Are generic formulations of carvedilol of inferior pharmaceutical quality compared with the branded formulation?

INTRODUCTION: Carvedilol is a comprehensive beta(1)-, beta(2)-, and alpha(1)-adrenoreceptor blocker marketed as Dilatrend by F. Hoffmann-La Roche Ltd. (Roche) and as Coreg by GlaxoSmithKline for the treatment of hypertension, stable angina pectoris, post myocardial infarction with left ventricular dysfunction and all degrees of symptomatic chronic heart failure. OBJECTIVES: In this report, the pharmaceutical qualities of Dilatrend 6.25 mg, 12.5 mg and 25 mg tablets and 35 randomly selected carvedilol generic products from 20 manufacturers in 19 countries have been assessed according to the European Pharmacopoeia and the Roche specifications. METHODS: The generic products were subjected to four key tests: carvedilol content, tablet hardness, tablet dissolution and purity. RESULTS: All three Dilatrend strengths conformed to specifications. At least 17/35 (48.6%) generic products failed the specifications due to: incorrect mean carvedilol content (outside 95-105%) - three products; excess impurities (> 0.3%) - one product; incorrect tablet hardness (outside 30-70 N) - 11 products; inadequate dissolution (< 75% in 30 min) - nine products. Seven products (20%) failed two tests, generally hardness and dissolution. CONCLUSION: The dose-for-dose substitution of the original formulation of carvedilol (Dilatrend) with a pharmaceutically different, and possibly inferior, generic copy may conceivably result in a change in the efficacy of the treatment, because of an unanticipated change in pharmacokinetics or bioequivalence, and/or in a change in tolerability due to impurities.     

Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria?

The cellular role of mitochondria includes ATP generation and the modulation of cytosolic calcium signals, besides being the "crossroads" for several cell death pathways. The maintenance of optimal mitochondrial functioning during the disease process increases the chances for survival. For example, ischaemia followed by reperfusion is known to negatively affect mitochondrial function, namely by inducing a deleterious condition called mitochondrial permeability transition (MPT). The MPT is responsible for mitochondrial dysfunction and can ultimately lead to cell death. Therefore, it seems important to protect mitochondrial function in cardiac disease. Carvedilol, a beta-adrenergic receptor antagonist with antioxidant properties, has a positive impact on cardiac mitochondria during in vitro, ex-vivo and in vivo models of cardiac dysfunction. Particularly, carvedilol was shown to inhibit MPT in isolated heart mitochondria and protect mitochondria against the oxidative damage induced by the xanthine oxidase/hypoxanthine pro-oxidant system. The observation that carvedilol acts as an inhibitor of mitochondrial complex-I is also of importance, since this mitochondrial system was proposed as cause of the cardiotoxicity associated with the anti-neoplasic drug doxorubicin. This review points out the major findings concerning the positive impact of carvedilol on mitochondrial function and its use in the treatment of myocardial diseases where oxidative stress is known to be involved.     

Are the long-acting intramuscular formulations of risperidone or paliperidone palmitate associated with post-injection delirium/sedation syndrome? An assessment of safety databases

Long-acting injectable (LAI) formulations of antipsychotics are valuable treatment alternatives for patients with psychotic disorders, and understanding their safe use is critical. Post-injection delirium/sedation syndrome (PDSS) has been reported following treatment with one atypical antipsychotic LAI. Clinical databases of risperidone LAI and paliperidone palmitate were explored to identify if cases of PDSS had been observed. No cases of PDSS were identified in 15 completed trials of 3,164 subjects (approximately 115,000 injections) or the postmarketing safety database of risperidone LAI. Only one case of PDSS was identified among 10 completed trials (3,817 subjects, 33,906 injections) of paliperidone palmitate-that case having been reported in a patient randomized to treatment with placebo. Examination of these prospective databases finds no evidence that risperidone LAI and paliperidone palmitate are associated with PDSS and suggest that findings seen with another antipsychotic LAI are not generalizable.     

Original and generic latanoprost for the treatment of glaucoma and ocular hypertension: Are they really the same?

We compared the intraocular pressure (IOP)‐lowering effect and safety profile of latanoprost (Xalatan) with its generic variant, Glautan (Unipharm, Tel Aviv, Israel). After 1 and 4 weeks of treatment, a randomized, prospective, cross‐over comparison was carried out that included patients with open‐angle glaucoma or ocular hypertension, either naïve or treated and well‐controlled, who were attending the Department of Ophthalmology, Tel Aviv Medical Centre, Tel Aviv, Israel, between May 2010 and November 2012. After a 3‐week washout period for the medicated subjects, the participants were randomized to 4 weeks of treatment with either Xalatan or Glautan once every evening and then, after a 3‐week washout period, crossed‐over to the other treatment for an additional 4 weeks. Efficacy was expressed by a change in intraocular pressure at three designated hours of the day after 1 week and 1 month of treatment, and tolerability was determined by ocular side‐effects as reported by the patient in a questionnaire. A total of 19 patients (mean age at initial diagnosis 66 ± 9 years, 14 females) were enrolled, of whom 17 had bilateral open‐angle glaucoma and two had unilateral disease. Both drugs lowered intraocular pressure after 1 week and 1 month (P = 0.06 and P = 0.04, respectively) of treatment. Xalatan had a tendency of greater efficacy than Glautan both after 1 week and 1 month, but the difference was not statistically significant (P =0.69 and P = 0.34, respectively). Drug safety was similar for Xalatan or Glautan, but more ocular side‐effects were reported after treatment with Glautan (21 vs 12 for Xalatan, P = 0.06).     

The importance of interfaces in protein drug delivery - why is protein adsorption of interest in pharmaceutical formulations?

INTRODUCTION: In the area of peptide and protein drug products, interfaces are present as part of the basic liquid formulation, when freeze-dried formulations are reconstituted and when particulate delivery systems are prepared. Proteins are known to interact with these interfaces, and the effects seen are often irreversible adsorption and structural changes. AREAS COVERED: This review focuses on the ways in which peptides and proteins interact with surfaces and interfaces, and the effect these interactions have on the stability and safety of the active protein in pharmaceutical formulations. It illustrates, through examples, what can be determined by an adsorption study, and what can change when either the protein or the interfaces are modified. Last but not least, it addresses the value of these studies. The reader will gain an update on the basics of protein adsorption, with a focus on pharmaceutically relevant interfaces and recent advances in the field. EXPERT OPINION: Protein adsorption is widely studied; however, a more unified approach is still needed, especially on the adsorption of pharmaceutically relevant proteins, modified proteins and surfaces.     

Suitability of κ-carrageenan pellets for the formulation of multiparticulate tablets with modified release

κ-Carrageenan is a novel pelletisation aid with high formulation robustness and quick disintegration leading to fast drug release unlike the matrix-like release from non-disintegrating microcrystalline cellulose pellets. Compression of pellets into tablets is cost effective. The feasibility of formulating multiparticulate tablets with coated κ-carrageenan pellets was investigated. Pellets containing a highly soluble drug in acid, namely bisacodyl and κ-carrageenan or MCC as pelletisation aid were prepared, enteric coated with a mixture of Kollicoat(?) MAE 30 DP and Eudragit(?) NE 30 D and compressed using silicified microcrystalline cellulose as embedding powder. The effect of coating level, type of pellet core, compression force and punch configurations on drug release were studied. A sufficient coating thickness for κ-carrageenan pellets was necessary to obtain multiparticulate tablets with adequate resistance in the acid stage regardless of the compression pressure used. While κ-carrageenan pellets and their tablets released over 80% of the drug during the neutral stage only about 20-24% was released from MCC pellets and their tablets. The type of punches used (oblong or round) did not significantly influence the drug release from the prepared tablets. Moreover, sufficient prolonged release properties were obtained with κ-carrageenan pellets containing theophylline as a model drug and coated with Kollicoat(?) SR 30 D using Kollicoat(?) IR as pore former. A lower coating level and higher amount of pore former were needed in case of theophylline pellets formulated with MCC as pelletisation aid. The sustained release properties of both coated pellet formulations were maintained after compression at different compression pressures.     

Recent trends in stabilising peptides and proteins in pharmaceutical formulation – considerations in the choice of excipients

In the area of peptide and protein pharmaceuticals, both the physical and chemical stability of biopharmaceuticals are critical and need to be optimised when formulating a drug product, in order to optimise the outcome after processing and storage. This review focuses on the effects on the stability from various types of excipient and the choices that have to be made during formulation of drug products containing peptides or proteins. It is illustrated, through examples, how the choice of one excipient over another can affect the stability of a protein drug formulation, along with other problems linked to this choice. The excipients used in pharmaceutical preparations are limited and from an academic point of view there is a clear requirement for new excipients.     

Will novel oral formulations change the management of inflammatory bowel disease?

Introduction: The traditional management of inflammatory bowel disease (IBD) with sulphasalazine/5-aminosalicylic acid, glucocorticoids and immunomodulators (i.e., thiopurines and methotrexate) was nearly two decades ago extended with intravenously or subcutaneously administered biologics (i.e., tumor necrosis factor inhibitors and later gut-selective integrin antagonists). However, recently, orally administered treatments with simple, well-characterized, and stable structures consisting of either small molecules or anti-sense therapy have been devised.

Areas covered: This review discusses the current approaches with promising new oral drugs with distinct modes of action, including: the Janus kinase inhibitors (i.e., tofacitinib, filgotinib and peficitinib); the immunomodulatory drug (laquinimod); a small α4 antagonist (AJM300); agonists for sphingosine-phosphate receptors (i.e., ozanimod, APD334, and amiselimod), as well as anti-sense therapy (mongersen) targeting SMAD7, drugs which directly target intracellular pathways of relevance for intestinal inflammation.

Expert opinion: A new avenue using easily administered oral therapies for the management of IBD is being introduced. While their place in the clinical armamentarium remains to be proven, it is likely that many of these drugs will find their place in the treatment algorithm of IBD in the next few years. Thus, we will face times in which IBD therapy will be based on significantly more tablets than prescribed today.