Development of Novel Formulation for Sustained Release of Drug to Prevent Swainsonine-Containing Plants Poisoning in Livestock

Animals : an Open Access Journal from MDPI · 8 authors, 2 centres

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This study developed a temperature-sensitive injectable gel formulation of "Jifang E" using poloxamer as a sustained-release matrix to prevent poisoning from swainsonine-containing plants in livestock. The formulation maintained effective blood drug concentrations for up to 5 days in mice, with an LD50 of 828.323 mg/kg and no significant muscle irritation in rabbits. This sustained-release injection offers a convenient, safe, and effective alternative to current oral administration methods, potentially reducing livestock deaths and economic losses.

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**Background:** Swainsonine-containing plants, widely distributed in grasslands globally, cause significant livestock poisoning and economic losses. The toxic component, swainsonine, inhibits α-mannosidase, leading to neurological signs and pathological changes. "Jifang E" is a drug used for prevention, but current oral administration via drinking water or pills has drawbacks including difficulty in dosage control, large inter-individual variation, and side effects. To overcome these issues, the authors aimed to develop a sustained-release injectable formulation using a temperature-sensitive poloxamer gel that solidifies at body temperature, providing convenient administration and controlled drug release.

**Methods:** The sustained-release injection was formulated using poloxamer 407 (P407) and poloxamer 188 (P188) as the gel matrix, with vitamin C as an antioxidant and PEG4000 as a binder. The optimal formulation was determined by screening gelling temperatures via the test tube inversion method. Physicochemical properties were evaluated: micelle hydrodynamic diameter and distribution were measured by dynamic light scattering at 25°C and 37°C; rheological properties (viscosity, elastic modulus G', viscous modulus G") were analyzed using a rotational rheometer; morphology after gelling was observed by Cryo-SEM. In vitro drug release was assessed using both membrane-free and membrane methods. Acute toxicity was tested in SPF Kunming mice (70 mice, 7 groups, doses 325–1820.6 mg/kg) to calculate LD50. Biocompatibility and muscle irritation were evaluated in New Zealand rabbits (n=3) via subcutaneous and intramuscular injections, with histopathological examination after 48 hours. Pharmacokinetics were studied in 40 SPF Kunming mice after a single subcutaneous injection of 150 mg/kg, with blood sampling over 168 hours and drug concentration measured by spectrophotometry.

**Key Results:** The optimal formulation consisted of P407 (24%), P188 (6%), Vitamin C (1%), PEG4000 (0.5%), and "Jifang E" (10%). The gelation temperature was suitable for injection at room temperature and gelation at body temperature. Micelle size decreased with temperature increase, and the addition of P188, additives, and drug improved stability and uniform dispersion. Rheological analysis showed pseudoplastic fluid behavior, with viscosity decreasing at high shear rates, facilitating injection. The gel exhibited shear thinning and good thixotropic properties. Cryo-SEM revealed a homogeneous pore structure after gelling, with denser structure upon drug addition. In vitro membrane-free release showed complete gel dissolution at 12 h (0 rpm) and 4 h (50 rpm), with strong correlation between dissolution and drug release (R²=0.9924 and 0.9954). Membrane release demonstrated sustained release for 3 days, with an initial burst within 12 h. Acute toxicity testing in mice yielded an LD50 of 828.323 mg/kg (95% confidence limits: 676.706–1013.911 mg/kg), indicating safety (LD50 > 200 mg/kg). Muscle irritation tests in rabbits showed slight swelling and congestion at the injection site, with a stimulation response level between 1 and 2 (acceptable for intramuscular injection). Histopathology revealed no significant pathological changes. Pharmacokinetic analysis after a single subcutaneous dose (150 mg/kg) showed a double-peak blood concentration profile, with a maximum concentration (Cmax) of 5.609 ± 0.43 μg/mL at 12 h. The area under the curve (AUC0-∞) was 131.002 ± 14.849 μg/mL·h, relative bioavailability was 63.17% compared to "Jifang E" solution, and the half-life was 32.821 ± 16.798 h. The effective blood concentration was maintained for approximately 5 days.

**Clinical Implications:** This novel sustained-release injection of "Jifang E" offers a practical and effective solution for preventing swainsonine-containing plant poisoning in livestock. It overcomes the limitations of current oral formulations by providing convenient administration, precise dosage control, and sustained drug release for up to 5 days. The formulation is safe, with low acute toxicity and good biocompatibility, showing no significant muscle irritation. This approach could reduce the frequency of dosing, minimize side effects, and improve compliance, ultimately decreasing livestock mortality and economic losses. The study provides a basis for field extension trials and further research into detoxification mechanisms.

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other

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veterinary medicine

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ORIGINAL PAPER

PMC10451943

Development of Novel Formulation for Sustained Release of Drug to Prevent Swainsonine-Containing Plants Poisoning in Livestock

Animals : an Open Access Journal from MDPI

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ABSTRACT

Simple Summary Swainsonine-containing plants are a poisonous plant widely distributed in grasslands around the world, poisoning by it can cause livestock deaths and economic losses to herdsmen. We have developed a sustained-release injection for the prevention of poisoning by swainsonine-containing plants. Compared to other formulation, e.g., powders and pills, injections have the advantage of convenient administration with easy dosage control. The injection uses poloxamer as the sustained-release matrix and can be solidified into a gel at physiological temperature. We have shown that this formulation is safe and can maintain an effective blood drug concentration for up to 5 days, providing a new approach for preventing swainsonine-containing plants poisoning livestock. Abstract Swainsonine-containing plants contain swainsonine which has been shown to cause neurological signs and pathological changes in farm animals. It causes a large number of livestock poisonings every year resulting in economic losses to the livestock industry. At present, “Jifang E” is used in the prevention of swainsonine-containing plants poisoning livestock, and the preventive effects have been well-documented. However, “Jifang E” is typically administered in drinking water, making it difficult to control the administered dosage, because of feeding difficulties and it may cause certain side effects that are unique to the water-dissolved powder. To overcome these difficulties, we developed a temperature-sensitive gel for injection and the optimal ratio of each formula of sustained-release injection is P407 (24%), P188 (6%), Vitamin C (1%), PEG4000 (0.5%), and “Jifang E” (10%). Our results suggest that novel formulation makes the micellar system more stable and the particles are uniformly dispersed. Colloidal morphological studies showed that each group formed a homogeneous pore structure after gelling, and the structure became more dense with the addition of “Jifang E”. The rheological study shows that “Jifang E” is a pseudoplastic fluid, and the addition of “Jifang E” reduces the viscosity of the formula, which is beneficial to the injection. In vitro and in vivo release rate studies have shown that the effective concentration of “Jifang E” can be maintained for 3 to 5 days. The acute toxicity test in SPF Kunming mice showed that its LD 50 was 828.323 mg/kg, with confidence limits of 676.706–1013.911 mg/kg, which is a safe dosage (LD 50 > 200 mg/kg). There were no observed reactions of muscle irritation or subcutaneous tissue irritation with the dosage used for New Zealand rabbits. In summary, we successfully developed the sustained-release injection formulation of “Jifang E” for the prevention of swainsonine-containing plants poisoning livestock, which provides the basis for subsequent field extension trials and the further study of its detoxification mechanism.

CITATION EXPORT

Bo Li, Congsheng Zhang, Yiru Zhu et al.. Development of Novel Formulation for Sustained Release of Drug to Prevent Swainsonine-Containing Plants Poisoning in Livestock. Animals : an Open Access Journal from MDPI. (2023). https://doi.org/10.3390/ani13162646

AUTHORS

8 · 2 CENTRES

Bo Li, Congsheng Zhang, Yiru Zhu, Pinzhi Sun, Shangrui Fan, Weina Wang, Yanan Tian, Hao Lu

1College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China; [email protected] (B.L.); [email protected] (C.Z.); [email protected] (Y.Z.); [email protected] (P.S.); [email protected] (S.F.); [email protected] (W.W.)
2Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA; [email protected]

EDITOR / REVIEWER

Yanzhu Zhu, Xu Yang, Ricardo Barbosa Lucena