KEYWORDS

 - Drug Delivery System

 - Graphene

 - Wearable microprocessor

 - Transmucosal drug delivery 

 - Pharmaceutical ingredients reservoir

 - Electrochemical biosensor

 - Graphene-based polymer nanocomposites

Description

The drug delivery device of the present invention is a proposal for innovative biotechnology for the targeted mucosa and transmucosal delivery and/or controlled release of active pharmaceutical ingredients for various therapeutic applications when on-demand drug administration is needed.  

Personal devices are provided for programmable or on-demand release of active pharmaceutical ingredients optimizing drug absorption across mucosal barriers and transmucosal drug delivery by improving pharmacokinetics and biomaterial interfaces. The miniaturized drug delivery device comprises a substrate reservoir containing graphene- and its derivatives-based nanocomposites, loaded with active pharmaceutical ingredients, embedded in a microprocessor system which can be able to deliver electrical current and/or a current-controlled magnetic field and/or to emit light. Such stimuli can determines the release of the pharmaceutical ingredient(s) conjugated to the graphene oxide from the drug reservoir. Intensity and timing of the stimuli tune different modalities of release of the drug, allowing a user to operate them through an electronical device connected to the microprocessor. The device may be attached to a support structure and positioned in tight contact to the mucosa. 

The biodevice is also composed by a biosensor system that may enable extraction of mucosa and submucosa body fluids monitoring systems to identify the biological characteristics related to several diseases. Integrating the presented biosensor system with a machine learning technique enables an interactive evaluation of the user’s need of drug delivery device intervention, with an objective estimate the biometric signal processing. 

Scientific Background 

Previous patented inventions in the field consisted mainly of sensors and of electrical therapy treatment for sleep disorder. Such an invention is also comprising a drug-delivery system, using a removable mandibular device with pharmaceutical compound reservoir for drug release to the oral mucosa upon electrical stimulation. Another published invention consisted of a drug-delivery microchip system, based on different reservoirs for subcutaneous drug release via an implantable device. This drug-release system is based on passive (i.e. drugs diffusion upon opening the reservoir cap) and active principles (i.e. ion-exchange properties). However, the systems of the prior art do not allow to finely regulate and control the rate, timing and speed of drug release. 

What the present invention proposes is a removable drug delivery system close to the above innovations, combining the drug-delivery operation principle applied to mucosa drug-release from multiples reservoirs. However, this invention takes advantage of the electrical conductivity properties of graphene and of its great potential to operate as a drug- and electron-carrier, to create a programmable drug delivery. These properties provide a miniaturized tunable drug-delivery system, capable of finely regulating rate, timing and speed of drug release. It has been widely explored the role of graphene as drug carrier for drug delivery system. In contrast to previously mentioned patented innovations, the present drug delivery device is capable of a controlled retainment and release of drugs for extended periods of time, as well as of an immediate release for quick action of drugs at different doses, on an as-needed basis. Therefore, the present innovation may combine both immediate-release system and zero-order release system improving pharmacokinetics of mucosa drug release.

Results    

Graphene provides great drug-loading capability due to the wide surface area. Graphene and graphene oxide have been widely explored as drug carrier for drug delivery system. The proposal of the present invention is to take advantage of graphene potential to operate as a drug- and electron-carrier, to create a programmable drug delivery device. These properties provide a miniaturized tunable drug-delivery system, capable of finely regulating rate, timing, and speed of drug release to the mucosa and transmucosal level. Furthermore, the present invention may be composed by a biosensor system that enable extraction of mucosa and submucosa body fluids. Thereby, the biosensor system collects biometric information that are transmitted to an electronic device, such as a smartphone, which is further connected with the microprocessor embedded in the drug reservoir, in a closed-loop system, enabling an interactive evaluation of the user’s need of drug delivery device intervention. Therefore, the present theranostics approach is expected to greatly improve the current pharmacological treatment of gastroenterology, hematology, infectious, neurology, psychiatry, endocrinology, nutrition and respiratory tract diseases. 

TRL Level: 4  

Potential Applications

The drug delivery device of the invention can be advantageously used for the treatment of any condition that would take advantage from a transmucosal administration of a pharmaceutical ingredient. Moreover, the present portable smart biodevice may allow users to measure their own mucosa and submucosa body fluids with high speed and accuracy for biological measurements and provide appropriated therapeutic treatment where a tuneable effect of drug is expected, with controllable time and dosage release. For instance, loading the programmable biodevice with the appropriate and already commercialised pharmaceutical drug, the device may be applied for the therapeutic treatment of gastroenterology, hematology, infectious, neurology, psychiatry, endocrinology, nutrition, genitourinary and respiratory tract diseases, in particular for the treatment of at least one disorder or condition selected from the following group: gastrointestinal disorders, genitourinary disorders, psychiatric disorder, neurological disorder and nutritional deficiency, including but not limited to adrenal insufficiency, allergy, anxiety disorder, asthma, attention-deficit hyperactivity disorder, bipolar disorder, chronic and acute pain, chronic bronchitis, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease, congestion, cramp, cyclic vomiting syndrome, dementias, dependence syndrome, diabetes mellitus, epilepsy, fever, genitourinary disorder, hypercholesterolemia, hormonal imbalance, hyperglycaemia, hypersalivation, hypertension, hypotension, hypothyroidism, infectious disease, inflammatory diseases, menopause, menstrual regulation, migraine, mood disorders, musculoskeletal pain, nausea, neoplasms, obesity, Parkinson's disease, pulmonary disease, respiratory disease, sexual dysfunction, sleep disorder, smoking cessation, vaginal diseases, vomiting. 

Companies involved in therapeutic and diagnostic areas of the diseases mentioned above, such as Menarini Group, Roche Pharma S.p.A., Novartis International AG, GlaxoSmithKline S.p.A., Eli Lilly & Co., Boston Scientific Neuromodulation Corporation, Avior Bio INC., Medical MicroInstruments SpA and Microchip Technology Inc, might be interested in invest in collaborative initiatives related to presented biomedical invention. 

Target Companies: Bio Chem Tec, Pharmaceutical, Microchip Technology 

Advantages

• Drug release period: it has been previously proposed a drug delivery device with either one-time release (i.e. for an acute treatment) or long-term operation (i.e. for chronic treatments, over 2-12 months). We are instead proposing a tunable drug-delivery system for both short- and long-term release profiles, even altering drug release schedule in real-time, constantly operating on a time-scale of a few minutes to hours. 

• Drug release stimuli: the use of electrical stimuli was previously proposed to actuate the drug reservoirs, in passive release or ion-responsive drug release systems. Somewhat similar, we are proposing electrical-, light- and magnetic-induced drug-release exploiting graphene properties and inducing an active compound release thanks to its drug- and electron-carrier properties. In this sense, electrical stimuli may modulate graphene’s ability to establish a balance between physicochemical properties of graphene and bioavailability of drugs. For instance, the amount of drug released at mucosa/submucosa level depend on the graphene electrical conductivity property, allowing on-demand release of drugs be controlled by the smartphone app. 

• Pharmaceutical compounds: previous proposals included reservoirs suitable for either one single or several drugs storage. However, in those devices the release actuation cannot be specified independently for each drug. We are instead proposing a drug reservoir suitable for either one single or several drugs, with various dosage. The properties of graphene as a drug-carrier system offer the peculiar ability to conjugate different drugs in a single graphene sheet, promoting a synergy and versatility of operation controlling additive effects of distinct pharmaceutical compounds. 

• Vehicle formulations properties: most of commercial transmucosal pharmaceutical formulations contains polymer composites that play an important role as a vehicle in the drug-delivery formulations, by providing controlled release of pharmacologic agents. However, due to its high density the availability of the drug for immediate release to the mucosal membranes progresses slowly. Graphene can instead overcome this problem and immediately deliver the drugs, requiring a reduced amount of polymer or even completely replacing it in the pharmaceutical formulation. Moreover, due to graphene electrical and nanocarriers properties, the electrical currents generated by the microprocessor may break ionic bonds of the drug-conjugated graphene compound, promptly releasing the drug and expelling it out of the reservoir, thus enhancing in situ availability.

Inventors

Audrey Franceschi Biagioni, Laura Ballerini, Michele Giugliano