WO2009047365A1

WO2009047365A1 - Drug delivery system

Info

Publication number: WO2009047365A1
Application number: PCT/EP2008/063740
Authority: WO
Inventors: Andreas Voigt
Original assignee: Capsulution Nanoscience Ag
Priority date: 2007-10-12
Filing date: 2008-10-13
Publication date: 2009-04-16

Abstract

Drug delivery system comprises a matrix comprising at least one pharmaceutical active compound and at least one permeability-enhancing agent; at least one electrode; and an RF-generator for generating a radio frequency electrical field, the at least one electrode being electrically connected with an output of the RF- generator.

Description

DRUG DELIVERY SYSTEM

[0001] This application claims the benefit of US-Provisional Application No. 60/979,409, filed 12 October 2007, and EP-Patent Application 07118407.1 filed on 12 October 2007. This description relates to embodiments pertaining to a system for drug delivery and a method for administering a drug.

BACKGROUND OF THE INVENTION

[0002] Mental illnesses are important causes of disability with major implications for overall health and productivity worldwide. Schizophrenia is one of the most severe, chronic and debilitating mental disorders and affects about 1 percent of the population throughout diverse cultures and geographic areas. To date, the disease remains poorly understood in terms of the fundamental pathology, pathogenesis, risk factors, response to various treatments and long-term prognosis. 3% of the expenditure of the National Health Service (NHS) is allotted to schizophrenia in the UK.

[0003] Antipsychotic medication is the mainstream treatment for schizophrenia. Two major classes of antipsychotic medication are used so far, whilst the underlying mechanisms of action of the medication are still not clear. The first generation antipsychotic drugs have a high affinity to dopamine 2 (D2) receptors and control only the positive symptoms of the disease as hallucinations or delusions. The most obvious side effects are involuntary movement disorders arising from the extrapyramidal system. Second generation antipsychotics have improved therapeutic and decreased side effects compared with first generation dopamine- blocking drugs. D2 receptor antagonism is no longer the sole therapeutic mechanism. But, many second-generation drugs have been increasingly reported to produce clinically significant weight gain and diabetes mellitus.

[0004] Generally, antipsychotic drugs are administered via the oral or parenteral route by injection and very rarely infusion. In order to act on their specific receptors within the brain after systemic administration, the drugs have to cross the blood brain barrier. The blood brain barrier (BBB) is a diffusion barrier, which impedes influx of most compounds from blood to brain and is formed by brain microvascular endothelial cells, pericytes and astrocytes. The BBB endothelial cells differ from endothelial cells in the rest of the body by the absence of fenestrations, more extensive tight junctions that limit paracellular permeability and sparse pinocytotic vesicular transport. For a small molecule drug to cross the BBB in pharmacologically significant amounts, the molecule must have the dual characteristics of: a) molecular mass under a 400-500-Da threshold, and b) high lipid solubility. Less than 2% of all small molecules fit in this category.

[0005] For many patients that suffer from mental illnesses, observing correct medication intervals, poses a problem. Studies revealed that 75% of the schizophrenic patients are not able to take their medication regularly. Without the intake of medication, the relapse probability is as high as 10% per month and leads to hospitalisation for the treatment of acute symptoms, whilst the social uprooting of the patients during hospitalisation plays an additional important role. Effectively, the hospitalisation and care at home makes up to ³A of the direct total costs for the treatment of schizophrenia.

[0006] In 2002, risperidone (Risperdal consta) came onto the market as the first atypical antipsychotic drug in depot formulation. Therefore, biodegradable polymers, which decompose at a controlled rate, have been used to encapsulate risperidone. These microspheres release the drug for two weeks and need to be administered by a deep intramuscular injection, which is often painful for the patient. Despite the substantial progress of the available depot formulations, there is an urgent clinical need for more effective and applicable drug formulations in order to treat schizophrenia and other mental illnesses and relieve the patients' medication intake.

[0007] Alternatively to the oral or parenteral route currently used for the treatment of schizophrenia, the intranasal or topical ocular application route is of interest. Several studies have demonstrated that intranasal application offers a practical, noninvasive route of administration as well as the avoidance of hepatic first-pass elimination for drug delivery to the brain. The olfactory region of the nasal passages has unique anatomical and physiological attributes that provide both extracellular and intracellular pathways into the CNS bypassing the blood-brain barrier. Olfactory sensory neurons are the only first order neurons cell bodies of which are located in a dista! epithelium. Their dendritic processes are directly exposed to the external environment in the upper nasal passage while their axons project through perforations in the cribriform plate of the ethmoid bone to synaptic glomeruli in the olfactory bulb. A direct extracellular pathway between the nasal passages and the brain was first conclusively demonstrated for the 4OkDa protein tracer horseradish peroxidase migrating through open intercellular clefts of the olfactory bulbs of rats, mice and squirrel monkeys within minutes after application. Conversely, the intracellular pathway from the nasal passages to the brain using anterograde axoplasmic transport within olfactory sensory neurons has been shown most convincingly for the lectin conjugate wheat germ agglutinin-horseradish peroxidase. The demonstration that a substantia! fraction of large molecular weight molecules are cleared from the CNS directly into the deep cervical lymph nodes, which receive afferent lymphatics from the nasal passages, provides additional support for the existence of a direct pathway connecting the submucosal compartment in the nasal passages to brain interstitial fluid or cerebrospinal fluid. Recent studies have shown that growth factor analogues, insulin, vasoactive intestinal peptide, nerve growth factor, fibroblast growth factor-2 and insulin-like growth factor-1 , are able to gain access to or have effects in brain tissue or CSF following intranasal administration.

SUMMARY OF THE INVENTION

[0008] According to an embodiment a drug delivery system is provided which comprises:

a matrix comprising at least one pharmaceutical active compound and at least one permeability-enhancing agent;

at least one electrode; and

an RF-generator for generating a radio frequency electrical field, the at least one electrode being electrically connected with an output of the RF-generator. [0009] According to another embodiment, a method for administering a pharmaceutical active compound is provided. The method comprises:

providing a matrix comprising at least one pharmaceutical active compound and at least one permeability-enhancing agent in close proximity to a biological barrier for administering the pharmaceutical active compound through the biological barrier;

arranging at least one electrode at least in close proximity to the matrix and the biological barrier; and

applying a radio frequency signal to the electrode.

[0010] According to another embodiment, a matrix for applying to a biological barrier is provided. The matrix comprises:

at least one pharmaceutical active compound;

at least one permeability-enhancing agent; and

at least one of conductive and dielectric particles.

[0011] To improve temporarily the permeability of a biological barrier or interface with respect to a pharmaceutical active compound the influence of a permeability- enhancing agent on that barrier is combined with the impact of a radio frequency (rf) electrical field. The impact of the electrical field can be easily controlled so that this combination allows a specific and selected permeability enhancement of the barrier. The radio frequency electric field, typically a rf alternating current electric field (ac- field), is transmitted to the extracorporeal part of the biological barrier or interface by at least on electrode or alternatively two or more electrodes such as simple shaped electrodes, for instance wires, or complex electrodes having a complex geometry, for instance electrode arrays formed by semiconductor technology and arranged on the biological barrier. The radio frequency electrical field is either of simple periodic manner with rf-ac pulses of any shape, for instance sinusoidal, or is comprised of a set of phase shifted signals being transferred to electrode arrays, for instance as travelling waves patterns. The RF-generator, also referred to as RF-AC-generator, provides a radio-frequency alternating current signal on at least one of its outputs which is used to apply an alternating current electric field to the biological barrier. Typically, the mean value of the radio-frequency alternating current signal is substantially zero.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] A full and enabling disclosure of the present invention, including the best mode thereof, to one of ordinary skill in the art, is set forth more particularly in the remainder of the specification, including reference to the accompanying figures. Therein:

[0013] Fig. 1 shows a drug delivery system according to an embodiment.

[0014] Fig. 2 shows a drug delivery system according to another embodiment.

[0015] Fig. 3 shows frequency spectra of particles used in a matrix for drug delivery systems of Fig. 2.

[0016] Fig. 4 shows concentration and attenuation of the electrical field by low conductive particles in a matrix.

[0017] Fig. 5 shows concentration and attenuation of the electrical field by high conductive particles matter in a matrix.

[0018] Fig. 6 shows the velocity of particles in a liquid matrix as a function of distance from the wire tip due to dielectrophoretic forces.

[0019] Fig. 7 shows the particle distribution around a single electrode.

[0020] Fig. 8 shows electrode structures according to certain embodiments.

[0021] Fig. 9 shows a flow diagram of a method for administering a pharmaceutical active compound. DESCRIPTION OF THE PREFERRED EMBODIMENT

[0022] Reference will now be made in detail to various embodiments, one or more examples of which are illustrated in the figures. Each example is provided by way of explanation, and is not meant as a limitation of the invention. For example, features illustrated or described as part of one embodiment can be used on or in conjunction with other embodiments to yield yet a further embodiment. It is intended that the present invention includes such modifications and variations. The examples are described using specific language which should not be construed as limiting the scope of the appending claims. The drawings are not scaied and are for illustrative purposes only.

[0023] In the context of this description, the term "biological barrier" (or interface) refers to any native functional and structural barrier of a human or animal, such as a mammal, to the environment. Such functional and structural barriers fulfil certain functions, for instance compartmentalisation. Examples are skin, blood-brain barrier (BBB), mucosa of the nasal cavity, epithels of external and internal (e.g. oral, rectal, vaginal) biointerfaces, ocular surfaces, conjunctiva, cornea (horny skin), buccal mucosa, gastric mucosa, intestinal mucosa, endometrium, and tight-junction mediated diffusion barriers.

[0024] The term "pharmaceutical active compound" refers to a composition which, when administered to a human or an animal such as a mammal, provides a desired therapeutic response which is not outweighed by unacceptably adverse effects provoked by that compound. Pharmaceutical active compounds may comprise substances for the prevention and treatment of diseases and disorders of the central nervous system, such diseases and disorders include, without being limited thereto, neurological conditions associated with memory loss, cognitive impairment and dementia, like Alzheimer^'s disease, Parkinson^'s type, Huntington^'s type, Pick^'s type, CJ-type, AIDS-related type, schizophrenia, bipolar disorders, depression, mania, Tourette^'s syndrome, epilepsy, brain malignancies, tumors, multiple sclerosis, mysasthenia gravis, attention deficit disorder, autism, dyslexia, forms of delirium, vascular stroke, brain injury, cranial bleeding. Moreover, the pharmaceutical active compound can also comprise substances for the prevention and treatment of diseases of any medical indication other than diseases and disorders of the central nervous system. In the following, the term drug is used when referring to a pharmaceutical active compound.

[0025] The drug is typically provided in molecular form in the matrix. Alternatively, the drug can be dispersed in the matrix as nanoparticles.

[0026] In an embodiment, the pharmaceutical active compound is suitable for the prevention and treatment of diseases and disorders. Typically, the pharmaceutical active compound is suitable for the prevention and treatment of diseases and disorders of the central nervous system. For administration of a drug to the central nervous system, intranasal application or ophthalmic application are particularly used to bypass the blood brain barrier. For systemic applications, drug administration through transdermal and topical applications are mainly used while other administration routes can also be used. It goes without saying that the drug delivery system can be adopted for any drug administration route.

[0027] The drug can be selected from the group containing low molecular weight substances, medium molecular weight substances and high molecular weight substances such as peptides, proteins, microproteins, prions, enzymes, antibodies, vectors, nucleotides, nucleic acids, RNAs, miRNAs, siRNAs, DNAs, aptamers, spiegelmers, carbohydrates and derivatives and mixtures thereof. In the context of this description, "low molecular weight" means a molecular weight in the range from about 20 Da to about 1000 Da; "medium molecular weight" means a molecular weight in the range from about 1000 Da to about 10 000 Da; while "high molecular weight" means a molecular weight in the range higher than about 10 000 Da.

[0028] The term "permeability-enhancing agent" as used herein refers to excipients for enhancing the uptake and/or the pharmaceutical acceptance of the drug. The permeability-enhancing agent can be provided in an under-critical concentration which would not be sufficient to significantly increase the permeability of the biological barrier with respect to the drug when applied alone. Applying the permeability-enhancing agent at reduced or controlled concentrations results in a certain "conditioning" of the biological barrier towards improved permeability or pharmaceutical acceptance of the drug, whilst a long-lasting and adverse disrupture or damage of the biological barrier can be prevented. To further improve the permeability at controlled rate, a radio frequency electrical field is applied as described further below.

[0029] The permeabiiity-enhancing agent can be selected from the group containing aggregation inhibitor, charge modifiers, agents for controlling and buffering pH, redox controlling agents, degradative enzyme inhibitors, mucolytic agents, ciliostatic agents, ligand agents for controlling the interaction between the drug and a biological membrane, absorption enhancing agents, and mixtures thereof. Specific examples of the permeability-enhancing agent are: (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome, or carrier system; (iii) an alcohoi; (iv) an enamine; (v) a nitric oxide donor compound; (vi) a long-chain amphipathic molecule; (vii) a small hydrophobic uptake enhancer; (viii) sodium or a salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) acyclodextrin or O-cyclodextrin derivative; (xi) a medium-chain or short-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or salt thereof; (xiv) an N-acetylamino acid or salt thereof; (xv) an enzyme degradative to a selected membrane component; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; (i) a modulatory agent of epithelial junction physiology; (j) a vasodilator agent; (k) a stabilizing delivery vehicle, carrier, support or complex-forming species with which the drug is effectively combined, associated, contained, encapsulated or bound resulting in complexing or stabilization of the drug for enhanced delivery over the biological barrier; (I) a humectant or other anti-irritant; and mixtures thereof.

[0030] The term "matrix" refers to a suitable reservoir for storing and releasing the permeability-enhancing agent and the drug. The matrix can comprise a gel or a liquid. The gel can be for instance a hydro-gel, an alcoholic gel, and a stimuli- responsive polymer gel such as pH-sensitive polymer gels and thermo-sensitive polymer gels, for instance PoIyNIPAMs. The liquid medium and the gel should be biocompatible and pharmaceutically acceptable with properties permitting sustained release of the drug and the permeability-enhancing agent. [0031] The matrix can be a single compact gel or liquid or viscous liquid which are suitably applied to the place of administering for instance by spraying, coating or placing. Alternatively, the matrix can comprise two or more separate compartments for separately storing the drug and the permeability-enhancing agent. Each of the separate compartments can be formed by one of a gel and a liquid. In some embodiments, the drug delivery system comprises two or more permeability- enhancing agents and two or more drugs. The permeability-enhancing agents and the drugs can be contained in a single compartment or in separate compartments. If appropriate, mixtures of the drugs and/or the permeability-enhancing agents can be stored in a common compartment while other single compounds (drugs and permeability-enhancing agents) or mixtures are stored in one or more separate compartments. The release characteristics of the respective compartments can be adjusted according to specific needs.

[0032] Typical examples for matrix systems applicable for the presented delivery systems are published in WO 2004/002402, EP 1 281 319, US 2007/0053984, US 2007/0065474, the entire content of which are incorporated herein by reference.

[0033] Figure 1 shows an embodiment of a drug delivery system. The drug delivery system as described herein is suitable for topical applications, intranasal applications and ophthalmic applications of the drug and for delivery of drugs to the brain, and transdermal delivery of drugs.

[0034] Typically, the drug delivery system comprises at least one electrode 400 which can be in contact with a matrix 300. Alternatively, the electrode 400 can be insulated from the matrix 300 but will typically remain in close vicinity thereto. Typically, the electrode will be in direct contact with the matrix to provide for a good electrical coupling. The electrodes can be coated with a dielectric layer, which should have a high permittivity to maintain the good electrical coupling. In some embodiments, the drug delivery system comprises a plurality of electrodes which can be of any shape and arrangement for instance interdigitated, spiral, chain-like, spot- like or lamellar electrodes in intimate contact with the site of drug application. The electrodes can be formed by wires, sheets, circuits, networks of wires, semiconductor processed electrodes or electrode arrays of different structure and geometry. An electrode is to be understood as an electrical conductive element having a conductivity which is equal to or higher than the conductivity of the matrix. Typically, the conductivity of the electrode is higher and, in particular, significantly higher than the conductivity of the matrix.

[0035] In addition to the "electrodes", "isolated electrodes" can be arranged in contact with the matrix or in close proximity thereto. The electrode or electrodes are electrically connected with the RF-generator, or RF-AC-generator, whilst the "isolated electrodes", though typically fixed and dimensionaily stable structures, remain disconnected from the RF-generator. The purpose of the isolated electrodes is to shape the electrical field and to increase the inhomogeneity of the electrical field at the biological barrier. The isolated electrodes can be excited by the radio frequency field supplied by the electrodes connected to the generator^'s output. Examples of isolated electrodes, without being limited thereto, are interdigitated or mesh-like structures.

[0036] The electrode or the electrodes are electrically connected with at least one output 610 of a high frequency RF-generator 600 for instance by (screened) wire 500 or other connectors. In case of more than one electrode, respective electrodes can be connected with respective outputs of the RF-generator. The RF-generator can comprise at least one output and a ground terminal. Alternatively, the RF-generator can comprise two or more outputs which can deliver radio frequency signals which are phase-shifted to each other by a given phase difference. For instance, the RF- generator can comprise four outputs each of which delivers a signal which is shifted to a signal of another output by 90°. Additionally, the RF-signals can be pulsed.

[0037] The RF-generator is arranged to provide one or more radio frequency alternating current signals. In the context of this description "radio frequency" means an ac-signal having a frequency in the range from about 5 kHz to about 3 GHz, and typically in the range from about 30 kHz or 100 kHz to about 500 MHz or to about 1 GHz. The RF-signais may have a root mean square amplitude between about 0.5 V and about 50 V. Typically, no electrochemical reactions (redox reactions) occur with electron transfer through the electrode/matrix/biological barrier. The ac signal, which has a given root mean square amplitude while its mean amplitude remains substantially zero, is defined with respect to a ground potential of the RF- or RF-AC- generator, i.e. the polarity of the provided voltage or electrical field, respectively, reverses with the radio-frequency of the signal. The ground potential may be provided at any of the outputs of the generator. The ground potential may define the counter electrode.

[0038] The main purpose of the RF-generator is to feed the electrode 400 for generating an inhomogeneous radio frequency electrical field, E, at and around the electrode or electrodes in the tip region 410, 420. The tip region 410, 420 can be formed by simple electrodes shaped like wires or by metallised capillaries as shown in Fig. 1. The capillary can also be used for application of the matrix droplet 300 through its tube to a biological barrier 200, parts of which are typically formed by cells 100. In this case, the interior of the capillary, which is filled with the matrix and which provides a dedicated and separate electrical connection to the matrix at the barrier 200, can be used as one electrode, while the metallised outer surface of the capillary can be used as another electrode. It is also possible that the internal and external walls of the capillary are metallised to provide two separate electrodes.

[0039] Since the electrode or electrodes are placed close to the site of the drug administration, i.e. close to the biological barrier 200, the electrical field induces inter alia an electromechanical stress or a dielectrophoretic force on the biological barrier. The strength of the electromechanical stress (and hence the dielectrophoretic force) depends on many factors such as the inhomogeneity of the electrical field across the interface 200 (z-direction), the inhomogeneity of the electrical field along the biological barrier 200 and the dielectric permittivity of the barrier and its surrounding medium. For sake of clarity the biological barrier 200 is drawn without any curvature. Those skilled in the art will appreciate that a deformation of the biological barrier will not qualitatively, i.e. in a topological sense, change the field distribution. Therefore, the given arguments also apply for non-flat biological barrier 200. However, the place on the biological barrier, were highest stress is applied, will depend on the geometry of the biological barrier. The dielectric permittivity of the surrounding medium, which can be formed by the matrix, can be adjusted appropriately while the inhomogeneity of the electrical field is influenced by the geometry and arrangement of the electrode or electrodes. In connection with this description, the term "dielectrophoretic force" refers to a force induced on particles or structures by an inhomogeneous alternating electrical field. It is not required that the particles or structures are charged since the electrical field induces a dipole moment in the particles and structures which interacts with the electrical field.

[0040] The static electrical conductivity of matrix can be in the range from about 1 mS/m to about 10 S/m and typically in the range from about 0.1 S/m to about 2 S/m. As it becomes more apparent from the description below, the electrical conductivity is typically a function of the frequency of the electrical field applied thereto. Highly viscous matrixes or gel matrixes exhibit typically stronger frequency dependence than liquid matrixes.

[0041] Basically, the electrode forms a capacitor electrode structure. In case that only one electrode is provided, an "open" capacitor is formed with the counter electrode being formed by the remote ground output of the RF-generator. When using two or more electrodes, each of which being connected with a separate output of the RF-generator, a complex capacitor structure can be formed.

[0042] As shown in Fig. 8, more complex electrode geometries can be used as electrode tip 420. The central illustration of Fig. 8 shows an electrode tip 420 with two interdigitated electrodes 450 and 460. Either one of the two or both electrodes are connected to the generator (not shown). If only one electrode is connected to the generator the other is floating. Applied electric fields are usually lower if only one electrode is connected to the generator. The radio frequency electrical field is either of simple periodic manner with pulses of any shape or is comprised of a set of phase shifted signals which are transferred to electrode arrays like travelling waves patterns as shown in the lower part of Fig. 8. The phase difference between neighbouring electrodes of the electrode array can e.g. be 30°, 60°, 90° or 180°.

[0043] With respect to Figure 2, another embodiment will be described. In addition to the drug and the permeability-enhancing agent, the matrix can comprise electrically conductive and/or dielectric particles 700. For reason of clarity the generator is not shown. The main function of these particles is to influence the distribution and shape of the electrical field within the matrix, in particular close to the biological barrier 200. For example, electrically conductive particles may "concentrate" the electrical field in close proximity to the biological barrier and thus enhance its influence. One the other hand, electrically insulating particles (dielectric particles) may "shadow" the electrical field in close proximity to the biological. In both cases the electric field becomes more inhomogenous close to the biological barrier. In particular, the electrical field inhomogeneity along the biological barrier increases which, in turn, results in increased induced stress. In some aspects, a mixture of dielectric and electrically conducting particles is used. Thereby, the electric field inhomogeneity can further be increased.

[0044] Typically, a particle is considered to be electrically conductive if it is either more conductive or more polarisable or both than the surrounding matrix at a given frequency. Different thereto, a particle is considered to be dielectric if it is less conductive and less polarisable than the surrounding matrix. The conductivity is therefore frequency dependent and, for a given frequency of the electrical field applied to the biological barrier, the interaction of the particles and their influence on the electrical field depends on the actual conductivity at that frequency. For example, metals form conductive particles for the frequency range of interest, while metal particles coated with an insulating layer are dielectric particles at low frequencies and become conductive particles at high frequencies. The terms "electrically conductive" and "dielectric" are defined more precisely below in connection with the Claussius- Mossotti-factor. The dielectric or conductive particles typically do not comprise the drug and are different to drug nanoparticles. If the drug is provided as drug nanoparticles, the drug nanoparticles will also influence the electrical field distribution. However, their influence vanishes when the drug nanoparticles becomes solved in the matrix.

[0045] To illustrate the field concentration and attenuation, consider the situation of a spherical particle, p, of radius, R, which is suspended in a matrix or liquid, /, and placed in a homogeneous, sinusoidal rf electric field E of radian frequency ω=2πf. In this case, the potential Φ of the electric field outside the particle reads in spherical coordinates (r>0, 0<φ≤2π, O≤Θ≤π):

[0046] Assuming the externa! electric field being parallel to the z-axis, Ε_z gives its magnitude and Θ describes the angle between the radius vector and the z-axis. Due to symmetry the potential does not depend on the angle φ. The electric field increases or decreases in a certain direction due to the presence of the particle depending on the Claussius-Mossotti-factor which reads for homogeneous spherical particle:

f_CM = ^{σp ~ σ}' (2)

^JcM σ_{p +} 2σ,

with complex admittance

σ = σ + iωε (3)

for both σ_p ^and σ_t where σ represents the conductivity and ε the absolute permittivity. For more complex particles, ε_p and σ_p in eq. (2) and (3) have to be replaced by effective frequency dependent values (see also below).

[0047] The time dependent electric field is determined as negative gradient of the potential Φ and is of the form

E{r , t) = Re[(E^re (r ) + iE^m (r )) exp[/ctf]] (4).

[0048] At each interface between two media of different charge relaxation time τ=ε/σ, the electric field lines are refracted. This results in a force or stress acting upon that interface which can be calculated using the Maxwell stress tensor:

T_aβ = εE_aE_β-0.5εE² (5) [0049] This electrically induced stress is used to enhance drug delivery through the biological barrier such as the BBB. As can be appreciated from eq. (5) the resulting stresses and force are, at given geometry, substantially proportional to the applied mean square electric field. Therefore, the ratio between the mean square electric field in the presence and absence of a particle is considered as a measure of field action. With the help of particles close to the biological barrier the field inhomogeneities can be increased.

[0050] The electrically conductive and/or dielectric particles can be coated. Such particles are referred to as composite particles. For example, conductive particles can be coated with a dielectric shell. For a shelled particle the effective complex admittance σ_p in eq. (3) has e.g. to be replaced by

(4)

with c = and shell (membrane) thickness h. The indices i and m refer to

R ~h particle interior and shell (membrane), respectively.

[0051] Fig. 3 shows the Claussius-Mossotti-factor as function of field frequency for four 10 μm particles suspended in matrix having a conductivity of 0.5 S/m and a relative permittivity of 78. Curve 20 corresponds to a particle of low permittivity (5) and high conductivity (1000 S/m). The curve 21 was obtained for a shelled particle having the same core as the particle of curve 20 and a 8 nm shell of low conductivity (1 μS/m) and low permittivity (3.5). Curve 22 and 23 correspond to a shelled particle with a core of lower conductivity (1 S/m) and a particle without shell and even lower core conductivity of 1 mS/m, respectively. Note that the frequency response depends on conductivites and permittivites. The terms "dielectric" (low conductive) and "electrically conductive" (high conductive) as used in this specification therefore intends to describe that the real part of the Claussius-Mosotti-factor is negative and positive at a given frequency, respectively. Negative and positive values of Re[fcwι] correspond to field attenuation and field concentration close to the particles and in direction of the external field, respectively. This is explained with reference to Figs. 4 and 5.

[0052] The upper parts of Figs. 4 and 5 show the time independent part of the potential distribution according to eq.(1) in the y=0-plane for a particles 700 placed in an external electric field which is parallel to the z-axis. The lower parts of Figs. 4 and 5 correspond to mean square electric field in z- and x-directions. As can be appreciated from these Figures the field is attenuated and concentrated in direction of the external field for low and high conductive particles, respectively. Further, the field concentration in direction of the external field is typically larger for high conductive particles compared to the field attenuation in x-direction of low conductive particles. The range of field attenuation and concentration is of the order of the particle size. To enhance the drug administration through the barrier 200 particles have to be placed close, in terms of their size, to the barrier 200. This can also be achieved using radio frequency, but inhomogeneous electric fields applied via the electrode 500. With the set-ups shown in Figs. 1 and 2 an inhomogeneous field which decreases in strength with increasing distance from the electrode tip 410 is usually applied. In an inhomogeneous field a polarisable particle will experience a force either attracting it to or repelling from regions of high field strength:

F_DEP = InS₁R' Re[Z₀₁, ]* VEL + O{R⁵ ) (6⁾

[0053] This is known as positive (pDΕP) and negative (nDΕP) dielectrophoresis. Negative and positive values of Re[fαvι] correspond to nDΕP and pDΕP, respectively.

[0054] In Figs. 6 and 7 the effect of negative dielectrophoretic particle motion close to a single electrode 31 is illustrated. Fig. 6 shows typical particle velocities and Fig. 7 a typical final particle distribution 32 around the single electrode. Using appropriate electrode configuration and RF-generators parameter, such particles are for instance pushed toward the biological barrier and still cause a "concentration" of the electrical field due to their conductive cores in the vicinity of the biological barrier. Note that the biological barrier 200 can be influenced by dielectrophoretic forces acting on the matrix particles 700 (eq. 6) and by the field "concentration" or "attenuation" due to the particles close to the interface (eq. 5).

[0055] With respect to Fig. 9 a method for administering a pharmaceutical active compound is explained. In a first step 1000 a matrix droplet 300, containing at least one pharmaceutical active compound and at least one permeability enhancer, is attached close to the biological barrier 200 e.g. the mucosa in the olfactory region. This is followed by applying an rf-field at a first frequency fi in step 2000. Thereby, an electromechanical stress is applied to the interface 200 which facilitates the drug administration through the barrier 200. As discussed above the rf-field may be pulsed or the voltage can varied in order to apply a time depend stress pattern to the biological barrier 200. For example, the electric field can be varied in accordance with a relaxation time of a membrane channel or protein. Further, a time dependent stress pattern can be generated by changing the field frequency in a step 3000 and repeating the steps 2000 and 3000 accordingly.

[0056] Alternatively and or additionally, the matrix droplet can contain electrically conductive and/or dielectric particles 700 which are pushed in step 2000 towards the interface 2000. In a preferred embodiment, particle 700 which shows both negative and positive values of Re[fcwι] at certain frequencies, as the shelled particles corresponding to the curves 21 and 22 of Fig. 3, are used. For pushing the particles to the biological barrier 200 the frequency fi where the particles have a negative value of Re[fαvι] is used. After the particles have reached the vicinity of the biological barrier 200 the field can be switched to a frequency f₂ where field concentration occurs. Further, the rf fields can be pulsed, voltage modulated and or switched between different frequencies to apply time pattern of stresses and or forces.

[0057] The present method is different to known methods for administering a drug. For example, iontophoresis employs a direct current (dc electric field) to propel a charged substance transdermally. Hence, ionotophoresis drives transdermal^ a charged drug under influence of a mean dc-fieid. Different thereto, an rf-ac field is applied. Further, the present invention does not require that the drug is charged since the drug itself is not propelled by the rf-ac field. In fact, the rf-ac field increases the permeability of the biological barrier by inducing electromechanical tensions. Hence, the present method does not directly drive the drug but temporarily destabilises the biological barrier with the alternating electrical field so that the drug can diffuse through the biological barrier. Therefore, the present methods provides for a delivery of charged and uncharged drugs. Furthermore, iontophoresis may lead to electrochemical reactions on the electrodes due to the applied average dc-voltage. Different thereto, the present method uses an ac-field which does not lead, due to the comparable high frequency and the alternating voltage, to electrochemical reactions.

[0058] In comparison to eiectroporation or electropermeabilisation, which employs a dc-pulse or dc-pulses to rupture temporarily a membrane, the present method does not form pores in the biological barrier by electrical discharge. Eiectroporation is only suitable for short-time applications. Long-lasting application of electrical discharge pulses would permanently rupture the barrier. Eiectroporation is therefore not suitable for sustained release applications.

[0059] Unlike the present method, cosmetic treatments results only in an adsorption of a compound into the skin by avoiding a penetration of the skin and a systemic distribution.

[0060] Different to the above described methods, the present method can be understood as a rf-mediated drug delivery through a biological barrier using an alternating electrical field.

[0061] Using different voltages can have a further advantage of being able to control the temperature in the matrix droplet 300. The induced temperature increase due to Ohmic heating δT is proportional to the electrical conductivity σ of the matrix drop, thermal conductivity λ, and the mean square voltage drop JJ T

' ]² r₁ ^■ ms ' dτ - ^σU™ (7) λ

[0062] In cell culture media (σ~1 S/m, λ~0.6 W/mK) the induced temperature increase is typically in the order of 1° per square voltage. This enables the usage of a matrix 300 comprised of an "intelligent" gel to trigger drug release either by temperature changes or by direct field effects. Further, the sol-gel transition could be used to apply forces to the biological barrier 200. It is, however, desired, to remain in a physiological temperature range and not to induce a harmful thermal stress.

[0063] In addition to that, the particles can be coated by an adhesion promoter to cause adhesion of the particles on the biological barrier to localise their influence close the biological barrier. If a gel is used, the particles can be concentrated in advance of administration on a side facing the biological barrier. This can be achieved, for instance, by applying a thin layer comprising the particles to the gel.

[0064] The conductive and/or dielectric particles are on the millimetre and sub- millimetre scale and touch or are intimately related with the site of the drug application. A typical particle size is in the range starting from 15 μm, 20 μm,.30 μm or 50 μm and reaching up to 500 μm, 1000 μm, 2000 μm or even 5000 μm. Example ranges are from 15 μm to 500 μm, 20 μm to 1000 μm, 30 μm to 2000 μm and 50 μm to 1000 μm. A skilled person will appreciate that any size range can be selected according to specific needs. The particles can be of any shape such as spherical, rod-like, elliptic, and cubic, and can be comprised in the bulk of the matrix or in single compartments thereof. In addition to that, the electrically conductive and/or dielectric particles can be sensitive with respect to effects induced by high frequency electric fields, such effects comprise temperature change, change in composition and orientation, change in mechanical and Theological properties. The electrically conductive and/or dielectric particles are provided for modifying and shaping of the rf electric fields in close vicinity of the site of drug permeation. Those particles do not penetrate into the biological side of the biological barrier and are not taken up by the biological body.

[0065] Moreover, the matrix can be confined, included, encased or embedded in an outer shell which can be flexible or rigid but which should allow release of the drug and the permeability-enhancing agent. The shell can provide separate compartments. The shell can comprise the electrode or electrodes.

[0066] The electrode and or the conductive elements can be patterned and arranged in a manner to act as a travelling electric wave structure 460, 470 induced by phase shifted radio frequency fields for generating electromechanical stress in the adjacent biological barrier.

[0067] The electrodes and/or the conductive and/or dielectric particles can be part of the capacitance between the generator outputs and thus passively respond with electrical oscillations induced by the radio frequency electrical field. The electrically conductive and/or dielectric particles may respond to the radio frequency electric fields by motion and/or orientation.

[0068] The matrix may further comprise particulate matter which can form the electrically conductive and/or dielectric particles or composite matter of different geometry, such as spheres, rods, and cubes. The maximum size of the electrically conductive and/or dielectric particles, i.e. their largest extension in a given direction, can be in the range from about 15 μm to about 5000 μm and typically in the range from about 30 μm to about 1000 μm.

[0069] The electrodes and the conductive and/or dielectric particles can be arranged such to allow induction of a strong inhomogeneous field in close vicinity of the adjacent biological barrier or interface to promote the drug uptake and drug permeation.

[0070] In some embodiments, the permeability-enhancing agent is provided in such a concentration that the permeability is only slightly enhanced when applied alone. However, by additionally applying a radio frequency electrical field the permeability of the biological barrier can be temporarily increased with respect to the drug.

[0071] The drug delivery system may comprise a release unit, for example a head, which comprise the at least one electrode and the matrix. The release unit is brought to the site of drug administration and is therefore appropriately designed. For instance, for topical or transdermal applications, the release unit can be formed sheet-like, strip-like or spot-like. For intranasal applications, the release unit is formed and shaped to allow insertion into the nasal cavity. Generally, if the target biological barrier is arranged in a cavity, the release unit is arranged and shaped to be insertable into that cavity.

[0072] The release unit can comprise one compartment. The compartment can be filled with the drug and the permeability-enhancing agent prior to administration. If the release unit comprises more than one compartment each compartment is filled prior to administration with one of the drug and the permeability-enhancing agent. Alternatively, the compartment can be filled with the drug only while the permeability- enhancing agent is applied separately to the site of drug administration.

[0073] Alternatively, both the drug and the permeability-enhancing agent are separately or together applied to the site of drug administration, for instance by spraying, and then an electrode is placed on this side to thus form a release unit.

[0074] In one embodiment, the drug delivery system comprises biocompatible gel loaded with a drug and a permeability-enhancing agent. An electrode is in direct contact with the gel to at least temporarily apply a frequency electrical field to the gel. The drug delivery system can be placed in close proximity to its anatomical target including the nasal cavity and the eye.

[0075] The drug delivery system can be placed non-invasively by state of the art techniques to the required site of drug delivery.

[0076] According to an embodiment, the primary components of a matrix are an alcoholic gel and a drug. The gel is typically composed of a gel matrix, water and alcohol. The physical chemical parameter can be adapted to the concrete anatomical and physiological conditions. The alcoholic component serves as a permeability-enhancing agent. The drug can comprise for instance a peptide and its derivates, which are active in the central nervous system. The gel can be contained in a suitable containment such as a sheet or a membrane, which can define the release properties of the device. The periphery is structured according to the needs of the application sides. It can be designed as a mechanically stable container, which determines the absolute amount of loaded drug, the release kinetics, the adaptation of the system to anatomical and physiological conditions of the side of application. Such a matrix is suitable for sustained release application, for example for more than 1 day, typically more than 3 days. Additionally, the matrix can comprise electrically conductive and/or dielectric particles.

[0077] Examples of an alcoholic gel are for instance a gel known as ACTENSA 2,3. This comprises a polymeric matrix which is mixture of cross-linked acrylic acid (Carbopol) and amine oxides containing a mid to long alkyl chain. The polymeric matrix can be prepared e.g. 0% w/w to 80% w/w alcohol, the rest is water and matrix polymer. Additionally, amine oxides can be comprised in the polymeric matrix as non-ionic surfactants. The actual concentration of the enhancer alcohol can be adapted as needed.

[0078] Another example is the cationic gel ACTENSA gel HTU 62. The polymeric matrix this gel is synthesised by free-radical polymerisation of diallyl-dimethyl ammonium chloride with small amounts of co-monomer (tetra-allyl ammonium salt) for cross-linking the polymeric chain. 1g ACTENSA gel HTU 62 swells in 40% w/w ethanol and 60% w/w water for 24h to render a 6Og alcoholic-water polymeric product, which is insoluble in ethanol, water and their mixtures. The concentrations of all components can be adapted to the task.

[0079] Generally, the drug release kinetics typically range from short time periods (minutes) to long time periods (months).

[0080] The drug delivery system can be part of an invasive medical treatment, procedure, implant, equipment and article. For example, the delivery system can be used as an implant for an invasive medical treatment when drug delivery through an intracorporeal biological barrier is desired without rupture of this barrier. Generally, the drug delivery device is, however, used non-invasively.

[0081] The placement of the drug delivery system is rather simple and can be done by experienced medical professionals as well as by the recipient himself. [0082] Target areas for the placement of the above mentioned drug delivery system include the nasal cavity for intranasal as well as the eye for ocular (ophthalmic) application.

[0083] The drug delivery system can be used for one of topical application; intranasal application; ophthalmic application; delivery of pharmaceutical active compounds to the brain; and transdermal delivery of pharmaceutical active compounds. Particularly, the drug delivery system can be used, and is arranged to be suitable, for drug delivery through mucous membranes. Examples of mucous membranes are intranasal mucosa, buccal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa and oral mucosa. The drug delivery system can therefore be arranged for one of intranasal application; ophthalmic application; and oral application.

[0084] The written description above uses specific embodiments to disclose the invention, including the best mode, and also to enable any person skilled in the art to make and use the invention. While the invention has been described in terms of various specific embodiments, those skilled in the art will recognise that the invention can be practiced with modification within the spirit and scope of the claims. Especially, mutually non-exclusive features of the embodiments described above may be combined with each other. The patentable scope is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

Claims

1. A drug delivery system, comprising:

at least one electrode; and

an RF-generator for generating a radio frequency electrical field, the at least one electrode being electrically connected with an output of the RF-generator.

2. The drug delivery system of claim 1 , wherein the matrix further comprises electrically conductive and/or dielectric particles.

3. The drug delivery system of claim 2, wherein the conductive and/or dielectric particles have a size between about 15 μm to about 5000 μm.

4. The drug delivery system of claim 2 or 3, wherein the conductive and/or dielectric particles comprise a coating.

5. The drug delivery system of any of the claims 1 to 4, wherein the matrix comprises one or more separate compartments.

6. The drug delivery system of any of the claims 1 to 5, wherein the matrix can be selected from the group containing gel, liquid and highly viscous liquid.

7. The drug delivery system of claim 6, wherein the matrix is a gel selected from the group containing alcoholic gel, hydrogel, stimuli-responsive polymer gel, and mixtures thereof.

8. The drug delivery system of any of the claims 1 to 7, wherein the permeability- enhancing agent is selected from the group containing aggregation inhibitor, charge modifiers, agents for controlling and buffering pH, redox controlling agents, degradative enzyme inhibitors, mucolytic agents, ciliostatic agents, ligand agents for controlling the interaction between the drug and a biological membrane, absorption enhancing agents, organic solvents, dehydrating agents, surfactants, and mixtures thereof.

9. The drug delivery system of any of the claims 1 to 8, comprising two or more permeability-enhancing agents.

10. The drug delivery system of any of the claims 1 to 9, wherein the pharmaceutical active compound can be selected from the group containing low molecular weight substances, medium molecular weight substances and high molecular weight substances such as amino acids, peptides, proteins, microproteins, prions, enzymes, antibodies, vectors, nucleotides, nucleic acids, RNAs, miRNAs, siRNAs, DNAs, aptamers, spiegelmers, carbohydrates, and derivatives and mixtures thereof.

11. The drug delivery system of any of the claims 1 to 10, comprising two or more pharmaceutical active compounds.

12. The drug delivery system of any of the claims 1 to 11 , wherein the electrode is in contact with the matrix.

13. The drug delivery system of any of the claims 1 to 12, wherein the electrode is insulated from the matrix.

14. The drug delivery system of any of the claims 1 to 13, further comprising two or more electrodes which can be arranged in a simple or complicated geometry like micro-structured electrode arrays or electrode patterns permitting field stimuli like travelling waves and electrical field traps

15. The drug delivery system of any of the claims 1 to 14, wherein the RF- generator is arranged to provide at least one high frequency electrical signal having a frequency in the range from about 5 kHz to about 3 GHz.

16. The drug delivery system of any of the claims 1 to 15, further comprising a release unit which comprises the electrode and the matrix, the release unit being separate from the RF-generator.

17. A method for administering a pharmaceutical active compound, comprising:

applying a radio frequency signal to the electrode.

18. The method of claim 17, wherein the radio frequency signal has a frequency in the range from about 5 kHz to about 3 GHz MHz.

19. The method of claim 17 or 18, wherein the radio high frequency signal is pulsed.

20. The method of any of the claims 17 to 19, wherein a plurality of electrodes are provided which are excited by phase shifted radio frequency signals to provide stimuli like travelling waves or electric field trap phenomena influencing the permeability of the biological barrier.

21. The method of any of the claims 17 to 20, wherein the matrix further comprises electrically conductive and/or dielectric particles.

22. A matrix comprises: at least one pharmaceutical active compound;

at least one permeability-enhancing agent; and

at least one of conductive and dielectric particles.

23. The matrix of claim 22, wherein the conductive particles have a dielectric coating.

24. The matrix of claim 22 or 23, wherein the conductive and/or dielectric particles have a size from about 15 μm to about 5000 μm.

25. Use of the drug delivery system of claim 1 for delivery of a pharmaceutical active compound through at least one of topical application; intranasal application; ophthalmic application; and transdermal application.