By D. Raid. Fort Hays State University.
Some of the early entrants into this field have expanded their activities into delivery routes other than their original core technology buy lisinopril 17.5mg on line, so that they can offer solutions in the transdermal buy lisinopril 17.5mg visa, inhalation and other fields as well as oral formulations. This is true of Alza, Elan and 3M, the latter being something of a hybrid since it is also a pharmaceutical company in the conventional sense. By contrast, some companies in this field are linked to specific routes of administration; Inhale Therapeutic systems, as its name implies, focuses on inhalation technology, while Pharmatec International, one of the oldest-established advanced drug delivery concerns, remains committed to the oral route. Drug delivery technology demands continual innovation in order to meet increasingly complex clinical demands and accommodate the needs of sophisticated new drugs. This places a heavy burden on existing specialist companies in terms of R&D commitment; it has led to the birth of a considerable number of small, research-driven concerns, often built around pharmaceutical specialists and teams from academia or the formulation departments of major pharmaceutical companies. Like companies in the biotechnology sector, these new ventures are set up to develop and exploit specific technologies, but their path to financial self- sufficiency is often shorter than that of a typical new biotech venture, because the regulatory hurdles are fewer when a new chemical entity is not involved. Here, the underlying technology is so new that it cannot even be described as “pharmaceutical” in any conventional sense. Likewise, the delivery technology is pushing back the boundaries of human knowledge, exploring the use of viruses as carriers for the genetic material, as well as other vehicles including liposomes. Since this applied research is, unusually, going hand-in-hand with fundamental research into the nature of the biological mechanisms involved, the development timetable is an extended one. In summary, the current structure of the advanced drug delivery industry is a complex one, embracing specialist companies which offer off-the-shelf and custom-developed delivery systems, some involved in a range of delivery routes, others concentrating on a single route of administration. There are leading-edge research teams in areas such as gene therapy, while some pharmaceutical concerns still maintain their own specialist advanced drug delivery formulation units developing essentially pharmaceutical solutions to formulation problems. What major contribution have advanced drug delivery systems made to anti-inflammatory drug therapy? Discuss the importance of the developing world as a market for advanced drug delivery systems. Systems are diversely referred to as “controlled release”, “sustained release”, “zero-order”, “reservoir”, “monolithic”, “membrane-controlled”, “smart”, “stealth” etc. Unfortunately, these terms are not always used consistently and, in some cases, may even be used inaccurately. For clarity and consistency, some common terms used in this book are defined as follows: • Prolonged/sustained release: the delivery system prolongs therapeutic blood or tissue levels of the drug for an extended period of time. Conventional drug delivery systems are simple oral, topical or injection formulations. Also, rate-control and drug targeting are treated as two separate issues in this book and are dealt with in detail in Chapters 4 and 5 respectively. Although there are literally hundreds of commercial products based on controlling drug release rate from delivery systems, there are in fact only a small number of mechanisms by which drug release rate is controlled: • Diffusion-controlled release mechanisms • Dissolution-controlled release mechanisms 57 Figure 3. If the drug concentration gradient remains constant, for example where solid drug particles are present and constant dissolution maintains the concentration of the drug in solution, the rate of drug release does not vary with time and zero- order controlled release is attained (see Chapter 4 and Figure 4. Diffusion-controlled reservoir devices are used in a wide variety of routes including those shown in Table 3. Regardless of a drug’s physical state in the polymeric matrix, such devices do not usually provide zero-order drug release properties. This is because as the drug molecules at the surface of the device are released, those in the centre of the device have to migrate longer distances to be released, which takes a longer time. This increased diffusion time results in a decrease in the release rate from the device with time. Generally the rate of release is found to decrease in proportion to the square root of time (“M t1/2” kinetics; see Chapter 4 and Figure 4. However, the decrease in drug release rate can be compensated for by designing systems of special geometry, which provide an increasing surface area over time. Examples of diffusion-controlled matrix devices in drug delivery are shown in Table 3. After a certain period of time the polymeric membrane dissolves, thereby releasing the drug; • matrix devices: in which the drug is distributed throughout a polymeric matrix, which dissolves with time, thereby releasing the drug. Since the dissolution of polymeric materials is the key to this mechanism, the polymers used must be water- soluble and/or degradable in water. The choice of a particular polymer for a particular controlled release dosage form depends on various factors such as the dissolution mechanism, delivery period, delivery route, the drug etc. In general, synthetic water-soluble polymers tend to be widely used for oral-controlled release dosage forms. Biodegradable polymers tend to be used for injectable, or implantable, drug delivery systems. Once the coating polymer dissolves, the drug is available for dissolution and absorption. Drug cores can be coated with polymers of different coating thickness, so that drug release can be delayed for certain periods, for example 1, 3, 6 and 12 h after administration. By using a dosage form incorporating a spectrum of different coating thicknesses, the overall drug release from the dosage form (as a whole, rather than from the individual microparticles) can adjust to give zero-order drug release.
Phenyl ester has also been used as C-terminal carboxy terminal protecting group  buy lisinopril 17.5mg fast delivery, as it is stable to acidolysis and catalytic hydrogenolysis and can be used while the N-terminal is protected with Boc (13) and Z (23) group order lisinopril 17.5mg with visa. Ph ester can be removed either by saponifcation or, under mild conditions, by peroxide ion and alkali in the presence of dimethyl sulfde in order to avoid the oxidation of sensitive residues (Met, Cys, etc. And last but not least, hydrazide and substituted hydrazide derivatives can be used as carboxy C-terminal protecting groups . Although hydrazide (72) is reactive to acylation by the activated amino-acid derivatives, and cannot provide suffcient protection to carboxy C-terminal, it is quite useful for segment coupling into a conver- gent strategy because it can be easily converted into acyl azide. Thus, only protected hydrazides can be used as protecting groups of C-carboxy terminal for peptide chain elongation at the N-terminal (Figure 2. This method has found extensive use in the synthesis of long peptides using the fragment conversation strategy. Specifcally, in this approach, the desired peptide is obtained after condensation in solution of two or more appropriate peptide fragments prepared mainly through solid phase synthesis. Assembling of two fragments can be performed either by the classical condensation method using coupling reagents or by the most modern technique of native chem- ical ligation. In the frst approach, the coupling of protected peptide fragments is assembled in typical organic solvents, followed by global deprotection of side chain protected groups (Figure 2. In the native chemical ligation method, the condensation of the fragments is carried out in water after their full deprotection, where the N-fragment is modifed as thioester at the C-terminal and the C-fragment to include a Cys residue at the N-terminal. Both approaches are valuable for the preparation of complex and long peptides and proteins and combine the benefts of both solid- and solution-phase strategies. The number and time of reactions are decreased when compared to the step-by-step solution syn- thesis. Even if coupling of peptide fragments is not completed, this kind of impurities is usually easily separated. An important consideration during the development of the segment condensa- tion approach is the evaluation and design of the appropriate fragments, taking into account their preparation frst and second, their condensation. Thus, the solubility of the fragments in condensation reactions has to be taken into account (an estimation or a prediction can be made but it is of no assurance without actual preparation). Fur- thermore, the potential epimerization during the condensation reaction is a common risk that should be avoided or reduced. Thus, Gly or Pro as C-terminal residues of the fragments is the priority if possible, in order to totally avoid racemization. Evaluation of the linker and the solid support is another cru- cial point to take into consideration. Side-chain-protecting groups have to be stable into the cleavage conditions of the peptide fragments of the projected peptide. Thus, Fmoc/tBu chemistry is commonly preferred, in combination with super acid-sensitive linkers/resins. Their development and commercial availability has allowed synthetic access to even longer peptide sequences. In the hybrid approach, the condensation of the protected fragments is carried out using the classical coupling reagents, which are described in Chapter 4 and Section 6. Two peptide fragments, one containing a C-terminal thioester and the other containing an N-terminal cysteine residue, are assembled by chemoselective coupling. Native chemical ligation is a reversible transthioesterifcation, followed by amide formation. Intramolecular nucleophilic attack of an α-amino group on the initial thioester product occurs only when the thiol is on the side chain of an N-terminal Cys, thus regenerating the thiol functional group of the Cys side chain and giving a fnal ligation product containing a native peptide bond at the site of ligation (Scheme 2. Initial thiol–thioester exchange step is fully reversible, whereas the second amide-forming step is irre- versible under the reaction conditions. Because of this, eventually, only the desired amide-containing product is formed, even in the presence of internal Cys residues in either peptide segment. This reversible-irreversible two step reaction mechanism is the essence of the native chemical ligation method. The main benefts of the native ligation strategy are the reduced solubility problems that commonly appear in the fragment-condensation strategy, and the absence of reagents that should be purifed. In this approach the side chain protecting groups of the fragments are removed before fragment ligation. The reaction takes place in an aqueous environment in neutral pH, in order to give a native peptide bond at the ligation point. Limitation of this hybrid technology is the mandatory use of a Cys residue at the N-terminal of the frst fragment, and the synthesis of an appropriate C-terminal thioester in the second fragment, which in some cases provides poor yields . Side chain protection of the fragments is not essential, but favors the reaction in aqueous media. More interestingly, a side-chain-assisted chemical ligation has been reported lately, with no limits to the assembled amino acids . Continuous improvement of ligation strategies provides an additional tool to peptide chemists to overcome more immediate challenges in view of the signifcantly increased demand for larger peptides.
Analysis of successful distribution chains order lisinopril 17.5mg fast delivery, such as the Coca-Cola distribu- tion chain discount 17.5mg lisinopril free shipping, suggests this is a false dichotomy, however (Yadav et al. ColaLife, a nonproft, has been using Coca-Cola’s fne-mesh distribution chain to bring oral rehydration and zinc supplements to remote areas since 2008 (ColaLife, 2012). Steps toward a more controlled and effcient wholesale market can protect patients in the markets most hurt by bad- quality drugs. A reduction in the number of licensed wholesalers and use of more effcient distribution chains can help the wholesale market around the world. With every transaction on the chain, there is a risk of the drug supply’s being compromised. Crimi- nals take advantage of places where the distribution chain breaks down and medicines depart from documented chain of custody. Drugs that leave the proper distribution system are called diverted drugs; the markets that trade diverted drugs, or more generally, markets that trade with little authorized oversight, are called gray markets. Drug diversion is the means through which medicines approved for sale in one country are sold in others, where they may not be registered. On the surface, drug diversion is not the public health threat that falsifed and substandard medicines are (Bate, 2012). Some countries have made legal provisions for importation of unregistered lifesaving drugs that are not available in local markets (Zaza, 2012). Others argue that thieves bring good-quality drugs to otherwise neglected markets, and that, issues of fraud aside, the end consumer is no worse off (Bate et al. If thieves traffcked solely in quality-assured medicines, then this point might be valid. Once a medicine leaves the responsible chain of custody, there is no way to ensure that it has been properly stored. As Chapter 3 explains, drug quality research indicates that unregistered medicines are sometimes dangerous (Bate et al. By chance, drug diversion may bring good Key Findings and Conclusions • When stolen drugs are reintroduced to the legitimate supply chain, there are no records of the products’ handling or storage conditions. Pedigree requirements prevent stolen drugs from entering the legitimate mar- kets and facilitate efcient recalls. Drug diversion is roughly synonymous with theft, and trade in diverted drugs is an indicator of the relative ease with which criminals exploit weak- nesses on the distribution chain. In the United States, for example, the resale of prescription drugs is a common problem, but illicit vendors also circumvent the regulated distribution chain at other points. In developing countries, the sale of donated drugs for proft is a common type of diversion (World Bank, 2005). Small-scale theft, also called pilfering, happens mostly between the vendor and patients; larger cargo heists tend to happen to bulk drug pack- ages, generally between the manufacturer and the vendor. Pilfering and Heists Many diverted drugs are donated ones, pilfered and resold by health workers (Ferrinho et al. The theft and resale of free drugs is engrained in the pharmacy and clinical culture in some countries, where it is seen as a professional perk for otherwise underpaid government health workers (Lim et al. This theft defrauds donors and con- tributes to drug shortages at legitimate dispensaries (Bate, 2012), thereby encouraging the distal causes of poor-quality drugs. In March 2010, $75 million worth of medicines were stolen from an Eli Lilly warehouse in Connecticut (Efrati and Loftus, 2010) and later partially recovered in Florida (Muskal, 2012). Freight Watch International, a supply chain security company, estimates that theft of pharmaceuticals in the United States increased 283 percent between 2006 and 2008 and have remained roughly constant since then (FreightWatch, 2011b). Ware- house heists such as the Lilly theft are relatively diffcult to orchestrate; by far the more common route is theft of a loaded trailer (see Table 5-2) (FreightWatch, 2011b). Cargo theft is not confned to the United States; Freight Watch Interna- tional sees it as a serious problem in Brazil, Great Britain, India, Mexico, Russia, and South Africa as well (Fischer, 2012; FreightWatch, 2011a). Countering the Problem of Falsified and Substandard Drugs 212 Copyright © National Academy of Sciences. Fund fnances a line of artemisinin combination therapies for the Affordable Medicine Facility in eight countries, including Nigeria and Ghana (Global Fund, 2012). These drugs are packaged differently from those meant for the public sector (Bate, 2012; Bate et al. Roger Bate was therefore able to recognize Global Fund products meant for Nigeria and Ghana in Lomé, Togo (Bate, 2012). Thirty percent of the diverted samples he collected in Togo failed quality tests, a failure his team attributed to degradation (Bate, 2012). Outward evidence of diversion is not always so clear, but a drug sold in a country where it is not registered is often diverted and therefore sus- pect. A national sample of essential medicines in Cambodia found that unregistered drugs are six times more likely to be falsifed than registered ones (Khan et al. Similarly, in Ghana, researchers found unregis- tered oxytocin samples to be uniformly substandard (Stanton et al.
Monoclonal Immunoglobulins: based on Many Iniximab order lisinopril 17.5 mg with visa, antibodies specicity for antigenic rituximab epitopes 4 17.5 mg lisinopril fast delivery. Gene therapy Vector-delivered gene sequences: 1 Alipogene replace decient/aberrant tiparvovec gene products 7. Pharmacological Small molecules: stabilize and/or 0 N/A chaperones reshape misfolded proteins aSmall molecules are low molecular weight (<900 Daltons) organic compounds and have been the main molecule platform for drug development. Large molecules (naturally occurring, recombinant, synthetic) comprise a broad cross-section of compound classes (e. LentiGlobin, which uses a similar vector but replaces beta-globin, is being evaluated for the treatment of beta thalassaemia major and sickle cell disease. Alipogene tiparvovec’s approval, based on clinical data from 27 patients, restricts prescribing to the subset of lipoprotein lipase deciency patients who have suﬀered repeated pancreatitis, and requires ongoing monitoring by the company, to demonstrate long-term eﬃcacy and safety. There are a number of arguments for the proposed price: high pharmaceutical R&D costs in general, and alipogene tiparvovec’s high-cost development programme in particular (i. Interestingly, uniQure has proposed an ‘annuity’ approach to charging health systems for alipogene tiparvovec (e. Duchenne’s, an X-linked disease characterised by progressively debilitating natural history disease stages, has a spectrum of manifesta- tions with important implications for selecting clinical end points and trial design, on a background of a wide array of exon-deletion abnormal- ities. Thelattertwostages,aﬀecting teenagers and older patients, exhibit more debilitating disease aﬀecting cardiac, pulmonary and upper limb function. Prosensa’s exon-targeting therapeutic approach, which would create a ‘menu’ of therapies for each exon-deletion abnormality, is inuenced by the decreasing prevalence of the target exon (e. Based on this background, the clinical development and regulatory approach will probably pursue a full devel- opment programme for compounds addressing the most prevalent target exon mutations (e. Chaperones bring about therapeutic eﬀect downstream of translation by ‘protecting’ their target proteins (e. Amicus Therapeutics, arguably the company with the broadest portfolio of small molecule pharmacological chaperones, is leveraging its technology platform to develop orally bioavailable therapies to address lysosomal storage disorders including Fabry, Gaucher and Pompe diseases. More so, orphan drug reim- bursement, by private or public payer, has traditionally been generous, aﬀording most patients in the small orphan disease communities with access to medicines, which are oen life-saving and/or provide signicant quality of life attributes. Some of these payer management tools, approaches and tactics include the use of restrictive tiers, prior authorisation, step therapy, increased patient coinsurance and/or co-payment, genetic testing (i. Creative risk-sharing schemes, in addition to traditional patient access programmes and manufacturer discounts, are increasingly playing an important role in the provision of orphan drugs to patients. This concept is taken further with performance-based risk-sharing agreements for ultra-orphan therapies, where price reductions can be entertained or negoti- ated if clinical outcomes are suboptimal or not compelling, which provides an approach to address the uncertainty regarding the long-term eﬀectiveness of costly ultra-orphan drugs. In summary, the key dimensions of commercialisation success around which companies must diﬀerentiate in order to win in the orphan drug market include understanding and exploiting orphan disease market fundamentals (e. There are two key evaluations or reports that have investigated this topic – the Drug Discovery Today article ‘Orphan Drug Development: An Economically Viable Strategy For Biopharma R&D’ (published in 2012), and EvaluatePharma’s ‘Orphan Drug Report’ (published in 2013). This indicates that mean per-year economic values of the orphan and non-orphan drug cohorts were almost equal, which underscores the value-creation viability of orphan drugs. View Online 102 Chapter 4 overall pharmaceutical market (excluding generics), as outlined in Figure 4. A separate analysis, in the same report, demonstrated a statistically signicant greater trend for multi-indication orphan drugs to target initial approval in an orphan vs. When the development plans for individual orphan drugs are being created, the cost, complexity, challenges and high-risk nature of pharmaceutical R&D in general should not be underestimated. The current trends in the orphan drug product development arena provide some interesting themes and an inno- vation imperative for inuencing the evolution of the biopharmaceutical landscape – for orphan drug R&D specically, as well as continual stimula- tion of biopharmaceutical R&D in general. Orphan drug R&D will make important contributions to life sciences research, drug discovery and translational medicine, thereby enhancing therapeutic development approaches (e. Indeed, orphan drug R&D experiences will help to advance the development and use of personalised/stratied medicine approaches and targeted medicines. Orphan drug R&D also has a key role in evolving clinical development paradigms (e. It will be interesting to see the extent to which ‘real world trials’ are included as part of ongoing orphan drug development programme eﬀorts to expand clinical data sets and update the risk–benet prole of orphan drugs. The ‘real world trial’ paradigm, gathering eﬃcacy and safety data across countries where feasible, could help encourage greater use of progressive (not only conditional) regulatory approval approaches for orphan drugs, which could help address concerns regarding the paucity of clinical data available at the time of marketing authorisation. Awareness, education, outreach and marketing approaches, for consumers and prescribers, will also be inuenced by the degree to which orphan drugs embrace social media and community connectivity models. Merkel and Rare Diseases Clinical Research Network, Mol Genet Metab, 2009, 96,20–26. View Online Treating Rare Diseases: Business Model for Orphan Drug Development 109 33. View Online Treating Rare Diseases: Business Model for Orphan Drug Development 111 76. Patient support groups, voluntary health organisations and disease advocacy organisations are just a few of the names by which advocacy and support for rare conditions is known. These organisations run the gamut from simple support for people aﬀected by a condition to full-blown research entities that rival some pharmaceutical companies in nancing and capacity. When specically considering drug development for rare diseases, it is more likely that the organisation lies at the research entity end of the spectrum.
Early in 2008, Sue Clark brought a handful of epigenetics researchers from Australia together to form the Australian Epigenetics Alliance. The AEpiA has now grown to a membership of nearly 300, with members spanning not only Australasia, but the globe. Last year we hosted our seventh flagship conference, Epigenetics 2017 in Brisbane, QLD, and the WA team are already busy preparing for Epigenetics 2019 – watch this space!
Past Epigenetics meetings: