DRUG DELIVERY – PLEX(TM) Local Drug Delivery Platform Enables Prolonged, Controlled-Release Medications
Common drugs are molecules that act via an interaction with their target molecule, within a specific location, in order to generate a specific therapeutic change. While systemic drug delivery is relatively convenient, it is often difficult to reach the target location due to limited extravasation from the bloodstream into the target tissue. There is often a need for higher dosages over time in order to maintain the requisite local concentration during the treatment period, which sometimes is not possible. The need for higher dosages increases the risk of toxicity and adverse side effects, which in some cases, are beyond acceptable limits. The situation becomes even more challenging when blood supply is minimal or preliminarily destroyed due to trauma or surgery. To overcome this major limitation, it is desirable to deliver active ingredients locally, targeting the medication directly to the disease site. This can be done by implanting a drug reservoir directly into the target area, and releasing the drug over the desired period and rate so as to be effective, while at the same time – non-toxic. Although highly desired, the release duration from the current local treatments is often too short to be effective. Furthermore, the release rate is often not controlled, and therefore, efficacy is compromised, and the risk of potential toxicity remains.
An optimal drug delivery system should be able to release drugs at a rate and profile that will support efficacy and reduce or eliminate potential toxicity, and should be able to do so over sufficient duration. Currently used drug delivery systems typically utilize either polymers or lipids, commonly in the form of liposomes. Whereas some of the polymer-based local drug delivery systems feature a long-lasting release, they also have the drawback of an initial high burst release. On the other hand, even though a liposome-based drug delivery system features a low burst release, it is still limited to a short-lasting release period.
Biodegradable polymers, such as poly (lactic-co-glycolic acid) (PLGA), chitosan, or collagen were tried as local drug delivery platforms. However, in many key indications, such polymeric drug delivery systems cannot maintain a constant and sufficient release rate of antibiotics over the prolonged period of time needed to fully eradicate the invading bacteria, for example.
Another major aspect that needs to be noticed is the stability of the entrapped drug within the reservoir. This is especially important to support the prolonged delivery of sensitive drugs. This major characteristic is not well covered by the current polymer-based local delivery, leading to the loss of the drug earlier than needed.
The PLEXTM (Polymer-Lipid Encapsulation matriX) platform is a matrix made of the combination of lipids and polymers (Figure 1). The substructure comprises alternating layers of polymers and lipids that entrap a therapeutic drug between them in order to form a protected reservoir that enables an effective localized drug delivery at the target site. The PLEX matrix protects the drug reservoirs in vivo, and enables prolonged delivery of sensitive drugs over periods ranging from days to several months.1 The application of PLEX technology enables optimizing drug treatment regimens by predetermining release rates as well as durations, a rare combination of attributes.
CONTROLLED & PROLONGED DELIVERY
The use of overall low drug doses is highly beneficial, from both safety and economic perspectives. The primary challenge is finding the right balance between administering low doses without compromising efficacy (Figure 2). PLEX significantly enhances efficacy by optimizing bioavailability of the active ingredient and permits the use of smaller drug doses over prolonged periods for greater safety. PLEX’s key attributes include the following:
Flexible Entrapment: The ability to accommodate many types of drugs, such as small molecules, peptides, proteins, and nucleic acids. Additionally, unstable and delicate drugs, such as heat-sensitive drugs and drugs that are sensitive to some organic solvents, pH levels or enzymes can also be encapsulated by PLEX. PLEX enables constant, controlled, prolonged delivery of all these different types of drugs.
Protected Reservoir: PLEX features a unique drug reservoir that protects the integrity of the encapsulated drug throughout its prolonged exposure to the hostile environment in the body, both from biological and water-related destruction.
Control Over the Release Profile: PLEX avoids an undesired effect of uncontrolled drug bursts resulting in enhanced safety and a preserved long-term reservoir.
Release Rate: PLEX can be predetermined to optimize the release rate of each drug according to the desired medical need. The release rate can be set to be a constant rate (zero-order kinetic) for most of the drug reservoir if so desired (Figure 3).
Release Duration: In order to improve efficacy, PLEX enables a predetermined and optimized drug-release period ranging from 1 day to several months.
Flexible Design: The technology permits local drug delivery in stand-alone products or even as coatings of medical devices, implants, or other substrates.
PLEXTM PLATFORM – BREADTH OF DRUG APPLICATIONS
Over 20 different drug types were encapsulated using PLEX, each of which demonstrated controlled zero-order kinetics release over prolonged periods. These include small molecules, such as dexamethasone, NSAIDs, and doxorubicin, peptides, proteins, and nucleic acids (Figure 4).
The advantages of our PLEX drug delivery system lie in its unique combined characteristics and attributes. The power of the PLEX technology is due to a unique combination of characteristics: a protected reservoir; a pre-designed release profile and controlled release rate; and the ability to tailor release duration. The power of PLEX is also in its versatility. It is suitable for use with many types of drugs ranging from small molecules and peptides, to proteins and even siRNA. The PLEX matrix can also enable the use of multiple drug types in a variety of combinations. Along with these combined advantages, the use of PLEX is also very practical from an industrial point of view. This is reflected by the following:
Off-the-Shelf Compounds: PLEX is composed of well-known components which are commercially available and extensively used in the pharmaceutical industry.
Supports a Simple Regulation Process: PLEX is composed of commercially available ingredients. No covalent bonds are created during the self-assembly of PLEX, either with the drug or between the formulating materials.
Simple & Mild Production Techniques: Production is performed under mild physical conditions and is based on self-assembly of chemical substances while synthesis is not required. The process is cost effective.
PLEX was validated in clinical settings via BonyPid-1000TM, a PLEX-based product comprising antibiotics loaded synthetic bone substitute intended for filling bone voids or defects while supporting an antibacterial protected bone healing process. BonyPid-1000 contains a broad-spectrum antibiotic (doxycycline) to reduce microbial colonization on the bone void filler. BonyPid-1000 has completed a clinical trial in severe open fractures indications, demonstrating excellent safety and efficacy results, including 0% infections in the target fractures and 0% amputations after 6-12-month follow-up (vs. an average of 25% and 7%, respectively, demonstrated in a historical control group and known literature).
Bone bacterial infection may result in bone destruction. Bone infections are difficult to cure due to the bone’s poor accessibility to systemically administrated antibiotics. This problem is compounded due to the fact that currently available local delivery systems may not be sufficiently effective due to their high burst and short lasting effect (Figure 5).
The clinical results in the use of BonyPid-1000 demonstrate that the 1-month release of doxycycline in a controlled manner provides a new, effective way for treating open fractures.
BonyPid-1000’s success attests to the safety and effectiveness of PLEX as a delivery system and indicates its applicability in other medical situations associated with local infections, such as in treating diabetic foot ulcers, infected implants, etc.
BonyPid-500 is a synthetic, doxycycline-eluting bone graft substitute, based on ß tri calcium phosphate (ßTCP) granules. BonyPid-500 is intended for use as a bone grafting material to fill, augment, or reconstruct periodontal or oral/maxillofacial defect, such as filling of periodontal/infrabony defects, ridge augmentation, filling of extraction sites (implant preparation/placement), and sinus lifts and filling of cystic cavities, while at the same time providing local infection protection.
Upon hydration in the body, the PLEX matrix gradually degrades and allows the antibiotic entrapped within PLEX layers to be released constantly into its surroundings while the bone filler acts as a scaffold to support osteoconductive bone recovery.
BonyPid-500 gradually resorbs and is replaced with new formed natural bone during the healing process. The antibacterial activity of the released antibiotic takes place in conjunction to the osteoconductive activity of the bone substitute, and prevents its potential rejection or early absorption by bacteria-related local bone infection. It also protects the surface of the graft from the development of biofilm. BonyPid-500 is now initiating clinical studies in patients with peri-implantitis.
D-PLEX is designed to combat Surgical Site Infections (SSI), which are the second most common hospital-acquired infections (HAI) and are considered a serious complication of surgical procedures. Such complications often lead to prolonged hospitalization, repeated surgeries, and may sometimes result in death.
D-PLEX is based on our PLEX platform and will provide a safe and effective local anti-bacterial (doxycycline) treatment of tissues or organs by administering a localized and protected drug reservoir during surgical procedures.
After implantation, the reservoir constantly releases the entrapped antibiotic over several weeks. In doing so, the D-PLEX reservoir allows for prolonged infection management and effective antibacterial activity, including management of hospital or community-acquired resistant bacteria that were most recently classified by the US government as a serious global threat.
Most recently, the US government classified community-acquired resistant bacteria as a serious global threat. In a rabbit study, PLEX-doxycycline coated implants were found to eradicate even doxycycline-resistant S. aureus bacteria.2
Systemic treatments are very effective for the treatment of inflamed conditions. However, wide use of anti-inflammatory agents is limited due to serious systemic side effects that include liver damage, heart disease, addiction, and pain. We are developing a PLEX-based platform for localized and controlled delivery of a very small, yet effective, dose of dexamethasone that carries minimal systemic side effects.
We have demonstrated safety and efficacy of a dexamethasone agent in a small animal model, thus completing a full pre-clinical package.
Systemic anti-cancer treatments have serious side effects. Our program is designed to treat cancer by extended localized release of common chemotherapeutic agents, such as doxorubicin. The program is aimed at reducing the overall dose of toxic agents for a prolonged local delivery, while achieving effectiveness that is at least comparable to systemic administration. We have successfully demonstrated eradication of cancerous cells in an animal model.
Current growth factors solutions have serious side effects, such as excessive bone growth. Our program, Growth Factors (BMP-2), is designed to promote bone growth by extended localized release of PLEX-formulated BMP-2 in spinal fusions or voids. By using only 1% of the overall commonly administered systemic dose in a prolonged, local delivery, we minimize potential side effects while achieving superior in vivo efficacy.
The potential therapeutic effect of various antibodies has been intensively studied throughout the past decades, and a variety of diseases and clinical disorders are treated by the administration of such drugs. A technological barrier to the use of antibody-based drugs is the need for practical, effective means for their local delivery location where blood supply is limited. Monoclonal antibodies were successfully encapsulated in PLEX, and were continuously released in vitro for at least 15 days. Animal studies are planned to start soon.
Pharmaceutical and biotechnology companies continuously develop new drugs to address the ever-changing medical landscape and health threats. However, many of the new drugs suffer from toxicity concerns or from limited systemic administration bioavailability that impede their safety and efficacy. Additionally, companies are looking for ways to extend exclusivity of their proprietary products, particularly in connection with drugs that are approaching patent expiration.
PolyPid’s proprietary platform, PLEX, is a protective drug encapsulation platform that allows a controlled, local release rate over extended periods of time (up to months). We have proved the versatility of our PLEX platform with preclinical trials and in some cases of clinical trials, using a variety of small molecules, peptides, and proteins. Partnering with us will provide companies with a targeted, local drug delivery vehicle that will optimize a drug therapeutic payload and clinical outcome, and where applicable, help overcome a looming patent cliff.
PLEX is a unique local drug delivery platform that brings numerous innovative solutions to the market in various fields, such as infections, inflammations, and cancer.
Infections, and specifically, management of antibiotic-resistant bacteria, are a global health concern to which there is no effective solution at the moment. PLEX offers ways to combat this. Our strengths include an experienced management team, world-class drug delivery R&D expertise, broad IP protection, and organizational flexibility.
1. Emanuel N, Rosenfeld Y, Cohen O, Applbaum YH, Segal D, Barenholz Y. A lipid-and-polymer-based novel local drug delivery system–BonyPid™: from physicochemical aspects to therapy of bacterially infected bones. J Control Release. 2012;160(2):353-361.
2. Metsemakers WJ, Emanuel N, Cohen O, Reichart M, Potapova I, Schmid T, Segal D, Riool M, Kwakman PH, de Boer L, de Breij A, Nibbering PH, Richards RG, Zaat SA, Moriarty TF. A doxycycline-loaded polymer-lipid encapsulation matrix coating for the prevention of implant-related osteomyelitis due to doxycycline-resistant methicillin-resistant Staphylococcus aureus. J Control Release. 2015;209:47-56.
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Dr. Noam Emanuel is Chief Technology Officer of PolyPid. He has vast experience in biotechnology projects, including development of drug delivery systems and immunology. His extensive expertise includes immunotherapy, vaccines, immunodiagnostics, systemic and local drug delivery, and medical devices. Dr. Emanuel has a number of approved patents in the field of drug delivery and diagnostics. He is a Co-founder of PolyPid and served as its CEO during the company’s first 3 years. He earned his PhD from the Faculty of Medicine at the Hebrew University of Jerusalem.
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