Preparation and Quality Evaluation of Bupivacaine Microemulsion Gel

doi:10.19894/j.issn.1000-0518.250026

Chinese Journal of Applied Chemistry ›› 2025, Vol. 42 ›› Issue (8): 1105-1114.DOI: 10.19894/j.issn.1000-0518.250026

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Preparation and Quality Evaluation of Bupivacaine Microemulsion Gel

Zi-Xin XING¹, Xiu-Lan MA¹, Zhe-Peng LIU², Peng-Kun FU¹, Hui-Qiao SONG¹, Yi-Jin YANG¹, Li-Rong NIE¹()

^1.School of Health Science and Engineering，University of Shanghai for Science and Technology，Shanghai 200093，China
^2.Shanghai PengTing Pharmaceutical Technology Co. ，Ltd. ，Shanghai 200093，China

Received:2025-01-24 Accepted:2025-05-27 Published:2025-08-01 Online:2025-08-11
Contact: Li-Rong NIE
About author:l.r.nie@usst.edu.cn
Supported by:
the National Natural Science Foundation of China(32372307)

Abstract

Abstract:

Bupivacaine is an amide-type local anesthetic with strong anesthetic effect. However， due to its short half-life， single injection analgesic time is limited， increasing the dose is easy to cause adverse reactions， and continuous small-dose infusion will aggravate the patient's discomfort and the burden of medical care， which limits its clinical application. To address the above problems， bupivacaine microemulsion was prepared by spontaneous emulsification， and a bupivacaine microemulsion gel for transdermal route of administration was prepared using hydroxypropyl methyl cellulose （HPMC） as the gel matrix. The prescription process of the microemulsion gel was optimized in terms of particle size， drug loading capacity and other physicochemical indexes， and a pharmacodynamic study was carried out. The results showed that the optimal prescription of the microemulsion gel was： pharmaceutical soybean oil-Tween 80-Span 80-anhydrous ethanol-water phase ratio of 9∶10.5∶4.5∶10∶66； HPMC mass fraction of 0.4%. The optimized microemulsion had a particle size of （64.58±0.29） nm， a PDI of 0.198±0.096， a drug loading capacity of 96.95 mg/g， a viscosity of （8.43±0.28） Pa·s， a pH value of 7.49， a good stability， and a spherical morphology as shown by transmission electron microscopy. The transdermal penetration of the microemulsion and microemulsion gel was significantly higher compared with the free drug， and the microemulsion gel prolonged the pain threshold in mice without skin irritation. Bupivacaine microemulsion gel is easy and controllable to prepare， and the finished product is stable， excellent spreading and non-irritating， so it is expected to have a good prospect for clinical application.

Key words: Bupivacaine, Pseudoternary phase diagram, Microemulsion gel, Local anesthesia, Quality evaluation

CLC Number:

O622.6

Zi-Xin XING, Xiu-Lan MA, Zhe-Peng LIU, Peng-Kun FU, Hui-Qiao SONG, Yi-Jin YANG, Li-Rong NIE. Preparation and Quality Evaluation of Bupivacaine Microemulsion Gel[J]. Chinese Journal of Applied Chemistry, 2025, 42(8): 1105-1114.

Figures/Tables 16

Table 1 Skin irritation scoring criteria

	Allergic reactions from stimuli	Score
Erythema	No erythema	0
	Barely visible erythema （mild）	1
	Visible erythema （moderate）	2
	Clearly visible large erythema （severe）	3
	Purple-red erythema with some degree of scab formation	4
Edema	No edema	0
	Barely visible edema （mild）	1
	Visible edema （moderate）	2
	Visible edema with a bulge of about 1 mm （severe）	3
	Severe edema with a bulge greater than 1 mm	4
	Cumulative maximum score	8

Table 2 Criteria for judging the intensity of skin irritation

Score	Irritation evaluation indicators
0~0.49	Non-irritating
0.50~2.99	Mildly irritating
3.00~5.99	Moderately irritating
6.00~8.00	Severely irritating

Fig.1 （A） Solubility of bupivacaine in different oil phases （Ⅰ.oleic acid； Ⅱ.isopropyl myristate； Ⅲ.medicated soybean oil； Ⅳ.oleic acid-isopropyl myristate （1∶1）； Ⅴ.isopropyl myristate-medicated soybean oil （1∶1）； Ⅵ.oleic acid-medicated soybean oil （1∶1））；（B） Particle size of blank microemulsions with different ratios

Fig.2 Pseudo-ternary phase diagrams for different values of Km

Fig.3 Effect of stirring temperature （A）， mixing time （B） and stirring speed （C） on particle size

Table 3 Effect of different HPMC dosages on permeability

w/%	R²	J_S/（μg·cm^-2·h^-1）
0.4	0.999 3	295.87
0.6	0.999 1	279.46
0.8	0.998 8	265.28

Fig.4 Particle size of blank microemulsion （A） and bupivacaine microemulsion （B）

Fig.5 TEM images of blank microemulsion （A） and bupivacaine microemulsion （B）

Table 4 Stability of BUP-ME-GEL

Conditions	Time/d	w/%	Viscosity/（Pa·s）	pH
65 ℃	0	100	8.36±0.35	7.42
	5	101.23	8.41±0.17	7.41
	10	101.69	8.39±0.24	7.38
4500 Lx	0	100	8.47±0.21	7.48
	5	100.89	8.36±0.19	7.47
	10	101.45	8.42±0.32	7.44

Fig.6 （A） Bupivacaine microemulsion gel viscosity；（B） Cumulative transdermal penetration of different bupivacaine preparations per unit area

Table 5 Results of transdermal absorption of different bupivacaine preparations in vitro

Bupivacaine preparations	R²	J_S/（μg·cm^-2·h^-1）
Bupivacaine	0.997 6	41.07
BUP-ME	0.998 9	481.23
BUP-ME-GEL	0.999 3	295.87

Fig.7 （A） Effects of different groups on tail flick test in mice （within 4 h）；（B） Increase rate of pain threshold in mice treated with different preparation groups

Table 6 Skin irritation scale （erythema） for different subjects

	1 h	12 h	24 h	48 h	72 h
Saline	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0
Blank preparation	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0
BUP-ME-GEL	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0	0/0/1/0

Table 7 Skin irritation rating scale （edema） for different subjects

	1 h	12 h	24 h	48 h	72 h
Saline	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0
Blank preparation	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0
BUP-ME-GEL	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0	0/0/0/0

Table 8 Skin irritation evaluation results for different subjects

	Saline	Blank preparation	BUP-ME-GEL
Score	0	0	0.25
Stimulus intensity	Non-irritating	Non-irritating	Non-irritating

Fig.8 Staining picture of skin tissue section

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Preparation and Quality Evaluation of Bupivacaine Microemulsion Gel

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