Nasal toxicological investigations of Carbopol 971P formulation of apomorphine: effects on ciliary beat frequency of human nasal primary cell culture and in vivo on rabbit nasal mucosa.
OBJECTIVE
The objective of this study was to investigate the nasal toxicity of a mucoadhesive Carbopol 971P formulation of apomorphine.


METHODS
The effects of different concentrations of Carbopol 971P and apomorphine on ciliary beat frequency (CBF) were studied in suspension cultures of human nasal epithelial cells. The rabbit nasal mucosal tolerance of the formulation and its components were investigated using light microscopy. Different groups of the rabbits received twice daily, air puffs, glucose, glucose/apomorphine, Carbopol 971P or Carbopol 971P/apomorphine for 1 week (glucose-treated rabbits) or 1, 2 and 4 weeks (other treatments).


RESULTS
Both Carbopol 971P and apomorphine showed both concentration- and time-dependent inhibitory effects on the CBF. The effects on CBF were: apomorphine, 1.0% w/v, irreversible ciliostasis; 0.1 and 0.5% w/v, reversible cilio-inhibition; 0.01%w/v, irreversible cilio-stimulation; and Carbopol 971P, 0.1 and 0.25% w/v, partially-reversible cilio-inhibition. Glucose and glucose/apomorphine physical mixture caused mild inflammation. Carbopol 971P (both with and without apomorphine) caused severe inflammation, which increased with duration of treatment. Necrosis, squamous metaplasia or ciliary degeneration was not observed.


CONCLUSIONS
Due to the severe inflammation caused by Carbopol 971P with and without apomorphine, we conclude that this polymer is not a suitable carrier for intranasal administration of apomorphine. This is in spite of the reversible effects of Carbopol 971P (0.1 and 0. 25% w/v) and apomorphine (0.1 and 0.5% w/v) on CBF.
Ugwoke
M I
MI
Laboratorium voor Farmacotechnologie en Biofarmacie, Campus Gasthuisberg O&N, Katholieke Universiteit Leuven, B-3000, Leuven, Belgium.
Agu
R U
RU
Jorissen
M
M
Augustijns
P
P
Sciot
R
R
Verbeke
N
N
Kinget
R
R
D000179:Acrylates / Q000008:administration & dosage / Q000633:toxicity*; D000269:Adhesives / Q000008:administration & dosage / Q000633:toxicity*; D000281:Administration, Intranasal; D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage / Q000633:toxicity*; D002478:Cells, Cultured; D002923:Cilia / Q000187:drug effects / Q000502:physiology; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D005612:Freeze Drying; D005947:Glucose / Q000008:administration & dosage; D006801:Humans; D008297:Male; D009297:Nasal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits
D000179:Acrylates; D000269:Adhesives; D018491:Dopamine Agonists; D004337:Drug Carriers; C117167:carbopol 974P NF; D005947:Glucose; D001058:Apomorphine