MLX existed also in crystalline state in SD1 (1:1).
The XRD patterns of MLX solid dispersions with higher PEG concentrations also demonstrated the crys-talline diffraction peaks of MLX, but with lesser intensity, which suggests that some portion of MLX was still in the crystalline state. As the concentration of PEG increased from 50% (1:1) in SD1 to 83.33% (1:5) in SD4, the char-acteristic peaks of MLX gradually decreased, indicat-ing that, when PEG concentration is sufficiently high, larger portion of MLX is converted to amorphous form or monomolecularly dispersed in the molten PEG base during solid dispersion preparation. Moreover, in order to assess the extent of MLX crystallinity in various solid dispersion preparations, representative peak heights of the distinctive peaks were compared in solid dispersions to the standard MLX peak heights. The relationship used for calculating the crystallinity was the relative degree of crystallinity:
RDC I /Isam ref=
(2)
where Isam
indicating the peak height of the solid disper-sions sample under investigation and I
ref is the peak height
at the same angle for the reference (pure MLX). MLX peaks at 13.06° and 25.84° were used to calculate RDC of PM and solid dispersions and presented in Table 1. The results suggested that MLX crystallinity was reduced with increasing PEG ratio; in SD4 (1:5) RDC was 0.335 indicating that most of the drug was in the amorphous or monomolecularly dispersed state. Similar results were obtained with ofloxacin solid dispersions by Okonogi and Puttipipatkhachorn,[29] and with prednisone by Leonardi et al.[33]
Figure 2 reveals the thermal behaviors of the pure components together with the thermal behaviors of the PM and solid dispersion systems prepared. MLX DSC thermogram shows single sharp endothermic peak at 261.3°C corresponding to its melting temperature; such sharp endothermic peak signifies that MLX used was mostly in pure crystalline state. The thermogram of PEG also shows single endothermic peak at 63.17°C consequent to the polymer melting; such m.p. is slightly higher than expected because PEGs are known to exist in more than one crystal form, exhibiting mul-tiple melting points in the region of 55–65°C.[34] There were no apparent differences between the DSC ther-mograms of PM and solid dispersions; they all verified complete disappearance of MLX characteristic peak and showed a single characteristic peak corresponding to PEG melting in a temperature ranging between 61.95 and 62.16°C.
Usually, the complete disappearance of the drug melting peak in DSC might indicate the conversion of the drug to an amorphous solid solution. However, when the results of both DSC and XRD are combined, it could be deduced that a portion of MLX is still in
crystalline state as indicated by XRD diffractograms (Figure 1). Consequently, the disappearance of MLX peak in the PM and solid dispersion thermograms (Figure 2) might be due to the dissolution of MLX before reaching its fusion temperature in the molten PEG base during the DSC scans. Similar results were previously observed with PEG solid dispersions with nifidipine[26] and ofloxacin.[29]
In vitro dissolution of MLX:PEG 4000 solid dispersions and PMIn vitro dissolution profiles of MLX from solid disper-sions containing various MLX:PEG ratios in compari-son to MLX alone and PM are presented in Figure 3.
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0 0.2 0.4 0.6
Relative Degree of MLX Crystallinity (RDC)
Mel
oxic
am d
isso
lved
(%)
Mel
oxic
am d
isso
lved
(%/ m
in)
0102030405060708090
100
0
2
4
6
8
10
12
14
16RDC vs PD 60RDC vs PD 15RDC vs IDR
0.8 1.0
R2=0.989
R2=0.9912
R2=0.983
1.2 1.4
Figure 4. Linear correlations between relative degree of MLX crystallinity (RDC) and the initial dissolution rate (IDR), percentage drug dissolved after 15 min (PD
15), and percentage
drug dissolved after 60 min (PD60
) each with its corresponding R2 value.
Incorporating MLX solid dispersion: Pilot pharmacokinetic study 7
MLX is known to have very poor aqueous solubility and wettability;[5] which is reflected in the extent of drug dis-solved after 15 min (PD
15 ≈ 11%). This hydrophobicity
causes the drug powder to float and accumulate on the surface preventing the dissolution media from contact-ing the surface drug particles and thus dissolving their molecules.
From Figure 3 and Table 1, it is clear that all MLX dissolution profiles showed two distinct phases of drug dissolution: an initial rapid phase in the first 15–30 min followed by a slower almost plateau phase. The disso-lution rates of MLX from the PM and all solid disper-sions were notably higher than that of MLX alone. The improvement of MLX dissolution from the PM (1:1) could be attributed to the local solubilizing effect of the hydrophilic PEG that reduces the interfacial tension between the hydrophobic MLX particles and the dis-solution medium in the microenvironment surrounding the drug particles.[35,36]
All MLX solid dispersions demonstrated enhanced dissolution profiles than both pure drug and PM. The enhanced dissolution of hydrophobic drugs from solid dispersions has been thoroughly discussed[21,26,29,35,37] and attributed to several reasons including: particle size reduction that leads to increase in the exposed drug’s surface area, reduction of agglomeration of drug’s particles, improved wettability and dispersability of the drug due to the highly hydrophilic PEG and the reduced interfacial tension of the drug in solid disper-sion systems. In addition, the hydrophilic carrier might enhance the drug solubilization due to the changes in the physical properties of the drug such as molecular dispersion, decreased crystallinity (amorphization), or polymorphic changes.
It was also noticeable that increasing MLX:PEG ratio (increasing PEG concentrations) resulted in cor-responding raise in MLX dissolution rate from the solid dispersions; the initial dissolution rate in the first 10 min for pure MLX was 0.83%/min, for PM was 1.23%/min, while for SD1 the IDR was 2.98%/min, for SD2 was 3.56%/min, for SD3 was 5.18%/min, and finally, for SD4 was 7.14%/min. The increased dissolution rates associated with higher PEG proportions ascertain that the carrier-controlled dissolution is the dominant type of release from the prepared solid dispersions. Lloyd et al.,[35] and Sjökvist Saers and Craig[38] suggested that, in solid dispersions having low drug contents, PEGs usually form polymer-rich diffusion layer. The drug releases into the bulk medium via dispersion of that diffusion layer.
In order to further investigate whether the amor-phization of MLX upon incorporation into solid disper-sion systems are correlated to the enhanced dissolution parameters of the solid dispersions, the relative degrees of crystallinity (RDC) of the prepared solid dispersion systems were plotted against the initial dissolution rate (IDR), the percentage of drug dissolved after 15 (PD
15)
and 60 min (PD60
) and presented in Figure 4. It is obvious
that a strongly linear relationship exists between RDC and each of the previously mentioned parameters as indi-cated by the R2 values of 0.989 for IDR, 0.99 for PD
15 and
0.983 for PD60
. Therefore, it could be suggested that both the percentage of PEG incorporated (MLX: PEG ratio) and the drug amorphization have significant effects on the improvement of MLX dissolution from the prepared solid dispersion systems.
Preparation of MLX ODT utilizing combined sublimation and high concentration of superdisintegrant techniquesThe utilized method for preparation of MLX ODTs combines the advantages of the most extensively used techniques. First, the use of superdisintegrant in high concentration which accelerates tablet disintegration by virtue of their ability to absorb large amounts of water when exposed to aqueous environment; second, the sub-limation technique that produces highly porous tablets susceptible to faster water penetration, and hence facili-tate the wicking action of the superdisintegrant leading to faster disintegration of the tablets in the mouth. Finally, the involvement of MLX in the form of solid dispersion is expected to improve the drug solubility and dissolution and, therefore, this may lead to improved in vivo absorp-tion rate.
In order to select the best types and concentrations of the subliming agents, the superdisintegrant, and the diluents to establish the factorial design for the prepara-tion of MLX ODTs, several preliminary trials have been performed. Camphor was selected as subliming material as it was previously proved to be efficient pore forming material and the camphor-containing tablets exhibited faster disintegration as compared with tablets contain-ing either menthol or thymol.[28,39] Preliminary trials using several camphor concentrations were tested and the hardness of all tablets was adjusted to 5 kg before sublimation. Camphor sublimation resulted in consid-erable reduction in tablets’ hardness. Concentrations above 10–12% resulted in highly fragile tablets that did
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Table 4. Characterization of 250 mg MLX ODT.
Formula numberAverage tablet weight
before sublimation (gm)Average tablet weight
after sublimation (gm)Percentage loss upon sublimation (%) ± SD1 Hardness2 (kg)
not maintain their compression after sublimation while those prepared with camphor concentrations less than 10% remained compressed. According to these prelimi-nary results, 5 and 10% camphor concentrations were used as pore forming agent to facilitate rapid disintegra-tion of MLX ODTs. In all ODT formulations, 1% colloidal silicon dioxide (Aerosil® 200) was incorporated. In addi-tion to its glidant properties, the addition of 1% colloidal silicone dioxide was previously reported to cause a mar-ginal decrease in disintegration time and significantly decrease tablets’ friability by helping restoring the bond-ing properties of the excipients.[39,40]
Water insoluble diluents as microcrystalline cellu-lose and dicalcium phosphate were omitted from the study because of the rough texture that causes unac-ceptable grittiness feeling in the mouth. Among the soluble diluents, granular mannitol (Pearlitol® 160C) was selected considering its advantages in terms of easy availability, cost-effectiveness, and negative heat of solu-tion that causes a uniquely cooling sensation and pleas-ant taste when used in formulating chewable or mouth dissolving tablets.[39–41] Agglomerated isomalt (galenIQ™ 721) was also selected based on its good disintegra-tion properties, good compactability. It also exhibits pleasant sugar-like natural sweet taste with very low glycemic and insulinemic response, making it a highly suitable excipient in formulations for all patient target groups.[42–44] Regarding the superdisintegrant, the result of the preliminary experiments suggested that 10–20% is the optimum concentrations of croscarmellose sodium in the formulations.
Characterization and statistical analysis of factorial design of MLX ODTTable 4 represents the collective data concerning the characteristics of MLX ODTs.
Weight uniformity testAs shown in Table 4, formulations prepared using 5% camphor, the weight loss upon sublimation ranged between 5.10% ± 0.41 and 6.02% ± 0.23, and for those prepared using 10% camphor the decrease in mean tablet weight was ranging from 9.74% ± 0.76 to 10.93% ± 0.69 which proves uniform camphor distribution throughout the formulations. Also, the agreement between the weight of the camphor added to the tablets and the loss in tablets’ weights resulting from camphor sublimation confirmed that almost all of camphor had sublimed from the tablets and that camphor was com-pletely replaced by pores.
Friability and hardness testsIn the friability test, the percentage weight loss for all formulations were less than 1% proving the suit-ability of the procedure and excipients selected for the preparation of MLX ODT. For hardness testing, during tablets preparation, the hardness of all tablets was adjusted to 5 kg before sublimation; however, camphor sublimation caused considerable reduction in tablets’ hardness and they all ranged between 2.2 and 4.5 kg. From the hardness test results presented in Table 4, it was apparent that all formulations prepared using isomalt as diluent had acceptable hardness (above 3 kg). It was reported that isomalt showed good binding properties.[44] Only formula 8 in the isomalt formulations showed lower hardness value of 2.73 kg which might be due to its composition that contains combined high concentrations of both camphor and croscarmellose sodium, both reduce the hardness as will be later explained. Tablets prepared using manni-tol as diluent resulted in lower hardness as they were lower than 3 kg except for formula 12 that had hard-ness value of 3.1 kg. It is generally well recognized that
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Table 5. Polynomial equations for the quantitative effect of independent variables (X1, X
2, X
3) on the responses DT1 and WT2 using coded
units.
Diluent type Equation3
Isomalt DT = 87.39 − 9.08 X1 − 17.69X
2 + 15.78X
3 + 3.13 X
1X
2 + 3.45 X
1X
3 + 13.12 X
2X
3 − 6.85 X
1X
2X
3
WT = 25.31 − 4.56 X1 − 5.31X
2 + 2.81X
3 − 0.69 X
1X
2 − 1.06 X
1X
3 − 1.31 X
2X
3 − 3.69 X
1X
2X
3
Mannitol DT = 36.92 − 2.92X1 − 2.284X
2 + 16.10 X
3 + 1.86 X
1X
2 − 2.50 X
1X
3 − 2.07 X
2X
3 + 2.07 X
1X
2X
3
WT = 15.25 − 3.50X1 − 3.00X
2 + 6.23 X
3 − 1.50 X
1X
2 − 3.13 X
1X
3 − 1.63 X
2X
3 − 1.63 X
1X
2X
3
1DT, disintegration time; 2WT, Wetting time; 3X1, % of camphor, X
2, % of croscarmellose sodium, and X
3 amount of PEG (in coded units).
−30 −20 −10 0
Standardized Effect
Normal Plot of the Standardized Effects(response is Disintegration time, Alpha = 0.05)
Perc
ent
1
510 B
A
a b
ABCAB
AB
ABC
BC
AC
A
C
B
AC
BC
C
20304050607080
9095
99
10 20 30 −10 0
Standardized Effect
Normal Plot of the Standardized Effects(response is Disintegration time, Alpha = 0.05)
Perc
ent
1
510
20304050607080
9095
99
10 20 30
FactorA Camphor%
Ac-Di-Sol%PEG
BC
Name
Not SignificantEffect Type
Significant
FactorA Camphor%
Ac-Di-Sol%PEG
BC
Name
Not SignificantEffect Type
Significant
Figure 5. Normal probability plots of disintegration time for (a) isomalt and (b) mannitol.
Incorporating MLX solid dispersion: Pilot pharmacokinetic study 9
tablet hardness is influenced primarily by two oppos-ing events: The inter-particle binding force (such as the surface molecular interaction and mechanical interlocking) and the inter-particle spacing (porosity) which decrease the number of contact points between the powder particles and based on the shape and diameter of constituent particles.[30,45] In the evaluation of the factors affecting tablets’ hardness, increasing camphor concentration, in all formulations, resulted in corresponding reduction in tablet hardness because higher camphor concentration is expected to produce more highly porous tablets which decrease the num-ber of possible contact points and the interparticlulate binding leading to reduced hardness and more fragile tablets.
It was also noticeable that moving from low to high croscarmellose sodium was associated with a decrease in tablets’ hardness. This effect could be correlated to the fact that the super-disintegration power of croscarmellose sodium is probably due to its unique fibrous nature; such fiber-shaped charac-teristic help forming hydrophilic channels that might result in increased porosity and facilitated wicking of water. Hence, the contact area over which interpar-ticulate force act would be decreased leading to less formation of solid bridges and lower values of tablets hardness.[30,46–48]
Statistical analysis of the in vitro disintegration time and wetting timeA two-level experimental design provides sufficient data to fit a polynomial equation, which is in the following form:
Y b b X b X b X b (X X )
b (X X ) b0 1 1 2 2 3 3 12 1 2
13 1 3
= + + + + + + 223 2 3 123 1 2 3 (X X ) b (X X X ) +
(3)
where Y is the dependent variable; b0 is the intercept and
b1–b
123 are the coefficients for the factors X
1, X
2 and X
3 and
their interaction terms. The polynomial equations after applying multiple regression analysis on the experimen-tal data are shown in Table 5. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (i.e. positive or negative).
Regarding the disintegration time test, Figure 5a and 5b represent normal probability plots of the effects of different formulations variables on disintegration time. The effects that lie along the normal probability line as round points are negligible (i.e. non-significant), whereas significant effects are those square points far from the normal probability line, i.e. not explained by natural experimental variation. The plot can be divided into two regions. The region lies on the right (or positive) side of the line, where the factors and their interactions
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10 A.A. Aboelwafa and R.H. Fahmy
Pharmaceutical Development and Technology
presented positive coefficients and the region on the left (or negative) side of the line, where the factors and their interaction presented negative coefficients. It is clear that all the selected factors and their interactions have significant effects on the disintegration time for both isomalt and mannitol, this may reflects the good selec-tion of these factors in the formulation of MLX ODT.
From the results shown in Figure 5 and from the values and signs of the coefficients of the factors in the polyno-mial equations (Table 5), it is clear that increasing PEG amount will delay the disintegration time of the tablets, because the coefficient b
3 bears a positive sign.
It worth noting that although the MLX SD4 (1:5) drug:polymer ratio was experimentally proven to pos-sess the best dissolution parameters in all the prepared solid dispersion preparations (Figure 3), its use in tablets preparation in the preliminary studies produced unac-ceptably delayed disintegration. All formulations pre-pared using SD4 disintegrated in more than 3 min due to its high PEG content (PEG constituted 30% of each tab-let), such that the tablets become totally unacceptable as ODTs. Lessening the concentration of PEG in tablets from 30% (using SD4) to 18% (using SD3) showed a significant reduction in tablet disintegration times. Therefore, only formulations having lower PEG concentrations; 6% PEG (using SD1) and 18% PEG (using SD3) were used in the formulation of ODT. This could be explained based on the thermo-mechanical properties of PEG. It melts at a temperature of approximately 55°C; consequently, PEG could plasticize, soften or melt during compression. Due to its waxy nature, heating in the vacuum oven could fill the pores within the tablet, thus, coating the disintegrants and other ingredients used in tablets with the fused PEG. After the release of the tableting pressure or cooling after sublimation, solidification of the fused material results in the formation of solid bridges between the particles, which then act as a binder, consequently increasing the disintegration time.[24,49] This may also explain the signifi-cant interaction between PEG and both of camphor and croscarmellose sodium.
Also, the coefficients b1 and b
2 bear negative signs
(Table 5) indicating that increasing the percentage of camphor or croscarmellose sodium significantly decreases the disintegration time. Both camphor and croscarmellose are used to counterbalance the strong effect of PEG. The faster tablets’ disintegration correlated to the increase in camphor concentration may be due to the increased number of pores after sublimation of cam-phor leading to higher porosity and therefore improved water penetration into the tablets.[50]
The significant interaction between camphor and croscarmellose sodium could be attributed to the fact that the first step in the disintegration process is the penetration of water into the tablet. Consequently, the tablet porosity has an important influence on the disin-tegration rate. Lower porosity will hinder the water from penetration into the tablet; therefore, the disintegration time will increase. Increasing the porosity, by increasing
camphor concentration, will lead to faster water pen-etration and consequently shorter disintegration time, but only to a certain limit. Increasing the porosity above this limit will cause the swelling force of the croscarmel-lose (disintegrant) to get lost in the cavities, so that more water volume is required to fulfill the disintegration process, resulting in a longer disintegration time of the tablet.[51]
Generally, the disintegration times of tablets prepared using isomalt as diluent are longer than those prepared using mannitol (Table 3). This difference in disintegra-tion time could be due to the difference in solubility between isomalt (40/100 g water at 20°C) and man-nitol (18/100 g water at 20°C).[27] Chebli and Cartilier[52] reported that, the more soluble is the filler, the longer is the disintegration of the tablet. This could be attrib-uted to the dissolution of polyols (such as isomalt) will increase the void spaces of the tablets, so that the swell-ing of croscarmellose will have less destructive effect on the tablets’ matrixes, so more water is required for croscarmellose to swell and achieve disintegration, consequently, the disintegration time is increased. Moreover, it is possible that isomalt, being more soluble, competes with croscarmellose for the water penetrat-ing into the tablets more successfully than mannitol. Bolhuis et al.[53] reported that the higher water solubility of isomalt, as compared with mannitol, inhibits water penetration, resulting in longer disintegration time. This was in agreement with the wetting time test that also revealed that the wetting times of tablets prepared using isomalt as diluent is longer than tablets prepared using mannitol (Table 3).
Wetting time of ODT is also an important parameter that when assessed, gives an insight into the disintegra-tion properties of the tablet; lower wetting times implies a quicker tablet disintegration.[10] Figures 6a and 6b represent the normal probability plots of the effects of different formulations variables on wetting time of ODTs prepared using either isomalt or mannitol and it is obvi-ous that all the selected factors have significant effects on the wetting times for both.
Table 3 clarifies that formulations contained 10% cam-phor showed shorter wetting times than the correspond-ing formulations prepared using the lower camphor concentration (5%); this is obviously because the higher camphor concentration formed tablets of higher poros-ity that allows for quicker water uptake and hence, faster wetting. Formulations prepared using lower PEG concen-trations SD1 (containing 6% PEG) showed faster tablets wetting than those containing higher PEG concentrations SD3 (containing 18% PEG); this might be because when water penetrates the tablet pores, it starts to dissolve the tablet constituents including PEG; at high PEG concen-trations, the initial water penetration is expected to result in highly viscous concentrated solution of the PEG at the pores that might block them and thus hinder the passage of the rest of the water leading to delayed wetting process and longer wetting times.
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−10.0 −7.5 −5.0 −2.5
Standardized Effect
Normal Plot of the Standardized Effects(response is Wetting time, Alpha = 0.05)
Perc
ent
1
510 B
A
ABC
AB
ACBC
C
A
C
B
AC
BCABC
AB
a b
20304050607080
9095
99
0.0 2.5 5.0 −10 −5 0 5
Standardized Effect
Normal Plot of the Standardized Effects(response is wetting time, Alpha = 0.05)
Perc
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1
510
20304050607080
9095
99
10 15 20
FactorA Camphor%
Ac-Di-Sol%PEG
BC
Name
Not SignificantEffect Type
Significant
FactorA Camphor%
Ac-Di-Sol%PEG
BC
Name
Not SignificantEffect Type
Significant
Figure 6. Normal probability plots of wetting time for (a) isomalt and (b) mannitol.
0 15 30 45 60Time (min)
Mel
oxic
am re
leas
ed (%
)
75 90
F 12F 4F 3MLX
0102030405060708090
100
105 120
Figure 7. Dissolution profiles of MLX alone and from the ODT formulations, F3, F4, and F12 in phosphate buffer (pH 6.8) at 37 ± 0.5°C, each is an average of three experiments.
Incorporating MLX solid dispersion: Pilot pharmacokinetic study 11
Water absorption ratio (WAR)The water absorption ratio (WAR) is an important crite-rion that gives an insight about the capacity of the super-disintegrant to absorb water and swell in the presence of little amount of water. The WAR as shown in Table 4 ranged between 21.26 for formulations 1 and 5 (con-taining the low croscarmellose sodium concentration) to 72.67 for formula 12 (having the high croscarmellose sodium concentration). Formulations prepared using lower superdisintegrant concentration (5%) showed lower water absorption ratios than those having higher croscarmellose sodium concentration (10%). This could be attributed to the fact that the higher superdisintegrant content absorb larger water amounts due to the previ-ously explained fibrous nature of croscarmellose sodium that facilitate water uptake and absorption.
In vitro dissolution study MLX ODTOn the basis of the previous results, tablet formulations which offered acceptable friability, hardness, and low disintegration times; namely, formulations F3, F4 and F12 were selected for the in vitro dissolution studies and compared to the dissolution pattern of pure MLX. The dissolution patterns of the selected formulations are presented in Figure 7. It is obvious from the dissolution profiles that MLX dissolution was noticeably higher in orodispersible formulations than from pure drug. All the dissolution parameters showed higher values than pure MLX; the initial MLX dissolution rate was 0.83%/min for pure MLX, while for F3, F4, and F12 was 3.47, 3.85, and 3.68%/min, respectively. In addition, the percentage MLX dissolved after 15 min (PD
15) was 11.06% for MLX
alone, 51.22% for F3, 40.89% for F4, and 46.84% for F12. Finally, the percentage MLX dissolved after 60 min (PD
60)
showed undoubted improvement of the MLX dissolu-tion from the orodispersible formulations; though the PD
60 from pure MLX was only 21.06%, F3 showed PD
60 of
88.29, F4 was 70.76%, and for F12 was 84.92%. All the pre-vious dissolution data confirm that MLX showed much enhanced dissolution from the solid dispersion ODT which may suggest improved in vivo absorption rate.
In vivo pharmacokinetic studiesAccording to the literature, the oral disintegration time of ODT should be 1 min or less, preferably about 30 s or less.[54] Formula 12 (Table 3) showed the shortest disinte-gration time (20 s) with acceptable hardness and friabil-ity, therefore it was selected for further evaluation.
Figure 8 shows the mean MLX plasma concentration vs. time profiles obtained after single oral administra-tions of both marketed IR tablet and the prepared MLX ODT (F12) and the mean pharmacokinetic characteris-tics are summarized in Table 6. The mean C
max for the ODT
(1.589 ± 0.159 µg/mL) was significantly higher (P = 0.037) than the mean C
max of the IR tablet (1.242 ± 0.203 µg/
mL). The 90% confidence intervals for the test/reference mean ratio of the log-transformed data of C
max (1.151–
1.442) failed to satisfy the bioequivalence criteria. The
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Table 6. The mean (± SD) pharmacokinetic parameters of MLX after oral administration of ODT tablet formulation and the marketed IR tablets to four healthy human volunteers under fasted condition.
ParameterODT
formulationIR
tabletStatistical
test (P)C
max (µg/mL) 1.589 ± 0.159 1.242 ± 0.203 0.037
tmax
(h)* 3.50 ± 0.750 5.75 ± 1.472 0.030
AUC0–24
(µg.h/mL) 32.763 ± 4.737 30.063 ± 2.763 0.086AUC
0-∞ (µg.h/mL) 40.189 ± 7.430 37.830 ± 9.879 0.168
t1/2
(h) 19.771 ± 2.176 19.326 ± 9.551 0.844
* Median.
0 2 4 6 8 10 12 14 16 18 20 22 24Time (hr.)
Mea
n M
LX p
lasm
a co
nc. (
µg/m
l)
26 28 30 32 34 36 38 40 42 44 46 48
MLX IRTMLX ODT
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Figure 8. Mean MLX plasma concentrations (µg/mL) (± SD) following the administration of 15 mg MLX orodispersible tablets in F12 (MLX ODT) and immediate release MLX tablets (MLX IRT).
12 A.A. Aboelwafa and R.H. Fahmy
Pharmaceutical Development and Technology
time for peak plasma concentration, tmax
, which reflects the rate of drug absorption, estimated from ODT and IR tablet were 3.5 ± 0.750 h and 5.75 ± 1.472 h, respec-tively, and the difference between the two treatments was statistically significant (P = 0.030). The higher C
max
and faster tmax
observed after ODT administration could be due to rapid disintegration and dissolution of the drug in the saliva, even in absence of water, resulting in very fast absorption from the buccal cavity.[11,12] Ghorab et al.[55] studied the effect of β-cyclodextrin complex formation on MLX absorption after oral administra-tion. In their study, the complexation of MLX with β-cyclodextrin enhanced the dissolution rate of MLX, resulting in, a significant shortening in t
max from 5.6–2.8 h
and increase in Cmax
from 1.2–1.76 µg/mL in humans. Similar results were also reported when a more soluble salt was formed between MLX and diethanolamine,[7] in this study, diethanolamine salt formation lead to about four-fold increase in the MLX dissolution rate, resulting in a significant reduction of t
max from 8.5 up to 0.5 h and
increase in Cmax
from 54.6–82.4 µg/mL in rats.The mean AUC
0–24 and AUC
0–∞ for ODT, which reflect
the total amount of drug absorbed, were estimated to be 32.763 ± 4.737 µg.h/mL and 40.189 ± 7.430 µg.h/mL, respectively, and they were proven to be statisti-cally insignificantly different (P > 0.05) from the mean AUC
0–24 and AUC
0–∞ for IR tablet (30.063 ± 2.763 µg.h/mL
and 37.830 ± 9.879 µg.h/mL, respectively). The 90% confidence intervals for the test/reference mean ratio of the log-transformed data of AUC
0–24 and AUC
0-∞ are
(1.031–1.143) and (0.992–1.163), respectively. The 90% confidence interval for AUC
0–24 and AUC
0-∞ are within
(0.8–1.25), which satisfied the bioequivalence criteria. Formulation of MLX into ODT and enhanced dissolu-tion rate showed insignificant effect on the extent of MLX absorption (AUC). This could be explained by the previous studies that proved that MLX is well absorbed after oral administration with an absolute bioavailability of 89% and is not markedly affected by concomitant food intake.[6] Statistical comparison of the half-life param-eter did not indicate significant difference (P = 0.844) between results from ODT (19.771 ± 2.176 h) and IR tab-lets (19.326 ± 9.551 h). The prepared ODT showed a mean oral disintegration time of 17 ± 3 s.
Based on these findings, it could be concluded that MLX ODT with significantly higher C
max and shorter t
max
than commercially available IR tablets was successfully designed and may be used for the earlier onset of action for MLX. Because MLX ODT needs not to be swallowed, it could be a good alternative for pediatric and geriatric patients.
Conclusion
The present investigation revealed the suitability of PEG 4000 as a carrier for the preparation of meloxicam solid dispersions, as demonstrated by XRD, DSC, and improved meloxicam dissolution and the successful incorporation of meloxicam PEG solid dispersion in orodispersible tablets. This was achieved by simple direct compres-sion method utilizing the combined techniques of using high concentration of superdisintegrant, croscarmellose sodium, and camphor sublimation technique to produce highly porous tablets. Meloxicam orodispersible tablet incorporating PEG solid dispersion exhibited significant faster absorption of meloxicam which may be used for the desired faster onset of action. This method can pro-duce orodispersible tablets by commonly used produc-tion methods and equipment, and can also be applied to a wide range of drugs.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.
References
1. Aghazadeh-Habashi A, Jamali F. Pharmacokinetics of meloxicam administered as regular and fast dissolving formulations to the rat: Influence of gastrointestinal dysfunction on the relative bioavailability of two formulations. Eur J Pharm Biopharm 2008;70:889–894.
2. Pairet M, van Ryn J, Schierok H, Mauz A, Trummlitz G, Engelhardt G. Differential inhibition of cyclooxygenases-1 and -2 by meloxicam and its 4′-isomer. Inflamm Res 1998;47:270–276.
Phar
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eutic
al D
evel
opm
ent a
nd T
echn
olog
y D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
nive
rsity
of
Con
nect
icut
on
10/2
0/12
For
pers
onal
use
onl
y.
Incorporating MLX solid dispersion: Pilot pharmacokinetic study 13
6. Tacca MD, Colucci R, Fornai M, Blandizzi C. Efficacy and tolerability of meloxicam, a COX-2 preferential nonsteroidal anti-inflammatory drug. Clin Drug Invest 2002;22:799–818.
7. Han HK, Choi HK. Improved absorption of meloxicam via salt formation with ethanolamines. Eur J Pharm Biopharm 2007;65:99–103.
8. Goel H, Vora N, Rana V. A novel approach to optimize and formulate fast disintegrating tablets for nausea and vomiting. AAPS Pharm Sci Tech 2008;9:774–781.
9. Chandrasekhar R, Hassan Z, Alhusban F, Smith AM, Mohammed AR. The role of formulation excipients in the development of lyophilised fast-disintegrating tablets. Eur J Pharm Biopharm 2009;72:119–129.
10. Bandari S, Mittapalli Rj, Gannu R, Rao YM. Orodispersible tablets: An overview. Asian J Pharma 2008;2:2–11.
11. Ahmed IS, Fatahalla FA.Pilot study of relative bioavailability of two oral formulations of ketoprofen 25 mg in healthy subjects. A fast-dissolving lyophilized tablet as compared to immediate release tablet. Drug Dev Ind Pharm 2007;33:505–511.
12. Shoukri RA, Ahmed IS, Shamma RN. In vitro and in vivo evaluation of nimesulide lyophilized orally disintegrating tablets. Eur J Pharm Biopharm 2009;73:162–171.
13. van Schaick EA, Lechat P, Remmerie BM, Ko G, Lasseter KC, Mannaert E. Pharmacokinetic comparison of fast-disintegrating and conventional tablet formulations of risperidone in healthy volunteers. Clin Ther 2003;25:1687–1699.
14. Liu YM, Liu GY, Liu Y, Li SJ, Jia JY, Zhang MQ, et al. Pharmacokinetic and bioequivalence comparison between orally disintegrating and conventional tablet formulations of flurbiprofen: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy Chinese male volunteers. Clin Ther 2009;31:1787–1795.
15. Chen L, Jiang X, Huang L, Lan K, Wang H, Hu L, et al. Bioequivalence of a single 10-mg dose of finasteride 5-mg oral disintegrating tablets and standard tablets in healthy adult male Han Chinese volunteers: A randomized sequence, open-label, two-way crossover study. Clin Ther 2009;31:2242–2248.
16. Singh R, Madan J. Optimization of mouth dissolving meloxicam tablets prepared by sublimation technique. Drug Invention Today 2009;1:146–149.
17. Swamy PV, Areefulla SH, Shirsand SB, Granda S, Prashanti B. Orodipersible tablet of meloxicam using disintegrant blends for improved efficacy. Indian J Pharm Sci 2007;69:836–840.
18. Lipka E, Amidon GL. Setting bioequivalence requirements for drug development based on preclinical data: Optimizing oral drug delivery systems. J Control Release 1999;62:41–49.
19. Ambrus R, Kocbek P, Kristl J, Sibanc R, Rajko R, Szabo- Revesz P. Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam. Int J Pharm 2009;381:153–159.
20. Vijaya Kumar SG, Mishra DN. Preparation, characterization and in vitro dissolution studies of solid dispersion of meloxicam with PEG 6000. Yakugaku Zasshi 2006;126:657–664.
21. Pathak D, Dahiya S, Pathak K. Solid dispersion of meloxicam: Factorially designed dosage form for geriatric population. Acta Pharm 2008;58:99–110.
22. Ghareeb MM, Abdulrasool AA, Hussein AA, Noordin MI. Kneading technique for preparation of binary solid dispersion of meloxicam with poloxamer 188. AAPS Pharm Sci Tech 2009;10:1206–1215.
23. Nassab PR, Rajko R, Szabo-Revesz P. Physicochemical characterization of meloxicam-mannitol binary systems. J Pharm Biomed Anal 2006;41:1191–1197.
24. Perissutti B, Rubessa F, Moneghini M, Voinovich D. Formulation design of carbamazepine fast-release tablets prepared by melt granulation technique. Int J Pharm 2003;256:53–63.
25. Verheyen S, Blaton N, Kinget R, Van den Mooter G. Mechanism of increased dissolution of diazepam and temazepam from poly-ethylene glycol 6000 solid dispersions. Int J Pharm 2002;249:45–58.
26. Suzuki H, Sunada H. Comparison of nicotinamide, ethylurea and polyethylene glycol as carriers for nifedipine solid dispersion systems. Chem Pharm Bull (Tokyo) 1997;45:1688–1693.
27. Rowe RC, Sheskey PJ, Owen SC, editors. Handbook of pharmaceutical excipients. 5th ed. London: Pharmaceutical Press and American Pharmacists Association; 2006.
28. Sammour OA, Hammad MA, Megrab NA, Zidan AS. Formulation and optimization of mouth dissolve tablets containing rofecoxib solid dispersion. AAPS Pharm Sci Tech 2006;7:E55.
29. Okonogi S, Puttipipatkhachorn S. Dissolution improvement of high drug-loaded solid dispersion. AAPS Pharm Sci Tech 2006;7:E52.
30. Sunada H, Bi Y. Preparation, evaluation and optimization of rapidly disintegrating tablets. Powder Technol 2002;122:188–198.
31. Bae JW, Kim MJ, Jang CG, Lee SY. Determination of meloxicam in human plasma using a HPLC method with UV detection and its application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2007;859:69–73.
32. Craig DQM. Polyethylene glycols and drug release. Drug Dev Ind Pharm 1990;16:2501–2526.
33. Leonardi D, Barrera MG, Lamas MC, Salomon CJ. Development of prednisone:polyethylene glycol 6000 fast-release tablets from solid dispersions: solid-state characterization, dissolution behavior, and formulation parameters. AAPS Pharm Sci Tech 2007;8:E108.
35. Lloyd GR, Craig DQ, Smith A. A calorimetric investigation into the interaction between paracetamol and polyethlene glycol 4000 in physical mixes and solid dispersions. Eur J Pharm Biopharm 1999;48:59–65.
36. Najib NM, Suleiman MS. Characterization of a diflunisal polyethylene glycol solid dispersion system. Int J Pharm 1989;51:225–232.
37. Craig DQ. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm 2002;231:131–144.
38. Sjökvist Saers E, Craig DQM. An investigation into the mechanisms of dissolution of alkyl p-aminobenzoates from polyethylene glycol solid dispersions. Int J Pharm 1982;83: 211– 219.
39. Gohel M, Patel M, Amin A, Agrawal R, Dave R, Bariya N. Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique. AAPS Pharm Sci Tech 2004;5:e36.
40. Patel DM, Patel M. Optimization of fast dissolving etoricoxib tablets prepared by sublimation technique. Indian J Pharm Sci 2008;70:71–76.
41. Sugimoto M, Matsubara K, Koida Y, Kobayashi M. The preparation of rapidly disintegrating tablets in the mouth. Pharm Dev Technol 2001;6:487–493.
42. Ndindayino F, Henrist D, Kiekens F, Van den Mooter G, Vervaet C, Remon JP. Direct compression properties of melt-extruded isomalt. Int J Pharm 2002;235:149–157.
43. Ndindayino F, Henrist D, Kiekens F, Vervaet C, Remon JP. Characterization and evaluation of isomalt performance in direct compression. Int J Pharm 1999;189:113–124.
45. Kottke MK, Rudnic EM. Modern pharmaceutics. 4th ed. Banker GS, Rhodes CT, editors. New York: Marcel Dekker Inc; 2002.
46. Zhao N, Augsburger LL. The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of
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hydrochlorothiazide from directly compressed tablets. AAPS Pharm Sci Tech 2005;6:E120–126.
47. Bi YX, Sunada H, Yonezawa Y, Danjo K. Evaluation of rapidly disintegrating tablets prepared by a direct compression method. Drug Dev Ind Pharm 1999;25:571–581.
48. Bi Y, Yonezawa Y, Sunada H. Rapidly disintegrating tablets prepared by the wet compression method: Mechanism and optimization. J Pharm Sci 1999;88:1004–1010.
49. Serajuddin AT. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 1999;88:1058–1066.
50. Koizumi K, Watanabe Y, Morita K, Utoguchi N, Matsurnoto M. New method of preparing high-porosity rapidly saliva soluble compressed tablets using mannitol with camphor, a subliming material. Int J Pharm 1997;152:127–131.
52. Chebli C, Cartilier L. Cross-linked cellulose as a tablet excipient: A binding/disintegrating agent. Int J Pharm 1998;171: 101–110.
53. Bolhuis GK, Rexwinkel EG, Zuurman K. Polyols as filler-binders for disintegrating tablets prepared by direct compaction. Drug Dev Ind Pharm 2009;35:671–677.
54. Kuno Y, Kojima M, Ando S, Nakagami H. Evaluation of rapidly disintegrating tablets manufactured by phase transition of sugar alcohols. J Control Release 2005;105:16–22.
55. Ghorab MM, Abdel-Salam HM, El-Sayad MA, Mekhel MM. Tablet formulation containing meloxicam and beta-cyclodextrin: Mechanical characterization and bioavailability evaluation. AAPS Pharm Sci Tech 2004;5:e59.
