EP1874212A1 - Dispositif de microporation destine a former des pores dans une membrane biologique, et systeme integre d'administration de permeants - Google Patents

Dispositif de microporation destine a former des pores dans une membrane biologique, et systeme integre d'administration de permeants

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Publication number
EP1874212A1
EP1874212A1 EP05742820A EP05742820A EP1874212A1 EP 1874212 A1 EP1874212 A1 EP 1874212A1 EP 05742820 A EP05742820 A EP 05742820A EP 05742820 A EP05742820 A EP 05742820A EP 1874212 A1 EP1874212 A1 EP 1874212A1
Authority
EP
European Patent Office
Prior art keywords
permeant
porator
initial
dataset
initial microporation
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05742820A
Other languages
German (de)
English (en)
Inventor
Thomas Bragagna
Reinhard Braun
Daniel Gfrerer
Bernhard Nussbaumer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pantec Biosolutions AG
Original Assignee
Pantec Biosolutions 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
Publication date
Application filed by Pantec Biosolutions AG filed Critical Pantec Biosolutions AG
Publication of EP1874212A1 publication Critical patent/EP1874212A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/203—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser applying laser energy to the outside of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00743—Type of operation; Specification of treatment sites
    • A61B2017/00747—Dermatology
    • A61B2017/00765—Decreasing the barrier function of skin tissue by radiated energy, e.g. using ultrasound, using laser for skin perforation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00452—Skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/06—Measuring instruments not otherwise provided for
    • A61B2090/062—Measuring instruments not otherwise provided for penetration depth

Definitions

  • This invention relates generally to the field of transmembrane delivery of permeants like drugs or bioactive molecules to an organism. More particularly, this invention relates to a microporator for porating a biological membrane and an integrated permeant administering system comprising the microporator for porating the biological member.
  • the device and method according to the invention utilize a micro- porator for porating a biological membrane like the skin, to create a microporation consisting of a plurality of individual pores.
  • a laser micro-porator is used.
  • the micro-porator ablates or punctures the biological membrane, in particular the stratum corneum and part of the epidermis of the skin. This affects individual micropores in the skin, which results in an increase in skin permeability to various substances, which allows a transdermal or intradermal delivery of substances applied onto the skin.
  • a microporation created by the micro-porator in one session comprises a plurality of individual pores, having a total number in the range between 10 and 1 million individual pores.
  • each individual pore a permeation surface within the skin is created.
  • an initial permeation surface is created, which is the sum of the permeation surfaces of all individual pores. Due to cell growth, the permeation surface of each individual pore decreases over time, and therefore also the total permeation surface, which is the sum of the permeation surface of all individual pores, decreases over time. The decrease of the permeation surface over time depends in particular on the geometrical shape of the individual pore.
  • the micro-porator according to the invention has the ability to reproducibly create a microporation with a predetermined initial permeation surface and preferably also with a predetermined function of the total permeation surface over time.
  • Any biological tissue, but in particular the skin, can be porated with a microporator according to the invention.
  • a microporator using a laser beam for creating pores is used.
  • a device for heating via conductive materials or a device generating high voltage electrical pulses can be used for creating pores.
  • US 6,148,232 disclose a technique for creating micro-channels by using an electrical field. This device could also be suitable for creating micropores of predetermined shapes, if provided with additional means to reproducibly create micropores, such as feedback means according to the , invention, to detect characteristics of the individual micropores.
  • the amount of substances delivered through the biological membrane depends on the permeation surface and its variation over time.
  • the present invention therefore also provides an integrated permeant administering system to provide a permeant like a drug, to provide an appropriate initial microporation dataset, and to provide a micro-porator to create a microporation according to the individual microporation dataset. After the microporation is created, a permeant is applied onto the skin, and the transdermal or intradermal delivery of the permeant takes place in a predetermined way.
  • the system allows, for a specific drug, to select an appropriate initial microporation dataset out of a plurality of initial microporation datasets, so that a microporation is created according to the appropriate initial microporation dataset.
  • the transdermal delivery of the drug in function of time is mainly determined by the function of the permeation surface over time.
  • the integrated permeant administering system therefore also allows to individually apply a drug, and for example to reach a predetermined concentration of a drug in the blood according to individual needs.
  • microporation means the formation of small holes or pores to a desired depth in or through the biological membrane or tissue, such as the skin, the mucous membrane or an organ of a human being or a mammal, or the outer layer of an organism or a plant, to lessen the barrier properties of this biological membrane to the passage of permeants or drugs into the body.
  • the microporation referred to herein shall be no smaller than 1 micron across and at least 1 micron in depth.
  • micropore As used herein, "micropore”, “pore” or 'Individual pore” means an opening formed by the microporation method.
  • ablation means the controlled removal of material which may include cells or other components comprising some portion of a biological membrane or tissue.
  • the ablation can be caused, for example, by one of the following:
  • the device causing the ablation is herein called the ablator.
  • tissue means any component of an organism including but not limited to, cells, biological membranes, bone, collagen, fluids and the like comprising some portion of the organism.
  • puncture or “micro-puncture” means the use of mechanical, hydraulic, sonic, electromagnetic, or thermal means to perforate wholly or partially a biological membrane such as the skin or mucosal layers of a human being or a mammqi, or the outer tissue layers of a plant.
  • puncture surface means the surface of the hole or pore at the outer surface of the biological membrane, which has been ablated or punctured.
  • transdermal or “percutaneous” or “transmembrane” or “transmucosal” or “transbuccal” or “transtissual” or “intratissual” means passage of a permeant into or through the biological membrane or tissue to deliver permeants intended to affect subcutaneous layers and further tissues such as muscles, bones. Ih the most preferred embodiment the transdermal delivery introduces permeants into the blood, to achieve effective therapeutic blood levels of a drug.
  • intradermal means passage of a pe ⁇ neant into or through the biological membrane or tissue to delivery the permeant to the dermal layer, to therein achieve effective therapeutic or cosmetic tissue levels of a permeant, or to store an amount of permeant during a certain time in the biological membrane or tissue, for example to treat conditions of the dermal layers beneath the stratum corneum.
  • permeation surface means the surface of the tissue surrounding the micropore or pore.
  • Permeation surface may mean the surface of an individual micropore or pore, or may mean the total permeation surface, which means the sum of all individual surfaces of all individual micropores or pores.
  • corrected permeation surface means the permeation surface corrected by a factor or a specific amount, for example by subtracting the surface of the micropore or pore which is part of the stratum corneum.
  • bioactive agent As used herein, the term "bioactive agent,” “permeant,” “drug,” or
  • pharmacologically active agent 1 or “deliverable substance” or any other similar term means any chemical or biological material or compound suitable for delivery by the methods previously known in the art and/or by the methods taught in the present invention, that induces a desired effect, such as a biological or pharmacological effect, which may include but is not limited to (1) having a prophylactic effect on the organism and preventing an undesired biological effect such as preventing an infection, (2) alleviating a lack or excess of substances (e.g.
  • a condition caused by a disease for example, alleviating pain or inflammation caused as a result of disease
  • the effect may be local, such as providing for a local anaesthetic effect, or it may be systemic.
  • This invention is not drawn to novel permeants or to new classes of active agents other than by virtue of the microporation technique, although substances not typically being used for transdermal, transmucosal, transmembrane or transbuccal delivery may now be useable. Rather it is directed to the mode of delivery of bioactive agents or permeants that exist in the art or that may later be established as active agents and that are suitable for delivery by the present invention.
  • Such substances include broad classes of compounds normally delivered into the organism, including through body surfaces and membranes, including skin as well as by injection, including needle, hydraulic, or hypervelocity methods.
  • this includes but is not limited to: Polypeptides, including proteins and peptides (e.g., insulin); releasing factors, including Luteinizing Hormone Releasing Hormone (LHRH); carbohydrates (e.g., heparin); nucleic acids; vaccines; and pharmacologically active agents such as antiinfectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; flnrtTiigfoi mining; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; anti
  • an "effective" amount of a permeant means a sufficient amount of a compound to provide the desired local or systemic effect and performance at a reasonable benefit/risk ratio attending any treatment.
  • carriers or “vehicles” refer to carrier materials without significant pharmacological activity at the quantities used that are suitable for administration with other permeants, and include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, microspheres, liposomes, microparticles, lipid complexes, or the like, that is sufficiently nontoxic at the quantities employed and does not interact with the drug to be administered in a deleterious manner.
  • suitable carriers include water, buffers, mineral oil, silicone, inorganic or organic gels, aqueous emulsions, liquid sugars, lipids, microparticles and nanoparticles, waxes, petroleum jelly, and a variety of other oils, polymeric 'materials and liposomes.
  • a "biological membrane” means a tissue material present within a living organism that separates one area of the organism from another and, in many instances, that separates the organism from its outer environment. Skin and mucous and buccal membranes are thus included as well as the outer layers of a plant. Also, the walls of a cell, organ, tooth, bone, or a blood vessel would be included within this definition.
  • transdermal flux rate is the rate of passage of any bioactive agent, drug, pharmacologically active agent, dye, particle or pigment in and through the skin separating the organism from its outer environment.
  • Transmembrane flux rate refers to such passage through any biological membrane.
  • the term "individual pore” as used in the context of the present application refers to a micropore or a pore, in general a pathway extending from the biological membrane. The biological membrane for example being the skin, the individual pore then extending from the surface of the skin through all or significant part of the stratum corneum.
  • Ih the most preferred embodiment the pathway of the individual pore extending through all the stratum corneum and part of the epidermis but not extending into the dermis, so that no bleeding occurs. Ih the most preferred embodiment the individual pore having a depth between 10 um (for newborns 5 ⁇ m) and 150 ⁇ m.
  • Initial microporation refers to the total number of pores created.
  • Initial microporation dataset refers to the set of data, wherein the initial microporation is defined.
  • the dataset including at least one parameter selected from the group consisting of: cross-section, depth, shape, permeation surface, total number of individual pores, geometrical arrangement of the pores on the biological membrane, minimal distance between the pores and total permeation surface of all individual pores.
  • the initial microporation dataset defines the shape and geometrical arrangement of all individual pores, which then will be created using the microporator, so that the thereby created initial microporation is exactly deployed and can be reproduced on various locations of the biological membrane, also on different objects, subjects or persons.
  • the present invention employs a micro- porator comprising a controller, an initial microporation dataset and an ablator for creating a microporation, the controller reading the initial microporation dataset, and the controller controlling the ablator based on the initial microporation dataset to create a microporation as defined by the initial microporation dataset.
  • a microporation is created with a predetermined initial permeation surface, and preferably also with a predetermined permeation surface over time.
  • the ablator can be built in various ways, using various techniques.
  • the ablator can for example consist of mechanically driven needles.
  • the needles may be heated to ablate the biological membrane by heating. Ih the most preferred embodiment a pulsed laser beam is used to create individual pores.
  • the laser micro-porator applies a parallel or quasi-parallel laser beam on the biological membrane, which facilitates control over the precise shape of the individual pore.
  • parallel or quasi-parallel laser beam refers to a laser beam that has a divergence of less than 3°, at least within a certain range of focus, the focus or focus range, extending in direction of the propagation direction of the laser beam, is a range of about 1 cm to 5 cm, preferably a range of 2 cm to 3 cm.
  • the laser micro-porator using a parallel or quasi- parallel laser beam allows creation of individual pores with highly reproducible permeation surfaces. Ih the most preferred embodiment the laser micro-porator comprises a feedback loop which is operatively coupled to the poration controller that actuates the laser source.
  • the poration controller compares the measured characteristic of an individual pore with a predetermined value and stops emitting further laser pulses on the individual pore if the characteristic of the individual pore corresponds to the preset value, or if the characteristic of the individual pore 2 is within a preset range. Most preferred the depth of the individual pore is monitored. This allows creation of an individual pore similar to drilling a hole in a material, in that the depth of the hole e.g. the pore is repeatedly measured. This allows to very accurately microporate a biological membrane so that the created microporation corresponds to the predetermined values of the initial microporation dataset.
  • the plurality of laser pulses applied onto the same pore allows creating individual pores having a reproducible shape of the wall surrounding the individual pore and preferably allows also creating a reproducible shape of the lower end of the individual pore.
  • the surface of the wall and the lower end is of importance, in particular the sum of the surface of the wall and the surface of the lower end which are part of the epidermis or the dermis, because this sum of surfaces forms a permeation surface through which most of the permeate passes into the tissue, for example into the epidermis and the dermis.
  • the micro- porator is able to detect the depth at which the stratum corneum ends, e.g. the epidermis starts, for example, by using a spectrograph.
  • the effect of the stratum corneum can be considered by calculating a corrected permeation surface.
  • This corrected permeation surface for example comprising only the permeation surface of the epidermis.
  • the total permeation surface of all individual pores can also be determined.
  • Knowing the corrected permeation surface which means the permeation surface of the epidermis, allows one to better control or predict the transdermal delivery of drug into the patient, e.g. to better control or predict the release of the drug into the patient.
  • the micro- porator can create a microporation having a number of individual pores in the range between 10 and up to 1 million, and having individual pores with a width between 0,01 and 0,5 mm, and a depth between 5 um and 200 um, as defined by the initial microporation dataset.
  • the micro-porator comprises an interface to at least read the initial microporation dataset, and to preferably read further parameters like permeant information, user information or porator application information.
  • the micro- porator comprises a database that stores a plurality of initial microporation datasets.
  • the micro-porator comprises a selector, which manually or automatically selects, for example based on user information such as the age, the most appropriate initial microporation dataset. lhe pores are then created according to this most appropriate initial microporation dataset.
  • the micro- porator can also comprise an inhibitor which inhibits the porator from porating if certain conditions are not fulfilled.
  • the micro- porator according to the invention allows creating on a biological membrane a wide variety of different, reproducible microporations, such as a wide variety of initial permeation surfaces and such as a wide variety of decreases of the permeation surface over time.
  • the permeation surface affects the transdermal or intradermal delivery of the permeant like the drug. Therefore even the same drug or the same amount of drug applied onto the skin can be delivered differently into the skin, depending on the permeation surface.
  • an integrated permeant administering system which considers relevant parameters regarding the permeant, the initial microporation dataset and the micro- porator, so that, after microporating the skin and after applying the drug onto the skin, the drug is released as requested into the skin, so that, for example, a defined blood-level profile is achieved.
  • a substance such as a drug is applied onto the skin, preferably in form of a transdermal patch.
  • the transdermal patch offers a variety of significant clinical benefits over other dosage forms. Because passive as well as active transdermal patches deliver a predetermined drug concentration, and because the permeation surface over time being known, the transdermal patch offers controlled release of the drug into the patient, which for example enables a defined blood-level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms. In addition, transdermal patches are user-friendly, convenient, painless, and offer multi-day dosing. Transdermal patches therefore offer improved patient compliance. A substance can also be applied for cosmetic purpose only, for example applied intradermal.
  • the micro-porator for porating a biological membrane may be designed, for example, as the laser micro-porator disclosed in PCT patent application No. PCT/EP2005/051704 of the same applicant, filed on the same day and entitled "Laser microporator and method for operating a laser microporator”.
  • the biological membrane may be porated according to a method, for example, as disclosed in PCT patent application No. PCT/EP2005/051703 of the same applicant, filed on the same day and entitled "Method for creating a permeation surface". All citations herein are incorporated by reference in their entirety.
  • Fig. 1 shows a schematic cross-section of one pore of a laser porated skin
  • Fig. 2 shows a laser micro-porator device
  • Fig. 2a shows a further micro-porator device
  • Fig. 3a shows a perspective view of a micro-poration of the skin
  • Fig. 3b shows a plan view of the skin with an array of micro-porations
  • Fig. 3c shows a schematic cross-section of a porated skin with a drug container attached to the skin surface
  • Fig. 4 shows the permeation surface of all micropores over time
  • Fig. 5a shows a given permeation surface and a created permeation surface
  • Fig. 5b shows transdermal delivery of a drug over time, in combination with a permeation surface
  • Fig. 6 shows a drug cassette containing two drug containers
  • FIg. 7 shows a schematic view of a laser micro- porator
  • Fig. 8 shows a schematic view of a further laser micro- porator
  • Fig. 9 shows a block diagram of an integrated drug administering system
  • Fig. 10a, 10b show the serum concentration of a drug over time, with the same amount of drug but different permeation surfaces.
  • Figure 1 shows a cross-sectional view of the top layers of the biological membrane 1, a human skin, including a stratum corneum Ia, an epidermal layer or epidermis Ib and a dermal layer or dermis Ic.
  • stratum corneum Ia Underlying the stratum corneum Ia is the viable epidermis or epidermal layer Ib, which usually is between 50 and 150 um thick.
  • the epidermis contains no blood vessels and freely exchanges metabolites by diffusion to and from the dermis Ic, located immediately below the epidermis Ib.
  • the dermis Ic is between 1 and 3 mm thick and contains blood vessels, lymphatics and nerves. Once a drug reaches the dermal layer, the drug will generally perfuse through system circulation.
  • Figure 1 also shows a parallel or quasi- parallel laser beam 4 having a circular shape with a diameter D and acting on the surface of the skin 1.
  • the impact of the laser beam 4 onto the skin 1 causes an ablation of the tissue.
  • a first shot of the laser beam 4 causes an individual pore 2 with a lower end 3a.
  • the first shot effecting a puncture surface B at the outer surface of the skin 1 in the size of about (D/2) 2 *p, which corresponds to the amount of the outer surface of the biological membrane, which has been ablated or punctured.
  • a second shot of the laser beam 4 at the same location causes an increase in depth of the individual pore 2 up to the lower end 3b, and a third and forth shot at the same location causes a further increase in depth up to the lower ends 3c and 3d.
  • the total surface of the tissue 1 surrounding the individual pore 2 corresponds to the permeation surface A. There is no tissue 1 at the puncture surface B, therefore the puncture surface B is not part of the permeation surface A.
  • Each individual pore 2 of the epidermis Ib has a cell growth of usually (untreated) 3 to 15 um per day, the cells usually growing from the lower end of the individual pore 2 in direction Z to the stratum corneum Ia. Which means the lower end 3d of the individual pore 2 is moving into the direction of the stratum corneum with a speed of about 3 to 15 ⁇ m/day, thereby reducing the permeation surface A.
  • the corrected permeation surface being the permeation surface of the epidermis Ib only, without the surface of the stratum corneum Ia, becomes the size of the puncture surface, which means the surface of the hole in the stratum corneum, as soon as the cells have reached the stratum corneum Ia.
  • the remaining hole in the stratum corneum Ia will by the time be filled by death cells of the epidermis, which significantly increases the barrier properties in the remaining hole, and which regenerates the stratum corneum.
  • the individual pore 2 has vanished due to cell growth, and the formerly ablated tissue is regenerated by new cells.
  • FIG. 2 shows a laser micro- porator 10 comprising a laser source 7 and a laser beam shaping and guiding device 8.
  • the laser source 7 comprises a laser pump cavity 7a containing a laser rod 7b, preferably Er doped YAG, an exciter 7c that excites the laser rod 7b, an optical resonator comprised of a high reflectance mirror 7d positioned posterior to the laser rod and an output coupling mirror 7e positioned anterior to the laser rod, and an absorber 7f positioned posterior to the laser rod.
  • a focusing lens 8a and a concave diverging lens 8b are positioned beyond the output coupling mirror 7e, to create a parallel or quasi-parallel laser beam 4.
  • the diverging lens 8b can be moved by a motor 8c in the indicated direction.
  • a variable absorber 8d driven by a motor 8e, is positioned beyond the diverging lens 8b, to vary the energy fluence of the laser beam 4.
  • a deflector 8f a mirror, driven by an x-y-drive 8g, is positioned beyond the absorber 8d for directing the laser beam 4 in various directions, to create individual pores 2 on the skin 1 on different positions.
  • the laser microporator 10 also comprises a control device 11, which connected by wires 11a with the laser source 7, drive elements 8c, 8e, 8g, sensors and other elements not disclosed in detail.
  • the laser porator 10 also includes a feedback loop.
  • the feedback loop comprises an apparatus 9 to measure the depth of the individual pore 2, and preferably includes a sender 9a with optics that produce a laser beam 9d, and a receiver with optics 9b.
  • the laser beam 9d has a smaller width than the diameter of the individual pore 2, for example five times smaller, so that the laser beam 9d can reach the lower end of the individual pore 2.
  • the deflection mirror 8f directs the beam of the sender 9a to the individual pore 2 to be measured, and guides the reflected beam 9d back to the receiver 9b.
  • the depth of the individual pore 2 is measured each time after a pulsed laser beam 4 has been emitted to the individual pore 2, allowing controlling the effect of each laser pulse onto the depth of the individual pore 2.
  • the feedback loop 13 may, for example, comprise a sender 9a and a receiver 9b, built as a spectrograph 14, to detect changes in the spectrum of the light reflected by the lower end of the individual pore 2. This allows, for example, detecting whether the actual lower end 3a, 3b, 3c, 3d of the individual pore 2 is part of the stratum corneum Ia or of the epidermis Ib.
  • the controller 11 also comprises a poration memory 12 containing at least specific data of the individual pores 2, in particular the initial microporation dataset.
  • the laser porator 10 preferably creates the individual pores 2 as predescribed in the poration memory 12.
  • the laser porator 10 also comprises one ore more input-output device 15 or interfaces 15, to enable data exchange with the porator 10, for example to enable the transfer of the parameters of the individual pores 2, the initial microporation dataset, into the poration memory 12, or to get data such as the actual depth or the total surface Ai of a specific individual pore 21
  • the pulse repetition frequency of the laser source 7 is within a range of 1 Hz to 1 MHz, preferably within 100 Hz to 100 kHz, and most preferred within 500 Hz to 10 kHz.
  • between 2 and 1 million individual pores 2 can be produced in the biological membrane 1, preferably 2 to 10000 individual pores 2, and most preferred 10 to 1000 individual pores 2, each pore 2 having a width in the range between 0,05 mm and 0,5 mm, and each pore 2 having a depth in the range between 5 ⁇ m and maximal 150 ⁇ m, but the lower end of the individual pore 2 being within the epidermis Ib.
  • the laser porator 10 also comprises an interlock mechanism, so that a laser pulse is emitted only when it is directed onto the skin 1.
  • the feedback loop 9 is operatively coupled to the poration controller 11, which, for example, can compare the depth of the individual pore 2 with a predetermined value, so that no further pulse of the laser beam 4 is directed to the individual pore 2 if the characteristic of the individual pore 2, for example, the depth, is greater than or equal to a preset value, or if the characteristic of the individual pore 2 is within a predetermined range. This allows creation of individual pores 2 with a predetermined depth.
  • the laser beam 4 is operated as follows: If, for example, the measured depth is close to the value of the predetermined depth, the emitted energy per pulse of the laser beam 4 can be reduced, to create a pulse that ablates a smaller amount of tissue per pulse, so that the final depth of the individual pore 2 can be reached more accurate.
  • FIG. 2a shows a further embodiment of a laser micro- porator 10 comprising a controller 11, a single laser source 7 and optics 8 which guide the laser beam 4 into a plurality of fiberoptics 8h, thereby splitting up the laser beam 4 into a plurality of individual laser beams 4a, 4b, 4c, 4d.
  • All fiberoptics 8h together form a deflector 8f, which directs the individual laser beams 4a, 4b, 4c, 4d in various directions.
  • the exit end of each fiberoptics Sh has an individually oriented surface, such that the individual laser beams 4a, 4b, 4c, 4d leaving the fiberoptics 8h form an array of, for example, parallel individual laser beams 4a, 4b, 4c, 4d.
  • the controller 11 comprises a poration memory 12, wherein at least an initial microporation dataset D can be stored.
  • Figure 3a shows an array of individual pores 2 in the skin 1, created by a micro-porator 10.
  • all individual pores 2 have about the same shape and depth.
  • the individual pores 2 may also have different shapes and depths, depending on the initial microporation dataset D.
  • Figure 3b shows a plan view of the skin having a regular array of individual pores 2 that collectively form a micro-poration.
  • the poration memory 12 contains the initial microporation dataset, which define the initial microporation.
  • the initial microporation dataset comprises any suitable parameters, including: width, depth and shape of each pore, total number of individual pores 2, geometrical arrangement of the pores 2 on the biological membrane, minimal distance between the pores 2, and so forth.
  • the laser porator 10 creates the pores 2 as defined by the initial microporation dataset D. This also allows arranging the individual pores 2 in various shapes on the skin 1.
  • Figure 3c discloses a transdermal patch 5 comprising a drug container 5a and an attachment 5b, which is attached onto the skin 1, the drug container 5a being positioned above an area comprising individual pores 2.
  • the area can have a surface, depending on the number and spacing of the individual pores 2, in the range between 1 mm 2 and 1600 mm 2 .
  • Preferred 20 x 20 mm e.g. a surface of 400 mm 2 .
  • the laser porator 10 comprises a distance measurement apparatus 9, which facilitates determining the permeation surface Ai very accurately.
  • the beginning of the epidermis is estimated by first determining the thickness of the stratum corneum. This in turn either permits determination of a corrected permeation surface Ai for each individual pore 2i, which establishes the effective permeation surface of the epidermis Ib, or which permits to increase the depth of the individual pore 2i by the thickness of the stratum corneum.
  • This permeation surface Ai can easily be calculated for each individual pore 2L If the individual pore 2i has the shape of, for example, a cylinder, the permeation surface Ai corresponds to the sum of D * p * H and (D /2) 2 * p, D being the diameter of the individual pore 2, and H being the total depth of the individual pore 2 or the depth of the individual pore 2 within the epidermis Ib.
  • the effective permeation surface Ai in the pore 2 often doesn't correspond exactly to the geometrical shape, ced by D and H because the surface of the pore 2 may be rough or may comprise artefacts, which means the effective permeation surface is bigger than the calculated permeation surface AL
  • the permeation surface Ai is at least a reasonable estimate of the effective permeation surface. Usually there is only a small or no difference between the permeation surface Ai and the effective permeation surface in the pore 2.
  • the total permeation surface A of n individual pores 2i is then the sum A of all permeation surfaces Ai of all individual pores 2i
  • Each individual pore 2 of the epidermis has a cell growth of usually 3 to 15 um per day, the cells growing from the lower end of the individual pore 2 in direction Z to the stratum corneum Ia.
  • This cell growth causes the permeation surface Ai of each individual pore 2L respectively the total permeation surface A of all individual pores 2 to decrease in function of time.
  • the total permeation surface in function of time can be varied in a wide range.
  • the initial permeation surface and also the decrease of the permeation surface over time can be predicted and calculated by an appropriate choice of the number of pores 2 and their geometrical shape.
  • This definition of all pores is stored as the initial microporation dataset D. Correction factors may be applied to this initial microporation dataset D, for example based on user information like individual speed of cell growth, or based on the optional use of regeneration delayer like occlusive bandage, diverse chemical substances, etc., which influence the speed of cell growth.
  • Figure 4 shows an example of the total permeation surface A as a function of time.
  • Figure 4 shows the corrected total permeation surface A(t), which is the total permeation surface A(t) of the epidermis Ia only, lhe laser- porator 10 allows to micro- porating a biological membrane 1 by the creation of an array of micropores 2 in said biological membrane 1, whereby the number of micropores 2 and the shape of these micropores 2 is properly selected so that the sum of the micropores 2 forming an initial permeation surface, and that the permeation surface A (t) of the initial permeation surface decreases in a predetermined function over time, due to cell growth in the micropores 2.
  • the initial microporation dataset D according to figure 4 comprises three groups of cylindrical micropores 2 with different shapes:
  • - a first group consisting of 415 pores with a diameter of 250 um, a depth of 50 um and a permeation surface Al as a function of time.
  • - a second group consisting of 270 pores with a diameter of 250 um, a depth of 100 um and a permeation surface A2 as a function of time.
  • - a third group consisting of 200 pores with a diameter of 250 um, a depth of 150 um and a permeation surface A3 as a function of time.
  • the total permeation surface A as a function of time is the sum of all three permeation surfaces Al, A2 and A3.
  • All individual pores 2i which means the initial microporation, are created within a very short period of time, for example, within a time range of less than a second, so that beginning with the time of poration TP, the sum of all created pores 2i forming an initial permeation surface of 90 mm 2 , which, due to cell growth, decreases as a function of time. At the time TC all individual pores 2i are closed, which means that the value of the permeation surface A becomes very small or zero. Depending on the number of pores 2 and their shape, in particular the diameter and depth of the pores 2, the function over time of the total permeation surface A can be varied in a wide range.
  • FIG. 4 shows the total permeation surface A over a time period of 9 days, starling with an initial permeation surface of 90 mm 2 .
  • the permeation surface A decreases within 9 days to a very small value or to zero.
  • the time period may be much shorter, for example, just 1 day, or even shorter, for example, a few hours.
  • FIG. 5a shows a given function AG of a permeation surface as a function of time.
  • Figure 5a also shows the permeation surface of different groups Al, A2, A3, A4, A5, .... of individual pores 2 over time.
  • Each group being defined by a number of pores, a diameter and a depth. All individual pores 2 have u cylindrical shape.
  • a permeation surface A(t) is achieved, which function over time is quite similar to the given function AG.
  • the different groups of individual pores, their number and their shape can be determined by mathematical methods known to those skilled in the art The definition of these groups is stored as the initial microporation dataset D.
  • Figure 3c shows a patch 5 containing a drug 5a and being fixed onto the skin 1, above the individual pores 2.
  • Figure 5b shows the serum concentration S of this drug as a function of time in the blood.
  • the drug is entering the permeation surface by passive diffusion.
  • the amount of drug entering the permeation surface is mainly determined by the permeation surface Ait) over time. Therefore, the serum concentration as a function of time can be determined by an appropriate poration of the skin 1 with an initial microporation.
  • Figure 6 shows a pe ⁇ neant 5a, which, for example, is a drug or a drug container containing a drug.
  • the permeant 5a comprises permeant information FI stored on a data carrier 5c.
  • a plurality of permeants 5a can be stored in a cassette 5d.
  • the cassette 5d can also comprise a data carrier 5d.
  • the permeant information FI contains at least one data selected from the group: manufacturer ID 1 product ID, specific product ID, specific drug, drug concentration, nominal drug volume, drug container size, serial number, lot number, expiration date, initial microporation dataset D.
  • the permeant information PI can also comprise information regarding doses, for example a minimal dose/day or a maximal dose/day.
  • the permeant information PI can also contain the information of the entire patient information leaflet.
  • Figure 2a shows a micro-porator 10 for porating a biological membrane 1, comprising: a controller 11, an initial microporation dataset D stored in the poration memory 12, and an ablator 10a for creating a microporation on the biological membrane 1, the controller 11 controlling the an ablator 10a based on the initial microporation dataset D, to create the microporation as defined by the initial microporation dataset D.
  • the micro-porator 10 may be programmed with just one fixed initial microporation dataset D.
  • This microporator IO can, for example, be sold in combination with a specific drug.
  • the data carrier 5c can be inserted into the micro-porator 10, the data carrier 5c containing the initial microporation dataset D.
  • Figure 7 shows a micro-porator 10 comprising a controller 11, an interface 15, a poration memory 12, a laser 7, optics 8 and a feedback loop 13.
  • the laser emitting a laser beam 4 to create pores 2 in the skin 1, and the feedback loop 13 emitting a laser beam 9d to measure the depth of the pores 2.
  • the controller 11 contains a poration controller 11a which controls the laser 7 so as to create pores 2 as defined in the poration memory.
  • the controller 11 also contains a main controller lib which communicates with the poration controller 11a and the interface 15.
  • the interface 15 allows reading at least one parameter selected from the group consisting of: permeant information PI, user information UI, initial microporation dataset D, p ⁇ rator application information PAL
  • the user information UI comprises data such as sex, age, permeants which may or may not be used, maximal or minimal dose, or user ID.
  • the porator application information PAI comprises information about how the porator is used, for example, at which time or date, for which user, for which drug etc. All data mentioned (PL UL D, PAI) may be stored on the data carrier 5c of the drug 5a. These data can, for example, be prescribed by a physician.
  • Figure 8 shows a further micro-porator 10.
  • the micro-porator 10 has an interface 15 comprising a user-interface 15a to display data and to input data manually, and a data interface 15b to communicate date.
  • the data interface 15b being able to communicate data selected from the group consisting of: 1-D, 2-D and 3-D bar codes, 1-D, 2-D and 3-D symbologies, holograms, written text, radio frequency identification devices (RFIDs), integrated chip smart cards, EEPROMs, magnetic strip, wire and wireless communication.
  • RFIDs radio frequency identification devices
  • the controller 11 of the porator 10 can comprise an internal database 20 v that stores a plurality of data of at least one parameter selected from the group consisting of: permeant information PL user information UI, initial microporation dataset D, porator application information PAI.
  • the database 20 may for example comprise two different initial microporation datasets D, each dataset defining the application of the same drug but with different speed, as disclosed in figures 10a to 10b.
  • the appropriate initial microporation dataset out of the two initial microporation datasets D may manually be selected, for example, based on the needs of the user.
  • the controller 11 of the porator 10 may also comprise a selector Hd that automatically selects the most appropriate initial microporation dataset D out of a plurality of initial microporation datasets D.
  • a selector Hd that automatically selects the most appropriate initial microporation dataset D out of a plurality of initial microporation datasets D.
  • several initial microporation datasets D are stored in the internal database 20, taking into account different ages or different weights of users. Based on user information UI (for example age, weight), the most appropriate initial microporation dataset D is selected.
  • the controller 11 may also comprise an inhibitor lie which inhibits the porator from porating when at least one of the following conditions is met: user information UI not correct, permeant information PI not correct, no valid initial microporation dataset D, user not allowed to apply the permeant, user not allowed to apply the initial microporation dataset D, user wants to apply the permeant outside a given timeframe (too early, too late), porator not directed onto the biological membrane.
  • This inhibitor 1 Ic allows a safe use of the microporator 10, or avoids a misuse of the microporator 10.
  • the controller 11 can for example be used as a reminder to apply a drug, for example for elderly people who may forget applying an important drug.
  • the controller 11 can be used to prevent suicide or addiction, in that the application of a certain drug is restricted, for example in time, in number or in amount.
  • the controller 11 can be used to prevent the application of a wrong drug.
  • the controller 11 can be used to prevent the application of a drug, for example, when the drug expired or when the drug, for certain reasons, may not be used any more.
  • the controller 11 of the porator 10 may also comprise a timer (lie) which recalls using the porator if it has not been used within a given period of time.
  • Figure 10a to 10b show the administration of the same drug, for example 100 mg acetylsalicylic acid, the drug being arranged on the skin 1 as disclosed in figure 3c.
  • the level of the serum concentration as well as the time period within which the drug is released can be predescribed.
  • the permeation surface Mt is chosen such that the ma y inrcqi serum concentration is about 25 g/1 over a short period of time of about two hours.
  • Figure 10b shows a Cast application (turbo) of the drug, with ⁇ ia y innai serum concentration of about 30 g/1 over a short period of time of about two hours.
  • One advantage of the invention is, that with transdermal application TO the serum concentration reaches an about constant value, in contrast to oral application OA, which shows a heavy fluctuation.
  • a further advantage is that the same amount of drug, e.g. the same patch, applied onto the skin 1, causes a different serum concentration, depending only on the function of the permeation surface A over time. This allows administering the same drug in different ways. This also allows administering the same drug in an individual way, in that the initial permeation surface is created depending on individual parameters of the person the drug is applied to.
  • the integrated permeant administering system comprises at least one permeant 5a, data of at least one initial microporation dataset D for the respective permeant 5a, and a micro- porator 10 for porating a biological membrane 1 as deployed by the initial microporation dataset D.
  • the micro- porator 10 comprises an interface 15 to read at least one parameter selected from the group consisting of: permeant information PI, initial microporation dataset D, user information UI, porator application information PAL
  • the permeant 5a comprises at least one parameter selected from the group consisting of: permeant information PI, initial microporation dataset D.
  • the system can further comprise a database 20 with a plurality of initial microporation datasets Di for the same permeant 5a, the various microporation datasets Di relating to at least one parameter selected from the group consisting of: user information UI, amount of permeant absorption, time function of permeant absorption.
  • the system can consisting of a database 20 comprising permeant information PI for a plurality of different permeants, and comprising at least one initial microporation dataset Di for each permeant.
  • Figure 9 shows a system comprising an external database 20, with which a plurality of micro- porators 10 can communicate.
  • the micro- porator 10 can read the data carrier 5c of a permeant 5a.
  • For each permeant 5a at least one initial microporation dataset D is stored in the external database 20, so the porator 10 can get the initial microporation dataset D for every permeant 5a.
  • a wireless communication is used for the data transfer.
  • the database 20 is provided and/ or updated by the company in charge for the permeant 5a, preferably pharmaceutical companies 50, 50a, 50b. These companies are in a position to provide the required data for combining a permeant 5a, for example a transdermal patch, with an appropriate initial microporation dataset D, to get an effective amount of permeant in the human body.
  • a physician may get access to the database 20 as well as to database 21 containing information regarding the permeant 5a.
  • the physician may tailor an initial microporation dataset D, based on data of the databases 20, 21 and based, for example, on individual needs of a patient, and transfer this initial microporation dataset D to the micro-porator 10.
  • the method for administering a permeant 5a with a micro-porator 10 comprises the steps of choosing a permeant 5a, getting an initial microporation dataset D for the respective permeant 5a, porating a biological membrane 1 as defined by the initial microporation dataset D, and applying the permeant 5a on the porated biological membrane 1.
  • a drug 5a comprises a data carrier 5c with an initial microporation dataset D. This dataset is transferred to the micro-porator, which then creates the micropores. The drug 5a is then applied onto the porated area of the skin.
  • a drug 5a comprises a data carrier 5c with a plurality of initial microporation datasets D, for example three datasets D, one for slow, medium and feist application of the drug, as disclosed in Figures 10a to 10b.
  • the user may through the user interface 15a select the appropriate initial microporation dataset D, according to which the micropores then are created.
  • Example 3
  • a drug 5a comprises at least a specific drug-ID.
  • the porator has access to an internal or external database 20 wherein initial microporation datasets D for a plurality of different drugs 5a are stored.
  • the microporator 10 reads the specific drug-ID and retrieves from the database 20 the corresponding initial microporation dataset D, according to which the micropores then are created.
  • the internal or external database 20 may be updated regularly, for example by data provided by pharmaceutical companies, so that the database 20 contains a library of an initial microporation datasets D for different drugs 5a.
  • the library may contain further data, for example minimal dose/day, maximal dose/day etc.
  • One advantage of this method is that the pharmaceutical company has direct influence to the administration of a drug. This makes the administration of the drug safer and also more efficient.
  • a drug 5a comprises at least a specific drug-ID.
  • the porator has access to an internal or external database 20 wherein initial microporation datasets D for a plurality of different individual parameters like sex, weight, age or individual restrictions are stored.
  • the microporator 10 reads the specific drug-ID, the microporator 10 reads the individual parameters of the user and then retrieves from the database 20 the corresponding initial microporation dataset D, according to which the micropores then are created.
  • a drug 5a comprises at least a specific drug-ID.
  • a physician has access to a database 21 of various drugs 5a as well as to an external database 20 containing a lot of initial microporation datasets. Base on these data the physician may create an individual initial microporation dataset D for a specific user. The microporator 10 reads the specific drug-ID, and the microporator 10 reads the individual initial microporation dataset D created by the physician, according to which the micropores then are created. lhese were only examples of a wide variety of possibilities about how to administer a permeant like a drug with the integrated pe ⁇ neant administering system according to the invention.
  • the database 20 can also be arranged within the micro-porator 10. This database 20 can regularly be updated, for example by use of a wireless link like GSM (Global Systems for Mobile Communications), SMS or Bluetooth, by access to the internet by access to a docking station, for example in a drug store, or by a physical data carrier.
  • GSM Global Systems for Mobile Communications

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Abstract

Selon l'invention, un dispositif de microporation (10) servant à former des pores dans une membrane biologique (1) comprend: a) un dispositif de commande (11); b) un ensemble de données de microporation initiale (D); c) et un dispositif d'ablation (10a) pour créer une microporation dans la membrane biologique (1). Le dispositif de commande exploite l'ensemble de données de microporation initiale (D) pour contrôler le dispositif d'ablation (10a) afin de créer la microporation comme elle est définie par l'ensemble de données de microporation initiale (D).
EP05742820A 2005-04-18 2005-04-18 Dispositif de microporation destine a former des pores dans une membrane biologique, et systeme integre d'administration de permeants Withdrawn EP1874212A1 (fr)

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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006111201A1 (fr) * 2005-04-18 2006-10-26 Pantec Biosolutions Ag Appareil laser de formation de micropores
US8372806B2 (en) 2005-10-06 2013-02-12 Pantec Biosolutions Ag Transdermal delivery system for treating infertility
US9078680B2 (en) 2006-04-12 2015-07-14 Lumenis Ltd. System and method for microablation of tissue
WO2010145855A1 (fr) 2009-06-15 2010-12-23 Pantec Biosolutions Ag Laser à solide monolithique à pompage latéral et procédé de fonctionnement associé
EP2443707B1 (fr) 2009-06-15 2015-09-30 Pantec Biosolutions AG Laser à solide monolithique à pompage latéral et applications

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5938657A (en) * 1997-02-05 1999-08-17 Sahar Technologies, Inc. Apparatus for delivering energy within continuous outline
WO2000053261A1 (fr) * 1999-03-08 2000-09-14 Asah Medico A/S Appareil de traitement des tissus, pourvu d'un écran affichant des caractéristiques des tissus
US6328733B1 (en) * 1995-01-23 2001-12-11 Lumenis Inc. Hand-held laser scanner

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6475138B1 (en) * 1995-07-12 2002-11-05 Laser Industries Ltd. Apparatus and method as preparation for performing a myringotomy in a child's ear without the need for anaesthesia
US5980934A (en) * 1997-05-19 1999-11-09 Motorola, Inc. Transdermal delivery apparatus
US6241701B1 (en) * 1997-08-01 2001-06-05 Genetronics, Inc. Apparatus for electroporation mediated delivery of drugs and genes
US5947956A (en) * 1997-11-04 1999-09-07 Karell; Manuel Leon Laser apparatus for making holes and etchings
JP2004510453A (ja) * 1998-07-21 2004-04-08 スペクトルクス，インコーポレイティド 連続状分析物監視用のシステムおよび方法
US6148232A (en) * 1998-11-09 2000-11-14 Elecsys Ltd. Transdermal drug delivery and analyte extraction
EP1180053A4 (fr) * 1999-05-17 2006-11-08 Kevin S Marchitto Liberation controlee a distance et locale de composes pharmaceutiques faisant appel a l'energie electromagnetique
EP1187572A1 (fr) * 1999-06-18 2002-03-20 Spectrx, Inc. Dispositif produisant et focalisant un faisceau lumineux
AUPR044000A0 (en) * 2000-09-28 2000-10-26 Norwood Abbey Ltd Diagnostic device
GB2369057A (en) * 2000-11-18 2002-05-22 Lynton Lasers Ltd Dermatological treatment apparatus
GB0203276D0 (en) * 2002-02-12 2002-03-27 Novartis Ag Organic compounds
US20040206365A1 (en) * 2003-03-31 2004-10-21 Knowlton Edward Wells Method for treatment of tissue

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6328733B1 (en) * 1995-01-23 2001-12-11 Lumenis Inc. Hand-held laser scanner
US5938657A (en) * 1997-02-05 1999-08-17 Sahar Technologies, Inc. Apparatus for delivering energy within continuous outline
WO2000053261A1 (fr) * 1999-03-08 2000-09-14 Asah Medico A/S Appareil de traitement des tissus, pourvu d'un écran affichant des caractéristiques des tissus

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2006111199A1 *

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