2.1 Drug profile of Drotaverine Hydrochloride [35-37] IUPAC Name : (Z)-1-(3,4-diethoxybenzylidene)-6,7-diethoxy-1,2,3,4- tetrahydroisoquinoline CAS Number : 985-12-6 Structure : Molecular formula : C 24H 31 NO 4. HCl Molecular Weight : 433.97 Description : Light yellow or slightly greenish yellow crystalline powder, almost odourless. Solubility Melting point Official status Therapeutic category Appearance : Sparingly soluble in water, soluble in ethanol(96%), freely soluble in chloroform, slightly soluble in acetone, practically insoluble in petroleum ether. : 197-200 C : DRT is not official in IP, BP, USP, JP. : Antispasmodic : Light yellow or greenish yellow crystalline powder Pka value : 6.3 Log P/ Lipophilicity : 5.35 Page 34
Pharmacokinetics and Pharmacodynamics: Dose Oral Adult: 40-80 mg (TID). Child: 1-6 yr: 20 mg 3-4 times daily; >6 yr: 40 mg tid may be with or without food. Mechanism of Action DRT has antispasmodic effect mediated via inhibition of phosphodiesterase-iv, specific for smooth muscle. It has a rapid and direct action on the smooth muscle. It acts to correct camp and Ca imbalance at the spastic site, thereby relieving smooth muscle spasm and pain. Administration Contraindications Special Precautions Adverse Drug Reactions Drug Interactions Half life May be taken with or without food. Severe renal/hepatic/cardiac dysfunction. Porphyria. Exercise caution in patients with renal/hepatic/cardiac dysfunction. Pregnacy, lactation. Vertigo, nausea, vomiting, dry mouth. May attenuate the action of levodopa. Concurrent use of analgesics, antimuscarinics or benzodiazepines. Additive beneficial effect with concurrent use of analgesics, antimuscarinics or benzodiazepines. 7-12 h Protein binding 80-90 % Bioavailability Highly variable and ranged from 24.5 to 91% Page 35
Table 2.1 Marketed dosage form for DRT (Innovator) Dosage form Strength Brand name Manufacturer/Company name Tablet 40 mg, 80 mg No-Spa (Tablets) Sanofi Injection 20 mg/ml No-Spa (Inj) Sanofi Domestic Brands: Doveran-M (United pharmacies), Drovet 40 mg(taurus labs), Abdospas- D (Signit Labs), eldrot-80 (captab biotech), Drovit (Shinto organics), Doverin (Intas pharma), Dotarin -80 mg (Elder pharma ), novaspas (Ultramark), Blaralgan DM (Sanofi), Drotikind -80 (Mankind), Drotis, DVN-forte (overseas healthcare), Dronac-SP (Pfizer), Drotikind-M (Mankind pharma) International brands:, Drovin (drukst biotech), Taverin (Beximco pharma), Doverin (Intas), Dro Spaz (sanofi), No-Spa Forte (Sanofi) Table 2.2 Composition of DRT Injection available in market Sr no Ingredients No SPA Drotin Verin Drotakind 1 Drotaverine hydrochloride 20 mg/ml 20 mg/ml 20 mg/ml 20 mg/ml 2 Sodium metabisulphite present present present present 3 Ethanol 8.0% v/v 8.0% v/v 8.0% v/v 8.0% v/v 4 Water for injection q.s. to 1ml q.s. to 1ml q.s. to 1ml q.s. to 1ml All the marketed available formulation containing ethanol as a cosolvent or solubilizer, which increases the cost of formulation as well as analysis of every batch for release purpose. Osmolality of ethanol containing formulation are very high, which causes pain or irritation at the site of action and discomfort to patient. Objective of development of liquid formulation of DRT are, Towards cost effective & achieving a stable injection formulation in a glass container. Having improved patient comfort. Page 36
Review of literature on Drotaverine Hydrochloride (DRT) [38-54] Table 2.3 Summary of reports published on DRT Author/s Details of publication Romics, I., et al. The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones Bolaji, O. O., et al. 9 Pharmacokinetics and bioavailability of drotaverine in humans Dash, Amitabh, et al. Intramuscular drotaverine and diclofenac in acute renal colic: a comparative study of analgesic efficacy and safety Thapa, Meena, et al. Effectiveness of drotaverine hydrochloride in progression of labour B. agoram, et al. Predicting the impact of physiological and biochemical processes on oral drug bioavailability L. x. yu, et al. An Integrated Model for Determining Causes of Poor Oral Drug Absorption Khatri, Deepak M et al., 12 Studies on stability indicating assay methods and impurity profiling of active pharmaceutical drugs Azhlwar, suganthi., et al. Stability indicating HPLC method for simultaneous determination of drotaverine and aceclofenac Gilpin, R. K et al, Analytical Pharmaceuticals and related drugs chemistry 79.12 (2007): 4275-4294 Dyderski, et al. 8 Bioavailability study of drotaverine from capsule and tablet preparation in healthy volunteers Pandey et al. 4 Co-processing of superdisintegrants for drug release of taste masked drotaverine HCl Anusha, P. et al. 5 Development and evaluation of Drotaverine taste masked tablets with improved dissolution efficiency using solid dispersion technique Bolaji, O. O., et al 9 Pharmacokinetics and bioavailability of drotaverine in humans Rosaida, M. S., et al. Use of drugs for acid related disorders Page 37
Vijayaraj, S et al., 17 Innovative Drug Discovery Patent no: WO2012159964 Sudhakara Rao, et al. Singh, Jagat, U.S. Patent Application 12/063,028. Sonis, Stephen T. et al., U.S. Patent Application 13/886,035 Fazekas, Patrik et al., U.S. Patent Application 13/148,219 16 Pharmaceutical composition comprising drotaverine Transdermal drug delivery formulation Compositions for treating cancer-related fatigue and methods of screening thereof Transdermal pharmaceutical preparations Lluel, Philippe et al., U.S. Patent New combination of active ingredients containing an a1- Application 13/059,760 11 antagonist and a PDE- 4 inhibitor Kumar, Saurabh et al.. 13 Serra, Gonzalo De Miquel et al., U.S. Patent Application 12/921,921 14 Casado, Rosa Lamarca et al., U.S. Patent Application 13/672,893 15 Formulation and evaluation of immediate release tablet of telmisartan Novel dosage and formulation Novel dosage and formulation From the available literature, patent search and information of drug published by regulatory bodies for public domain, important points are enlisted here, 1. DRT is poorly water soluble drug and having strong ph dependent solubility (due to ionization of molecule) 2. All marketed injectable composition of DRT containing alcohol as excipient. 3. DRT is highly susceptible to Oxidation. Page 38
2.2 Drug profile of Nepafenac [55-57] Drug name IUPAC Name : Nepafenac : 2-amino-3-benzoylbenzeneacetamide CAS Number : 78281-72-8 Structure : Molecular formula : C 15 H 14 N 2 O 2 Molecular Weight : 254.28 Description Solubility Melting point Official status Therapeutic category : Yellow crystalline powder : Insoluble in water. Soluble in DMSO and Methanol. : 178.5 180.0 C : Not official in in IP, BP, USP, JP. : Ophthalmic suspension Pharmacology Indication For the treatment of pain and inflammation associated with cataract surgery. Pharmacodynamics Low but quantifiable plasma concentrations of nepafenac and amfenac were observed in the majority of subjects 2 and 3 hours postdose, respectively, following bilateral topical ocular TID dosing of nepafenac ophthalmic suspension, 0.1%. The mean steady-state Cmax for nepafenac and for amfenac were 0.310 ± 0.104 ng/ml and 0.422 ± 0.121 ng/ml, respectively, following ocular administration. Mechanism of action Absorption Protein binding Nepafenac is a prodrug. After penetrating the cornea, nepafenac undergoes rapid bioactivation to amfenac, which is a potent NSAID that uniformly inhibits the COX1 and COX2 activity. Nepafenac rapidly crosses the cornea (6 times faster than diclofenac in vitro). Amfenac has high affinity toward serum albumin proteins. In vitro, the percent bound to human albumin and human serum was 95.4% and 99.1% respectively. Page 39
Metabolism Route of elimination Toxicity Nepafenac (prodrug) is deaminated to amfenac (active compound) in the ciliary body epithelium, retina, and choroid by intraocular hydrolases. Subsequently, amfenac undergoes extensive metabolism to more polar metabolites involving hydroxylation of the aromatic ring leading to glucuronide conjugate formation. After oral administration of C 14 -nepafenac to healthy volunteers, urinary excretion was found to be the major route of radioactivity elimination, accounting for approximately 85% of the dose, while fecal excretion represented approximately 6% of the dose. Nepafenac (prodrug) and amfenac (active compound) were not quantifiable in the urine. Ocularly applied non-steroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery. Domestic Brands: Neypac (Intas), Nevanac (Alcon), Avanep (Alembic), Nepalect(sun) International brands: Nevanac (Alcon) Marketed dosage form for NEP (Innovator) Dosage form Strength Brand name Manufacturer/Company name Ophthalmic 1 mg/ml Nevanac (Sus) Alcon Page 40
Review of literature on Nepafenac (NEP) [58-67] Table 2.4 Summary of reports published on NEP Author/s Colin, Joseph et al., 22 Donnenfeld, Eric D., et al.. 23 Lane, Stephen S., et al., 24 Donnenfeld, Eric D, et al,. 25 Colin, Joseph. et al., 26 O Brien, Traper. et al., 27 Gaynes, Bruce I. et al., 28 Nardi, Maute., et al., 29 Details of publication Comparison of the analgesic efficacy and safety of nepafenac ophthalmic suspension compared with diclofenac ophthalmic solution for ocular pain and photophobia after excimer laser surgery: A phase II, randomized, double-masked trial Bromfenac ophthalmic solution 0.09% (Xibrom) for postoperative ocular pain and inflammation Management of ocular inflammation and pain following cataract surgery: focus on bromfenac ophthalmic solution Global experience with Xibrom (bromfenac ophthalmic solution) 0.09%: the first twice-daily ophthalmic nonsteroidal antiinflammatory drug The role of NSAIDs in the management of postoperative ophthalmic inflammation Emerging guidelines for use of NSAID therapy to optimize cataract surgery patient care optical ophthalmic NSAIDs: a discussion with focus on nepafenac ophthalmic suspension Analgesic and anti-inflammatory effectiveness of nepafenac 0.1% for cataract surgery Walters, Tom, et al., 30 In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac Ali Yusuf et al., 21 Topical ophthalmic pharmaceutical vehicles WO2010065730A2 US 8324281, Warren Wong, Alcon, Inc. Patent no: EP 1819362 Patent pub no. Topical nepafenac formulations US20060122277, Warren Wong, Alcon, Inc. US20140128329 Ophthalmic compositions comprising polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft copolymers Pharmaceutical suspension Topical nepafenac formulations Topical nepafenac formulations: Studies of the Effect and Mechanism Page 41
B1, Penn Jems et al of Action of Topical Nepafenac in a Rat Model of ROP BIOSIS, 2002, XP002247860 US20060257487, Suspension formulations of nepafenac and other ophthalmic drugs for Geoffrey Owen,et al, topical treatment of ophthalmic disorders Alcon, Inc. From the available literature, patent search and information of drug published by regulatory bodies for public domain, important points are enlisted here, 1. NEP is poorly water soluble drug; require surfactant and polymer for formulation stabilization 2. Combination formulation is not available for NEP. 3. NEP is thermally susceptible drug. 4. NEP is available as a ophthalmic suspension, in market other than ophthalmic dosage form is not available. Page 42
2.3 Drug profile of Moxifloxacin [31-33] Drug name IUPAC Name : Moxifloxacin : 2-amino-3-benzoylbenzeneacetamide CAS Number : 354812-41-2 Structure : Molecular formula : C 21 H 24 FN 2 O 4 Molecular Weight : 401.43 Description : Yellow crystalline powder. Solubility : Insoluble in water. Melting point : 238-242 C Therapeutic category : Ophthalmic drops/solution Official status : Official in IP, BP, USP Pharmacology Indication Pharmacodynamics For the treatment of sinus and lung infections such as sinusitis, pneumonia, and secondary infections in chronic bronchitis. Also for the treatment of bacterial conjunctivitis (pinkeye). Moxifloxacin is a quinolone/fluoroquinolone antibiotic. Moxifloxacin can be used to treat infections caused by the following bacteria: Aerobic Gram-positive microorganisms: Corynebacterium species, Micrococcus luteus, Staphylococcus aureus, Staphylococcus Page 43
epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus warneri, Streptococcus pneumoniae, and Streptococcus viridans group. Aerobic Gram-negative microorganisms: Acinetobacter lwoffii, Haemophilus influenzae, and Haemophilus parainfluenzae. Other microorganisms: Chlamydia trachomatis. Moxifloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Moxifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gramnegative bacteria. Mechanism of action Absorption Volume of distribution Protein binding Metabolism The bactericidal action of moxifloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. Well absorbed from the gastrointestinal tract. Absolute oral bioavailability is approximately 90%. Food has little effect on absorption. 1.7 to 2.7 L/kg 50% bound to serum proteins, independent of drug concentration. Approximately 52% or oral or intravenous dose is metabolized via glucuronide and sulphate conjugation. Page 44
The cytochrome P450 system is not involved in metabolism. The sulphate conjugate accounts for 38% of the dose, and the glucuronide conjugate accounts for 14% of the dose. Route of elimination Half life Clearance Toxicity Affected organisms Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (~20% in urine and ~25% in feces). 11.5-15.6 hours (single dose, oral) 12 + 2 L/hr Symptoms of overdose include CNS and gastrointestinal effects such as decreased activity, somnolence, tremor, convulsions, vomiting, and diarrhea. The minimal lethal intravenous dose in mice and rats is 100 mg/kg. Enteric bacteria and other eubacteria Domestic Brands: Milfox, Milfox plus, Milfox-DM (Sun pharma), Vigamox (Alcon), Combace (Cipla), Mefotas (Intas), Staxom (Ranbaxy) International brands: Nevanac (Alcon) Marketed dosage form for MXP (Innovator) Dosage form Strength Brand name Manufacturer/Company name Ophthalmic 5 mg/ml Vigamox (Eye Drops) Alcon Tablet 400 mg Avelox Bayer Healthcare Page 45
Review of literature on Moxifloxacin (MXP) [68-73] Table 2.5 Summary reports published on MXP Author/s McDonald, Marguerite, et al 34. Hariprasad, Seenu., et al 35. Cagle, Gerald, et al. 36 Cagle, Gerald, et al 37 Cagle, Gerald, et al. 38 Schlech, Barry, et al. 39 Patent no; WO 2013065029 A1, Rajesh Kshirsagar, et al, Micro labs EP 2211835 A1, Dixit Suresh, et al,alcon research Ltd. Us 6716830 B2, Gerald Cagle, et al,alcon research Ltd. Details of publication Efficacy and safety of besifloxacin ophthalmic suspension 0.6% compared with moxifloxacin ophthalmic solution 0.5% for treating bacterial conjunctivitis Efficacy and safety of besifloxacin ophthalmic suspension 0.6% compared with moxifloxacin ophthalmic solution 0.5% for treating bacterial conjunctivitis Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous Methods for treating otic and ophthalmic infections Ophthalmic antibiotic compositions containing moxifloxacin Compositions and methods for treating ophthalmic and otic infections Future of ophthalmic anti-infective therapy and the role of moxifloxacin ophthalmic solution 0.5%(VIGAMOX ) Fixed dose combination containing moxifloxacin and prednisolone for treatment of ocular infections Topical ophthalmic or otic solution formulations containing moxifloxacin hydrochloride and dexamethasone phosphate For therapy and prophylaxis of ophthalmic, otic or nasal infections and attendant inflammation From the available literature, patent search and information of drug published by regulatory bodies for public domain, important points are enlisted here, 1. Moxifloxacin hydrochloride is soluble, while MXP is insoluble drug. 2. MXP is available as a individual as well as in combination with other drug as ophthalmic solution/drops. Page 46
Table 2.6 BCS data for MXP[74]: Compound: Moxifloxacin CAS: 151096-09-2 Category: Subcategory: Formula: Molecular Weight: 401.43 Lowest Solubility (mg/ml): Human Permeability (x 10^4 cm/s): clogp: -0.333 logp: 1.68 Country List: Minimum Dose (mg) Low Permeability Low Permeability Maximum Dose (mg) Anti-infective Agents Antibiotics (Quinolones) C21 H24 F N3 O4 N/A N/A Do (min) Do (max) Solubility BCS Class (clogp) BCS Class (logp) US 400.0 400.0 N/A N/A N/A N/A N/A Page 47
2.4 Reference: 35. http://www.chemicalbook.com/chemicalproductproperty_en_cb9245093.htm 36. http://chem.sis.nlm.nih.gov/chemidplus/rn/985-12-6 37. http://pubchem.ncbi.nlm.nih.gov/compound/6437861 38. Pandey, Bipin Kumar, and Santanu Mallik. "co-processing of superdisintegrants for drug release of taste masked drotaverine hcl." Novel Science International Journal of Pharmaceutical Sciences 1.11-12 (2013). 39. Syed Mohammed et al.. "development and evaluation of drotoverine taste masked tablets with improved dissolution efficiency using solid dispersion technique." 40. Use of drugs for acid related disorders: Rosaida, Maik, et al. 41. Gilpin, R., and Gilpin C., "Pharmaceuticals and related drugs." Analytical chemistry 79.12 (2007): 4275-4294. 42. Dyderski, Stanislaw, et al. "Bioavailability study of drotaverine from capsule and tablet preparations in healthy volunteers." Arzneimittelforschung 54.05 (2004): 298-302. 43. Bolaji, O., et al. "Pharmacokinetics and bioavailability of drotaverine in humans." European journal of drug metabolism and pharmacokinetics 21.3 (1996): 217-221. 44. Singh, Jagat. "Transdermal Drug Delivery Formulation." U.S. Patent Application 12/063,028. 45. Lluel, Philippe, Stefano Palea, and Maurice Sofeir. "new combination of active ingredients containing an a1-antagonist and a pde 4 inhibitor." U.S. Patent Application 13/059,760. 46. Khatri, Deepak "Studies on stability indicating assay methods and impurity profiling of active pharmaceutical drugs." (2013). 47. Kumar, Saurabh, Gupta Pravin, and Dev Rahul. "Formulation and Evaluation of Immediate Release Tablet of Telmisartan." 48. Serra, Gonzalo De Miquel, and Rosa Lamarca Casado. "Novel dosage and formulation." U.S. Patent Application 12/921,921. 49. Casado, Rosa Lamarca, and Gonzalo De Miquel Serra. "Novel dosage and formulation." U.S. Patent Application 13/672,893. 50. Fazekas, Patrik, and Endre Mikulasik. "Transdermal pharmaceutical preparations." U.S. Patent Application 13/148,219. 51. Vijayaraj, S., Gandhimathi R., and Sarathkumar V. "Innovative Drug Discovery." Page 48
52. http://pubchem.ncbi.nlm.nih.gov/compound/nepafenac 53. Nevanac, Alcon research, inc., Chemistry review(s), application number 21-862, centre for drug evaluation and research 54. http://www.tcichemicals.com/eshop/en/ap/commodity/n0932 55. Yusuf Ali, and Reed Kenneth. "Topical ophthalmic pharmaceutical vehicles." U.S. Patent No. 5,461,081. 24 Oct. 1995. 56. Joseph Colin, and Paquette Bertrand. "Comparison of the analgesic efficacy and safety of nepafenac ophthalmic suspension compared with diclofenac ophthalmic solution for ocular pain and photophobia after excimer laser surgery: a phase II, randomized, double-masked trial." Clinical therapeutics 28.4 (2006): 527-536. 57. Donnenfeld, Eric., et al. "Bromfenac ophthalmic solution 0.09%(Xibrom) for postoperative ocular pain and inflammation." Ophthalmology 114.9 (2007): 1653-1662. 58. Lane, Stephen., et al. "Nepafenac ophthalmic suspension 0.1% for the prevention and treatment of ocular inflammation associated with cataract surgery." Journal of Cataract & Refractive Surgery 33.1 (2007): 53-58. 59. Donnenfeld, Eric., and Ashley Donnenfeld. "Global experience with Xibrom (bromfenac ophthalmic solution) 0.09%: the first twice-daily ophthalmic nonsteroidal anti-inflammatory drug." International ophthalmology clinics 46.4 (2006): 21-40. 60. Colin, Joseph. "The role of NSAIDs in the management of postoperative ophthalmic inflammation." Drugs 67.9 (2007): 1291-1308. 61. O Brien, T. "Emerging guidelines for use of NSAID therapy to optimize cataract surgery patient care." Current Medical Research and Opinion 21.7 (2005): 1131-1137. 62. Gaynes, Bruce, and Anne Onyekwuluje. "Topical ophthalmic NSAIDs: a discussion with focus on nepafenac ophthalmic suspension." Clinical ophthalmology (Auckland, NZ) 2.2 (2008): 355. 63. Nardi, Maute., et al. "Analgesic and anti-inflammatory effectiveness of nepafenac 0.1% for cataract surgery." Clinical ophthalmology (Auckland, NZ) 1.4 (2007): 527. 64. Walters, Tom, et al. "In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac." Journal of Cataract & Refractive Surgery 33.9 (2007): 1539-1545. 65. http://www.medscape.com/viewarticle/409517_2 66. www.fda.gov/ohrms/dockets/ac/99/slides/3558s1i/sld016.htm Page 49
67. http://www.chemicalbook.com/chemicalproductproperty_en_cb3191433.htm 68. McDonald, Marguerite, et al. "Efficacy and safety of besifloxacin ophthalmic suspension 0.6% compared with moxifloxacin ophthalmic solution 0.5% for treating bacterial conjunctivitis." Ophthalmology 116.9 (2009): 1615-1623. 69. Hariprasad, Seenu, et al. "Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous." Archives of ophthalmology 123.1 (2005): 39-44. 70. Cagle, Gerald, et al. "Methods of treating ophthalmic, otic and nasal infections and attendant inflammation." U.S. Patent No. 6,395,746. 28 May 2002. 71. Cagle, Gerald, et al. "Combination of tobramycin and dexamethasone for topical ophthalmic use." U.S. Patent No. 5,149,694. 22 Sep. 1992. 72. Cagle, Gerald, et al. "Compositions and methods for treating ophthalmic and otic infections." U.S. Patent No. 6,440,964. 27 Aug. 2002. 73. Schlech, Barry., and Joseph Blondeau. "Future of ophthalmic anti-infective therapy and the role of moxifloxacin ophthalmic solution 0.5% (VIGAMOX )." Survey of ophthalmology 50.6 (2005): S64-S67. 74. http://tsrlink.com/resources/services, MXP BCS classification details. 14 Januaray, 2011 Page 50