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INTRODUCTIONINTRODUCTION

Bilayer tableting

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Bilayer tablets can be a primary option to avoid chemical incompatibilities between API by physical separation, and to enable the development of different drug release profiles (immediate release with extended release)1.

ADVANTAGESADVANTAGES 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

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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

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Hypertension

Heart Disease

Diabetes

Hyperlipidemia

Obesity

Co-morbid Conditions2

Co-morbid Conditions means pertaining to a disease or other pathological process that occurs simultaneously with another18.

Treat different ailments in the same patient (co-morbidity), at the same time and with one pill

Example: Combination of β- blocker and ACE inhibitor or Diuretics is beneficial to treat Hypertention and Heart failure.

Only Allows for synergistic combination

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)

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DIFFERENT TYPESDIFFERENT TYPES

Bilayer modified release tabletExample:

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.

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Bilayer floating tabletExample: 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.

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Bilayer bucoadhesive tabletExample:

Propranolol HCLNon-selective β-adrenergic blocker; t/2 = 3-5 hrs; high first pass

metabolism.

Drug in buccoadhesive layer, Backing layer is consist of Ethyl Cellulose.

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PRACTICAL PROBLEMS IN DEVELOPING PRACTICAL PROBLEMS IN DEVELOPING BILAYER TABLETSBILAYER TABLETS

What are Fixed Dose Combinations???15, 16, 17What are Fixed Dose Combinations???15, 16, 17

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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 / t½

Where, b = Immediate release dose h = time for release t½ = biological half life

Layer-separation

Order of layer sequence

Layer weight ratio

Elastic mismatch of the adjacent Layers

Cross contamination between layers.

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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.

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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

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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.

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16. Gosh R., Modern concept in pharmacology and therapeutics, 24th 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/comorbid20. http://congestive-heart-failure.emedtv.com/amiloride/side-

effects-of-amiloride.html21. http://blood-pressure.emedtv.com/hydrochlorothiazide/side-

effects-of-hydrochlorothiazide.html15

THANK THANK YOUYOU

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