The objective of the present study was to develop and evaluate a pulsatile system of theophylline based on chronopharmaceutical considerations. The basic design consists of an impermeable capsule body, which contains the drug and is closed by an erodible tablet plug. The body portion of the hard gelatin capsules was cross-linked by the combined effect of formaldehyde and heat treatment. The formulation variables such as type of plug material, capsule content, different plug composition, plug weight and plug hardness was investigated to characterize the lag time (t10).The results indicated that drug release from the pulsatile capsule exhibited an initial lag period, followed by a stage of rapid drug release. For the complete and rapid drug release from the capsule body, 15% of effervescent agent had to be included in the capsule content. The lag time criterion of 5 hrs was satisfied by the tablet plug containing 16%HPMC K100LV. A good correlation was observed between erodible tablet weight and lag time.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Mahajan, Ashok N.

Pancholi, Shyam S.

SEDICI - Repositorio de la UNLP

153ISSN 0326-2383
KEY WORDS: Chronotherapy, Lag time, Pulsatile capsule.
* Author to whom correspondence should be addressed. E-mail: apmcashok@rediffmail.com
Latin American Journal of Pharmacy
(formerly Acta Farmacéutica Bonaerense)
Lat. Am. J. Pharm. 29 (1): 153-6 (2010)
Short Communication
Received: July 17,  2009
Accepted: August 24, 2009
Pulsatile Drug Delivery for the Treatment of Nocturnal Asthma:
a Chronopharmaceutical Approach
Ashok N. MAHAJAN * 1 & Shyam S. PANCHOLI 2
1 A.P.M.C. College of Pharmacy, College Campus, Himatnagar-383001, Gujarat, India
2 S.K. Patel College of Pharmacy, Mehesana, Kherva-382711, Gujarat, India
SUMMARY. The objective of the present study was to develop and evaluate a pulsatile system of theo-
phylline based on chronopharmaceutical considerations. The basic design consists of an impermeable cap-
sule body, which contains the drug and is closed by an erodible tablet plug. The body portion of the hard
gelatin capsules was cross-linked by the combined effect of formaldehyde and heat treatment. The formu-
lation variables such as type of plug material, capsule content, different plug composition, plug weight and
plug hardness was investigated to characterize the lag time (t10).The results indicated that drug release
from the pulsatile capsule exhibited an initial lag period, followed by a stage of rapid drug release. For the
complete and rapid drug release from the capsule body, 15% of effervescent agent had to be included in
the capsule content. The lag time criterion of 5 hrs was satisfied by the tablet plug containing 16%HPMC
K100LV. A good correlation was observed between erodible tablet weight and lag time.
INTRODUCTION 
Recently pulsatile systems are gaining a lot
of interest and attention, as they deliver the
drug at the right site of action at right time and
in right amount, thus providing spatial and tem-
poral delivery and increasing patient compli-
ance. A pulsatile release profile is characterized
by a lag time followed by rapid and complete
drug release, which is useful for the treatment
of certain diseases which exhibit circadian
rhythm such as asthma, gastric ulcer, hyperten-
sion, ischemic heart disease and arthritis 1,2. For
this purpose, several technologies have been
described which include pulsatile implants 3,
pulsatile microspheres 4, time clock system 5, os-
motic systems 6, compression coated tablets 7
and floating pulsatile beads systems 8.
A review of the chronobiology of asthma
highlighted that airway resistance, bronchocon-
striction, exacerbation of symptoms and worsen-
ing of lung function, increase progressively at
night 9,10. It has been reported that risk of asth-
ma attacks is l00 fold greater during the night
time h (around 2.00 am) than during other times
of day, an observation which has nicely been
confirmed in modern epidemiologic studies in
asthmatic patient 11,12.
In the light of the chronobiologic and
chronopathologic findings, this study attempts
to design and evaluate chronomodulated pul-
satile drug delivery system consisting of imper-
meable capsule body, which contains the drug
and is closed by an erodible tablet plug. It was
aimed to have a lag time of five h i.e., the sys-
tem is taken at bed time and expected to release
the drug after a period of 5 h (around 2.00 am)
when the asthma attacks are more prevalent.
The lag time (t10) was defined as intersection
point on the time axis when 10% of the drug
contained was released. Effect of various formu-
lations parameters such as type of plug material,
capsule content (effervescent agent), different
plug composition, plug weight and plug hard-
ness was investigated to characterize the lag
time. 
154
MAHAJAN A.N. & PANCHOLI S.S.
MATERIALS AND METHODS
Materials 
Theophylline was obtained as gift sample
from Cipla Ltd, Mumbai. Two viscosity grades of
Hydroxypropylmethylcellulose, HPMC K100LV
and HPMC K4M cps were obtained as gift sam-
ple from Coloron Asia Ltd. Lactose, magnesium
stearate, sodium bicarbonate and citric acid
were purchased from S. D. Fine chemicals Ltd.
Mumbai. All other chemicals were laboratory
grade.
Preparation of impermeable capsule body
The body and the cap of the hard gelatin
capsules (size 0) were separated.  Capsule bod-
ies was exposed to formaldehyde vapors for six
h at room temperature and dried at 50 °C for 12
h in hot air oven. Afterwards the capsule body
and the untreated soluble cap were stored in
desiccators for further use. The efficacy of the
treated capsules was checked by disintegration
(Model Electrolab-ED2, Mumbai) test 13.
Filling of capsule bodies
The impermeable capsule body was filled
with drug and excipient mixture. Theophylline
(100 mg) and lactose, the filler (200 mg) was
passed through a 100 mesh sieve, followed by
hand filling of the mixture into the capsule bod-
ies(Fill weight 300 mg).To investigate the influ-
ence of effervescent agent on drug release, lac-
tose was partly replaced by 5 or 15% of a mix-
ture of sodium bicarbonate and citric acid (1:1
ratio).
Preparation of erodible tablet plug
Direct compression method was used to pre-
pare the erodible tablet plug. The formulations
containing 4, 8, 12, 16, 20 and 50% HPMC
K100LV were prepared by weighing 4, 8, 12, 16,
20 and 50 g of HPMC K100LV and adding lac-
tose to 99 g. Each formulation was mixed for 10
min, followed by addition of 1 gm of magne-
sium stearate to each blend. The resultant
blends were mixed for 5 min and directly com-
pressed into tablets using single punch tablet
machine. (Cadmach Machines Ltd Ahmedabad,
India) The diameter of the tablet plug was 8
mm and the weight and hardness (Monsanto
hardness tester) were varied between 100-
200mg and 5-7 kg/cm2.
Determination of erosion rate
The time required for complete erosion of
the tablet plug (plug weight 150 mg ) was deter-
mined with a disintegration tester.(900ml pH 1.2
buffer for 2 h, thereafter pH 6.8 phosphate
buffer, 37 °C,(n  = 3)
Pulsatile capsule assembly
Assembly of pulsed release capsule device
proceeded as follows (Fig. 1), drug and filler
mixed with 15% of effervescent agent was filled
at the bottom of impermeable capsule body. An
erodible HPMC K100LV/lactose tablet plug was
inserted into the mouth of the capsule so that
upper surface of the erodible tablet flushed with
the open end of the capsule body. The erodible
tablet plug fitted snuggly with the wall of the
capsule. Finally the soluble capsule cap was
placed over the impermeable capsule body.
Figure 1. Assembly of pulsed release capsule device.
Dissolution studies of pulsatile capsule
device
The dissolution study of pulsatile capsule
was carried out using USP I basket apparatus,
model VDA-6D (Veego Ltd). The capsule was
placed in the basket and the speed was adjusted
at 50 rpm. The temperature was maintained at
37 ± 0.5 °C. First 900 ml of buffer pH 1.2 was
used as dissolution medium up to 2 h. There af-
ter the dissolution medium was replaced by
phosphate buffer (pH 6.8) and the dissolution
test was continued in the new medium. Aliquots
of the dissolution medium were removed at 1 h
intervals and amount of theophylline released
was estimated by spectrophotometer (Shimadzu
UV1700 pharmaspec) at a wavelength of 272
nm. Each dissolution data point represents the
mean of at least three individual trials in Figures
2-5.
RESULT AND DISCUSSION 
Formaldehyde treatment of hard gelatin
capsule
Gelatin is readily soluble in biological fluids
at body temperature. Formaldehyde and heat
treatment was employed to modify the solubility
of the hard gelatin capsule 14,15. The treated cap-
155
Latin American Journal of Pharmacy - 29 (1) - 2010
sules were subjected to disintegration test. The
results revealed that all the six capsule caps dis-
integrated and solubilized within 25 min in the
disintegration tests of empty capsules, while the
formaldehyde treated body of the capsule re-
mained intact for more than 12 h. Thus drug
will be released from a limited surface area of
open end of the hard gelatin capsule body,
which indicates the suitability for pulsed release
dosage form.
Effect of capsule content on drug release
To achieve pulsatile release, the drug should
be released rapidly once the capsule contents
are exposed to the medium. The effect of addi-
tion of effervescent agents to the capsule con-
tents is shown in Figure 2. The addition of 15%
effervescent agents resulted in complete drug
release within 10min. The drug released in-
creased with increasing concentration of effer-
vescent agents. The results concluded that ex-
tent of lag time prior to the drug release is pri-
marily controlled by the rate of erosion of tablet
plug; the subsequent drug release phase will be
determined by the composition of capsule con-
tent.
Figure 2. Effect of effervescent agent on drug release
from capsules without tablet plug.
Effect of different plug composition on
drug release
In order to identify proper plug material, two
different viscosity grades of HPMC (K100LV and
K4M) were evaluated. To control and to in-
crease the erosion rate, water soluble filler lac-
tose was added to the hydrophilic tablet plug.
The time required for complete erosion of
HPMC K4M: lactose (1:1) tablet plug was more
than 8 hrs and for HPMC K100LV: lactose (1:1)
was in between 3.5 to 4 h. The higher viscosity
grade HPMC K4M swelled, but eroded too slow-
ly to be suitable choice for pulsatile system. The
low viscosity grade (K100LV) did not form
stronger gel and eroded faster as compared to
higher viscosity grade. Considering the fact that
exposed area (erosion area) of the tablet plug
positioned within the capsule body is limited to
one side than the surface area of free plugs in
disintegration test, therefore low viscosity grade
HPMC K100LV was selected for further study.
After evaluating the plug material and the
capsule content separately, the complete pul-
satile drug delivery system was investigated
next. It consisted of formaldehyde treated cap-
sule body containing theophylline, lactose the
filler mixed with 15% of effervescent agents and
erodible tablet plug having different composi-
tion. The effect of different plug composition on
theophylline release is shown in Figure 3. The
release profiles revealed pulsatile characteristics.
The lag time (t10) for the formulations contain-
ing 4, 8, 12, 16 and 20% of HPMC K100LV in
tablet plug  was 0.2 h, 2 h, 3.2 h, 5.1 h and 6.35
h, respectively. Increasing the concentration of
HPMC K100LV in tablet plug resulted in increase
in lag time. In accordance with the chronomod-
ulated therapy of asthma, the lag time criterion
of 5 h was satisfied by formulation containing
16% of HPMC K100LV.
Figure 3. Effect of different plug composition on pul-
satile release of theophylline (plug weight 150 mg).
Effect of tablet plug hardness on drug
release 
To study the effect of tablet hardness on
drug release, the erodible tablet hardness was
varied between 5-7 kg/cm2. The results are
156
MAHAJAN A.N. & PANCHOLI S.S.
shown in Figure 4. Within the range of 5-7
kg/cm2, drug release profiles remained relatively
unchanged. The results concluded that tablet
hardness did not influence the drug release
within the ranges studied.
Effect of tablet plug weight on lag time
Maintaining the same composition of erodi-
ble tablet (16% HPMC K100LV), plugs of differ-
ent weights such as 100, 150 and 200mg were
evaluated for lag time. The relationship between
plug weight and lag time is shown in Figure 5.
A good correlation was observed between them.
(r2 = 0.9899). Increasing tablet plug weight
seemed to prolong lag time since the time re-
quired to complete the dissolution or erosion of
the tablet plug would be longer. This suggested
that the lag time could also be adjusted by
changing the plug weight.
CONCLUSION  
A chronomodulated pulsatile drug delivery
system of theophylline was successfully devel-
oped. In accordance with the chronomodulated
therapy of asthma, the lag time criterion of 5 h
was satisfied by formulation containing 16% of
HPMC K100LV. The dosage form can be taken
at bed time and will release the contents in the
early morning h when asthma attacks are more
prevalent.
Figure 4. Effect of tablet hardness on drug release
(composition of tablet plug 8% HPMC K100LV).
Figure 5. Influence of tablet plug weight on lag time.
REFERENCES
1. Alessandra, M., Z. Lucia, C. Matteo & M. Sangal-
li (2005) Expert. Opin. Drug. Deliv. 2: 855-71.
2. Arora, S., J. Ali, A. Ahuja & S. Baboota (2006)
Ind. J. Pharm. Sci. 68: 295-300.
3. Gusea, C., S. Koennings, T. Blunk, J. Siepmann
& A. Goepferich (2006) Int. J. Pharm. 314:
161-9.
4. Makino, K., T. Mogi & N. Ohtake (2000) Col-
loid. Surface B. 19: 173-9.
5. Pozzi, F., P. Furlani, A. Gazzaniga, S. Davis,
I.R. Wilding (1994) Int. J. Pharm. 31: 99-108.
6. Hong, L.L., Y.L. Shyr, K.L. Ying, H. Hsiu &
W.L. Yo (2008) Eur. J. Pharm. Biopharm. 70:
289-301.
7. Toyohiro, S., K. Hiromu, N. Hiroshi, S. Kazuhi-
ro & H. Masahiro (2004) Int. J. Pharm. 280:
103-11.
8. Sameer, S. & P. Atmaram (2006) Int. J. Pharm.
313: 150-8.
9. Smolensky, M.H., A.E. Reinberg & B. Lemmer
(2007) Adv. Drug Deliver. Rev. 59: 852-82
10. Burioka, N., M. Miyata, M. Endo, Y. Fukuoka &
H. Suyama (2005) Chronobiol. Int. 22: 383-90.
11. Qureshi, J., A. Mohd, S. Arora, A. Ahuja & S.
Baboota (2008) Ind. J. Pharm. Sci. 70: 351-6.
12. Zhang, Y., Z. Zhang & F. Wu (2003) J. Control.
Release 89: 47-55.
13. Gohel, M. & S. Manhapra (2002) J. Control. Re-
lease. 79: 157-64.
14. Digenis, G., T. Gold & V. Shah (1994) J.
Pharm. Sci. 83: 915-21.
15. Sripathy M., M.Srinath & K. Paranjothy (1999)
Eastern Pharmacist 42: 97-8.


English

Pulsatile drug delivery for the treatment of nocturnal asthma: a chronopharmaceutical approach

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Servicio de Difusión de la Creación Intelectual

153ISSN 0326-2383KEY WORDS: Chronotherapy, Lag time, Pulsatile capsule.* Author to whom correspondence should be addressed. E-mail: apmcashok@rediffmail.comLatin American Journal of Pharmacy(formerly Acta Farmacéutica Bonaerense)Lat. Am. J. Pharm. 29 (1): 153-6 (2010)Short CommunicationReceived: July 17,  2009Accepted: August 24, 2009Pulsatile Drug Delivery for the Treatment of Nocturnal Asthma:a Chronopharmaceutical ApproachAshok N. MAHAJAN * 1 & Shyam S. PANCHOLI 21 A.P.M.C. College of Pharmacy, College Campus, Himatnagar-383001, Gujarat, India2 S.K. Patel College of Pharmacy, Mehesana, Kherva-382711, Gujarat, IndiaSUMMARY. The objective of the present study was to develop and evaluate a pulsatile system of theo-phylline based on chronopharmaceutical considerations. The basic design consists of an impermeable cap-sule body, which contains the drug and is closed by an erodible tablet plug. The body portion of the hardgelatin capsules was cross-linked by the combined effect of formaldehyde and heat treatment. The formu-lation variables such as type of plug material, capsule content, different plug composition, plug weight andplug hardness was investigated to characterize the lag time (t10).The results indicated that drug releasefrom the pulsatile capsule exhibited an initial lag period, followed by a stage of rapid drug release. For thecomplete and rapid drug release from the capsule body, 15% of effervescent agent had to be included inthe capsule content. The lag time criterion of 5 hrs was satisfied by the tablet plug containing 16%HPMCK100LV. A good correlation was observed between erodible tablet weight and lag time.INTRODUCTION Recently pulsatile systems are gaining a lotof interest and attention, as they deliver thedrug at the right site of action at right time andin right amount, thus providing spatial and tem-poral delivery and increasing patient compli-ance. A pulsatile release profile is characterizedby a lag time followed by rapid and completedrug release, which is useful for the treatmentof certain diseases which exhibit circadianrhythm such as asthma, gastric ulcer, hyperten-sion, ischemic heart disease and arthritis 1,2. Forthis purpose, several technologies have beendescribed which include pulsatile implants 3,pulsatile microspheres 4, time clock system 5, os-motic systems 6, compression coated tablets 7and floating pulsatile beads systems 8.A review of the chronobiology of asthmahighlighted that airway resistance, bronchocon-striction, exacerbation of symptoms and worsen-ing of lung function, increase progressively atnight 9,10. It has been reported that risk of asth-ma attacks is l00 fold greater during the nighttime h (around 2.00 am) than during other timesof day, an observation which has nicely beenconfirmed in modern epidemiologic studies inasthmatic patient 11,12.In the light of the chronobiologic andchronopathologic findings, this study attemptsto design and evaluate chronomodulated pul-satile drug delivery system consisting of imper-meable capsule body, which contains the drugand is closed by an erodible tablet plug. It wasaimed to have a lag time of five h i.e., the sys-tem is taken at bed time and expected to releasethe drug after a period of 5 h (around 2.00 am)when the asthma attacks are more prevalent.The lag time (t10) was defined as intersectionpoint on the time axis when 10% of the drugcontained was released. Effect of various formu-lations parameters such as type of plug material,capsule content (effervescent agent), differentplug composition, plug weight and plug hard-ness was investigated to characterize the lagtime. 154MAHAJAN A.N. & PANCHOLI S.S.MATERIALS AND METHODSMaterials Theophylline was obtained as gift samplefrom Cipla Ltd, Mumbai. Two viscosity grades ofHydroxypropylmethylcellulose, HPMC K100LVand HPMC K4M cps were obtained as gift sam-ple from Coloron Asia Ltd. Lactose, magnesiumstearate, sodium bicarbonate and citric acidwere purchased from S. D. Fine chemicals Ltd.Mumbai. All other chemicals were laboratorygrade.Preparation of impermeable capsule bodyThe body and the cap of the hard gelatincapsules (size 0) were separated.  Capsule bod-ies was exposed to formaldehyde vapors for sixh at room temperature and dried at 50 °C for 12h in hot air oven. Afterwards the capsule bodyand the untreated soluble cap were stored indesiccators for further use. The efficacy of thetreated capsules was checked by disintegration(Model Electrolab-ED2, Mumbai) test 13.Filling of capsule bodiesThe impermeable capsule body was filledwith drug and excipient mixture. Theophylline(100 mg) and lactose, the filler (200 mg) waspassed through a 100 mesh sieve, followed byhand filling of the mixture into the capsule bod-ies(Fill weight 300 mg).To investigate the influ-ence of effervescent agent on drug release, lac-tose was partly replaced by 5 or 15% of a mix-ture of sodium bicarbonate and citric acid (1:1ratio).Preparation of erodible tablet plugDirect compression method was used to pre-pare the erodible tablet plug. The formulationscontaining 4, 8, 12, 16, 20 and 50% HPMCK100LV were prepared by weighing 4, 8, 12, 16,20 and 50 g of HPMC K100LV and adding lac-tose to 99 g. Each formulation was mixed for 10min, followed by addition of 1 gm of magne-sium stearate to each blend. The resultantblends were mixed for 5 min and directly com-pressed into tablets using single punch tabletmachine. (Cadmach Machines Ltd Ahmedabad,India) The diameter of the tablet plug was 8mm and the weight and hardness (Monsantohardness tester) were varied between 100-200mg and 5-7 kg/cm2.Determination of erosion rateThe time required for complete erosion ofthe tablet plug (plug weight 150 mg ) was deter-mined with a disintegration tester.(900ml pH 1.2buffer for 2 h, thereafter pH 6.8 phosphatebuffer, 37 °C,(n  = 3)Pulsatile capsule assemblyAssembly of pulsed release capsule deviceproceeded as follows (Fig. 1), drug and fillermixed with 15% of effervescent agent was filledat the bottom of impermeable capsule body. Anerodible HPMC K100LV/lactose tablet plug wasinserted into the mouth of the capsule so thatupper surface of the erodible tablet flushed withthe open end of the capsule body. The erodibletablet plug fitted snuggly with the wall of thecapsule. Finally the soluble capsule cap wasplaced over the impermeable capsule body.Figure 1. Assembly of pulsed release capsule device.Dissolution studies of pulsatile capsuledeviceThe dissolution study of pulsatile capsulewas carried out using USP I basket apparatus,model VDA-6D (Veego Ltd). The capsule wasplaced in the basket and the speed was adjustedat 50 rpm. The temperature was maintained at37 ± 0.5 °C. First 900 ml of buffer pH 1.2 wasused as dissolution medium up to 2 h. There af-ter the dissolution medium was replaced byphosphate buffer (pH 6.8) and the dissolutiontest was continued in the new medium. Aliquotsof the dissolution medium were removed at 1 hintervals and amount of theophylline releasedwas estimated by spectrophotometer (ShimadzuUV1700 pharmaspec) at a wavelength of 272nm. Each dissolution data point represents themean of at least three individual trials in Figures2-5.RESULT AND DISCUSSION Formaldehyde treatment of hard gelatincapsuleGelatin is readily soluble in biological fluidsat body temperature. Formaldehyde and heattreatment was employed to modify the solubilityof the hard gelatin capsule 14,15. The treated cap-155Latin American Journal of Pharmacy - 29 (1) - 2010sules were subjected to disintegration test. Theresults revealed that all the six capsule caps dis-integrated and solubilized within 25 min in thedisintegration tests of empty capsules, while theformaldehyde treated body of the capsule re-mained intact for more than 12 h. Thus drugwill be released from a limited surface area ofopen end of the hard gelatin capsule body,which indicates the suitability for pulsed releasedosage form.Effect of capsule content on drug releaseTo achieve pulsatile release, the drug shouldbe released rapidly once the capsule contentsare exposed to the medium. The effect of addi-tion of effervescent agents to the capsule con-tents is shown in Figure 2. The addition of 15%effervescent agents resulted in complete drugrelease within 10min. The drug released in-creased with increasing concentration of effer-vescent agents. The results concluded that ex-tent of lag time prior to the drug release is pri-marily controlled by the rate of erosion of tabletplug; the subsequent drug release phase will bedetermined by the composition of capsule con-tent.Figure 2. Effect of effervescent agent on drug releasefrom capsules without tablet plug.Effect of different plug composition ondrug releaseIn order to identify proper plug material, twodifferent viscosity grades of HPMC (K100LV andK4M) were evaluated. To control and to in-crease the erosion rate, water soluble filler lac-tose was added to the hydrophilic tablet plug.The time required for complete erosion ofHPMC K4M: lactose (1:1) tablet plug was morethan 8 hrs and for HPMC K100LV: lactose (1:1)was in between 3.5 to 4 h. The higher viscositygrade HPMC K4M swelled, but eroded too slow-ly to be suitable choice for pulsatile system. Thelow viscosity grade (K100LV) did not formstronger gel and eroded faster as compared tohigher viscosity grade. Considering the fact thatexposed area (erosion area) of the tablet plugpositioned within the capsule body is limited toone side than the surface area of free plugs indisintegration test, therefore low viscosity gradeHPMC K100LV was selected for further study.After evaluating the plug material and thecapsule content separately, the complete pul-satile drug delivery system was investigatednext. It consisted of formaldehyde treated cap-sule body containing theophylline, lactose thefiller mixed with 15% of effervescent agents anderodible tablet plug having different composi-tion. The effect of different plug composition ontheophylline release is shown in Figure 3. Therelease profiles revealed pulsatile characteristics.The lag time (t10) for the formulations contain-ing 4, 8, 12, 16 and 20% of HPMC K100LV intablet plug  was 0.2 h, 2 h, 3.2 h, 5.1 h and 6.35h, respectively. Increasing the concentration ofHPMC K100LV in tablet plug resulted in increasein lag time. In accordance with the chronomod-ulated therapy of asthma, the lag time criterionof 5 h was satisfied by formulation containing16% of HPMC K100LV.Figure 3. Effect of different plug composition on pul-satile release of theophylline (plug weight 150 mg).Effect of tablet plug hardness on drugrelease To study the effect of tablet hardness ondrug release, the erodible tablet hardness wasvaried between 5-7 kg/cm2. The results are156MAHAJAN A.N. & PANCHOLI S.S.shown in Figure 4. Within the range of 5-7kg/cm2, drug release profiles remained relativelyunchanged. The results concluded that tablethardness did not influence the drug releasewithin the ranges studied.Effect of tablet plug weight on lag timeMaintaining the same composition of erodi-ble tablet (16% HPMC K100LV), plugs of differ-ent weights such as 100, 150 and 200mg wereevaluated for lag time. The relationship betweenplug weight and lag time is shown in Figure 5.A good correlation was observed between them.(r2 = 0.9899). Increasing tablet plug weightseemed to prolong lag time since the time re-quired to complete the dissolution or erosion ofthe tablet plug would be longer. This suggestedthat the lag time could also be adjusted bychanging the plug weight.CONCLUSION  A chronomodulated pulsatile drug deliverysystem of theophylline was successfully devel-oped. In accordance with the chronomodulatedtherapy of asthma, the lag time criterion of 5 hwas satisfied by formulation containing 16% ofHPMC K100LV. The dosage form can be takenat bed time and will release the contents in theearly morning h when asthma attacks are moreprevalent.Figure 4. Effect of tablet hardness on drug release(composition of tablet plug 8% HPMC K100LV).Figure 5. Influence of tablet plug weight on lag time.REFERENCES1. Alessandra, M., Z. Lucia, C. Matteo & M. Sangal-li (2005) Expert. Opin. Drug. Deliv. 2: 855-71.2. Arora, S., J. Ali, A. Ahuja & S. Baboota (2006)Ind. J. Pharm. Sci. 68: 295-300.3. Gusea, C., S. Koennings, T. Blunk, J. Siepmann& A. Goepferich (2006) Int. J. Pharm. 314:161-9.4. Makino, K., T. Mogi & N. Ohtake (2000) Col-loid. Surface B. 19: 173-9.5. Pozzi, F., P. Furlani, A. Gazzaniga, S. Davis,I.R. Wilding (1994) Int. J. Pharm. 31: 99-108.6. Hong, L.L., Y.L. Shyr, K.L. Ying, H. Hsiu &W.L. Yo (2008) Eur. J. Pharm. Biopharm. 70:289-301.7. Toyohiro, S., K. Hiromu, N. Hiroshi, S. Kazuhi-ro & H. Masahiro (2004) Int. J. Pharm. 280:103-11.8. Sameer, S. & P. Atmaram (2006) Int. J. Pharm.313: 150-8.9. Smolensky, M.H., A.E. Reinberg & B. Lemmer(2007) Adv. Drug Deliver. Rev. 59: 852-8210. Burioka, N., M. Miyata, M. Endo, Y. Fukuoka &H. Suyama (2005) Chronobiol. Int. 22: 383-90.11. Qureshi, J., A. Mohd, S. Arora, A. Ahuja & S.Baboota (2008) Ind. J. Pharm. Sci. 70: 351-6.12. Zhang, Y., Z. Zhang & F. Wu (2003) J. Control.Release 89: 47-55.13. Gohel, M. & S. Manhapra (2002) J. Control. Re-lease. 79: 157-64.14. Digenis, G., T. Gold & V. Shah (1994) J.Pharm. Sci. 83: 915-21.15. Sripathy M., M.Srinath & K. Paranjothy (1999)Eastern Pharmacist 42: 97-8.

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Pulsatile drug delivery for the treatment of nocturnal asthma: a chronopharmaceutical approach

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