Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

Domino Printing Sciences, announced that it has launched a new ultra-fast-drying ink for companies that require "item level serialization whilst maintaining line speeds.” The new ink (BK652) takes less than one second to dry and is four times more resistance to fading than typical inks used in retail packaging, stated Domino in its 

The ink was developed in response to the EU Falsified Medicines Directive (FMD) according to Domino's life sciences manager, Craig Stobie. "Under the legislation pharmaceutical product will be authenticated at the point of dispensation, making long term ink lightfastness and contrast vitally important, even after what could be years in the supply chain." 

Alan Mutch, product manager for thermal ink jet at Domino, said that this product was “reformulated in light of the legislative requirements in Europe and US.” Designed for use with Domino’s G-Series thermal ink jets, the ink can print high-definition coding onto various substrates such as cartons, sachets, pouches, labels and blister packs. 

The rapid drying means that data and codes can be fixed and bonded without delaying packaging productivity. Operational efficiency can be increased as cartons with data printed using BK652 can be picked up in the second and third operations on the packaging line much quicker. The ink also cuts de-cap time and thereby reduces initial rejects that manufacturers tend to see after the machine has been left idle. 

Articles

The new ink takes less a second to dry and is four times more fade resistant than inks that are typically used in retail packaging.

Domino Introduces Fast-Drying Ink for High-Speed Coding

Almac announced that it has expanded its service offering for dispensing and bottling solid dosage products by introducing enhanced containment equipment and processes at its EU and US clinical services sites. The facilities are now in operation following successful installation and validation. 

Dr Robert Dunlop, managing director of Almac clinical services said in a 

 that there has been an increase in demand for facilities equipped to handle compounds of a higher potency in the drug-development industry and Almac has responded by expanding its service offering to address this need. 

Almac introduces handling and bottling capabilities in EU and US headquarters.

Almac Adds Contained Drug Handling and Bottling Capabilities

 that it has entered into an antibody-drug conjugate (ADC) collaboration with Bayer. Under the terms of the agreement, Bayer will pay upfront and option exercise fees of up to $20 million for worldwide rights to use Seattle Genetics’ auristatin-based ADC technology with antibodies to several cancer targets. 

Seattle Genetics is also eligible to receive up to approximately $500 million in milestone payments and royalties on sales of any products resulting from the collaboration. Bayer will conduct research and development and be responsible for manufacturing and commercialization of all products under this collaboration. 

ADCs are monoclonal antibodies that selectively deliver cytotoxic agents to targeted cancer cells. Seattle Genetics has developed proprietary technology to attach synthetic cytotoxic agents to the antibody using stable linker systems that are designed to be stable in the bloodstream. The targeted delivery spares healthy cells from the many toxic effects of traditional chemotherapy while enhancing antitumor activity. 

Seattle Genetics has also extended its collaboration pact with Agensys, an affiliate of Astellas, and 

 co-development of an additional ADC under the companies’ existing ADC agreement. The ADC, called ASG-15ME, targets the tumor antigen SLITRK6, known to be expressed on bladder and lung cancer. Agensys has submitted an investigational new drug (IND) application to FDA for initiation of a Phase I trial of ASG-15ME. 

Seattle Genetics could potentially receive approximately $500 million in fees, milestones and royalties.

Seattle Genetics Forms ADC Pact with Bayer

The design and development of controlled-release drug-delivery systems have been traditionally used to extend a product's lifecycle, for example, by modifying an existing drug product that requires multiple dosing a day to a once-daily formulation to maintain dominance over generic competition (1, 2). While this rationale still holds true today, the number of compounds formulated into controlled-release systems are increasing because of their added value and well-recognized advantages such as improved systemic bioavailability, more favorable pharmacokinetic profiles (e.g., the maintenance of drug levels within a desired range without exposing patients to potentially toxic or subtherapeutic levels), reduced side effects, and better patient compliance among others (3–5). From a strategic perspective, commercial and industrial advantages of controlled-release drug delivery, apart from prolonging product lifecycle, include patent extension, market expansion, and product differentiation (6, 7). 

	Controlled-release technologies play a vital role in today's current healthcare market, given the strong emphasis placed on product value and cost effectiveness. Treatment of many diseases requires a dosage regimen that delivers acceptable therapeutic concentrations of the drug at the site of action, which can be attained immediately and then constantly maintained over the desired duration of treatment (8). Controlled-release drug delivery offers solutions to conventional problems of drug administration by regulating the patterns of drug release and absorption as well as the localization of therapeutic agents. The maintenance of stable drug levels in the plasma over a defined and extended period, achieved with controlled-release systems, minimizes peak-to-trough variations of drug concentration in the systemic circulation and allows dosing frequency to be reduced, thereby improving patient compliance and overall clinical utility (1, 6). There are, however, potential disadvantages of controlled-release systems that should not be overlooked, such as dose dumping, possible toxicity or nonbiocompatibility of the materials used, undesirable by-products of degradation, higher manufacturing costs, and for implants, the requirement of surgical procedures to insert or remove these systems as well as possible patient discomfort from the delivery device (4, 5).

Osmotically controlled oral drug-delivery systems


	One way to control drug release is by using osmotic systems, which operate on the principles of osmosis (i.e., the movement of solvent through a semipermeable membrane into a region of higher solute concentration until the solute concentrations are equal on both sides of the membrane). Osmotic systems consist of a drug core contained within a semipermeable polymer membrane that is permeable to water molecules but not to the drug, with an orifice for drug delivery. Drug release is driven by the osmotic pressure generated within the drug core upon exposure to water and is, to a large extent, independent of physiological factors (9, 10). Release characteristics can be modulated by optimizing the properties of both the drug and system (4).

	Osmotically controlled oral drug-delivery systems have gained popularity because of the following advantages over other controlled-release strategies (9, 11, 12):

		Zero-order kinetic release is achievable.

		The drug is delivered at a constant rate that is independent of time and drug concentration.

		The release rate is highly predictable.

		Higher release rates are possible compared with conventional drug-delivery systems.

		Drug release is independent of physiological factors of the gastrointestinal tract, including gastric pH and hydrodynamic conditions.

		Drug release is generally not affected by the presence of food.

		The release rate can be programmed by modulating release-control parameters.

		Delivery may be delayed or pulsed if desired.

		Soluble and insoluble compounds can be delivered.


	Osmotic systems essentially contain a drug and a semipermeable membrane. Ideal candidates for these systems are drugs with short biological half-life, which require prolonged treatment, such as drugs for hypertension (e.g., nifedipine) or diabetes (e.g., glipizide) (12).

	Drugs with good water solubility may act as an osmotic agent or osmogen that draws water into the osmotic core. However, if the drug does not possess osmogenic properties, osmogenic salts (e.g., sodium chloride and potassium chloride) and sugars can be incorporated into the formulation (11). When selecting an osmogen, the two most important properties to consider are water solubility and osmotic activity.

	The semipermeable membrane is an important component because it controls the rate of water influx into the drug core as well as retains water-soluble components within the core to create the osmotic pressure gradient that drives the osmotic system (9). The semipermeable membrane must possess certain performance criteria, such as sufficient wet strength and water permeability, and should be selectively permeable to water and biocompatible (13). Cellulose acetate, a water-insoluble film-forming polymer, is commonly used in osmotic systems. Release rate is affected by the molecular weight and acetyl content of the various grades of cellulose acetate. The semipermeable membrane usually contains a plasticizer, which moderates the permeability of the membrane, and in some cases, surfactants, flux regulators and pore-forming agents (11).

Formulation factors affecting drug release


	Key parameters (i.e., drug solubility, osmotic pressure, the size of the delivery orifice and semipermeable membrane) that influence the design of osmotically controlled drug-delivery systems are briefly summarized.

 To achieve optimized drug release, the API for osmotic delivery should have sufficient water solubility, given that the release rate is directly proportional to the solubility of the API within the core. Drugs with extremes of solubility are generally poor candidates for osmotic delivery. There are, however, approaches to modify the solubility of such drugs within the core so that the desired release patterns can be attained.

	For compounds with low solubility, solubilizing strategies can be employed; for example, by using alternative salt forms or cyclodextrins. Swellable polymers (e.g., vinyl acetate copolymer and polyethylene oxide) can also be added; the uniform swelling of these polymers facilitates drug release at a constant rate. Wicking agents help to increase the contact surface area of the drug with incoming fluids. The use of wicking agents can help enhance the rate of drug release from the orifice of the osmotic system (12, 14).

 The osmotic pressure gradient between the drug core of the osmotic system and the external environment is another important factor that controls drug release, with release rate being directly proportional to the osmotic pressure of the core. The simplest and most predictive way to achieve constant osmotic pressure would be to maintain a saturated solution of osmotic agent in the drug-core compartment (3).

 The size of the orifice must be within a certain range for controlled release. The typical range is 0.5 mm to 1.0 mm in diameter (9). For an optimal zero-order delivery profile, the cross-sectional area of the orifice must be small enough to minimize drug passage through the orifice but large enough to minimize the build-up of hydrostatic pressure within the osmotic system (14). The orifice can be created by using a mechanical drill or by laser drilling, which is now a well-established technology that offers reliability at low costs. Other methods to create an orifice are by indentation with modified punches that have a needle on the upper punch or by using leachable substances in the semipermeable coating (13).

 Drug release rate is affected by the type and nature of the membrane-forming polymer used, membrane thickness, and the presence of other additives (e.g., type and nature of plasticizers used). Membrane permeability can be increased or decreased by the proper choice of membrane-forming polymers and other additives (3).

Evolution of osmotically controlled-release systems 

Osmotically controlled oral drug-delivery systems have come a long way. The first elementary osmotic pump, invented by Theeuwes, consists of a single compartment containing the drug and an osmotic agent surrounded by a semipermeable membrane (15, 16). Upon ingestion, water is drawn into the core through the semipermeable membrane to saturate the drug, which is then released in liquid form at a controlled rate through the orifice(s) (see 

	The limitation of the elementary osmotic pump, however, is that it can only deliver water-soluble drugs. The design was further improved by Cortese and Theeuwes, resulting in the development of the push-pull osmotic pump, which is a bilayer tablet capable of delivering both highly and poorly soluble drugs (17). The upper layer (i.e., the drug layer, also known as the pull layer) consists of the drug and an osmotic agent while the lower layer (i.e., the push layer) consists of water-swellable polymers and osmotic agents (see 

). Both layers are coated with a semipermeable membrane that regulates water influx into the system. As water enters the tablet, pressure increases and the polymer swells to push against the drug layer, thereby releasing the drug solution or suspension through the laser-drilled orifice(s).

	Zentner et al. reported on the development of the controlled-porosity osmotic pump in the mid-1980s. The controlled-porosity osmotic pump does not require a delivery orifice for drug release, hence eliminating the need for complicated laser-drilling procedures (18, 19). It consists of the drug and an osmotic agent in a tablet core surrounded by a semipermeable coating membrane containing leachable pore-forming agents, which dissolves upon contact with water, forming pores through which the drug solution is pumped out. The rate of drug release is dependent on the thickness of the coating membrane, levels of leachable pore-forming agents, the amount of soluble components incorporated in the coating, drug solubility within the tablet core and the osmotic pressure differences across the membrane, but unaffected by pH and gastrointestinal motility (20–22).

	In the mid-1990s, Herbig et al. described a new type of membrane coating for osmotic drug delivery. The new coating has an asymmetric structure, similar to asymmetric membranes made for reverse osmosis or ultrafiltration, in that the coating consists of a porous substrate with a thin outer skin (23). Asymmetric membranes are made from water-insoluble polymers (usually cellulose derivatives, such as cellulose acetate, ethyl cellulose and cellulose acetate butyrate) and pore-forming agents (e.g., glycerol, sorbitol, polyethylene glycol, polyglycolic acid and polylactic acid) using a phase-inversion process.

	The use of asymmetric membrane coatings in osmotically controlled oral drug-delivery systems has increased in the past decade because of the advantages it offers. These benefits include: a higher rate of water influx, which facilitates osmotic delivery of poorly soluble drugs and enables higher release rates of such drugs; more controlled-release of freely soluble drugs; pH-independent release and minimized exposure to the gastrointestinal tract, which results in reduced gastric irritation and degradation of drugs (23–25).

	Water permeability of the coating can be adjusted by controlling the membrane structure, thereby allowing control of release kinetics without altering the coating materials used or significantly varying the coating thickness. The porosity of the membrane can also be controlled to minimize the lag time that occurs before drug delivery begins (23).

	Asymmetric membrane coatings can be applied on pharmaceutical tablets and capsules (23, 26, 27). The basic design of an asymmetric membrane capsule is similar to a hard-gelatin capsule, except that the shell contains pore-forming water-soluble additives, which dissolve after coming in contact with water, resulting in an 

 formation of a microporous structure (28, 29). A delivery orifice is, therefore, not required due to the 

pore formation of the asymmetric membrane.

Asymmetric membrane capsules in application


	An asymmetric membrane capsule for controlled release of terbutaline sulfate was recently described by Gobade et al. (29). The drug is a beta agonist used in the treatment of asthma. The oral dosage regimen of terbutaline sulfate is 5 mg twice or three times daily. The plasma half-life is approximately 3–4 hours. The asymmetric membrane was prepared using ethyl cellulose as the polymer and sorbitol as the pore-forming agent. Dissolution studies showed that the formulation provided zero-order drug release over a 12-hour period.

	Philip and Pathak developed a nondisintegrating, controlled-release, asymmetric membrane capsule of ketoprofen and evaluated the 

correlation of the formulation (30). Ketoprofen is a nonsteroidal anti-inflammatory drug, used in treatment of rheumatoid arthritis, osteoarthritis, and musculoskeletal disorders. Multiple dosing is required to achieve and maintain therapeutic concentration because of its short half-life (4.2 h) and poor solubility. The asymmetric membrane capsule was made of ethyl cellulose and glycerol. Sodium chloride was used as an osmotic agent and citric acid as a solubilizer. The formulation provided controlled release of ketoprofen and the half-life of the drug was prolonged for more than 16 hours. 

pharmacokinetic studies showed excellent level A correlation (r2 > 0.99), demonstrating that the 

drug-release profile of ketoprofen from the asymmetric membrane capsule could be used to accurately predict the 

	A double-membrane system of cefadroxil using ethyl cellulose as the inner membrane and cellulose acetate phthalate as the outer membrane has been developed by Philip et al. (31). The asymmetric membrane in a membrane capsule was prepared on glass pins using a two-step phase-inversion process. The first step was to form a nondisintegrating, asymmetric membrane capsule and the second step involved formation of a pH-sensitive, disintegrating, asymmetric membrane formed over the nondisintegrating membrane. This double-membrane formulation was able to delay the release of cefadroxil for the first two hours in the gastric medium and provide controlled release in the intestinal medium for an extended 12-hour period. Drug release was independent of pH and agitation intensity and followed zero-order release kinetics.

	More recently, Garg et al. reported on the development of asymmetric membrane capsules with two compartments for simultaneous delivery of two poorly soluble antihypertensive drugs, atenolol and amlodipine (32). Scanning electron microscopy showed a dense outer region and a porous inner region of the asymmetric membrane before dissolution. Pore size of the outer and inner layers increased after dissolution. Buffering agents were used to increase the solubility of atenolol and amlodipine. The formulation followed zero-order release kinetics, which was not affected by the agitation intensity of the dissolution fluid. Drug release was dependent on the diffusion rate of the drug across the membrane and the osmotic pressure. The effect of membrane thickness on dissolution fluid entering the asymmetric membrane capsule showed that as the membrane thickness increased, the volume of dissolution fluid entering into the system decreased.

	A gastroretentive asymmetric membrane capsule of famotidine was recently developed by Guan et al. (33). The drug is used for the treatment of duodenal, gastric and peptic ulcers. It has a relatively short half-life (3 h) and a low bioavailability (45–50%). Increasing gastric residence time would allow the drug to penetrate through the gastric mucus layer and produce a more pronounced effect. Polyethylene oxide was used as floating agent in the formulation. Pharmacokinetic studies in beagle dogs showed that the gastroretentive asymmetric membrane capsule displayed complete drug delivery with zero-order release kinetics and a 12-hour floating time. The system had the ability to prolong drug action, minimize dosing frequency, and reduce the average peak plasma concentration.

	Chauhan et al. also reported on the design of a floating asymmetric membrane capsule for site-specific delivery of ranitidine in a controlled manner (34). Ranitidine was given 150 mg twice daily or 300 mg once daily as an oral dosage form. Dosing has to be increased to 150 mg 4–5 times a day for the treatment of endoscopically diagnosed erosive esophagitis. The conventional formulations could only inhibit acid secretion for up to 5 hours, hence, requiring frequent dosing, which would cause fluctuations of drug levels in the plasma. The aim was to develop a buoyant asymmetric capsule with density less than the gastric fluid for controlled release of ranitidine in the gastric cavity. The capsule shell was prepared by the phase-inversion process wherein the polymeric membrane was precipitated on glass pins by dipping them in a solution of cellulose acetate followed by quenching. The solubility of ranitidine was suppressed by the ion effect, using optimized coated sodium chloride crystals as a formulation component. Drug release with zero-order kinetics was achieved and the asymmetric membrane capsule demonstrated floating ability for up to 12 hours.


	Osmotic systems will continue to play an important role in controlled-release drug delivery for decades to come. Today, there is available a wide range of osmotic drug-delivery systems that can be adapted to various drug properties and dosage requirements. The area of controlled-release remains a challenge, but advances in technology promise bright prospects for the future of healthcare.


	1. S.I. Shen, B.R. Jasti and X. Li, "Design of Controlled Release Drug Delivery Systems," in 

Standard Handbook of Biomedical Engineering

 & Design, M Kutz Ed. (McGraw-Hill, New York, 2003), pp. 221-235.

	2. N. Basta, Pharmaceutical Commerce website, "Drug Delivery Technologies for Controlled Release Score with Manufacturers," 

	3. R.K. Verma, D.M. Krishna and S. Garg, 

	6. R.A. Siegel and M.J. Rathbone, "Overview of Controlled Release Mechanisms," in 

Fundamentals and Applications of Controlled Release Drug Delivery

, J. Siepmann, R.A. Siegel and M.J. Rathbone Eds. (Springer, New York, 2012), pp. 19-43.

	8. A. Gauniya (2007), Pharmainfo website, "A Review on Latest Advancement in Patented Controlled/Sustained Release Drug Delivery System," 

	9. D. Barbieri and E. Tocce, "Optimizing Controlled Release: The Use of Osmotic Oral Delivery Systems," 

	13. H.M. Prajapati, S.T. Prajapati and C.N. Patel, Int. 

	16. F. Theeuwes, "Osmotic System for Delivering Selected Beneficial Agents Having Varying Degrees of Solubility," US Patent 4111201 (Sept 1978).

	17. R. Cortese and F. Theeuwes, "Osmotic Device with Hydrogel Driving Member,: US Patent 4327725 (May 1982).

	18. G.M. Zentner, G.S. Rork, and K.J. Himmelstein, 

	19. G.M. Zentner, G.S. Rork and K.J. Himmelstein, "Controlled Porosity Osmotic Pump," European Patent 0169105 B1 (Aug 1991).

	20. A.G. Thombre, G.M. Zentner, K.J. Himmelstein, 

	22. G.M. Zentner, G. A. McClelland and S.C. Sutton, 

	29. N. G. Gobade, M. Koland and K. H. Harish, Ind

	31. A.K. Philip, K. Pathak, and P. Shakya, 

	34. M.S. Chauhan, A. Kumar and K. Pathak, 

Osmotic systems offer versatility for delivering drugs with varied properties and dosage requirements.

Controlling Drug Release Through Osmotic Systems

, organised by UBM Live, is calling for entries to the annual CPhI Pharma Awards as it celebrates its 10th consecutive year. Open to the entire pharma industry for the first time, the awards honour pharma innovators across three categories—formulation, process development and packaging—with one winner for each award. The winners will be announced on 22nd October during the CPhI Worldwide 2013 exhibition at the Messe Frankfurt.  

Andrew Pert, Pharma Brand Director, noted that the CPhI Pharma Awards present an ideal opportunity to share exciting, breakthrough innovations to the pharmaceutical industry. “We are proud to be entering our 10th year of running the awards to acknowledge and recognise the sheer determination and efforts that companies pour into their work,” said Pert. “Not only do companies receive the recognition that they deserve for their outstanding innovations, but entry into the Pharma Awards also gives unrivalled exposure to the media, whilst raising company profiles amongst key pharmaceutical industry professionals and VIPs.”  

Last year at the Feria de Madrid in Spain, Haemopharm Healthcare won the gold award in the Best Innovation category for their needle free vial closure- designed to connect a syringe and vial without any further components; the innovative needle-free system facilitated an easier administration of parenteral drugs. Merck Millipore took silver for their drug delivery platform using silica, which takes full advantage of the large surface area and good transport properties that silica possesses. The bronze award went to Bioclin for its Multi-Oral Remin remineralization gel, applied in the oral cavity to treat and prevent bleeding gums and tooth erosion. 

CPhI is now accepting applications for the 2013 CPhI Pharma Awards until Friday 26th July. Entries are open to individuals and companies who have developed innovations in pharma over the past year. For more information, or to submit an award entry, please visit 

Entries open to any company across three categories - formulation, process development and best packaging.

2013 CPhI Pharma Awards Now Open

Lundbeck and eight other pharmaceutical companies have been fined a total of €146 million for delaying generic entry of the blockbuster antidepressant, Celexa (citalopram), into the market.

Lundbeck and eight other pharmaceutical companies have been fined a total of €146 million by the European Commission (EC) for delaying generic entry of the blockbuster antidepressant, Celexa (citalopram), into the market. 

Following a three-year investigation on Lundbeck, the EC concluded that an agreement between Lundbeck and several generic drugmakers, which effectively prevented cheaper generic versions of Celexa from entering the market, was a violation of the EU antitrust rules that prohibit anticompetitive agreements (Article 101 of the Treaty on the Functioning of the European Union – TFEU). Lundbeck incurred a fine of €93.8 million, while the other generic companies involved in the infringement, including Alpharma (now part of Zoetis), Merck KGaA, Generics UK (part of Mylan), Actavis unit Arrow and Ranbaxy, were fined a total of €52.2 million. 

"It is unacceptable that a company pays off its competitors to stay out of its market and delay the entry of cheaper medicines. Agreements of this type directly harm patients and national health systems, which are already under tight budgetary constraints. The Commission will not tolerate such anticompetitive practices," said Joaquín Almunia, vice-president of the EC, in a 

Celexa was Lundbeck's best-selling product for many years. Following the expiry of Lundbeck’s basic patent for the citalopram molecule, generics could have entered the market but the Danish drugmaker paid incentives to generic manufacturers, such as cash sums and stock purchases, to keep their generic versions of the drug off the market. Lundbeck also offered guaranteed profits as part of distribution agreement, according to the EC. The EC’s fines were based on its 2006 guidelines on fines (IP/06/857 and MEMO/06/256). 

Lundbeck and eight other pharmaceutical companies have been fined for delaying generic entry of the blockbuster antidepressant, Celexa (citalopram), into the market.