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Anionic polymers based buccoadhesive wafers controlled the release of anticandidal drug miconazole nitrate

Yıl 2024, Cilt: 28 Sayı: 3, 749 - 761, 28.06.2025

Niva Rani Gogoi Ekta Yadav Pankajkumar Yadav Prakash Rajak

Öz

Oropharyngeal candidiasis, an opportunistic fungal infection, is caused by Candida albicans. Conventional formulations of antifungal drug, miconazole nitrate (MN), have limited retention on the infected oral mucosa, leading to its rapid clearance from the affected site. Aim of present study was to design and optimize MN buccal mucoadhesive wafer formulation for enhanced retention time as well as controlled drug release. Varying ratios of anionic, cationic and nonionic polymers were used to prepare wafers by freeze-drying method. Drug excipient interaction studies were performed by fourier transform infrared (FT-IR) and differential scanning calorimetry (DSC) analysis. Formulations were further evaluated by various wafer quality assessment parameters. Scanning electron microscopy (SEM) analysis and X-ray diffraction (XRD) studies were performed for surface analysis and solid state characterization, respectively, of prepared formulations. In vitro drug release studies of optimized formulations were performed and release kinetics was evaluated. Wafer formulations with anionic polymers exhibited acceptable results of swelling, adhesiveness and folding endurance analysis. Optimized formulations showed controlled release of MN by non-Fickian diffusion. Results suggest that buccoadhesive wafer formulated by anionic polymers may be utilized to achieve desired therapeutic effects of MN.

Anahtar Kelimeler

Mucoadhesive polymer antifungal formulation release kinetics

Kaynakça

  • [1] Singh A, Verma R, Murari A, Agrawal A. Oral candidiasis: An overview. J Oral Maxillofac Pathol. 2014;18(S1):S81–S85. https://doi.org/10.4103/0973-029X.141325
  • [2] Zhang L-W, Fu J-Y, Hua H, Yan Z-M. Efficacy and safety of miconazole for oral candidiasis: a systematic review and meta-analysis. Oral Dis. 2016;22(3):185–195. https://doi.org/10.1111/odi.12380
  • [3] Rizzetto L, De Filippo C, Cavalieri D. Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease. Eur J Immunol. 2014;44(11):3166–3181. https://doi.org/10.1002/eji.201344403
  • [4] Mady OY, Donia AM, Al-Madboly LA. Miconazole-urea in a buccal film as a new trend for treatment of resistant mouth fungal white patches. Front Microbiol. 2018; 9: 837. https://doi.org/10.3389/fmicb.2018.00837
  • [5] Collins CD, Cookinham S, Smith J. Management of oropharyngeal candidiasis with localized oral miconazole therapy: efficacy, safety, and patient acceptability. Patient Prefer Adherence. 2011; 5: 369–374. https://doi.org/10.2147/PPA.S14047
  • [6] Vazquez JA, Sobel JD. Miconazole mucoadhesive tablets: a novel delivery system. Clin Infect Dis. 2012;54(10):1480–1484. https://doi.org/10.1093/cid/cis205
  • [7] Isham N, Ghannoum MA. Antifungal activity of miconazole against recent Candida strains. Mycoses. 2010; 53 :434–437. https://doi.org/10.1111/j.1439-0507.2009.01728.x
  • [8] Fothergill AW. Miconazole: A historical perspective. Expert Rev Anti Infect Ther. 2006;4(2):171–175. https://doi.org/10.1586/14787210.4.2.171
  • [9] Cevher E, Taha MM, Orlu M, Araman A. Evaluation of mechanical and mucoadhesive properties of clomiphene citrate gel formulations containing carbomers and their thiolated derivatives. Drug Deliv. 2008;15(1):57–67. https://doi.org/10.1080/10717540701829234
  • [10] Yehia SA, El-Gazayerly ON, Basalious EB. Design and in vitro/in vivo evaluation of novel mucoadhesive buccal discs of an antifungal drug: relationship between swelling, erosion, and drug release. AAPS PharmSciTech. 2008;9(4):1207–1217. https://doi.org/10.1208/s12249-008-9166-1
  • [11] Mazzarino L, Borsali R, Lemos-Senna E. Mucoadhesive films containing chitosan-coated nanoparticles: A new strategy for buccal curcumin release. J Pharm Sci. 2014;103(11):3764–3771. https://doi.org/10.1002/jps.24142
  • [12] Anlar S, Capan Y, Hincal AA. Physico-chemical and bioadhesive properties of polyacrylic acid polymers. Pharm. 1993;48(4):285–287
  • [13] Park H, Robinson JR. Physico-chemical properties of water insoluble polymers important to mucin/epithelial adhesion. J Control Release. 1985;2:47–57. https://doi.org/10.1016/0168-3659(85)90032-X
  • [14] Shojaei AH, Zhuo SL, Li X. Transbuccal delivery of acyclovir (II): feasibility, system design, and in vitro permeation studies. J Pharm Pharm Sci. 1998;1(2):66–73.
  • [15] Chen X, Yan J, Yu S, Wang P. Formulation and ın vitro release kinetics of mucoadhesive blend gels containing matrine for buccal administration. AAPS PharmSciTech. 2018;19(1):470–480. https://doi.org/10.1208/s12249-017-0853-7
  • [16] Boateng JS, Matthews KH, Auffret AD, Humphrey MJ, Stevens HN, Eccleston GM. In vitro drug release studies of polymeric freeze-dried wafers and solvent-cast films using paracetamol as a model soluble drug. Int J Pharm. 2009;378(1-2):66–72. https://doi.org/10.1016/j.ijpharm.2009.05.038
  • [17] Eouani C, Piccerelle P, Prinderre P, Bourret E, Joachim J. In-vitro comparative study of buccal mucoadhesive performance of different polymeric films. Eur J Pharm Biopharm. 2001;52(1):45–55. https://doi.org/10.1016/s0939-6411(01)00146-1
  • [18] Patel VM, Prajapati BG, Patel MM. Effect of hydrophilic polymers on buccoadhesive eudragit patches of propranolol hydrochloride using factorial design. AAPS PharmSciTech. 2007;8(2):E119–E126. https://doi.org/10.1208/pt0802045
  • [19] Lalla RV, Bensadoun R-J. Miconazole mucoadhesive tablet for oropharyngeal candidiasis. Expert Rev Anti Infect Ther. 2011;9(1):13–17. https://doi.org/10.1586/eri.10.152
  • [20] Puratchikody A, Prasanth VV, Mathew ST, Kumar BA. Development and characterization of mucoadhesive patches of salbutamol sulfate for unidirectional buccal drug delivery. Acta Pharm Zagreb Croat. 2011;61(2):157–170. https://doi.org/10.2478/v10007-011-0011-9
  • [21] Ko SY, Sand A, Shin NJ, Kwark Y-J. Synthesis and characterization of superabsorbent polymer based on carboxymethyl cellulose-graft-itaconic acid. Fibers Polym. 2018;19:255–262. https://doi.org/10.1007/s12221-018-7837-9
  • [22] Dong Y, Sang D, He C, Sheng X, Lei L. Mxene/alginate composites for lead and copper ion removal from aqueous solutions. RSC Adv. 2019;9:29015–29022. https://doi.org/10.1039/C9RA05251H
  • [23] Morales JO, McConville JT. Manufacture and characterization of mucoadhesive buccal films. Eur J Pharm Biopharm. 2011;77(2):187–199. https://doi.org/10.1016/j.ejpb.2010.11.023
  • [24] Tejada G, Barrera MG, Piccirilli GN, Sortino M, Frattini M, Salomón CJ, Lamas MC, Leonardi D. Development and evaluation of buccal films based on chitosan for the potential treatment of oral candidiasis. AAPS PharmSciTech. 2017;18(4):936–946. https://doi.org/10.1208/s12249-017-0720-6
  • [25] Hassan N, Ali M, Ali J. Novel buccal adhesive system for anti-hypertensive agent nimodipine. Pharm Dev Technol. 2010;15(2):124–130. https://doi.org/10.3109/10837450903055494
  • [26] Chakraborty P, Dey S, Parcha V, Bhattacharya SS, Gosh A. Design expert supported mathematical optimization and predictability study of buccoadhesive pharmaceutical wafers of loratadine. BioMed Res Int. 2013;2013:197398. https://doi.org/10.1155/2013/197398
  • [27] ElMeshad AN, El Hagrasy AS. Characterization and optimization of orodispersible mosapride film formulations. AAPS PharmSciTech. 2011;12(4):1384–1392. https://doi.org/10.1208/s12249-011-9713-z
  • [28] Abruzzo A, Bigucci F, Cerchiara T, Cruciani F, Vitali B, Luppi B. Mucoadhesive chitosan/gelatin films for buccal delivery of propranolol hydrochloride. Carbohydr Polym. 2012;87(1):581–588. https://doi.org/10.1016/j.carbpol.2011.08.024
  • [29] Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2011;13(2):123–133. https://doi.org/10.1016/S0928-0987(01)00095-1
  • [30] Rai VK, Dwivedi H, Yadav NP, Chanotiya CS, Saraf SA. Solubility enhancement of miconazole nitrate: binary and ternary mixture approach. Drug Dev Ind Pharm. 2014;40(8):1021–1029. https://doi.org/10.3109/03639045.2013.801487
  • [31] Bhalekar MR, Pokharkar V, Madgulkar A, Patil N, Patil N. Preparation and evaluation of miconazole nitrate-loaded solid lipid nanoparticles for topical delivery. AAPS PharmSciTech. 2009;10(1):289–296. https://doi.org/10.1208/s12249-009-9199-0
  • [32] Nair AB, Kumria R, Harsha S, Attimarad M, Al-Dhubiab BE, Alhaider IA. In vitro techniques to evaluate buccal films. J Control Release. 2013;166(1):10–21. https://doi.org/10.1016/j.jconrel.2012.11.019
  • [33] Karki S, Kim H, Na S-J, Shin D, Jo K, Lee J. Thin films as an emerging platform for drug delivery. Asian J Pharm Sci. 2016;11(5):559–574. https://doi.org/10.1016/j.ajps.2016.05.004
  • [34] Nafee NA, Ismail FA, Boraie NA, Mortada LM. Mucoadhesive buccal patches of miconazole nitrate: in vitro/in vivo performance and effect of ageing. Int J Pharm. 2003;264(1-2):1–14. https://doi.org/10.1016/S0378-5173(03)00371-5
  • [35] M. Ways TM, Lau WM, Khutoryanskiy VV. Chitosan and Its derivatives for application in mucoadhesive drug delivery systems. Polymers. 2018;10(3):267. https://doi.org/10.3390/polym10030267
  • [36] Bhatia MS, Deshmukh R, Choudhari P, Bhatia NM. Chemical modification of pectins, characterization and evaluation for drug delivery. Sci Pharm. 2008;76(4):775–784. https://doi.org/10.3797/scipharm.0805-23
  • [37] Peppas NA, Buri PA. Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissues. J Control Release. 1985;2:257–275. https://doi.org/10.1016/0168-3659(85)90050-1
  • [38] Hu Y, Hu S, Zhang S, Dong S, Hu J, Kang L, Yang X. A double-layer hydrogel based on alginate-carboxymethyl cellulose and synthetic polymer as sustained drug delivery system. Sci Rep. 2021;11:9142. https://doi.org/10.1038/s41598-021-88503-1
  • [39] Jadach B, Świetlik W, Froelich A. Sodium alginate as a pharmaceutical excipient: Novel applications of a well-known polymer. J Pharm Sci. 2022;111(5):1250-1261. https://doi.org/10.1016/j.xphs.2021.12.024

Yıl 2024, Cilt: 28 Sayı: 3, 749 - 761, 28.06.2025

Niva Rani Gogoi Ekta Yadav Pankajkumar Yadav Prakash Rajak

Öz

Kaynakça

  • [1] Singh A, Verma R, Murari A, Agrawal A. Oral candidiasis: An overview. J Oral Maxillofac Pathol. 2014;18(S1):S81–S85. https://doi.org/10.4103/0973-029X.141325
  • [2] Zhang L-W, Fu J-Y, Hua H, Yan Z-M. Efficacy and safety of miconazole for oral candidiasis: a systematic review and meta-analysis. Oral Dis. 2016;22(3):185–195. https://doi.org/10.1111/odi.12380
  • [3] Rizzetto L, De Filippo C, Cavalieri D. Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease. Eur J Immunol. 2014;44(11):3166–3181. https://doi.org/10.1002/eji.201344403
  • [4] Mady OY, Donia AM, Al-Madboly LA. Miconazole-urea in a buccal film as a new trend for treatment of resistant mouth fungal white patches. Front Microbiol. 2018; 9: 837. https://doi.org/10.3389/fmicb.2018.00837
  • [5] Collins CD, Cookinham S, Smith J. Management of oropharyngeal candidiasis with localized oral miconazole therapy: efficacy, safety, and patient acceptability. Patient Prefer Adherence. 2011; 5: 369–374. https://doi.org/10.2147/PPA.S14047
  • [6] Vazquez JA, Sobel JD. Miconazole mucoadhesive tablets: a novel delivery system. Clin Infect Dis. 2012;54(10):1480–1484. https://doi.org/10.1093/cid/cis205
  • [7] Isham N, Ghannoum MA. Antifungal activity of miconazole against recent Candida strains. Mycoses. 2010; 53 :434–437. https://doi.org/10.1111/j.1439-0507.2009.01728.x
  • [8] Fothergill AW. Miconazole: A historical perspective. Expert Rev Anti Infect Ther. 2006;4(2):171–175. https://doi.org/10.1586/14787210.4.2.171
  • [9] Cevher E, Taha MM, Orlu M, Araman A. Evaluation of mechanical and mucoadhesive properties of clomiphene citrate gel formulations containing carbomers and their thiolated derivatives. Drug Deliv. 2008;15(1):57–67. https://doi.org/10.1080/10717540701829234
  • [10] Yehia SA, El-Gazayerly ON, Basalious EB. Design and in vitro/in vivo evaluation of novel mucoadhesive buccal discs of an antifungal drug: relationship between swelling, erosion, and drug release. AAPS PharmSciTech. 2008;9(4):1207–1217. https://doi.org/10.1208/s12249-008-9166-1
  • [11] Mazzarino L, Borsali R, Lemos-Senna E. Mucoadhesive films containing chitosan-coated nanoparticles: A new strategy for buccal curcumin release. J Pharm Sci. 2014;103(11):3764–3771. https://doi.org/10.1002/jps.24142
  • [12] Anlar S, Capan Y, Hincal AA. Physico-chemical and bioadhesive properties of polyacrylic acid polymers. Pharm. 1993;48(4):285–287
  • [13] Park H, Robinson JR. Physico-chemical properties of water insoluble polymers important to mucin/epithelial adhesion. J Control Release. 1985;2:47–57. https://doi.org/10.1016/0168-3659(85)90032-X
  • [14] Shojaei AH, Zhuo SL, Li X. Transbuccal delivery of acyclovir (II): feasibility, system design, and in vitro permeation studies. J Pharm Pharm Sci. 1998;1(2):66–73.
  • [15] Chen X, Yan J, Yu S, Wang P. Formulation and ın vitro release kinetics of mucoadhesive blend gels containing matrine for buccal administration. AAPS PharmSciTech. 2018;19(1):470–480. https://doi.org/10.1208/s12249-017-0853-7
  • [16] Boateng JS, Matthews KH, Auffret AD, Humphrey MJ, Stevens HN, Eccleston GM. In vitro drug release studies of polymeric freeze-dried wafers and solvent-cast films using paracetamol as a model soluble drug. Int J Pharm. 2009;378(1-2):66–72. https://doi.org/10.1016/j.ijpharm.2009.05.038
  • [17] Eouani C, Piccerelle P, Prinderre P, Bourret E, Joachim J. In-vitro comparative study of buccal mucoadhesive performance of different polymeric films. Eur J Pharm Biopharm. 2001;52(1):45–55. https://doi.org/10.1016/s0939-6411(01)00146-1
  • [18] Patel VM, Prajapati BG, Patel MM. Effect of hydrophilic polymers on buccoadhesive eudragit patches of propranolol hydrochloride using factorial design. AAPS PharmSciTech. 2007;8(2):E119–E126. https://doi.org/10.1208/pt0802045
  • [19] Lalla RV, Bensadoun R-J. Miconazole mucoadhesive tablet for oropharyngeal candidiasis. Expert Rev Anti Infect Ther. 2011;9(1):13–17. https://doi.org/10.1586/eri.10.152
  • [20] Puratchikody A, Prasanth VV, Mathew ST, Kumar BA. Development and characterization of mucoadhesive patches of salbutamol sulfate for unidirectional buccal drug delivery. Acta Pharm Zagreb Croat. 2011;61(2):157–170. https://doi.org/10.2478/v10007-011-0011-9
  • [21] Ko SY, Sand A, Shin NJ, Kwark Y-J. Synthesis and characterization of superabsorbent polymer based on carboxymethyl cellulose-graft-itaconic acid. Fibers Polym. 2018;19:255–262. https://doi.org/10.1007/s12221-018-7837-9
  • [22] Dong Y, Sang D, He C, Sheng X, Lei L. Mxene/alginate composites for lead and copper ion removal from aqueous solutions. RSC Adv. 2019;9:29015–29022. https://doi.org/10.1039/C9RA05251H
  • [23] Morales JO, McConville JT. Manufacture and characterization of mucoadhesive buccal films. Eur J Pharm Biopharm. 2011;77(2):187–199. https://doi.org/10.1016/j.ejpb.2010.11.023
  • [24] Tejada G, Barrera MG, Piccirilli GN, Sortino M, Frattini M, Salomón CJ, Lamas MC, Leonardi D. Development and evaluation of buccal films based on chitosan for the potential treatment of oral candidiasis. AAPS PharmSciTech. 2017;18(4):936–946. https://doi.org/10.1208/s12249-017-0720-6
  • [25] Hassan N, Ali M, Ali J. Novel buccal adhesive system for anti-hypertensive agent nimodipine. Pharm Dev Technol. 2010;15(2):124–130. https://doi.org/10.3109/10837450903055494
  • [26] Chakraborty P, Dey S, Parcha V, Bhattacharya SS, Gosh A. Design expert supported mathematical optimization and predictability study of buccoadhesive pharmaceutical wafers of loratadine. BioMed Res Int. 2013;2013:197398. https://doi.org/10.1155/2013/197398
  • [27] ElMeshad AN, El Hagrasy AS. Characterization and optimization of orodispersible mosapride film formulations. AAPS PharmSciTech. 2011;12(4):1384–1392. https://doi.org/10.1208/s12249-011-9713-z
  • [28] Abruzzo A, Bigucci F, Cerchiara T, Cruciani F, Vitali B, Luppi B. Mucoadhesive chitosan/gelatin films for buccal delivery of propranolol hydrochloride. Carbohydr Polym. 2012;87(1):581–588. https://doi.org/10.1016/j.carbpol.2011.08.024
  • [29] Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2011;13(2):123–133. https://doi.org/10.1016/S0928-0987(01)00095-1
  • [30] Rai VK, Dwivedi H, Yadav NP, Chanotiya CS, Saraf SA. Solubility enhancement of miconazole nitrate: binary and ternary mixture approach. Drug Dev Ind Pharm. 2014;40(8):1021–1029. https://doi.org/10.3109/03639045.2013.801487
  • [31] Bhalekar MR, Pokharkar V, Madgulkar A, Patil N, Patil N. Preparation and evaluation of miconazole nitrate-loaded solid lipid nanoparticles for topical delivery. AAPS PharmSciTech. 2009;10(1):289–296. https://doi.org/10.1208/s12249-009-9199-0
  • [32] Nair AB, Kumria R, Harsha S, Attimarad M, Al-Dhubiab BE, Alhaider IA. In vitro techniques to evaluate buccal films. J Control Release. 2013;166(1):10–21. https://doi.org/10.1016/j.jconrel.2012.11.019
  • [33] Karki S, Kim H, Na S-J, Shin D, Jo K, Lee J. Thin films as an emerging platform for drug delivery. Asian J Pharm Sci. 2016;11(5):559–574. https://doi.org/10.1016/j.ajps.2016.05.004
  • [34] Nafee NA, Ismail FA, Boraie NA, Mortada LM. Mucoadhesive buccal patches of miconazole nitrate: in vitro/in vivo performance and effect of ageing. Int J Pharm. 2003;264(1-2):1–14. https://doi.org/10.1016/S0378-5173(03)00371-5
  • [35] M. Ways TM, Lau WM, Khutoryanskiy VV. Chitosan and Its derivatives for application in mucoadhesive drug delivery systems. Polymers. 2018;10(3):267. https://doi.org/10.3390/polym10030267
  • [36] Bhatia MS, Deshmukh R, Choudhari P, Bhatia NM. Chemical modification of pectins, characterization and evaluation for drug delivery. Sci Pharm. 2008;76(4):775–784. https://doi.org/10.3797/scipharm.0805-23
  • [37] Peppas NA, Buri PA. Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissues. J Control Release. 1985;2:257–275. https://doi.org/10.1016/0168-3659(85)90050-1
  • [38] Hu Y, Hu S, Zhang S, Dong S, Hu J, Kang L, Yang X. A double-layer hydrogel based on alginate-carboxymethyl cellulose and synthetic polymer as sustained drug delivery system. Sci Rep. 2021;11:9142. https://doi.org/10.1038/s41598-021-88503-1
  • [39] Jadach B, Świetlik W, Froelich A. Sodium alginate as a pharmaceutical excipient: Novel applications of a well-known polymer. J Pharm Sci. 2022;111(5):1250-1261. https://doi.org/10.1016/j.xphs.2021.12.024
Toplam 39 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Eczacılık Bilimleri
Bölüm Articles
Yazarlar

Niva Rani Gogoi 0000-0001-8900-6756

Ekta Yadav 0000-0003-3614-1094

Pankajkumar Yadav 0000-0002-3985-0235

Prakash Rajak 0000-0001-7072-7705

Yayımlanma Tarihi 28 Haziran 2025
Yayımlandığı Sayı Yıl 2024 Cilt: 28 Sayı: 3

Kaynak Göster

APA Gogoi, N. R., Yadav, E., Yadav, P., Rajak, P. (2025). Anionic polymers based buccoadhesive wafers controlled the release of anticandidal drug miconazole nitrate. Journal of Research in Pharmacy, 28(3), 749-761.
AMA Gogoi NR, Yadav E, Yadav P, Rajak P. Anionic polymers based buccoadhesive wafers controlled the release of anticandidal drug miconazole nitrate. J. Res. Pharm. Haziran 2025;28(3):749-761.
Chicago Gogoi, Niva Rani, Ekta Yadav, Pankajkumar Yadav, ve Prakash Rajak. “Anionic Polymers Based Buccoadhesive Wafers Controlled the Release of Anticandidal Drug Miconazole Nitrate”. Journal of Research in Pharmacy 28, sy. 3 (Haziran 2025): 749-61.
EndNote Gogoi NR, Yadav E, Yadav P, Rajak P (01 Haziran 2025) Anionic polymers based buccoadhesive wafers controlled the release of anticandidal drug miconazole nitrate. Journal of Research in Pharmacy 28 3 749–761.
IEEE N. R. Gogoi, E. Yadav, P. Yadav, ve P. Rajak, “Anionic polymers based buccoadhesive wafers controlled the release of anticandidal drug miconazole nitrate”, J. Res. Pharm., c. 28, sy. 3, ss. 749–761, 2025.
ISNAD Gogoi, Niva Rani vd. “Anionic Polymers Based Buccoadhesive Wafers Controlled the Release of Anticandidal Drug Miconazole Nitrate”. Journal of Research in Pharmacy 28/3 (Haziran 2025), 749-761.
JAMA Gogoi NR, Yadav E, Yadav P, Rajak P. Anionic polymers based buccoadhesive wafers controlled the release of anticandidal drug miconazole nitrate. J. Res. Pharm. 2025;28:749–761.
MLA Gogoi, Niva Rani vd. “Anionic Polymers Based Buccoadhesive Wafers Controlled the Release of Anticandidal Drug Miconazole Nitrate”. Journal of Research in Pharmacy, c. 28, sy. 3, 2025, ss. 749-61.
Vancouver Gogoi NR, Yadav E, Yadav P, Rajak P. Anionic polymers based buccoadhesive wafers controlled the release of anticandidal drug miconazole nitrate. J. Res. Pharm. 2025;28(3):749-61.