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WO2009047365A1 - Système d'administration de médicament - Google Patents

Système d'administration de médicament Download PDF

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Publication number
WO2009047365A1
WO2009047365A1 PCT/EP2008/063740 EP2008063740W WO2009047365A1 WO 2009047365 A1 WO2009047365 A1 WO 2009047365A1 EP 2008063740 W EP2008063740 W EP 2008063740W WO 2009047365 A1 WO2009047365 A1 WO 2009047365A1
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WO
WIPO (PCT)
Prior art keywords
matrix
drug delivery
delivery system
electrode
drug
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Application number
PCT/EP2008/063740
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English (en)
Inventor
Andreas Voigt
Original Assignee
Capsulution Nanoscience Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Publication of WO2009047365A1 publication Critical patent/WO2009047365A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/327—Applying electric currents by contact electrodes alternating or intermittent currents for enhancing the absorption properties of tissue, e.g. by electroporation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0472—Structure-related aspects
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36025—External stimulators, e.g. with patch electrodes for treating a mental or cerebral condition

Definitions

  • 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.
  • BBB blood brain barrier
  • the blood brain barrier 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.
  • the molecule 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.
  • 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.
  • intranasal or topical ocular application route is of interest.
  • 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.
  • 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.
  • a drug delivery system which comprises:
  • a matrix comprising at least one pharmaceutical active compound and at least one permeability-enhancing agent
  • a method for administering a pharmaceutical active compound comprises:
  • 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;
  • a matrix for applying to a biological barrier comprises:
  • a radio frequency (rf) electrical field 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)
  • 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.
  • the mean value of the radio-frequency alternating current signal is substantially zero.
  • Fig. 1 shows a drug delivery system according to an embodiment.
  • Fig. 2 shows a drug delivery system according to another embodiment.
  • Fig. 3 shows frequency spectra of particles used in a matrix for drug delivery systems of Fig. 2.
  • Fig. 4 shows concentration and attenuation of the electrical field by low conductive particles in a matrix.
  • Fig. 5 shows concentration and attenuation of the electrical field by high conductive particles matter in a matrix.
  • Fig. 6 shows the velocity of particles in a liquid matrix as a function of distance from the wire tip due to dielectrophoretic forces.
  • Fig. 7 shows the particle distribution around a single electrode.
  • Fig. 8 shows electrode structures according to certain embodiments.
  • Fig. 9 shows a flow diagram of a method for administering a pharmaceutical active compound. DESCRIPTION OF THE PREFERRED EMBODIMENT
  • biological barrier 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.
  • BBB blood-brain barrier
  • mucosa of the nasal cavity e.g. oral, rectal, vaginal
  • 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.
  • 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.
  • the drug is typically provided in molecular form in the matrix.
  • the drug can be dispersed in the matrix as nanoparticles.
  • the pharmaceutical active compound is suitable for the prevention and treatment of diseases and disorders.
  • the pharmaceutical active compound is suitable for the prevention and treatment of diseases and disorders of the central nervous system.
  • intranasal application or ophthalmic application are particularly used to bypass the blood brain barrier.
  • 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.
  • 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.
  • 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
  • high molecular weight means a molecular weight in the range higher than about 10 000 Da.
  • permeability-enhancing agent 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.
  • a radio frequency electrical field is applied as described further below.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the drug delivery system comprises at least one electrode 400 which can be in contact with a matrix 300.
  • the electrode 400 can be insulated from the matrix 300 but will typically remain in close vicinity thereto.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the RF-generator is arranged to provide one or more radio frequency alternating current signals.
  • 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.
  • no electrochemical 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.
  • 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.
  • 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.
  • the electrical field induces inter alia an electromechanical stress or a dielectrophoretic force on the biological barrier.
  • the strength of the electromechanical stress 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.
  • 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.
  • the given arguments also apply for non-flat biological barrier 200.
  • 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.
  • 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.
  • 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.
  • 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.
  • the electrode forms a capacitor electrode structure.
  • an "open" capacitor is formed with the counter electrode being formed by the remote ground output of the RF-generator.
  • a complex capacitor structure can be formed.
  • FIG. 8 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°.
  • the matrix can comprise electrically conductive and/or dielectric particles 700.
  • 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.
  • electrically conductive particles may "concentrate” the electrical field in close proximity to the biological barrier and thus enhance its influence.
  • electrically insulating 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.
  • a mixture of dielectric and electrically conducting particles is used. Thereby, the electric field inhomogeneity can further be increased.
  • 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.
  • 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.
  • 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.
  • 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.
  • the time dependent electric field is determined as negative gradient of the potential ⁇ and is of the form
  • the electrically conductive and/or dielectric particles can be coated. Such particles are referred to as composite particles.
  • conductive particles can be coated with a dielectric shell.
  • the effective complex admittance ⁇ p in eq. (3) has e.g. to be replaced by
  • indices i and m refer to
  • Fig. 3 shows the Claussius-Mossotti-factor as function of field frequency for four 10 ⁇ m 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 ⁇ S/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.
  • the lower parts of Figs. 4 and 5 correspond to mean square electric field in z- and x-directions.
  • the field is attenuated and concentrated in direction of the external field for low and high conductive particles, respectively.
  • 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.
  • 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.
  • 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).
  • a method for administering a pharmaceutical active compound is explained.
  • 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.
  • an rf-field at a first frequency fi in step 2000.
  • an electromechanical stress is applied to the interface 200 which facilitates the drug administration through the barrier 200.
  • 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.
  • the electric field can be varied in accordance with a relaxation time of a membrane channel or protein.
  • 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.
  • the matrix droplet can contain electrically conductive and/or dielectric particles 700 which are pushed in step 2000 towards the interface 2000.
  • particle 700 which shows both negative and positive values of Re[fcw ⁇ ] at certain frequencies, as the shelled particles corresponding to the curves 21 and 22 of Fig. 3, are used.
  • the frequency fi where the particles have a negative value of Re[f ⁇ v ⁇ ] is used.
  • the field can be switched to a frequency f 2 where field concentration occurs.
  • the rf fields can be pulsed, voltage modulated and or switched between different frequencies to apply time pattern of stresses and or forces.
  • the present method is different to known methods for administering a drug.
  • iontophoresis employs a direct current (dc electric field) to propel a charged substance transdermally.
  • ionotophoresis drives transdermal ⁇ a charged drug under influence of a mean dc-fieid.
  • an rf-ac field is applied.
  • the present invention does not require that the drug is charged since the drug itself is not propelled by the rf-ac field.
  • the rf-ac field increases the permeability of the biological barrier by inducing electromechanical tensions.
  • 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.
  • 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.
  • cosmetic treatments results only in an adsorption of a compound into the skin by avoiding a penetration of the skin and a systemic distribution.
  • the present method can be understood as a rf-mediated drug delivery through a biological barrier using an alternating electrical field.
  • 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 ⁇ T is proportional to the electrical conductivity ⁇ of the matrix drop, thermal conductivity ⁇ , and the mean square voltage drop JJ T
  • the induced temperature increase is typically in the order of 1° per square voltage.
  • a matrix 300 comprised of an "intelligent" gel to trigger drug release either by temperature changes or by direct field effects.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m, 20 ⁇ m,.30 ⁇ m or 50 ⁇ m and reaching up to 500 ⁇ m, 1000 ⁇ m, 2000 ⁇ m or even 5000 ⁇ m.
  • Example ranges are from 15 ⁇ m to 500 ⁇ m, 20 ⁇ m to 1000 ⁇ m, 30 ⁇ m to 2000 ⁇ m and 50 ⁇ m to 1000 ⁇ m.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m to about 5000 ⁇ m and typically in the range from about 30 ⁇ m to about 1000 ⁇ m.
  • 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.
  • 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.
  • 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.
  • the release unit can be formed sheet-like, strip-like or spot-like.
  • the release unit is formed and shaped to allow insertion into the nasal cavity.
  • the target biological barrier is arranged in a cavity, the release unit is arranged and shaped to be insertable into that cavity.
  • 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.
  • 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.
  • 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.
  • the drug delivery system can be placed non-invasively by state of the art techniques to the required site of drug delivery.
  • 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.
  • Such a matrix 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.
  • a matrix is suitable for sustained release application, for example for more than 1 day, typically more than 3 days.
  • the matrix can comprise electrically conductive and/or dielectric particles.
  • 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.
  • 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.
  • ACTENSA gel HTU 62 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.
  • concentrations of all components can be adapted to the task.
  • the drug release kinetics typically range from short time periods (minutes) to long time periods (months).
  • the drug delivery system can be part of an invasive medical treatment, procedure, implant, equipment and article.
  • 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.
  • the drug delivery device is, however, used non-invasively.
  • 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.
  • 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.
  • the drug delivery system can be used, and is arranged to be suitable, for drug delivery through mucous membranes.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un système d'administration de médicament qui comprend une matrice comprenant au moins un composé pharmaceutique actif et au moins un agent d'amélioration de la perméabilité ; au moins une électrode ; et un générateur RF destiné à générer un champ électrique radiofréquence, la ou les électrodes étant reliées électriquement à une sortie du générateur RF.
PCT/EP2008/063740 2007-10-12 2008-10-13 Système d'administration de médicament WO2009047365A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US97940907P 2007-10-12 2007-10-12
EP07118407 2007-10-12
US60/979,409 2007-10-12
EP07118407.1 2007-10-12

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WO2009047365A1 true WO2009047365A1 (fr) 2009-04-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7610785B2 (ja) 2020-05-28 2025-01-09 コーニンクレッカ フィリップス エヌ ヴェ 口腔ケア装置及び方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5843015A (en) * 1993-12-28 1998-12-01 Becton Dickinson And Company Molecules for iontophoretic delivery
US5857993A (en) * 1996-07-12 1999-01-12 Empi, Inc. Process of making an iontophoresis electrode
EP1177813A1 (fr) * 1999-04-13 2002-02-06 Hisamitsu Pharmaceutical Co. Inc. Dispositif d'iontophorese
US20020065533A1 (en) * 2000-06-08 2002-05-30 Massachusetts Institute Of Technology Localized molecular and ionic transport to and from tissues
WO2005044366A2 (fr) * 2003-10-31 2005-05-19 Alza Corporation Systeme et methode d'administration de vaccin transdermique
US20050273046A1 (en) * 2004-06-03 2005-12-08 Kwiatkowski Krzysztof C Transdermal delivery of therapeutic agent

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5843015A (en) * 1993-12-28 1998-12-01 Becton Dickinson And Company Molecules for iontophoretic delivery
US5857993A (en) * 1996-07-12 1999-01-12 Empi, Inc. Process of making an iontophoresis electrode
EP1177813A1 (fr) * 1999-04-13 2002-02-06 Hisamitsu Pharmaceutical Co. Inc. Dispositif d'iontophorese
US20020065533A1 (en) * 2000-06-08 2002-05-30 Massachusetts Institute Of Technology Localized molecular and ionic transport to and from tissues
WO2005044366A2 (fr) * 2003-10-31 2005-05-19 Alza Corporation Systeme et methode d'administration de vaccin transdermique
US20050273046A1 (en) * 2004-06-03 2005-12-08 Kwiatkowski Krzysztof C Transdermal delivery of therapeutic agent

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7610785B2 (ja) 2020-05-28 2025-01-09 コーニンクレッカ フィリップス エヌ ヴェ 口腔ケア装置及び方法

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