Panda et al.

Future Journal of Pharmaceutical Sciences

https://doi.org/10.1186/s43094-020-0021-x
(2020) 6:4
Future Journal of
Pharmaceutical Sciences

RESEARCH Open Access

Formulation and development of floating

multiple-unit minitablets of Nimodipine
without using a gas-generating agent:
in vitro and in vivo characterization
M. Panda1*, M. E. B. Rao1, C. N. Patra1, J. Panda1, K. C. Panigrahi1 and G. Patro2

Abstract
Background: Floating drug delivery systems have been reported for different active pharmaceutical ingredients as
single-unit tablets with gas-generating agents. In this present research, the formulation of floating multiple-unit
minitablets of Nimodipine without using gas-generating agent was attempted with an objective of increased
residence time, sustain-release and improved oral bioavailability. Solid dispersion with different ratios (1:0.5, 1:1, 1:
1.5, 1:2, 1:2.5) of drug with the lipophilic carrier such as Compritol ATO 888, Gelucire 43/01, G39/01 and Precirol ATO
05 was formulated using melt granulation technique. The adsorbent Sylysia 350 to lipophilic carrier is maintained at
1:1. The granules were compressed into minitablets weighing 15 mg and were filled into a ‘0’ size capsule.
Results: Differential scanning calorimetry study justified no interaction of the drug with excipients. The formulations
which exhibited desirable flow property, floating lag time less than 1 min and floating time of 12 h were further
characterized for various post-compression parameters. The optimized single-dose (capsule) of floating multiple-unit
minitablets of Nimodipine consisting of 60 mg of drug, 120 mg of G43/01 and 120 mg of Sylysia 350 showed an
average of floating lag time within 24.48 s, floating time of 14.32 h and sustained-release up to 12 h.
Pharmacokinetic study of the optimized formulation (F9) showed nearly 2.5 times increase in area under the curve
with increased residence time in comparison to aqueous suspension of Nimodipine. The stability study revealed no
significant change in various parameters before and after storage.
Conclusion: Hence, gelucire 43/01-based multiple-unit minitablets of Nimodipine can be considered a promising
approach for sustaining the drug release with gastric retention for 12 h without using gas-generating agent.
Keywords: Floating multiple unit minitablets, Pharmacokinetic study, Lipophilic carriers

Background dosage form due to polymer failure [5, 6]. Like other
For a long time, oral-controlled release (CR) formulations multiple-unit systems, minitablets can be considered a
are popularly used for controlling the release of drugs. Short promising approach which releases the drug from the sub-
transit time of drug with the absorption window in the units (minitablets) after the disintegration of capsule [7, 8].
stomach causes the release of drug in the non-absorbing The drug having short biological half-life favours develop-
distal segment of GIT leading to poor bioavailability [1, 2]. ment of a sustained-release (SR) while drug with absorption
These features are responsible for the design of gastro- window in upper GI tract favours the development of float-
retentive formulations [3, 4]. Dose-dumping is the main ing drug delivery system, respectively [9–12]. Even though
disadvantage associated with sustained-release single-unit Nimodipine was developed as a calcium channel blocker,
but later, it was used more frequently in preventing a major
complication of subarachnoid haemorrhage. Hydrophobic
* Correspondence: [email protected]
1
Roland Institute of Pharmaceutical Sciences, Berhampur, Biju Patnaik
polymer can be used in the preparation of sustained and
University of Technology, Rourkela, Odisha 760010, India floating formulations. Hydrophobicity of certain carriers
Full list of author information is available at the end of the article

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made.
Panda et al. Future Journal of Pharmaceutical Sciences (2020) 6:4 Page 2 of 9

such as Compritol ATO 888 (COM), Gelucire 43/01(G43/ min from room temperature up to 220 °C. An empty
01), Gelucire 39/01 (G39/01) and precirol ATO 05 (PRE) is aluminum pan was used as a reference. The DSC curve
the reason for their release retarding ability [13]. Hydropho- was plotted over a temperature range in order to predict
bic polymer retards the hydration rate of the matrix which the thermodynamic compatibility [18].
results variability in release profile. Hydrophobicity of car-
riers such as COM, G43/01, G39/01 and PRE is due to the Micromeritic properties of granules
presence of the certain hydrophobic group in their molecu- The pure drug Nimodipine and solid dispersion granules
lar structure. It can be inferred from their low HLB value. of all the prepared formulations were characterised for
This is the reason for retarding the matrix wetting rate by various micromeritic properties. The bulk density, tap
using these polymers as carrier. Their low melting point density, angle of repose, Carr’s Index, and Hausner’s
makes them suitable for melt granulation method thereby ratio of all the formulations were determined as per
obviating the need for organic solvents for solubilization. standard procedure [19].
The higher concentration of lipophilic carriers promotes
better control of the drug release because of the increase of In vitro buoyancy studies
lipid matrix density and long diffusion path length [14, 15]. Measurement of floating lag time
Many researchers have attempted floating granules and tab- The FLT was determined by conducting in vitro buoy-
lets using lipid carriers alone and also in combination with ancy studies for each of the formulation. The required
polymers like hydroxypropylmethylcellulose and ethylcellu- number of FMM was placed in a beaker containing 100
lose [16]. Hence, in the present research work, it is planned mL of 0.1 N HCl. FLT may be defined as the time re-
to use hydrophobic carriers in the formulation of floating quired for each of the minitablets to start floating on the
multiple-unit minitablets (FMM) of Nimodipine to achieve surface of the dissolution media [20].
floating with sustain-release for 12 h.
Measurement of floating time
Materials FMM tablets were placed in USP dissolution apparatus-
Nimodipine was received as a gift sample from Aurobindo II containing 900 mL of 0.1 N HCl to determine FT of
Pharma (Hyderabad, India). SYL was kindly provided as each formulation. FT is the total time or duration of
ex-gratis by Fuji Chemicals Pvt. Ltd. (Japan). COM, G43/ floating when a dosage form is placed in a dissolution
01, G39/01 and PRE were provided as gift samples from media [21].
Gattefosse Pvt. Ltd. (Mumbai, India). All other chemicals
and solvents were of analytical grade or highest quality Evaluation of post-compression parameters
and were used as such as obtained. The compressed minitablets were subjected to various
quality control tests such as weight variation, hardness,
Methods friability, disintegration and drug content as per the stand-
Preparation of FMM of Nimodipine ard procedure [22]. Weight variation was determined by
Melt granulation technique was adopted for preparing weighing 20 minitablets individually, hardness was deter-
the solid dispersion of Nimodipine and lipophilic carrier mined by taking 6 tablets from each formulation using a
such as COM, G43/01, G39/01 and PRE. The lipophilic digital hardness tester (Electro lab Ltd., India), friability
carrier was heated on a water bath in a temperature was determined taking minitablets equivalent to 6.5 g in a
range of 50 to 60 °C with continuous stirring. To the Roche® friabilator (Electrolab Pvt. Ltd., India), which was
molten lipid dispersion, Nimodipine powder was added rotated for 4 min at 25 rpm. The disintegration test was
and stirred for 10 min. The SYL in 1:1 ratio with lipo- performed for 1 h in 0.1 N HCl by taking 6 minitablets.
philic carrier was added to the dispersion with continued Drug content was determined by taking ten weighed mini-
mixing for 10 min in order to solidify the molten mass. tablets from each formulation and finely powdered. The
Then, solid dispersion was sieved through mesh no. # powder equivalent to 25 mg of Nimodipine was weighed
40. The resultant granules were compressed into 3-mm and taken in a 25-ml volumetric flask, extracted with 0.1
circular minitablets and were filled into a gelatine cap- N HCl. The mixture was then filtered and 1 ml of the
sule of size ‘0’ [17]. filtrate was suitably diluted and analysed at 350 nm
spectrophotometrically.
Compatibility studies using differential scanning calorimeter
The pure drug Nimodipine and its solid dispersions with In vitro dissolution studies
carriers were examined for compatibility study employing The in vitro dissolution studies of different FMM were
DSC (Shimazu Ltd., Japan). All the accurately weighed conducted in a USP dissolution apparatus-II (paddle
samples were placed in sealed aluminum pans before pla- method with a paddle speed of 50 rpm) taking 900 mL
cing the pan on sample holder at a scanning rate of 10 °C/ 0.1 N HCl as dissolution medium maintained at 37 ±
Panda et al. Future Journal of Pharmaceutical Sciences (2020) 6:4 Page 3 of 9

Table 1 Composition of nimodipine solid dispersion systems

Formulations Nimodipine (g) Compritol ATO 888 (g) Gelucire 43/01 (g) Gelucire 39/01 (g) Precirol ATO 5 (g) Sylysia 350 (g)
F1 1 0.5 – – – 0.5
F2 1 1 – – – 1
F3 1 1.5 – – – 1.5
F4 1 2 – – – 2
F5 1 2.5 – – – 2.5
F6 1 – 0.5 – – 0.5
F7 1 – 1 – – 1
F8 1 – 1.5 – – 1.5
F9 1 – 2 – – 2
F10 1 – 2.5 – – 2.5
F11 1 – – 0.5 – 0.5
F12 1 – – 1 – 1
F13 1 – – 1.5 – 1.5
F14 1 – – 2 – 2
F15 1 – – 2.5 – 2.5
F16 1 – – – 0.5 0.5
F17 1 – – – 1 1
F18 1 – – – 1.5 1.5
F19 1 – – – 2 2
F20 1 – – – 2.5 2.5

Table 2 Composition of minitablet (weight of each minitablet 15 mg)

Formulation Quantity drug and excipient (mg) in each solid dispersion formulation Number
of
Nimodipine Compritol ATO 888 Gelucire 43/01 Gelucire 39/01 Precirol ATO 5 Sylysia 350
tablets
for 60
mg dose
F1 7.5 3.75 – – – 3.75 8
F2 5 5 – – – 5 12
F3 3.75 5.625 – – – 5.625 16
F4 3 6 – – – 6 20
F5 2.5 6.25 – – – 6.25 24
F6 7.5 – 3.75 – – 3.75 8
F7 5 – 5 – – 5 12
F8 3.75 – 5.625 – – 5.625 16
F9 3 – 6 – – 6 20
F10 2.5 – 6.25 – – 6.25 24
F11 7.5 – – 3.75 – 3.75 8
F12 5 – – 5 – 5 12
F13 3.75 – – 5.625 – 5.625 16
F14 3 – – 6 – 6 20
F15 2.5 – – 6.25 – 6.25 24
F16 7.5 – – – 3.75 3.75 8
F17 5 – – – 5 5 12
F18 3.75 – – – 5.625 5.625 16
F19 3 – – – 6 6 20
F20 2.5 – – – 6.25 6.25 24
Panda et al. Future Journal of Pharmaceutical Sciences (2020) 6:4 Page 4 of 9

0.5 °C. A total of 5 mL sample was withdrawn at regular In vivo pharmacokinetic study
time intervals up to 12 h (0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 Twelve number of male albino rabbits of body weight
h) and were analysed using UV-spectrophotometer at 1.5 kg were selected from the stock of animal house.
354 nm. The kinetics of drug release were analysed from They were divided into 2 groups having 6 animals in each
the dissolution data by using zero-order, first order, group for test (minitablet administration) and standard
Higuchi, and Korsmeyer-Peppas model [23, 24]. (aqueous suspension of nimodipine). They were treated
Zero order equation is Q = K0t. with hygienic food and fresh water twice daily. All animals
First order equation is ln (100 − Q) = ln 100 − K1t were maintained for a wash-out period of 15 days prior to
Higuchi Equation is Q = K2 √ t the study. The dose of nimodipine was calculated as 4.2
Korsmeyer Peppa’s equation is log M Mt
∞
¼ logK þ n logt mg for each rabbit of weight approx. 1.5 kg.
where Q is the amount of drug released at time t, K0
zero order release rate constant, K1 is first order release The dose for rabbit was calculated as follows
rate constant, the time, K2 diffusion rate constant, is the Total dose ðin humansÞ  0:07ðfactor for each 1:5 kg weight of rabbit Þ
amount of drug released at time t, Mt is the amount of ¼ ð60  0:07  1:5Þ=1:5 ¼ 4:2 mg for 1:5 kg rabbit
drug released at time t, M∞ is the amount of drug released
at infinite time, initial amount of the drug in solution, K The optimised formulation (minitablet) and aqueous
release rate constant and n is diffusional exponent. dispersion of Nimodipine were administered in the
form of dispersion to six male rabbits each in two
groups using Ryle’s tube [26]. At different time points
Stability study (0.5, 2, 4, 8, 12 and 24 h), blood sample of 0.5 mL was
Stability study of the prepared FMM of Nimodipine was con- withdrawn from the marginal ear vein of the rabbit.
ducted for a period of 6 months as prescribed in ICH guide- Each blood samples was centrifuged for 10 min at 3000
lines. The formulations were examined at the time points of rpm and the supernatant layer, i.e. serum was collected
0, 1, 3 and 6 months for the different parameters [25]. using micropipette. All the samples were analysed using

Fig. 1 DSC thermo-gram of a: pure drug Nimodipine, b: solid dispersion of Nimodipine with Compritol ATO 888 (1:1), c: Solid dispersion of Nimodipine
with Gelucire 43/01 (1:1), d: Solid dispersion of Nimodipine with Gelucire 39/01(1:1), e: Solid dispersion of Nimodipine with Precirol ATO 05(1:1)
Panda et al. Future Journal of Pharmaceutical Sciences (2020) 6:4 Page 5 of 9

reverse-phase ultrafast liquid chromatographic (UFLC) carrier such as COM, G43/01, G39/01 and PRE are
method. The various pharmacokinetic parameters like given in Table 1. The adsorbent SYL to lipophilic carrier
elimination rate constant (K), half-life (t1/2), peak is maintained at 1:1. Each minitablet weighing 15 mg is
plasma concentration (Cmax), time to attain the peak filled into a ‘0’ size capsule. The composition of each
plasma concentration (Tmax), area under the curve formulation of FMM is illustrated in Table 2.
(AUC) and area under the first moment curve (AUMC)
were calculated. The animal experiments complied with
Compatibility studies using differential scanning calorimeter
the ARRIVE guidelines and carried out in accordance
FMM DSC study revealed that the pure drug Nimodi-
with the U.K. Animals (Scientific Procedures) Act, 1986
pine showed a sharp endothermic peak at 124.6 °C with
and associated guidelines, EU Directive 2010/63/EU for
a narrow melting range with an onset temperature of
animal experiments. The pharmacokinetic study was
122 °C and end set temperature of 128 °C. The peaks
approved by Institutional Animals Ethics committee
remained nearly the same in all representative formula-
[926/PO/Re/5/06/CPCSEA, Approval No.97]. Anaes-
tion such as F1, F6, F11 and F16. Figure 1 confirms that
thetic agents are not used since the procedures associ-
no significant overlapping or shifting of the peak in the
ated with routine blood withdrawal. Euthanasia method
thermograms, however, broadening of peaks was ob-
is not applicable for this study since the animals were
served in all formulations indicating the formation of
rehabilitated after the study period as per the standard
solid dispersion.
procedure. The animals were procured from Saha En-
terprise, Kolkata, India (CPCSEA Regd no: 1828/PO/
Bt/S/15/CPCSEA). Micromeritic properties of granules
The micromeritic parameters for all the formulation as
well as the pure drug were studied and the results are
Results depicted in Table 3. The micromeritic properties of pure
The composition of solid dispersion with different ratios drug revealed that the flowability and compressibility were
(1:0.5, 1:1, 1:1.5, 1:2, 1:2.5) of drug with the lipophilic very poor for processing into tablet dosage form. All the
Table 3 Micromertics properties of solid dispersions Table 4 Determination of density, floating lag time and floating
Formulations *Angle of repose *Carr’s index *Hausner’s ratio time of minitablets
(0) (C.I) (H.R)
Formulations *Density *Floating lag *Floating *%
Nimodipine 42 ± 2.4 29 ± 2.1 1.46 ± 0.8 (g.cm−3) time (s) duration (h) Floating
F1 24.23 ± 2.1 15.62 ± 1.6 1.19 ± 0.4 F1 0.20 ± 0.01 NF IF IF
F2 22.67 ± 1.9 16.18 ± 1.2 1.22 ± 0.7 F2 0.21 ± 0.02 NF IF IF
F3 22.48 ± 2.2 14.42 ± 1.2 1.18 ± 0.2 F3 0.24 ± 0.01 235 ± 12 1 ± 0.06 50 ± 2
F4 20.67 ± 1.9 16.89 ± 1.2 1.22 ± 0.7 F4 0.22 ± 0.01 128 ± 7 1.5 ± 0.08 70 ± 3
F5 24.23 ± 2.1 17.62 ± 1.6 1.19 ± 0.4 F5 0.21 ± 0.03 85 ± 3 1 ± 0.04 80 ± 2
F6 23.23 ± 2.1 15.62 ± 1.6 1.19 ± 0.4 F6 0.21 ± 0.01 65 ± 2 6 ± 0.2 90 ± 4
F7 22.67 ± 1.9 16.89 ± 1.2 1.22 ± 0.7 F7 0.20 ± 0.02 56 ± 2 10 ± 0.3 95 ± 2
F8 22.48 ± 2.2 15.39 ± 1.2 1.18 ± 0.2 F8 0.21 ± 0.02 35 ± 3 12 ± 0.4 94 ± 3
F9 24.48 ± 2.2 14.32 ± 1.2 1.18 ± 0.2 F9 0.24 ± 0.02 18 ± 1 14 ± 0.3 100 ± 4
F10 21.67 ± 1.9 18.89 ± 1.2 1.22 ± 0.7 F10 0.23 ± 0.01 15 ± 1 16 ± 0.2 100 ± 3
F11 22.23 ± 2.1 16.62 ± 1.6 1.19 ± 0.4 F11 0.20 ± 0.01 70 ± 2 7 ± 0.2 92 ± 3
F12 24.67 ± 1.9 17.89 ± 1.2 1.22 ± 0.7 F12 0.24 ± 0.02 62 ± 3 9 ± 0.3 96 ± 4
F13 22.48 ± 2.2 15.46 ± 1.2 1.19 ± 0.2 F13 0.20 ± 0.01 38 ± 2 11 ± 0.2 94 ± 3
F14 24.48 ± 2.2 14.25 ± 1.2 1.18 ± 0.2 F14 0.23 ± 0.01 22 ± 1 14 ± 0.4 98 ± 3
F15 22.67 ± 1.9 16.89 ± 1.2 1.22 ± 0.7 F15 0.21 ± 0.03 17 ± 1 16 ± 0.3 100 ± 3
F16 21.54 ± 2.1 17.13 ± 1.6 1.15 ± 0.4 F16 0.22 ± 0.01 NF IF IF
F17 23.61 ± 1.9 16.16 ± 1.4 1.23 ± 0.3 F17 0.24 ± 0.01 NF IF IF
F18 21.24 ± 3.1 14.31 ± 1.2 1.22 ± 0.2 F18 0.21 ± 0.02 345 ± 11 1.5 ± 0.06 45 ± 2
F19 25.15 ± 2.2 15.16 ± 2.6 1.21 ± 0.2 F19 0.23 ± 0.02 226 ± 8 1.2 ± 0.04 65 ± 3
F20 21.56 ± 1.9 13.14 ± 1.2 1.19 ± 0.7 F20 0.23 ± 0.01 175 ± 9 2 ± 0.01 70 ± 2
*Mean ± SD, n = 6 *Mean ± SD, n = 6, NF Not Floating, IF Instant floating
Panda et al. Future Journal of Pharmaceutical Sciences (2020) 6:4 Page 6 of 9

Table 5 Quality control tests of minitablets

Formulations *Drug content (%) *Hardness (Kg/sq. cm) *Friability (%) Disintegration test for 1 h
F8 98.5 ± 2.1 4.1 ± 0.3 0.1 ± 0.004 Not disintegrated
F9 98 ± 3.4 4.5 ± 0.4 0.8 ± 0.03 Not disintegrated
F10 98.5 ± 3.2 5.2 ± 0.2 0.7 ± 0.02 Not disintegrated
F14 98 ± 4.3 4.9 ± 0.2 0.6 ± 0.02 Not disintegrated
F15 99 ± 4.2 5.6 ± 0.3 0.4 ± 0.01 Not disintegrated
*Mean ± SD, n = 6

dispersion granules showed that the value of angle of re- Evaluation of post-compression parameters
pose, C. I and H. R were within the specified limit. The result of the quality control test of the different
formulations F8, F9, F10, F14 and F15 is depicted in
In vitro buoyancy studies Table 5. The obtained result showed that the various pa-
The in vitro buoyancy study was done and the value of rameters such as drug content, hardness, friability, disin-
density, floating lag time and floating time for all the tegration test were within the acceptable specification.
prepared formulations are illustrated in Table 4. As the
density of all FMM was much lower than the density of In vitro dissolution studies
GI fluid, it was expected that all minitablets will float. The in vitro dissolution study of the formulations was
However, peculiar results were observed in floating be- carried out and the plot of cumulative percentage drug re-
haviour. Minitablets formulated with G43/01 and G39/ lease against time is illustrated in Fig. 2. The resultant plot
01 showed an excellent floating behaviour with less than suggests that formulation F9 and F14 found to achieve the
1 min floating lag time and floating duration of more desirability of sustaining the drug release for 12 h. The
than 12 h (F8, F9, F10, F14 and F15) whereas FMM for- results of different drug release kinetic coefficients for for-
mulated with COM and PRE did not exhibit floating in mulation F8, F9, F10, F14 and F15 infer higher correlation
spite of low density of minitablets [27]. coefficient for zero-order release kinetics. All formulations

Fig. 2 Plot depicting the cumulative % drug release profile of formulation F8, F9, F10, F14 and F15
Panda et al. Future Journal of Pharmaceutical Sciences (2020) 6:4 Page 7 of 9

Table 6 Accelerated stability study

Time in Characterisation of F9 formulation Characterisation of F14 formulation
months
Drug content Floating lag time Floating duration T95%* Drug content Floating lag time Floating duration T95% (h)*
(%)* (s)* (h)* (%)* (h)* (h)*
0 98 ± 3.4 18 ± 1 14 ± 0.3 12 ± 0.4 98 ± 4.3 22 ± 1 14 ± 0.4 12 ± 0.6
1 97.5 ± 2.1 16 ± 0.5 13.5 ± 0.5 12 ± 0.2 97 ± 3.2 20 ± 0.7 11.5 ± 0.3 10.5 ± 0.5
3 97 ± 2.6 14 ± 0.6 13 ± 0.2 12 ± 0.1 96.5 ± 2.5 18 ± 0.5 10.5 ± 0.7 10 ± 0.3
6 97 ± 3.1 15 ± 1 13 ± 0.4 12 ± 0.2 96 ± 4.1 13 ± 0.6 9 ± 0.3 9.5 ± 0.4
*Mean ± SD, n = 6, T95%: Time required for more than 95% drug release

exhibited a higher correlation for Higuchi equation. All mobile phase acetonitrile: water (70:30), C18 column, flow
formulations showed release exponent greater than 0.5 rate 1 ml/min estimates retention time of 5.39 min. Table 7
less than 1. illustrates the calculated values of different pharmacoki-
netic parameters. The Tmax for the pure drug was found
Accelerated stability study to be 4 h whereas Tmax in case of best formulation (F9)
Formulation F9 and F14 were examined for 6 months of formulation was found to be 5 h, indicating slow release of
stability study as prescribed in the method section. The the drug. The AUC value of F9 was 57,438.19 ng.h/ml,
parameters such as drug content, FLT, FT, time for whereas it was found to be 21,678.98 ng.h/ml for pure
more than 95 percentage drug release (T95%) of F9 and drug indicating that SR FMM (F9) showed better bioavail-
F14 at various intervals are illustrated in Table 6. These ability, which is nearly 2.5 times than that of the pure drug
values indicated that there is no significant change in nimodipine. Cmax for Nimodipine was found to be
the parameters during the stability study period for F9. 2882.95 ng/mL whereas for optimized formulation, it was
However, it was found that parameters such as FLT, FT found to be 3498.21 ng/ml. Nearly 1. 2 times increase in
and T95% significantly changed for F14 formulation. Cmax value for F9 indicated better absorption of the drug
Hence, FMM formulation F9 was selected for further from the formulation. Elimination rate constant for pure
pharmacokinetic study. drug and F9 was 288.12 and 382.94 respectively. Higher
mean residence time (MRT) for F9 indicates increased
In vivo pharmacokinetic study residence time of the dosage form.
Figure 3 illustrates the mean serum drug concentration of
nimodipine vs. time graph of the optimized formulation Discussion
F9 and pure drug after conducting the pharmacokinetic Each of the prepared minitablet consists of a particular
study. UFLC method for estimation of Nimodipine using composition of lipophilic carrier (such as COM, G43/01,

Fig. 3 Plot depicting the mean serum concentration vs time of optimized FMM and Pure drug Nimodipine
Panda et al. Future Journal of Pharmaceutical Sciences (2020) 6:4 Page 8 of 9

Table 7 Determination of in vivo pharmacokinetic parameters release of drug from the hydrophobic matrix of G43/01.
Pharmacokinetic parameters Nimodipine OPT. formulation SR FMM (F9) showed better bioavailability, which is
*K (h− 1) 0.308 ± 0.012 0.054 ± 0.002 evident from 2.5 times increase in AUC. The better bio-
*Cmax (ng/mL) 2882.95 ± 123 3498.21 ± 152
availability is due to high residence time of the optimized
formulation than that of the pure drug. Hence it may be
*Tmax(h) 4 ± 0.1 5 ± 0.2
inferred that it is possible to prepare gastro-retentive
*AUC(ng.h/mL) 21,678.98 ± 78 57,438.19 ± 54 minitablets using G43/01 and G39/01 as lipid matrix with-
2
*AUMC (ng.h /mL) 66,337.67 ± 98 445,145.97 ± 58 out using gas-generating agent.
*MRT (h) 3.06 ± 0.12 7.75 ± 0.32
*Mean ± SD, n = 6 Conclusion
In this present research work, formulation and develop-
G39/01 and PRE), adsorbent SYL and drug. These re- ment of FMM Nimodipine were carried out with desired
sults of DSC ratifies that the carriers used in the present sustainability and gastric residence time. Solid dispersion
study are compatible with nimodipine. This may be due with different ratios (1:0.5, 1:1, 1:1.5, 1:2, 1:2.5) of drug with
to the engulfment of the drug in the molecular structure the lipophilic carrier such as COM, G43/01, G39/01 and
of the lipid matrix. Due to high oil adsorption capacity, PRE was formulated using melt granulation technique.
high specific surface area of SYL, it helps to improve From the above research work, it may be concluded that
compressibility and flowability of the prepared dispersion sustain-release gastro-retentive minitablets can be prepared
which can be predicted from their micromeritic properties. using both G43/01 and G39/01 without using gas generat-
Minitablets formulated with G43/01 and G39/01(F8, ing agents. Whereas the same was not observed with PRE
F9, F10, F14 and F15) showed excellent floating behav- and COM-based minitablets inspite of similar hydrophobi-
iour with desired floating lag time and floating time. city and density. Hence G43/01 based minitablets can be
Whereas FMM formulated with COM and PRE do not considered as the promising approach for formulation of
achieve the desirability. The in vitro buoyancy study re- sustain release with gastric retention. The pharmacokinetic
veals that hydrophobic lipid coat around the surface of profile of the optimized sustain release gastro-retentive
drug particle is the prime reason for floating behaviour. minitablet was found to be superior as compared with
It is also predicted that hydrophobicity and density alone aqueous suspension of pure drug, which can be therapeut-
may not responsible for achieving desirable floating. ically and commercially exploited.
Nature of the lipid matrix also played a significant role
Abbreviations
in achieving desired floating characteristics. COM: Compritol ATO 888; DSC: Differential scanning calorimeter;
F9 and F14 found to achieve the desirability of sustain- FLT: Floating lag time; FMM: Floating multiple unit minitablets; FT: Floating
ing the drug release for 12 h. Hence, lipid carrier G43/01 time; G39/01: Gelucire 39/01; G43/01: Gelucire 43/01; GI: Gastrointestinal;
h: Hour; HCl: Hydrochloric acid; min: Minute; ng: Nanogram; OPT: Optimised;
and G39/01 are effective in controlling the drug release PRE: Precirol ATO 05; SR: Sustained-release; SYL: Sylysia 350; UV: Ultraviolet
in a particular composition. The higher correlation coeffi-
cient for Higuchi equation suggests drug release was pri- Acknowledgements
marily by diffusion mechanism. All formulations showed Authors would like to thank the Principal and Management of Roland
Institute of Pharmaceutical Sciences, Berhampur, India for providing
release exponent greater than 0.5 and less than 1, signify- necessary facilities to carry out the research work.
ing non-fickian diffusion-controlled release mechanism.
Hence, on the basis of dissolution study, F9 and F14 can Authors’ contributions
All authors (PM, RB, PN, PJ, PC and PG) have contributed to this research
be predicted to satisfy all the criteria for a floating multiple work. All authors have read and approved the manuscript. PM as
unit minitablet. corresponding author executed the work and approved the manuscript from
Formulation F9 and F14 were examined for 6 months all co-authors. RB contributed to the conception and design of work. PN has
substantially revised the manuscript. PJ has contributed in the interpretation
of stability study which revealed no significant change of of data. PK has assisted in the execution of research work. PG contributed in
the parameters during the stability study period for F9. design of pharmacokinetic study.
However, it was found that parameters such as FLT, FT
Funding
and T95% significantly changed for F14 formulation No funding was received.
which may be attributed to softening of G39/01 based
FMM at the stability study temperature of 400 due to its Availability of data and materials
All data and material are available upon request
low melting point.
Pharmacokinetic study showed higher Cmax for mini- Ethics approval and consent to participate
tablets because of the increased residence time of float- The animal experiments complied with the ARRIVE guidelines and carried
ing minitablets in the upper part of the GI tract, i.e. the out in accordance with the U.K. Animals (Scientific Procedures) Act, 1986 and
associated guidelines, EU Directive 2010/63/EU for animal experiments. The
absorption window for Nimodipine. Longer Tmax for pharmacokinetic study was approved by Institutional Animals Ethics
the optimized minitablet (F9) can be attributed to slow committee [926/PO/Re/5/06/CPCSEA, Approval No.97].
Panda et al. Future Journal of Pharmaceutical Sciences (2020) 6:4 Page 9 of 9

Consent for publication 20. Arora S, Ali J, Ahuja A, Khar RK, Baboota S (2005) Floating drug delivery
Not Applicable systems: a review. AAPS Pharm Sci Tech 6(3):E372–E390
21. Shakya R, Thapa P, Saha RN (2013) In vitro and in vivo evaluation of
Competing interests gastroretentive floating drug delivery system of ofloxacin. Asian J Pharm Sci
The authors declare that they have no competing interests. 8(3):191–198
22. Aulton ME, Taylor K (2013) Aulton’s pharmaceutics : the design and
Author details manufacture of medicines. Elsevier Health Science, London
1
Roland Institute of Pharmaceutical Sciences, Berhampur, Biju Patnaik 23. Boldhane S, Kuchekar B (2010) Development and optimization of
University of Technology, Rourkela, Odisha 760010, India. 2College of metoprolol succinate gastroretentive drug delivery system. Acta Pharma
Pharmaceutical Sciences, Berhampur, Odisha, India. 60(4):415–425
24. Thakkar VT, Shah PA, Soni TG, Parmar MY, Gohel MC, Gandhi TR (2009)
Received: 30 August 2019 Accepted: 30 January 2020 Goodness-of-fit model-dependent approach for release kinetics of
levofloxacin hemihydrates floating tablet. DissolutionTechnol 16(1):35–39
25. Quality Guidelines: http://www.ich.org/products/guidelines/quality/article/
quality-guidelines.html. Accessed 20 Jan 2019
References 26. Panigrahi KC, Jena J, Jena GK, Patra CN, Rao MEB (2018) QBD-based systematic
1. Thapa P, Jeong S (2018) Effects of formulation and process variables on development of Bosentan SNEDDS: formulation, characterization and
gastroretentive floating tablets with a high-dose soluble drug and pharmacokinetic assessment. J Drug Deliv Sci Technol 47(October):31–42
experimental design approach. Pharmaceutics 10(3):E161 27. Chauhan B, Shimpi S, Mahadik KR, Paradkar A (2005) Preparation and
2. Hoffman A (1998) Pharmacodynamic aspects of sustained release evaluation of floating risedronate sodium–gelucire1 43/01 formulations.
preparations. Adv Drug Deliv Rev 33(3):185–199 Drug Dev Ind Pharm 31(9):851–860
3. Streubel A, Siepmann J, Bodmeier R (2006) Gastroretentive drug delivery
systems. Expert Opin Drug Deliv 3(2):217–233
4. Pawar VK, Kansal S, Garg G, Awasthi R, Singodia D, Kulkarni GT (2011) Publisher’s Note
Gastroretentive dosage forms: a review with special emphasis on floating Springer Nature remains neutral with regard to jurisdictional claims in
drug delivery systems. Drug Deliv 18(2):97–110 published maps and institutional affiliations.
5. Abdul S, Chandewar AV, Jaiswal SB (2010) A flexible technology for
modified-release drugs: multiple-unit pellet system (MUPS). J Control
Release 147(1):2–16
6. Kawashima Y, Niwa T, Takeuchi H, Hino T, Ito Y (1991) Preparation of
multiple unit hollow microspheres (microballoons) with acrylic resin
containing tranilast and their drug release characteristics (in vitro) and
floating behavior (in vivo). J Control Release 16(3):279–289
7. Lingam M, Ashok T, Venkateswarlu V, MadhusudanRao Y (2008) Design and
evaluation of a novel matrix type multiple units as biphasic gastroretentive
drug delivery systems. AAPS PharmSciTech 9(4):1253
8. Ichikawa M, Watanabe S, Miyake Y (1991) A new multiple-unit oral floating
dosage system. I: preparation and in vitro evaluation of floating and
sustained-release characteristics. J Pharm Sci 80(11):1062–1066
9. Singh BN, Kim KH (2000) Floating drug delivery systems: an approach to
oral controlled drug delivery via gastric retention. J Control Release 63(3):
235–259
10. Lopes CM, Bettencourt C, Rossi A, Buttini F, Barata P (2016) Overview on
gastroretentive drug delivery systems for improving drug bioavailability. Int
J Pharma 510(1):144–158
11. Tomassoni D, Lanari A, Silvestrelli G, Traini E, Amenta F (2008) Nimodipine
and its use in cerebrovascular disease: evidence from recent preclinical and
controlled clinical studies. ClinExpHypertens 30(8):744–766
12. Wu W, Zhou Q, Zhang HB, Ma GD, Fu CD (1997) Studies on nimodipine
sustained-release tablet capable of floating on gastric fluid with prolonged
gastric resident time. Yao Xue Xue Bao 32(10):786–790
13. Panigrahi KC, Patra CN, Jena GK, Ghose D, Jena J, Panda SK (2018) Gelucire:
a versatile polymer for modified release drug delivery system. Futur J Pharm
Sci 4(1):102–108
14. Jain SK, Gupta A (2009) Development of gelucire 43/01 beads of metformin
hydrochloride for floating delivery. AAPS PharmSciTech 10(4):1128
15. Patel DM, Patel NM, Patel VF, Bhatt DA (2007) Floating granules of ranitidine
hydrochloride-gelucire 43/01: formulation optimization using factorial
design. AAPS PharmSciTech 8(2):E25–E31
16. Mohamed MAE, Teaima MH, El-Monem RAA, Nabarawy NAE, Gaber DA
(2017) Formulation, release characteristics, and bioavailability study of
gastroretentive floating matrix tablet and floating raft system of Mebeverine
HCl. Drug Des Devel Ther 11:1081–1093
17. Jammula S, Patra CN, Swain S, Panigrahi KC, Nayak S, Dinda SC (2015)
Design and characterization of cefuroxime axetil biphasic floating
minitablets. Drug Deliv 22(1):125–135
18. Zheng X, Yang R, Tang X, Zheng L (2007) Part I: characterization of solid
dispersions of nimodipine prepared by hot-melt extrusion. Drug Dev Ind
Pharm 33(7):791–802
19. Fonner DE, Banker GS, Swarbrick J (1966) Micromeritics of granular
pharmaceutical solids I: physical properties of particles prepared by five
different granulation methods. J Pharm Sci 55(2):181–186