Ionic Liquid Forms of Weakly Acidic Drugs in Oral Lipid Formulations: Preparation, Characterization, in Vitro Digestion, and in Vivo Absorption Studies.

This study aimed to transform weakly acidic poorly water-soluble drugs (PWSD) into ionic liquids (ILs) to promote solubility in, and the utility of, lipid-based formulations. Ionic liquids (ILs) were formed directly from tolfenamic acid (Tolf), meclofenamic acid, diclofenac, and ibuprofen by pairing with lipophilic counterions. The drug-ILs were obtained as liquids or low melting solids and were significantly more soluble (either completely miscible or highly soluble) in lipid based, self-emulsifying drug delivery systems (SEDDS) when compared to the equivalent free acid. In vivo assessment of a SEDDS lipid solution formulation of Tolf didecyldimethylammonium salt and the same formulation of Tolf free acid at low dose (18 mg/kg, where the free acid was soluble in the SEDDS), resulted in similar absorption profiles and overall exposure. At high dose (100 mg/kg), solution SEDDS formulations of the Tolf ILs (didecyldimethylammonium, butyldodecyldimethylammonium or didecylmethylammonium salts) were possible, but the lower lipid solubility of Tolf free acid dictated that administration of the free acid was only possible as a suspension in the SEDDS formulation or as an aqueous suspension. Under these conditions, total drug plasma exposure was similar for the IL formulations and the free acid, but the plasma profiles were markedly different, resulting in flatter, more prolonged exposure profiles and reduced Cmax for the IL formulations. Isolation of a weakly acidic drug as an IL may therefore provide advantage as it allows formulation as a solution SEDDS rather than a lipid suspension, and in some cases may provide a means of slowing or sustaining absorption. The current studies compliment previous studies with weakly basic PWSD and demonstrate that transformation into highly lipophilic ILs is also possible for weakly acidic compounds.

Transformation of poorly water-soluble drugs into lipophilic ionic liquids enhances oral drug exposure from lipid based formulations.

Absorption after oral administration is a requirement for almost all drug products but is a challenge for drugs with intrinsically low water solubility. Here, the weakly basic, poorly water-soluble drugs (PWSDs) itraconazole, cinnarizine, and halofantrine were converted into lipophilic ionic liquids to facilitate incorporation into lipid-based formulations and integration into lipid absorption pathways. Ionic liquids were formed via metathesis reactions of the hydrochloride salt of the PWSDs with a range of lipophilic counterions. The resultant active pharmaceutical ingredient-ionic liquids (API-ILs) were liquids or low melting point solids and either completely miscible or highly soluble in lipid based, self-emulsifying drug delivery systems (SEDDS) comprising mixtures of long or medium chain glycerides, surfactants such as Kolliphor-EL and cosolvents such as ethanol. They also readily incorporated into the colloids formed in intestinal fluids during lipid digestion. Itraconazole docusate or cinnarizine decylsulfate API-ILs were subsequently dissolved in long chain lipid SEDDS at high concentration, administered to rats and in vivo exposure assessed. The data were compared to control formulations based on the same SEDDS formulations containing the same concentrations of drug as the free base, but in this case as a suspension (since the solubility of the free base in the SEDDS was much lower than the API-ILs). For itraconazole, comparison was also made to a physical mixture of itraconazole free base and sodium docusate in the same SEDDS formulation. For both drugs plasma exposure was significantly higher for the API-IL containing formulations (2-fold for cinnarizine and 20-fold for itraconazole), when compared to the suspension formulations (or the physical mixture in the case of itraconazole) at the same dose. The liquid SEDDS formulations, made possible by the use of the API-ILs, also provide advantages in dose uniformity, capsule filling, and stability compared to similar suspension formulations. The data suggest that the formation of lipophilic ionic liquids provides a means of increasing dissolved-drug loading in lipid based formulations and thereby promoting the exposure of poorly water-soluble drugs after oral administration.

The Effectiveness of Neuromuscular Electrical Stimulation in Patients With Subacromial Impingement Syndrome: A Randomized Controlled Study.

OBJECTIVE: The aim of the study is to compare the effects of exercise training plus neuromuscular electrical stimulation with exercise training alone on shoulder function, pain, range of motion, and muscle strength in patients with subacromial impingement syndrome. DESIGN: Patients were randomly divided into groups of exercise training ( n = 24) and exercise training + neuromuscular electrical stimulation ( n = 24). Shoulder function was evaluated with the Disabilities of the Arm, Shoulder and Hand Questionnaire, pain level was assessed with a visual analog scale, range of motion was measured with a goniometer, and muscle strength was assessed with a handheld dynamometer baseline and at the end of treatment (week 8). RESULTS: In both groups, shoulder function, range of motion, and muscle strength (except flexion muscle strength in the exercise training group) increased, while pain decreased ( P < 0.05). Compared with the exercise training group, visual analog scale-activity and visual analog scale-night decreased more, and external-rotation range of motion and whole muscle strength increased more in the exercise training + neuromuscular electrical stimulation group ( P < 0.05). On the other hand, the effect sizes were medium to large for both groups. CONCLUSIONS: The addition of neuromuscular electrical stimulation treatment to exercise training did not improve shoulder function, which is the primary outcome, more than exercise training alone, but increased muscle strength and range of motion (external-rotation only) and decreased pain (activity-night), which are the secondary outcomes.

Reliability and Validity of the Turkish Version of the American Orthopaedic Foot and Ankle Society Hallux Metatarsophalangeal-Interphalangeal Joint Scale.

BACKGROUND: The American Orthopaedic Foot and Ankle Society Hallux Metatarsophalangeal-Interphalangeal (AOFAS Hallux MTP-IP) scale is one of the most widely used outcome measures to evaluate hallux pathologies. This study aimed to translate the AOFAS Hallux MTP-IP scale into Turkish and investigate its psychometric properties. METHODS: The psychometric properties of the Turkish version of the AOFAS Hallux MTP-IP (AOFAS Hallux MTP-IP-T) scale were tested in 66 patients with hallux pathologies (52 women; mean age, 47.64 ± 12.75 years). Cronbach's alpha was used to assess internal consistency. The intraclass correlation coefficient (ICC) was used to estimate test-retest. Construct validity was analyzed with the Turkish version of the Manchester-Oxford Foot Questionnaire (MOXFQ), Visual Analogue Scale (VAS), and 12-item Short-Form Health Survey(SF-12). RESULTS: The AOFAS Hallux MTP-IP-T scale had adequate internal consistency (α = 0.71) and test-retest reliability (ICC2,1 = 0.93 for pain, ICC2,1 = 0.97 for function, and ICC2,1 = 0.97 for total score). The AOFAS Hallux MTP-IP-T total score has a moderate to strong correlation with VAS-activity and MOXFQ (ρ = -0.77, P = .001; ρ = -0.69, P = .001, respectively). The weakest correlation was found between the AOFAS Hallux MTP-IP-T and the SF-12 mental component scale (ρ = 0.31, P = .01). CONCLUSION: AOFAS Hallux MTP-IP-T has sufficient reliability and validity to evaluate Turkish-speaking individuals with a variety of forefoot pathologies including the hallux. LEVELS OF EVIDENCE: Level II.

Stabilising disproportionation of lipophilic ionic liquid salts in lipid-based formulations.

Lipid based formulations (LBFs) can enhance oral bioavailability, however, their utility may be restricted by low drug loading in the formulation. Converting drugs to drug-ionic liquids (drug-ILs) or lipophilic salts can significantly increase lipid solubility but this approach is complicated in some cases by salt disproportionation, leading to a reduction in solubility and physical instability. Here we explore the physical stability of the weakly basic model drug, cinnarizine (CIN), when paired with a decanoate counterion (Dec) to form the drug-IL, cinnarizine decanoate (CIN.Dec). Consistent with published studies of salt disproportionation in aqueous solution, weakly acidic counterions such as Dec lead to the generation of drug-IL lipid solutions with pHs below pHmax. This leads to CIN deprotonation to the less soluble free base and precipitation. Subsequent studies however, show that these effects can be reversed by acidification of the formulation (either with excess decanoic acid or other lipid soluble acids), stimulating a pH shift to the salt plateau of CIN.Dec and the formation of stable lipid solutions of CIN.Dec. Altering formulation pH to more acidic conditions, therefore stabilises drug-ILs formed using weakly acidic lipophilic counterions, and is a viable method to promote formulation stability via inhibition of disproportionation of some drug-ILs.

Ionic liquids provide unique opportunities for oral drug delivery: structure optimization and in vivo evidence of utility.

Ionic liquids (ILs) have been exploited to improve the absorption of poorly water-soluble drugs. Custom-made ILs solubilized very high quantities of the poorly water-soluble drugs, danazol and itraconazole, and maintained drug solubilization under simulated gastro-intestinal conditions. A danazol-containing self-emulsifying IL formulation gave rise to 4.3-fold higher exposure than the crystalline drug and prolonged exposure compared with a lipid formulation.