![Drug profile
Name of Drug Abacavir (BCS class-3)
Chemical name {(1S,
4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclo
pent-2-en-1-yl}methanol
Molecular formula C14H18N6O
Molecular weight 286.332 g/mol
Category An Reteroviral
Description White to almost white powder.
solubility Freely soluble in water.
dosage The recommended oral dose of abacavir tablet for
adults is 600 mg daily, administered as either 300 mg
twice daily or 600 mg once daily.](https://image.slidesharecdn.com/developmentandin-vitrocharacterizationofhivdrugscombination-210803180820/85/Development-and-in-vitro-characterization-of-HIV-drugs-combination-10-320.jpg)
![Drug profile
Name of Drug Zidovudine (BCS class-1)
Chemical name 1-[(2R,4S,5S)-4-Azido-5-(hydroxymethyl)oxolan-2-yl]-5-
methylpyrimidine-2,4-dione
Molecular formula C10H13N5O4
Molecular weight 267.242 g/mol
Category An reteroviral
Description Mostly white in colour
solubility Soluble in water to about 20 mg/ml
dosage For the treatment of HIV infection the recommended
oral dose for adults is 100 mg every 4 hours.](https://image.slidesharecdn.com/developmentandin-vitrocharacterizationofhivdrugscombination-210803180820/85/Development-and-in-vitro-characterization-of-HIV-drugs-combination-12-320.jpg)
Development and in vitro characterization of HIV drugs combination
- 1. Development and in-vitro characterization of abacavir and zidovudine tablet in combination JOGINPALLY B. R. PHARMACY COLLEGE YENKAPALLY, MOINABAD. BY B.SATYA DEVI (12DQ1S0302) UNDER THE GUIDANCE OF Mr. M. Srinivas M.Pharm Department of Pharmaceutics
- 2. CONTENTS: ➢ INTRODUCTION ➢ REVIEW OF LITERATURE ➢ AIM & OBJECTIVE ➢ PLAN OF WORK ➢ DRUG PROFILE ➢ EXCEPIENTS PROFILE ➢ MATERIALS AND EQTIPMENTS ➢ METHODOLOGY ➢ RESULTS & DISCUSSION ➢ SUMMARY & CONCLUSION ➢ REFERENCES
- 3. INTRODUCTION ➢ The oral route of drug administra on is the most important route of administering drugs for systemic effect. About 90% of drugs used to produce systemic effects are administered by oral route. HIV weakens the body's immune system and reduces the body's ability to fight infec ons. ➢ An -HIV medicines do not kill the virus but they slow down or stop the HIV virus from making copies of it-self ➢ An -HIV medicines are most effec ve when taken in combina on with other an -HIV-medicines. Combina on therapy reduces the chances of the virus becoming resistant to a single medicine and also produces synergis c ac vity. Resistance to medicines makes HIV treatment more difficult.
- 4. ADVANTAGES ➢ They are unit dosage forms, they offers greatest capabili es of all oral dosage forms for the greatest dose precision and the least variability ➢ Direct compression is less me consuming , economical , easy. ➢ Creates mul ple obstacles to HIV replica on ➢ Keeps off springs low ➢ Decrease viral load ➢ Poten ate synergis c ac vity with one another ➢ Reduces individual medica ons ➢ Reduce possibility of superior muta ons
- 5. LIMITATIONS: ■ Time of ini a on ■ Dose recommended ■ Lacta on ■ Recommended only when the CD4 cells are highly a acked. ■ High doses –increased weight-important for HIV pa ent to engage in some physical exercises.
- 6. MECHANISM OF ACTION NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
- 7. RIVIEW OF LITERATURE NAME OF SCIENTIST YEAR WORK Vikramjith singh 2012 Study on tablets containing Zidovudine and lamivudine D.Varun 2011 Controlled release tablets of abacavir with different polymers Srikanth thota 2011 Immediate release tablets of lamivudine,zidovudine,nevirapine-HAART Kayitare E 2009 Fixed dose combina on of zidovudine and lamivudine in paediatric use Punna rao ravi 2008 Oral release tablets of zidovudine Navarrete MS 1998 Combina on of two NRTIs
- 8. Aim & objective AIM: The main aim is to develop and evaluate immediate release tablets of abacavir and zidovudine with different composi ons of common excipients which will meet the standards to that of the reference product with the subsequent achievement of In-vitro correla on with the reference product. OBJECTIVE: The main objec ve of this work is to formulate conven onal release oral solid dosage form of Abacavir and Zidovudine which is considered to be stable. ➢ The developed tablets were evaluated for various compression characteris cs like, weight varia on, friability, hardness, diameter and thickness etc. ➢ To check drug excipients compa bility by using FTIR. ➢ To ascertain the release mechanics and kine cs of drug release from tablets. ➢ To perform accelerated stability studies as per ICH guidelines.
- 9. PLAN OF WORK ➢ Selec on of drugs and excepients sutable for combina on ➢ Conduct Preformula on studies such as Bulk density, Tapped density, Compressibility index, Hausner’s ra o and Angle of repose on excipients and drug. ➢ Evaluate the formulated tablets according to the pharmacopoeial standards by evalua ng the formulated tablets for Physical Appearance, Hardness, Weight Varia ons, Friability, Thickness, Disintegra on, Dissolu on, Drug content. ➢ Conduct compara ve release studies with that of the marketed products and selec ng the best formula on ➢ Evaluate the mechanics and release kine cs of drug from the prepared tablets. ➢ Arrive at on op mized formula on of abacavir and zidovudine tablet compara ve to marketed immediate release products. ➢ Conduct drug and excipients compa bility using FTIR. ➢ Perform accelerated stability studies according to standards.
- 10. Drug profile Name of Drug Abacavir (BCS class-3) Chemical name {(1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclo pent-2-en-1-yl}methanol Molecular formula C14H18N6O Molecular weight 286.332 g/mol Category An Reteroviral Description White to almost white powder. solubility Freely soluble in water. dosage The recommended oral dose of abacavir tablet for adults is 600 mg daily, administered as either 300 mg twice daily or 600 mg once daily.
- 11. Mechanism of abacavir: Slows down the production of reverse transcriptase enzyme decreases the viral load and increases CD4+ cell count in HIV patients Absorption Rapid and extensive after oral administration Bioavailability (83% bioavailability, tablet). Metabolism Hepatic, by alcohol dehydrogenase and glucuronosyltransferase Elimination Urine and fecal routes Half life 1.54 ± 0.63 hours Plasma protein binding App 50%
- 12. Drug profile Name of Drug Zidovudine (BCS class-1) Chemical name 1-[(2R,4S,5S)-4-Azido-5-(hydroxymethyl)oxolan-2-yl]-5- methylpyrimidine-2,4-dione Molecular formula C10H13N5O4 Molecular weight 267.242 g/mol Category An reteroviral Description Mostly white in colour solubility Soluble in water to about 20 mg/ml dosage For the treatment of HIV infection the recommended oral dose for adults is 100 mg every 4 hours.
- 13. Mechanism of zidovudine: ZDV converts into Zidovudine triphosphate(active form) in body similar to thymidine triphosphate(used by HIV to form DNA) hence HIV uses Zidovudine triphosphate instead of thymidine triphosphate & interferes with the reverse transcriptase enzyme Absorption Rapid and nearly complete Bioavailability 75% Metabolism Hepa c by glucuronide conjugation Elimination Unchanged in urine Half life 0.5 to 3 hours Plasma protein binding 30-38%
- 14. MARKETED PRODUCTS: ADVERSE EFFECTS: Abacavir: Musculoskeletal pain (5-7%),Hypertriglyceridemia (6%),Hepa c: AST Increased (6%),Depression (4-6%),Fever/chills (3-6%),Viral respiratory infec ons (5%),Ear/nose /throat infec ons (4-5%),Rash (4-5%),Anxiety (3-5%),Thrombocytopenia (1%) Zidovudine: Liver damage, pancrea s - severe pain in your upper stomach spreading to your back, fast heart rate, peripheral neuropathy - numbness, ngling, or pain in your hands or feet, easy bruising or bleeding, unusual weakness, pale skin, white patches or sores inside your mouth or on your lips, fever.
- 15. materials RAW MATERIALS CATEGORY MANUFACTURER Abacavir API Aurobindo pharma ltd.,hyd Zidovudine API Aurobindo pharma ltd.,hyd Microcrystalline cellulose Diluent,Polymer Signet chemicals,mumbai Sodium starch glycolate Disintegrant Signet chemicals,mumbai Talc An adherant Signet chemicals,mumbai Lactose Diluent Aurolab,Madurai Magnesium stearate Lubricant SD fine chemicals ltd,mumbai
- 16. equipments EQUIPMENTS MODEL MANUFACTURERS Digital balance AND GP-12K Electro lab Bulk density apparatus TD 1025 Lab india 16 sta on compression machine CM D3-16 Cadmach Tablet hardness tester PTB-311E Pharmatest Disintegra on test apparatus ED-2L Thermolab Tablet dissolu on apparatus(8 bowls) 14000(auto) Lab india UV- Visible spectrophotometer 3000+ Lab india
- 17. methodology 1.Manufacturing a)formulation planning -selection of API - diluent,polymer -disintegrant -other excepients b)preparation 2.Drug execipient compatibility studies 3.Determination of λ max 4.Pre formulation studies a)bulk density Bulk density = weight of the powder/ bulk volume b)tapped density Tapped density = weight of powder / tapped volume. c)compressibility index Carr’s index=(Tapped density- Bulk density/Tapped density)*100
- 18. d)Hausners ratio Hausner’s ratio=Tapped Density/Bulk Density e)Angle of repose 5.Post compression studies a)physical appearance b)hardness test c)tablet size and thickness d)friability % friability = (initial weight – final weight) / initial weight * 100 e)average weight of tablets f)disintegration test g)drug content uniformity h)dissolution 6.Release kinetics 7.Stability studies a)long term,intermediate,acclerated b)forced degradation
- 19. formulae INGREDIENTS F1 F2 F3 F4 F5 F6 Abacavir 300 300 300 300 300 300 Zidovudine 300 300 300 300 300 300 Micro crystalline cellulose 95.25 86.75 91 82.5 99.5 103.75 Lactose 95.25 86.75 91 82.5 99.5 103.75 Sodium starch glycolate 42.5 59.5 51 68 34 25.5 Magnesium stearate 8.5 8.5 8.5 8.5 8.5 8.5 Talc 8.5 8.5 8.5 8.5 8.5 8.5 Total weight(mg) 850 850 850 850 850 850
- 20. Results and discussion ABACAVIR Conc.(µg / ml) Absorbance (277 nm) 0 0 10 0.0997 20 0.1821 30 0.2861 40 0.3752 50 0.4695
- 21. ZIDOVUDINE Conc.(µg / ml) Absorbance (278nm) 0 0 10 0.0999 20 0.2009 30 0.2977 40 0.3949 50 0.4879
- 22. PRE COMPRESSION PARAMETERS S. No Formula on s Bulk Density (gms/ml) Tapped Density (gms/ml) Angle of Repose C.Index Hausner’s Ra o 1 F1 0.5443 0.6766 25.74 19.5652 1.2432 2 F2 0.5795 0.6710 26.28 13.6363 1.1579 3 F3 0.5669 0.6714 26.06 15.5555 1.1842 4 F4 0.5802 0.6718 27.40 13.6363 1.1579 5 F5 0.5797 0.6712 28.72 13.6363 1.1579 6 F6 0.5668 0.6712 28.65 15.5555 1.1842
- 23. POST COMPRESSION PARAMETERS S. No Formula ons Weight Varia on (mg) Hardness (kg/cm2 ) Drug Content Uniformity (%) Friability (%) Disintegra on Time(min) 1 F1 849.6 4.18 100 0.32 12.50 2 F2 850.3 4.28 99 0.26 10.03 3 F3 850.9 4.35 100 0.25 11.11 4 F4 849.1 4.42 100 0.26 13.55 5 F5 850.5 4.90 99 0.23 12.85 6 F6 849.7 5.00 99 0.26 11.52
- 24. FTIR GRAPH ABACAVIR & ZIDOVUDINE
- 25. IN-VITRO DISSOLUTION Time (min) % Cumula ve Drug release F1 F2 F3 F4 F5 F6 0 0 0 0 0 0 0 10 21 27 30 33 29 31 20 39 41 44 49 44 46 30 45 55 54 54 52 59 40 48 61 62 64 71 73 50 61 68 85 88 87 89 60 67 72 87 92 94 98
- 26. COMPARISION OF IN-VITRO DISSOLUTION OF FORMULATIONS F1-F6
- 27. RELEASE PROFILE OF OPTIMISED FORMULATION (F6)WITH MARKETED PRODUCT ZIAGEN & RETROVIR
- 28. RELEASE KINETICS Formulation Code Zero Order First Order Higuchi’s Peppas’s F6 0.9370 0.9790 0.9812 0.9720
- 29. HIGUCHI AND KORSEMEYER PEPPAS PLOT
- 30. Percentage Cumulative release for stability samples of optimized formulation (F6) at 400 C / 75% RH and 550 C for 1 & 3 MONTHS % Cumula ve Drug Release 3 months 3months Time (Min) Initial 550 C (Forced Degradatio n) 1 month 400 C / 75% RH (Acclerated) 1 month 550 C (Forced Degradation ) 400 C / 75% RH (Acclerated) 0 0 0 0 0 0 10 31±5.0 30±4.5 30±4.1 30±4.8 29±5.1 20 46±4.9 45±4.1 44±3.5 45±4.1 44±5.2 30 59±4.0 59±3.2 59±2.9 57±3.5 57±2.6 40 73±3.2 72±4.1 71±1.8 72±2.1 71±4.2 50 89±2.1 89±4.0 88±1.1 88±2.0 87±2.9 60 98±2.0 97±2.1 96±1.0 97±1.8 96±1.2
- 31. Dissolution profiles of 1 & 3 months stability samples at different conditions initial, 400 C / 75% RH and 550 C
- 32. Evaluation for stability studies of optimized formulation (F6) after 1 & 3 months stability testing Parameter Ini al 550 C 1 month 400 C / 75% RH 1 month 550 C 3 months 400 C / 75% RH 3 months Color White White White White White Surface Smooth Smooth Smooth Smooth Smooth Thickness (mm) 6.40 mm 6.40 mm 6.41 mm 6.42 mm 6.41 mm Hardness (kg/cm2 ) 4.0-5.0 4.0-5.0 4.0-5.0 4.0-5.0 4.0-5.0 Weight (mg) 850 ± 0.11 850 ± 0.76 850 ± 1.89 850 ± 0.76 850 ± 1.89 Assay 99.12% 98.45% 97.99% 98.90% 97.98%
- 33. Summary & conclusion ➢For the treatment of Acquired immunodeficiency syndrome (AIDS), Abacavir and Zidovudine immediate release tablets are formulated. The Zidovudine added to the formula on to poten ate the synergis c ac vity of the Abacavir. Which can be beneficial for future development . ➢These current results demonstrated that F6 formula on showing good characteris cs in pre ,post compression studies, release kine cs even when compared to their marketed products. ➢A result from stability studies confirms that the developed formula on is stable and could not show any altera ons. ➢Thus, the present study concludes that medicines must con nually improve which becomes a building blocks towards novel inven on .
- 34. references ➢ Vikramjit Singh, Nawazish Alam, Monika Sharma, Md. Sarfaraz Alam, Md. Sajid Ali, Md. Intakhab Alam. Development, Evalua on and Stability Studies of Zidovudine and Lamivudine (ZILA) Tablet Dosage Form. Singh et al. / Journal of Applied Pharmaceu cal Science 2 (09); 2012: 149-154. ➢ D. Varun, B.V.P. Deepthi, P.V. Ayodhya Neelima, G. Suma Latha, M. Srikar, B. Anuhya and V. Siva Lalitha. Formula on and In Vitro Assessment of Controlled Release Matrix Tablets of Abacavir.RJPDFT 2011:3(6); 298-303 ➢ Srikanth Thota, A.k.Radhalakshmi, .lamivudine,zidovudine and nevirapine. Thota et al., IJPSR, 2011; Vol. 2(7): 1772-1776. ➢ Kayitare E, Vervaet C, Ntawukulilyayo J, Seminega B, Bortel V, Remon J. Development of fixed dose combina on tablets containing zidovudine and lamivudine for paediatric applica ons. Int J Pharm. 2009; 370:41–46. ➢ Punna Rao Ravi, Udaya Kanth Kotreka, Ranendra Narayan Saha. Controlled Release Matrix Tablets of Zidovudine: Effect of Formula on Variables on the In Vitro Drug Release Kine cs. AAPS Pharmscitech March 2008, Volume 9, Issue 1, pp 302-313. ➢ Navarrete MS, Castelo A. Zidovudine (ZDV) and Lamivudine (3TC) Combina on Therapy for HIV Infec on - A Review. Braz J Infect Dis. 1998 Feb; 2(1):1-9.