FORMULATION DEVELOPMENT AND EVALUATION OF LANSOPRAZOLE DR ODT

MATERIALS AND METHODS MATERIALS
Lansoprazole was obtained as gift sample from Active Pharmaceutical Ingredient, Sugar Granules, MCC , HPC and Mg Carbonate   from Alkem Research Centre.

METHODS
Preparation of Lansoprazole microGranules
The prototype microGranules of lansoprazole were prepared using MCC Sphere to optimize the various parameters such as inlet temperature, outlet temperature and air pressure of Fluid Bed Coater. Then formulations of delayed release microGranules of lansoprazole were done using HPC as a release retardant in different concentrations (table 1).

Drug Loading
MCC Spheres  were  sieved  through  30#40  and 33%  of Granules  was  taken for  drug loading from total batch size. Required quantity of drug was taken and dispersed in specified ml of purified water solution and stirred for 10 minutes. The required quantity of MCC Spheres was taken and dispersed in specified ml of purified water and stirred for 10 minutes to obtain a clear solution.  Purified water Solution was mixed with dispersed MCC Sphere solution with stirring. Granules were loaded using dispersion both in to FBC bowl and coated.

Barrier coating
Required  quantity  of  Drug  loaded  Granules  was taken for Barrier coating. Required quantity of HPMC was taken and dissolved in specified ml of purified water and stirred until a clear solution was obtained and coating was done (table 2).

Enteric coating
Specified quantity of Barrier coated Granules were taken for Enteric coating. Required quantity of Eudragit L30 D55, Talc, Titanium Dioxide, Iron oxide Red and citric acid (Table 2)were taken and dispersed in specified ml of purified water and stirred for 10 minutes to obtain a clear solution. The prepared dispersion was mixed with Eudragit solutions with required quantity of Water solution for pH adjustment and coating was done.

Evaluation of powder blend and Granules
The formulated powder blend were evaluated for compatibility, particle size shape analysis using Malvern particlesizer (MS 2000)5, angle repose6, hausner’s ratio, compressibility index, bulk density, true density and Granule density5, flow rate, Carr’s Index.

Compression of Tablets
The prepared blend was compressed in round shaped tablet 20mg . The weight of tablet 140-160mg , Hardness 60-80N , thickness 2.50-2.60mm and DT is 2-4 min.

In-vitro Dissolution studies
The   release   of   drug   from   the   developed formulations in the environment of gastrointestinal tract was   determined   using   the   USP   XXIII   dissolution apparatus   II   (Electro   lab   TDT   –   08L).   Tablets equivalent to 20 mg of Lansoprazole in beaker containing 900 ml of 0.1N HCl of dissolution media maintained at 37 ± 0.5°C and 100 rpm. After 1 hour the medium was drained without losing the Granules and 900 ml of pre heated buffer solution of pH 6.8 added, study was further continued for 60 minutes at 75 rpm.  Aliquot  of samples  were withdrawn at  every  15 minutes  each  time  which  was  replaced  by  the  same amount of fresh medium.
The samples were Centrifuge at 5000 rpm for 5 minutes of the above solution, and clear supernatant liquid was used. Correction factors for each aliquot were considered in calculation of release profile. Absorbance of sample after proper dilution was measured at  285  nm  using  HPLC  Dionex  (chromeleon)  against blank. Concentration of drug was determined from the standard plots of the drug in buffer and the percentage drug release was calculated at each sampling time.

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Dissolution  profile  Comparisons  (Using  a  Similarity Factor)
A  simple  model  independent  approach  uses  a difference  factor  (f1)  and  a  similarity  factor  (f2)  to compare dissolution profiles. The difference factor (f1) calculates  the percent (%)  difference between the two curves at each point and is a measurement to the relative error between the two curves:

f1= {[∑n=1 n?Rt – Tt ?]/ [∑t=1 n Rt ]}*100

Where n is the number of time point, Rt is the dissolution
value  of  the  reference  batch  at  time  t,  and  Tt   is  the dissolution value of the test batch at time t.

The similarity factor (f2) is the logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) dissolution between the two curves.
f2 = 50 • log {[1+ ( 1/n) ∑t=1n ( Rt – Tt )2 ]-0.5•100}

For the curves to be considered similar, f1 values should be close to 0, and f2 values should be close to 100.
Generally, f1 values up to (0-15) and f2 values greater than 50 (50-100) ensures sameness or equivalence of the two curves and thus, of the performance of the test and reference products. The comparative dissolution was performed using Lanzol 20mg7.

Gasric Resistance Study
The release of drug from the developed formulations in the environment of gastrointestinal tract was   determined   using   the   USP   XXIII   dissolution apparatus   II   (Electro   lab   TDT   –   08L).   Capsules containing micro Granules equivalent to 30 mg of Lansoprazole in beaker containing 900ml 0.1 HCl N of dissolution media maintained at 37 ± 0.5°C and 75 rpm. After 1 hour the medium was drained without losing the Granules transfer it to a filter paper and dry the Granules by blotting with filter paper.  Granules were transferred into 100 ml volumetric flask, 40ml of 0.1M NaOH was added and sonicator to dissolve. Further it was diluted up to 100 ml with 0.1M NaOH. About 15 ml of solution was centrifuged for 5 minutes. 5 ml of the clear supernatant liquid   was   diluted   to   50   ml   with   mobile   phase. Absorbance of sample after proper dilution was measured at 285 nm using HPLC Dionex (chromeleon) against blank.

Drug Content
Equivalent  weights  to  equivalent  to  20mg  of Lansoprazole into a dry 100 ml volumetric flask added about 50 ml of 0.1 M NaOH and sonicate to dissolve. The volume was make up to the mark with 0.1 M sodium hydroxide  and  mix.  20  to  30  ml   of  solution  was transferred into dry stoppered test-tube and it was centrifuge at 5000rpm for 5 minutes. Samples were analyzed using HPLC Dionex (chromeleon) at a wavelength of 285nm. The drug content was determined by diluting 5 ml of the supernatant solution to 50ml with mobile phase.

Accelerated stability studies
Formulation were stored at various temperature viz. 25°C/60% RH, 30°C/65% RH and 40°C/75% RH as per    ICH    guidelines    and    various    physicochemical parameter (appearance, percentage drug content and release   profile)   were   monitored   periodically   for   3 months8.

RESULTS AND DISCUSSION
Lansoprazole  DR ODT was  formulated,  using HPMC as release retardant in various concentration with an enteric coating. Lansoprazole micro Granules were prepared by applying optimized pressure and temperature in fluid bed coater technique. Lansoprazole meets all the ideal characteristics to formulate in the form of oral drug delivery system.

Under   Preformulation   study,   FTIR   analysis between the drug and enteric polymer mixture showed no unaccountable extra peaks, which confirms the absence of chemical interaction between the drug and polymer.

Physical characterization
Powder blend of Lansoprazole and micro Granules were evaluated for various physiochemical parameters.

The  organoleptic  properties  were  complied  with  the British Pharmacopeia specification.   Physical properties such  as  particle  size  analysis,  bulk  density  of  raw material powder, Melting point. Solution properties solubility evaluated, results were complied with the pharmacopeia specification. Loss on drying was within the British Pharmacopeia limit and the result of angle of repose of powder showed the poor flow properties. Angle of repose and flow rates  of the  different formulations were compared with bulk drug, Lansoprazole, which shows that after Granules formulation flow properties and flow rate were excellent. Assay of Lansoprazole was carried out using HPLC and it was found to be 99.6% (figure 5). Technological characterizations of formulated Lansoprazole powder blend and microGranules formulation are shown in (table 3).

In Vitro Dissolution Studies
The  dissolution  rate  studies  for  each  of  the formulations were performed in order to assess the effect of increase in surfactant concentration on release profile. In dissolution studies, 900ml solution of 0.1N HCl was taken for  one hour  and followed by 900ml  phosphate buffer pH 6.8 to mimic the cumulative release of drug in stomach. Result of in vitro dissolution rate studies are shown in (table 4) (figure 1).

Dissolution profile Comparisons (Similarity Factor)
The     dissolution     comparisons     by     model independent approach using a similarity factor f1 is found to be 2.18 and f2 found 86.53 (table 5) (figure2).

Gastric Resistance study
Acid resistances study shows that the optimized formulation F9  is  more  stable in the  acidic  media  i.e.
99.36% of drug was released in 60 minutes. Result of acid resistances studies are correlated in (table 4) (figure3).

Accelerated stability studies
The  selected  formulations  were  subjected  for accelerated stability studies as per the ICH guidelines.
There were no changes in appearances and percentage drug content of Granules stored at different temperature for drug remaining vs. time at 25°C/60% RH, 30°C/65% RH and 40°C/75% RH. All the parameter were within the limit after 90 days.

CONCLUSION
The study was undertaken with an aim to develop delayed    release    micro    pellet    dosage    form    for Lansoprazole, which is a benzimidazole anti ulcer agent and is one of the most widely used drug for treating mild and severe ulcers.
Based on the Drug-Excipient compatibility   data   and   prototype   formulations,   the formula that found to be giving the desired drug release pattern was considered as the optimized formulation and further studies were conducted on this formulation F9 to have a detailed study over that formulation. By the observations made, it was concluded that the formulation F9 shows delayed release profile and it was within the USP  limits,  and  also  this  formulation  done  by  FBC process which is a sophisticated method.

Then this formulation was compared with marketed product by an in vitro study, which definitely improves patient’s compliances   and   reduces   the   gastric   side   effects.

Table 1. Formulation of Lansoprazole pellets

Table 2.Technological characterization of coating formula on optimized formulation F9

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Table 3. Technological characterization of formulated Lansoprazole powder blend and microGranules formulation*

Table 4. In vitro Release Profile of Percentage Cumulative Drug Release from various formulations and Acid Resistance Dissolution Data*

Table 5. Comparative Dissolution Profile of F9 with Reference

REFERENCES
1. Ghebre-Sellassie I., In Pharmaceutical Pellitization Technology (Ghebre–Sellassie), Marcel Dekker, Ist ed. 1989, 1-13.
2. rug data sheet.com
3. Tetsunori Hasebe et. al., Tokai J. Exp. Clinical Med., 1998, l(23), 177-182.
4. Sean R. Tunis et. al., Clinical Theraputics, 1997, 19, 4.
5. Subramanyam      C.V.S.,       Text      Book       of Pharmaceutics, New Delhi: Vallabh Prakashan, 2nd ed. 198-200, 223-224.
6. Sinha   V.R,   Agrawal   M.K.,   and   Kumria   R., Influence of formulation and excipient variables on the pellet properties prepared by extrusion spheronization, C. Drug Del.,  2005, 5, 1-8.
7. Moore, Statistical Design and Analysis of Stability Studies, Published by CRC Press., 2007, 330.
8. Paulo   Costa.   And   Jose   Manuel   Sausalobe., Modeling and compression of dissolution profiles. Eur. J. Pharm. Sci., 2001, 13, 123-133.

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