Definitions

• This invention relates to an improved method and kit to facilitating treatment of a skin related disease or disorder.
• the invention further relates to the use of a drug in the manufacture of a medicament for treatment of a skin related disease or disorder.
• an immunologic response is generally desirable in most instances (e.g., to combat infection)
• an auto- or alloimmune response is typically detrimental (e.g., in skin transplantation).
• Treatment of many skin diseases and conditions is often local and topical in response to an eti
• topical treatment is often relatively simple and effective in many cases, treatment of diseases and conditions that manifest themselves in a relatively large area or have a systemic component is significantly more difficult.
• two treatment options are available.
• a drug may be applied over a relatively large-area (e.g., by application of topical ointment), but efficacy is often undesirable as the skin presents a permeability barrier to most compounds with molecular weight greater 500 Dalton. Even when the drug is a relatively small molecule, hydrophilic drugs will typically not be effectively delivered.
• Several strategies have been developed to circumvent at least some of these problems, including chemical approaches (e.g., micro/nanovesicle delivery via encapsulation into liposome and other lipophilic carriers; penetration enhancers, such as azone, alphahydroxy acids, etc) and mechanical approaches (e.g., partial removal of stratum corneum by tape stripping, dermabrasion, etc.).
• topically delivered dosages are often not high enough to achieve a desired effect, or when high enough, often result in systemic exposure with undesirable side effects.
• a drug may be orally or parenterally administered which typically allows for effective delivery.
• administration frequently has numerous drawbacks.
• many so administered drugs are metabolized and/or excreted at a relatively high rate. Therefore, serum concentration high enough to achieve sufficient exposure of the drug to compartments such as the skin might be difficult to achieve and result in undesirable or even harmful effects.
• the inventors have now discovered that drugs can be safely and effectively applied to a large area of skin in relatively high concentrations without eliciting undesirable systemic effects by creating a plurality of micropores with predetermined geometry. More preferably, the pores will have a depth that is sufficient to create a channel in the stratum corneum to allow delivery of a drug to the epidermis, and more preferably to the epidermis and the dermis.
• the majority of micropores is dimensioned such that the pore walls do not intersect with a (capillary) blood vessel.
• the micropore walls define an area of access of a drug to the epidermal and dermal tissue layer where the amount of the drug in the systemic circulation is strongly reduced compared to injection.
• the side walls of micropores according to the inventive subject matter need not necessarily be straight. Indeed, it should be especially recognized that geometry of the wall of the micropores will have a significant influence on at least two factors that are critical for drug delivery: Among other things, the total inner surface can be easily modified by increasing the pore diameter and/or pore depth.
• the wall angle may also deviate from a right angle (relative to the average surface of the stratum corneum), and as such will lead to an increase of total inner pore surface, and with that an increase in the potential area of drug delivery. Still further increases can be achieved by stepping the side walls of a pore.
• the micropore geometry will also determine the time available for delivery of a drug across the micropore walls.
• drugs applied to the micropore walls will not readily migrate into the circulation.
• suitable devices may employ heat, electric arcs and/or high-voltage pulses.
• 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 configured to reproducibly create micropores (e.g., via feedback devices according to the inventive subject matter to detect characteristics of the individual micropores).
• microporators using a laser beam for creating pores are especially preferred.
• the laser of a laser porator is operated during pore formation in a q-switched mode and with pulse widths and energies such that laser irradiation will result in a blow-off effect without leading to coagulation.
• photoablation and/or photodisruption is particularly preferred. Such irradiation will typically vaporize the tissue with negligible creation of thermal damage.
• suitable ranges of irradiance will be at least 10 4 W/cm 2 , and more preferably at least 10 5 W/cm 2 , even more preferably between 10 5 W/cm 2 and 10 9 W/cm 2 , and most preferably between 10 5 W/cm 2 and 10 12 W/cm 2 where energy doses of between about 0.01 J/cm 2 to 1000 J/cm 2 , and more typically 0.1 J/cm 2 to 100 J/cm 2 are employed. Consequently, the laser pulse width/tissue exposure time is preferably less than 1 ms, more preferably less than 100 ⁇ s, even more preferably between 100 ⁇ s and 10 ns, and most preferably between 100 ⁇ s and 0.1 ps.
• the inventive subject matter may also be desirable to at least partially coagulate the pore walls A, and most typically the pore bottom 3e as exemplarily depicted in the left pore 2 in Figure 16.
• the pore 2 to the left was first vertically formed in the skin 1 using q-switched laser mode or short pulsed to reduce thermal damage.
• the stratum corneum Ia, the epidermal layer Ib and the derma layer Ic are shown.
• the laser is applied several times into the same pore 2 so that the lower end 3a, 3b, 3c, 3d of the pore 2 increases with each laser pulse applied.
• laser irradiation may also include a protocol in which a pore 2 is formed using the laser in a switched mode to operate under photoablative and/or photodisruptive conditions, and in which one or more laser pulses are applied with significantly longer duration.
• the bottom 3e of the pore 2 (and/or the side walls A where desirable) may be irradiated with the same laser or a second laser or the same laser with a second wavelength or a second laser with a second wavelength in a non q-switched or short pulsed "free -running" mode to achieve at least partial coagulation. Due to the fact that the e.g. bottom 3e of the pore 2 is sealed, the diffusion B into the epidermal layer Ib can only be achieved through the e.g. walls A of the pores 2. This leads to a decelerated delivery of the drug to the systemic circulation in the dermal layer.
• such partially sealed pores 2 will provide a horizontal drug delivery (i.e., parallel to surface of skin), which may delay the rate of delivery for at least some time.
• a suitable time for irradiation to achieve coagulation and it is generally contemplated that appropriate pulse widths will be in the range of about 10 ⁇ s to about 1000 ⁇ s, more preferably in the range of about 100 ⁇ s to about 500 ⁇ s.
• contemplated methods are also suitable for administration of a drug in large areas. It should further be especially appreciated that using contemplated methods, compositions, and devices will allow delivery of a drug into the skin of a patient at a dosage that would (a) otherwise generate adverse effects if systemically administered, and/or (b) otherwise not be obtainable when administered using conventional manners. Moreover, due to the control over drug delivery kinetic and dynamic via control of the pore geometry, drugs delivery can be personalized to accommodate different skin locations in a patient as well as different skin types among different patients.
• drug delivery kinetic and dynamic can be tailored to a specific drug (e.g., slow delivery for fast acting drug, fast and high quantity delivery for instable drugs, etc.).
• a specific drug e.g., slow delivery for fast acting drug, fast and high quantity delivery for instable drugs, etc.
• Especially preferred porators, exemplary methods, and configurations are provided in the applicants' copending patent applications with the following serial numbers, all of which are incorporated by reference herein:
• a micro -porator for porating a biological membrane to create a poration may be designed, for example, as the laser micro-porator disclosed in PCT patent application No. PCT/EP2006/061639 of the same applicant, 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, and entitled "Method for creating a permeation surface".
• a micro-porator for porating a biological membrane and an integrated permeant administering system may be designed, for example, as the micro-porator disclosed in PCT patent application No. PCT/EP2005/051702 of the same applicant, and entitled "Microporator for porating a biological membrane and integrated permeant administering system".
• a system for transmembrane administration of a permeant and a method for administering a permeant may be designed, for example, as the system disclosed in PCT patent application No. PCT/EP2006/050574 of the same applicant, and entitled "A system for transmembrane administration of a permeant and method for administering a permeant".
• a transdermal delivery system for administration of a drug and a method for administering the drug may be designed, for example, as the system disclosed in PCT patent application No. PCT/EP2006/067159 of the same applicant, and entitled "Transdermal delivery system and method for treating infertility".
• the inventors contemplate a method of treating a skin related disease or disorder in which an area of porated skin is formed and wherein the area comprises a plurality of pores.
• the area is equal or greater than 1 cm , more typically equal or greater than 10 cm , even more typically equal or greater than 25 cm , and most typically equal or greater than 100 cm .
• the number of pores may vary considerably, and suitable numbers include those in the range of between about 10-100,000. However, and especially where large areas are treated, higher numbers are also contemplated. Therefore, the number of pores/cm may generally vary between about 1-10, more typically 10- 100, or 100-1000, and in rare cases even higher.
• the pattern of pores in the skin may vary as well, and isotropic distribution is generally preferred. However, and especially where anatomically and/or physiologically advisable, anisotropic distribution is also contemplated. For example, areas of relatively slow drug diffusion (e.g., fibrotic tissue, thick dermis, etc.) may have a higher number of pores, whereas other areas may have less. Similarly, areas with disease focus may concentrate the pores in the focus and reduce the number of pores in the periphery. Similarly, areas that require a high dosage or volume of the drug may have a higher density in pores than those that require a lower dosage.
• areas of relatively slow drug diffusion e.g., fibrotic tissue, thick dermis, etc.
• areas with disease focus may concentrate the pores in the focus and reduce the number of pores in the periphery.
• areas that require a high dosage or volume of the drug may have a higher density in pores than those that require a lower dosage.
• the pores have a predetermined geometry that is at least in part a function of the drug.
• the predetermined geometry will preferably control the inner pore surface area, the time to pore re-closure, and/or the pore depth (i.e., layer of epidermis or dermis that is contacted with the drug).
• the drug (or drugs) is then applied to the area of porated skin, which may be done in single, repeated, or continuous (e.g., under occlusion) manner. While numerous alternative wavelengths are deemed suitable, particularly preferred wavelengths for laser ablation is at a wavelength of at least 2500 nm, and most preferably at about 2950 nm.
• Contemplated skin related disease or disorder are preferably those that are responsive to treatment with an immunomodulatory, immunostimulatory, or immunosuppressive drug
• immunomodulatory, immunostimulatory, and immunosuppressive drugs include interferons, tacrolimus, alefacept, cyclosporin A, mycophenolate, rapamycin, everolimus, glucocorticoids, infliximab, alemtuzumab, etanercept, mofetil, methotrexate, azathioprine, and ribavirin.
• especially contemplated skin related diseases or disorders include skin graft rejection, limb (e.g., finger, hand, etc.) transplant rejection, and autoimmune diseases of the skin.
• skin related diseases or disorders includes all diseases or disorders in which skin is diseased or has a disorder, or in which skin is involved in an at least mediatory role.
• hand transplant rejection is thought to be mediated by lymphocytic and eosinophilic infiltration in the dermis and epidermis.
• the total administered amount is greater than an amount given in an oral or parenteral administration, and that the drug or drugs are topically administered to the porated area in variable schedules.
• a typical treatment schedule will include multiple porations over an extended period of time, such as once daily, weekly, or monthly over at least several days, weeks, months, and even years, wherein subsequent porations may be performed at the same, an overlapping, or different site.
• the amount administered will vary between about 1 pmol/cm 2 to 1 nmol/cm 2 , or 1 nmol/cm 2 to 1 ⁇ mol/cm 2 , or even 1 ⁇ mol/cm 2 to 1 mmol/cm 2 (or even higher).
• application of the drug may be continuous (under occlusion or with large supply), or may be in more or more applications in form of a patch, spray, cream, emulsion, etc.
• the patch can be applied (e.g. after a hand transplantation) like a tape around the forearm. In case of strong side effects the patch can be removed immediately.
• an immunomodulatory, immunostimulatory, or immunosuppressive drug is employed in the manufacture of a medicament for treatment of a skin related disease or disorder, wherein the drag is formulated for topical administration to porated skin.
• skin will typically have a plurality of pores with predetermined geometry such that the concentration of the drag in combination with the predetermined geometry of the pores are effective in treatment of the skin related disease or disorder.
• suitable drugs will include tacrolimus and cyclosporin A to pores that have a depth reaching at least the epidermal layer but not the dermal layer.
• the pores may then be formed to have a larger diameter/depth/angle (for high delivery area per pore) or a smaller diameter/depth/angle (for moderate delivery area per pore).
• the number of pores may be increased.
• the predetermined geometry will preferably control the inner pore surface, the time to pore re-closure, and/or the delivery depth (and with that the target tissue).
• the pores have a geometry such that topical administration will not (or only to a minor degree [e.g., less than 10% of total dose, less than 5% of total dose, or less than 2% of total dose]) result in systemic delivery of the drag.
• an adequate formulation of the relevant drag together with an adjusted number and geometry of pores enables for application of topical immunosuppressive compounds adjusted in dose and concentration in order to inhibit or entirely block lymphocyte infiltration into the dermis.
• concentration of the immunosuppressant in the dermis is high enough to block chemotaxis or lymphocyte transmigration for a time of for example 2 weeks or longer.
• the relevant drug could be co-delivered with a conjugating substance, for example a small organic molecule, a biomolecule (e.g., proteins, polysaccharides, a deactivated virus particle), a polymeric substance or a supramolecular system such as micelles, reversed micelles, nanovesicles or liposomes, to form a conjugate, in which the relevant drag is either physically or chemically bound to the conjugating substance.
• a conjugating substance for example a small organic molecule, a biomolecule (e.g., proteins, polysaccharides, a deactivated virus particle), a polymeric substance or a supramolecular system such as micelles, reversed micelles, nanovesicles or liposomes.
• a conjugating substance for example a small organic molecule, a biomolecule (e.g., proteins, polysaccharides, a deactivated virus particle), a polymeric substance or a supramolecular system such as micelles, reversed micelles, nanove
• Contemplated drugs may therefore be bundles with instructions to form a kit comprising a drug that is effective in treatment of the skin related disease or disorder, and an instruction to apply the drug to an area of porated skin that has a plurality of pores, wherein the information specifies that the area is equal or greater than 1 cm 2 , and wherein the information also specifies that at least some of the plurality of pores have a predetermined geometry that is effective to prevent systemic administration of the drug.
• the instructions will also include one or more laser poration parameters (e.g., number, shape, density, etc, optionally as function of skin type) that determine the predetermined geometry.
• the laser porator preferably comprises a disposable tip through which the laser beam is projected onto the skin.
• the tip will also include a tissue biasing element that, upon contact with the tip, will force the tissue to be treated into a predetermined geometry.
• the predetermined geometry will ensure that the average distance between the laser mirror that steers the beam over the skin and the skin that is to be treated is substantially the same.
• the tissue biasing element will deform the skin such that the skin that is to be treated will be at the focal point of the laser beam throughout the area that is to be treated.
• tissue biasing will allow for consistent application of a laser beam with known and/or uniform parameters.
• Figure 1 shows an exemplary longitudinal section of a tip suitable for a laser operated micro-porator
• Figure 2 shows an exemplary surface of the tip
• Figure 3 shows a perspective view of an exemplary tip
• Figure 4 shows a longitudinal section of a further embodiment of a tip along (B-B);
• Figure 5 shows a cross section along (A-A) of the tip of figure 4.
• Figure 6 shows a longitudinal section of a further embodiment of a tip along (B-B);
• Figure 7 shows a cross section along (A-A) of the tip of figure 6;
• Figure 8 shows a longitudinal section of a further embodiment of a tip along (B-B);
• Figure 9 shows a cross section along (A-A) of the tip of figure 8.
• Figure 10 shows the front end of a longitudinal section of a further tip
• FIG 11 shows a front view of a tissue biasing element 8a of a further tip
• Figure 12 shows a perspective view of the tissue biasing element 8a according to figure i i;
• Figure 13 shows a front view of a tissue biasing element 8a of a further tip
• Figure 14 shows a front view of a tissue biasing element 8a of a further tip
• Figure 15 shows an intersection of the element of figure 11 in detail.
• Figure 16 shows a schematic cross-section of two pores of a laser porated skin.
• Figure 17 shows a laser porator
• Figure 18 shows a cross section of a forearm with a laser micro-porator device attached
• Figures 19a and 19b a perspective view of examples of shapes of micro-porations
• Figure 19c - 19e show a plan view of the skin with an array of micro-porations
• Figure 20 shows the permeation surface of all micropores overtime
• Figure 1 shows a tip 8 coupled to laser housing 9 of a laser-porator, wherein the tip is positioned proximal to the ablation site.
• the laser-porator comprises at least one swivel-mounted deflecting mirror 8f to deflect a laser beam 4, 4a into various directions onto the skin 1.
• the tip 8 forms a container with a cylindrical wall 8n and a protective glass 8i. This container collects the ablated tissue and other matter released by the ablation.
• the tip 8 is preferably shaped so as to allow easy attachment and removal of the tip 8 from the housing 9 of the laser-porator.
• the protective glass 8 i is an at least partially transparent medium for the laser beam 4 and may be made of glass, polycarbonate, or another medium that is at least partial transparent for the laser beam 4. Instead of the protective glass 8i a F-Theta lense may be arranged. The use of the F-
• Theta lense is advantageous in conjunction with the scanning mirror 8f to create a similar pattern of the laser beam 4 on the skin 1, independent of the deflection of the scanning mirror 8f.
• the tip 8 comprises tissue biasing element 8a which biases the portion of skin 1 that is within the opening of the tip 8 into a predetermined shape (e.g., downward, to create a bowl shape) as indicated by the line Ia.
• tissue biasing element 8a creates a concave shape having its center of curvature at point R of the deflecting mirror 8f, wherein Point R is the reflecting point of laser beam 4. Therefore, tissue biasing element 8a will allow Laser beam 4 to have about equal length between the deflecting mirror 8f and the surface Ia of the skin 1, which in turn allows to create a highly reproducible geometry of the pores within the skin.
• the tip 8 may further comprise electrical contact elements 8o, 8q that are electrically coupled to an electrical wire 8p.
• the contact elements 8q are connected with the contact elements 9a of the laser housing 9. This arrangement allows measuring various physiological parameters (e.g., impedance of the skin 1 between the contact elements 8o) of the skin.
• the contacts may also be used in a locking mechanism to ensure that the tip 8 is properly positioned on the skin, before the laser source is activated.
• the tip 8 can comprise further sensors, for example, sensors to measure humidity, temperature, or pH of the skin. Because laser beam 4 might cause injuries if not handled properly, it is important that the laser beam 4 is only activated when the tip 8 is placed onto the skin.
• the disposable tip 8 can include a safety mechanism 8s which allows using the tip 8 only once.
• the safety mechanism 8s comprises two contact elements 8t, 8u, with mating contacts in the laser housing 81, and a fusing element 8v that evaporates after a current has been applied, or breaks mechanically, or is an electronic device (e.g., a microchip), which can be reprogrammed. After poration is finished, a change is applied to the safety mechanism 8s such as burning a fuse element. The status of the safety mechanism 8s is controlled by the laser porator 10 so that the tip 8 can only be used once.
• the tissue biasing element 8a of the tip 8 shown in figure 4 is a mesh, which may be fabricated from numerous materials, including metal, metal alloys, polymers, and all reasonable combinations thereof.
• the exemplary cross section illustrated in figure 5 shows that the wires are spaced apart to leave an intermediate space in which the laser beam 4 may irradiate the skin surface Ia.
• the exemplary tissue biasing element 8a of the tip 8 depicted in figure 6 comprises four projecting pins 8a.
• the cross section depicted in figure 7 shows the four projecting pins 8a leaving an intermediate space between the projecting pins 8a as well as in the centre.
• the tissue biasing element 8a of the tip 8 comprises one projecting pin 8a.
• the cross section illustrated in exemplary figure 9 shows the projecting pins 8a leaving two intermediate spaces between the projecting pin 8a and the side wall 8n.
• the disposable tips 8 as shown in one of the figure 1 to 9 are removably coupled to the housing of the laser-porator.
• the laser beam 4 is triggered and deflected so that the tissue biasing element 8 a is not hit by the laser beam 4 but that only the skin surface Ia is hit.
• the laser-porator comprises a detector to detect shape and orientation of the tissue biasing element 8a, to deflect and trigger the laser beam 4 such as to hit only the intermediate spaces of the tissue biasing element 8a.
• the biasing element may have a identifier (e.g., bar code, reflective element, electronic circuit) that provides directly or indirectly information to the porator to identify the tip to the porator.
• the tip 8 may further comprise one or more elements 8w to stretch the skin 1 , for example, an elastic ring as shown in figure 10.
• an elastic ring as shown in figure 10.
• FIG 11 shows a front view and figure 12 a perspective view of a further tissue biasing element 8a having the shape of a partly hemispherical mesh, and comprising elastic material (e.g., metallic wire or plastic element), or comprising a rigid material (e.g., metal).
• the tissue biasing element 8a includes metallic wires 8b connected with an outer ring 8c (preferably made from the same material as the element 8b). As appropriate, the outer ring 8c may be attachable to the cylindrical wall 8n, or may be integral part of the tip 8.
• Figure 13 shows a front view of an exemplary tissue biasing element 8a leaving an intermediate space in its center.
• Figure 14 shows a front view of an exemplary tissue biasing element 8a having two sensors 8d arranged on the outer ring 8c (the sensors 8d may be electrically coupled via wires 8p).
• the tip 8 comprises an indicator 8f which allows detecting the position of the tip 8 with respect to the housing 9.
• the indicator 8f can be a reflective surface on the tissue biasing element 8a, which may be arranged on the cross section 8e of the elements 8b as illustrated in figure 15.
• the orientation of the indicator 8f can be detected with a sensor or with the laser beam 4 in combination with a sensor.
• the indicator 8f may be a reflective area.
• the indicator 8f may be used as safety mechanism 8s in which the properties of the indicator 8f are altered when the tip 8 is used.
• the laser beam 4 may be directed onto the indicator 8f after porating the skin, to alter or destroy a small reflective layer forming the indicator 8f.
• a controller of the laser porator may, by using the laser beam 4 or another sensor, check the status of the indicator 8f, and depending on properties of the indicator 8f, permit or deny poration.
• Figure 17 shows a laser micro-porator 10 comprising a Q-switched or short pulsed laser source 7 and a laser beam shaping and guiding device 17.
• the laser source 7 has a light source 7c for optical excitation of a laser active material 7b, and a set of reflecting mirrors 7d,7e.
• the laser source 7 comprises a laser cavity 7a containing a laser crystal 7b , preferably Er and optional additionally Pr doped YAG, which is pumped by an exciter 7c, the exciter 7c being a single emitter laser diode or a set of single emitter laser diode arrays like emitter bars or stacks of emitter bars.
• the laser source 7 further comprising an optical resonator comprised of a high reflectance mirror 7d positioned posterior to the laser crystal 7b and an output coupling mirror 7e positioned anterior to the laser crystal 7b, and a saturable absorber 7f positioned posterior to the laser crystal.
• the saturable absorber 7f works as a Q-switch.
• a focusing lens 17a and a diverging lens 17b are positioned beyond the output coupling mirror 7e, to create a parallel or quasi-parallel laser beam 4 or a focused laser beam 4.
• the microporator 10 could comprise different optical means 17a, 17b, which, for example, focus the laser beam 4 onto the surface of the skin 1.
• the diverging lens 17b can be moved by a motor 17c in the indicated direction. This allows a broadening or narrowing of the laser beam 4, which allows changing the width of the laser beam 4 and the energy fluence of the laser beam 4.
• a variable absorber 17d driven by a motor 17e, is positioned beyond the diverging lens 17b, 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 17d for directing the laser beam 4 in various directions, to create individual pores 2 on the skin 1 on different positions.
• a control device 11 is connected by wires 1 Ia with the laser source 7, drive elements 17c, 17e, 8g, sensors and other elements not disclosed in detail.
• the laser porator 10 also includes a feedback loop 13 respectively a feedback mechanism.
• the feedback loop 13 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.
• This distance measurement device 9 which can be built in different way, allows measuring the position of the lower end e.g.
• 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 can be built in various ways to be able to measure a feedback signal of an 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.
• the laser porator 10 also comprises a poration memory 12 containing 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, in particular 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 2i.
• the input-output device 15 can be a card reader, a scanner, a wired interface or for example a wireless connection such as Bluetooth.
• the porator further can comprise one or more input-output devices or user interfaces 15 for manually exchange date like data of substances, individuals and much more.
• the user interface can for example comprise displays, buttons, voice control or a finger print sensor.
• the laser source 7 may, for example, be built as a laser diode with optics that create a beam 4 of fixed width, for example a width of 250 ⁇ m.
• 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 10 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 or up to 1 mm, and each pore 2 having a depth in the range between 5 ⁇ m and 200 ⁇ m, but the lower end of the individual pore 2 being preferably within the epidermis Ib. If necessary the porator 10 is also able to create pores of more than 200 ⁇ m depth.
• 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 13 could for example be used to detect whether the pulse is directed onto the skin 1.
• Figure 17 discloses a circular laser beam 4 creating a cylindrical individual pore 2.
• the individual pore 2 can have other shapes, for example in that the laser beam 4 has not a circular but an elliptical shape, a square or a rectangle.
• the individual pore 2 can also be shaped by an appropriate movement of the deflector 8f, which allows creation of individual pores 2 with a wide variety of shapes.
• Figure 18 shows a cross-section of a forearm.
• a laser micro-porator device 10 may releasable be attached to the forearm using an elastic belt 10a comprising a connector 10b. This attachment allows suppressing or reducing a relative movement between the micro-porator 10 and the area of the forearm on which the front part of the micro-porator 10 is arranged.
• To porate a skin area of equal or greater than 1 cm 2 it might be useful to release the elastic belt 1 Oa after porating, to remove the ablator 10 relative to the skin, and to again fix the elastic belt 10a, so that the ablator 10 may porate an additional area of the skin.
• the ablator 10 may also be used without fixing it's position by repeatedly pressing the tip of the ablator onto the skin area to be porated, and by then activating the ablator.
• the ablator 10 may also be mounted on a scanner which is able to position and to control position of the ablator 10 with respect to the skin, thus allowing a very accurate and controllable poration of a large area of the skin.
• Figure 19a shows an array of individual pores 2 in the skin 1. All individual pores 2 have about the same shape and depth.
• Figure 19b shows individual pores 2a to 2f of various shapes, which can be created with support of the poration controller 11 controlling the laser porator 10.
• the laser porator 10 varies the cross-section and/or the energy density of each consecutive pulsed laser beam 4, which allows creation of individual pores 2 with numerous different shapes.
• Figure 19c 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 preferably 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, locations on the skin the porator has to porate the skin, and so forth.
• the laser porator 10 creates the pores 2 as defined by the initial microporation dataset.
• Figure 19e discloses a further advantageous arrangement of the pores in the skin.
• the density of the number of pores 2 is increasing or decreasing. This allows a certain area in the skin to be supplied with a larger or smaller amount of drug.
• Figures 20 shows an example of the total permeation surface A as a function of time.
• the laser-porator 10 allows to micro-porating the tissue such as the skin 1 by the creation of an array of micropores 2 in said tissue 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 according to figure 20 comprises three groups of cylindrical micropores 2 with different shapes: - a first group consisting of 415 pores with a diameter of 250 ⁇ m, a depth of 50 ⁇ m and a permeation surface Al as a function of time.
• - a second group consisting of 270 pores with a diameter of 250 ⁇ m, a depth of 100 ⁇ m and a permeation surface A2 as a function of time.
• - a third group consisting of 200 pores with a diameter of 250 ⁇ m, a depth of 150 ⁇ m 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, is created within a very short period of time, for example, within a time range of a fraction to a few seconds up to a few seconds or a view minutes, so that beginning with the time of poration TP, the sum of all created pores 2i forming an initial permeation surface, 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 barrier properties significantly increase.
• a patient receives after bilateral hand transplantation alemtuzumab (2x20mg) for induction therapy.
• Prophylactic immunosuppression preferably includes administration of tacrolimus, mycophenolate mofetil, and steroids, typically at an initial dosage of 500 mg with a rapid taper to 5 mg maintenance therapy.
• Tacrolimus is administered at two daily oral doses to achieve trough levels of 15-20 ng/ml early after transplantation and is subsequently tapered to 10 ng/ml.
• a first rejection episode may be observed at two months after transplantation, with lesions being restricted to the dorsal side of the hand and spreading over an area of approximately 12-15 cm 2 .
• Conventional treatment would typically employ systemic administration of bolused steroids together with an increase of maintenance immunosuppression for treatment of rejection.
• topical application of e.g. tacrolimus or alemtuzmab to porated skin may replace or complement conventional therapy.
• tacrolimus or alemtuzmab to porated skin may replace or complement conventional therapy.
• the drugs will be rapidly available to the site of action and may therefore present an effective route with significantly reduced potential adverse effects.
• So administered drugs may be applied to the porated skin under various schedules, including once daily (or less) to several times a day at constant, increasing, or decreasing dosages. With respect to appropriate dosages, the same considerations as provided above apply.
• Immunosuppression after e.g. hand or face transplantation could be follows: Induction therapy with alemtuzumab or anti-thymozyte globulin is followed by tacrolimus monotherapy aiming for trough levels of as low as 5-8 ng/ml.
• the skin of the transplant is prepared for drug uptake by creating porated areas of the skin scattered on the transplant at a distance of abut 3-5 cm in all directions.
• suitable drugs e.g., efomycin
• Topical treatment of the skin is repeated as needed (e.g., every three weeks during the first six months continued by application at intervals of 6 weeks until the end of the first year). Thereafter the regimen of topical treatment is continued at predefined intervals.
• Psoriatic lesions can be restricted to small areas of the skin or spread over large areas with often debilitating effect on a patient's daily activities.
• Systemic therapies are limited by drug toxicity but recently, treatment with efalizumab has been shown to attenuate the disease in 22- 28% of patients. It is likely that limitations of efficacy of efalizumab treatment are caused by inadequate concentrations and/or distribution to all affected skin areas. Consequently, the inventors therefore contemplate that preparation of all affected skin areas by creating porated areas prior to topical application of efalizumab or a comparable inhibitor of lymphocyte migration might substantially improve the efficacy of such a therapeutic approach.
• the following list discloses by example a list of drugs suitable to be used in combination with the laser porator, in particular for wide-area treatment of skin related conditions.
• the tip 8 described herein is configured to be used in combination with a laser porator. Therefore, it should be recognized that such tips may not only be used for treating skin related conditions but may also be used independently in applications where microporation, and particularly microporation with predetermined pore geometry or drug delivery kinetic/dynamic is required.
• contemplated alternative uses include application of the tip to create pores for systemic, transdermal administration of permeants and drugs, such as the administration of high amount of drugs, and also the transdermal administration through an area of equal or less than 1 cm 2 .

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• 2007
  • 2007-10-25 EP EP07821863A patent/EP2097062A2/de not_active Ceased

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