Plop, fizz … fizzle

How the “fizz, fizz” part is all too often missing in today’s new drug formulations

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Dr. Sami Karaboni, who works in formulations at XenoPortInc. after prior experience in the same capacity with Merck & Co. Inc.,estimates that 70 percent of new drugs exhibit poor dissolutioncharacteristics. As biopharmaceuticals such as XenoPort's recently U.S. Foodand Drug Administration (FDA)-approved Horizant continue to make greater inroads,solubility is likely to remain a significant challenge for pharmaceuticalscientists and chemical engineers like Karaboni. Hot-melt extrusion,spray-drying, nanomilling, a range of adhesives and coatings, dissolvablefilms, microneedles, magnetically controlled pills, polysaccharides and otherinnovations are all being investigated for use to help dissolve recalcitrantmolecules.
Karaboni points out that both nanomilling and spray dryingproduce very small particle sizes to enhance dissolution. APIs can also be inliquid form, he notes, in capsules that also contain one or two surfactants.The active ingredient needs to be thermodynamically stable, which he admits isoften tough to achieve. XenoPort also takes a molecule with poor solubility orabsorption and adds a moiety that, for example, converts a hydrophobic moleculeto one that is hydrophilic. This prodrug may be 20-times more soluble than theparent molecule which increases absorption and reduce GI irritation because itdoesn't stay against the gut lining as long. Then, in the bloodstream, thesolubility-promoting moiety that was added is released and the drug can exertits therapeutic effect. 
Even the College of Natural Resources at Virginia Tech hasbecome involved in drug delivery. A Virginia Tech-developed advanced drugdelivery system that can help HIV and tuberculosis patients may soon beproduced. Pharmaceutical companies have contacted Kevin Edgar, a professor inthe College of Natural Resources' Department of Wood Science and ForestProducts, about the polysaccharide-based drug-delivery system that he reportsallows oral antibacterial drugs to be slowly absorbed in the bloodstream,reducing costs, side effects and variability between patients. The complexsugars of certain polysaccharides help to dissolve otherwise insoluble drugsand enhance their ability to get from the gut into the bloodstream. Thisresults in lower dosages, given less often, which increases the number ofpatients who can be treated for a given amount of money.
"Oncology has the most promise with this type of drugdelivery system," says Edgar. "We started with viral medications because thematerials are safer, but we are almost ready to take on the more complex anddifficult challenge of drugs that treat cancer."
Edgar and collaborator Dr. Lynne Taylor, a solid-phasephysical chemist at Purdue University, are still discovering the rules of howto correctly design polysaccharide-based delivery systems to work with specificdrugs and combat individual diseases. This enhanced understanding has thepotential to foster faster, more effective drug development and create theability to tackle even more challenging problems, such as putting cancer drugsinto pill form.
Edgar explains that polysaccharides based on cellulose,although not exclusively, can be converted into amorphous-matrix drug deliverysystems.
"Dispersing drugs in this high energy amorphous form canresult in more than three orders of magnitude enhancement of solubility," hesays.
Cellulose is very hydrophilic and crystalline, Edgar pointsout. Modifying it to perform as a drug-delivery system requires substitution atthe molecular level that is not too regular or it will become crystallineagain. Differential pH found in the stomach and intestine can be used totrigger drug release.
In the third world, he notes, drug cost and availability are"hugely important," and he thinks polysaccharides may be one answer toimproving bioavailability and reducing dosage, side effects and cost.
Post-surgical pain
DURECT Corp.'s POSIDUR is a long-acting local anestheticbeing developed for the treatment of post-surgical pain. It is administeredduring surgery to the surgical site, where it continuously releases therapeuticlevels of bupivacaine in a controlled fashion, providing up to 72 hours ofuninterrupted local analgesia. This investigational drug is currently in PhaseIII clinical studies in the United States and in Phase II clinical testing inEurope.
The company cites data published by the Center for DiseaseControl and Prevention showing there are approximately 72 million ambulatoryand inpatient procedures performed in the United States annually.Epidemiological studies indicate that almost all surgical patients experiencepostoperative pain, with 50 to 75 percent reporting inadequate pain relief.
The current standard of care for post-surgical pain includesoral opiate and non-opiate analgesics, transdermal opiate patches and musclerelaxants. While oral analgesics can effectively control post-surgical pain,they commonly cause side effects such as drowsiness, constipation and cognitiveimpairment. Effective pain management can be compromised if patients fail toadhere 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 shortduration of action. POSIDUR may reduce use of narcotics for post-operativepain, which should in turn reduce opioid-related side effects.
Squishable gel
DURECT'S Remoxy is an oral, long-acting oxycodone gelatincapsule under development with Pain Therapeutics, for which DURECT has licensedexclusive, worldwide, development and commercialization rights under adevelopment and license agreement entered into in December 2002, explainsMatthew Hogan, the company's chief financial officer. Subsequently, PainTherapeutics has sublicensed the commercialization rights of Remoxy to KingPharmaceuticals, which in turn was acquired by Pfizer in February.
"Remoxy is formulated with our ORADUR technology," says JoeStauffer, the company's chief medical officer. "It traps the API in viscous,molasses-like material inside a gel cap, which combines properties designed toresist common methods of prescription drug misuse and abuse with theconvenience of twice-a-day dosing of oxycodone."
Stauffer notes that opioids are a gateway to drug abuse, andthat the FDA has actively encouraged drug companies to develop delivery systemsthat will reduce abuse. Extended release oxycodone oral painkillers achievedannual sales greater than $3 billion in 2010 in the United States, whileemergency room visits increased from more than 40,000 in 2004 to more than100,000 in 2008.
The key to the ORADUR platform is sucrose acetate isoburate,which in its native state resembles molasses, Stauffer says. When abusersattempt to crush the intact capsule, it deforms under the pressure but does notrelease its contents. In a similar manner, when the attempt is made to dissolvethe gel cap in water or alcohol, plasma levels of the API oxycodone never reachthat needed to produce an opioid "high."
Nanoparticles, DNA& DOX
Meanwhile, Dr. James Dabrowiak, a professor of bioinorganicchemistry, and Dr. Mathew Maye, also a chemistry professor, are working atSyracuse University to combine their skills with inorganic complexes asdrugs—platinum complexes use in chemotherapy, for example—with nanoscience, thespecialties of Dabrowiak and Maye, respectively. They are designing and testingnanoparticles to absorb many drug molecules and then release them at the tumorsite when triggered, for example by certain types of light. The drug they'reusing, doxorubicin or DOX, is FDA-approved and is currently used againstcancers of the breast and others.
"Our particles are multilayer gold, with double-stranded DNAcells in GTC sequence,  intercalated withthe 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 isconfident that they can design particles that will bind to several hundred drugmolecules. They are using about 100 drug molecules per particle in a current in-vitro toxicology study where they arecomparing the potency of the nanoparticle-drug combination to that of DOXalone. Then, depending on the results, additional funding will be sought inorder to move into animal studies.
The team makes all of its own nanoparticles and isexperimenting with different sizes, shapes and compositions, which are storedas colloidal dispersions. Sizes vary from 5 to 100 nm and shapes from spheresto tube rods. Depending on their physical characteristics, the nanoparticlesgravitate to different parts of the body, which may ultimately be useful indirecting therapeutic agents to where they are needed most.
Magnetic attraction
The problem with administering many medications orally isthat a pill often will not dissolve at exactly the right site in thegastrointestinal tract where the medicine can be absorbed into the bloodstream.A new magnetic pill system developed by Brown University researchers couldsolve the problem by safely holding a pill in place in the intestine whereverit needs to be.
The scientists described the harmless operation of theirmagnetic pill system in rats in a recent online issue of the Proceedings of the National Academy ofSciences. Applied to people in the future, says senior author EdithMathiowitz, the technology could provide a new way to deliver many drugs topatients, including those with cancer or diabetes. It could also act as apowerful research tool to help scientists understand exactly where in theintestine different drugs are best absorbed.
As a magnet moves closer and farther from a small magneticpill 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 maximizeabsorption of the medicine it carries.
"With this technology, you can now tell where the pill isplaced, take some blood samples and know exactly if the pill being in thisregion really enhances the bioavailability of the medicine in the body," saysMathiowitz, professor of medical science in Brown University's Department ofMolecular Pharmacology, Physiology and Biotechnology. "It's a completely newway to design a drug delivery system."

The two main components of the system areconventional-looking gelatin capsules that contain a tiny magnet, and anexternal magnet that can precisely sense the force between it and the pill andvary that force, as needed, to hold the pill in place. The external magnet cansense the pill's position, but because the pill is opaque to x-rays, theresearchers are also able to see the pill in the rat's bodies during theirstudies.
The system is not the first attempt to guide pillsmagnetically, but it is the first one in which scientists can control theforces on a pill so that it's safe to use in the body. They designed theirsystem to sense the position of pills and hold them there with a minimum offorce.
"The most important thing is to be able to monitor theforces that you exert on the pill in order to avoid damage to the surroundingtissue," says Mathiowitz. "If you apply a little more than necessary force, yourpill will be pulled to the external magnet, and this is a problem."
To accomplish this the team, including lead author andformer graduate student Bryan Laulicht, took careful measurements and built anexternal magnet system with sophisticated computer control and feedbackmechanisms.
"The greatest challenges were quantifying the required forcerange for maintaining a magnetic pill in the small intestines and constructinga 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 1/60thof what would be damaging. The next step in the research is to begin deliveringdrugs using the system and testing their absorption, Mathiowitz and Laulichtsay.
"Then it will move to larger animal models and ultimatelyinto the clinic," Laulicht adds. "It is my hope that magnetic pill retentionwill be used to enable oral drug delivery solutions to previously unmet medicalneeds."
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 bothlocalized and systemic drug delivery, says Martha Sloboda, business manager atARx.
She says the platform continues to be embraced by patientsand caregivers alike for the desired benefits of ease-of-delivery, portabilityand accurate dosing. Since the first commercial launch of OTFs for systemicdrug delivery in 2004, the platform has evolved as more pharmaceuticalresearchers evaluate ways to apply the benefits of this technology across moremarkets and therapeutic classes. OTFs offer fast, accurate dosing in a safe,efficacious format that is convenient and portable, without the need for wateror measuring devices.
As a result of these efforts, researchers have extended theuse of the technology into ethical, nutritional, and veterinary applications.Advances in chemistries and the manufacturing processes employed during theformulation and scale-up of this technology play a significant role inadvancing the potential of OTFs beyond immediate-release oral applications. 
When selecting an OTF to replace an existing product, thefilm's dissolution rate, material selection and absorption rate are allconsidered so that an equivalent or an improved product profile may be producedover existing liquids, capsules and tablets. Ongoing research is extending the dissolvable film technology to morecomplicated systems for modified or controlled release.
In some cases, there is convergence with transdermaltechnology that enables films to have more tangible adhesive properties such asincreased dwell time in the mouth or other alternative delivery sites. Thiswork relies on a strong understanding of the suitability, compatibility andavailability of material sets. Formulators can modify a film's physicalproperties such as dissolution rate, thickness, material composition, tastemasking and API absorption rates to broaden the potential of this technologyfor application into other areas, including, topical applications, as bindingagents, and as buccal, sublingual and mucosal delivery systems. 
Looking forward, the use of micronized and nanoparticle APIsin OTFs opens the door for potentially more effective drug-delivery methods.With the increased surface area of the API and the larger direct-contactsurface area of the film, there is the possibility to improve bioavailabilityand to increase uptake from the mucosal surface. By modifying the residencetime of the OTF on the mucosal tissue in conjunction with the micronized ornano-API, early stage work by ARx suggests that this type of system has thepotential to effectively deliver drugs in a shorter timeframe.
Transdermal patches
Since the introduction of the scopolamine transdermal patchin the late 1970s for motion sickness, pharmaceutical-grade, pressure-sensitiveadhesives have played a critical role in the function and accurate delivery oftransdermal drug delivery systems (TDDS). Today, transdermal patches address arange of treatments that is expanding beyond the delivery of compounds with lowmolecular weight, such as those that provide treatment for short-termconditions like motion sickness, to longer-term therapies like hormonereplacement.
Passive transdermal patches, such as the nicotine patch, areapplied to a patient's skin, to safely and comfortably deliver a defined doseof medication over a controlled period of time as the drug is absorbed throughthe skin into the bloodstream. Scientists are developing new patches to treatchronic conditions through the continued use of a daily delivery device.Examples of this include the first rivastigmine patch for the treatment ofAlzheimer's disease, and the rotigotine patch that recently launched in Europeto treat some forms of Parkinson's disease.
Fueling this trend are drug manufacturers' efforts to extendlifecycle applications for solid-dose formats coming off patent protection. Thepatch platform is also being investigated as an alternative delivery system forpeptide drugs that are vulnerable to proteolytic attack and tend to undergoaggregation, adsorption and denaturation. 
While transdermal patches offer many advantages, passivesystems are restricted to low-dosage lipophilic and low molecular-weightmolecules (<500 Daltons). Work to expand the range of use for passive TDDSfirst began with incorporating chemical penetration enhancers to decreasebarrier resistance of the stratum coreum layer of the skin, to allow deliveryof higher molecular weight compounds. An adhesive patch may include one or morecompounds to increase diffusion, including: sulfoxides, alkyl-azones,pyrrolidones, alcohols and alkanols, glycols, surfactants and terpenes.
Much of the current growth for transdermal drug delivery isfocused on active systems to meet the demand of delivering drug compounds withhigher molecular weights including proteins such as vaccines. As such, thetechnology has evolved into active TDDS, including applications usingultrasound, microneedles, iontophoresis or other mechanical treatment of theskin to drive larger molecule drugs through the stratum corneum.
As transdermal product designs and capabilities continue toevolve, adhesive manufacturers are embracing opportunities to formulate highlyspecialized pressure-sensitive adhesives, coatings and related polymertechnologies to meet the requirements of these delivery systems. Some adhesivetechnologies used in either existing commercial products or programs in variousstages of clinical developments include:
  • Conductiveadhesives, which overcome the traditional insulative properties of an adhesiveto allow current or ion transport (z-direction);
  • High-moisturevapor transmission rate (MVTR) polymer coatings, which absorb moisture and/orallow moisture to pass through the coatings and thus away from the surface ofthe skin;Porousadhesives, which are coated systems with tailored pore size/density to allowcontrolled fluid transfer or doping to create biphasic formulations (like anadhesive membrane with chemically and mechanically stable pore geometry);
  • Hydrogels,which are high-fluid content coatings to form an interface between skin andsensing element (typically conductive);
  • Molecularly imprinted polymers(MIPs) that are synthesized with the unique chemical and physical "imprint" ofa target molecule. MIP compounds can be formulated into adhesive coatings tocapture or release target molecules in diagnostic or drug deliveryapplications. 
Iontophoretic devices
Iontophoretic devices offer a non-invasive alternative fordelivering therapeutic substances via the electrotransport of molecules thatwould not normally diffuse across the skin. A small electric current passesthrough the patient's skin, between a positively charged cathode and anegatively charged anode. The drug or active substance is located at one of theelectrode sites, depending upon the drug's polarity. The active electroderepels the charged drug, forcing it into the skin by electrorepulsion, where itis picked up by the blood or lymph system. Charged drug molecules are attractedto electrodes of the opposite polarity. The rate of drug delivery is controlledby the strength of the electrical current to transport the drug rapidly andaccurately, via on-demand dosing or patterned/modulated drug delivery.
Needle-free delivery of therapeutics and vaccines canpotentially address the growing global issues associated with diseases that arepassed intravenously through the improper use and disposal of needles.Patch-based, needle-free immunization systems for the safe and convenientdelivery of vaccines are currently in clinical trials. The construction of thevaccine patch is similar to that of a transdermal patch, but contains anantigen and an immune-boosting adjuvant to stimulate the body's immune system.The patch works by delivering the vaccine to a group of antigen-presentingcells in the skin called Langerhans cells, which transport the vaccine tonearby lymph nodes to produce a sustained immune response.
Microneedle patches
Adhesive and substrate thickness control from lot to lot iscrucial for applications where any thickness variations can negatively impactdosing. For example, some microprojection designs involve an array ofdrug-treated microneedles—solid metal, hollow metal or polymer needles—that areadhered to the skin with a PSA. The combined thickness of the device's componentscontrols how deeply the microneedles penetrate the skin to release the druginto the bloodstream or lymphatic system. If penetration is too shallow, theuser may not receive the proper dose; alternatively, if the needles penetratetoo deeply, the user could experience some discomfort or pain.
Extended wear patches
The majority of transdermal patches available today areremoved within 24 hours; however, extended-wear patches can be envisioned fortime periods up to seven days. To ensure a healthy skin environment for properdosing, it is important that the adhesives selected for longer-term wear enablethe skin to breathe to prevent overhydrating or skin maceration, which canpotentially affect drug bioavailability.

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