van der Vossen A C, van der Velde I, Smeets O S N M, Postma D J, Eckhardt M, Vermes A, Koch B C P, Vulto A G, Hanff L M
Department of Hospital Pharmacy, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
Department of Hospital Pharmacy, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
Eur J Pharm Sci. 2017 Mar 30;100:205-210. doi: 10.1016/j.ejps.2017.01.025. Epub 2017 Jan 23.
Many drugs are unavailable in suitable oral paediatric dosage forms, and pharmacists often have to compound drugs to provide paediatric patients with an acceptable formulation in the right dose. Liquid formulations offer the advantage of dosing flexibility and ease of administration to young patients, but drug substances often show poor aqueous solubility. The objective of this work was to study different solvents and matrices to design a liquid formulation for poorly water soluble drugs, using lorazepam as model drug.
Three different formulation strategies were explored to improve the solubility. Firstly, water-soluble organic solvents were used to improve the aqueous solubility directly, secondly, ionic surfactants were used to solubilise the model drug, and thirdly, complexation of lorazepam with cyclodextrin was studied. Specific attention was paid to excipients, adequate taste correction and palatability. For the final formulation, physical and chemical stability and microbiological quality were assessed for 12months.
An organic solvent based formulation, containing a mixture of polyethylene glycol and glycerol 85%, with a minimum amount of propylene glycol, proved to be physically and chemically stable. Development of the non-ionic surfactants formulation was discontinued due to taste problems. The cyclodextrin formulations were physically stable, but lorazepam content declined to 90% within five months. The final formulation contained in volume concentration (%v/v) 87% glycerol, 10% polyethylene glycol 400 and 3% propylene glycol. Orange essence was the preferred taste corrector. The formulation remained stable for 12months at 4°C, with lorazepam content remaining >95%. Related substances increased during the study period but remained below 2%. In-use stability was proven up to 4weeks.
An organic solvent based oral formulation was shown to be superior to a non-ionic surfactant based formulation or a cyclodextrin formulation. These results may help to formulate paediatric formulations of other poorly water soluble drugs, to aid pharmacy compounding.
许多药物没有合适的儿科口服剂型，药剂师常常需要配制药物，以便为儿科患者提供合适剂量且可接受的制剂。液体制剂具有给药灵活性高以及便于给年幼患者用药的优点，但原料药的水溶性往往较差。本研究的目的是以劳拉西泮作为模型药物，研究不同的溶剂和基质，以设计一种用于水溶性差的药物的液体制剂。
探索了三种不同的制剂策略来提高溶解度。首先，使用水溶性有机溶剂直接提高水溶性；其次，使用离子型表面活性剂增溶模型药物；第三，研究劳拉西泮与环糊精的络合作用。特别关注了辅料、适当的口味矫正和适口性。对于最终制剂，评估了其12个月的物理和化学稳定性以及微生物质量。
一种基于有机溶剂的制剂，含有聚乙二醇和85%甘油的混合物以及最少量的丙二醇，被证明在物理和化学性质上是稳定的。由于口味问题，非离子表面活性剂制剂的研发被终止。环糊精制剂在物理性质上是稳定的，但劳拉西泮含量在五个月内降至90%。最终制剂的体积浓度（%v/v）为87%甘油、10%聚乙二醇400和3%丙二醇。橙子香精是首选的口味矫正剂。该制剂在4℃下12个月保持稳定，劳拉西泮含量保持>95%。在研究期间，有关物质有所增加，但仍低于2%。使用期稳定性被证明可达4周。
一种基于有机溶剂的口服制剂被证明优于基于非离子表面活性剂的制剂或环糊精制剂。这些结果可能有助于配制其他水溶性差的药物的儿科制剂，以辅助药房配制。
