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A Pharmaceutical Study on Certain
Aminosalicylates
By
Ibrahim Al Sharabi
Under the supervision of
Prof. Dr. Ahmed Abd Elba...
Introduction
Inflammatory bowel diseases
(IBDs)
• Affect 4 million people worldwide.
• Symptoms include:
Diarrhea, abdominal pain, hema...
Ulcerative Colitis
• Anatomic Extent of Disease
Distal
(Proctitis)
Left-Sided
(Distal Colitis)
Pancolitis
(Extensive)
18%4...
UC and Aminosalicylates
• 5-ASA products remain the first line treatment for patient with UC.
• 5-ASA is thought to work t...
Commercially applied colon
targeting techniques for 5-ASA
Prodrugs Modified release formulations
• Delayed release product...
In-vivo distribution of 5-ASA Formulations
Pulsatile type oral
preparations
Conventional
sustained release
preparations
En...
Aim of the study
Chapter 1
Preformulation Studies
Physicochemical properties of 5-ASA
• Name: 5-Aminosalicylic acid(5-ASA), m-aminosalicylic acid,
fisalamine, mesalamine or...
Experimental
Spectral study
Determination of aqueous
solubility of
5-ASA at different pH values
Compatibility study
(DSC a...
Stability indicating assay of 5-ASA.
Chromatographic Condition:
• Mobile phase: methanol-phosphate buffer (pH 4.6) (20:80,...
Results and discussion-Spectral study
λmax = 330λmax = 303
λmax = 299
5-ASA calibration curves at different pH
y = 0.024x + 0.000
R² = 0.999
y = 0.024x + 2E-06
R² = 0.999
y = 0.021x + 0.000
R²...
Aqueous solubility of 5-ASA at different pH
values
9.99
1.73
9.23
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8
Solubility(mg/ml)
pH
DSC of 5-ASA, pharmaceutical excipients and
their 1:1 w/w physical mixtures.
FT-IR of 5-ASA, pharmaceutical excipients and their 1:1 w/w
physical mixtures.
Stability Indicating assay of 5-ASA
y = 85157x
R² = 0.994
0
5000000
10000000
15000000
0 25 50 75 100 125 150
AUP
Concentra...
Chromatogram obtained following injection of 5-ASA 1(100µg/ml) in
phosphate buffer (pH 4.5) kept in ambient conditions for...
Conclusion
• 5-ASA has a pH dependent solubility profile.
• 5-ASA was shown to be physically and chemically
compatible wit...
Chapter 2
Formulation and evaluation of 5-ASA
matrix tablets
Formulation Design
• pH dependent polymer
dissolving at pH > 6
(Eudragit® L and
Eudragit® S).
Delaying drug
release
• Hydr...
Batches
Carbopol
(%)
Eudragit RS
(%)
Eudragit S
(%)
Eudragit L
(%)
Crospovidone
(%)
Croscarmellose Na
(%)
F1 - 2.5 - - - -...
Experimental
Preparation of
tablets
Characterization of tablets
Hardness
Friability
Drug content
In-vitro release
studies ...
In-vitro release studies
pH1.2
pH4.5
pH7.4
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16
Time (h)
350 ml
600 ml
9...
Kinetic Analysis
• Zero order kinetics : Mt/M∞ = kt
• Higuchi model : Mt/M∞ = k(t)0.5 + C
• Korsmeyer-Peppas: Mt/M∞ = ktn ...
Results and discussion
• Hardness (8-12 kg)
• Friability (<0.5%)
• Drug content (± 6.5 %)
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18
%5-ASAReleased
Time (hr)
F1
F2
F3
In-vitro release studies
In-vi...
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18
%5-ASAReleased
Time (hr)
Ideal Targeted Profile
F4
F5
F6
In-vitr...
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18
%5-ASAReleased
Time (hr)
F16
F17
F18
F19
F20
0
10
20
30
40
50
60...
Conclusion
• Incorporation of pH dependent polymers (Eudragit®
S and Eudragit® L) and Carbopol® in the used levels
was ins...
Chapter 3
Once Daily, High Dose 5-ASA Controlled Release
Tablets for Colonic Delivery: Optimization Of
Formulation Variabl...
1200 mg 5-ASA
pH dependent polymer
Sustained release polymer
Superdisintegrant
Experimental Design
Formulation variables
Level used
(-1) (0) (+1)
X1= Carbopol® content (%) 0 4 8
X2= Eudragit® RS conten...
Composition of Box-Behnken formulations
Run
Factors
X1 X2 X3
1 0 5.5 2
2 4 5.5 1
3 0 5.5 0
4 8 10 1
5 4 1 2
6 8 5.5 0
7 4 ...
Preparation of
granules to be
compressed
Evaluation of granules to
be compressed
• Angle of Repose
• The percentage
compre...
Results and discussion
• Granules
– Angles of repose between 27 and 31 suggesting a
reasonable flow.
– Carr’s index values...
In-vitro release profiles of all formulations.
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18
%5-ASAreleased
Ti...
Observed responses from randomized
runs in Box-Behnken design
Run
Responses
Y1 Y2 Y3
1 6.8 32.7 53.3
2 11.0 44.7 84.3
3 3....
Summary of statistical analysis
Source Y1 Y2 Y3
Sum of squares P > F Sum of squares P > F Sum of
squares
P > F
(a) Model a...
Effect of the contents of Eudragit® RS (X1) and croscarmellose Na (X2) on 5-ASA
release at 6h using response surface plot ...
Effect of the contents of Eudragit® RS (X1) and croscarmellose Na (X2) on 5-ASA
release at 10h and 14 h using response sur...
Optimization of drug release
Overlay plot showing the optimized parameters suggested by the
software to get the responses ...
Validation of the optimized formulation
Responses (predicted, %) Observed (%) Predicted error (%)
Y1 (7.58) 8 5.54
Y2(45.5...
Release rate kinetics for the Box-Behnken
and the optimized formulations
Run
r2
Mechanism
Correlation time
span (h)
t20% t...
Accelerated stability study for the optimized
formulation
• No Physical changes.
– No cracking.
– No change in color.
• No...
Conclusion
• Box-Behnken design was successfully used to evaluate and optimize
the formulation variables.
• The optimized ...
Chapter 4
Development, Evaluation and Optimization of
Novel Colonic Targeting 5-ASA Microspheres
Rational for formulating 5-ASA into
microspheres
• Controlling rate and site of drug release while providing:
– Less varia...
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16
Time (h)
Formulation Design
Drug Particles
pH1.2
pH4.5
pH7.4
5-ASA and
Mg stearate
Polymers
dissolved in
acetone
30 min
5 min
• Preparation of microspheres.
Experimental
Liquid paraffin
4⁰C premixed
with 2% span
Acetone
2000 rpm for 5 min1000 rpm for 4-6 hr
Hexane
Morphological
and particle
size analyses
Production
yield
Encapsulation
efficiency
DSC and
FTIR
studies
In-vitro
release
s...
Composition of microspheres formulations
Formulation
5-ASA
(mg)
Drug: ES100
ratio
ES 100
(%)
Drug :EC
Ratio
Mg Stearate
(%...
Effects of varying proportion of Eudragit® S to internal phase
Formulation Physical Appearance Particle Size (µm) Yield (%...
Composition of microspheres formulations
Formulation
5-ASA
(mg)
Drug: ES100
ratio
ES 100
(%)
Drug :EC
Ratio
Mg Stearate
(%...
Effects of internal phase to external phase ratio.
Formulation Physical Appearance Particle Size (µm) Yield (%) Entrapment...
Composition of microspheres formulations
Formulation
5-ASA
(mg)
Drug: ES100
ratio
ES 100
(%)
Drug :EC
Ratio
Mg Stearate
(%...
Effects of varying proportion of Eudragit® S to drug .
Formulation Physical Appearance Particle Size (µm) Yield (%) Entrap...
Composition of microspheres formulations
Formulation
5-ASA
(mg)
Drug: ES100
ratio
ES 100
(%)
Drug :EC
Ratio
Mg Stearate
(%...
Physical characterization of EC-Eudragit® S formulations.
Formulation Physical Appearance Particle Size(µm) Yield (%) Entr...
DSC and FTIR studies of EC-Eudragit® S formulations.
In-vitro release profiles of Eudragit® S-EC formulations
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18
%5-ASAR...
Kinetic analysis of EC-Eudragit® S formulations.
Formulation
r2
Mechanism
Correlation
time span
(hr)
t20% t50% t80%
Zero o...
Scanning electron micrographs of microspheres from batch MES100EC15
before drug release (330X)
Scanning electron micrographs of microspheres from batch MES100EC10
before drug release (140X)
Scanning electron micrographs of inner part of the microspheres from batch
MES100EC10 before drug release (1000X)
Scanning electron micrographs of microspheres from batch MES100EC10
after drug release (200X)
Scanning electron micrographs of microspheres from batch MES100EC10
after drug release (2000X)
Accelerated Stability Study for selected
formulation MES100EC10
• No Physical changes.
– No change in color.
• No degradat...
Conclusion
• Oil/oil solvent evaporation method resulted in preparation
of microspheres suitable for colon targeting with ...
Publishment
Publishment
Publishment
A pharmaceutical study on certain aminosalicylates  master defense
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A pharmaceutical study on certain aminosalicylates master defense

  1. 1. A Pharmaceutical Study on Certain Aminosalicylates By Ibrahim Al Sharabi Under the supervision of Prof. Dr. Ahmed Abd Elbary Abd Elrahman Professor of Pharmaceutics and Industrial Pharmacy Ex- Dean of faculty of pharmacy-Cairo University. Dr. Ahmed A. Aboelwafa Lecturer of Pharmaceutics Cairo University
  2. 2. Introduction
  3. 3. Inflammatory bowel diseases (IBDs) • Affect 4 million people worldwide. • Symptoms include: Diarrhea, abdominal pain, hematochezia, abdominal mass, malnutrition and abdominal distension. Types Ulcerative Colitis (UC): Inflammation and ulcers only in the mucosa of the colon Crohn’s disease (CD): Inflammation of all layers and sites of the GIT
  4. 4. Ulcerative Colitis • Anatomic Extent of Disease Distal (Proctitis) Left-Sided (Distal Colitis) Pancolitis (Extensive) 18%40% 40%
  5. 5. UC and Aminosalicylates • 5-ASA products remain the first line treatment for patient with UC. • 5-ASA is thought to work topically on the inflamed mucosa. • 5-ASA is extremely absorbed from the proximal small intestine and then extensively metabolized to inactive metabolite (Low availability at the distal part of the GIT – systemic side effects.) • Large doses of 5-ASA are required in induction and maintenance therapy of UC (up to 4.8 g/d). • large number of tablets (up to 12/day in 3 or 4 divided doses). • Rate of adherence to maintenance treatment ≈ 40%. • High rate of relapse. • Un treated UC is an important risk factor for colonic cancer.
  6. 6. Commercially applied colon targeting techniques for 5-ASA Prodrugs Modified release formulations • Delayed release products – Salofalk® – Asacol® • Extended release products – Pentasa® O NHS O Sulfasalazine Olsalazine Inert Carrier Balsalazide
  7. 7. In-vivo distribution of 5-ASA Formulations Pulsatile type oral preparations Conventional sustained release preparations Enteric coated – extended release preparations Lialda (Mezavant) Apriso
  8. 8. Aim of the study
  9. 9. Chapter 1 Preformulation Studies
  10. 10. Physicochemical properties of 5-ASA • Name: 5-Aminosalicylic acid(5-ASA), m-aminosalicylic acid, fisalamine, mesalamine or mesalazine. • Molecular formula is C7H7N03 and molecular weight of 153.14. • Melting Point :283°C • Very slightly soluble in water, practically insoluble in organic solvents. • The drug powder exhibits poor flowability.
  11. 11. Experimental Spectral study Determination of aqueous solubility of 5-ASA at different pH values Compatibility study (DSC and FTIR)
  12. 12. Stability indicating assay of 5-ASA. Chromatographic Condition: • Mobile phase: methanol-phosphate buffer (pH 4.6) (20:80, v/v). • Flow rate : 0.8 ml/min. • Detection wavelength : 220 nm. • Injection volume : 5 l. • Method validation: – linearity – Precision – Accuracy – Specificity
  13. 13. Results and discussion-Spectral study λmax = 330λmax = 303 λmax = 299
  14. 14. 5-ASA calibration curves at different pH y = 0.024x + 0.000 R² = 0.999 y = 0.024x + 2E-06 R² = 0.999 y = 0.021x + 0.000 R² = 0.999 0 0.2 0.4 0.6 0.8 1 0 4 8 12 16 20 24 28 32 36 Absorbance Concentration µg/ml pH 1.2 pH 4.5 pH 7.4
  15. 15. Aqueous solubility of 5-ASA at different pH values 9.99 1.73 9.23 0 2 4 6 8 10 12 0 1 2 3 4 5 6 7 8 Solubility(mg/ml) pH
  16. 16. DSC of 5-ASA, pharmaceutical excipients and their 1:1 w/w physical mixtures.
  17. 17. FT-IR of 5-ASA, pharmaceutical excipients and their 1:1 w/w physical mixtures.
  18. 18. Stability Indicating assay of 5-ASA y = 85157x R² = 0.994 0 5000000 10000000 15000000 0 25 50 75 100 125 150 AUP Concentration (µg/ml)
  19. 19. Chromatogram obtained following injection of 5-ASA 1(100µg/ml) in phosphate buffer (pH 4.5) kept in ambient conditions for 72 hr
  20. 20. Conclusion • 5-ASA has a pH dependent solubility profile. • 5-ASA was shown to be physically and chemically compatible with most of all of the tested excipients.
  21. 21. Chapter 2 Formulation and evaluation of 5-ASA matrix tablets
  22. 22. Formulation Design • pH dependent polymer dissolving at pH > 6 (Eudragit® L and Eudragit® S). Delaying drug release • Hydrophobic polymers Eudragit® RS. • Hydrophilic polymer Carbopol® Release sustainment • Superdisintegrant Disintegrating • Minimizing the level of excipients High loading 1200 mg 5-ASA pH dependent polymer Sustained release polymer Superdisintegrant
  23. 23. Batches Carbopol (%) Eudragit RS (%) Eudragit S (%) Eudragit L (%) Crospovidone (%) Croscarmellose Na (%) F1 - 2.5 - - - - F2 - 5 - - - - F3 - 10 - - - - F4 2.5 - - - - - F5 5 - - - - - F6 10 - - - - - F7 2.5 - 2.5 - - - F8 2.5 - 5 - - - F9 2.5 - 10 - - - F10 20 - 5 - - - F11 25 - 5 - - - F12 20 - - 5 - - F13 10 - 20 - - - F14 10 2 18 - - - F15 10 2 10 8 - - F16 5 5 - - - - F17 5 5 - - - 5 F18 - 5 - - 5 - F19 10 5 - - - - F20 10 5 - - 5 - Composition of matrix tablets formulations
  24. 24. Experimental Preparation of tablets Characterization of tablets Hardness Friability Drug content In-vitro release studies and kinetics analysis
  25. 25. In-vitro release studies pH1.2 pH4.5 pH7.4 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 Time (h) 350 ml 600 ml 900 ml 50 rpm
  26. 26. Kinetic Analysis • Zero order kinetics : Mt/M∞ = kt • Higuchi model : Mt/M∞ = k(t)0.5 + C • Korsmeyer-Peppas: Mt/M∞ = ktn + C. Mt/M∞
  27. 27. Results and discussion • Hardness (8-12 kg) • Friability (<0.5%) • Drug content (± 6.5 %)
  28. 28. 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time (hr) F1 F2 F3 In-vitro release studies In-vitro release profile of 5-ASA from matrix tablets with varying proportion of Eudragit® RS. ↑ Eudragit® RS  ↓ DR
  29. 29. 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time (hr) Ideal Targeted Profile F4 F5 F6 In-vitro release profile of 5-ASA from matrix tablets with varying proportion of Carbopol®®. ↑ Carbopol®  No significant effect
  30. 30. 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time (hr) F16 F17 F18 F19 F20 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time (hr) F7 F8 F9 F10 F11 F12 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time (hr) F13 F14 F15 There was no sufficient retardation in precolonic stage of release studies even with inclusion of high con. Of pH dependent polymers
  31. 31. Conclusion • Incorporation of pH dependent polymers (Eudragit® S and Eudragit® L) and Carbopol® in the used levels was insufficient to achieve the targeted release profile proposed in this study. • Application of coat may be necessary to prevent abrupt initial release of 5-ASA .
  32. 32. Chapter 3 Once Daily, High Dose 5-ASA Controlled Release Tablets for Colonic Delivery: Optimization Of Formulation Variables Using Box-Behnken Design.
  33. 33. 1200 mg 5-ASA pH dependent polymer Sustained release polymer Superdisintegrant
  34. 34. Experimental Design Formulation variables Level used (-1) (0) (+1) X1= Carbopol® content (%) 0 4 8 X2= Eudragit® RS content (%) 1 5.5 10 X3= Croscarmellose Na content (%) 0 1 2 Responses variables Constraints Y1 = Release (%) after 6 hr 7.5% ≤ Y1 ≤ 22.5% Y2 = Release (%) after 10 hr 42.5% ≤ Y2 ≤ 57.5 % Y3 = Release (%) after 14 hr 72.5% ≤ Y3 ≤ 87.5%
  35. 35. Composition of Box-Behnken formulations Run Factors X1 X2 X3 1 0 5.5 2 2 4 5.5 1 3 0 5.5 0 4 8 10 1 5 4 1 2 6 8 5.5 0 7 4 5.5 1 8 4 1 0 9 4 5.5 1 10 8 1 1 11 4 10 2 12 4 10 0 13 0 10 1 14 8 5.5 2 15 0 1 1
  36. 36. Preparation of granules to be compressed Evaluation of granules to be compressed • Angle of Repose • The percentage compressibility (Carr's Index). • The Hausner ratio Preparation of 5-ASA core tablets Evaluation of 5-ASA core tablets. • Hardness. • Friability . • Drug content. Coating of the core tablets and in-vitro release studies Preparation and Characterization of experimental runs
  37. 37. Results and discussion • Granules – Angles of repose between 27 and 31 suggesting a reasonable flow. – Carr’s index values indicate fair flow properties for all formulations while Hausner ratios suggest a low inter- granular friction . • Core tablets – Drug content (± 5% of the theoretical amount). – Hardness was set to be in the range of (10-11). – Friability (< 0.9%).
  38. 38. In-vitro release profiles of all formulations. 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAreleased Time (hr) Ideal targeted release Run1 Run2 Run3 Run4 Run5 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAreleased Time (hr) Ideal targeted release Run6 Run7 Run8 Run9 Run10 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAreleased Time (hr) Ideal targeted release Run11 Run12 Run13 Run14 Run15
  39. 39. Observed responses from randomized runs in Box-Behnken design Run Responses Y1 Y2 Y3 1 6.8 32.7 53.3 2 11.0 44.7 84.3 3 3.0 11.3 20.5 4 2.0 13.6 44.7 5 17.2 65.4 95.1 6 4.5 20.2 49.2 7 10.5 66.4 90.3 8 12.1 63.2 93.5 9 9.0 69.2 92.7 10 7.9 39.0 83.5 11 11.0 44.7 84.3 12 2.0 6.6 15.6 13 3.5 12.2 18.3 14 4.3 46.9 92.1 15 16.0 60.1 92.2
  40. 40. Summary of statistical analysis Source Y1 Y2 Y3 Sum of squares P > F Sum of squares P > F Sum of squares P > F (a) Model analysis Mean vs. total 953.44 25918.13 69559.39 Linear vs. mean 203.43 0.0115 3817.85 0.0609 8647.99 0.0087 2FIa vs. linear 18.75 0.7118 455.62 0.8094 1457.86 0.3927 Quadratic vs. 2FI 81.69 0.0487 3517.22 0.0023 3032.47 0.0092 Cubic vs. quadratic 23.69 0.0667 238.23 0.0899 385.41 0.0628 Residual 1.12 15.44 17.04 Total 1282.11 33962.49 83100.16 (b) Lack of fit Linear 124.13 0.0395 4211.07 0.0163 4875.74 0.0156 2FI 105.38 0.0311 3755.45 0.0122 3417.88 0.0148 Quadratic 23.69 0.0667 238.23 0.0899 385.41 0.0628 Cubic 0.000 0.000 0.000 Pure error 1.12 15.44 17.04 R2 Ra 2 PRESS R2 Ra 2 PRESS R2 Ra 2 PRESS (c) R2 analysis Linear 0.619 0.5150 258.03 0.475 0.3313 6764.99 0.637 0.5401 8608.39 2FI 0.676 0.4330 524.30 0.531 0.1797 10468.81 0.746 0.5561 10430.84 Quadratic 0.925 0.7886 381.63 0.968 0.9117 3846.43 0.970 0.9168 6204.88 Cubic 0.997 0.9762 ND b 0.998 0.9866 ND 0.999 0.9912 ND
  41. 41. Effect of the contents of Eudragit® RS (X1) and croscarmellose Na (X2) on 5-ASA release at 6h using response surface plot and its contour plot at 4% Carbopol® content. sign-Expert® Software ease at 6 hours Design points above predicted value Design points below predicted value 17.21 2.01 = B: Eudragit RS = C: Croscarmellose Na tual Factor Carbopol = 4.00 1.00 3.25 5.50 7.75 10.00 0.00 0.50 1.00 1.50 2.00 2 6 10 14 18 Releaseat6hours B: Eudragit RS C: Croscarmellose Na
  42. 42. Effect of the contents of Eudragit® RS (X1) and croscarmellose Na (X2) on 5-ASA release at 10h and 14 h using response surface plot and its contour plot at 4% Carbopol® content. 1.00 3.25 5.50 7.75 10.00 0.00 0.50 1.00 1.50 2.00 6 24 42 60 78 Releaseat10hours B: Eudragit RS C: Croscarmellose Na Design-Expert® Software Release at 14 hours Design points above predicted value Design points below predicted value 96.12 15.6042 X1 = A: Carbopol X2 = C: Croscarmellose Na Actual Factor B: Eudragit RS = 5.50 0.00 2.00 4.00 6.00 8.00 0.00 0.50 1.00 1.50 2.00 20 40.25 60.5 80.75 101 Releaseat14hours A: Carbopol C: Croscarmellose Na
  43. 43. Optimization of drug release Overlay plot showing the optimized parameters suggested by the software to get the responses in the required range.
  44. 44. Validation of the optimized formulation Responses (predicted, %) Observed (%) Predicted error (%) Y1 (7.58) 8 5.54 Y2(45.54) 46.2 1.45 Y3(78.83) 82.3 4.40 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAreleased Time (hr) Ideal targeted release Optimized formulation ODMP ƒ2 = 67.7
  45. 45. Release rate kinetics for the Box-Behnken and the optimized formulations Run r2 Mechanism Correlation time span (h) t20% t50% t80% Zero order Diffusion Peppas Run1 0.9809 0.9965 0.9743 Diffusion (6-16) 7.60 13.48 22.16 Run2 0.9993 0.9960 0.9979 Zero order (5-14) 7.01 10.49 13.98 Run3 0.9746 0.9853 0.9844 Diffusion (5-16) 14.40 45.72 97.96 Run4 0.9974 0.9900 0.9960 Zero order (8-16) 9.74 15.16 20.57 Run5 0.9961 0.9966 0.9910 Diffusion (5-16) 5.99 8.51 12.05 Run6 0.9855 0.9806 0.9894 Peppas (6-16) 9.50 15.04 19.79 Run7 0.9928 0.9861 0.9921 Zero order (5-12) 6.22 9.56 12.91 Run8 0.9856 0.9618 0.9921 Peppas (5-12) 8.12 10.44 12.10 Run9 0.9845 0.9776 0.9892 Peppas (5-12) 6.99 9.97 12.51 Run10 0.9991 0.9929 0.9965 Zero order (6-14) 7.36 10.76 14.17 Run11 0.9961 0.9715 0.9989 Peppas (5-14) 7.30 10.76 13.77 Run12 0.9576 0.9016 0.9813 Peppas (5-16) 14.97 22.72 28.62 Run13 0.9878 0.9923 0.9805 Diffusion (5-16) 15.03 51.33 112.94 Run14 1.0000 0.9977 0.9798 Zero order (6-12) 7.42 10.38 13.34 Run15 0.9956 0.9798 0.9970 Peppas (5-12) 6.68 9.67 12.33 Optimized formulation 0.9974 0.9917 0.9898 Zero order (5-14) 7.12 10.47 13.82
  46. 46. Accelerated stability study for the optimized formulation • No Physical changes. – No cracking. – No change in color. • No degradation. • No significant change in release profile. 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time (hr) Zero Time 3 Months 6 Months
  47. 47. Conclusion • Box-Behnken design was successfully used to evaluate and optimize the formulation variables. • The optimized hydrophilic-hydrophobic, high loading 5-ASA matrix tablets demonstrated a zero order drug release kinetics potentially suitable for once daily administration. • The optimized formulation, containing 5.72 % Carbopol®, 9.77% Eudragit® RS and 1.45 % croscarmellose sodium in addition to other excipients, was fabricated utilizing the simple wet granulation technique and produced a release profile comparable to that of the marketed product.
  48. 48. Chapter 4 Development, Evaluation and Optimization of Novel Colonic Targeting 5-ASA Microspheres
  49. 49. Rational for formulating 5-ASA into microspheres • Controlling rate and site of drug release while providing: – Less variations in gastric emptying. – Better distribution in the GIT. – Less liability of dose dumping.
  50. 50. 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 Time (h) Formulation Design Drug Particles pH1.2 pH4.5 pH7.4
  51. 51. 5-ASA and Mg stearate Polymers dissolved in acetone 30 min 5 min • Preparation of microspheres. Experimental
  52. 52. Liquid paraffin 4⁰C premixed with 2% span Acetone 2000 rpm for 5 min1000 rpm for 4-6 hr
  53. 53. Hexane
  54. 54. Morphological and particle size analyses Production yield Encapsulation efficiency DSC and FTIR studies In-vitro release studies and kinetics analysis Characterization of microspheres
  55. 55. Composition of microspheres formulations Formulation 5-ASA (mg) Drug: ES100 ratio ES 100 (%) Drug :EC Ratio Mg Stearate (%) Internal : external phase ratio Surfactant (%) Microparticles prepared with varying polymer to internal phase ratio MF1 500 1:1 2 - 5 1:2 2 MF2 500 1:1 1 - 5 1:2 2 MF3 500 1:1 0.667 - 5 1:2 2 Microparticles prepared with different internal-to-external phase ratio MF2 500 1:1 1 - 5 1:2 2 MF4 500 1:1 1 - 5 1:4 2 MF5 500 1:1 1 - 5 1:6 2 MF6 500 1:1 1 - 5 1:8 2 Microparticles prepared with varying drug to ES 100 ratio MF7 500 1:0.25 1 - 5 1:2 2 MF8 500 1:0.5 1 - 5 1:2 2 MF9 500 1:0.7 1 - 5 1:2 2 MF2 500 1:1 1 - 5 1:2 2 MF10 500 1:2 1 - 5 1:2 2 Microparticles with varying drug to polymeric blends ratio MES70EC10 500 1:0.7 1 1:0.1 5 1:2 2 MES70EC15 500 1:0.7 1 1:.0.15 5 1:2 2 MES70EC20 500 1:0.7 1 1:0.2 5 1:2 2 MES85EC10 500 1:0.85 1 1:0.1 5 1:2 2 MES85EC15 500 1:0.85 1 1:0.15 5 1:2 2 MES185EC20 500 1:0.85 1 1:0.2 5 1:2 2 MES100EC10 500 1:1 1 1:0.1 5 1:2 2 MES100EC15 500 1:1 1 1:0.15 5 1:2 2 MES100EC20 500 1:1 1 1:0.2 5 1:2 2
  56. 56. Effects of varying proportion of Eudragit® S to internal phase Formulation Physical Appearance Particle Size (µm) Yield (%) Entrapment Efficiency (%) MF1 Spherical, discrete 83.35±22.74 84.45 ± 2.45 82.15 ± 2.54 MF2 Spherical, discrete 264.04±42.10 94.42 ± 1.88 90.55 ± 3.45 MF3 Spherical, discrete 105.38±26.95 83.52 ± 2.17 87.94 ± 1.48 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time (hr) MF1 MF2 MF3
  57. 57. Composition of microspheres formulations Formulation 5-ASA (mg) Drug: ES100 ratio ES 100 (%) Drug :EC Ratio Mg Stearate (%) Internal : external phase ratio Surfactant (%) Microparticles prepared with varying polymer to internal phase ratio MF1 500 1:1 2 - 5 1:2 2 MF2 500 1:1 1 - 5 1:2 2 MF3 500 1:1 0.667 - 5 1:2 2 Microparticles prepared with different internal-to-external phase ratio MF2 500 1:1 1 - 5 1:2 2 MF4 500 1:1 1 - 5 1:4 2 MF5 500 1:1 1 - 5 1:6 2 MF6 500 1:1 1 - 5 1:8 2 Microparticles prepared with varying drug to ES 100 ratio MF7 500 1:0.25 1 - 5 1:2 2 MF8 500 1:0.5 1 - 5 1:2 2 MF9 500 1:0.7 1 - 5 1:2 2 MF2 500 1:1 1 - 5 1:2 2 MF10 500 1:2 1 - 5 1:2 2 Microparticles with varying drug to polymeric blends ratio MES70EC10 500 1:0.7 1 1:0.1 5 1:2 2 MES70EC15 500 1:0.7 1 1:.0.15 5 1:2 2 MES70EC20 500 1:0.7 1 1:0.2 5 1:2 2 MES85EC10 500 1:0.85 1 1:0.1 5 1:2 2 MES85EC15 500 1:0.85 1 1:0.15 5 1:2 2 MES185EC20 500 1:0.85 1 1:0.2 5 1:2 2 MES100EC10 500 1:1 1 1:0.1 5 1:2 2 MES100EC15 500 1:1 1 1:0.15 5 1:2 2 MES100EC20 500 1:1 1 1:0.2 5 1:2 2
  58. 58. Effects of internal phase to external phase ratio. Formulation Physical Appearance Particle Size (µm) Yield (%) Entrapment Efficiency (%) MF2 Spherical, discrete 264.04±42.10 94.42 ± 1.88 90.55 ± 3.45 MF4 Spherical, discrete 190.54±29.21 89.25 ± 0.47 81.79 ± 0.98 MF5 Irregular in shape 151.68±56.61 91.54 ± 2.96 79.25 ± 1.22 MF6 Irregular in shape 139.76±69.40 96.24 ± 2.54 74.68 ± 2.17 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time (hr) MF2 MF4 MF5 MF6
  59. 59. Composition of microspheres formulations Formulation 5-ASA (mg) Drug: ES100 ratio ES 100 (%) Drug :EC Ratio Mg Stearate (%) Internal : external phase ratio Surfactant (%) Microparticles prepared with varying polymer to internal phase ratio MF1 500 1:1 2 - 5 1:2 2 MF2 500 1:1 1 - 5 1:2 2 MF3 500 1:1 0.667 - 5 1:2 2 Microparticles prepared with different internal-to-external phase ratio MF2 500 1:1 1 - 5 1:2 2 MF4 500 1:1 1 - 5 1:4 2 MF5 500 1:1 1 - 5 1:6 2 MF6 500 1:1 1 - 5 1:8 2 Microparticles prepared with varying drug to ES 100 ratio MF7 500 1:0.25 1 - 5 1:2 2 MF8 500 1:0.5 1 - 5 1:2 2 MF9 500 1:0.7 1 - 5 1:2 2 MF2 500 1:1 1 - 5 1:2 2 MF10 500 1:2 1 - 5 1:2 2 Microparticles with varying drug to polymeric blends ratio MES70EC10 500 1:0.7 1 1:0.1 5 1:2 2 MES70EC15 500 1:0.7 1 1:.0.15 5 1:2 2 MES70EC20 500 1:0.7 1 1:0.2 5 1:2 2 MES85EC10 500 1:0.85 1 1:0.1 5 1:2 2 MES85EC15 500 1:0.85 1 1:0.15 5 1:2 2 MES185EC20 500 1:0.85 1 1:0.2 5 1:2 2 MES100EC10 500 1:1 1 1:0.1 5 1:2 2 MES100EC15 500 1:1 1 1:0.15 5 1:2 2 MES100EC20 500 1:1 1 1:0.2 5 1:2 2
  60. 60. Effects of varying proportion of Eudragit® S to drug . Formulation Physical Appearance Particle Size (µm) Yield (%) Entrapment Efficiency (%) MF7 Irregular in shape 60.22±23.15 93.45 ± 0.71 77.13 ± 1.81 MF8 Irregular in shape 68.22±37.23 89.78 ± 0.87 76.37 ± 1.74 MF9 Spherical, discrete 180.25±56.48 94.99 ± 1.24 85.85 ± 2.88 MF2 Spherical, discrete 264.04±42.10 94.42 ± 1.88 90.55 ± 3.45 MF10 Spherical, discrete 197.15±49.54 89.24 ± 2.78 99.28 ± 3.04 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time (hr) MF2 MF7 MF8 MF9
  61. 61. Composition of microspheres formulations Formulation 5-ASA (mg) Drug: ES100 ratio ES 100 (%) Drug :EC Ratio Mg Stearate (%) Internal : external phase ratio Surfactant (%) Microparticles prepared with varying polymer to internal phase ratio MF1 500 1:1 2 - 5 1:2 2 MF2 500 1:1 1 - 5 1:2 2 MF3 500 1:1 0.667 - 5 1:2 2 Microparticles prepared with different internal-to-external phase ratio MF2 500 1:1 1 - 5 1:2 2 MF4 500 1:1 1 - 5 1:4 2 MF5 500 1:1 1 - 5 1:6 2 MF6 500 1:1 1 - 5 1:8 2 Microparticles prepared with varying drug to ES 100 ratio MF7 500 1:0.25 1 - 5 1:2 2 MF8 500 1:0.5 1 - 5 1:2 2 MF9 500 1:0.7 1 - 5 1:2 2 MF2 500 1:1 1 - 5 1:2 2 MF10 500 1:2 1 - 5 1:2 2 Microparticles with varying drug to polymeric blends ratio MES70EC10 500 1:0.7 1 1:0.1 5 1:2 2 MES70EC15 500 1:0.7 1 1:.0.15 5 1:2 2 MES70EC20 500 1:0.7 1 1:0.2 5 1:2 2 MES85EC10 500 1:0.85 1 1:0.1 5 1:2 2 MES85EC15 500 1:0.85 1 1:0.15 5 1:2 2 MES185EC20 500 1:0.85 1 1:0.2 5 1:2 2 MES100EC10 500 1:1 1 1:0.1 5 1:2 2 MES100EC15 500 1:1 1 1:0.15 5 1:2 2 MES100EC20 500 1:1 1 1:0.2 5 1:2 2
  62. 62. Physical characterization of EC-Eudragit® S formulations. Formulation Physical Appearance Particle Size(µm) Yield (%) Entrapment Efficiency (%) MES70EC10 Spherical, discrete 151.29±84.54 91.00 ± 3.45 84.15 ± 2.93 MES70EC15 Spherical, discrete 353.99±82.27 98.52 ± 1.82 87.57 ± 1.91 MES70EC20 Spherical, discrete 177.22±55.70 94.75 ± 2.73 90.93 ± 1.53 MES85EC10 Spherical, discrete 147.89±42.83 94.99 ± 1.99 90.44 ± 1.26 MES85EC15 Spherical, discrete 527.42±64.98 85.76 ± 3.14 93.62 ± 1.97 MES85EC20 Spherical, discrete 254.73±38.81 88.35 ± 2.42 94.97 ± 2.05 MES100EC10 Spherical, discrete 595.27±86.40 98.75 ± 1.55 92.89 ± 2.35 MES100EC15 Spherical, discrete 361.14±103.21 85.45 ± 0.69 95.78 ± 0.78 MES100EC20 Spherical, discrete 515.64±123.08 92.33 ± 2.45 92.73 ± 2.11
  63. 63. DSC and FTIR studies of EC-Eudragit® S formulations.
  64. 64. In-vitro release profiles of Eudragit® S-EC formulations 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time MES70EC10 MES85EC10 MES100EC10 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time MES85EC15 MES100EC15 MES70EC15 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAReleased Time MES70EC20 MES85EC20 MES100EC20
  65. 65. Kinetic analysis of EC-Eudragit® S formulations. Formulation r2 Mechanism Correlation time span (hr) t20% t50% t80% Zero order Diffusion Peppas MES70EC10 0.894 0.923 0.844 Diffusion (4-8) 5.02 8.30 13.84 MES70EC15 0.948 0.960 0.903 Diffusion (4-6) 5.27 8.14 12.67 MES70EC20 0.931 0.945 0.925 Diffusion (4-6) 4.24 6.72 11.88 MES85EC10 0.952 0.972 0.930 Diffusion (5-12) 6.63 10.74 16.76 MES85EC15 0.944 0.968 0.931 Diffusion (5-12) 6.50 10.45 16.25 MES85EC20 0.989 0.996 0.985 Diffusion (5-12) 6.30 10.08 15.66 MES100EC10 0.980 0.993 0.952 Diffusion (5-12) 6.87 11.07 17.13 MES100EC15 0.956 0.973 0.927 Diffusion (5-10) 6.46 10.19 15.59 MES100EC20 0.945 0.958 0.921 Diffusion (5-8) 5.82 8.88 13.44
  66. 66. Scanning electron micrographs of microspheres from batch MES100EC15 before drug release (330X)
  67. 67. Scanning electron micrographs of microspheres from batch MES100EC10 before drug release (140X)
  68. 68. Scanning electron micrographs of inner part of the microspheres from batch MES100EC10 before drug release (1000X)
  69. 69. Scanning electron micrographs of microspheres from batch MES100EC10 after drug release (200X)
  70. 70. Scanning electron micrographs of microspheres from batch MES100EC10 after drug release (2000X)
  71. 71. Accelerated Stability Study for selected formulation MES100EC10 • No Physical changes. – No change in color. • No degradation. • No significant change in release profile. 0 10 20 30 40 50 60 70 80 90 100 0 2 4 6 8 10 12 14 16 18 %5-ASAreleased Time (hr) Zero Time 3 Months 6 Months
  72. 72. Conclusion • Oil/oil solvent evaporation method resulted in preparation of microspheres suitable for colon targeting with 5-ASA. • Pulsatile type colon targeting microspheres could be successfully achieved with formulation MF2 however such formulation could not suitable sustained release purposes. • Controlled release profile for 10hr after a lag time of 4hr was achieved with formulation MES100EC10 which seems potential for once daily dosing purposes. • Acceptable spherical morphology and size characters were observed for both of these formulations.
  73. 73. Publishment
  74. 74. Publishment
  75. 75. Publishment

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