Development and Evaluation of In-situ
gel containing Linezolid and Diclofenac Sodium in the treatment of
Periodontitis
Inayathulla*, Prakash Goudanavar, Ankit Acharya
Department of
Pharmaceutics, Sri Adichunchanagiri College of Pharmacy,
B.G. Nagara,
Karnataka -571448, India.
*Corresponding Author E-mail: ankitbaba99@gmail.com
ABSTRACT:
Periodontal treatment aims at
reduction of infection and inflammation. Linezolid is a synthetic antibacterial
agent of a new class of antibiotics, the oxazolidinones, which has clinical
utility in the treatment of infections caused by aerobic and anaerobic bacteria
susceptible organisms methicillin and vancomycin-resistant in the
treatment of periodontitis. Diclofenac sodium is anti-inflammatory agent and in-situ
gel containing Linezolid and Diclofenac sodium in this study may have a
potential additive effect. Hence, there is broad scope for research in local
application of antimicrobial and anti-inflammatory combination drug (s) in
periodontitis. Linezolid and Diclofenac sodium. In-situ gel
containing Linezolid in combination with Diclofenac sodium was prepared using
combination of carbopol-HPMC and carbopol-NaCMC. The prepared in-situ gel
formulation showed satisfactory results for in-vitro gelling capacity,
rheology, and other physical properties. In-vitro drug release profile
was dependent up on the concentration of polymer, i.e. drug release was
decreased with increase in polymer concentration and vice versa. The
formulations of batches LDCF1, LDCF2, LDCF3, LDSF1, LD SF2 and LDSF3 failed to
extend the drug release up to 12 hours. Thus, the formulation of batches LDCF4
and LDSF4 containing carbopol: HPMC and carbopol: NaCMC in 1:2 ratios were
considered as optimum formulation on the basis of optimum viscosity, gelation
time, gelation temperature, gelling capacity, and their capacity to extend the in-vitro
drug release up to 12 hours. Hence, prepared formulations showed sustain drug
release behaviour.
KEYWORDS: Linezolid,
Diclofenac sodium, carbopol, HPMC, NaCMC.
INTRODUCTION:
Periodontal
diseases are mainly of bacterial etiology in initiation and progression of
periodontal diseases. Periodontal treatment aims at reduction of infection and
inflammation and adjunctive use of drugs such as anti-microbial agents and
anti-inflammatory agents1. Linezolid is a synthetic antibacterial
agent of a new class of antibiotics, the oxazolidinones, which has clinical
utility in the treatment of infections caused by aerobic and anaerobic bacteria
susceptible organisms methicillin and vancomycin-resistant2. In
situ gels are systems which are applied as solutions and are capable of
undergoing rapid sol-to-gel transformation triggered by external stimulus such
as pH-triggered system (e.g. cellulose acetate hydrogen phthalate latex and
Carbopol), Temperature dependent system (eg. pluronics and tetronics), and. Ion
activated system (eg. gelrite). In situ gel based drug delivery
systems consist of pharmaceutical active ingredients, polymer, co-polymer and
excipients. The use of carbopol as in situ gel forming system was
substantiated by the property to transform into stiff gels when the pH is
increased. Hydroxy Propyl Methyl Cellulose (HPMC) is incorporated as a
viscosity enhancer to further aid in accomplishment of sustained drug delivery.
HPMC is semi synthetic, inert, viscoelastic polymer which is non-ionic
nontoxic, a good carrier for pharmaceutical application which exhibits high
swelling capacity3. Hence it was a challenge to formulate in-situ
periodontal gel containing Linezolid and Diclofenac sodium with rate
controlling polymers which provides a longer duration of action and local
antibacterial effect without loss of dosage4,5.
MATERIALS AND METHODS:
Preparation of in-situ
gelling systems:
In-situ gels were prepared
by cold method using varying concentration of carbopol 934P and hydroxy propyl
methyl cellulose (HPMC) (LDCF1, LDCF2, LDCF3 and LDCF4) and carbopol 934P and
sodium carboxy methyl cellulose (NaCMC) (LDSF1, LDSF2, LDSF3 and LDSF4).
Optimum batch was selected based on gelling time and gelling capacity. First
polymers were prepared by adding the polymers to deionised water and heated to
90° while stirring. After cooling to below 40° appropriate amounts of calcium
chloride (0.05% w/v) was added into the solution. Separately drugs were
dissolved in propylene glycol. The drug solution was slowly added to the
polymer dispersion. To this solution, 2-3 drops triethanolamine was added to
adjust the pH. Above mixture was stirred by using a magnetic stirrer to ensure
thorough mixing. Finally, methylparaben and propylparaben were added to the above
formulation mixture. This solution was allowed to stand for 2 hour for removal
of air bubble. The final solution
was kept in well closed container refrigerator at 4°C until evaluation.3
The formulation design of in-situ gel formulation was tabulated
in Table 1.
Drug-polymer
compatibility study:
FTIR spectrum of
pure drug and mixture of drug and polymers are shown in Fig. 1. From the
spectral study, it was observed that there was no significant change in the
peaks of pure drug and drug polymer mixture. Hence, no specific interaction was
observed between the drug and the polymers used in the formulations.
Table 1: Formulation of various concentrations
|
Batch |
D (%w/v) |
L (%w/v) |
HPMC (%w/v) |
NaCMC (%w/v) |
Carbopol 934P (%w/v) |
Calcium chloride (%w/v) |
MP (%w/v) |
PP (%w/v) |
Deionized water |
|
LDCF1 |
0.1 |
0.5 |
0.5 |
-- |
0.5 |
0.05 |
0.15 |
0.02 |
q.s |
|
LDCF2 |
0.1 |
0.5 |
0.5 |
-- |
1.0 |
0.05 |
0.15 |
0.02 |
q.s |
|
LDF3 |
0.1 |
0.5 |
0.5 |
-- |
1.5 |
0.05 |
0.15 |
0.02 |
q.s |
|
LDCF4 |
0.1 |
0.5 |
0.5 |
-- |
2.0 |
0.05 |
0.15 |
0.02 |
q.s |
|
LDCSF1 |
0.1 |
0.5 |
-- |
0.5 |
0.5 |
0.05 |
0.15 |
0.02 |
q.s |
|
LDSF2 |
0.1 |
0.5 |
-- |
0.5 |
1.0 |
0.05 |
0.15 |
0.02 |
q.s |
|
LDSF3 |
0.1 |
0.5 |
-- |
0.5 |
1.5 |
0.05 |
0.15 |
0.02 |
q.s |
|
LDSF4 |
0.1 |
0.5 |
-- |
0.5 |
2.0 |
0.05 |
0.15 |
0.02 |
q.s |
Note: D; Diclofenac
sodium, L; Linezolid, HPMC; Hydroxy propyl methyl cellulose, NaCMC; Sodium
carboxy methyl cellulose, MP; methyl paraben, PP; propyl paraben, q.s; quantity
sufficient to 100 ml.
Figure 1: FTIR spectrum of drug
linezolid, Diclofenac sodium and physical mixture
Evaluation of in-situ
gel:
Appearance:
All prepared
formulations were evaluated from the visual inspection.6
pH measurement:
pH is one of the
most important parameter involved in the in-situ gel formulation and it
is measured directly with the help of digital pH meter.
Drug content estimation:
For determination of drug
content, 1ml of in-situ gel formulation was placed in a vial containing
5 ml of 6.8 pH PBS (simulated
salivary pH), equilibrated at 37°C and gel formation was assessed
visually. As soon as whole gel body was formed, the whole formulations were
taken into separate dialysis tubes. The tubes were kept in a beaker containing
50ml of distilled water and formulations were dialyzed for 30 min at 50rpm and
dialysis medium was replaced with fresh quantities of distilled water in
between so as to ensure complete removal of unentrapped drug. The concentration
of LZ and DS was determined spectrophotometrically at 250 nm and 276 nm, after
suitable dilution and filtration using 6.8 pH buffer as blank.7,8
Gelling Capacity:
All formulations
were evaluated for gelling capacity in order to identify the compositions
suitable for use as in-situ gelling systems. The gelling capacity was
determined by visual method, in which coloured solution of prepared
formulations were prepared. Gelling capacity was estimated by placing 2ml of
6.8 pH phosphate buffer in a 10ml test tube and maintained at 37°C temperature.
One millilitre of coloured formulation solution was added to the phosphate
buffer. As the formulation comes into contact with phosphate buffer it was
immediately converted into a stiff gel-like structure. The gelling capacity of
formulation was evaluated on the basis of stiffness of formed gel and time
period for which formed gel remains as such. The in-vitro gelling
capacity was graded in four categories on the basis of gelation time and the
time taken for the gel formed to dissolve. (-) no gelation; (+), gels after few
minutes, dispersed rapidly; (++), gelation immediate, remains for few hours;
and (+++), gelation immediate, remains for an extended period.7,8
Gelation
temperature:
10 ml of the sample
solution and a magnetic bead were put into a 30ml transparent vial placed in a
low temperature digital water bath. A thermometer was placed in the sample
solution. The solution was heated at the rate of 1°/min with the continuous
stirring. The temperature at which the magnetic bead stopped moving due to
gelation was considered as gelation temperature.7
Gelation time:
Gelation time of
prepared in-situ gel formulation was measured by placing 2ml of the gel
in 15ml borosilicate glass test tube. This test tube was placed in water bath
(37oC) and gelation time was noted when there was no flow of the gel
when test tube was inverted.7
Viscosity and
rheological studies:
Brookfield digital
viscometer was used for the determination of viscosity and rheological
properties of atorvastatin in situ gel using spindle no LC. 50g of the gel was
taken in a beaker and the spindle was dipped in it. The viscosity of gel was
measured at different angular velocities at a temperature of 25°. A typical run
comprised changing of the angular velocity from 10 to 60 rpm.
Syringeability:
All prepared formulations were
transferred into an identical 5ml plastic syringe placed with 21 gauge needle
to a constant volume (1ml). The solutions which were easily passed from syringe
was termed as pass and difficult to pass were termed as fail.
In-vitro drug release
studies:
Drug release
profile of in-situ gel formulation was carried out by using Franz
diffusion cell (25ml). One gram of linezolid in-situ gel formulation was
placed in donor compartment and 25ml of dissolution medium of pH 6.8 (simulated salivary pH) in receptor
compartment. Between donor and receptor compartment chicken cheek mucous membrane is placed. Sols were added from the top so that upon
contact with the salivary fluid get converted to gel form. The whole
assembly was placed on the thermostatically controlled magnetic stirrer. The
temperature of the medium was maintained at 37°C ± 0.5°C. 1ml of sample was
withdrawn at predetermined time interval for 0.5 hours to 12 hours and same
volume of fresh medium was replaced. The withdrawn samples were diluted to 10ml
in a volumetric flask with same buffer medium and analyzed by UV
spectrophotometer at 250nm and 276nm using reagent blank. The drug content was
calculated using the equation generated from standard calibration curve. The %
cumulative drug release (% CDR) was calculated.8
Accelerated
stability studies:
Optimized bathes of
in-situ gel were placed in ambient colored vials and sealed with
aluminium foil for a short term accelerated stability study at 25±2°C and 60±5%
RH and 40±2°C and 75±5% RH as per International Conference on Harmonization
states Guidelines. Samples were analyzed every month for clarity, pH, gelling
capacity and drug content.8
RESULTS AND DISCUSSION:
Appearance:
All batches of in-situ gel
formulations were clear and there was absence of foreign particles.
pH of prepared in-situ
gel:
The pH of the formulations was
found in the range of 6.2-6.8, which was required pH for periodontal treatment.
The pH values of all prepared formulations were within the limit of neutral pH;
this indicates formulations can be used without any irritation in the oral
cavity.9
Syringeability:
Syringeability test showed that
prepared in-situ gel formulations were easily injectable through 21
gauge needle at room temperature (25°C), hence passes the syringeability test.
This facilitate to injection of sol directly into the periodontal pocket.
Gelling time, temperature and
capacity:
Optimization of in-situ
gel was done based upon its gelling time, temperature and gelling capacity. The
formulation should undergo rapid sol-to-gel transition due to ionic
interaction. Moreover, to facilitate sustained release of the drug to the
periodontal cavity, the formed gel should preserve its integrity without
dissolving or eroding for a prolonged period of time. In-situ gels were
prepared using various concentration of carbopol (0.5-2.0%) and
concentration of NaCMC and HPMC was kept constant. Gelation temperature of
solution was observed in the range of desired gelation temperature (35-39oC).
Gelation temperature is the temperature at which the liquid phase makes a
transition to gel. The gelation temperature of an in-situ gel would be
higher than 25°C. If the gelation temperature of the formulation is lower than
25°C, gelation occurs at storage temperature, leading to difficulty in
manufacturing, handling, and administering.10
Except the formulations of
batches LDCF1, LDSF1 and LDSF2, all the batches showed instantaneous
gelation when contacted with gelation fluid (Simulated Saliva). However, the
nature of the gel formed depended upon the polymer concentration. Among all
batches, formulation LDCF4 (containing 1:4 ratio of HPMC and carbopol) showed
shortest gelation time i.e. 2.14 min. Batches LDCF1, LDSF1 and LDSF2 showed the
weakest gelation, which could be due to the presence of very low concentration
of carbopol. Batches LDCF2, LDCF4, SF3 and SF4 showed immediate gelation but
the formed gels did not remain for an extended period of time ranging from 7.21
- 8.3min. This indicates that the formed gel might be less stiff and erodes
within a few hours, which could be due to the relatively low concentration of
carbopol. Batches LF4 showed immediate gelation (2.14 min) and the gel formed
was stiff and remained for an extended period of time.
Drug content uniformity:
Drug content estimation was
done by using simultaneous estimation of Linezolid (LZ) and for Diclofenac
sodium (DS) in 6.8 pH buffer. The percent drug content was found to be
in acceptable range for all formulations. The percent drug content of all
in-situ gel formulations was found to be in between 97.88% to 99.91% for
Linezolid (LZ) and for Diclofenac sodium (DS) it lies between 96.84% to 98.29%.
Viscosity and
rheological studies:
Viscosity of
prepared in-situ gel formulations were evaluated
before and after gelation. It was found that as the shear rate increased the
viscosity of gel decreased in both cases. Results of viscosity studies
showed that viscosity of prepared formulation was drastically increased after
gelation. The viscosity of in-situ gel was increased after gelation. As
indicated, a formulation suitable for application to the periodontal pocket
should ideally have a low viscosity when applied, and after instillation have a
high viscosity in order to stay at the application site. From the phase
behaviour, the presently studied formulations seem promising for achieving such
behaviour.
Viscosity of prepared gel was
also dependent on the concentration of the gel based on increasing the
concentration of polymer ratio, the viscosity of the gel was increased. These findings indicated the differences
between viscosity of gels and their corresponding sols. Rheological
evaluation of selected formulation exhibited pseudoplastic flow before and
after gelling. It was also reported that,
in polymer solutions, the various interactions
between polymer chains regarded as localized junctions are responsible for an
increase in viscosity and exhibit non-Newtonian flow.10 Further, it was also found that, all the
formulations were liquid at room temperature and underwent rapid gelation when
the pH was raised to 6.8. The viscosity of formulation contributed to the
product adhesiveness, reflecting the importance of product rheology on this
parameter. Additionally, the gel formed in-situ should maintain
its integrity without dissolving or eroding for a prolonged period. Results of
rheological studies are shown in Table 2 and 3 and Fig 2 and Fig 3.
Table 2:
|
Viscosity before gelation (cps) |
||||||||
|
Formulation |
||||||||
|
RPM |
LDCF1 |
LDCF2 |
LDCF3 |
LDC F4 |
LDSFF1 |
LDS F2 |
LDS F3 |
LDSF4 |
|
10 |
880 |
1115 |
1288 |
1327 |
799 |
920 |
948 |
1020 |
|
20 |
760 |
926 |
954 |
1095 |
531 |
810 |
866 |
915 |
|
30 |
547 |
710 |
756 |
815 |
468 |
665 |
680 |
718 |
|
40 |
430 |
622 |
645 |
710 |
220 |
419 |
420 |
485 |
|
50 |
297 |
385 |
460 |
480 |
165 |
258 |
268 |
316 |
|
60 |
110 |
219 |
352 |
390 |
92 |
103 |
112 |
225 |
Table 2: Continued
|
Viscosity after gelation (cps) |
||||||||
|
Formulation |
||||||||
|
R P M |
LDC1 |
LDC2 |
LDC3 |
LDC4 |
LDSF1 |
LDSF2 |
LDSF3 |
LDSF4 |
|
10 |
1880 |
3011 |
3233 |
3633 |
1760 |
2610 |
3169 |
3270 |
|
20 |
1650 |
2380 |
2471 |
2541 |
1620 |
1968 |
2381 |
2230 |
|
30 |
1270 |
1375 |
1878 |
1944 |
1235 |
1244 |
1775 |
1850 |
|
40 |
985 |
1128 |
1519 |
1669 |
951 |
1076 |
1334 |
1690 |
|
50 |
870 |
892 |
1236 |
1250 |
866 |
865 |
1023 |
1125 |
|
60 |
565 |
636 |
680 |
891 |
539 |
560 |
646 |
720 |
Figure 2:
Rheological profile of prepared in-situ gel before gelling
Figure 3:
Rheological profile of prepared in-situ gel after gelling
In-vitro drug release
studies:
The cumulative amount of
Linezolid and Diclofenac sodium released vs time profile for the selected
formulations is shown in Figure 3. First sampling was done 0.5 hour after the
formulation placed on the synthetic cellulose membrane of the donor compartment
of Franz Diffusion Cell. Half an hour time for first sampling was selected in
order to evaluate the effect of increasing polymer concentration on the cumulative
amount of drug released. The results showed that the amount of drug released in
the 0.5 hour decreased with increasing polymer concentration, and the trend
continued for the entire duration of the study. This might be due to increase
in concentration of polymers showed higher viscosity which in term delayed the
drug release from the formulation. From the drug release studies we also
observed that almost 35% of drug released from all formulations within 2 hours.
The initial burst release of the drug from the prepared formulations could be
explained by the fact that these systems were formulated in an aqueous vehicle.
The matrix formed on gelation was already hydrated and hence hydration and
water permeation could no longer limit the drug release, the remaining drug was
released at a slower rate (second phase). This bi phasic pattern of release is
a characteristic feature of matrix diffusion kinetics. The formulation LDCF1, LDCF2, LDCF3, LDCF1, LDSF2 and LDSF3
completes more than 80% of drug release within 6 hours, whereas formulation
LDCF4 and LDSF4 containing 2% carbopolshowed drug release up to 12 hours, which
might be due to higher viscosity and gelation capacity of these formulations.
Based on the release studies, formulation LDCF4 and LDSF4 was selected for
further studies.
Figure 3: The in vitro
release profiles of Linozolid (LZ)
and Diclofenac sodium (DS) for optimized batches (LDCF4 and LDSF4) of in-situ
gels
Table 3: In-vitro drug release profile of prepared in-situ
gel formulations
|
Time (hours) |
Cumulative percentage drug release (%CDR) |
|||||||||||||||
|
LDCF1 |
LDCF2 |
LDCF3 |
LDCF4 |
LDSF1 |
LDSF2 |
LDSF3 |
LDSF4 |
|||||||||
|
LZ |
DS |
LZ |
DS |
LZ |
DS |
LZ |
DS |
LZ |
DS |
LZ |
DS |
LZ |
DS |
LZ |
DS |
|
|
0 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
|
0.5 |
19.64 |
20.44 |
16.18 |
18.18 |
14.92 |
16.85 |
10.08 |
12.08 |
21.82 |
22.85 |
19.12 |
20.09 |
15.22 |
17.74 |
12.33 |
15.65 |
|
1 |
35.05 |
32.62 |
29.92 |
30.92 |
27.54 |
25.32 |
25.64 |
20.64 |
38.24 |
34.66 |
28.54 |
31.65 |
29.82 |
28.92 |
29.24 |
24.08 |
|
2 |
59.71 |
56.78 |
54.06 |
52.55 |
50.44 |
51.07 |
36.62 |
34.62 |
61.76 |
52.82 |
55.88 |
47.32 |
53.91 |
44.01 |
40.66 |
32.33 |
|
4 |
81.69 |
87.92 |
70.27 |
74.82 |
64.78 |
66.65 |
44.77 |
48.82 |
88.08 |
84.39 |
71.33 |
69.36 |
68.74 |
63.85 |
48.83 |
41.78 |
|
6 |
98.86 |
96.75 |
88.71 |
85.79 |
82.32 |
88.39 |
50.92 |
55.92 |
99.02 |
97.84 |
84.09 |
87.75 |
83.77 |
82.62 |
54.04 |
58.94 |
|
8 |
-- |
-- |
99.05 |
98.65 |
96.63 |
99.85 |
59.96 |
62.96 |
-- |
-- |
98.47 |
99.43 |
95.11 |
98.92 |
61.72 |
67.39 |
|
10 |
-- |
-- |
-- |
-- |
-- |
-- |
68.02 |
70.02 |
-- |
-- |
-- |
-- |
-- |
-- |
70.07 |
75.73 |
|
12 |
-- |
-- |
-- |
-- |
-- |
-- |
75.19 |
80.66 |
-- |
-- |
-- |
-- |
-- |
-- |
79.65 |
81.07 |
Note: LZ;
linezolid, DS; Diclofenac sodium
Stability studies:
Stability study of two
optimized batches LDCF4 and LDSF4 was performed for 3 months in stability
conditions as per ICH guidelines. The formulations were examined for
appearance, drug content, pHand gelling capacity for every 1 month for 3
months. It was observed that there was no change in the physical appearance of
the formulation. The drug content was analyzed and there was marginal
difference between the formulations kept at different temperatures from the
result obtained it can be said that the prepared in-situgel formulation
was stable as it showed non-significant difference (p<0.05) in appearance,
pH, drug content and gelling capacity.
CONCLUSION:
In this work in-situ
gel containing the drug linezolid and Diclofenac sodium with a combination of
carbopol-HPMC and carbopol-NaCMC was developed. The developed formulations
showed satisfactory results for in-vitro gelling capacity, rheology, and
other physical properties. In-vitro drug release studies showed a
polymer concentration-dependent decrease in drug release. All the formulations
developed by using different concentrations of Carbopol (0.5-2.0%). The
formulations of batches LDCF1, LDSF1, and LDSF2 did not showed gelation up to
45°C, which is not desirable for in-situ gel. The formulations of
batches LDCF1, LDCF2, LDCF3, LDSF1, LDSF2 and LDSF3 failed to extend the drug
release up to 12 hours. Thus, the formulation of batches LDCF4 and LDSF4
containing carbopol: HPMC and carbopol: NaCMC in 1:2 ratios were considered as
optimum formulation on the basis of optimum viscosity, gelation time, gelation
temperature, gelling capacity, and their capacity to extend the in-vitro
drug release up to 12hours.
Further,
it was also found that, all the formulations were liquid at room temperature
and underwent rapid gelation when the pH was raised to 6.8. The viscosity of formulation
contributed to the product adhesiveness, reflecting the importance of product
rheology on this parameter. Additionally, the gel formed in-situ maintained
its integrity without dissolving or eroding for a prolonged period.
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Accepted on 28.01.2020 ©Asian Pharma Press All
Right
Reserved
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