Multidrug, Anti-HIV Amorphous Solid Dispersions: Nature and Mechanisms of Impacts of Drugs on Each Other’s Solution Concentrations,Molecular Pharmaceutics

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Multidrug, Anti-HIV Amorphous Solid Dispersions: Nature and Mechanisms of Impacts of Drugs on Each Other’s Solution Concentrations
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-09-25 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00203
Hale Çiğdem Arca ₁ , Laura I. Mosquera-Giraldo ₂ , Durga Dahal ₃ , Lynne S. Taylor ₂ , Kevin J. Edgar _{1,

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Affiliation

Drug therapy has been instrumental in prolonging the lives of patients infected by human immunodeficiency virus (HIV). In order to combat development of resistance, therapies involving three or more drugs in combination are recommended by the World Health Organization (WHO) to suppress HIV and prevent development of acquired immune deficiency syndrome (AIDS). It is desirable for multidrug combinations to be coformulated into single dosage forms where possible, to promote patient convenience and adherence to dosage regimens, for which amorphous solid dispersion (ASD) is particularly well-suited. We investigated multidrug ASDs of three model anti-HIV drugs, ritonavir (Rit), etravirine (Etra), and efavirenz (Efa), in cellulosic polymer matrices. We hypothesized that the presence of multiple drugs would reduce crystallization tendency, thereby providing stable, supersaturating formulations for bioavailability enhancement. We explored new ASD polymers including cellulose acetate suberate (DS_Sub 0.9, CASub) and cellulose acetate adipate propionate (DS_Ad 0.9, CAAdP), and control commercial cellulosic polymers including 6-carboxycellulose acetate butyrate (CCAB) and carboxymethyl cellulose acetate butyrate (CMCAB). We succeeded in preparing three-drug ASDs containing very high drug loadings (45% drug total; 15% of each drug); each polymer tested was effective at stabilizing the amorphous drugs in the solid phase, as demonstrated by XRD, SEM, and DSC studies. In pH 6.8 dissolution studies ASDs released each anti-HIV drug over 8 h, affording supersaturated solutions of each drug, but unexpectedly failing in some cases to reach maximum possible supersaturation. In a second set of dissolution studies (pH 6.8), the cause of the observed solution concentration limitations was investigated by studying release from single- and two-drug ASDs. Concentrations of Rit, Etra, and Efa achieved from three-drug ASDs were higher than those achieved from crystalline drugs. Surprisingly, however, there was a decrease in the achieved drug concentrations of both Rit and Efa when they dissolved together, while Etra solution concentration was enhanced by the presence of Rit and Efa in the ASD. We demonstrate that these effects have to do primarily with solution phase interactions between the anti-HIV drugs, rather than from the drugs influencing each other’s release rate, and we suggest that such observations may indicate an important, previously inadequately recognized, and general phenomenon for ASDs containing multiple hydrophobic drugs.

中文翻译：

多药，抗HIV无定形固体分散体：药物对彼此溶液浓度的影响的性质和机理

药物治疗在延长被人类免疫缺陷病毒（HIV）感染的患者的生命中发挥了重要作用。为了对抗耐药性的发展，世界卫生组织（WHO）建议使用包含三种或更多种药物结合的疗法来抑制HIV和预防获得性免疫缺陷综合症（AIDS）的发展。希望在可能的情况下将多药组合共配制成单一剂型，以促进患者的便利性和对剂量方案的依从性，对此特别适合使用无定形固体分散体（ASD）。我们研究了纤维素聚合物基质中三种模型抗HIV药物利托那韦（Rit），依曲韦林（Etra）和依非韦伦（Efa）的多药ASD。我们假设多种药物的存在会降低结晶趋势，从而提供稳定的，过饱和的制剂，以提高生物利用度。我们探索了新的ASD聚合物，包括辛二酸乙酸纤维素（DS_子0.9，CASub）和醋酸纤维素酯丙酸酯（DS_广告0.9，CAAdP），并对照商业纤维素聚合物，包括6-羧基乙酸丁酸纤维素酯（CCAB）和羧甲基乙酸丁酸纤维素酯（CMCAB）。我们成功地制备了载药量非常高的三药ASD（药物总量为45％；每种药物为15％）；通过XRD，SEM和DSC研究证明，每种测试的聚合物都能有效地稳定固相中的无定形药物。在pH 6.8溶出度研究中，ASD在8小时内释放了每种抗HIV药物，提供了每种药物的过饱和溶液，但出乎意料的是在某些情况下未能达到最大可能的过饱和。在第二组溶出度研究（pH 6.8）中，通过研究单药和两药ASD的释放来研究观察到的溶液浓度限制的原因。Rit，Etra，三药自闭症患者获得的Efa和Efa均高于结晶药物。但是，令人惊讶的是，当Rit和Efa一起溶解时，达到的药物浓度降低了，而ASD中Rit和Efa的存在提高了Etra溶液的浓度。我们证明这些影响主要与抗HIV药物之间的溶液相相互作用有关，而不是与影响彼此释放速率的药物有关，并且我们建议此类观察结果可能表明一种重要的，以前未被充分认识的普遍现象。包含多种疏水性药物的ASD。而ASD中Rit和Efa的存在会提高Etra溶液的浓度。我们证明这些影响主要与抗HIV药物之间的溶液相相互作用有关，而不是与影响彼此释放速率的药物有关，并且我们建议此类观察结果可能表明一种重要的，以前未被充分认识的普遍现象。包含多种疏水性药物的ASD。而ASD中Rit和Efa的存在会提高Etra溶液的浓度。我们证明这些影响主要与抗HIV药物之间的溶液相相互作用有关，而不是与影响彼此释放速率的药物有关，并且我们建议此类观察结果可能表明一种重要的，以前未被充分认识的普遍现象。包含多种疏水性药物的ASD。

更新日期：2017-09-26

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