Abstract
Background: The current research aimed to create and analyze a new long-acting Brexpiprazole (BRX) injectable for successful anti-psychotic drug therapy in order to decrease dosage frequency and increase patient compliance. Systems for drug transport to particular body sites or regulating release rates with accuracy are known as drug delivery systems (DDS). By affixing the drug to a carrier particle like liposomes, nanoparticles, microspheres, etc., which modifies the drug's absorption and release properties, using carrier technology, drugs may be delivered in an intelligent manner.
Methods: Utilizing Resomer RG 502 H and RESOMER® RG 752 H extended-release Polymer, Using a quasi-emulsion solvent diffusion, microspheres were made, and emulsification and solvent evaporation process.
Results: The produced microspheres were assessed for stability tests, in vitro drug release, flow characteristics, and drug entrapment efficiency. FTIR experiments were used to establish how well the drug excipients worked together. The acarbose microspheres that were created had an 89.9 to 96.1 percent drug entrapment efficiency. The impact of factors like polymer content on medication release was studied. The Stability study of the formulation was carried out under different conditions, and data were established. Comparative pharmacokinetic studies between marketed oral formulation and Brexpirazole microsphere test formulations in Wistar/SD Rats were carried out and concluded.
Conclusion: Brexpiprazole (BRX) novel long-acting injectable formulation, could be used effectively for the treatment of mentally challenged anti-psychotic patients worldwide.
Graphical Abstract
[1]
Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007; 70(3): 461-77.
[http://dx.doi.org/10.1021/np068054v] [PMID: 17309302]
[http://dx.doi.org/10.1021/np068054v] [PMID: 17309302]
[2]
Iqbal MA, Md S, Sahni JK, Baboota S, Dang S, Ali J. Nanostructured lipid carriers system: Recent advances in drug delivery. J Drug Target 2012; 20(10): 813-30.
[http://dx.doi.org/10.3109/1061186X.2012.716845] [PMID: 22931500]
[http://dx.doi.org/10.3109/1061186X.2012.716845] [PMID: 22931500]
[3]
Vasir JK, Tambwekar K, Garg S. Bioadhesive microspheres as a controlled drug delivery system. Int J Pharm 2003; 255(1-2): 13-32.
[http://dx.doi.org/10.1016/S0378-5173(03)00087-5] [PMID: 12672598]
[http://dx.doi.org/10.1016/S0378-5173(03)00087-5] [PMID: 12672598]
[4]
Schwendeman SP, Shah RB, Bailey BA, Schwendeman AS. Injectable controlled release depots for large molecules. J Control Release 2014; 190: 240-53.
[http://dx.doi.org/10.1016/j.jconrel.2014.05.057] [PMID: 24929039]
[http://dx.doi.org/10.1016/j.jconrel.2014.05.057] [PMID: 24929039]
[5]
Park K. Controlled drug delivery systems: Past forward and future back. J Control Release 2014; 190: 3-8.
[http://dx.doi.org/10.1016/j.jconrel.2014.03.054] [PMID: 24794901]
[http://dx.doi.org/10.1016/j.jconrel.2014.03.054] [PMID: 24794901]
[6]
de Bartolomeis A, Barone A, Begni V, Riva MA. Present and future antipsychotic drugs: A systematic review of the putative mechanisms of action for efficacy and a critical appraisal under a translational perspective. Pharmacol Res 2022; 176: 106078.
[http://dx.doi.org/10.1016/j.phrs.2022.106078] [PMID: 35026403]
[http://dx.doi.org/10.1016/j.phrs.2022.106078] [PMID: 35026403]
[7]
Bjornestad J, Lavik KO, Davidson L, Hjeltnes A, Moltu C, Veseth M. Antipsychotic treatment – a systematic literature review and meta-analysis of qualitative studies. J Ment Health 2020; 29(5): 513-23.
[http://dx.doi.org/10.1080/09638237.2019.1581352] [PMID: 30862219]
[http://dx.doi.org/10.1080/09638237.2019.1581352] [PMID: 30862219]
[8]
Ur-Rehman T, Tavelin S, Gröbner G. Chitosan in situ gelation for improved drug loading and retention in poloxamer 407 gels. Int J Pharm 2011; 409(1-2): 19-29.
[http://dx.doi.org/10.1016/j.ijpharm.2011.02.017] [PMID: 21335076]
[http://dx.doi.org/10.1016/j.ijpharm.2011.02.017] [PMID: 21335076]
[9]
Kumar Saxena A, Sharma A, Verma N. Microspheres as therapeutically effective multiparticulate drug delivery system: A systemic review. Res J Pharm Technol 2021; 14(6): 3461-70.
[http://dx.doi.org/10.52711/0974-360X.2021.00602]
[http://dx.doi.org/10.52711/0974-360X.2021.00602]
[10]
Verma R, Verma S, Kumar S. Microsphere-a novel drug delivery system. Res Chronic Health Sci 2019; 5(1): 5-14.
[11]
Singh MN, Hemant KS, Ram M, Shivakumar HG. Microencapsulation: A promising technique for controlled drug delivery. Res Pharm Sci 2010; 5(2): 65-77.
[PMID: 21589795]
[PMID: 21589795]
[12]
Tang B, Cheng G, Gu JC, Xu CH. Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms. Drug Discov Today 2008; 13(13-14): 606-12.
[http://dx.doi.org/10.1016/j.drudis.2008.04.006] [PMID: 18598917]
[http://dx.doi.org/10.1016/j.drudis.2008.04.006] [PMID: 18598917]
[13]
Ribardière A, Tchoreloff P, Couarraze G, Puisieux F. Modification of ketoprofen bead structure produced by the spherical crystallization technique with a two-solvent system. Int J Pharm 1996; 144(2): 195-207.
[http://dx.doi.org/10.1016/S0378-5173(96)04746-1]
[http://dx.doi.org/10.1016/S0378-5173(96)04746-1]
[14]
Palmieri GF, Bonacucina G, Di Martino P, Martelli S. Microencapsulation of semisolid ketoprofen/polymer microspheres. Int J Pharm 2002; 242(1-2): 175-8.
[http://dx.doi.org/10.1016/S0378-5173(02)00148-5] [PMID: 12176242]
[http://dx.doi.org/10.1016/S0378-5173(02)00148-5] [PMID: 12176242]
[15]
Goto S, Kawata M, Nakamura M, Maekawa K, Aoyama T. Eudragit RS and RL (acrylic resins) microcapsules as pH insensitive and sustained release preparations of ketoprofen. J Microencapsul 1986; 3(4): 293-304.
[http://dx.doi.org/10.3109/02652048609021799] [PMID: 3508190]
[http://dx.doi.org/10.3109/02652048609021799] [PMID: 3508190]
[16]
Hishimoto A, Yasui-Furukori N, Sekine D, Matsukawa M, Yamada S. Treatment discontinuation among patients with schizophrenia treated with brexpiprazole and other oral atypical antipsychotics in Japan: A retrospective observational study. Adv Ther 2022; 39(9): 4299-314.
[http://dx.doi.org/10.1007/s12325-022-02252-9] [PMID: 35904721]
[http://dx.doi.org/10.1007/s12325-022-02252-9] [PMID: 35904721]
[17]
Siwek M, Wojtasik-Bakalarz K, Krupa AJ, Chrobak AA. Brexpiprazole—pharmacologic properties and use in schizophrenia and mood disorders. Brain Sci 2023; 13(3): 397.
[http://dx.doi.org/10.3390/brainsci13030397] [PMID: 36979208]
[http://dx.doi.org/10.3390/brainsci13030397] [PMID: 36979208]
[18]
Tyagi R, Singh H, Singh J, et al. Identification, synthesis, and control of process-related impurities in the antipsychotic drug substance brexpiprazole. Org Process Res Dev 2018; 22(11): 1471-80.
[http://dx.doi.org/10.1021/acs.oprd.8b00074]
[http://dx.doi.org/10.1021/acs.oprd.8b00074]
[19]
Kirson NY, Weiden PJ, Yermakov S, et al. Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs. J Clin Psychiatry 2013; 74(6): 568-75.
[http://dx.doi.org/10.4088/JCP.12r08167] [PMID: 23842008]
[http://dx.doi.org/10.4088/JCP.12r08167] [PMID: 23842008]
[20]
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: A meta-analysis of randomized trials. Schizophr Bull 2014; 40(1): 192-213.
[http://dx.doi.org/10.1093/schbul/sbs150] [PMID: 23256986]
[http://dx.doi.org/10.1093/schbul/sbs150] [PMID: 23256986]
[21]
Leucht C, Heres S, Kane JM, Kissling W, Davis JM, Leucht S. Oral versus depot antipsychotic drugs for schizophrenia—A critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res 2011; 127(1-3): 83-92.
[http://dx.doi.org/10.1016/j.schres.2010.11.020] [PMID: 21257294]
[http://dx.doi.org/10.1016/j.schres.2010.11.020] [PMID: 21257294]
[22]
D'Souza S, Jabar AF, Stefano G, Patrick PD. Development of risperidone PLGA microspheres. J Drug Deliv 2014; 2014: 620464.
[23]
Patel M, Sawant K. A quality by design concept on lipid based nanoformulation containing antipsychotic drug: Screening design and optimization using response surface methodology. J Nanomed Nanotechnol 2017; 8(3): 1-11.
[24]
Park EJ, Amatya S, Kim MS, et al. Long-acting injectable formulations of antipsychotic drugs for the treatment of schizophrenia. Arch Pharm Res 2013; 36(6): 651-9.
[http://dx.doi.org/10.1007/s12272-013-0105-7] [PMID: 23543652]
[http://dx.doi.org/10.1007/s12272-013-0105-7] [PMID: 23543652]
[25]
Ward AR, Parmar VS, Sandhu G, Francis C, Sellers T. Effectiveness of oral antipsychotic versus long-acting-injectable antipsychotics: A comparison of suicidality, relapse, and recidivism. Int J Emerg Ment Health 2017; 19(4): 1-6.
[http://dx.doi.org/10.4172/1522-4821.1000373]
[http://dx.doi.org/10.4172/1522-4821.1000373]
[26]
Ramstack M, Grandolfi GP, Mannaert E, D’Hoore P, Lasser RA. Long-acting risperidone: Prolonged-release injectable delivery of risperidone using medisorbò microsphere technology. Schizophr Res 2003; 60(1): 314-4.
[http://dx.doi.org/10.1016/S0920-9964(03)80260-8]
[http://dx.doi.org/10.1016/S0920-9964(03)80260-8]
[27]
Lieberman JA, Bymaster FP, Meltzer HY, et al. Antipsychotic drugs: Comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 2008; 60(3): 358-403.
[http://dx.doi.org/10.1124/pr.107.00107] [PMID: 18922967]
[http://dx.doi.org/10.1124/pr.107.00107] [PMID: 18922967]
[28]
Su ZX, Shi YN, Teng LS, et al. Biodegradable poly(D, L-lactide-co-glycolide) (PLGA) microspheres for sustained release of risperidone: Zero-order release formulation. Pharm Dev Technol 2011; 16(4): 377-84.
[http://dx.doi.org/10.3109/10837451003739297] [PMID: 20370594]
[http://dx.doi.org/10.3109/10837451003739297] [PMID: 20370594]
[29]
Hargarter L, Cherubin P, Bergmans P, et al. Intramuscular long-acting paliperidone palmitate in acute patients with schizophrenia unsuccessfully treated with oral antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry 2015; 58: 1-7.
[http://dx.doi.org/10.1016/j.pnpbp.2014.11.006] [PMID: 25448776]
[http://dx.doi.org/10.1016/j.pnpbp.2014.11.006] [PMID: 25448776]
[30]
Liu C-C, Shan J-C, Chiang C-L, et al. Initiating long-acting injectable antipsychotics during acute admission for patients with schizophrenia – A 3-year follow-up. J Formos Med Assoc 2015; 114(6): 539-45.
[http://dx.doi.org/10.1016/j.jfma.2013.01.004]
[http://dx.doi.org/10.1016/j.jfma.2013.01.004]
[31]
Zhao J, Wang L, Fan C, et al. Development of near zero-order release PLGA-based microspheres of a novel antipsychotic. Int J Pharm 2017; 516(1-2): 32-8.
[http://dx.doi.org/10.1016/j.ijpharm.2016.11.007] [PMID: 27825865]
[http://dx.doi.org/10.1016/j.ijpharm.2016.11.007] [PMID: 27825865]
[32]
Heres S, Lambert M, Vauth R. Treatment of early episode in patients with schizophrenia: The role of long acting antipsychotics. Eur Psychiatry 2014; 29(S2): 1409-13.
[http://dx.doi.org/10.1016/S0924-9338(14)70001-X] [PMID: 25455704]
[http://dx.doi.org/10.1016/S0924-9338(14)70001-X] [PMID: 25455704]
[33]
Schreiner A, Bergmans P, Cherubin P, et al. A prospective flexible-dose study of paliperidone palmitate in nonacute but symptomatic patients with schizophrenia previously unsuccessfully treated with oral antipsychotic agents. Clin Ther 2014; 36(10): 1372-1388.e1.
[http://dx.doi.org/10.1016/j.clinthera.2014.08.014] [PMID: 25444566]
[http://dx.doi.org/10.1016/j.clinthera.2014.08.014] [PMID: 25444566]
[34]
Pilon D, Tandon N, Lafeuille MH, et al. Treatment patterns, health care resource utilization, and spending in medicaid beneficiaries initiating second-generation long-acting injectable agents versus oral atypical antipsychotics. Clin Ther 2017; 39(10): 1972-1985.e2.
[http://dx.doi.org/10.1016/j.clinthera.2017.08.008] [PMID: 28919292]
[http://dx.doi.org/10.1016/j.clinthera.2017.08.008] [PMID: 28919292]
[35]
Naber D, Hansen K, Forray C, et al. Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia. Schizophr Res 2015; 168(1-2): 498-504.
[http://dx.doi.org/10.1016/j.schres.2015.07.007] [PMID: 26232241]
[http://dx.doi.org/10.1016/j.schres.2015.07.007] [PMID: 26232241]
[36]
Mutsatsa S. The use of long-acting injectable antipsychotic medication. Br J Ment Health Nurs 2017; 6(3): 114-7.
[http://dx.doi.org/10.12968/bjmh.2017.6.3.114]
[http://dx.doi.org/10.12968/bjmh.2017.6.3.114]
[37]
Kawaguchi H. Functional polymer microspheres. Prog Polym Sci 2000; 25(8): 1171-210.
[http://dx.doi.org/10.1016/S0079-6700(00)00024-1]
[http://dx.doi.org/10.1016/S0079-6700(00)00024-1]
[38]
Llorca PM, Bobes J, Fleischhacker WW, et al. Baseline results from the European non-interventional Antipsychotic Long acTing injection in schizOphrenia (ALTO) study. Eur Psychiatry 2018; 52: 85-94.
[http://dx.doi.org/10.1016/j.eurpsy.2018.04.004] [PMID: 29734130]
[http://dx.doi.org/10.1016/j.eurpsy.2018.04.004] [PMID: 29734130]
[39]
Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front Pharmacol 2015; 6: 286.
[http://dx.doi.org/10.3389/fphar.2015.00286] [PMID: 26648870]
[http://dx.doi.org/10.3389/fphar.2015.00286] [PMID: 26648870]
[40]
D’Souza S, Faraj J, DeLuca P, DeLuca PP. Microsphere delivery of risperidone as an alternative to combination therapy. Eur J Pharm Biopharm 2013; 85(3): 631-9.
[http://dx.doi.org/10.1016/j.ejpb.2013.07.012] [PMID: 23892159]
[http://dx.doi.org/10.1016/j.ejpb.2013.07.012] [PMID: 23892159]
[41]
Muralidhar P, Bhargav E. Controlled release injectable drug delivery: An over view. Asian J Biomater Res 2017; 3(1): 6-15.
[42]
Yapar EA, İnal Ö, Özkan Y, Baykara T. Injectable in situ forming microparticles: A novel drug delivery system. Trop J Pharm Res 2012; 11(2): 307-18.
[http://dx.doi.org/10.4314/tjpr.v11i2.19]
[http://dx.doi.org/10.4314/tjpr.v11i2.19]
[43]
Agrawal M, Limbachiya M, Sapariya A, Patel G. A review on parenteral controlled. Drug Deliv Syst 2012; 3(10): 3657-69.
[44]
Varde NK, Pack DW. Microspheres for controlled release drug delivery. Expert Opin Biol Ther 2004; 4(1): 35-51.
[http://dx.doi.org/10.1517/14712598.4.1.35] [PMID: 14680467]
[http://dx.doi.org/10.1517/14712598.4.1.35] [PMID: 14680467]
[45]
Anwekar H, Patel S, Singhai AK. Liposome- as drug carriers. nt. J of Pharm & Life Sci 2011; 2(7): 945-51.
[46]
Akbarzadeh A, Rezaei-Sadabady R, Davaran S, et al. Liposome: Classification, preparation, and applications. Nanoscale Res Lett 2013; 8(1): 102.
[http://dx.doi.org/10.1186/1556-276X-8-102] [PMID: 23432972]
[http://dx.doi.org/10.1186/1556-276X-8-102] [PMID: 23432972]
[47]
Hatefi A, Amsden B. Biodegradable injectable in situ forming drug delivery systems. J Control Release 2002; 80(1-3): 9-28.
[http://dx.doi.org/10.1016/S0168-3659(02)00008-1] [PMID: 11943384]
[http://dx.doi.org/10.1016/S0168-3659(02)00008-1] [PMID: 11943384]
[48]
Whyte A, Parker C. A review of the efficacy and tolerability of antipsychotic long-acting injections. Prog Neurol Psychiatry 2016; 20(4): 22-8.
[http://dx.doi.org/10.1002/pnp.436]
[http://dx.doi.org/10.1002/pnp.436]
[49]
Okada H, Doken Y, Ogawa Y, Toguchi H. Preparation of three-month depot injectable microspheres of leuprorelin acetate using biodegradable polymers. Pharm Res 1994; 11(8): 1143-7.
[http://dx.doi.org/10.1023/A:1018936815654] [PMID: 7971715]
[http://dx.doi.org/10.1023/A:1018936815654] [PMID: 7971715]
[50]
Shenoy DB, D’Souza RJ, Tiwari SB, Udupa N. Potential applications of polymeric microsphere suspension as subcutaneous depot for insulin. Drug Dev Ind Pharm 2003; 29(5): 555-63.
[http://dx.doi.org/10.1081/DDC-120018644] [PMID: 12779285]
[http://dx.doi.org/10.1081/DDC-120018644] [PMID: 12779285]
[51]
Ravivarapu HB, Moyer KL, Dunn RL. Sustained activity and release of leuprolide acetate from an in situ forming polymeric implant. AAPS PharmSciTech 2000; 1(1): E1.
[PMID: 14727850]
[PMID: 14727850]
[52]
Mehta R.C . jeyanthi R, Calis S, Thanoo BC, Burton KW, DeLuca PP. Biodegradable microspheres as depot system for parenteral delivery of peptide drugs. J Control Release 1994; 29: 375-84.
[http://dx.doi.org/10.1016/0168-3659(94)90082-5]
[http://dx.doi.org/10.1016/0168-3659(94)90082-5]
[53]
Fan Y, Zhang Q. Development of liposomal formulations: From concept to clinical investigations. Asian J Pharm Sci 2013; 8: 81-7.
[54]
Ruel-Gariépy E, Leroux JC. In situ-forming hydrogels—review of temperature-sensitive systems. Eur J Pharm Biopharm 2004; 58(2): 409-26.
[http://dx.doi.org/10.1016/j.ejpb.2004.03.019] [PMID: 15296964]
[http://dx.doi.org/10.1016/j.ejpb.2004.03.019] [PMID: 15296964]
[55]
Kempe S, Mäder K. In situ forming implants — an attractive formulation principle for parenteral depot formulations. J Control Release 2012; 161(2): 668-79.
[http://dx.doi.org/10.1016/j.jconrel.2012.04.016] [PMID: 22543012]
[http://dx.doi.org/10.1016/j.jconrel.2012.04.016] [PMID: 22543012]
[56]
Ahmed TA, Alharby YA, El-Helw AR, Hosny KM, El-Say KM. Depot injectable atorvastatin biodegradable in situ gel: Development, optimization, in vitro, and in vivo evaluation. Drug Des Devel Ther 2016; 10: 405-15.
[PMID: 26855565]
[PMID: 26855565]
[57]
Paquette SM, Dawit H, Hickey MB, Merisko-Liversidge E, Almarsson Ö, Deaver DR. Long-acting atypical antipsychotics: Characterization of the local tissue response. Pharm Res 2014; 31(8): 2065-77.
[http://dx.doi.org/10.1007/s11095-014-1308-4] [PMID: 24558010]
[http://dx.doi.org/10.1007/s11095-014-1308-4] [PMID: 24558010]
[58]
Saraf A. Preparation and evaluation of microspheres-based long-acting depot injection using a novel biomaterial as a polymer. World J Pharm Pharm Sci 2014; 3(10): 733-9.
[59]
Harrington KJ, Rowlinson-Busza G, Syrigos KN, Uster PS, Vile RG, Stewart JSW. Pegylated liposomes have potential as vehicles for intratumoral and subcutaneous drug delivery. Clin Cancer Res 2000; 6(6): 2528-37.
[PMID: 10873109]
[PMID: 10873109]
[60]
Li J, Wang X, Zhang T, et al. A review on phospholipids and their main applications in drug delivery systems. Asian J Pharm Sci 2015; 10: 81-98.
[61]
Chaudhary B, Verma S. Preparation and evaluation of novel in situ gels containing acyclovir for the treatment of oral herpes simplex virus infections. ScientificWorldJournal 2014; 2014: 1-7.
[http://dx.doi.org/10.1155/2014/280928] [PMID: 24790559]
[http://dx.doi.org/10.1155/2014/280928] [PMID: 24790559]
