Bioequivalence of topical generic products. Part 1: Where are we now?

Regulatory accepted methods for bioequivalence assessment of topical generic products generally involve long and expensive clinical endpoint studies. The only alternative relies on pharmacodynamic trials, solely applicable to corticosteroids. Considerable efforts have been channeled towards the development and validation of other analytical surrogates. The majority of these alternative methods rely on in vitro methodologies that allow a more sensitive and reproducible bioequivalence assessment, avoiding at the same time the financial burden that deeply characterizes clinical trials. The development and validation of these methods represent interesting areas of opportunities for generic drugs, since by enabling faster submission and approval processes, an enlargement of topical drug products with generic version is more easily attainable. This review aims to present a critical discussion of the most promising alternative methods, with particular emphasis on in vitro permeation studies and near infrared spectroscopy studies. Since the last technique is not broadly forecast as a bioequivalence assessment tool, its suitability is assessed by a careful analysis of patents that claim the use of NIR radiation in the skin. In fact, the extensive coverage of the devices that use this technology highlights its applicability towards a better understanding of the mechanism underlying topical drug delivery.

A Comparison of the Phosphorus Content in Prescription Medications for Hemodialysis Patients in Japan.

A high dietary intake of phosphorus is considered to be a significant health threat for hemodialysis (HD) patients. Prescription medications, which might be a major source of phosphorus, is largely unrecognized in Japan. However, the amount of phosphorus indicated on the package label, is not quantified. In this study, the phosphorus content of 22 of the most widely prescribed medications that are used in conjunction with HD therapy were examined and differences between branded and generic prescription medications were compared. All samples were selected from medications that are typically prescribed for HD patients. The samples were ground prior to analysis. Phosphorus was measured using the Wako L-Type Phosphate method. All instruments used in the study were calibrated according to the manufacturers' specifications. Amlodipine (15 mg/tablet) and paroxetine (30.0 mg/tablet) were found to contain higher contents of phosphorus than the medications tested. Differences in phosphorus content between branded and generic drugs was also determined. The phosphorus content of all generic paroxetine preparations was significantly lower than the values for identical branded medications. On the other hand, the phosphorus content of several generic amlodipine preparations were significantly different from those of similar, branded preparations. Specific information regarding the phosphorus content of prescribed medications used by HD patient needs to be made available to the dialysis community.

Establishing "abuse-deterrence equivalence" for generic abuse-deterrent opioid formulations: A proposed development framework.

Abuse-deterrent formulations are one strategy for mitigating the epidemic of prescription opioid abuse. Regulatory guidance documents describe the requirements for developing abuse-deterrent formulations of novel drugs and formulations; however, they do not address "abuse-deterrence equivalence" for generic formulations. As generics may be produced with different excipients and formulations compared to reference drugs, differences in their properties may impact their abuse-deterrent features. Currently, it is unclear what specific studies are needed to support generic abuse-deterrence claims. This commentary outlines several recommendations on the in vitro and in vivo testing required, including the conditions for conducting a human abuse potential study.

A dearth of data: the problem of phosphorus in prescription medications.

A high dietary intake of phosphorus is considered by most to be a significant health threat for dialysis patients. Efforts to include the phosphorus content of foods on the nutrition label in the US have, to date, been fruitless. Another source of phosphorus, largely unrecognized, is prescription medications. These may contain phosphorus as indicated on their package label; the amount is not quantified. We examined the labels of the branded forms of 200 of the most widely prescribed medications in Dialysis Clinic centers in the United States and found that 23 (11.5%) contained phosphorus. A sampling of different doses and manufacturers (generic and branded) of these drugs was analyzed for phosphorus content and found levels as high as 111.5 mg/dose (40 mg paroxetine). Notable were the phosphorus content of a generic 10 mg lisinopril (32.6 mg) and a generic 10 mg amlodipine (40.1 mg). The significant potential for iatrogenic injury accruing from the use of these drugs warrants efforts at remediation. Specific information on the phosphorus content of medications used by dialysis population needs to be made available to the dialysis community.

[Original preparations versus generics--latanoprost: how similar is different?]. / Originalpräparat versus Generika--Latanoprost : Wie gleich ist unterschiedlich?

BACKGROUND: To test the interchangeability of the commercially available (in Germany) latanoprost drugs and their generics respectively, the concentration of the active substance was tested. Guidelines of the European Medicines Agency postulate a sufficient bioequivalence, if the range of the agent is within 80-125% of the original drug. METHODS: All compounds of latanoprost were procured registered. The concentration of latanoprost and benzalkoniumchloride was measured by high-performance liquid chromatography (HPLC) in a validated reference labroratory for 23 generics. In addition, the mean volume of drops and the pH of the formulation were measured. The packaging label and the readability of the enclosed information leaflet were checked. RESULTS: All products contained less than 50 µg/ml latanoprost. The deviating reduction of the active substance (mean: - 7.39%, ± 2.8%) was accompanied by fluctions of the eyedrops' mass (mean: 0.03 g, ± 0.002 g). The concentration of benzalkonium chloride was mostly increased (median: 5.45%, min: - 2.5%, max: 11.5%). The pH of the original drug and the generics (median 6.78, min: 6.62, max: 6.81) was similar to the original drug, but was significantly different from an unpreserved formulation (pH 7.18). Due to type size, the packaging leaflet was illegible for humans with impaired vision. CONCLUSIONS: Before prescribing generics in ophthalmology, different factors have to be considered, which might influence the amount of IOP lowering in effect. In the absence of healthcare research it is still unclear, how different bottle forms of eyedrops--such as appearance (e.g. Cyrillic characters) or pressure point (administration)--reduce the adherence of glaucoma patients.

Bioavailability and stability of intravenous iron sucrose originator versus generic iron sucrose AZAD.

CONTEXT: Severe iron deficiency requires intravenous iron supplementation to replenish iron stores. Intravenous iron sucrose has been used for decades for the treatment of anemia. New generic iron sucrose products are now marketed for the use in several countries and there is an ongoing discussion about the safety and efficacy of iron sucrose similars. OBJECTIVE: In this study, we compared the iron sucrose originator Venofer® and the generic iron sucrose AZAD (ISA) regarding bioavailability, toxicity and stability in human THP-1 cells and HepG2 cells. METHODS: The bioavailability of Venofer® and ISA was investigated in both cell types by a ferrozin-based assay. The release of incorporated iron was assayed by atomic absorption spectroscopy. Ferritin content was measured by enzyme-linked immunosorbent assay (ELISA). HepG2 cells were used to investigate the intracellular labile iron pool (LIP), which was measured by the fluorescent calcein assay. The amount of redox-active iron within the iron formulations was assayed using fluorescent dichlorofluorescein. RESULTS: We found no significant differences in all parameters between Venofer® and ISA in regard of bioavailability, toxicity and stability in vitro. DISCUSSION: ISA shows identical physico-chemical features and identical bioavailability in vitro. This study is a profound basis for future clinical tests with generic iron sucrose compounds.

Short-term stability of a new generic sodium ferric gluconate in complex with sucrose.

BACKGROUND: Sodium ferric gluconate in complex (SFG) is used to treat iron deficiency anemia in patients aged ≥6 years undergoing chronic hemodialysis and receiving supplemental epoetin therapy. Both the branded product (Ferrlecit, branded SFG) and a new generic version of sodium ferric gluconate in complex (Nulecit; generic SFG) are provided in 5 mL vials. SFG may be administered by slow intravenous (IV) injection of the undiluted product or by 1 h IV infusion after dilution in 100 mL 0.9% sodium chloride. This study evaluated the short-term stability of undiluted and diluted generic SFG at room temperature and under refrigeration. METHODS: Samples of generic SFG undiluted in 10 mL syringes or diluted in IV infusion bags containing 0.9% sodium chloride solution were stored at room temperature or under refrigerated conditions (2-8°C). Samples at room temperature were stored for ≤48 h if undiluted and for ≤24 h if diluted. All refrigerated samples were stored for ≤7 days. Parameters evaluated were elemental iron (Fe) concentration and SFG apparent molecular weight. All tests were performed on two lots of the generic product. RESULTS: Fe concentrations were identical in both lots and did not vary substantially over time under different conditions of storage or dilution. SFG apparent molecular weight varied across all samples from 306,000 to 354,000 Daltons, well within the range of 289,000 to 440,000 Daltons specified as the molecular weight in the FDA-approved prescribing information. CONCLUSION: Iron content and SFG apparent molecular weight were stable under all experimental conditions. Undiluted generic SFG was stable for ≥2 days at room temperature and ≥7 days under refrigerated conditions, and generic SFG diluted in IV infusion bags containing 0.9% sodium chloride solution was stable for ≥1 day at room temperature and ≥7 days under refrigerated conditions.

Dissolution testing for generic drugs: an FDA perspective.

In vitro dissolution testing is an important tool used for development and approval of generic dosage forms. The objective of this article is to summarize how dissolution testing is used for the approval of safe and effective generic drug products in the United States (US). Dissolution testing is routinely used for stability and quality control purposes for both oral and non-oral dosage forms. The dissolution method should be developed using an appropriate validated method depending on the dosage form. There are several ways in which dissolution testing plays a pivotal role in regulatory decision-making. It may be used to waive in vivo bioequivalence (BE) study requirements, as BE documentation for Scale Up and Post Approval Changes (SUPAC), and to predict the potential for a modified-release (MR) drug product to dose-dump if co-administered with alcoholic beverages. Thus, in vitro dissolution testing plays a major role in FDA's efforts to reduce the regulatory burden and unnecessary human studies in generic drug development without sacrificing the quality of the drug products.

On the industrial applications of MCRs: molecular diversity in drug discovery and generic drug synthesis.

During the last decades, multicomponent chemistry has gained much attention in pharmaceutical research, especially in the context of lead finding and optimization. Here, in particular, the main advantages of multicomponent reactions (MCRs) like ease of automation and high diversity generation were utilized. In consequence of these beneficial properties, a plethora of new MCRs combined with appropriate classical reaction sequences have been published, the accessible chemical space was extended steadily. In the meantime, the desired high diversity became a challenge itself, because by now the systematic use of this huge and unmanageable space for drug discovery was limited by the lack of suitable computational tools. Therefore, this article provides an insight for the rational use of this enormous chemical space in drug discovery and generic drug synthesis. In this context, a short overview of the applied chemo informatics, necessary for the virtual screening of the biggest available chemical space, is given. Furthermore, some examples for recently developed multicomponent sequences are presented.

[Analysis of generic drug supply in France]. / Analyse de l'offre de médicaments génériques.

BACKGROUND: The list of generic medicines (LGM), published since 1997 by the Agence Française de Sécurité Sanitaire des Produits de Santé (AFFSSaPS), the French Medicine Agency, concerns a special part of the medicines reimbursed by the National Health Insurance (Social Security). The objectives of the present study were: i) to describe the components of this list, based on pharmaceutical, economical and therapeutic characteristics, ii) to study differences between generic and reference products (formulations, excipients, prices, etc.), iii) to analyze information on excipients provided to health care professionals. METHODS: The 21st version of the LGM (April 2001) was used. Therapeutic value was retrieved from the 2001 AFSSaPS report on the therapeutic value of 4490 reimbursed medicines. Information on excipients in the LGM and the Vidal dictionary (reference prescription book in France) was compared. RESULTS: The products included in the LGM represent 20% of all reimbursed medicines. The mean price differences between generics and their reference products vary between 30 and 50% for more than two thirds of the generic groups. The therapeutic value of the products of the LGM was judged important in 71% of cases (vs 63% for the 4409 assessed medicines) and insufficient in 13% of cases (vs 19%). Information on excipients is often missing and sometimes erroneous. CONCLUSION: Although the LGM is regularly revised and thus the generic market in perpetual change, the 2001 cross description of this pharmaceutical market provides much informations and raises some concern.

Quality evaluation of generic drugs by dissolution test: changing the USP dissolution medium to distinguish between active and non-active mebendazole polymorphs.

Mebendazole is practically insoluble in water and studies of its polymorphism has led to the identification and characterization of three polymorphic forms (A, B, C) displaying solubility and therapeutic differences that show that polymorph C is therapeutically favored. The objective of this study was to adjust the USP dissolution test for mebendazole so that it was able to distinguish between the dissolution properties of three mebendazole polymorphs. This would provide generic manufacturers with one more test to ensure that the therapeutically active polymorph C is used. The results obtained in this study show that the USP dissolution test conditions were not able to distinguish between the dissolution properties of completely dispersed mebendazole polymorphs with comparable particle sizes. When sodium lauryl sulfate was removed from the dissolution medium, the percentage dissolved versus time profiles changed so that polymorph C dissolved faster (70% within 120 min) compared to polymorph B (37% within 120 min) and polymorph A (20% within 120 min).