PMID- 32238709
OWN - NLM
STAT- MEDLINE
DCOM- 20201130
LR  - 20201130
IS  - 1347-5215 (Electronic)
IS  - 0918-6158 (Linking)
VI  - 43
IP  - 4
DP  - 2020
TI  - Examination of Aggregate Formation upon Simultaneous Dissolution of Methacrylic 
      Acid Copolymer LD Enteric Coating Agent, Pharmaceutical Additives, and 
      Zwitterionic Ingredients.
PG  - 682-687
LID - 10.1248/bpb.b19-00924 [doi]
AB  - We previously showed that adhesive aggregates were formed when levofloxacin 
      hydrate tablets and lansoprazole orally disintegrating (OD) tablets were 
      suspended in water in the clinical context. In this study, we have clarified the 
      factors causing aggregate formation, focusing on the role of pharmaceutical 
      additives and electrostatic interaction. Co-suspension of enteric-coated proton 
      pump inhibitor (PPI) esomeprazole magnesium hydrate with levofloxacin resulted in 
      aggregate formation, whereas the non-enteric-coated PPI vonoprazan fumarate did 
      not. A comparison of pharmaceutical additive in the two PPIs highlighted 
      polysorbate 80 and methacrylic acid copolymer LD as candidates causing 
      aggregation. When these pharmaceutical additives were added to levofloxacin, only 
      methacrylic acid copolymer LD induced aggregate formation. Since levofloxacin is 
      zwitterionic, we examined another zwitterionic ingredient, ampicillin sodium, and 
      found that it also formed aggregates with methacrylic acid copolymer LD, while 
      benzylpenicillin sodium, which is not zwitterionic, did not form aggregates. When 
      we next examined a series of zwitterionic quinolone antimicrobial drugs, we found 
      that ofloxacin, which is highly soluble, formed aggregates with lansoprazole OD 
      tablets, whereas poorly soluble quinolone antimicrobial drugs did not form 
      aggregates. Further, although cefepime hydrochloride and cephalexin did not form 
      aggregates with methacrylic acid copolymer LD in tap water, aggregates were 
      formed when a suspension of cefepime hydrochloride or cephalexin with methacrylic 
      acid copolymer LD was adjusted to pH 7.0. Our results indicate that electrostatic 
      interaction between zwitterionic ingredients and methacrylic acid copolymer LD 
      can result in aggregate formation under conditions where the drug and methacrylic 
      acid copolymer LD are both sufficiently soluble.
FAU - Nakagawa, Yukiko
AU  - Nakagawa Y
AD  - Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, 
      Kanazawa University.
AD  - Department of Hospital Pharmacy, University Hospital, Kanazawa University.
FAU - Suzuki, Takuya
AU  - Suzuki T
AD  - Department of Hospital Pharmacy, University Hospital, Kanazawa University.
FAU - Suga, Yukio
AU  - Suga Y
AD  - Department of Clinical Drug Informatics, Faculty of Pharmacy, Institute of 
      Medical, Pharmaceutical & Health Science, Kanazawa University.
FAU - Shimada, Tsutomu
AU  - Shimada T
AD  - Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, 
      Kanazawa University.
AD  - Department of Hospital Pharmacy, University Hospital, Kanazawa University.
FAU - Sai, Yoshimichi
AU  - Sai Y
AD  - Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, 
      Kanazawa University.
AD  - Department of Hospital Pharmacy, University Hospital, Kanazawa University.
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - Biol Pharm Bull
JT  - Biological & pharmaceutical bulletin
JID - 9311984
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Polymethacrylic Acids)
RN  - 0 (Sulfur Compounds)
RN  - 0 (Tablets, Enteric-Coated)
RN  - 0 (beta-Lactams)
RN  - 1548R74NSZ (Tegafur)
RN  - 5E8K9I0O4U (Ciprofloxacin)
RN  - A4P49JAZ9H (Ofloxacin)
SB  - IM
MH  - Anti-Bacterial Agents/chemistry
MH  - Ciprofloxacin/chemistry
MH  - Drug Liberation
MH  - Ofloxacin/chemistry
MH  - Polymethacrylic Acids/*chemistry
MH  - Static Electricity
MH  - Sulfur Compounds/chemistry
MH  - Tablets, Enteric-Coated
MH  - Tegafur/chemistry
MH  - beta-Lactams/chemistry
OTO - NOTNLM
OT  - aggregation
OT  - electrostatic interaction
OT  - levofloxacin
OT  - methacrylic acid copolymer LD
OT  - zwitterionic ingredient
EDAT- 2020/04/03 06:00
MHDA- 2020/12/01 06:00
CRDT- 2020/04/03 06:00
PHST- 2020/04/03 06:00 [entrez]
PHST- 2020/04/03 06:00 [pubmed]
PHST- 2020/12/01 06:00 [medline]
AID - 10.1248/bpb.b19-00924 [doi]
PST - ppublish
SO  - Biol Pharm Bull. 2020;43(4):682-687. doi: 10.1248/bpb.b19-00924.