Patent Application
20090306576
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 system for transmembrane administration of a permeant by using a microporator for porating a biological membrane. This invention further relates to a method for administering a permeant comprising porating the biological member.
Many new drugs, including vaccines, antigen-presenting cells, proteins, peptides and DNA constituents, have been developed for better and more efficient treatment for disease and illness. Especially due to recent advances in molecular biology and biotechnology, increasingly potent pharmaceutical agents, such as recombinant human insulin, growth hormone, follicle stimulating hormone, parathyroid hormone, etanercept, and erythropoietin are available. However, one significant limitation in using these new drugs is often a lack of an efficient drug delivery system, especially where the drug needs to be transported across one or more biological barriers at therapeutically effective rates and amounts.
Among other things, currently known methods, devices and systems fail to allow controlled and reproducible administration of drugs. Currently known methods and devices also fail to provide prompt initiation and cut-off of drug delivery with improved safety, efficiency and convenience. It is therefore an object of the present invention to provide systems, devices and methods to improve transmembrane delivery of molecules, permeants including drugs and biological molecules, across biological membranes, such as tissue or cell membranes. This problem is solved with a system for transmembrane administration of a permeant comprising the features of claim 1. Dependent claims 2 to 23 disclose optional features. The problem is further solved with a method for operating a micro-porator comprising the features of claim 24. Dependent claims 25 to 32 disclose optional features. The problem is further solved with a method for administering a permeant comprising the features of claim 33, with dependent claims 34 to 36 disclosing optional features.
The system, 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. In a preferred embodiment 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. By each individual pore a permeation surface within the skin is created. Depending on the number and shape of the individual pores 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. By an appropriate choice of the number of individual pores and their shape, not only the initial permeation surface but also the decrease of the total permeation surface over time can be determined. The appropriate choice of number and shape can be calculated and stored as an initial microporation dataset. The system 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.
Various techniques can be used for creating pores in biological tissues. Preferably a microporator using a laser beam for creating pores is used. But, for example, also a device for heating via conductive materials or a device generating high voltage electrical pulses can be used for creating pores. U.S. Pat. No. 6,148,232, for example, 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, in particular from the surface of the skin to within the animal, mammal or human body, depends on the permeation surface and its variation over time. The present invention therefore also provides a system for transmembrane administration of a permeant, 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 initial 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. To apply the permeant effectively, it is important to fit properties of the permeant and the microporation accordingly, to ensure a desired local or systemic effect, for example to ensure a predetermined concentration of a drug in the blood.
According to one preferred embodiment, 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. When the respective drug is applied onto the skin, 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. In a preferred embodiment and method, also personalised parameters of the mammal or human are taken into account when choosing or calculating a personalised initial microporation dataset, so the permeant is administered on personalised needs, to for example ensure for an individual person an optimal, personally adapted concentration or level of a drug in the blood.
As used herein, blood level, serum concentration, concentration level means the level or concentration of the permeant at a specific location, for example in a tissue, liquid, organ. Amount means the total amount of the permeant at a specific location. Amount over time, concentration over time, concentration level over time, is the function of time of the amount or concentration level.
As used herein, “poration” or “microporation” means the formation of small holes or pores or channels 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.
As used herein, “micropore”, “pore” or “individual pore” means an opening formed by the microporation method.
As used herein “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:
As used herein, “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.
As used herein, “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, a mammal, a bird or the outer tissue layers of a plant.
To the extent that “ablation” and “puncture” accomplish the same purpose of poration, i.e. the creating a hole or pore in the biological membrane optionally without significant damage to the underlying tissues, these terms may be used interchangeably.
As used herein “puncture surface” means the surface of the hole or pore at the outer surface of the biological membrane, which has been ablated or punctured.
As used herein the terms “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. In the most preferred embodiment the transdermal delivery introduces permeants into the blood, to achieve effective therapeutic blood levels of a drug
As used herein the term “intradermal” means passage of a permeant 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.
As used herein, “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.
As used herein, “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.
As used herein, the term “bioactive agent,” “permeant,” “drug,” or “pharmacologically active agent” 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. vitamins, electrolytes, etc.), (3) alleviating a condition caused by a disease, for example, alleviating pain or inflammation caused as a result of disease, (4) either alleviating, reducing, or completely eliminating the disease from the organism, and/or (5) the placement within the viable tissue layers of the organism of a compound or formulation which can react, optionally in a reversible manner, to changes in the concentration of a particular analyte and in so doing cause a detectable shift in this compound or formulation's measurable response to the application of energy to this area which may be electromagnetic, mechanical or acoustic. The effect may be local, such as providing for a local anaesthetic effect, it may be systemic, or it may be non systemic, for example the administration of a radiopaque material, a contrast medium or a liquid to scour a tissue. This invention is not only 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 permeants or bioactive agents that exist in the art or that may later be established as active or passive 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. In general, this includes but is not limited to: Antigen-presenting cells (APC), Polypeptides, including proteins and peptides (e.g., insulin); releasing factors, including Luteinizing Hormone Releasing Hormone (LHRH), Luteinizing Hormone (LH); follicle stimulating hormone (FSH); human chorionic gonadotropin (HCG); human growth hormone (HGH); Botulinum Toxin; 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; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; parasympathomimetics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; vasoconstrictors; cough and cold preparations, including decongestants; hormones such as estradiol, testosterone, progesterone and other steroids and derivatives and analogs, including corticosteroids; hypnotics; narcotics; immunosuppressives; muscle relaxants; parasympatholytics; sympatholytics; psychostimulants; sedatives; and tranquilizers. By the method of the present invention, both ionized and nonionized permeants may be delivered, as can permeants of any molecular weight including substances with molecular weights ranging from less than 10 Daltons to greater than 1,000,000 Daltons or nano- or microparticles having weights ranging up to or greater than 1 mg.
As used herein, 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. The local effect could also be a sufficient local concentration of the permeant such as a radiopaque material or a contrast medium or a material to test the kidney.
As used herein, “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. Examples of suitable carriers for use herein 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.
As used herein, 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, finger nails, toe nails, cartilage or a blood vessel would be included within this definition.
As used herein, “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. In 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. In the most preferred embodiment the individual pore having a depth between 10 μm (for newborns 5 μm) and 150 μm.
As used herein the term “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. Preferably 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 defined and can be reproduced on various locations of the biological membrane, also on different objects, subjects or persons. Even though the initial microporation is exactly defined by the initial microporation dataset, this doesn't mean that the initial microporation created in the biological membrane has the exact features as defined by the initial microporation dataset. For example, if the initial microporation dataset only defines the total number of individual pores, lets say 100, the initial microporation in the biological membrane will most probably comprise 100 individual pores. If the initial microporation dataset for example also defines the depth, shape or permeation surface, the initial microporation will most probably not have the exact geometrical parameters as defined with the initial microporation dataset, but the geometrical parameters will be in a certain range. The micro-porator may comprise feedback means, which scan the created pores, so the parameters of the created initial microporation can be measured and afterwards are known. Based on the feedback, the created pores may also be reshaped by the micro-porator, so the finally created pores respectively the initial microporation becomes more similar to the pores as defined by the initial microporation dataset.
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 and feedback means to create a microporation as defined by or similar to the initial microporation dataset. Thereby 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. In the most preferred embodiment a pulsed laser beam is used to create individual pores.
In a preferred embodiment, 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. The term “parallel or quasi-parallel laser beam” used herein refers to a laser beam that has a divergence of less than 30 to 5° for a minimum of 90% of the beam energy, 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. In 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 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 preferably 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, or tissue 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.
In a further embodiment 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. This allows measuring the thickness of the stratum corneum and for example altering the total depth of created pores. With the initial microporation dataset, also the final depth of each individual pore may be defined. This final depth can now be corrected in that the thickness of the stratum corneum is added. The individual pore is then created with this corrected depth, which means the individual pore becomes deeper, and which means that the permeation surface of the epidermis corresponds to the given permeation surface. This is of importance, because the transdermal flux rate, depending on the drug applied, often depends on the size of permeation surface which allows a high passage of drugs, which might be the permeation surface of the epidermis only.
If the depth of the individual pore is not corrected by the thickness of the stratum corneum, 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 μm and 200 μm, as defined by the initial microporation dataset.
In a preferred embodiment 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 and/or porator application information. In a further preferred embodiment the micro-porator comprises a database that stores a plurality of initial microporation datasets. In a further preferred embodiment the micro-porator comprises a selector, which manually or automatically selects, generates or modifies, for example based on personalised user information (such as the age, weight, sex, and others) the most appropriate initial microporation dataset, which then becomes the personalised initial microporation dataset. The pores are then created according to this most appropriate personalised initial microporation dataset.
The micro-porator can also comprise an inhibitor which inhibits the porator from porating if certain conditions are not fulfilled, for example if the porator is not oriented onto the skin.
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. According to the invention an integrated permeant administering system is proposed, 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.
After the poration is completed, 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 comprise or being part of an integrated drug administering system, for example, as the system 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”. 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, 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”. All citations herein are incorporated by reference in their entirety.
The present invention can be better understood and its advantages appreciated by those skilled in the art by referencing to the accompanying drawings, which are incorporated herein by reference. Although the drawings illustrate certain details of certain embodiments, the invention disclosed herein is not limited to only the embodiments so illustrated. Unless otherwise apparent from the context, all ranges include the endpoints thereof.
a shows a further micro-porator device;
a shows a perspective view of a micro-poration of the skin;
b shows a plan view of the skin with an array of micro-porations;
c shows a schematic cross-section of a porated skin with a drug container attached to the skin surface;
a shows a given permeation surface and a created permeation surface;
b shows transdermal delivery of a drug over time, in combination with a permeation surface;
a, 10b show the serum concentration of a drug over time, with the same amount of drug but different permeation surfaces;
a to 11f show different methods for administering a permeant;
Due to the natural skin renewal process the cells building the epidermis 1b and the stratum corneum 1a grow out of the basal layer. The basal layer is the skin layer between the epidermis 1b and the dermis 1c. Usually 3 to 15 μm a day are renewed. After about 14 days the cells die and build the stratum corneum. After a further period of about 14 days the cells scale off from the skin. So one can say the lower end 3d of each individual pore 2 is moving into the direction of the stratum corneum with a speed of about 3 to 15 μm/day, thereby reducing the permeation surface A. The corrected permeation surface, being the permeation surface of the epidermis 1b only, without the surface of the stratum corneum 1a, becomes the size of the puncture surface, which means the surface of the hole in the stratum corneum 1a. The remaining hole in the stratum corneum 1a will be closed after the already mentioned 14 days. This mechanism of cell growth and death is not described herein in detail. The constant growing of the cells increases the thickness of the stratum corneum and thus significantly increases the barrier properties in the remaining hole and regenerates the stratum corneum. At the end the individual pore 2 has vanished due to cell growth and the formerly ablated tissue is regenerated by new cells.
In a preferred embodiment the laser porator 10 also includes a feedback loop and feedback means. In
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. Within one application of the laser porator 10, 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 μm and maximal 150 μm, but the lower end of the individual pore 2 being within the epidermis 1b.
The laser porator 10 also comprises an interlock mechanism, so that a laser pulse is emitted only when it is directed onto the biological membrane like the skin 1.
In a preferred embodiment 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 quite accurately creating the depth of individual pores 2 with a predetermined depth. The feedback loop 9 may also be operated as a feed forward loop, to control the creation of new individual pores 2 based on data of already created individual pores 2. In a further embodiment, 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.
a 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 8h 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. In the embodiment according to
a shows an array of individual pores 2 in the skin 1, created by a micro-porator 10. In this example, 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.
b shows a plan view of the skin having a regular array of individual pores 2 that collectively form a micro-poration. The micro-poration on the biological membrane, after the laser porator 10 has finished porating, is called “initial microporation”. 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.
c 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 mm2 and 1600 mm2. Preferred 20×20 mm, e.g. a surface of 400 mm2.
For each individual pore 2i, the surface of the inner wall and the surface of the lower end are of importance, in particular the permeation surface Ai, being the sum of both of these surfaces. In a preferred embodiment, the laser porator 10 comprises a distance measurement apparatus 9, which facilitates determining the permeation surface Ai very accurately. In a further preferred embodiment, 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 1b, 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 2i. If the individual pore 2i has the shape of, for example, a cylinder, the permeation surface Ai corresponds to the sum of D*π*H and (D/2)2*π, 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 1b. The effective permeation surface Ai in the pore 2 often doesn't correspond exactly to the geometrical shape, defined 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 Ai. 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 μm per day, the cells growing from the lower end of the individual pore 2 in direction Z to the stratum corneum 1a. This cell growth causes the permeation surface Ai of each individual pore 2i, respectively the total permeation surface A of all individual pores 2 to decrease in function of time. Depending on the total number of individual pores 2, which can be in a range of up to 100 or 1000 or 10000 or even more, the geometrical shape of the individual pores 2, and taking into account the effect of cell growth, 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.
The initial microporation dataset D according to
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 mm2, 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. This makes it clear that the poration of individual pores 2 does not only determine the initial permeation surface, but also the function of the total permeation surface A over time.
Almost any permeation surface A(t) as a function of time may be establish by a proper selection of the number and the shape of the individual pores 2.
c shows a patch 5 containing a drug 5a and being fixed onto the skin 1, above the individual pores 2.
a 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 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 10 can, for example, be sold in combination with a specific drug. In a further embodiment, the data carrier 5c, can be inserted into the micro-porator 10, the data carrier 5c containing the initial microporation dataset D.
The controller 11 of the porator 10 can comprise an internal database 20 that stores a plurality of data of at least one parameter selected from the group consisting of: permeant information PI, 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
The controller 11 of the porator 10 may also comprise a selector 11d that automatically selects the most appropriate initial microporation dataset D out of a plurality of initial microporation datasets D. For example several initial microporation datasets D are stored in the internal database 20, taking into account different ages or different weights of users. Based on basic user information UI (for example age, weight) or based on more specific user information UI (for example allergies, specific diseases) or based on more sophisticated user information UI (for example just in time measured parameters like blood pressure, blood sugar, electrolyte balance), the most appropriate initial microporation dataset D is selected.
The controller 11 may also comprise an inhibitor 11c 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 11c 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 clumsy or 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 (11e) which recalls using the porator if it has not been used within a given period of time.
a 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
b shows the level over time of a further transdermal application TD2. The increase and the decrease of the level TD2 is similar to the one caused by an injection using a syringe. Such a level TD2 is for example suitable when a high peak during a short period of time has to be reached, for example when administering a contrast medium.
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 defined 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 PAI. 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.
In a preferred embodiment 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.
Also 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 personalised needs of a patient, and prescribe this personalised initial microporation dataset D to the patient, and may transfer this personalised initial microporation dataset D to the micro-porator 10.
After determining the need or the disease of a person, the method for administering a permeant 5a with a micro-porator 10 comprises, as disclosed in
This method if further explained by way of examples:
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 fast application of the drug, as disclosed in
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.
b discloses a further method for administering a permeant 5a. In the first step 60 a permeant 5a is chosen. 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 personalised parameters like sex, weight, age or personalised restrictions are stored. In a next step 61a the microporator 10 reads the specific drug-ID, the microporator 10 reads the personalised parameters of the user and then retrieves from the database 20 the corresponding personalised initial microporation dataset D, according to which in step 62 the micropores then are created. In final step 63 the permeant 5a is applied on the porated biological membrane 1.
c discloses a further method for administering a permeant 5a. In the first step 60 a permeant 5a is chosen. In a second step 61a personalised initial microporation dataset D is provided, based for example:
A specific example of the method disclosed in
There are various other approaches about how to get data for the initial microporation dataset D. One approach would be to derive the initial microporation dataset out of a desired level or a level over time of the chosen permeant.
Very often when applying a permeant, in particular a drug, there is a so call therapeutic window, which means a range of for example a concentration level, within which the drug can create the desired effect. If the drug is applied in a concentration of too high or too low value, the desired effect doesn't take place, or even worse, an adverse effect is caused. In
e discloses a further method for administering a permeant 5a, which considers personalised parameters, in particular individual pharmacokinetic parameters. The first two steps 60 and 61b are the same as those disclosed in the method according to
Taking into account the information of step 65, in successive step 66 a needed individual level M(t) of the permeant can be evaluated. Step 66 considers at least one of the following effects:
In a successive step 64, just in time analysed individual parameters JITAP may be considered, as describe in
In step 61c, a personalised initial microporation dataset D is determined, and in addition an appropriate patch containing the permeant may be selected, to get the needed personalised level M(t). In step 61c a table as disclosed in
In step 61c, the personalised initial microporation dataset D can be determined by various different methods. For example a computer model may be used, which could be based on formulas, statistical models, measured data or neuronal networks, and which could consider permeant information PI or user information UI, to for example calculate the initial total permeation surface A and the total permeation surface over time A(t).
The method disclosed in
In a further method for administering permeants, at least two different permeants may be administered, the method comprising the steps of:
These were only examples of a wide variety of possibilities about how to administer a permeant like a drug with the integrated permeant 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, preferably by wire or wireless communication, or for example by use of a serial or parallel interface, or 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.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/EP2005/051702 | Apr 2005 | EP | regional |
| PCT/EP2005/051703 | Apr 2005 | EP | regional |
| PCT/EP2005/051704 | Apr 2005 | EP | regional |
| PCT/EP2005/055061 | Oct 2005 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/050574 | 1/31/2006 | WO | 00 | 7/22/2009 |
