Validated high-performance anion-exchange chromatography with pulsed amperometric detection method for the determination of residual keratan sulfate and other glucosamine impurities in sodium chondroitin sulfate.

An efficient and sensitive analytical method based on high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) was devised for the determination of glucosamine (GlcN) in sodium chondroitin sulfate (CS). Glucosamine (GlcN) is intended as marker of residual keratan sulfate (KS) and other impurities generating glucosamine by acidic hydrolyzation. The latter brings CS and KS to their respective monomers. Since GlcN is present only in KS we developed a method that separates GlcN from GalN, the principal hydrolytic product of CS, and then we validated it in order to quantify GlcN. Method validation was performed by spiking CS raw material with known amounts of KS. Detection limit was 0.5% of KS in CS (corresponding to 0.1µg/ml), and the linear range was 0.5-5% of KS in CS (corresponding to 0.1-1µg/ml). The optimized analysis was carried out on an ICS-5000 system (Dionex, Sunnyvale, CA, USA) equipped with a Dionex Amino Trap guard column (3mm×30mm), Dionex CarboPac-PA20 (3mm×30mm) and a Dionex CarboPac-PA20 analytical column (3mm×150mm) using gradient elution at a 0.5ml/min flow rate. Regression equations revealed good linear relationship (R2=0.99, n=5) within the test ranges. Quality parameters, including precision and accuracy, were fully validated and found to be satisfactory. The fully validated HPAEC-PAD method was readily applied for the quantification of residual KS in CS in several raw materials and USP/EP reference substance. Results confirmed that the HPAEC-PAD method is more specific than the electrophoretic method for related substance reported in EP and provides sensitive determination of KS in acid-hydrolyzed CS samples, enabling the quantitation of KS and other impurities (generating glucosamine) in CS.

Medication adherence and the use of new pharmaceutical formulations: the case of levothyroxine.

According to World Health Organization, medication adherence refers not only to pharmacological treatment, but also extends to all behaviors which guarantee patient's health. Poor medication adherence is the main cause of low efficacy of pharmacological therapy and it is more common in chronic diseases. For example, among hypothyroid patients, it was estimated that after 5 years of levothyroxine therapy 21.5% of patients still have a TSH level >5.0 mU/L due to poor medication adherence. Moreover, it was found that almost 40% of pediatric patients had at least one episode of non-compliance following thyroidectomia. Several strategies can be adopted in order to improve medication adherence. These include self-monitoring drug therapy and self-management programs, simplified dosing regimens, directly involving pharmacists in drug therapy management, use of pharmaceutical formulations more attractive to the patient and through the therapeutic drug monitoring. The effects mediated by the thyroid gland, the clinical symptoms of hypothyroidism and the main characteristics of levothyroxine therapy have been discussed. In order to give an overview of interactions with food and drinks, pharmacokinetic characteristics, efficacy/safety profile, as well as the impact on medication adherence of levothyroxine in oral solution and soft gel capsule formulations, a literature search was performed. The results of 21 clinical studies were reviewed. Levothyroxine oral solution and soft gel capsule formulations showed irrelevant interactions with food and drinks, with a dissolution profile minimally influenced by pH variations. According to pharmacokinetic study results, bioequivalence between these formulations and levothyroxine tablets was confirmed. Regarding the efficacy/safety profile, while some studies did not detect any difference between levothyroxine formulations, other studies suggested that oral solution and soft gel capsule were associated to a higher efficacy compared to levothyroxine tablet. It was also demonstrated that removing the demand for fasting, patients would prefer to take the medication at breakfast. Therefore, most of the patients treated with levothyroxine oral solution preferred to continue this therapy instead of treatment with tablets. An increase in patient's compliance was observed. All the characteristics of new levothyroxine oral liquid formulations allow to administer the drug also in patients with gastrointestinal comorbidities or patients who are already treated with other drugs. The availability of different dosages let the clinician to adapt the treatment for each individual patient. These benefits contribute to a better medication adherence and to the maintenance of normal TSH levels. In conclusion, the use of different pharmaceutical formulations represents a therapeutic approach innovative, effective and inexpensive in the treatment of the hypothyroid patient.

Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data.

BACKGROUND: According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg. OBJECTIVES AND METHODS: The effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-ß-cyclodextrin (HPßCD) and progesterone/HPßCD associations. RESULTS: The results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPßCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPßCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the new formulation of progesterone was shown to be safe and not inferior to other products already on the market, with the exception of progesterone administered vaginally. CONCLUSIONS: As shown by the results of clinical studies presented in this review, the newly approved medicines containing cyclodextrins have been found to be as effective and as well-tolerated as other medicinal products that do not contain cyclodextrins. Moreover, the newly approved lower dose of diclofenac associated with cyclodextrins is consistent with the European Medicines Agency recommendations reported in the revision of the Assessment Report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk. Finally, the use of cyclodextrins led to significant increases in solubility and bioavailability of drugs, such as diclofenac and progesterone, and improvement in the efficacy and safety of these drugs.