INTRODUCTION:
Now-a-days there is the paradigm shift in the pharmaceutical
technology especially in the domain of dosage form development. The conventional
concept of dosage form which was mostly limited to administration and palatability
of a drug has now inculcated the concept of drug delivery.
The latter is a more scientific technological approach which ponders on
the temporal and spatial aspects of delivery of the drug meanwhile the present
ability of the dosage form has also gained much importance. Formulation of drugs
into a presentable form is the basic requirement and need of toda.1 In
general, the dosage form can be understood as the means to administer the drug to
the living system. Dosage forms are not only limited to tablets, gels, ointments,
syrups, suspensions, suppositories, eye drops, patches, however, the most common
form is a tablet only. Each dosage form is tagged with its inherited pros and cons,
leaving the void for further exploration for an ideal drug administration/delivery
system. To exhibit the maximum dosage utilization efficiency, the system should
be such that it should encompass the temporal component of the supply of drug at
the desired rate to the spatial/desired site in a safer and effective manner. In
order to get the desired effects, the drug should be delivered to its site of action
at such rate and concentration to achieve the maximum therapeutic effect and minimum
adverse effect.2-4 In order to improve the pharmacokinetic profile, pharmacodynamic
performance, safety profile and alleviate the concerns of multiple dosing, a better
understanding of the physicochemical characteristics of the drug, pharmaceutical
profile of the excipients and physiological understanding of the biological milieu
is a mandate.3,5 In general, a majority of drugs follow the transcellular
and paracellular route of transport to cross the biological membranes, which is
further governed by the crystal structure of the system, the molecular size, pore
size, pore structure and the nature of the matrix of the dosage form.6,7
The most common mechanism of dug transport is the passive transport by diffusion
that is governed by Fick's first law. In this process, there is mobility of drug
molecules from its higher concentration to the lower concentrations, whereas the
active transport is exhibited on the cost of cellular energy, i.e., ATPs.6
Cassia fistula gum, which is a natural polymer, comprising of β-(1→4)
attached units of d-mannopyranose randomly with the units of β-(1 →6)
linked d-galactopyranose in the thrice molar ratio. This gum is extracted from the
seeds of the plant and has been extensively used for the development of various
kinds of tablets as vital excipient. Chemical derivatization including carboxymethylation,
carboxyethylation and cross linking with metals like calcium have been explored
and it has been observed that these chemical treatments not only improve the solubility
in cold water, but also results in a gum with better viscosity and microbial resistance.8
Nifedipine is a dihydropyridine-type calcium channel blocker, widely prescribed
for the management of hypertension. Though a promising molecule, it is relatively
less available to the central compartment (~53% oral bioavailability) due to extensive
first-pass metabolism.9 In an attempt to increase the oral bioavailability
of the drug by reducing its first pass metabolism, it was envisioned to develop
calcium cross-linked Cassia fistula gum (CCG)-based orodispersible tablet
loaded with nifedipine exploring various formulation approaches.
MATERIALS AND METHODS:
Materials:
Nifedipine was kindly supplied by Torrent Pharma,
Baddi, Himachal Pradesh. Crosscarmellose sodium was
kindly supplied by Tidal Laboratories Pvt. Ltd, Himachal Pradesh, India. Seeds of
cassia fistula were supplied by Sugatu Global, Uttarakhand, India. Nifedipine, hydroxy propyl methyl cellulose and
PEG 400 were procured from M/s Sigma- Aldrich, Bangalore, India. The buffer ingredients,
polyvinyl pyrrolidone, mannitol, magnesium stearate, lactose, talc, gelatin and
croscarmellose sodium were purchased from M/s Central Drug House, New Delhi, India.
HPLC solvents and Oyster BDS premium C18 (250 x 4.6, 5 µm; Batch No: 43/053) HPLC
column were supplied by M/s Merck Specialities Pvt Ltd., Mumbai, India. Double distilled
water was used throughout the studies and the chemicals provided were used as such
without any further purification.
Methods:
Extraction of Cassia fistula Gum:
Seed kernel powder of Cassia fistula (20g),
were used for the extraction of the gum. The powder slurry was prepared by soaking
the powder in 200 ml of cold distilled water. To this slurry, 800ml of boiling distilled
water was added, subsequently boiled for 20 min using a water bath, assisted with
continuous stirring. The boiling was stopped after the scheduled time period and
the system was left undisturbed for overnight to facilitate the sedimentation of
protein and fibres. The clear supernatant was harvested after centrifugation for
20 minutes at 5000rpm. The precipitation of the polysaccharides was completed by
pouring the supernatant in the twice volume of ethanol while stirring. The obtained
precipitate was washed sequentially with ethanol, diethyl ether and petroleum ether
followed by drying at 40-45ºC. The final product was sifted through sieve number
120 and desiccated till further use.8,10,11 Analytical techniques like
FT-IR and NMR were employed to characterize the gum.
Carboxymethylation of Cassia fistulaGum:
The previously reported method by Goyal et
al.was employed to derivatize cassia fistula gum to carboxymethylated
cassia fistula gum (CCG).12 To be price, the extracted gum (5g)
was suspended in 16 ml of 11.25 M NaOH solution, maintained at 1-4ºC. After complete
dispersion, 7ml of 7.93 M chloroacetic acid was added with stirring. The stirring
was continued for 1 h at ambient temperature. After 1 h, the temperature was raised
to 75°C and the system was further stirred for 30 min. A solution of methanol and
water in the volume ratio of 8:2 was prepared and neutralized by adding ethanoic
acid. The reaction mixture was cooled and added into the methanolic solution to
precipitate the CCG and the precipitates were collected on muslin cloth. The filtrate
was washed thrice with the neutralized methanolic solution and the harvested solid
was dried for 4 h at 50°C and sifted across sieve number 80. The final product was
vacuum desiccated till further use.8
Preparation of Calcium Crosslinked CCG:
The calcium cross linked derivative of CCG
was prepared by method reported by Rai et al.8 The CCG (2.5g) was dispersed in 50 ml of deionized water
to fetch 5% w/v dispersion. To this dispersion, 50ml of 0.45 M calcium chloride
was added drop wise assisted with constant stirring, followed by drop wise addition
of 50 ml of isopropyl alcohol. The thick and gelatinous mass of the calcium cross
linked CCG was harvested and washed with deionized water to remove the unreacted
CCG. The end point of the washing was determined by the disappearance of red colour
of the filtrate when mixed with standard magnesium–EDTA complex solution containing
Eriochrome black T indicator solution. The precipitates were freeze dried and passed
from sieve number 80 and desiccated till further use.8
Development and Optimization of Orodispersible
Tablets:
For the development of ODTs of nifedipine,
two methods of preparation viz. lyophilization method, cotton candy process and
disintegrant addition technique (wet granulation and dry granulation technique).
Lyophilization Method:
Formula was developed in such a way that each
tablet contains 10mg of nifedipine each with different amounts of binder and disintegrants
as shown in Table 1. A total of 8 formulations were developed where the percentages
of the binder (gelatin) and the disintegrant (cassia fistula gum) were kept
fixed and the amount of diluent, i.e., mannitol was varied.
Physical Characterization of the Blend:
Various techniques were employed to prepare
the granules for the tablet. The blend for the compression of tablets was prepared
using wet and dry granulation techniques and was characterized for angle of repose,
bulk density, tapped denisty, hausner’s ratio and
compressibility index.20-22
Characterization of the Prepared Orodispersible
Tablets:
The organoleptic evaluation like colour, shape
and texture were evaluated by the senses. Size (thickness) of the individual tablets
out of a sample of 20 tablets was measured using verniercaliper and it was expressed
in mm.23 For weight variation from each batch of tablets
randomly 20 tablets were selected and weighed individually and collectively too.
Individual weight and average weight of tablets were determined. Values were reported
in the average of three readings.23 For the determination of hardness
of prepared tablets, monsanto hardness tester was used.24, Roche friabilator was used for the friability testing of
the tablets. Friability of 0-1% is considered as acceptable range.25 To determine the wetting time, a piece of tissue paper
was double folded and placed in a petri plate containing 10ml of water. A tablet
was placed on the paper and time required for the completing wetting was note down.
Disintegration time of the tablets was determined using the method established
in the USP. The USP disintegration apparatus used for the determination of disintegration
time of ODTs and conventional tablets was same.26-28
In vitro Drug Release Studies:
USP dissolution apparatus Type-II (paddle)
was used to determine the percent drug release profile of the tablets by using sorenson’s
buffer pH 6.8 at 37±0.5°C. Release kinetic models like zeroorder, first order, higuchi,
korsmeyer pappas equations were used to know the pattern of release for the tablets.29,30
In vivo Studies of the Promised Orodispersible Tablets
(C1):
Animals:
All the animals (unisex wistar rats) involved
in the study are housed under the standard conditions and were provided free access
to pellet, food and water. All the animals were divided into groups with 2 animals
each (age: 4-8weeks; weight: 200-250g). The
institutional animal ethical clearance (vide letter no. ASCB/IAEC/ 13/19/141) was obtained before conducting the studies.
Group-I contained control animals; Group-II was administered with pure nifedipine;
group-III with nifedipine tablets prepared using cassia fistula gum using cotton
candy method and Group-IV comprised with marketed nifedipine tablets (Cacigard Tab-10mg).
Pharmacokinetic Studies:
All the animals were kept under overnight fasting
before the experiment and food was provided the post 2 h administration of the dosing.
During the administration of tablets, animals were placed into the animal body restraint
device so that the head of the animal alone was exposed. Both the jaws of the mouth
were separated by a wooden tongue depressor and the tablets were placed in the mouth
of the animals. The dose of nifedipine was 3 mg/kg was employed.31,32.
2ml of water was supplied as it helps in the disintegration of the tablet. Mouth
of the animal was kept open for 1 min using gentle strain to allow complete disintegration
and prevention of chewing. Blood samples (0.2ml each) were collected from the retro
orbital plexus/tail vein of the pre-anaesthetized animals at the regular time intervals
(0.5, 1, 2, 4, 8, 12 and 24 h) after the administration of the tablet. All the collected
blood samples were centrifuged at 3000rpm for 10 min for the extraction of plasma.
Drug content was analyzed using HPLC method discussed above33. The obtained
data was fitted into one compartmental open body model by peroral route and various
pharmacokinetic parameters were calculated using PK solver software.
Bio-distribution Studies:
After 24 h of drug administration, animals
were sacrificed and various body organs like the brain, kidney, liver, lungs, heart
and spleen were collected to know the amount of drug distributed to each organ.
Collected organs were washed in normal saline and perfused to remove the blood traces.
Homogenates were prepared in the saline by using homogenizer. The drug was extracted
from the homogenates and analyzed using HPLC method.34,35
Antihypertensive Activity:
Intra-peritoneal injection of N-nitro-L-arginine
methyl ester (L-NAME) at the dose of 185µmol/kg was used twice daily to induce hypertension
in wistar rats for one week. The injection volume was kept as 1ml per 100g of the
animal weight. The blood pressure of the animals was monitored daily and the animals
with systolic blood pressure in the range of 160-190mm of Hg after one week of the
L-NAME administration were labelled as the hypertensive rats for the anti-hypertensive
protocols.36,37 The selected hypertensive animals were divided
into a total of 3 groups of two animals each (n =06), i.e., groups receiving plain
nifedipine, marketed product and the optimized ODT (C1) of the drug. One analogous
control group was also maintained which received only distilled water. The other
groups received prescribed treatment at the equivalent dose of 3mg/kg for nifedipine.
Subsequent to the dose administration, to study the antihypertensive effect, the
systolic blood pressure was measured at time intervals of 0 min, 15 min, 30 min,
1 h and 2 h. The non-invasive tail cuff method was employed to measure the systolic
blood pressure of each animal at the predetermined time point using an experimental
blood pressure system.
Stability Studies:
In accordance to ICHQ1A (R2) guidelines, accelerated
stability studies for the C1 was performed at 40±2°C and 75±5% RH for 06 months.38
The developed ODTs packed in blister packs were charged for stability studies and
the observations were made on the basis of the disintegration time, dissolution
and drug assay over an interval of two month. The obtained values of % drug assay
at three observation points, i.e., 2 months, 4 months and 06 months were reported
as per ICH guidelines.
RESULTS AND DISCUSSION:
Characterization of pureandcross linked CCSGum by FT-IR and NMR:
The
peaks observed in the region of 3500–3200 cm−1 are the characteristic
absorption bands owing to the stretching hydroxyl groups, whereas the stretching
in the range of 3000–2850 cm−1 were result of the aliphatic stretching
and the ones observed in the range of 1650 cm−1 were resultant
of -CH-O- strechings. These peaks are characteristic of natural gums. On the other
hand, at the wavenumbers of 1020 cm-1, 1070 cm-1, and 1155
cm−1 the C-OH strechings due to the presence of glucan and mannose
structures were observesd. The peaks corresponding to the streching of N-H and C-N
at 1541 cm -1 and 1080 cm−1, which were conspicuous
in naïve gum, disappeared after crosslinking. In the FTIR spectrum of the crosslinked
gum, a higher shifting in the wavenumber of the absorption band at 3446 cm−1
was observed. This peak represents the streching of -OH groups, which decreased
substantially after cross linking The appearance of two additional peaks at 1411
cm-1 and 1028 cm-1 ensured the presence of the carboxy methyl
groups in the crosslinked gum, representing the respective strechings of C-O and
C=O groups.
Fig. 1: FTIR spectra of both the naïve gum and the
crosslinked gum
The proton-NMR data have been represented in Fig 2 and Fig 3.
Many researchers employ NMR as a tool to characterize natural polymers, but even
the International Union of Pure and Applied Chemistry (IUPAC) is also of the opinion
that the NMR is a relatively less sensitive tool to characterize the complex materials.39
Fig 2: 1H-NMR of native cassia fistula gum
Fig 3: 1H-NMR of calcium crosslinked
carboxymethylated cassia fistula gum
X-Ray Diffraction:
The X-ray diffraction pattern of the powder
of nifedipine, the excipients and the physical mixture of drug with excipients has
been shown in Fig 4. As vivid from the diffraction pattern, the plain drug
was crystalline in nature and the excipients were predominantly in amorphous form.
The physical mixture was also observed to be more of amorphous nature vouching lower
intermolecular attraction and enhanced dissolution rate potentials.
Fig 4: Power X-ray diffraction pattern of (a) Pure
nifedipine (b) The excipients (c) The physical mixture
Differential Scanning Calorimetry:
The endothermic peak at 173.48 ºC in the DSC
endotherm represents the melting point of the plain drug as shown in Fig 5.
The excipients represented by the blue line do not show any fixed melting point
as per natural behaviour. However, the physical mixture also exhibited an endotherm
at 173.48 ºC clearly ruling out any incompatibility between the drug and the excipients.
Fig 5: DSC thermogram of the nifedipine, excipients and
the physical mixture of the drug and excipients
Flow Properties of the Blends:
For wet and dry granulation process blends
were prepared and were analyzed for flow properties. Both the blends offered good
flow characteristics. Angle of repose, hausner’s ratio and carr’s index were found
to be not more than 25º, 1.25 and 15 respectively. Blend of both wet and dry granulation
were shown in Table 2. Both cotton candy and lyophilization methods
does not require any flowability, henceforth these parameters were not evaluated.
Evaluated flow parameters of powder blend were reported in Table3. These
results help in achievement of granules with desired quality and flow properties,
which indeed results in tablets with good quality. Based on various parameters determining
flow characteristics, it was confirmed that the hopper of the tablet machine will
not be clogged and uniformity can be assured during the manufacturing process.40
In-vitro Drug Release Studies:
The drug release profile data obtained for
all the selected products has been shown in Fig 7. For a sparingly water-soluble
drug, the ODTs developed. The molecular dispersions of the drug within the matrix
of the tablet and hydrotropic dispersion formation have resulted in the desired
pattern of drug release and profile.41
Fig 7: Drug release profile of nifedipine
from the selected ODTs (n = 3)
The data from the drug release studies was
fitted into various kinetic models, as already disclosed in the methods section.
Table 5 represents the values of the coefficient of determination (r2)
for the studied models.
Table 5: Coefficient Value of determination
obtained from the data fitting of the drug release profile in various drug
release models
|
Formulation
|
Coefficient Values (r2)
|
|
Zero order
|
First order
|
Higuchi
|
Korsmeyer Peppas
|
|
Cotton candy method (C1)
|
0.891
|
0.978
|
0.941
|
0.819
|
|
Lyophilization method (L8)
|
0.881
|
0.955
|
0.922
|
0.845
|
|
Wet granulation method (W2)
|
0.944
|
0.959
|
0.951
|
0.856
|
|
Dry granulation method (F2)
|
0.953
|
0.972
|
0.945
|
0.872
|
As vivid from the values of r2,
all the developed systems offered a first order drug release profile. This is the
most common drug release mechanism where there is erosion and dissolution of the
polymer (sugar in this case) followed by the polymer relaxation due to matrix swelling
and drug dissolution.42
Pharmacokinetic Studies
It was found that the plasma concentration
of nifedipine at every studied point in the rodents administered with nifedipine
ODT was substantially greater than that of the group receiving plain nifedipine
dispersion (p < 0.05). The values of various pharmacokinetic parameters determined
as per one compartment per-oral open body model have been tabulated in Table
6. The ODT resulted in absorption mechanism which bypassed the hepatic portal
system and the effects are exhibited in the form of elevated plasma concentrations
and enhanced bioavailability. Even in comparison to the marketed product, the pharmacokinetic
performance by the developed ODT was found to be superior for every pharmacokinetic
property at p < 0.05. However, the marketed product performance was improvised
than that of the plain drug (p < 0.05).
Table 6: Pharmacokinetic parameters of
nifedipine in rodents administered with plain drug and the ODT
|
Pharmacokinetic
Parameters
|
Plain Drug
|
Marketed Product
|
C1
|
|
 (ng ml-1 h-1)
|
142.39
|
182.78
|
292.47
|
|
K (h-1)
|
0.47
|
0.41
|
0.30
|
|
Ka (h-1)
|
0.93
|
0.95
|
1.47
|
|
Cmax (ng/ml)
|
43.74
|
59.85
|
78.45
|
|
Tmax (h)
|
1.49
|
1.48
|
0.19
|
|
MRT (h)
|
3.15
|
3.56
|
5.01
|
Biodistribution Studies:
The results of single point biodistribution
studies have been presented in the form of a bar graph in Fig 8. The results
evidenced that the drug bypassed the hepatic system after its buccal absorption
and avoided the microsomal enzymes from the ODT product. This resulted in enhanced
plasma concentration and obviously the pharmacological response will also be improved
with ODT
Fig
8: Concentration of nifedipine per gram of the organ mentioned after 24 hours
of dose administration
Antihypertensive Activity:
The results obtained from the antihypertensive
pharmacological studies measuring the systolic pressure of the rats at various time
points has been shown in Fig 9. The normal systolic pressure of the rats
is 118.5 ± 2.09 mm of Hg. However, the average systolic pressure in the disease
control, i.e., the hypertensive rat group not receiving any treatment was observed
to be around 180 mm of Hg, vouching the successful induction of the diseased state.
From the observed data, it can be easily inferred that the reduction in the blood
pressure was more pronounced in the group receiving optimized ODT product vis-à-vis
marketed product as well plain drug at p < 0.05. In a shorter duration of
15 minutes, the animals receiving the nifedipine-loaded ODT exhibited a substantial
reduction in the systemic blood pressure, whereas the equivalent effect was observed
in the marketed product receiving animal group at 60 minutes. The data unequivocally
established the superiority of the developed system over the marketed product as
well as the plain drug. The enhanced pharmacodynamic response of the developed system
can be ascribed to the faster rates of absorption and slower elimination coupled
with lower Tmax and elevated Cmax as inferred from the pharmacokinetic
studies. Needless to mention that these characteristics of the BCS class II drug
are evidently influenced by the rate and extend of dissolution. The fast dissolving
nature of the developed ODT has resulted in the overall improvement of the pharmacokinetic
and biodistribution profile of the drug, which is reflected from the pharmacodynamic
performance.
Fig. 9: Graph showing the pattern of systolic blood
pressure in the various treatment groups (*n = 3)
Stability Studies:
The selected cotton candy based nifedipine
loaded ODT offered the best physicochemical and the biological outcomes in the real
time scenario. Henceforth, the study of the stability of the system over a period
of time is crucial, as the ultimate goal of formulation development is the perseverance
of the desired profile over the shelf-life. Over the 6 months accelerated stability
assessment, it was observed that no variation in the physical appearance and other
studied parameters was observed, as shown in Table 7
Table 7: Accelerated stability data of the
optimized ODT (C1) product over a period of six months
|
Parameter
|
0 Day
|
2 Month
|
4 Month
|
6 Month
|
|
Disintegration Time (sec)
|
13.9 ± 0.4
|
14.13 ± 0.3
|
13.77 ± 0.5
|
14.09 ± 0.6
|
|
Dissolution (%)
|
92.4 ± 5.36
|
92.1 ± 2.36
|
91.9 ± 1.78
|
91.7 ± 2.18
|
|
Assay (%)
|
100.2 ± 1.01
|
99.98 ± 0.97
|
99.79 ± 0.85
|
98.97 ± 0.81
|
|
Hardness (Kg/cm2)
|
2.8±0.1
|
2.8±0.3
|
2.7±0.4
|
2.6±0.2
|
±SD, *n=3
Also, the drug content of the stored samples
did not vary substantially at the storage conditions (p < 0.05), the mean values
ranging between 100.2 ± 1.01% and 98.97 ± 0.81%. This clearly indicated the robustness
of the developed product in the primary pack to maintain the desired attributes
even in the extremes of temperature and humidity as per the ICH guidelines for a
time period of 06 months.
CONCLUSION:
The research carried out has successfully explored
the various methods to develop ODTs of widely prescribed antihypertensive drug nifedipine. Numerous batches of all the selected methods
were developed using the novel gum as well as an established superdisintegrant.
The studies have unequivocally established the superiority of the selected novel
gum over the conventional superdisintegrant and the superiority of the cotton candy
method over the other techniques. The developed systems not only employed simpler
and scalable methods but also generated the evidence that the ODTs using this novel
material can pave a path for the formulations with enhanced bioavailability and
efficacy for both the drugs. The pharmacokinetic, biodistribution and pharmacological
evidences coupled with the results from the in-vitro parameters like wetting
time, disintegration time and drug release profile provide a ray of hope for a commercially
viable ODT product for nifedipine to manage the hypertension related problems.
REFERENCES:
1. Joseph A. Pharmaceutical dosage forms and
drug delivery systems. Journal of Pharmaceutical Sciences. 1990; 79 (11):1044.
2. Tejas
K, Ganesh
D.A Review on Orodispersible
Tablets: A Novel Approach. Research Journal of Pharmacy and Technology.2019;
12(8): 3993-4001.
3. Jaybhaye A, Joshi S, Deshmukh G. Orodispersible Tablets: A Comprehensive Review. Research Journal of
Pharmacy and Technology.2014; 7(3): 368-375.
4. Srinivasa S., Narayana RC,
Satyanarayana D S, Srilakshmi D. Formulation and Evaluation of Orodispersible
Tablets of an Antiulcer Agent. Research Journal of Pharmacy and Technology.
2017; 10(3): 747-750.
5. Barich DH, Zell MT, Munson EJ.
Physicochemical Properties, formulation, and drug delivery.Wiley Online
Library.https:// doi.org/10.1002/9781118833322.ch3
6. Hannan PA, Khan JA, Khan A, Safiullah S.
Oral dispersible system: A new approach in drug delivery system. Indian Journal
of Pharmaceutical Sciences. 2016;78 (1): 2–7.
7. Pade V, Stavchansky S. Estimation of the
relative contribution of the transcellular and paracellular pathway to the
transport of passively absorbed drugs in the Caco-2 cell culture model. Pharm.
Research. 1997; 14 (9):1210–1215.
8. Rai PR, Tiwary AK., Rana V. Superior
disintegrating properties of calcium cross-linked Cassia fistula gum
derivatives for fast dissolving tablets. Carbohydrate Polymer. 2012a ;87
(2):1098–1104.
9. Leucuţa SE, Vida-Simiti L, Căprioară
MG, Făgărăşan E, Olinic N, Manasia M, Vlaicu R.
Bioavailability of nifedipine from different oral dosage forms in healthy
volunteers. Die Pharmazie .1989;44 (5): 336–338.
10. Killedar SG, Nale AB, More HN, Nadaf SJ,
Pawar AA, Tamboli US. Isolation, characterization, and evaluation of Cassia
fistula Linn. seed and pulp polymer for pharmaceutical application.
International. Journal of Pharmaceutical Investigation. 2014; 4 (4): 215–225.
11. Singh SK., Singh S. Evaluation of cassia
fistula linn. Seed Mucilage in tablet formulations. International Journal of
PharmTech Research. 2010;2 (3): 1839-1846
12. Goyal P, Kumar V, Sharma P. 2007.
Carbohydrate polymers., Carbohydrate polymers. Elsevier Science Pub. Co.
13. Dave V, Yadav RB, Ahuja R, Yadav S.
Formulation design and optimization of novel fast dissolving tablet of
chlorpheniramine maleate by using lyophilization techniques. Bulletin of
Faculty of Pharmacy. 2017;55:31–39.
14. Shoukri R, Ahmed IS, Shamma RN . In vitro
and in vivo evaluation of nimesulide lyophilized orally disintegrating tablets.
European Journal of Pharmaceutics and Biopharmaceutics.2009; 73 (1): 162–171.
15. Gerald E Battist, Richard C. Fuisz Garry L
Myers. Process and apparatus for making rapidly dissolving dosage units and
product therefrom. European Patent Office ; EP0764019A4.1995.
16. Jaybhaye A, Joshi S, Deshmukh G. Orodispersible Tablets: A Comprehensive Review. Research Journal of
Pharmacy and Technology.2014; 7(3): 368-375.
17. Sahu
SK, Ajazuddin, Banjare T, Gupta S, Bhandarkar A, Sahu
H, Diwedi SD, Sahu
P, Agrawal P, Pooja Yadav, Bhatt A, Sahu K, Dewangan D, Thapa H, Deepika, Sahu G, Sharma
M, Tripathi DK, Alexander A. Formulation and evaluation of orodispersible
tablet of montelukast sodium. Research Journal of Pharmacy and Technology.2018;
11(3): 1112-1118.
18. Gorle AP, Rajput RB. 2016. Formulation and
evaluation of tatse mask orally dispersible paracetamol tablet. Journal of Drug
Delivery and Therapeutics. 2016;6 (2):30–36.
19. Sheshala R, Khan N, Chitneni M, Darwis Y.
Formulation and in vivo evaluation of ondansetron orally disintegrating tablets
using different superdisintegrants. Archieves of Pharmacal. Research. 2011; 34
(11):1945–1956.
20. Chowhan Z. Moisture, hardness, disintegration
and dissolution interrelationships in compressed tablets prepared by the wet
granulation process. Drug Development and Industrial Pharmacy.1979; 5 (1):
41–62.
21. Iqbal Z, Babar A, Ashraf M.Controlled
release naproxen using micronized ethyl cellulose by wet granulation and solid
dispersion method. Drug Development and Industrial Pharmacy.2002;28 (2)
:129–134.
22. Mandal S, Basu SK., Sa B. Sustained release
of a water-soluble drug from alginate matrix tablets prepared by wet granulation
method. AAPS PharmSciTech. 2009;10 (4):1348-1356.
23. Devi
NKD, Rani AP, Madhavi BR, Mrudula BS, Swetha A. Formulation
and Optimization of Orodispersible Tablets of Olanzapine. Research Journal of
Pharmacy and Technology.2010; 3 (2): 543-546.
24. Srinivasa DS, Narayana Charyulu R, Satyanarayana DS, Srilakshmi D. Formulation and in vitro comparative evaluation of orodispersible
tablets of Pantoprazole. Research Journal of
Pharmacy and Technology.2015; 8(10): 1389-1393.
25. Deshmukh
H, Chandrashekhara S., C. Nagesh, Patil M, Majethiya V. Comparative Evaluation of Disintegrant in
Orodispersible Tablet of Aceclofenac. Research Journal of Pharmacy and
Technology.2012; 5(6): 775-779.
26. Patel BP, Patel JK., Rajput GC,Thakor RS.
Formulation and evaluation of mouth dissolving tablets of cinnarizine. Indian
Journal of Pharmaceutical Sciences.2010; 72 (4): 522–525.
27. Krishnaraj K., Chandrasekar MJ, Nanjan MJ,
Muralidharan S, Manikandan D. Development of sustained release antipsychotic
tablets using novel polysaccharide isolated from Delonix regia seeds and its
pharmacokinetic studies. Saudi Pharmaceutical Journal. 2012; 20 (3):239-248.
28. Sarfraz R, Khan H, Mahmood A, Ahmad M,
Maheen S, Sher M. Formulation and evaluation of mouth disintegrating tablets of
atenolol and atorvastatin. Indian Journal of Pharmaceutical Sciences. 2015;77
(1): 83-90.
29. Mohire
NC, Yadav AV, Gaikwad VK. Novel Approaches in Development of
Metronidazole Orodispersible Tablets. Research
Journal of Pharmacy and Technology.2009; 2(2): 283-286.
30. Asha D,
Jeganath S, UVNV Arjun, Sathesh Kumar S.Design and Characterization of Levofloxacin
Orodispersible Tablets. Research Journal of
Pharmacy and Technology.2018; 11(4): 1467-1474.
31. Anroop BN, Shery J. A simple practice guide
for dose conversion between animals and human. Journal of Basic and Clinical
Pharmacy. 2016;7:27-31.
32. Kim YIl, Fluckiger L, Hoffman M,
Lartaud-Idjouadiene I, Atkinson J, Maincen P. The antihypertensive effect of
orally administered nifedipine-loaded nanoparticles in spontaneously
hypertensive rats. British. Journal of Pharmacolgy. 1997; 120 (3): 399–404.
33. Wiederhold NP. Pharmacokinetics and safety
of posaconazole delayed-release tablets for invasive fungal infections.Clinical
Pharmacology:Advances and Applications. 2016; 8:1-8.
34. Huang M, Chen J, Hu X, Liu J, Wu G, Zhou H,
Zhu MX, Wu L, ShenTu J. Comparative bioavailability and pharmacokinetics of
sirolimus tablets in healthy Chinese volunteers. Intenational Journal of
Clinical Pharmacology Therapy and Toxicology. 2013;51 (10): 816–822.
35. Raoof AA, Chiu P, Ramtoola Z, Cumming IK.,
Teng C, Weinbach SP, Hardee GE, Levin AA, Geary RS. Oral bioavailability and
multiple dose tolerability of an antisense oligonucleotide tablet formulated
with sodium caprate. Journal of Pharmaceutical Sciences. 2004;93 (6):1431–1439.
36. Saravanakumar M, Raja B. Veratric acid, a
phenolic acid attenuates blood pressure and oxidative stress in L-NAME induced
hypertensive rats. European Journal of Pharmacology. 2011; 671 (1-3): 87–94.
37. Sung JH, Jo YS, Kim SJ, Ryu JS, Kim MC, Ko
HJ, Sim SS. Effect of lutein on L-NAME-induced hypertensive rats. Korean
Journal of Physiology and Pharmacology. 2013; 17 (4) :339–345.
38. Patil GB, Patil ND, Deshmukh PK, Patil PO,
Bari SB. Nanostructured lipid carriers as a potential vehicle for Carvedilol
delivery: Application of factorial design approach. Artificial cells,
Nanomedicine and Biotechnology. 2016; 44 (1): 12–19.
39. Brus, J., Brus, ©, 2005. UNESCO/IUPAC
Course NMR Spectroscopy of Polymers.
40. Shah RB, Tawakkul MA, Khan MA. Comparative
evaluation of flow for pharmaceutical powders and granules. AAPS PharmSciTech. 2008; 9 (1): 250–258.
41. Sareen S, Joseph L, Mathew G. Improvement
in solubility of poor water-soluble drugs by solid dispersion. International
Journal of Pharmaceutical Investigation.2012;2(1):12-17.
42. Abbasi S, Yousefi G, Ansari AA,
Mohammadi-Samani S. Formulation and in vitro evaluation of a
fast-disintegrating/ sustained dual release bucoadhesive bilayer
tablet of captopril for treatment of hypertension crises. Research in
Pharmaceutical Sciences.2016; 11(4): 274–283.
43. Fuhr U, Beckmann-Knopp S, Jetter A, Lück H,
Mengs U. The effect of silymarin on oral nifedipine pharmacokinetics. Planta
Medica.2007; 73 (14): 1429–1435.