2. INTRODUCTION
Bilayer tablets can be a
Bilayer primary option to avoid
tableting chemical incompatibilities
between API by physical
separation, and to enable the
+ development of different
drug release profiles
(immediate release with
extended release)1.
2
3. ADVANTAGES
Release of both drugs starts immediately
Combination of incompatible drugs2
Physical/chemical incompatibility can be prevented by physical
separation of two drugs.
Combination of different release profiles
Immediate release and sustained release profile can be achieved in
single tablet by forming IR layer and SR layer.
Reduced Pill Burden
By reducing individual dose of two drug due to their additive effect .
Example: Salbutamol + Theophylline
3
4. Reduce the side effects Reduced by using one drug of the
combination for this purpose2.
Amiloride may prevent hypokalemia caused by
hydrochlorthiazide19, 20
Elegance to the product
4
5. Co-morbid Co-morbid Conditions means
Conditions 2 pertaining to a disease or other
pathological process that occurs
simultaneously with another18.
Hypertension
Heart Disease Treat different ailments in the same
patient (co-morbidity), at the same time
Obesity and with one pill
Diabetes
Example: Combination of β- blocker and ACE
Hyperlipidemia inhibitor or Diuretics is beneficial to treat
Hypertention and Heart failure.
Only Allows for synergistic
combination
5
6. Drug produces additive/synergistic effect
Anti- asthmatic: Salbutamol + Theophylline
Drugs having opposite side effects, may reduce the side effect
Omeprazole + NSAIDS
Hydroclorothiazide + Amiloride
Incompatible drugs
Low biological half life (ideal for modified release bilayer)
Unstable at intenstinal pH ( ideal for bilayer floating)
High first pass metabolism with low biological half life (ideal for
buccoadhesive bilayer)
6
7. DIFFERENT TYPES
Bilayer modified release tablet
Example:
Aceclofenac9 : NSAIDS, COX-2 inhibitor; t/2 = 3-4 hrs
Metoclopramide HCL + Ibuprofen13, 14:
Metoclopramide HCL is anti emetic; Given as immediate release
dose and Ibuprofen is NSAID; given as SR dose, due to its low t/2
(2 hrs).
This is widely used combination in treatment of migraine. It improve
the absorbance of Ibuprofen, whose absorption is less due to
gastric stasis10 especially in migraine.
7
8. Bilayer floating tablet
Example:
Rosiglitazone maleate6,7,8
Oral anti-diabetic; t/2 = 3-4 hrs; its solubility is decreased by
increasing pH.
Metoprolol Tartrate3,4,5
Β1-selective adrenergic blocker; t/2 = 3-4 hrs; it degraded in colon
Captopril11,12
ACE inhibitor; 37.5 – 75 mg dose is required in three times; most
stable at 1.2 pH.
8
9. Bilayer bucoadhesive tablet
Example:
Propranolol HCL
Non-selective β-adrenergic blocker; t/2 = 3-5 hrs; high first pass
metabolism.
Drug in buccoadhesive layer, Backing layer is consist of Ethyl
Cellulose.
9
10. PRACTICAL PROBLEMS IN DEVELOPING
BILAYER TABLETS
What are Fixed Dose Combinations???15, 16, 17
15, 16, 17
Maintenance Dose (A) =(KE × Minimum Effective
Concentration ×Vd)/1000
(mg/hr)
Where, KE = elimination rate constant
Vd = volume of distribution
A = 0.693 × b ×h / t ½
Where, b = Immediate release dose
h = time for release
t ½ = biological half life
10
11. Layer-separation
Order of layer sequence
Layer weight ratio
Elastic mismatch of the adjacent Layers
Cross contamination between layers.
11
12. 1. Patel Mehul, et al; Challenges in the formulation of bilayered
tablets: a review. IJPRD; Vol. 2; 2010, 30-42.
2. Pharmaceutical Development with Focus
on Paediatric formulations. WHO/FIP TRAINING WORKSHOP;28
April 2008 – 2 May 2008.
3. Hoffman BB. Catecholamines, sympathomimetics drugs, and
adrenergic receptor antagonists. In: Hardman JG, Limbird LE,
eds. Goodman and Gilman’s The Pharmacological Basis of
Therapeutics. 10th ed. New York, NY: McGraw-Hill;
2001:255Y256.
4. Kendall MJ, Maxwell SR, Sandberg A, Westergren G. Controlled
release metoprolol. Clinical pharmacokinetic and therapeutic
implications. Clin Pharmacokinet. 1991;21:319Y330.
5. Hwang SJ, Park H, Park K. Gastric retentive drug-delivery
systems. Crit Rev Ther Drug Carrier Syst. 1998;15:243Y284.
12
13. 6. J. E. F. Reynolds. Martindale-the extra Pharmacopoeia. Director
of the Council of Royal Pharmaceutical Society of Great Britain,
2005, 34: 345.
7. G. K. McEvoy. AHFS Drug Information. Authority of the board of
the American Society of the Health-System Pharmacists, 2004,
3055-3058.
8. M. C. Chapel Sky, K. Thompson-culkin, A. K. Miller, et al.
Pharmacokinetics of rosiglitazone in patients with varying
degrees of renal insuffi ciency. J. Clin. Pharmacol., 2003, 43:
252-259.
9. British Pharmacopoeia 2005 v1983ol-1. P.No:40 & http/www
.medindia .net/doctors/drug-information/aceclofenac htm.
10. http://en.wikipedia.org/wiki/Gastric_stasis
13
14. 11. C. Dollery, Therapeutics Drugs, Churchill Livingstone, New York
1999, pp. c38–c43.
12. N. H. Anaizi and C. Swenson, Instability of captopril solution, Am.
J. Hosp. Pharm. 50 (1993) 486–488.
13. B. G. Wells, J. T. DiPiro, T. L. Schwinghammer, and C. W.
Hamilton. Pharmacotherapy Handbook, McGraw-Hill, New York,
2006, pp. 535–547.
14. Bhavesh Shiyani, Surendra Gattani and Sanjay Surana.
Formulation and Evaluation of Bi-layer Tablet of Metoclopramide
Hydrochloride and Ibuprofen, AAPS PharmSciTech, Vol. 9, No. 3,
September 2008, 818-827.
15. Deelip Derle, Omkar Joshi, Ashish Pawar, Jatin Patel, Amol
Jagadale; formulation and evaluation of buccoadhesive bi-layer
tablet of propranolol hydrochloride. International Journal of
Pharmacy and Pharmaceutical Sciences, Vol. 1, Issue 1, July-
Sep. 2009; 206-212.
14
15. 16. Gosh R., Modern concept in pharmacology and therapeutics, 24 th
edition, Hilton and Co., p 761.
17. Chong H. Choe, Selim S. Bouhaouala, Itzhak Brook, Thomas B.
Elliott, Gregory B. Knudson. In Vitro development of resistance
to Ofloxacin and doxycycline in Bacillus anthracis sterne,
Antimicrobial agents and chemotherapy. June 2000; 44(6): 1766.
18. Cedillo-Ramírez E, Villafuerte-Robles L, Hernandez-leon A Effect
of added Pharmatose DCL11 on the sustained-release of
metronidazole from Methocel K4M and Carbopol 971P NF
floating matrices, Dev Ind Pharm 2001; 31(4): 200-208.
19. http://medical-dictionary.thefreedictionary.com/comorbid
20. http://congestive-heart-failure.emedtv.com/amiloride/side-
effects-of-amiloride.html
21. http://blood-pressure.emedtv.com/hydrochlorothiazide/side-
effects-of-hydrochlorothiazide.html
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