Amarnath Reddy et al: Drug-Excipient Interaction during Formulation Development of Gastroretentive Drug Delivery… 2281 Research Paper

Drug-Excipient Interaction during Formulation Development, in vitro andin vivo Evaluation of Gastroretentive Drug Delivery System for Nizatidine

Ramireddy Amarnath Reddy, Bomma Ramesh and Veerabrahma Kishan* Department of Pharmaceutics, University College of Pharmaceutical Sciences, Kakatiya University, Warangal-506 009, Andhra Pradesh, India.

Received June 6, 2013; accepted July 6, 2013 ABSTRACT

The present investigation dealswith the development and evaluation of floating tablets of nizatidine to prolong the gastric residence time, increase local delivery of drug to the H2-receptor of the parietal cell wall to reduce stomach acid secretion. The drug-excipient compatibility studies were conducted by using FTIR, DSC and visual observations. Citric acid inclusion in formulations resulted in incompatibility and the composition was modified to eliminate the problem of incompatibility. Floating matrix tablets of nizatidine were developed by direct compression method using hydroxypropyl methylcellulose (HPMC K4M) and polyox WSR 1105 alone as release retardants and sodium bicarbonate as a gas-generating agent. Alleleven formulations exhibited satisfactory physicochemical characteristics andin vitro buoyancy. Formulations F6 and F10 exhibited controlled and prolonged drug release for 10

h with zero order release. Formulation (F10) was selected as optimized formulation based on physicochemical properties and in vitro drug release and was used inradiographic studies by incorporating BaSO4. The radiographic studies were conducted in comparison with plain controlled release tablets. These studies revealed that gastric retention time of floating and plain controlled release tablets in fasting state were 2 ± 0.86 h and ≤ 0.5 h respectively in human volunteers. Gastric retention time of floating and plain controlled release tablets in fed state were 5.33 ± 0.57 h and 1.66 ± 0.28 h respectively in human volunteers. In conclusion, optimal floating matrix tablet for nizatidine with desired in vitro buoyancy, in vivo gastric retention time and prolonged release could be prepared.

KEYWORDS: Floating tablets; drug-excipients compatibility; gastric residence time; nizatidine.

Introduction Oral drug delivery is the preferred route for drug

administration because of its convenience, low cost, and high patient compliance when compared with several other routes. About 90 percent of drug products are administered via the oral route (Kokate et al., 2006).Controlled-release (CR) pharmaceutical dosage forms may offer one or more advantages over immediate release dosage forms of the same drug, including a reduced dosing frequency, a decreased incidence and/or intensity of adverse effects, a greater selectivity of pharmacologic activity, and a reduction in drug plasma fluctuation resulting in a more constant or prolonged therapeutic effect (Malinowski and Marroum, 1999).However, this CR approach is facing problems with several physiological difficulties such as inability to restrain and locate controlled drug delivery system within the desired region of gastrointestinal tract (GIT), due to variable gastric emptying and motility.Control of placement of drug delivery system in specific region of GIT offers advantage for variety of important drugs

characterized by narrow absorption window in GIT or drugs with stability problem (Garg and Gupta, 2008). Various approaches that have been proposed to control the gastric residence time of drug delivery systems in the upper part of the GIT include floating drug delivery systems (FDDS) (Brahma and Kim, 2000), high-density DDS (Caldwell et al., 1998), mucoadhesive systems (Lehr, 1994), swelling and expanding DDS (Urquhart and Theeuwes, 1984; Mamajek and Moyer, 1980), modified shape systems(Fix et al., 1993), and other delayed gastric devices (Gröning and Heun, 1989).

FDDS have a bulk density lower than the gastric fluid and thus remain buoyant in the stomach, without affecting the gastric emptying rate for a prolonged period of time. While the systemis floating on the gastric contents, the druggets released slowly (Arora et al., 2005). Based on the mechanism of buoyancy, two distinctly different technologies, i.e., non-effervescent and effervescent system, have been utilized in the development of FDDS. The effervescent system utilizes matrices prepared with swellable polymers and effervescent components, e.g., sodium bicarbonate and

 

International Journal of Pharmaceutical Sciences and Nanotechnology

Volume 6 • Issue 4• December 2013 (extra issue) IJPSN-6-6-13-KISHAN

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2282 Int J Pharm Sci Nanotech Vol6;Issue 4•December 2013 (extra issue) citric acid or adipic acid. The matrices are fabricated such that in the stomach carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the swollen gel of hydrocolloid. This produces an upward motion of the dosage form and maintains its buoyancy (Rubinstein and Friend, 1994). In non-effervescent FDDS, the drug is mixed with a gel-forming hydrocolloid, which swells on contact with the gastric fluid after oral administration and maintains relative integrity of shape and a bulk density of less than unity within an outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms (Sheth and Tossounian, 1979).

Ranitidine HCl was formulated as FDDS by lowering the density. The local delivery of Ranitidine HCl increased the stomach wall receptor site bioavailability to reduce stomach acid secretion (Raval et al., 2007). Similarly, nizatidine is also an histamine H2-receptor antagonist that inhibits stomach acid production and commonly used in the treatment of peptic ulcer and Gastro Esophageal Reflux disease.It reduces the acid secretion by directly acting on parietal cell wall (Davis, 1997). It is having an oral bioavailability of 70% with a biological half-life of 1-2 h. Due to the above mentioned characteristics it becomes a suitable candidate for the development of gastroretentive delivery system.

The present investigation was concerned with the development and evaluation of floating tablets of nizatidine by using hydroxyl-propyl-methyl cellulose (HPMC K4M) or polyethylene oxide (Polyox WSR 1105) as sole release retardant, and sodium bicarbonate and citric acid were incorporated as gas-generating agents in the formulations to prolong the gastric residence time, increase local delivery of drug to the H2-receptor of the parietal cell wall. Initially, drug-excipients compatibility problemswere studied by using Fourier transform infrared (FTIR), differential scanning calorimetry (DSC) and visual observation of the prepared tablets for one month. The optimized formulation possessed good floating, extended and controlled drug release properties and was chosen for further in vivo radiological investigation to determine the mean gastric retention time.

Materials and Methods

Materials Nizatidine was obtained as a generous gift sample

from Dr. Reddy’s laboratories, Pydibheemavaram, India.Hydroxy propyl methyl cellulose (HPMC) K4M and polyethylene oxide (PEO) WSR 1105 were obtained as gift samples from M/s Orchid Chemicals and Pharmaceuticals Ltd., Chennai, India. Microcrystalline cellulose (Avicel pH102), Sodium bicarbonate were purchased from M/s S.D Fine chemicals Ltd., Mumbai, India. All other ingredients used were of laboratory grade.

Methods Drug-excipient compatibility studies

(i) Fourier transform infrared (FTIR) spectroscopy The FTIR spectra of samples were obtained

using FTIR spectrophotometer (BX I, Perkin Elmer, USA). Pure drug, individual polymers and optimised formulations were subjected to FTIR study. About 2–3 mg of sample was mixed with dried potassium bromide (KBr) of equal weight and compressed to form a KBr disk. The samples were scanned from 400 to 4000 cm−1.

(ii) Differential scanning calorimetry (DSC) The DSC experiments were carried out to find

out the presence of any interaction among drug and the excipients. Pure drug, individual polymers and optimised formulation were subjected to the study. About 5-15 mg of sample to be analysed was taken in the pierced DSC aluminium pan and scanned in the temperature range of 50–250 °C. The heating rate was 10°C/min; nitrogen served as purged gas and the system was cooled down by liquid nitrogen. The differential thermal analyser (DSC 822 e/200, Mettler Toledo, Switzerland) was used for this purpose.

(iii) Visual observation Initially, the tablets of nizatidine were prepared

by using either HPMC K4M or Polyox WSR 1105 as release retardant, sodium bicarbonate and citric acid as gas generating agents, Avicel pH102 as bulking agent, magnesium stearate as lubricant and talc as glidant in the formulations. After compression of the mixture into tablets, the change in physical appearance was observed during storage at room temperature. The visual observation was carried out for one month by excluding one of the ingredients from the composition. Finally, the composition was modified to eliminate the problem of incompatibility due to citric acid.

Development of tablets

Accurately weighed quantities (Table 1) of polymer and Avicel pH102 were taken in a mortar and mixed geometrically. To this required quantity of nizatidine was added and mixed slightly with pestle. Weighed quantity of sodium bicarbonate was taken separately in a mortar and powdered with pestle. The powder was passed through sieve no. 40 and mixed with the drug blend which was also passed through sieve no. 40. The whole mixture was collected in a plastic bag and mixed for 3 min. To this talc was added and mixed for 2 minutes, later magnesium stearate was added and mixed for 3 min. The mixture equivalent to 500 mg was compressed into tablets using rotary tablet machine (Riddhi, Model- RDD3, Ahmedabad) with 10 mm round concave punches at a hardness of 6 kg/cm2.

Amarnath Reddy et al: Drug-Excipient Interaction during Formulation Development of Gastroretentive Drug Delivery… 2283 TABLE 1

Composition of various formulations of nizatidine floating tablets.

Name of ingredients Formulation codes and ingredients (mg)

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 Nizatidine 270 270 270 270 270 270 270 270 270 270 270 HPMC K4M 100 80 70 60 75 75 80 - - - - Polyox WSR 1105 - - - - - - - 80 100 110 115 Sodium bicarbonate 50 50 50 50 50 60 60 60 60 60 60 Citric acid anhydrous 10 10 10 10 10 - - - - - - Avicel PH 102 56 76 86 96 81 81 76 76 56 46 41 Talc 7 7 7 7 7 7 7 7 7 7 7 Magnesium stearate 7 7 7 7 7 7 7 7 7 7 7 Total tablet weight 500 500 500 500 500 500 500 500 500 500 500

TABLE 2

Physical parameters of nizatidine floating tablets.

Formulation Code

Weight(mg) Hardness(kg/cm2) Thickness (mm) Friability(%) Floating lag time (s) Assay(%)

F1 506 ±9.06 5.1 ± 0.2 6.13 ± 0.05 0.27 50±3 100.85 F2 506 ± 8.43 5 ± 0.3 6.19 ± 0.03 0.35 38±2 99.03 F3 502.5 ± 9.78 6.1 ± 0.3 6.16 ± 0.04 0.24 46±3 99.21 F4 501 ± 11 5.8 ± 0.5 6.11 ± 0.06 0.30 44±5 99.91 F5 501.5 ± 6.25 6 ± 0.3 6.13 ± 0.05 0.32 36±3 100.7 F6 501.5 ± 7.83 6.1 ± 0.2 6.13 ± 0.04 0.18 85±5 98.3 F7 500.5 ± 7.24 5.9 ± 0.4 6.16 ± 0.04 0.19 92±4 98.9 *F8 507 ± 8.56 6.1 ± 0.3 6.30 ± 0.03 0.18 65±3 99.28 *F9 506.5 ± 10.28 6.2 ± 0.2 6.34 ± 0.04 0.20 83±4 97.48 F10 504.5 ± 10.91 5.9 ± 0.3 6.32 ± 0.04 0.17 114±5 98.96 F11 504.5 ± 8.64 6.1 ± 0.2 6.33 ± 0.04 0.18 171±6 98.29

Note: All the formulations floated for more than 10 h. Formulations *F8 and *F9 floated for 6 h and 8 h respectively.

Physical evaluation of floating tablets of nizatidine

The prepared tablets were evaluated in terms of their weight variation, hardness, thickness, friability and drug content (Table 2).

In vitro buoyancy studies

The in vitro buoyancy studies were carried out for the prepared floating tablets as per published method (Rosa et al., 1994). The tablets were placed in a 100 mL beaker containing 0.1 N HCl. The time required for a tablet to rise to the surface for floating was determined as floating lag time. The duration of time for which the dosage form constantly remained on the surface of medium was determined as the total floating time.

In vitro drug release studies

In vitro dissolution studies were carried out using a USP 29 type II (paddle type) dissolution apparatus (Electro Lab, TDT 06P). A floating tablet of nizatidine was dropped into 900 mL of 0.1 N HCl (pH 1.2), maintained at 37 ± 0.5°C and stirred at a speed of 50 rpm. At different times, 5 ml aliquots were withdrawn and replaced with an equivalent amount of plain dissolution medium kept at 37°C. The collected samples were filtered and analysed at λmax 314 nm using a UV–Visible spectrophotometer (Elico Pvt. Ltd., SL 159). The cumulative percentage of drug released was calculated using standard calibration curve of nizatidine.

Analysis of in vitro drug release data

Model dependent methods

To analyze the mechanism of drug release from the tablets, the in vitro dissolution data was subjected to the zero-order (Chen and Hao, 1998), first-order (Shah et al., 1987), Higuchi (Higuchi, 1961), and Korsmeyer-Peppas kinetic models (Ritger and Peppas, 1987; Korsmeyer et al., 1983). The equations for the kinetic models are given below.

Zero-order: Qt = Q0 + K0t…..(1) First order: logC = logC0 – k1t/2.303 …..(2) Higuchi: Qt = K2t1/2 …..(3) Qt/Q∞ = kptn …..(4)

Where Q0, Qt and Q∞ are the amounts of drug dissolved initially, at any time t and at ∞ time. C0 and C are the concentration of the drug initially and at any time t, and k0, k1, k2 and kp are the rate constants obtained from the linear curves of the respective models.

Model independent methods

For the comparison of release profiles of reference and test products, “difference factor” f1 and “similarity factor” f2, were calculated (Moore and Flanner, 1996). The difference factor (f1) measures the percent error between the two curves over all time points and is calculated by the following equation:

   Σ

Σ

nj=1 j j

1 nj=1 j

R – Tf = ×100

R

2284 Int J Pharm Sci Nanotech Vol6;Issue 4•December 2013 (extra issue)

where n is the number of sampling points, and Rj and Tj are the percent dissolved of the reference and test products at each time point j. The two release profiles are considered to be similar if f1 value is lower than 15 (between 0 and 15). The similarity factor (f2) is a logarithmic transformation of the sum of squared error of differences between the test Tj and the reference products Rj over all time points. It is calculated by using following equation:

 n 2

j j jj 1

1[1 W R T ]n

=

⎧ ⎫⎛ ⎞+ Σ −⎨ ⎬⎜ ⎟⎝ ⎠⎩ ⎭

-0.5

2f = 50 log ×100

Where Wj is an optional weight factor and other terms are as defined earlier. The two dissolution profiles are considered to be similar if f2 value is more than 50 (between 50 and 100).

Tablet preparation for in vivo radiographic studies

Radiological (X-Ray)study was used for determination of the anatomical location of nizatidine floating tablets in the GI tract. To make the tablets X-ray opaque, the incorporation of BaSO4 was necessary. For this purpose, 65 mg of the drug was replaced with BaSO4 (65 mg BaSO4 + 205 mg nizatidine) and all other ingredients were kept constant. Plain controlled release tablets of nizatidine were used as a control. The optimized formulation F10 was selected for the radiological study, which contained 41% drug, 13% BaSO4 as radio opaque agent, 22% polyox WSR 1105 as polymer and 12% NaHCO3 as gas generating agent, 9.2% Avicel pH 102, 1.4% magnesium stearate and 1.4% talc. The plain controlled release tablets were prepared with same composition, in which gas generating agent NaHCO3 was replaced with Avicel pH 102.

In vivo radiographic studies

Six healthy male volunteers participated in the studies after giving informed written consent. The studies were approved by the Ethical Committee of University College of Pharmaceutical Sciences (UCPSc), Kakatiya University, Warangal, India. The study was conducted by administering to each subject one floating/plain controlled release tablet in one session. The healthy male volunteers, weighing between 65±10 kg and in the age group of 25±2 years were included in the study. Study was conducted in fasted and fed state, 3 volunteers each. (a) Fasting state: The BaSO4-loaded floating/plain

controlled release tablet was administered orally to each volunteer with 200 mL of water. During the study they were not allowed to eat but the water was made available ad libitum. The first X-ray photograph was taken 30 min after administration of tablet. Further, the next pictures were taken at different time intervals viz., 1.5, 3, and 5 h in a standing position under the supervision of an expert

radiologist. The source of X-rays and the subject was kept constant for all images. Thus, the observation of the tablet movements could be easily noticed. The mean gastric residence time was calculated.

(b) Fed state: After overnight fasting, the volunteers were fed with a low calorie food. Half an hour later, a BaSO4-loaded floating/plain controlled release tablet was administered orally to each volunteer with 200 mL of water. At different time intervals (0.5, 1.5, 3, 5 and 7 h post administration of tablet), the volunteers were exposed to abdominal X-ray imaging and the mean gastric residence time was calculated.

Results and Discussion Drug-excipient compatibility studies

(i) Fourier Transform Infrared (FTIR) Spectroscopy Chemical interaction between drug and polymer

could change the therapeutic efficacy of the drug. To investigate the possibility of chemical interaction between drug and excipients, samples were analyzed over the range 400 – 4000 cm−1.

The FTIR spectra of pure drug, drug-HPMCK4M and drug-Polyox WSR 1105 were obtained and shown in Figure 1. The major peaks were observed at 754.5, 1017.8 and 1229.8 cm-1 for pure drug. These results suggested the compatibility between nizatidine, HPMC K4M and polyox WSR1105, because FTIR spectra of nizatidine-HPMC K4M and nizatidine-Polyox WSR 1105 mixture displayed all the characteristic bands of drug, without any significant spectral shift.

Figure 1d suggested that there was incompatibility between nizatidine and citric acid because FTIR spectrum of nizatidine and citric acid mixture (1:1), which was immediately analyzed after preparation, showed an extra peak at 1700 - 1800 cm-1 indicated by an arrow other than characteristic bands of drug. This was confirmed further byFT-IR spectrum of nizatidine and citric acid mixture (Figure 1e), which was preserved for one month and analyzed, showed entirely different peaks and lacking characteristic bands of drug. But, in contrast the Figure 1f and 1g showing FTIR spectra of the formulation F5 containing citric acid displayed all the characteristic bands of drug, without any significant spectral shift. This suggested absence of chemical interaction between the components of the formulation and probably, due to very low concentration of citric acid in formulation (0.02 % w/w).

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idine floating tab

ing Formulation

g release as based the drug

developed g release

% in 3 h, 00±3% in

that the e release mulative

1, F2, F3, 08 ± 1.4, vely. All 0 hours. the drug lease the 3 and F4 heoretical ime. The

various different

ained the eased the mulations ible with

developed

foinflthdththcowpo

WpreCF±resuFrewrepFfogp

blets prepared w

n Development

The cumuormulations Fn 10 hours rloated for 10 he drug relea

drug within thhe drug releahe drug withionsidered as

with HPMC Kprofiles of varif different con

The formulWSR 1105. Frpolymer polyoelease of d

Cumulative peF8, F9, F10 an± 1.4 and 9espectively. Fustain the

Formulations elease as the

within the deelease profile

presence of Formulation ormulation am

good sustainedprofile.

with HPMC K4M

of Gastroreten

ulative percenF6 and F7 warespectively. h. Formulatiase as theorehe desired timase as theoretin the desiredbest formulatK4M. The diious formulatncentrations olations F8-F1rom Figure 8 x WSR 1105

drug from tercentage of dnd F11 were 97.19 ± 0.4 Formulations

drug releaF10 and F11 oretical profilesired time. es of various

different cF10 was co

mong all the fd release ver

M (n = 3).

ntive Drug Deliv

ntage of druas 97.82 ± 1.4These two foion F7 was uetical profile bme. Formulatitical profile ad time. So formtion among alifference in ttions was dueof polymer. 11 were prepa it could be ob had sustainithe floating drug release fr99.14 ± 1.7, 10in 6, 8, 10 F8 and F9 se for the were able to le and also reThe differenformulations

concentrationnsidered as

four formulatiry near to th

very… 22

ug release fr4 and 92.72 ± ormulations a

unable to sustbut released ion F6 sustain

and also releamulation F6 wll these prepathe drug relee to the prese

ared with Polbserved that ing effect on

matrix tabrom formulati00.39 ± 1.0, 98 and 10 howere unable

desired tisustain the deleased the d

nce in the d was due to s of polymbest optimi

ions as it showheoretical rele

289

rom 1.4 also tain the ned

ased was

ared ease ence

lyox the the

blet. ions 8.01 ours e to me.

drug drug drug

the mer. ized wed ease

2290

Fig. 8. In v

Analy

The dwasanalyfirst ordevalues ofmechanisFickian d0.45 to 0.If the n vSuper cathe releaclear thabecause tzero-ordeF1-F5 anfollowed F6 and formulatibetween 0

For thtest produf2, were optimizedrespectivrespectiv

vitro dissolution p

ysis of in vitro

data obtainedysed by usinger, Higuchi af Korsmeyer-Psms of drug rdiffusion is ap.89 it represevalue reachesse II transpo

ase would follat F6, F7, F10they showed er when compnd F8 followethe Higuchi m

F10 followions (except F0.45 and 0.89 he comparisonucts, “differen calculated. d formulationely. Similarlyely.

profiles of nizati

o drug release

d from in vitrg different moand Peppas ePeppas equatrelease. If thepparent, if thents anomalous 0.89 and abort are indicalowzero order0 and F11 fohigh regressipared to otheed the Peppasmodel. The op

wed zero-ordeF3, F4, F8 a indicating an

n of release prnce factor” f1 a

The similans (F6 and Fy, the differen

idine floating tab

data

tro dissolutionodels viz., zerequation. Diftion indicate e n value is 0e n value ranus diffusion trbove then casated, which shr. From table

ollowed the zeion coefficienters. The forms model. Wheptimized former release.

and F9) have nomalous tranrofiles of referand “similaritarity factor F10) were 78nce factor was

Int J Pha

blets prepared w

n studies ro order, fferent n different

0.45 then nges from ransport. se II and how that e 3 it is ero-order t (R2) for

mulations ereas F9

mulations All the

n value nsport. ence and ty factor”

for the 8 and 86 s 4 and 3

flcoemFdoa1thflScoo

dostthwmre1rest

arm Sci Nanote

with Polyox WSR

In vivo rad

The in vitloating tabletompared to thxpected bec

manufacturer,Figure 9 shodifferent time ne volunteer

appeared at th1.5 h. Later, the intestine. loating tablet

Similarly, meontrolled relenly ≤ 0.5 h, s

Figure 11 different time ne volunteer tomach for thhe tablet sli

within the stommoved from stetention time

12) was 5.33 etention timetate was 1.66

ech Vol6;Issu

R 1105 (n = 3).

iographic stud

itro buoyancys were 240 ±3he original forcause BaSO has a higherows the rad periods of Bar under fasthe same positthe tablet mo The mean gt in fasting ean gastric rease tablet (Cshown in Figushows the r

periods of Baunder fed sta

he first 3 h atightly movedmach till 5 h. omach into th

e of the floatin ± 0.57 h (n of the plain c±0.28 h (n=3)

ue 4•December

dies

y lag time o35 s. The incrrmula of F10 O4, as repr relative den

diographic imaSO4-loaded fting state. Htion in the stoved down frogastric retentstate was 2.retention timCRDDS) in faure 10. adiographic iaSO4-loaded fate.The tablet t different posd downwards In the next phe intestine. Tng tablet in f

n=3). Whereacontrolled rele.

r 2013 (extra iss

of BaSO4-loarease in lag tim (105 ±15 s), wported by nsity (4.5 g/cmmages taken floating tablet

Here, the tabtomach for abom stomach ition time of .0±0.86 h (n=

me of the plasting state w

images takenfloating tablet remained in sitions. Later s, yet remainicture, the tab

The mean gasfed state (Fig

as, mean gasease tablet in

ssue)

ded me, was

its m3). at t in blet

bout into the =3). lain was

n at t in the on, ned blet

stric gure stric fed

Amarnath

TABLE 3

Regression

Formulatio

F1 F2

F3 F4

F5 F6

F7 F8

F9 F10

F11

Fig. 9. X-ra

Fig. 10. X-

Reddy et al: D

coefficient (R2) v

on Zero-order

R2

0.936 0.896

0.904 0.818

0.980 0.979

0.980 0.820

0.944 0.987

0.995

ay photographs

ray photographs

Drug-Excipient I

values of nizatid

First-order

R2

0.996 0.987

0.924 0.921

0.789 0.804

0.789 0.893

0.831 0.834

0.830

of GRDDS table

s of CRDDS tabl

Interaction duri

dine floating tabl

Higuchi

R2

0.995 0.999

0.992 0.976

0.974 0.958

0.955 0.974

0.985 0.954

0.928

t containing BaS

et (shown by an

ing Formulation

lets for different

Korsmeyer – Pe

R2

0.997 00.999 0

0.994 00.984 0

0.988 00.971 0

0.968 00.992 0

0.965 00.941 0

0.962 0

SO4 (shown by a

arrow) in fastin

n Development

t kinetic models.

ppas

n

.609

.461

.377

.252

.501

.472

.473

.255

.393

.470

.655

n arrow) in fasti

ng state at differe

of Gastroreten

ing state at diffe

ent time points.

ntive Drug Deliv

erent time points

very… 22

s.

291

2292

Fig. 11. X-

Fig. 12. X-

Conclu

The cwere sucusing HPand NaHexcipientnizatidineincompatexcipientsubjectedF10 wereas optimiselected fThese stucontrolledretentionrelease taand ≤ 0floating tstate werespectivconfirmedretention

ray photographs

ray photographs

usions

controlled releccessfully devPMC K4M anHCO3 as effes compatibilie had an inttibility existes. Drug rel

d to curve fitte best fits for ized. One of thfor the radioudies were cod release tab

n time of floaablets in fasti.5 hours resp

tablets and plaere 5.33 ±0ely in healthyd the superio

n over plain or

s of GRDDS tabl

s of CRDDS tabl

ease floating veloped by efnd Polyox WServescent ageity study, itteraction wit

ed between lease data oting analysis.F zero-order rehe optimized flogical study

onducted in cblets. This rating tablets ing state werepectively. Gasain controlled

0.57 h and y human voluority of GRDr controlled re

let (shown by an

et (shown by an

tablets of nffervescent teSR 1105 as pent. From tht was observth citric acidthe drug anof formulatioFormulationselease and coformulations, by includingomparison wirevealed that

and plain coe 2 ± 0.86 houstric retentiond release table

1.66±0.28 unteers. These

DDS design inlease tablets.

Int J Pha

arrow) in fed st

arrow) in fed st

izatidine echnique polymers he drug-ved that and no

nd other ons was , F6 and

onsidered F10 was g BaSO4. ith plain t gastric ontrolled urs (n=3) n time of ets in fed h (n=3) e studies n gastric

in

aARpPH

A

B

C

arm Sci Nanote

ate at differentt

ate at different t

Conflict of

The authonterest.

Acknowled

One of acknowledges AICTE, New DReddy’s laborproviding nizPharmaceuticaHPMC K4M an

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Address correspondence to:Prof. V. Kishan, Departmentof Pharmaceutics, University College of PharmaceuticalSciences, Kakatiya University, Warangal-506009, AP, India. Tel: +91 870 2438844; E-mail: vbkishan@yahoo.com