"Drug delivery devices
have traditionally been viewed by many in the pharmaceutical industry as a low
value and perhaps inconvenient part of the process of creating the
pharmaceutical product. In recent years this view has changed to accommodate new
healthcare policy, competition and the needs of new therapies such as biological
molecules. The increasing pressure to improve patient compliance and reduce
healthcare costs, amidst increasing competition from generic suppliers, has
brought the need to differentiate drug products with new device forms more
sharply into focus. We have moved so quickly and come so far that some new
enabling technologies appear poised to revolutionise the market. These are
exciting times for our industry..."
1.) The Aging Patient Population
The exponential rise in global population puts increasing strain on many aspects of our society, and healthcare is no exception. The dynamics of this increase are important too. For example, the increases in the elderly population will have a significantly disproportionate impact on our healthcare system, driven by a more rapid increase in patient need over the ability of our society to pay. Increasing numbers of patients, at a time when therapy costs are already high, puts strain on the management of disease in an often over-stretched system. Many delegates recognised that governments are beginning to view future treatments by outcome, in an attempt to find ways to reduce the overall cost burden. For example, agencies such as the National Institute for Health and Clinical Excellence (NICE) in the UK are pricing treatment options on just such a basis. Within this system, a number of drivers are being debated, including the trend towards home-based care to offset pressure on hospitals and local surgeries, and the efficiencies offered through better patient and outcome data management. The move towards home-based care raises the prospect of more simplified drug delivery devices, based on two characteristics of this new market. The first is that the prescribers and carers may no longer be doctors, so instruction on use/training should be simple and effective. The second is that the patient themselves or their non-professional carer may be required to administer drugs previously given in a clinic, requiring simple and low-risk mechanisms to ensure safety and efficacy.
2.) The Patent Cliff...
The patent cliff steepens
Many blockbuster drugs are facing expiry of their US patents in the next 2 years, which is expected to lead to plummeting sales owing to competition from generic versions of these drugs. “The patent cliff facing the industry is very real, with billions of dollars being stripped from companies' revenues," Michael Hay - Sagient Research Systems analyst.
Pharma tries to avoid falling off ‘patent cliff’ - May 2012
For four years Chris Viehbacher has been bracing himself for a nasty turn. Since being appointed Sanofi’s chief executive in 2008, he has been diversifying the French drugmaker to prepare for the moment it loses US patent protection on one of its most lucrative products. “It’s T-minus 3 weeks,” Mr Viehbacher says. Along with its US partner Bristol-Myers Squibb – Sanofi is set to see sales of Plavix, the blood-thinner that is the world’s top selling medicine, drop sharply this year from nearly €7bn in 2011. Along with many of his peers in the pharmaceutical industry, he faces a “patent cliff” of expiries that has pushed companies to adopt widely divergent responses and helps explain a recent flurry of licensing deals and acquisitions. Les Funtleyder, analyst and fund manager at Miller Tabak, says: “The cost of capital is pretty cheap and may not be forever. If you don’t have a good R&D engine, you have to find other ways to support the engine you do have.”
Pfizer this week was among the companies to report a drop in first-quarter sales and earnings as generic rivals diluted its sales of Lipitor, the cholesterol-lowering drug that was itself the world’s top seller until patent expiries began to bite. Late last month, similar gloomy forecasts at AstraZeneca on sales and earnings weighed heavily in the abrupt resignation of David Brennan as its chief executive amid growing investor pressure for change. The industry has faced expiries before, but Tim Anderson, pharmaceutical analyst with Bernstein, says: “Nothing like this has ever been seen before. A series of products are near simultaneously going off patent. In years past, the rates of erosion were substantially less.” - Source
3.) ...and the pursuing Generic Giants
OTC firms focus on new directions
Procter & Gamble is teaming up with Teva, GlaxoSmithKline is putting itself on a par with the best fast-moving consumer goods firms, and Merck & Co and Pfizer are considering their options. Relentless is a good way to describe merger and acquisition activity in the consumer healthcare industry over the past 12 months. Procter & Gamble, meanwhile, has taken a different direction to develop its OTC business. The US-based consumer-goods giant announced recently that it had signed a “master agreement” with the world’s largest generics company, Israel’s Teva Pharmaceutical Industries, to create a consumer healthcare partnership. Shlomo Yanai, Teva’s president and chief executive officer, insisted the tie-up had the “potential to reshape the entire global OTC market”. He explained that the partnership would enable “two global leaders” not only to combine their businesses and research and development portfolios, but also to bring together a set of “complementary capabilities” that were “unmatchable in the healthcare industry”. Yanai’s counterpart at Procter & Gamble, Bob McDonald, pointed out that Teva’s extensive portfolio in categories such as allergy, gastrointestinal and respiratory would provide a pipeline of potential prescription-to-non-prescription switches that could become either new lines or extensions to Procter & Gamble brands such as Metamucil, Pepto-Bismol and Vicks. When finalised, the deal will see Procter & Gamble retain full control of its North American OTC operations, while a joint venture – in which Procter & Gamble will hold 51% and Teva 49% – will combine the two companies’ non-prescription operations in all markets outside of North America. The joint venture will have annual sales of more than US$1 billion on formation, and Teva believes it could become a US$4 billion business within a few years. - OTC firms focus on new directions
Generics Rise Sparks Delivery Technology Need - May 2012
4.) The Need for Better Methods of Drug Delivery
TDDS and TMDS offer advantages over other dosage forms by delivering prolonged, systemic drug levels to allow for simplified dosing regimens and overcome limitations in oral bioavailability or first-pass metabolism.
NeedlesNeedles and syringes are the most common method of administering macromolecular drugs; an estimated 12 billion injections are given annually worldwide. Despite their common use, needles have several limitations, including needle phobia and accidental needle stick injuries. In addition, concerns have arisen about the unsafe use of needles, as exemplified by the overwhelming number of HIV, hepatitis C, and hepatitis B infections that are thought to originate each year from the re-use of needles and syringes.
Noncompliance with medical treatment regimes is also a significant issue. It has been estimated that most patients do not adhere to prescribed dosing regimens, even in developed countries. Non-compliance is linked to several factors, including pain, needle phobia, and forgetfulness, and can result in serious medical complications. In fact, noncompliance is a leading cause of hospitalizations when the carefully designed drug concentration profile is altered in a way that becomes harmful to the patient.
Typically, the blood concentration levels of both injectable and oral drugs that are administered repeatedly vary, depending on the schedule of their administration and the speed at which they are absorbed and distributed by the body. Deviations from the therapeutic range of blood concentrations cause undesirable effects. For these reasons, it is important that drug developers, in addition to considering the efficacy and safety of a drug, must also carefully consider how a drug-delivery system may affect patient compliance.
The limitations of conventional methods of drug delivery can be overcome by needle-free delivery of drugs through the skin or mucosal surfaces of the mouth, nose, or lungs. Although these represent viable alternatives to needle-based methods, these surfaces also present significant barriers to drug entry into the body, and breaching them in a safe, effective way is a major goal of drug-delivery research.
Oral Drug DeliveryOral drug delivery is the most common, and the preferred type of drug administration. A large number of small molecules, including those prescribed for the treatment of pain, heart disease, and blood pressure, are already delivered orally. Drugs delivered orally are typically absorbed across the intestinal epithelium into the bloodstream via two mechanisms. The trans-cellular route involves the transport of drugs through the cell membrane to cross the barrier, either by partitioning of the drug into cell membranes or through the generation of small pores in the outer cell membrane, which allows entry into the cell.
Alternatively, the drug may permeate through the paracellular pathway, which entails transport through the tight junctions between epithelial cells. A tight junction is a dynamic network of tightly packed proteins in the interstitial spaces of a cell monolayer. Tight junctions have been likened to gatekeepers, as their primary function is to maintain the barrier properties of the epithelium and only permit the transport of very small molecules (<4 nm in diameter).
The oral delivery of proteins and peptides has elicited a great deal of interest in recent years because of the availability of novel therapeutics through the advent of recombinant DNA technology. Proteins and peptides are macromolecules with a wide variety of functions in biological catalysis, the regulation of cellular processes, and immune-system protection.
Effective oral delivery of a protein or peptide requires that a therapeutic molecule be delivered to the site of interest and cross the intestinal epithelium barrier intact before being transported to the portal circulation system. Unfortunately, this process is difficult and results in only a small fraction of drug being absorbed in the bloodstream. The delivery of proteins and peptides is further limited by their susceptibility to enzymatic degradation in the gastrointestinal tract.
The scientific community has made a major effort in recent years to overcome the obstacles to oral delivery through the development of a large number of new, innovative drug-delivery techniques. These methods include enzyme inhibitors, permeation enhancers, mucoadhesive polymers, chemical modification of drugs, targeted delivery, and encapsulation.
Enzyme inhibitors are used to counteract the natural functions of the enzymes of the gastrointestinal tract that break down ingested proteins. Many studies have been performed in which inhibitors were co-administered with a drug, but these strategies have seldom been successful unless they included absorption enhancers.
Permeation enhancers have also been used, similar to the way they are used in transdermal drug delivery. Permeation enhancers, such as surfactants, fatty acids, and bile salts, either disrupt the epithelial membrane of the intestine or loosen the tight junctions between epithelial cells. While numerous studies have demonstrated that certain enhancers can be very potent delivery aids, safety concerns abound.
Mucoadhesives
Mucoadhesive strategies have also been used to localize drugs to a small, defined region of the intestine through attractive interactions between the carrier and the intestinal epithelium. This kind of localization results in a high concentration gradient of the drug across the epithelial barrier, which improves drug bioavailability. In addition, a strong adhesion force prolongs the residence time of the dosage at the site of drug absorption, which reduces the dosing frequency and, in turn, increases patient compliance.
Certain mucoadhesive polymers, such as polycarbophil and chitosan derivatives, have been shown to simultaneously act as permeation enhancers and enzyme inhibitors.
Encapsulation Technologies
Encapsulation technologies are another alternative for the oral administration of drugs. Using commercially available pH-sensitive polymers, it is possible to target particular regions of the intestine for drug delivery. Enteric coatings made from these pH-sensitive polymers enable drug-delivery devices to pass through the acidic environment of the stomach unscathed and rapidly dissolve in the intestine. Studies to evaluate these polymers for targeted oral delivery are ongoing in various laboratories.
Other techniques involve the targeting of M-cells in the intestine to improve mucosal vaccine delivery. M-cells, which are present in the Peyer’s patches of the intestine, have the unique ability to take up antigens; targeting can be achieved by using M-cell-specific lectins in combination with a drug-delivery formulation.
Other encapsulation strategies, including micro-particles, nanoparticles, and liposomes, have been developed. These strategies can protect proteins from enzymatic degradation in the intestine and/or facilitate protein uptake across the epithelium.
Transdermal Drug Delivery
Skin, the largest human organ, provides a painless, compliant interface for systemic drug administration. However, because skin evolved to impede the flux of toxins into the body, it naturally has low permeability to the movement of foreign molecules. A unique, hierarchical structure of lipid-rich matrix with embedded corneocytes in the stratum corneum (the upper strata [15 µm] of skin), is responsible for this barrier.
Corneocytes, cross-linked keratin fibers (about 0.2–0.4 microns thick and about 40 microns wide) held together by corneodesmosomes, provide structural stability to the stratum corneum. Lipids, which provide the primary barrier function in the stratum corneum, consist of several components; the primary constituents are ceramides, cholesterol, and fatty acids. The layer of lipids immediately adjacent to the corneocytes is covalently bound to them and plays an important role in maintaining the barrier function. The stratum corneum is continuously desquamated, with a renewal period of about one week, and is actively repaired by the secretion of lamellar bodies following the disruption of the barrier properties or other environmental insults.
Transdermal drug delivery involves placing a drug on the skin in the form of a patch, cream, or lotion wherein the drug permeates across the skin and enters the bloodstream. Key advantages of transdermal delivery include the easy accessibility of skin, which encourages patient compliance, avoidance of the gastrointestinal tract, and sustained release over extended periods of time.
A number of drugs, including scopolamine, nitroglycerin, nicotine, clonidine, fentanyl, estradiol, testosterone, lidocaine, and oxybutinin, are routinely delivered transdermally by skin patches. The patches, which generally last from one to seven days, depending on the drug, have enabled new therapies and reduced first-pass effects and severe side effects. For example, estradiol patches, which are widely used, have eliminated liver damage, which was a side effect of the drug when it was delivered orally. Transdermal clonidine, nitroglycerin, and fentanyl patches also have fewer adverse effects than the same drugs delivered orally. Nicotine patches have prevented, or at least reduced, smoking and increased lifespans.
Two classes of transdermal patches are currently available: (1) reservoir-type patches and (2) matrix-type patches. A reservoir-type patch holds the drug in a solution or gel, and the rate of delivery is governed by a rate-controlling membrane. Reservoir-type patches offer more flexibility in terms of drug formulation and tighter control over delivery rates than matrix-type patches. However, they are usually associated with greater design complexity. In matrix-type patches, the drug, adhesive, and mechanical backbone of the patch are combined into a single layer. Thus matrix-type patches are easier to fabricate, but they pose even more significant design constraints than reservoir-type patches.
Drugs that are currently administered transdermally have two common characteristics—low molecular weight and high lipophilicity. Opening the transdermal route to large hydrophilic drugs, a major challenge in the field of transdermal drug delivery, will require the development of technologies that enable the controlled, reproducible transdermal delivery of macromolecular drugs.
Passive Methods
Technologies that facilitate transdermal drug delivery can work either passively or actively, depending on whether an external source of energy is used to facilitate skin permeation. Passive methods include chemical enhancers, micelles, liposomes, and peptides. Examples of chemical enhancers include fatty acids, fatty esters, solvents, and surfactants. These enhancers facilitate transdermal transport by making drugs more soluble, increasing partitioning into the skin, fluidizing the crystalline structure of the topmost layer of skin, or dissolving skin lipids.
Various modes of
transdermal drug delivery. (A) Liquid-jet injections deliver drugs into
intramuscular, subcutaneous, or intradermal regions. (B)
Permeability-based methods of transdermal drug delivery: (i) delivery through
hair follicles; (ii) tape-stripping
removes the stratum corneum and facilitates drug absorption; (iii) thermal or
radio frequency wave-mediated ablation of the stratum corneum creates micropores
that enhance drug delivery; (iv) colloidal
carriers, such as microemulsions and transfersomes, enhance the dermal
absorption of topically applied drugs; (v) low-frequency
ultrasound increases drug delivery by making the skin more permeable; (vi) chemical
enhancers or peptides for drug delivery; (vii)
electroporation of the stratum corneum enhances drug delivery into the
epidermis; (viii)
microneedles penetrate into the epidermis to deliver drugs. (C) Powder
injection delivers dry drug powders into superficial skin layers (epidermis and
superficial dermis).
Although individual chemical enhancers have had some success, combinations of chemical enhancers are more effective. However, so far, the rational design of combinations of enhancers has been limited by the lack of information on interactions between individual chemical enhancers and the stratum corneum. The number of randomly generated formulations for binary mixtures is in the millions, and the number for higher order formulations (for example, ternary or quaternary mixtures) is even higher. Screening of these formulations is beyond the scope of traditional methods (e.g.,Franz diffusion cells).
High-throughput methods of screening transdermal formulations can open this bottleneck and may lead to the discovery of previously unknown mixtures. A new high-throughput method for screening transdermal formulations is >100-fold more efficient than Franz diffusion cells with this method, up to 1,000 experiments a day can be conducted, an experimental space well beyond the scope of traditional tools. Recent studies have also shown that peptides may effectively increase skin permeability. Specifically, peptides discovered using phage-display methodology have been shown to deliver macromolecules, such as insulin, in vivo (Chen et al., 2006).
Chemical enhancers are relatively easy to incorporate into transdermal patches and can be calibrated to deliver predetermined amounts of a drug by changing the application area. However, passive methods cannot dynamically control the drug dose.
Active Methods
Active methods can be controlled in real time by varying appropriate parameters. The device and application parameters can also be adjusted to match the patient’s skin properties. A growing number of researchers are now exploring transdermal devices with active mechanisms for skin permeation, such as microneedles, jet injectors, ultrasound, iontophoresis, and electrophoresis.
Microneedles are arrays of micrometer-sized shallow needles that penetrate only into the superficial layers of skin, thereby eliminating the pain associated with standard hypodermic needles. Microneedles have been made from a variety of materials, including metals, semiconductors, polymers, and glass, and have been shown to be effective in drug delivery. They have also been produced in solid and hollow forms. Solid microneedles are used to render skin permeable, whereas hollow microneedles actively deliver drugs into the skin at a controlled rate.
In contrast, jet injectors deliver a high-velocity liquid jet stream into the skin, delivering drugs into various skin layers, depending on the jet parameters. Jet injectors have a long history, particularly in the delivery of vaccines, insulin, and growth hormone. Ultrasound enhances skin permeability by cavitation, which temporarily disrupts skin structure. Iontophoresis and electroporation use electric fields to alter skin structure and/or provide additional driving force for drug penetration through the skin.
Combined Technologies
Although many individual technologies have been shown to facilitate transderml drug transport, combinations of technologies are often more effective than any of them alone. A combination of two or more technologies may not only increase the enhancement, but may also potentially be safer. Understanding the synergies between technologies and selecting the right combinations is a fruitful area for research that is still largely unexplored.
Summary
In the last decade, significant new insights have been developed into the structural organization and barrier formation of the skin. In the past, skin was considered primarily a barrier, but it is now known to be a smart material that controls its own structure and function in response to the environment. This new knowledge must be incorporated into the future development and evaluation of transdermal technologies.
Areas for Ongoing Research
Novel, painless, patient-friendly methods of drug delivery represent an unmet need in the field of health care. Discoveries in the last decade have demonstrated the feasibility of using several different methodologies for enhancing drug delivery through skin and other mucosal surfaces. These methods have shown the potential to deliver several molecules, including macro-molecules such as insulin and vaccines.
The development of mathematical models to describe and predict transport across the skin and mucosal barriers is another area of active research that has provided useful insights into the development of novel strategies. With the variety of engineering tools at hand, the future of drug delivery looks brighter than ever. The challenge is to convert these discoveries into useful products. - Source
5.) The Residual Drug Issue with currently marketed Transdermal Delivery Technologies
Currently marketed TDDS, TMDS, and topical patches may retain 10-95 percent of the initial total amount of drug as the residual drug after the intended use period. This raises a potential safety issue not only to the patient, but also to others including family members, caregivers, children, and pets. For example, adverse events due to a patient’s failure to remove TDDS at the end of the intended use period have been reported and are generally related to an increased or prolonged pharmacological effect of the drug. Also, some children have died from inadvertent exposure to discarded TDDS. - FDA Guidance for Industry: Q8(R2) Pharmaceutical Development
FDA Guidance for Industry: Residual Drug in Transdermal and Related Drug Delivery Systems
6.) The Regulatory Risk Factor - Drug Discovery Vs Drug Delivery
"The process of discovering and developing new medicines and vaccines is long and expensive and requires innovation and creativity. Industry development times are typically 10–15 years for new medicines and vaccines, with costs of up to £1 billion for each approved product. The R&D process often involves thousands of patients in trials to investigate the safety and efficacy of potential new treatments. Consumer Healthcare relies on product innovation, brand loyalty and trademark protection to be competitive and create value. Development timelines for new consumer healthcare products are significantly shorter than for pharmaceuticals and vaccines and the pace of innovation is rapid. The application of science and consumer insights are key to driving successful product innovation for consumer brands."
Collaborate to Innovate
7.) The Partnerships
GSK Consumer Healthcare
More than 600 people in the UK, USA, India and China are dedicated to our R&D efforts in Consumer Healthcare. We invested £153 million in 2011, up from £124 million in 2008. Developing a sustainable flow of new, scientifically differentiated products – our ‘innovation portfolio’ – is a critical element of our Consumer Healthcare strategy. These can include new technologies and formulations as well as product line extensions. We also carry out ongoing research to assess the efficacy and value of our products so that we can make validated claims to consumers.
Example of innovation in 2011:"In Oral healthcare, the business
launched a new breakthrough in
dental care through Sensodyne
Repair & Protect. The Repair & Protect
formulation is the first everyday
fluoride toothpaste to contain
patented NovaMin technology."
GSK Net Sales 2011
Pharmaceuticals £18.7 billion
Vaccines £3.5 billion
Consumer Healthcare OTC £2.5 billion
Oral healthcare £1.7 billion
Nutritional healthcare £1.0 billion"Sensodyne Repair & Protect, a strong contributor to growth in the Consumer Healthcare business, is the first everyday fluoride toothpaste to contain NovaMin technology, which is proven to repair sensitive teeth. Since its launch in February 2011, Sensodyne Repair & Protect has been available in 30 markets across Europe, Asia and the Middle East, with 20 additional launches planned for 2012. The Sensodyne franchise has registered double-digit growth for 11 consecutive quarters."
In May 2010 this article was first published about a small struggling biotech company which struck up a deal with GSK worth $135 million dollars for the NovaMin technology. GSK was keeping the deal confidential, but word slowly started leaking out in the local biotech community after the acquisition was mentioned in the company's 2009 annual report. A GSK spokeswoman would only confirm at the time that the deal was completed in December 2009.
Perhaps this allows one to consider what value GSK might place on innovative technologies which are found to enhance the performance of Oral Care products, and additionally what role confidentiality might play for GSK in regards to protecting new innovation in todays competitive fast moving consumer world
Imagine if GSK could find new innovative applications for enhancing product performance as well as reducing active chemical ingredients which would also reduce the chemical waste, lower the cost and increase profit margins.
GSK 2011 Annual Report
Would certainly be an interesting exercise to do a discounted cash flow analysis on OBJ when taking into consideration a company like P&G as their joint development partner, and the overwhelming evidence of powerful marketing leadership skills shining through in these sales figures...
P&G Net Sales 2011 ($ billions)
2011 Net Sales by Business Segment
Beauty $20.1 billion
Grooming $8.0 billion
Health Care $12.0 billion
Snacks and Pet Care $3.2 billion
Fabric Care and Home Care $24.8 billion
Baby Care and Family Care $15.6 billionP&G 2011 Notes to Consolidated Financial Statements
8.) Tools and techniques driving new innovation
Optical Coherence Tomography, multiphoton microscopy, Atomic force microscopy, and confocal microscopy, etc...
Nanoparticles and microparticles for skin drug delivery
Tarl W. Prow, Jeffrey E. Grice, Lynlee L. Lin, Rokhaya Faye, Margaret Butler, Wolfgang Becker, Elisabeth M.T. Wurm, Corinne Yoong, Thomas A. Robertson, H. Peter Soyere, Michael S. Roberts - Science Direct
Metabolic state of stratum basale treated with folic acid cream for 6 days. In vivo multiphoton images show untreated (left) and folic acid-treated (right, Product B) stratum basale. Free NAD(P)H lifetime contribution over protein-bound NAD(P)H contribution ratios (a1%/a2%)are inversely related to the metabolic rate. The τ1 component is related to free NAD(P)H in the cytosol, while the τ2 component changes when NAD(P)H protein-binding changes.
Atomic force microscopy (panels a and b) show two distinct size ranges of the SLN. The fluorescent nature of podophyllotoxin enables direct drug tracking by confocal microscopy (panel d). The drug appears to accumulate in the furrows (arrow) and hair follicles in addition to coating the surface of the skin.
1.) The Aging Patient Population
The exponential rise in global population puts increasing strain on many aspects of our society, and healthcare is no exception. The dynamics of this increase are important too. For example, the increases in the elderly population will have a significantly disproportionate impact on our healthcare system, driven by a more rapid increase in patient need over the ability of our society to pay. Increasing numbers of patients, at a time when therapy costs are already high, puts strain on the management of disease in an often over-stretched system. Many delegates recognised that governments are beginning to view future treatments by outcome, in an attempt to find ways to reduce the overall cost burden. For example, agencies such as the National Institute for Health and Clinical Excellence (NICE) in the UK are pricing treatment options on just such a basis. Within this system, a number of drivers are being debated, including the trend towards home-based care to offset pressure on hospitals and local surgeries, and the efficiencies offered through better patient and outcome data management. The move towards home-based care raises the prospect of more simplified drug delivery devices, based on two characteristics of this new market. The first is that the prescribers and carers may no longer be doctors, so instruction on use/training should be simple and effective. The second is that the patient themselves or their non-professional carer may be required to administer drugs previously given in a clinic, requiring simple and low-risk mechanisms to ensure safety and efficacy.
2.) The Patent Cliff...
The patent cliff steepens
Many blockbuster drugs are facing expiry of their US patents in the next 2 years, which is expected to lead to plummeting sales owing to competition from generic versions of these drugs. “The patent cliff facing the industry is very real, with billions of dollars being stripped from companies' revenues," Michael Hay - Sagient Research Systems analyst.
Pharma tries to avoid falling off ‘patent cliff’ - May 2012
For four years Chris Viehbacher has been bracing himself for a nasty turn. Since being appointed Sanofi’s chief executive in 2008, he has been diversifying the French drugmaker to prepare for the moment it loses US patent protection on one of its most lucrative products. “It’s T-minus 3 weeks,” Mr Viehbacher says. Along with its US partner Bristol-Myers Squibb – Sanofi is set to see sales of Plavix, the blood-thinner that is the world’s top selling medicine, drop sharply this year from nearly €7bn in 2011. Along with many of his peers in the pharmaceutical industry, he faces a “patent cliff” of expiries that has pushed companies to adopt widely divergent responses and helps explain a recent flurry of licensing deals and acquisitions. Les Funtleyder, analyst and fund manager at Miller Tabak, says: “The cost of capital is pretty cheap and may not be forever. If you don’t have a good R&D engine, you have to find other ways to support the engine you do have.”
Pfizer this week was among the companies to report a drop in first-quarter sales and earnings as generic rivals diluted its sales of Lipitor, the cholesterol-lowering drug that was itself the world’s top seller until patent expiries began to bite. Late last month, similar gloomy forecasts at AstraZeneca on sales and earnings weighed heavily in the abrupt resignation of David Brennan as its chief executive amid growing investor pressure for change. The industry has faced expiries before, but Tim Anderson, pharmaceutical analyst with Bernstein, says: “Nothing like this has ever been seen before. A series of products are near simultaneously going off patent. In years past, the rates of erosion were substantially less.” - Source
3.) ...and the pursuing Generic Giants
OTC firms focus on new directions
Procter & Gamble is teaming up with Teva, GlaxoSmithKline is putting itself on a par with the best fast-moving consumer goods firms, and Merck & Co and Pfizer are considering their options. Relentless is a good way to describe merger and acquisition activity in the consumer healthcare industry over the past 12 months. Procter & Gamble, meanwhile, has taken a different direction to develop its OTC business. The US-based consumer-goods giant announced recently that it had signed a “master agreement” with the world’s largest generics company, Israel’s Teva Pharmaceutical Industries, to create a consumer healthcare partnership. Shlomo Yanai, Teva’s president and chief executive officer, insisted the tie-up had the “potential to reshape the entire global OTC market”. He explained that the partnership would enable “two global leaders” not only to combine their businesses and research and development portfolios, but also to bring together a set of “complementary capabilities” that were “unmatchable in the healthcare industry”. Yanai’s counterpart at Procter & Gamble, Bob McDonald, pointed out that Teva’s extensive portfolio in categories such as allergy, gastrointestinal and respiratory would provide a pipeline of potential prescription-to-non-prescription switches that could become either new lines or extensions to Procter & Gamble brands such as Metamucil, Pepto-Bismol and Vicks. When finalised, the deal will see Procter & Gamble retain full control of its North American OTC operations, while a joint venture – in which Procter & Gamble will hold 51% and Teva 49% – will combine the two companies’ non-prescription operations in all markets outside of North America. The joint venture will have annual sales of more than US$1 billion on formation, and Teva believes it could become a US$4 billion business within a few years. - OTC firms focus on new directions
Generics Rise Sparks Delivery Technology Need - May 2012
4.) The Need for Better Methods of Drug Delivery
TDDS and TMDS offer advantages over other dosage forms by delivering prolonged, systemic drug levels to allow for simplified dosing regimens and overcome limitations in oral bioavailability or first-pass metabolism.
NeedlesNeedles and syringes are the most common method of administering macromolecular drugs; an estimated 12 billion injections are given annually worldwide. Despite their common use, needles have several limitations, including needle phobia and accidental needle stick injuries. In addition, concerns have arisen about the unsafe use of needles, as exemplified by the overwhelming number of HIV, hepatitis C, and hepatitis B infections that are thought to originate each year from the re-use of needles and syringes.
Noncompliance with medical treatment regimes is also a significant issue. It has been estimated that most patients do not adhere to prescribed dosing regimens, even in developed countries. Non-compliance is linked to several factors, including pain, needle phobia, and forgetfulness, and can result in serious medical complications. In fact, noncompliance is a leading cause of hospitalizations when the carefully designed drug concentration profile is altered in a way that becomes harmful to the patient.
Typically, the blood concentration levels of both injectable and oral drugs that are administered repeatedly vary, depending on the schedule of their administration and the speed at which they are absorbed and distributed by the body. Deviations from the therapeutic range of blood concentrations cause undesirable effects. For these reasons, it is important that drug developers, in addition to considering the efficacy and safety of a drug, must also carefully consider how a drug-delivery system may affect patient compliance.
The limitations of conventional methods of drug delivery can be overcome by needle-free delivery of drugs through the skin or mucosal surfaces of the mouth, nose, or lungs. Although these represent viable alternatives to needle-based methods, these surfaces also present significant barriers to drug entry into the body, and breaching them in a safe, effective way is a major goal of drug-delivery research.
Oral Drug DeliveryOral drug delivery is the most common, and the preferred type of drug administration. A large number of small molecules, including those prescribed for the treatment of pain, heart disease, and blood pressure, are already delivered orally. Drugs delivered orally are typically absorbed across the intestinal epithelium into the bloodstream via two mechanisms. The trans-cellular route involves the transport of drugs through the cell membrane to cross the barrier, either by partitioning of the drug into cell membranes or through the generation of small pores in the outer cell membrane, which allows entry into the cell.
Alternatively, the drug may permeate through the paracellular pathway, which entails transport through the tight junctions between epithelial cells. A tight junction is a dynamic network of tightly packed proteins in the interstitial spaces of a cell monolayer. Tight junctions have been likened to gatekeepers, as their primary function is to maintain the barrier properties of the epithelium and only permit the transport of very small molecules (<4 nm in diameter).
The oral delivery of proteins and peptides has elicited a great deal of interest in recent years because of the availability of novel therapeutics through the advent of recombinant DNA technology. Proteins and peptides are macromolecules with a wide variety of functions in biological catalysis, the regulation of cellular processes, and immune-system protection.
Effective oral delivery of a protein or peptide requires that a therapeutic molecule be delivered to the site of interest and cross the intestinal epithelium barrier intact before being transported to the portal circulation system. Unfortunately, this process is difficult and results in only a small fraction of drug being absorbed in the bloodstream. The delivery of proteins and peptides is further limited by their susceptibility to enzymatic degradation in the gastrointestinal tract.
The scientific community has made a major effort in recent years to overcome the obstacles to oral delivery through the development of a large number of new, innovative drug-delivery techniques. These methods include enzyme inhibitors, permeation enhancers, mucoadhesive polymers, chemical modification of drugs, targeted delivery, and encapsulation.
Enzyme inhibitors are used to counteract the natural functions of the enzymes of the gastrointestinal tract that break down ingested proteins. Many studies have been performed in which inhibitors were co-administered with a drug, but these strategies have seldom been successful unless they included absorption enhancers.
Permeation enhancers have also been used, similar to the way they are used in transdermal drug delivery. Permeation enhancers, such as surfactants, fatty acids, and bile salts, either disrupt the epithelial membrane of the intestine or loosen the tight junctions between epithelial cells. While numerous studies have demonstrated that certain enhancers can be very potent delivery aids, safety concerns abound.
Mucoadhesives
Mucoadhesive strategies have also been used to localize drugs to a small, defined region of the intestine through attractive interactions between the carrier and the intestinal epithelium. This kind of localization results in a high concentration gradient of the drug across the epithelial barrier, which improves drug bioavailability. In addition, a strong adhesion force prolongs the residence time of the dosage at the site of drug absorption, which reduces the dosing frequency and, in turn, increases patient compliance.
Certain mucoadhesive polymers, such as polycarbophil and chitosan derivatives, have been shown to simultaneously act as permeation enhancers and enzyme inhibitors.
Encapsulation Technologies
Encapsulation technologies are another alternative for the oral administration of drugs. Using commercially available pH-sensitive polymers, it is possible to target particular regions of the intestine for drug delivery. Enteric coatings made from these pH-sensitive polymers enable drug-delivery devices to pass through the acidic environment of the stomach unscathed and rapidly dissolve in the intestine. Studies to evaluate these polymers for targeted oral delivery are ongoing in various laboratories.
Other techniques involve the targeting of M-cells in the intestine to improve mucosal vaccine delivery. M-cells, which are present in the Peyer’s patches of the intestine, have the unique ability to take up antigens; targeting can be achieved by using M-cell-specific lectins in combination with a drug-delivery formulation.
Other encapsulation strategies, including micro-particles, nanoparticles, and liposomes, have been developed. These strategies can protect proteins from enzymatic degradation in the intestine and/or facilitate protein uptake across the epithelium.
Transdermal Drug Delivery
Skin, the largest human organ, provides a painless, compliant interface for systemic drug administration. However, because skin evolved to impede the flux of toxins into the body, it naturally has low permeability to the movement of foreign molecules. A unique, hierarchical structure of lipid-rich matrix with embedded corneocytes in the stratum corneum (the upper strata [15 µm] of skin), is responsible for this barrier.
Corneocytes, cross-linked keratin fibers (about 0.2–0.4 microns thick and about 40 microns wide) held together by corneodesmosomes, provide structural stability to the stratum corneum. Lipids, which provide the primary barrier function in the stratum corneum, consist of several components; the primary constituents are ceramides, cholesterol, and fatty acids. The layer of lipids immediately adjacent to the corneocytes is covalently bound to them and plays an important role in maintaining the barrier function. The stratum corneum is continuously desquamated, with a renewal period of about one week, and is actively repaired by the secretion of lamellar bodies following the disruption of the barrier properties or other environmental insults.
Transdermal drug delivery involves placing a drug on the skin in the form of a patch, cream, or lotion wherein the drug permeates across the skin and enters the bloodstream. Key advantages of transdermal delivery include the easy accessibility of skin, which encourages patient compliance, avoidance of the gastrointestinal tract, and sustained release over extended periods of time.
A number of drugs, including scopolamine, nitroglycerin, nicotine, clonidine, fentanyl, estradiol, testosterone, lidocaine, and oxybutinin, are routinely delivered transdermally by skin patches. The patches, which generally last from one to seven days, depending on the drug, have enabled new therapies and reduced first-pass effects and severe side effects. For example, estradiol patches, which are widely used, have eliminated liver damage, which was a side effect of the drug when it was delivered orally. Transdermal clonidine, nitroglycerin, and fentanyl patches also have fewer adverse effects than the same drugs delivered orally. Nicotine patches have prevented, or at least reduced, smoking and increased lifespans.
Two classes of transdermal patches are currently available: (1) reservoir-type patches and (2) matrix-type patches. A reservoir-type patch holds the drug in a solution or gel, and the rate of delivery is governed by a rate-controlling membrane. Reservoir-type patches offer more flexibility in terms of drug formulation and tighter control over delivery rates than matrix-type patches. However, they are usually associated with greater design complexity. In matrix-type patches, the drug, adhesive, and mechanical backbone of the patch are combined into a single layer. Thus matrix-type patches are easier to fabricate, but they pose even more significant design constraints than reservoir-type patches.
Drugs that are currently administered transdermally have two common characteristics—low molecular weight and high lipophilicity. Opening the transdermal route to large hydrophilic drugs, a major challenge in the field of transdermal drug delivery, will require the development of technologies that enable the controlled, reproducible transdermal delivery of macromolecular drugs.
Passive Methods
Technologies that facilitate transdermal drug delivery can work either passively or actively, depending on whether an external source of energy is used to facilitate skin permeation. Passive methods include chemical enhancers, micelles, liposomes, and peptides. Examples of chemical enhancers include fatty acids, fatty esters, solvents, and surfactants. These enhancers facilitate transdermal transport by making drugs more soluble, increasing partitioning into the skin, fluidizing the crystalline structure of the topmost layer of skin, or dissolving skin lipids.
Although individual chemical enhancers have had some success, combinations of chemical enhancers are more effective. However, so far, the rational design of combinations of enhancers has been limited by the lack of information on interactions between individual chemical enhancers and the stratum corneum. The number of randomly generated formulations for binary mixtures is in the millions, and the number for higher order formulations (for example, ternary or quaternary mixtures) is even higher. Screening of these formulations is beyond the scope of traditional methods (e.g.,Franz diffusion cells).
High-throughput methods of screening transdermal formulations can open this bottleneck and may lead to the discovery of previously unknown mixtures. A new high-throughput method for screening transdermal formulations is >100-fold more efficient than Franz diffusion cells with this method, up to 1,000 experiments a day can be conducted, an experimental space well beyond the scope of traditional tools. Recent studies have also shown that peptides may effectively increase skin permeability. Specifically, peptides discovered using phage-display methodology have been shown to deliver macromolecules, such as insulin, in vivo (Chen et al., 2006).
Chemical enhancers are relatively easy to incorporate into transdermal patches and can be calibrated to deliver predetermined amounts of a drug by changing the application area. However, passive methods cannot dynamically control the drug dose.
Active Methods
Active methods can be controlled in real time by varying appropriate parameters. The device and application parameters can also be adjusted to match the patient’s skin properties. A growing number of researchers are now exploring transdermal devices with active mechanisms for skin permeation, such as microneedles, jet injectors, ultrasound, iontophoresis, and electrophoresis.
Microneedles are arrays of micrometer-sized shallow needles that penetrate only into the superficial layers of skin, thereby eliminating the pain associated with standard hypodermic needles. Microneedles have been made from a variety of materials, including metals, semiconductors, polymers, and glass, and have been shown to be effective in drug delivery. They have also been produced in solid and hollow forms. Solid microneedles are used to render skin permeable, whereas hollow microneedles actively deliver drugs into the skin at a controlled rate.
In contrast, jet injectors deliver a high-velocity liquid jet stream into the skin, delivering drugs into various skin layers, depending on the jet parameters. Jet injectors have a long history, particularly in the delivery of vaccines, insulin, and growth hormone. Ultrasound enhances skin permeability by cavitation, which temporarily disrupts skin structure. Iontophoresis and electroporation use electric fields to alter skin structure and/or provide additional driving force for drug penetration through the skin.
Combined Technologies
Although many individual technologies have been shown to facilitate transderml drug transport, combinations of technologies are often more effective than any of them alone. A combination of two or more technologies may not only increase the enhancement, but may also potentially be safer. Understanding the synergies between technologies and selecting the right combinations is a fruitful area for research that is still largely unexplored.
Summary
In the last decade, significant new insights have been developed into the structural organization and barrier formation of the skin. In the past, skin was considered primarily a barrier, but it is now known to be a smart material that controls its own structure and function in response to the environment. This new knowledge must be incorporated into the future development and evaluation of transdermal technologies.
Areas for Ongoing Research
Novel, painless, patient-friendly methods of drug delivery represent an unmet need in the field of health care. Discoveries in the last decade have demonstrated the feasibility of using several different methodologies for enhancing drug delivery through skin and other mucosal surfaces. These methods have shown the potential to deliver several molecules, including macro-molecules such as insulin and vaccines.
The development of mathematical models to describe and predict transport across the skin and mucosal barriers is another area of active research that has provided useful insights into the development of novel strategies. With the variety of engineering tools at hand, the future of drug delivery looks brighter than ever. The challenge is to convert these discoveries into useful products. - Source
5.) The Residual Drug Issue with currently marketed Transdermal Delivery Technologies
Currently marketed TDDS, TMDS, and topical patches may retain 10-95 percent of the initial total amount of drug as the residual drug after the intended use period. This raises a potential safety issue not only to the patient, but also to others including family members, caregivers, children, and pets. For example, adverse events due to a patient’s failure to remove TDDS at the end of the intended use period have been reported and are generally related to an increased or prolonged pharmacological effect of the drug. Also, some children have died from inadvertent exposure to discarded TDDS. - FDA Guidance for Industry: Q8(R2) Pharmaceutical Development
FDA Guidance for Industry: Residual Drug in Transdermal and Related Drug Delivery Systems
6.) The Regulatory Risk Factor - Drug Discovery Vs Drug Delivery
"The process of discovering and developing new medicines and vaccines is long and expensive and requires innovation and creativity. Industry development times are typically 10–15 years for new medicines and vaccines, with costs of up to £1 billion for each approved product. The R&D process often involves thousands of patients in trials to investigate the safety and efficacy of potential new treatments. Consumer Healthcare relies on product innovation, brand loyalty and trademark protection to be competitive and create value. Development timelines for new consumer healthcare products are significantly shorter than for pharmaceuticals and vaccines and the pace of innovation is rapid. The application of science and consumer insights are key to driving successful product innovation for consumer brands."
Collaborate to Innovate
7.) The Partnerships
GSK Consumer Healthcare
More than 600 people in the UK, USA, India and China are dedicated to our R&D efforts in Consumer Healthcare. We invested £153 million in 2011, up from £124 million in 2008. Developing a sustainable flow of new, scientifically differentiated products – our ‘innovation portfolio’ – is a critical element of our Consumer Healthcare strategy. These can include new technologies and formulations as well as product line extensions. We also carry out ongoing research to assess the efficacy and value of our products so that we can make validated claims to consumers.
Example of innovation in 2011:"In Oral healthcare, the business
launched a new breakthrough in
dental care through Sensodyne
Repair & Protect. The Repair & Protect
formulation is the first everyday
fluoride toothpaste to contain
patented NovaMin technology."
GSK Net Sales 2011
Pharmaceuticals £18.7 billion
Vaccines £3.5 billion
Consumer Healthcare OTC £2.5 billion
Oral healthcare £1.7 billion
Nutritional healthcare £1.0 billion"Sensodyne Repair & Protect, a strong contributor to growth in the Consumer Healthcare business, is the first everyday fluoride toothpaste to contain NovaMin technology, which is proven to repair sensitive teeth. Since its launch in February 2011, Sensodyne Repair & Protect has been available in 30 markets across Europe, Asia and the Middle East, with 20 additional launches planned for 2012. The Sensodyne franchise has registered double-digit growth for 11 consecutive quarters."
In May 2010 this article was first published about a small struggling biotech company which struck up a deal with GSK worth $135 million dollars for the NovaMin technology. GSK was keeping the deal confidential, but word slowly started leaking out in the local biotech community after the acquisition was mentioned in the company's 2009 annual report. A GSK spokeswoman would only confirm at the time that the deal was completed in December 2009.
Perhaps this allows one to consider what value GSK might place on innovative technologies which are found to enhance the performance of Oral Care products, and additionally what role confidentiality might play for GSK in regards to protecting new innovation in todays competitive fast moving consumer world
Imagine if GSK could find new innovative applications for enhancing product performance as well as reducing active chemical ingredients which would also reduce the chemical waste, lower the cost and increase profit margins.
GSK 2011 Annual Report
Would certainly be an interesting exercise to do a discounted cash flow analysis on OBJ when taking into consideration a company like P&G as their joint development partner, and the overwhelming evidence of powerful marketing leadership skills shining through in these sales figures...
P&G Net Sales 2011 ($ billions)
2011 Net Sales by Business Segment
Beauty $20.1 billion
Grooming $8.0 billion
Health Care $12.0 billion
Snacks and Pet Care $3.2 billion
Fabric Care and Home Care $24.8 billion
Baby Care and Family Care $15.6 billionP&G 2011 Notes to Consolidated Financial Statements
8.) Tools and techniques driving new innovation
Optical Coherence Tomography, multiphoton microscopy, Atomic force microscopy, and confocal microscopy, etc...
Nanoparticles and microparticles for skin drug delivery
Tarl W. Prow, Jeffrey E. Grice, Lynlee L. Lin, Rokhaya Faye, Margaret Butler, Wolfgang Becker, Elisabeth M.T. Wurm, Corinne Yoong, Thomas A. Robertson, H. Peter Soyere, Michael S. Roberts - Science Direct
Metabolic state of stratum basale treated with folic acid cream for 6 days. In vivo multiphoton images show untreated (left) and folic acid-treated (right, Product B) stratum basale. Free NAD(P)H lifetime contribution over protein-bound NAD(P)H contribution ratios (a1%/a2%)are inversely related to the metabolic rate. The τ1 component is related to free NAD(P)H in the cytosol, while the τ2 component changes when NAD(P)H protein-binding changes.
Atomic force microscopy (panels a and b) show two distinct size ranges of the SLN. The fluorescent nature of podophyllotoxin enables direct drug tracking by confocal microscopy (panel d). The drug appears to accumulate in the furrows (arrow) and hair follicles in addition to coating the surface of the skin.
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