Aggregation versus inclusion complexes to solubilize drugs with cyclodextrins. A case study using sulphobutylether-ß-cyclodextrins and remdesivir.

The formation of small hybrid aggregates between excipient and drug molecules is one of the mechanisms that contributes to the solubilization of active principles in pharmaceutical formulations. The characterization of the formation, governing interactions and structure of such entities is not trivial since they are highly flexible and dynamic, quickly exchanging molecules from one to another. In the case of cyclodextrins, this mechanism and the formation of inclusion complexes synergistically cooperate to favour the bioavailability of drugs. In a previous study we reported a detailed characterization of the possible formation of inclusion complexes with 1:1 stoichiometry between remdesivir, the only antiviral medication currently approved by the United States Food and Drug Administration for treating COVID-19, and sulphobutylether-ß-cyclodextrins. Here we extend our study to assess the role of the spontaneous aggregation in the solubilization of the same drug, by molecular dynamics simulations at different relative concentrations of both compounds. The number of sulphobutylether substitutions in the cyclodextrin structure and two different protonation states of the remdesivir molecule are considered. We aim to shed light in the solubilization mechanism of sulphobutylether-ß-cyclodextrins, broadly used as an excipient in many pharmaceutical formulations, in particular in the case of remdesivir as an active compound.

Sulfobutylether-ß-cyclodextrin/5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphine nanoassemblies with sustained antimicrobial phototherapeutic action.

Nowadays, novel less-expensive nanoformulations for in situ-controlled and safe delivery of photosensitisers (PSs) against opportunistic pathogens in body-infections areas need to be developed. Antimicrobial photodynamic therapy (aPDT) is a promising approach to treat bacterial infections that are recalcitrant to antibiotics. In this paper, we propose the design and characterization of a novel nanophototherapeutic based on the trade cyclodextrin CAPTISOL® (sulfobutylether-beta-cyclodextrin, SBE-ßCD) and 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphine tetrakis(p-toluenesulfonate) (TMPyP) to fabricate efficient biocompatible systems for aPDT. Spherical nanoassemblies of about 360 nm based on CAPTISOL®/TMPyP supramolecular complexes with 1:1 stoichiometry and apparent equilibrium binding constant (Kb â‰… 1.32 × 105 M-1) were prepared with entrapment efficiency of â‰… 100% by simple mixing in aqueous media and freeze-drying. These systems have been characterized by complementary spectroscopy and microscopy techniques. Time resolved fluorescence pointed out the strong interaction of porphyrin monomer within nanoassemblies (τ2 â‰… 11 ns with an amount of ca 90%) and scarce self-aggregation of porphyrins have been observed. Singlet oxygen comparative determination (Ï•Δ CAPTISOL®/TMPyP = 0.58) assessed their photodynamic potential. Release and photostability studies have been carried out under physiological conditions pointing out the role of CAPTISOL® to sustain porphyrin release for more than 2 weeks and to protect PS from photodegradation. Finally, photoantimicrobial activity of nanoassemblies vs free porphyrin have been investigated against Gram-negative P. aeruginosa, E. coli and Gram-positive S. aureus. The proposed nanosystems were able to photokill both Gram-positive and -negative bacterial cells similarly to TMPyP at MBC90 = 6 µM of TMPyP and at 42 J/cm2 light dose. However, with respect to the less selective free TMPyP in biological sites, nanoassemblies exhibit sustained release properties and a higher photostability thus optimizing the PDT effect at the site of action. These results can open routes for in vivo translational studies on nano(photo)drugs and nanotheranostics based on less expensive formulations of CD and PS.

Efficacy and Safety of the Glucagon Receptor Antagonist RVT-1502 in Type 2 Diabetes Uncontrolled on Metformin Monotherapy: A 12-Week Dose-Ranging Study.

OBJECTIVE: Evaluate the safety and efficacy of RVT-1502, a novel oral glucagon receptor antagonist, in subjects with type 2 diabetes inadequately controlled on metformin. RESEARCH DESIGN AND METHODS: In a phase 2, double-blind, randomized, placebo-controlled study, subjects with type 2 diabetes (n = 166) on a stable dose of metformin were randomized (1:1:1:1) to placebo or RVT-1502 5, 10, or 15 mg once daily for 12 weeks. The primary end point was change from baseline in HbA1c for each dose of RVT-1502 compared with placebo. Secondary end points included change from baseline in fasting plasma glucose (FPG) and safety assessments. RESULTS: Over 12 weeks, RVT-1502 significantly reduced HbA1c relative to placebo by 0.74%, 0.76%, and 1.05% in the 5-, 10-, and 15-mg groups (P < 0.001), respectively, and FPG decreased by 2.1, 2.2, and 2.6 mmol/L (P < 0.001). The proportions of subjects achieving an HbA1c <7.0% were 19.5%, 39.5%, 39.5%, and 45.0% with placebo and RVT-1502 5, 10, and 15 mg (P ≤ 0.02 vs. placebo). The frequency of hypoglycemia was low, and no episodes were severe. Mild increases in mean aminotransferase levels remaining below the upper limit of normal were observed with RVT-1502 but were reversible and did not appear to be dose related, with no other liver parameter changes. Weight and lipid changes were similar between RVT-1502 and placebo. RVT-1502-associated mild increases in blood pressure were not dose related or consistent across time. CONCLUSIONS: Glucagon receptor antagonism with RVT-1502 significantly lowers HbA1c and FPG, with a safety profile that supports further clinical development with longer-duration studies (NCT02851849).

Slow-release of famotidine from tablets consisting of chitosan/sulfobutyl ether ß-cyclodextrin composites.

An intermolecular complex formed from a 1:1 weight ratio of chitosan (CS, molecular weight 30 kDa) and sulfobutyl ether ß-cyclodextrin (SBE-ß-CyD, degree of substitution 7) was less soluble than either of the original components. The release of famotidine from tablets composed of a simple mixture of CS and SBE-ß-CyD is slower in media at pH 1.2 than at 6.8. Macroscopic observation of tablets and a kinetic analysis of release profiles suggested that, at pH 1.2, the drug was slowly released from the less-soluble CS/SBE-ß-CyD complex formed on the surface of the tablet immediately after exposure to water, accompanied by the dissolution of the interpolymer complex and, ultimately, the erosion and disintegration of the tablet. In the case of the medium at pH 6.8, the formation of a gel by CS was the cause of the slow release, especially for CS/SBE-ß-CyD tablets which were significantly gelated and both the diameter and thickness of the tablet had expanded. The in vitro slow releasing characteristic of the CS/SBE-ß-CyD tablet was reflected in the in vivo absorption of the drug after oral administration to rats. These results suggest that a simple mixing of CS and SBE-ß-CyD is potentially useful for the controlled release of a drug.

Effects of Selected Anionic ß-Cyclodextrins on Persistence of Blood Glucose Lowering by Insulin Glargine after Subcutaneous Injection to Rats.

Insulin glargine is a synthetic long-acting insulin product used for patients with diabetes mellitus. In this study, to obtain the further desirable blood-glucose lowering profile of insulin glargine, we investigated the effects of ß-cyclodextrin sulfate (Sul-ß-CyD) and sulfobutylether ß-cyclodextrin (SBE7-ß-CyD) on physicochemical properties of insulin glargine and pharmacokinetics/pharmacodynamics of insulin glargine after subcutaneous injection to rats. Sul-ß-CyD and SBE7-ß-CyD increased solubility of insulin glargine. SBE7-ß-CyD suppressed the formation of oligomer and enhanced the dissolution rate of insulin glargine from its precipitate, compared to that of Sul-ß-CyD. Additionally, we revealed that after subcutaneous administration of an insulin glargine solution, SBE7-ß-CyD, but not Sul-ß-CyD, increased bioavailability and sustained the blood-glucose lowering effect, possibly due to the inhibitory effects of SBE7-ß-CyD on the enzymatic degradation at the injection site. These results suggest that SBE7-ß-CyD could be a useful excipient for sustained release of insulin glargine.

Effect of sulfobutyl ether-ß-cyclodextrin on bioavailability of insulin glargine and blood glucose level after subcutaneous injection to rats.

Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. To obtain the further bioavailability and the sustained glucose lowering effect of insulin glargine, in the present study, we investigated the effect of sulfobutyl ether-ß-cyclodextrin (SBE4-ß-CyD), with the degree of substitution of sulfobutyl ether group of 3.9, on pharmaceutical properties of insulin glargine and the release of insulin glargine after subcutaneous injection to rats. SBE4-ß-CyD increased the solubility and suppressed aggregation of insulin glargine in phosphate buffer at pH 9.5, probably due to the interaction of SBE4-ß-CyD with aromatic amino acid residues such as tyrosine of insulin glargine. In addition, SBE4-ß-CyD accelerated the dissolution rate of insulin glargine from its precipitates, compared to that of insulin glargine alone. Furthermore, we revealed that subcutaneous administration of an insulin glargine solution with SBE4-ß-CyD to rats enhanced the bioavailability of insulin glargine and sustained the glucose lowering effect, possibly due to the inhibitory effects of SBE4-ß-CyD on the enzymatic degradation at the injection site. These results suggest that SBE4-ß-CyD can be a useful excipient for sustained release of insulin glargine.

Solubilized nasal steroid (CDX-947) when combined in the same solution nasal spray with an antihistamine (CDX-313) provides improved, fast-acting symptom relief in patients with allergic rhinitis.

Studies indicate that allergy sufferers remain dissatisfied with available antiallergic therapies. A new convenient formulation of solubilized steroid combined in the same nasal spray solution with antihistamine may provide added symptom relief. The objective was to evaluate effects of CDX-947 (solubilized budesonide) and CDX-313 (solubilized azelastine + budesonide) against their suspension-type comparators (budesonide [Rhinocort Aqua {RA}] or azelastine + budesonide [Astelin] {AS} + RA]) and placebo on nasal allergy symptoms of patients exposed to controlled levels of ragweed pollen in an environmental exposure chamber (EEC). Two separate EEC studies that enrolled 173 patients were analyzed. Total nasal symptom score (TNSS) and onset of action were captured. Mean change from baseline of TNSS was compared with analysis of covariance and the onset of action determined. Meta-analysis was performed to allow cross-comparisons between studies. All active treatments significantly reduced TNSS when compared with placebo and both CDX-947 and CDX-313 showed increased improvement over the suspension-type comparators. CDX-313 provided significantly faster onset of action for itchy nose and sneezing. No clinically significant adverse events were reported in this study. The novel combination product, CDX-313, provided fast, long-lasting relief for allergic rhinitis symptoms. Compared with products where corticosteroid remains suspended, the new solubilized nasal spray formulation provides added benefit including faster onset of action and superior, convenient dosing of two therapeutics in one convenient product.