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Plop, fizz … fizzle
May 2011
by Lloyd Dunlap  |  Email the author


Dr. Sami Karaboni, who works in formulations at XenoPort Inc. after prior experience in the same capacity with Merck & Co. Inc., estimates that 70 percent of new drugs exhibit poor dissolution characteristics. As biopharmaceuticals such as XenoPort's recently U.S. Food and Drug Administration (FDA)-approved Horizant continue to make greater inroads, solubility is likely to remain a significant challenge for pharmaceutical scientists and chemical engineers like Karaboni. Hot-melt extrusion, spray-drying, nanomilling, a range of adhesives and coatings, dissolvable films, microneedles, magnetically controlled pills, polysaccharides and other innovations are all being investigated for use to help dissolve recalcitrant molecules.  
Karaboni points out that both nanomilling and spray drying produce very small particle sizes to enhance dissolution. APIs can also be in liquid form, he notes, in capsules that also contain one or two surfactants. The active ingredient needs to be thermodynamically stable, which he admits is often tough to achieve. XenoPort also takes a molecule with poor solubility or absorption and adds a moiety that, for example, converts a hydrophobic molecule to one that is hydrophilic. This prodrug may be 20- times more soluble than the parent molecule which increases absorption and reduce GI irritation because it doesn't stay against the gut lining as long. Then, in the bloodstream, the solubility-promoting moiety that was added is released and the drug can exert its therapeutic effect.
Polysaccharide drug-delivery  
Even the College of Natural Resources at Virginia Tech has become involved in drug delivery. A Virginia Tech-developed advanced drug delivery system that can help HIV and tuberculosis patients may soon be produced. Pharmaceutical companies have contacted Kevin Edgar, a professor in the College of Natural Resources' Department of Wood Science and Forest Products, about the polysaccharide-based drug-delivery system that he reports allows oral antibacterial drugs to be slowly absorbed in the bloodstream, reducing costs, side effects and variability between patients. The complex sugars of certain polysaccharides help to dissolve otherwise insoluble drugs and enhance their ability to get from the gut into the bloodstream. This results in lower dosages, given less often, which increases the number of patients who can be treated for a given amount of money.  
"Oncology has the most promise with this type of drug delivery system," says Edgar. "We started with viral medications because the materials are safer, but we are almost ready to take on the more complex and difficult challenge of drugs that treat cancer."  
Edgar and collaborator Dr. Lynne Taylor, a solid-phase physical chemist at Purdue University, are still discovering the rules of how to correctly design polysaccharide-based delivery systems to work with specific drugs and combat individual diseases. This enhanced understanding has the potential to foster faster, more effective drug development and create the ability to tackle even more challenging problems, such as putting cancer drugs into pill form.  
Edgar explains that polysaccharides based on cellulose, although not exclusively, can be converted into amorphous-matrix drug delivery systems.
"Dispersing drugs in this high energy amorphous form can result in more than three orders of magnitude enhancement of solubility," he says.  
Cellulose is very hydrophilic and crystalline, Edgar points out. Modifying it to perform as a drug-delivery system requires substitution at the molecular level that is not too regular or it will become crystalline again. Differential pH found in the stomach and intestine can be used to trigger drug release.
In the third world, he notes, drug cost and availability are "hugely important," and he thinks polysaccharides may be one answer to improving bioavailability and reducing dosage, side effects and cost.
Post-surgical pain
DURECT Corp.'s POSIDUR is a long-acting local anesthetic being developed for the treatment of post-surgical pain. It is administered during surgery to the surgical site, where it continuously releases therapeutic levels of bupivacaine in a controlled fashion, providing up to 72 hours of uninterrupted local analgesia. This investigational drug is currently in Phase III clinical studies in the United States and in Phase II clinical testing in Europe.  
The company cites data published by the Center for Disease Control and Prevention showing there are approximately 72 million ambulatory and inpatient procedures performed in the United States annually. Epidemiological studies indicate that almost all surgical patients experience postoperative pain, with 50 to 75 percent reporting inadequate pain relief.  
The current standard of care for post-surgical pain includes oral opiate and non-opiate analgesics, transdermal opiate patches and muscle relaxants. While oral analgesics can effectively control post-surgical pain, they commonly cause side effects such as drowsiness, constipation and cognitive impairment. Effective pain management can be compromised if patients fail to adhere to recommended dosing regimens because they are sleeping or disoriented. Post-surgical pain can be treated effectively with local anesthetics; however, the usefulness of current conventional medications is limited by their short duration of action. POSIDUR may reduce use of narcotics for post-operative pain, which should in turn reduce opioid-related side effects.  
Squishable gel
DURECT'S Remoxy is an oral, long-acting oxycodone gelatin capsule under development with Pain Therapeutics, for which DURECT has licensed exclusive, worldwide, development and commercialization rights under a development and license agreement entered into in December 2002, explains Matthew Hogan, the company's chief financial officer. Subsequently, Pain Therapeutics has sublicensed the commercialization rights of Remoxy to King Pharmaceuticals, which in turn was acquired by Pfizer in February.
"Remoxy is formulated with our ORADUR technology," says Joe Stauffer, the company's chief medical officer. "It traps the API in viscous, molasses-like material inside a gel cap, which combines properties designed to resist common methods of prescription drug misuse and abuse with the convenience of twice-a-day dosing of oxycodone."  
Stauffer notes that opioids are a gateway to drug abuse, and that the FDA has actively encouraged drug companies to develop delivery systems that will reduce abuse. Extended release oxycodone oral painkillers achieved annual sales greater than $3 billion in 2010 in the United States, while emergency room visits increased from more than 40,000 in 2004 to more than 100,000 in 2008.  
The key to the ORADUR platform is sucrose acetate isoburate, which in its native state resembles molasses, Stauffer says. When abusers attempt to crush the intact capsule, it deforms under the pressure but does not release its contents. In a similar manner, when the attempt is made to dissolve the gel cap in water or alcohol, plasma levels of the API oxycodone never reach that needed to produce an opioid "high."  
Nanoparticles, DNA & DOX
Meanwhile, Dr. James Dabrowiak, a professor of bioinorganic chemistry, and Dr. Mathew Maye, also a chemistry professor, are working at Syracuse University to combine their skills with inorganic complexes as drugs—platinum complexes use in chemotherapy, for example—with nanoscience, the specialties of Dabrowiak and Maye, respectively. They are designing and testing nanoparticles to absorb many drug molecules and then release them at the tumor site when triggered, for example by certain types of light. The drug they're using, doxorubicin or DOX, is FDA-approved and is currently used against cancers of the breast and others.  
"Our particles are multilayer gold, with double-stranded DNA cells in GTC sequence,  intercalated with the DOX drug," says Maye. The DNA makes the gold particle more biocompatible, he says, so the drug slides into the DNA, perfusing and binding. Maye is confident that they can design particles that will bind to several hundred drug molecules. They are using about 100 drug molecules per particle in a current in-vitro toxicology study where they are comparing the potency of the nanoparticle-drug combination to that of DOX alone. Then, depending on the results, additional funding will be sought in order to move into animal studies.
The team makes all of its own nanoparticles and is experimenting with different sizes, shapes and compositions, which are stored as colloidal dispersions. Sizes vary from 5 to 100 nm and shapes from spheres to tube rods. Depending on their physical characteristics, the nanoparticles gravitate to different parts of the body, which may ultimately be useful in directing therapeutic agents to where they are needed most.  
Magnetic attraction  
The problem with administering many medications orally is that a pill often will not dissolve at exactly the right site in the gastrointestinal tract where the medicine can be absorbed into the bloodstream. A new magnetic pill system developed by Brown University researchers could solve the problem by safely holding a pill in place in the intestine wherever it needs to be.  
The scientists described the harmless operation of their magnetic pill system in rats in a recent online issue of the Proceedings of the National Academy of Sciences. Applied to people in the future, says senior author Edith Mathiowitz, the technology could provide a new way to deliver many drugs to patients, including those with cancer or diabetes. It could also act as a powerful research tool to help scientists understand exactly where in the intestine different drugs are best absorbed.  
As a magnet moves closer and farther from a small magnetic pill in a rat's intestine, it keeps track of the force between it and the pill. The technology can be used to safely hold a pill in the right place to maximize absorption of the medicine it carries.  
"With this technology, you can now tell where the pill is placed, take some blood samples and know exactly if the pill being in this region really enhances the bioavailability of the medicine in the body," says Mathiowitz, professor of medical science in Brown University's Department of Molecular Pharmacology, Physiology and Biotechnology. "It's a completely new way to design a drug delivery system."

The two main components of the system are conventional-looking gelatin capsules that contain a tiny magnet, and an external magnet that can precisely sense the force between it and the pill and vary that force, as needed, to hold the pill in place. The external magnet can sense the pill's position, but because the pill is opaque to x-rays, the researchers are also able to see the pill in the rat's bodies during their studies.
The system is not the first attempt to guide pills magnetically, but it is the first one in which scientists can control the forces on a pill so that it's safe to use in the body. They designed their system to sense the position of pills and hold them there with a minimum of force.  
"The most important thing is to be able to monitor the forces that you exert on the pill in order to avoid damage to the surrounding tissue," says Mathiowitz. "If you apply a little more than necessary force, your pill will be pulled to the external magnet, and this is a problem."  
To accomplish this the team, including lead author and former graduate student Bryan Laulicht, took careful measurements and built an external magnet system with sophisticated computer control and feedback mechanisms.  
"The greatest challenges were quantifying the required force range for maintaining a magnetic pill in the small intestines and constructing a device that could maintain intermagnetic forces within that range," says Laulicht, who is now a postdoctoral scholar at MIT.  
Even after holding a pill in place for 12 hours in the rats, the system applied a pressure on the intestinal wall that was less than 1/60th of what would be damaging. The next step in the research is to begin delivering drugs using the system and testing their absorption, Mathiowitz and Laulicht say.  
"Then it will move to larger animal models and ultimately into the clinic," Laulicht adds. "It is my hope that magnetic pill retention will be used to enable oral drug delivery solutions to previously unmet medical needs."
Dissolvable films
ARx LLC, a wholly owned subsidiary of Adhesives Research, specializes in dissolvable film technology that is tailored for oral delivery. The dissolvable oral thin film (OTF) platform is proven and accepted for both localized and systemic drug delivery, says Martha Sloboda, business manager at ARx.  
She says the platform continues to be embraced by patients and caregivers alike for the desired benefits of ease-of-delivery, portability and accurate dosing. Since the first commercial launch of OTFs for systemic drug delivery in 2004, the platform has evolved as more pharmaceutical researchers evaluate ways to apply the benefits of this technology across more markets and therapeutic classes. OTFs offer fast, accurate dosing in a safe, efficacious format that is convenient and portable, without the need for water or measuring devices.  
As a result of these efforts, researchers have extended the use of the technology into ethical, nutritional, and veterinary applications. Advances in chemistries and the manufacturing processes employed during the formulation and scale-up of this technology play a significant role in advancing the potential of OTFs beyond immediate-release oral applications.
When selecting an OTF to replace an existing product, the film's dissolution rate, material selection and absorption rate are all considered so that an equivalent or an improved product profile may be produced over existing liquids, capsules and tablets.  Ongoing research is extending the dissolvable film technology to more complicated systems for modified or controlled release.
In some cases, there is convergence with transdermal technology that enables films to have more tangible adhesive properties such as increased dwell time in the mouth or other alternative delivery sites. This work relies on a strong understanding of the suitability, compatibility and availability of material sets. Formulators can modify a film's physical properties such as dissolution rate, thickness, material composition, taste masking and API absorption rates to broaden the potential of this technology for application into other areas, including, topical applications, as binding agents, and as buccal, sublingual and mucosal delivery systems.
Looking forward, the use of micronized and nanoparticle APIs in OTFs opens the door for potentially more effective drug-delivery methods. With the increased surface area of the API and the larger direct-contact surface area of the film, there is the possibility to improve bioavailability and to increase uptake from the mucosal surface. By modifying the residence time of the OTF on the mucosal tissue in conjunction with the micronized or nano-API, early stage work by ARx suggests that this type of system has the potential to effectively deliver drugs in a shorter timeframe.  
Transdermal patches  
Since the introduction of the scopolamine transdermal patch in the late 1970s for motion sickness, pharmaceutical-grade, pressure-sensitive adhesives have played a critical role in the function and accurate delivery of transdermal drug delivery systems (TDDS). Today, transdermal patches address a range of treatments that is expanding beyond the delivery of compounds with low molecular weight, such as those that provide treatment for short-term conditions like motion sickness, to longer-term therapies like hormone replacement.  
Passive transdermal patches, such as the nicotine patch, are applied to a patient's skin, to safely and comfortably deliver a defined dose of medication over a controlled period of time as the drug is absorbed through the skin into the bloodstream. Scientists are developing new patches to treat chronic conditions through the continued use of a daily delivery device. Examples of this include the first rivastigmine patch for the treatment of Alzheimer's disease, and the rotigotine patch that recently launched in Europe to treat some forms of Parkinson's disease.
Fueling this trend are drug manufacturers' efforts to extend lifecycle applications for solid-dose formats coming off patent protection. The patch platform is also being investigated as an alternative delivery system for peptide drugs that are vulnerable to proteolytic attack and tend to undergo aggregation, adsorption and denaturation.
While transdermal patches offer many advantages, passive systems are restricted to low-dosage lipophilic and low molecular-weight molecules (<500 Daltons). Work to expand the range of use for passive TDDS first began with incorporating chemical penetration enhancers to decrease barrier resistance of the stratum coreum layer of the skin, to allow delivery of higher molecular weight compounds. An adhesive patch may include one or more compounds to increase diffusion, including: sulfoxides, alkyl-azones, pyrrolidones, alcohols and alkanols, glycols, surfactants and terpenes.
Much of the current growth for transdermal drug delivery is focused on active systems to meet the demand of delivering drug compounds with higher molecular weights including proteins such as vaccines. As such, the technology has evolved into active TDDS, including applications using ultrasound, microneedles, iontophoresis or other mechanical treatment of the skin to drive larger molecule drugs through the stratum corneum.  
As transdermal product designs and capabilities continue to evolve, adhesive manufacturers are embracing opportunities to formulate highly specialized pressure-sensitive adhesives, coatings and related polymer technologies to meet the requirements of these delivery systems. Some adhesive technologies used in either existing commercial products or programs in various stages of clinical developments include:
  • Conductive adhesives, which overcome the traditional insulative properties of an adhesive to allow current or ion transport (z-direction);
  • High-moisture vapor transmission rate (MVTR) polymer coatings, which absorb moisture and/or allow moisture to pass through the coatings and thus away from the surface of the skin;Porous adhesives, which are coated systems with tailored pore size/density to allow controlled fluid transfer or doping to create biphasic formulations (like an adhesive membrane with chemically and mechanically stable pore geometry);
  • Hydrogels, which are high-fluid content coatings to form an interface between skin and sensing element (typically conductive);
  • Molecularly imprinted polymers (MIPs) that are synthesized with the unique chemical and physical "imprint" of a target molecule. MIP compounds can be formulated into adhesive coatings to capture or release target molecules in diagnostic or drug delivery applications. 
Iontophoretic devices  
Iontophoretic devices offer a non-invasive alternative for delivering therapeutic substances via the electrotransport of molecules that would not normally diffuse across the skin. A small electric current passes through the patient's skin, between a positively charged cathode and a negatively charged anode. The drug or active substance is located at one of the electrode sites, depending upon the drug's polarity. The active electrode repels the charged drug, forcing it into the skin by electrorepulsion, where it is picked up by the blood or lymph system. Charged drug molecules are attracted to electrodes of the opposite polarity. The rate of drug delivery is controlled by the strength of the electrical current to transport the drug rapidly and accurately, via on-demand dosing or patterned/modulated drug delivery.  
Needle-free delivery of therapeutics and vaccines can potentially address the growing global issues associated with diseases that are passed intravenously through the improper use and disposal of needles. Patch-based, needle-free immunization systems for the safe and convenient delivery of vaccines are currently in clinical trials. The construction of the vaccine patch is similar to that of a transdermal patch, but contains an antigen and an immune-boosting adjuvant to stimulate the body's immune system. The patch works by delivering the vaccine to a group of antigen-presenting cells in the skin called Langerhans cells, which transport the vaccine to nearby lymph nodes to produce a sustained immune response.  
Microneedle patches
Adhesive and substrate thickness control from lot to lot is crucial for applications where any thickness variations can negatively impact dosing. For example, some microprojection designs involve an array of drug-treated microneedles—solid metal, hollow metal or polymer needles—that are adhered to the skin with a PSA. The combined thickness of the device's components controls how deeply the microneedles penetrate the skin to release the drug into the bloodstream or lymphatic system. If penetration is too shallow, the user may not receive the proper dose; alternatively, if the needles penetrate too deeply, the user could experience some discomfort or pain.  
Extended wear patches  
The majority of transdermal patches available today are removed within 24 hours; however, extended-wear patches can be envisioned for time periods up to seven days. To ensure a healthy skin environment for proper dosing, it is important that the adhesives selected for longer-term wear enable the skin to breathe to prevent overhydrating or skin maceration, which can potentially affect drug bioavailability.
Code: E051130



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