Transdermal delivery system for dried particulate

Tag : liquid sorbitol


Abstract
The present invention provides a system for transdermal delivery ofdried or lyophilized pharmaceutical compositions and methods usingthereof. The system comprises an apparatus for facilitatingtransdermal delivery of an agent that generates hydrophilicmicro-channels, and a patch comprising a therapeutically activeagent. The present invention is useful for transdermal delivery ofhydrophilic agents, particularly of high molecular weight proteins.
Description of the Invention
SUMMARY OF THE INVENTION

The present invention relates to an effective system and methodsfor transdermal delivery of an active dried or lyophilized agent.The present invention relates to an apparatus and methods forablating the skin and transdermally delivering an active agentpackaged in a dried or lyophilized form to the pretreated skin.

Particularly, the present invention relates to apparatus andmethods for transdermally delivering an active dried or lyophilizedagent using a suitable medical skin patch.

The present invention also relates to a medical skin patchcomprising a dried hydrophilic active agent. Particularly, thepresent invention relates to printed patches and method ofpreparation thereof, for transdermal delivery of an active driedagent.

The compositions and the methods of the present invention aresuitable for use with many of the patches known in the art, thoughapplication of the drug with the system of the present inventionusing a printed patch has proven particularly effective and hasyielded unexpectedly advantageous exemplary results.

It is now disclosed for the first time that use of a patchcomprising a dried or lyophilized pharmaceutical compositioncomprising a therapeutically active agent, placed on an area of theskin pretreated by an apparatus that generates micro-channelsunexpectedly provides therapeutically effective serum levels of theactive agent. The dose efficiency or bioavailability obtained wasadequate to provide therapeutic effects in a subject.

These results were totally unexpected due to the fact that usuallyin transdermal delivery, bioavailability values are low. Moreover,the unexpected results were achieved even for a very large moleculewith very poor diffusion coefficient.

In addition, it is disclosed that a patch, and particularly aprinted patch, comprising a dried or lyophilized pharmaceuticalcomposition comprising a therapeutically active agent providesstability and long shelf life of the active agent, which isotherwise unstable in solution or suspension.

It is also disclosed that a patch, and particularly a printedpatch, comprising a dried or lyophilized pharmaceutical compositioncomprising a therapeutically active agent provides a means fortransdermal delivery of the active agent in a known, accurate andcontrolled dosage. According to the invention, printing of apharmaceutical composition comprising a therapeutically activeagent on a patch provides uniform and even distribution of theactive agent on the printed patch, thereby highly improvestransdermal delivery and bioavailability of the active agent ascompared to the delivery from a powder patch. This improvedtransdermal delivery from a printed patch compared to a powderpatch is most pronounced when the amount of the active agentapplied on the patch is low (up to several hundreds of micrograms).

The principles of the invention are exemplified herein below withhuman growth hormone, human insulin, salmon calcitonin, and with afragment of human parathyroid hormone (hPTH) having the amino acidresidues 1-34 of the full-length hormone. It is explicitly intendedthat the compositions and methods comprising the system of theinvention are applicable to a wide variety of proteins,polypeptides, peptides, polynucleotides, oligonucleotides, andother bioactive molecules including, but not limited to, growthfactors and hormones.

According to a first aspect, the present invention provides asystem for transdermal delivery of an active therapeutic agent froma dried pharmaceutical composition comprising: an apparatus forfacilitating transdermal delivery of a therapeutically active agentthrough skin of a subject, said apparatus capable of generating aplurality of micro-channels in an area on the skin of the subject,and a patch comprising at least one therapeutically active agent ina dried pharmaceutical composition.

The term "micro-channel" as used throughout thespecification and claims refers to a hydrophilic pathway generallyextending from the surface of the skin through all or a significantpart of the stratum corneum, through which pathway molecules candiffuse. The patch is placed over the treated region in which themicro-channels are present.

According to one currently preferred embodiment of the invention,the system comprises an apparatus for facilitating transdermaldelivery of an active through the skin of a subject, said apparatuscomprising: a. an electrode cartridge, optionally removable,comprising a plurality of electrodes; and b. a main unit comprisinga control unit which is adapted to apply electrical energy to theplurality of electrodes when the plurality of electrodes are invicinity of the skin, typically generating current flow or one ormore sparks, enabling ablation of stratum corneum in an areabeneath said plurality of electrodes, thereby generating aplurality of micro-channels.

According to another embodiment, the control unit of the apparatuscomprises circuitry to control the magnitude, frequency, and/orduration of the electrical energy delivered to the plurality ofelectrodes, so as to control the current flow or spark generation,and thus the width, depth and shape of the plurality ofmicro-channels. Preferably, the electrical energy is at radiofrequency.

In a currently preferred embodiment, the electrode cartridge of theapparatus comprising the plurality of electrodes enables generatinga plurality of micro-channels of uniform shape and dimensions.

According to some embodiments, the pharmaceutical composition ishydrophilic. According to additional embodiments, thepharmaceutical composition comprises at least one hydrophilictherapeutically active agent. According to additional embodiments,the hydrophilic therapeutically active agent within thepharmaceutical composition is selected from the group consisting ofproteins, polypeptides, peptides, polynucleotides,oligonucleotides, growth factors, hormones, and salts thereof.According to further embodiments, the polypeptide within thepharmaceutical composition has up to two hundred amino acidresidues. In a currently exemplary embodiment, the polypeptide ishuman growth hormone (hGH). In another currently exemplaryembodiment, the polypeptide is human insulin. In further exemplaryembodiment, the polypeptide is calcitonin. In a certain exemplaryembodiment, the polypeptide is salmon calcitonin. In yet furtherexemplary embodiment, the polypeptide is parathyroid hormone (PTH)or a fragment thereof. In another exemplary embodiment, thepolypeptide is human PTH (hPTH) or a fragment thereof. In a furtherexemplary embodiment, the polypeptide is an active fragment of hPTHdesignated hPTH (1-34) having the amino acid sequence from aminoacid 1 to amino acid 34 of the full-length hPTH.

According to additional embodiments, the pharmaceutical compositioncan comprise a preservative, an anti-oxidant, a buffering agent, astabilizer, and other additives as are well known in the art.According to further embodiments, the stabilizer is a simple orcomplex carbohydrate. According to certain embodiments, thecarbohydrate is selected from the group consisting of mannose,glucose, galactose, raffinose, cellobiose, gentobiose, sucrose andtrehalose.

According to some embodiments, the pharmaceutical compositionfurther comprises an acidic component to yield a pH in the rangefrom about 3 to about 6 in solution before drying. In an exemplaryembodiment, the pharmaceutical composition comprises hPTH (1-34),sucrose and acetic acid to yield a pH of about 4.0 in solutionbefore drying. In another exemplary embodiment, the pharmaceuticalcomposition comprises hPTH (1-34), trehalose and citric acid toyield a pH of about 4.0 in solution before drying.

According to a further aspect, the present invention provides aprinted patch comprising a dried or lyophilized pharmaceuticalcomposition comprising at least one therapeutically active agent.According to one embodiment, the pharmaceutical composition of theprinted patch is hydrophilic. According to another embodiment, thetherapeutically active agent within the pharmaceutical compositionof the printed patch is hydrophilic. According to furtherembodiments, the therapeutically active agent within thepharmaceutical composition of the printed patch is selected fromthe group consisting of proteins, polypeptides, peptides,polynucleotides, oligonucleotides, growth factors, hormones, andsalts thereof. According to additional embodiments, the polypeptidewithin the pharmaceutical composition of the printed patch has upto two hundred amino acid residues.

In one currently exemplary embodiment, the pharmaceuticalcomposition within the printed patch comprises human Growth Hormone(hGH), optionally further comprising mannitol and sucrose ortrehalose. In another currently exemplary embodiment, thepharmaceutical composition within the printed patch comprises humaninsulin. In a further embodiment, the pharmaceutical compositionwithin the printed patch comprises calcitonin. In a certainexemplary embodiment, the pharmaceutical composition within theprinted patch comprises salmon calcitonin. In yet further exemplaryembodiment, the pharmaceutical composition within the printed patchcomprises PTH or a fragment thereof. In a certain exemplaryembodiment, the pharmaceutical composition within the printed patchcomprises human PTH or a fragment thereof. In another exemplaryembodiment, the pharmaceutical composition within the printed patchcomprises hPTH (1-34).

The pharmaceutical composition of the printed patch may furthercomprise a stabilizer. According to some embodiments, thestabilizer can be a simple or complex carbohydrate. According toadditional embodiments, the carbohydrate is selected from the groupconsisting of glucose, galactose, raffinose, cellobiose,gentiobiose, sucrose and trehalose.

The pharmaceutical composition of the printed patch can furthercomprise an acidic component to yield a pH in the range from 3 toabout 6 in solution before drying. According to an exemplaryembodiment, the pharmaceutical composition of the printed patchcomprises hPTH (1-34), sucrose and acetic acid to yield a pH ofabout 4.0 in solution before drying. According to additionalembodiment, the pharmaceutical composition of the printed patchcomprises hPTH (1-34), trehalose and citric acid to yield a pH ofabout 4.0 in solution before drying.

The printed patch may further comprise an additional hydrophilicdried agent. The patch may also comprise any suitable compositionand be of any suitable geometry provided that it is adapted forstable and, optionally microbiologically controlled, aseptic orsterile, storage of the active agent prior to its use.

According to yet another embodiment, the printed patch furthercomprises at least one of the following: a backing layer, anadhesive layer, and a microporous liner layer.

According to further aspect, the present invention provides amethod for preparing a printed patch containing a therapeuticallyactive agent comprising: a. preparing a pharmaceutical solution orsuspension comprising at least one therapeutically active agent; b.placing at least one measured volume of the solution of (a) on asuitable matrix; and c. drying the matrix of (b) by drying meansthat maintain the therapeutic activity of the therapeuticallyactive agent of (a).

The simplicity of the essential ingredients of the patch stems fromthe fact that the patch is specifically designed for use inconjunction with the apparatus for generating micro-channels in theskin of the subject.

According to additional aspect, the present invention provides amethod for transdermal administration of a dried or lyophilizedpharmaceutical composition comprising at least one therapeuticallyactive agent using an apparatus and a patch according to theembodiments of the present invention.

The present invention thus provides a method for transdermaladministration of a dried or lyophilized pharmaceutical compositioncomprising: generating a plurality of micro-channels in an area ofthe skin of a subject; and affixing a patch, preferably a printedpatch, comprising a dried or lyophilized pharmaceutical compositioncomprising at least one therapeutically active agent to the area ofskin in which the plurality of micro-channels are present.

According to preferred embodiments the therapeutically active agentin the context of the dried or lyophilized pharmaceuticalcomposition of the invention to be administered according to themethod of the present invention is hydrophilic and selected fromthe group consisting of proteins, polypeptides, peptides,polynucleotides, oligonucleotides and pharmaceutically acceptablesalts thereof. Currently exemplary embodiments are human GrowthHormone (hGH), human insulin, calcitonin and PTH. In certainexemplary embodiments, the therapeutically active agent to beadministered by the method of the present invention is salmoncalcitonin, hPTH, and hPTH (1-34).

According to yet further aspect, the present invention provides amethod for transdermal administration of a dried pharmaceuticalcomposition comprising at least one therapeutically active agent,the method comprising: generating a plurality of micro-channels inan area of the skin of a subject; affixing a patch, preferably aprinted patch, comprising a dried pharmaceutical compositioncomprising a therapeutically effective amount of at least onetherapeutically active agent to the area of skin in which theplurality of micro-channels are present; and achieving doseefficiency of at least 10%, thereby attaining a therapeutic effect.According to some embodiments, the therapeutically active agent isa peptide or polypeptide having up to two hundred amino acidresidues. Currently exemplary embodiments of peptides orpolypeptides are human Growth Hormone (hGH) and human insulin.Currently additional exemplary embodiments are calcitonin and PTHincluding, but not limited to, salmon calcitonin, human PTH (hPTH)and fragments thereof such as hPTH (1-34). According to oneembodiment, the subject is human.

The term "dose efficiency" used herein refers to acalculated ratio (%) between a first calculated amount of atherapeutically active agent present in blood of a subject aftertransdermal delivery from a patch comprising the active agent, thepatch affixed to the skin of the subject where micro-channels havebeen generated using the apparatus of the present invention, and asecond amount of said active agent applied or printed on the patch.The calculated amount of a therapeutically active agent present inthe blood of a subject is calculated based on the area under curve(AUC) values over a period of time obtained for the patch comparedto the AUC values obtained over the same period of time using acommercially available injectable form of the same active agent.

According to some embodiments, the dose efficiency to be achievedby the method of the invention is of at least 20%. According toadditional embodiments, the dose efficiency to be achieved is of atleast 30%. According to further embodiments, the dose efficiency isof at least 40%. According to yet further embodiments, the doseefficiency to be achieved is of at least 50%.

According to further embodiments, generating the plurality ofmicro-channels in the area of the skin of the subject is of adensity of about 75 to about 450 micro-channels/cm.sup.2. Accordingto certain embodiments, generating the plurality of micro-channelsin the area of the skin of the subject is at a density of about 150to about 300 micro-channels/cm.sup.2. Preferably, the plurality ofmicro-channels have uniform shape and dimensions.

It is to be understood that the method of the present invention,which comprises generating a plurality of micro-channels ispreferably performed by the apparatus of the present invention,which apparatus comprises an electrode cartridge comprising aplurality of electrodes and a main unit comprising a control unit,which is adapted to apply electric energy between the plurality ofelectrodes. According to some embodiments, the electrodes have adiameter of about 30 microns to about 150 microns. According tocertain embodiments, the electrodes have a diameter of about 80microns. According to further embodiments, the electrodes have alength of about 50 microns to about 100 microns. According tocertain embodiments, the electrodes have a length of about 95microns. According to additional embodiments, the electrical energyapplied by the control unit of the apparatus of the presentinvention is of radio frequency.

According to certain embodiments, the present inventionincorporates the techniques for creating micro-channels by inducingablation of the stratum corneum using radio frequency (RF) energy,including the apparatus referred to as ViaDerm or MicroDerm,disclosed in one or more of the following: U.S. Pat. Nos.6,148,232; 6,597,946; 6,611,706; 6,711,435; 6,708,060; Sintov etal., J. Controlled Release 89: 311-320, 2003; the content of whichis incorporated by reference as if fully set forth herein. It ishowever emphasized that although some preferred embodiments of thepresent invention relate to transdermal delivery obtained byablating the skin by the aforementioned apparatus, substantiallyany method known in the art for generating channels in the skin ofa subject may be used.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides formulations, methods andpharmaceutical technologies for delivering dried or lyophilizedmedications, preferably of hygroscopic formulations, throughtreated skin in which micro-channels have been generated.

The current transdermal patches are designed to deliver drugmolecules through the stratum corneum (SC). As such they haveseveral characteristics: a. The delivery of the molecules occursthrough all the area under the patch. b. The interface between thepatch and the skin tends to be hydrophobic. This facilitatesdelivery of drug molecules from one hydrophobic matrix (patch) tothe other (SC). c. The patches usually contain enhancers. Thepurpose of these molecules is to change and disrupt the structureof the SC, thus elevating the solubility of the drug molecules inthe SC matrix. Enhancers are also responsible for undesired sideeffects like erythema, edema or pruritis.

Micro-channel or electroporation treatment creates aqueousmicro-channels through the SC into the epidermis, thus drugmolecules do not need to pass through the lipoid SC in order to getinto viable tissues. This has several implications: 1. The deliveryof the molecules occurs mainly through the micro-channels, whichoccupy less than 1% of the treated skin area. 2. The transdermaldelivery rate of agents through the micro-channels is notrestricted by the limited permeability of the SC. 3. There is noneed to include enhancers in the formulations, thus improving skinsafety.

Based on these considerations, the system of the present inventionis highly suitable for delivery of dried or lyophilized hydrophilicmacromolecules through the new skin environment, which is createdby the ablation of the stratum corneum. The main advantage of usingdried or lyophilized formulations is the potential stability of thepharmaceutically active ingredients as compared with liquidformulations. This advantage is especially relevant for activeingredients in the form of peptides and proteins. Accordingly, avariety of formulations may provide efficient delivery of a varietyof drugs, particularly and advantageously of dried or lyophilizedhygroscopic formulations. As a consequence, the system of thepresent invention does not necessitate the use of permeationenhancers for transdermal drug delivery and is therefore notsusceptible to the problems attendant therewith, particularlyirritation. Irritation occurs as the skin reacts to topicallyapplied agents, particularly those maintained under occlusion, byblistering or reddening accompanied by unpleasant burning, itching,and stinging sensations. It is desirable to avoid or to keep thenumber of possibly irritating agents in a transdermal deliverysystem to a minimum.

It is now disclosed for the first time that use of a patchcomprising a dried or lyophilized pharmaceutical compositioncomprising a therapeutically active agent, placed on an area of theskin pretreated by an apparatus that generates micro-channelsprovides unexpectedly therapeutically effective serum levels of theactive agent. The dose efficiency or bioavailability obtained wasadequate to provide therapeutic effects in a subject. Moreover,these unexpected results were achieved even for very largemolecules with low diffusion coefficient.

These results were totally unexpected due to the fact that usuallyin transdermal delivery, bioavailability values low. For example,estradiol patch (Climara.RTM. by 3M) or testosterone patch(Androderm.RTM. by TheraTech, Inc.) are known to achievebioavailability values of about 9% or 20%, respectively.

The term "dried or lyophilized pharmaceuticalcomposition" as used in the context of the presentspecification and claims refers to a pharmaceutical composition ofwhich the residual moisture is below 20%, preferably below 10%,more preferably below 5%, and most preferably below 3% of the finalcomposition's weight.

The term "micro-channel" as used in the context of thepresent specification and claims refers to a hydrophilic pathwaygenerally extending from the surface of the skin through all or asignificant part of the stratum corneum and may reach into theepidermis or dermis, through which molecules can diffuse. Althoughsome preferred embodiments of the present invention are describedwith respect to ablating the stratum corneum by electric current orspark generation, preferably at radio frequency (RF), substantiallyany method known in the art for generating channels in the skin ofa subject may be used (see e.g. U.S. Pat. Nos. 5,885,211,6,022,316, 6,142,939 6,173,202, 6,148,232 and WO 02/085451 and WO02/092163). The term "micro-pore" is used interchangeablyherein.

The term "new skin environment" as used herein, denotes askin region created by the ablation of the stratum corneum andformation of at least one micro-channel, using the system of thepresent invention.

Suitable therapeutically active agents for use in conjunction withthe principles of the invention are dried or lyophilized largemolecules, including a wide variety of proteins, polypeptides,peptides, polynucleotides, oligonucleotides, other bioactivemolecules and pharmaceutically acceptable salts thereof including,but not limited to, insulin, proinsulin, follicle stimulatinghormone, insulin like growth factor-1 and insulin like growthfactor-2, platelet derived growth factor, epidermal growth factor,fibroblast growth factors, nerve growth factor, colony stimulatingfactors, transforming growth factors, tumor necrosis factor,calcitonin, parathyroid hormone, growth hormone, bone morphogenicprotein, erythropoietin, hemopoietic growth factors, luteinizinghormone, glucagon, clotting factors such as factor VIIIC, factorIX, tissue factor, and von Willebrand factor, anti-clotting factorssuch as Protein C, atrial natriuretic factor, lung surfactant,plasminogen activator, such as urokinase or tissue-type plasminogenactivator, including human tissue-type plasminogen activator(t-PA), bombesin, thrombin, enkephalinase, collagen; a collagendomain, mullerian-inhibiting agent, relaxin A-chain, relaxinB-chain, prorelaxin, Dnase, inhibin, activin, vascular endothelialgrowth factor, receptors for hormones or growth factors, integrin,protein A or D, rheumatoid factors, neurotrophic factor such asbone-derived neurotrophic factor (BDNF), neurotrophin-3, -4, -5,and -6 (NT-3, NT-4, NT-5, or NT-6), CD proteins such as CD-3, CD-4,CD-8, and CD-19, osteoinductive factors, immunotoxins, interferonsuch as interferon-alpha, -beta, and -gamma, colony stimulatingfactors (CSFs), e.g., M-CSF, GM-CSF, and G-CSF, interleukins (ILs),e.g., IL-1 to IL-10, superoxide dismutase, T-cell receptors,surface membrane proteins, decay accelerating factor, viral antigensuch as, for example, a portion of the AIDS envelope, transportproteins, homing receptors, addressins, regulatory proteins,antibodies, and fragments of any of the above-listed polypeptides.According to some preferred embodiments, the therapeutically activeagent is a peptide or polypeptide having up to two hundred aminoacid residues. Examples of peptides or polypeptides include, butnot limited to, human growth hormone, human insulin, salmoncalcitonin, human parathyroid hormone (hPTH), and fragmentsthereof. Examples of hPTH fragments include, but are not limitedto, hPTH (1-34), hPTH (1-37), hPTH (1-38), and hPTH (1-41).

As used herein, "a pharmaceutically acceptable salt"refers to a derivative of the disclosed agents wherein the parentagent is modified by making acid or base salts of the agent. Forexample, acid salts are prepared from the free base (typicallywherein the neutral form of the drug has a neutral --NH.sub.2group) using conventional means known in the art, involvingreaction with a suitable acid. Suitable acids for preparing acidsalts include both organic acids, e.g., acetic acid, propionicacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like, as well as inorganic acids, e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Conversely, preparation of basicsalts of acid moieties which may be present on a drug are preparedusing a pharmaceutically acceptable base such as sodium hydroxide,potassium hydroxide, ammonium hydroxide, calcium hydroxide,trimethylamine, or the like.

Several general embodiments are covered by the invention, includingembodiments in which the therapeutically active agent in the driedpharmaceutical composition is hydrophilic and embodiments in whichthe dried pharmaceutical composition further comprises an inert(not containing a drug) hydrophilic dried agent. It is known in theart that a combination of dried hGH with mannitol may beadvantageous for dissolution of the hGH powder.

As used herein, "pharmaceutical composition" or"medication" used herein interchangeably, refers to apharmaceutical composition comprising a therapeutically effectiveamount of an active agent, wherein the pharmaceutical compositionor medication may be dried or lyophilized while retaining atherapeutic activity. The terms "therapeutically activeagent" and "drug" are used herein interchangeably todenote the active ingredient of the pharmaceutical composition.

In a preferred embodiment of the present invention, the driedpharmaceutical composition can comprise more than onetherapeutically active agent.

The pharmaceutical composition for use according to principle ofthe invention can be optimized to take into consideration issueslike stability. In this specification the term "stable"refers to a composition that is robust enough to retain at least80% of the active ingredient in its original chemical form for aperiod of at least three months at ambient or below ambienttemperatures.

According to the invention, the dried or lyophilized pharmaceuticalcomposition may comprise at least one stabilizer."Stabilizers" as defined herein stabilize an activeagent, preferably a protein, a polypeptide, or a peptide, duringstorage. Stabilizers may also aid delivery of the active agent.Stabilizers known in the art include, but are not limited to,carbohydrates such as, for example, mannose, glucose, galactose,raffinose, cellobiose, gentiobiose, sucrose and trehalose, andhydrophobically-derivatised carbohydrates (HDCS) such as sorbitolhexaacetate, .alpha.-glucose pentaacetate, .beta.-glucosepentaacetate, trehalose octaacetate, trehalose octapropanoate,sucrose octaacetate, sucrose octapropanoate, cellobioseoctaacetate, cellobiose octapropanoate, raffinose undecaacetate andraffinose undecapropanoate. The composition may also comprise anamino acid so as to increase drug stability. Amino acids that maybe added to the pharmaceutical composition include, but are notlimited to, histidine and glutamic acid.

Typically, proteins modified by a covalent attachment ofwater-soluble polymers are known to exhibit substantially longerhalf-lives in blood following intravenous injection than do thecorresponding unmodified proteins. Such modifications may alsoincrease the protein's solubility in aqueous solution, eliminateaggregation, enhance the physical and chemical stability of theprotein, and greatly reduce the immunogenicity and antigenicity ofthe protein. Thus, the pharmaceutical composition according to thepresent invention may comprise polymers, preferably water-solublepolymers such as polyethylene glycol, copolymers of polyethyleneglycol and polypropylene glycol, carboxymethyl cellulose, dextran,polyvinyl alcohol, polyvinylpyrrolidone or polyproline,hydroxypropyl metharylamide, and the like.

The pharmaceutical composition may also include diluents of variousbuffer content (e.g., Tris-HCl, phosphate, citrate, acetate), pHand ionic strength, additives such as albumin or gelatin to preventadsorption to surfaces, detergents (e.g., Tween 20, Tween 80,Pluronic F68, Pluronic 127), anti-oxidants (e.g., ascorbic acid,sodium metabisulfite), and preservatives (e.g., Thimerosal, benzylalcohol, parabens, m-cresol). The formulation of the pharmaceuticalcomposition comprising a therapeutically active agent according tothe present invention is determined so as to provide improvedstability of the active agent while retaining or improving itsbioavailability. Methods to detect stability of an agent areexemplified herein below by HPLC analysis. However, other methodsknown in the art may be used to determine the stability of anactive agent.

The amount of therapeutically active agent in the pharmaceuticalcomposition necessary to provide the desired amounts andconcentration in the serum can be determined by methods describedherein below and by methods known in the art. Thus, theconcentration or the quantity of the therapeutically active agentper dried pharmaceutically composition or per patch can be variedindependently in order to achieve a desired therapeutic effect.

Powder Patch

The present invention discloses for the first time the use ofpatches that comprise a dry pharmaceutical composition, as adelivery system for hydrophilic macromolecules, such as peptides orproteins, as well as for other highly water soluble drugs. Afterapplication of such a patch on the pretreated new skin environment,the pharmaceutical composition is dissolved in fluid that comes outof the micro-channels, and is then absorbed through themicro-channels into the body. This approach is particularlysuitable for drugs that do not irritate the skin even at highconcentrations.

According to certain embodiments of the present invention, it ispossible to monitor and to obtain a relative evaluation of the lossof fluids that come out from the micro-channels in the new skinenvironment with respect to the loss of fluids that come out fromthe skin prior to ablation of the stratum corneum. This type ofmeasurement is also termed herein "transepidermal waterloss" or "TEWL", and is described in the foregoingexamples.

Thus, a patch based on a drug in the solid state may have severaladvantages: i. Improved stability, due to the absence of solventsand other excipients; ii. Relatively high delivery rates, due tothe delivery from a saturated solution or suspension; iii. Mayenable production of thin and convenient patch, instead ofreservoir patches, even for sensitive active materials that are notsuitable for a drug-containing adhesive type of patch; iv.Practical as it enables usage of very small amounts of expensiveagents.

Methods for preparing different types of powder patches,specifically methods that are suitable for accurately placing smallamounts of an active agent including proteins, as a dry agent ontoa solid support from which they will be released are disclosedherein.

A. Printing

Printing methods encompass techniques in which small droplets of asolution or suspension of a pharmaceutical composition are placedon a uniform liner in a controlled manner. The droplets dry rapidlyand leave solid dots of the pharmaceutical composition. The dose isaccurately determined by the concentration of the active agent inthe solution or suspension and the configuration and programming ofthe manufacturing instrument. Besides the therapeutically activeagent, the pharmaceutical composition may advantageously includeother materials, such as solubility increasing agents, stabilizers,and polymers.

In order to penetrate into the skin and the blood circulation, thepharmaceutical composition within the printed dots on the liner isdissolved in the fluids that are exuded from the skin throughmicro-channels.

Methods known in the art for applying droplets include a smallvolume (one to several microliter) syringe or an array of syringes,a combination of a small volume syringe or an array of syringeswith a metering pump, an array of small pins, tips of the pinsdipped in the solution/suspension, printing with a device like anink jet printer, printing with a cartridge containing the solutionof the pharmaceutical composition, spraying of a thin film of asolution of active drug on a liner and the like.

To enable adhesion of the printed patch to the new environment skinthe printing is prepared on a transdermal adhesive backing liner.Alternatively, a suitable adhesive can be printed between theprints of the drug, on a non-adherent liner.

B. Non-uniform Liners

Suitable liners for this purpose are various liners with precisecavities. Basically the liner is dipped or soaked in the solutionof the therapeutically active material, and then dried byair-drying or lyophilization or any other suitable means of dryingor evaporation. The amount of solution of therapeutically activematerial that is applied on the liner is determined by thestructure of the liner itself and its chemical and surfacecharacteristics.

Various methods for preparing non-uniform dried drug-containingliners are known in the art including soaking a filter paper or afilter membrane with the solution of the drug and drying it,dipping a micronic net or screen into the active solution anddrying it (as exemplified herein below), using a sheet with smalland precise indentations or pores in a specific density or patternand either filling the pores with the solution of the active drug,and drying or flipping the indentation so as to leave the activepowder film on the protruding convexities, preparing a sheet withsmall projections on it then dipping the tips of the projectionsinto the pharmaceutical active solution such that a small drop isleft on each projection and drying.

Drying can be carried under controlled conditions for example bychanging the temperature, humidity or pressure.

Various types of materials may be used to form the liners,including without limitation screens and fabrics in various patternand synthetic woven meshes prepared from various polymers selectedfrom the group of polyamide, polyester, polypropylene, Teflon, polyolefins such as polyethylene and polybutylene, polyurethane,polyvinyl butyrate, polysulphone, polyethersulphone, polyvinylchloride, polycarbonate, polytetrafluoroethylene, polyvinylidenefluoride, cellulose acetate, cellulose triacetate, cellulosenitrate. A current preferred liner material is a polyester screencontaining a mesh of 45 .mu.m and 39% open area. Another preferredmaterial is a dense nylon (polyamide) fabric (as exemplified hereinbelow by Sefar Nitex.TM., G Bopp & Co Ltd, Derbyshire, UK).

C. Direct Application of Powder

A basic approach for the application of pharmaceutical powder is todirectly apply the powder on the treatment site. According to oneembodiment, spots of powder are embedded onto a soft flat sheetthat is attached to the new skin environment by an additionaladhesive layer. Alternatively, the sheet itself may beself-adherent. According to a second embodiment the powder isencapsulated within water-soluble films. The powder capsules can beprepared by distributing the powder over a water-soluble filmcontaining an array of wells, filling the wells and removingexcessive powder. The sheet is then covered with a similar sheet,such that the wells of both sheets are at similar positions.Alternatively, the pores in the water-soluble sheet are coveredwith a flat sheet, which is a water-soluble film. The powder patchcan be then attached to the skin such that either the flat sheet orthe well-containing sheet is facing the new skin environment. Theflat sheet may be also made of a non-soluble backing liner.

To enable adhesion to the new skin environment the drug powder canbe dispersed over a liner, which contains microscopic suction cupson its surface.

The powder patch according to the present invention may be furtherincorporated into a medical patch. The medical patch comprising thepowder patch may further comprise at least one of the following: abacking layer, an adhesive, and a suitable microporous liner layersuch that the drug containing layer is disposed between the backinglayer and the microporous liner layer.

The term "backing layer" defines any protective layer notpermeable to the drug that is provided to physically seal and henceprotect the patch, specifically the drug containing layer. Thebacking layer may be made of a polyester, polyethylene orpolypropylene.

Application of a medical patch to the new skin environment isaccomplished after at least partial removal of any covering orpackaging, before use. This exposes the drug-containing layer,which may itself have adhesive properties, or may further comprisean adhesive layer attached to the drug-containing layer. Properadherence to usage instructions generally ensures that the patchcan be placed in a sterile manner.

According to the invention the powder patch may be modular so as tocontain in each module a known amount of the therapeutically activeagent. A known amount of the active agent may be, for example, aunit dose. Thus, affixing the modular patch to the new skinenvironment will enable transdermal delivery of an accurate andcontrolled dosage of the therapeutically active agent.

Devices for Enhancing Transdermal Delivery of Dried or LyophilizedMedication

The system of the present invention further contains an apparatusfor enhancing transdermal delivery of an agent. According to theprinciples of the invention the apparatus is used to generate a newskin environment through which a dried or lyophilized medication isdelivered efficiently.

In preferred embodiment of the present invention, the apparatus forenhancing transdermal delivery of an agent using RF energy is asdisclosed in U.S. Pat. No. 6,148,232 and continuations thereto(U.S. Pat. Nos. 6,597,946; 6,611,706; 6,711,435; 6,708,060; andSintov et al. J. Controlled Release 89: 311-320, 2003, the contentof which is incorporated by reference as if fully set forth),comprising: an electrode cartridge, optionally removable,comprising at least one electrode and a main unit wherein the mainunit loaded with the electrode cartridge is also denoted hereinViaDerm.

The control unit is adapted to apply electrical energy to theelectrode typically by generating current flow or one or moresparks when the electrode cartridge is in vicinity of the skin. Theelectrical energy in each electrode within the electrode arraycauses ablation of stratum corneum in an area beneath theelectrode, thereby generating at least one micro-channel.

The control unit comprises circuitry which enables to control themagnitude, frequency, and/or duration of the electrical energydelivered to an electrode, in order to control current flow orspark generation, and consequently to control the dimensions andshape of the resulting micro-channel. Typically, the electrodecartridge is discarded after one use, and as such is designed foreasy attachment to the main unit and subsequent detachment from theunit.

To minimize the chance of contamination of the cartridge and itsassociated electrodes, attachment and detachment of the cartridgeis performed without the user physically touching the cartridge.Preferably, cartridges are sealed in a sterile cartridge holder,which is opened immediately prior to use, whereupon the main unitis brought in contact with a top surface of the cartridge, so as toengage a mechanism that locks the cartridge to the main unit. Asimple means of unlocking and ejecting the cartridge, which doesnot require the user to touch the cartridge, is also provided.

Optionally the electrode cartridge may further comprise means tomark the region of the skin where micro-channels have been created,such that a medical patch can be precisely placed over the treatedregion of the skin. It is noted that micro-channel generation (whenpracticed in accordance with the techniques described in theabove-cited US patent or continuation patent applications toAvrahami et al., assigned to the assignee of the present patentapplication) does not generally leave any visible mark, becauseeven the large number of micro-channels typically generated are notassociated with appreciable irritation to the new skin environment.

The term "about" used herein refers generally tovariation within one standard deviation of the mean.

Methods for Using the System of the Invention

The current invention also provides a method for treatment with adried or lyophilized medication using the system of the invention.In general embodiments, the procedure for forming the new skinenvironment comprises the step of placing over the skin theapparatus for generating at least one micro-channel. Preferably,prior to generating the micro-channels the treatment sites will beswabbed with sterile alcohol pads. Preferably, the site should beallowed to dry before treatment.

In preferred embodiments of the current invention, the type ofapparatus used to generate micro-channels is disclosed in U.S. Pat.No. 6,148,232 and Sintov et al. J. Controlled Release 89: 311-320,2003. The apparatus, containing the electrode array, is placed overthe site of treatment, the array is energized by RF energy, andtreatment is initiated. In principle, the ablation and generationof micro-channels is completed within seconds. The apparatus isremoved after micro-channels are generated at limited depth,preferably limited to the depth of the SC and the epidermis. Anypatch known in the art that is suitable for usage in the system ofthe invention as described above, comprising a therapeuticallyactive agent, is attached to the new skin environment.

The present invention further provides a method for transdermaladministration of a dried pharmaceutical composition comprisingtherapeutically active agent, the method comprising: generating aplurality of micro-channels in a region of the skin of a subject,affixing a patch comprising a dried pharmaceutical compositioncomprising a therapeutically effective amount of a therapeuticallyactive agent to the region of skin in which the micro-channels arepresent, and achieving dose efficiency of at least 10%, therebyattaining a therapeutically effective blood concentration of theactive agent for at least a therapeutically relevant period of timeleading to a therapeutic effect.

As defined herein "Therapeutically effective bloodconcentration" means a concentration of an active agent, whichresults in a therapeutic effect, preferably in humans. Bloodconcentrations at ranges expected to exert therapeutic effect areobtained in animal models. As exemplified herein below therapeuticblood concentrations of human insulin in hyperglycemic rats, whichresult in normal glucose level (100 mg/dl to 200 mg/dl glucose)were obtained within approximately 1-3 hours for a period of about4-6 hours. It is to be understood that the present inventionencompasses methods for transdermal administration of a driedpharmaceutical composition, which achieve therapeutic bloodconcentrations for longer periods of time. Additionally, astherapeutic blood concentrations of hydrophilic active agents ofthe invention are known in the art, the period of time forachieving and maintaining therapeutic blood concentrations can bedetermined by methods described herein below or by any other methodknown in the art. For example, therapeutic blood concentrations ofhPTH (1-34) in human ranges from about 20 to 250 pg/ml for a periodof 2-4 hours.

The present invention encompasses methods for transdermaladministration of a dried pharmaceutical composition comprising atherapeutically active agent, wherein the active agent is a peptideor polypeptide having up to two hundred amino acid residues.Examples of peptides or polypeptides, which can be administeredtransdermally by the methods of the present invention include, butare not limited to, hGH, human insulin, calcitonin, human PTH or afragment thereof. Human PTH fragments that can be administeredtransdermally by the methods of the present invention include, butare not limited to, hPTH (1-34), hPTH (1-37), hPTH (1-38), hPTH(1-41), and hPTH (1-84).

The term "dose efficiency" used herein refers to acalculated ratio (%) between a first estimated amount of atherapeutically active agent present in blood of a subject aftertransdermal delivery from a patch comprising the active agent, thepatch affixed to the skin of the subject where micro-channels havebeen generated using the apparatus of the present invention, and asecond amount of said active agent applied or printed on the patch.

In pharmacokinetic studies, relative bioavailability reflects thebioavailability of a drug administered by any route ofadministration, other than I.V. injection, to the bioavailabilityof the same drug injected at the same dose I.V. If the drug isadministered transdermally, relative bioavailability is calculatedaccording to formula I:(AUC.sub.transdermal/Dose.sub.transdermal)/(AUC.sub.IV/Dose.sub.IV)*100=R-elative Bioavailability (%).

In formula I, AUC defines the area under curve when measuring drugconcentration in blood along a predetermined period of time, thedose of the drug administered transdermally is identical to thedose of the drug administered intravenously.

However, due to the fact that it is not clinically feasible toinject to a human subject the same dose of a drug or active agentas applied on a patch, the inventors of the present inventioncalculated dose efficiency, which provides an estimate of therelative bioavailability. Dose efficiency is calculated accordingto formula II:(AUC.sub.transdermal/Dose.sub.transdermal)/(AUC.sub.SC/Dose.sub.SC)*100=D-ose efficiency (%).

In formula II, the dose of the drug or active agent administeredtransdermally is generally higher than the dose of the drug oractive agent administered subcutaneously and the administrationroute, which is used as a reference, is subcutaneous administrationrather than I.V. injection. AUC defines the area under curve whenmeasuring drug or active agent concentration in blood along apredetermined period of time. Thus, for calculating dose efficiencyof a therapeutically active agent such as, for example, hPTH(1-34), administered transdermally from a patch to human subjects,a dose of 20 .mu.g of hPTH (1-34) was injected subcutaneously,which dose is approved by the FDA, and the AUC.sub.SC of 20 .mu.gof hPTH (1-34) along 12 hrs was used as 100%. A higher dose of hPTH(1-34) was applied or printed on a patch and theAUC.sub.transdermal of hPTH (1-34) was measured along the sameperiod of time, i.e., 12 hrs. The AUC.sub.SC of 20 .mu.g of hPTH(1-34), taken as 100%, was then used to calculate the amount ofhPTH (1-34) delivered transdermally from the patch, based on theAUC.sub.transdermal measured. The calculated amount of hPTH (1-34)delivered transdermally was then divided by the amount of hPTH(1-34) applied or printed originally on the patch, and that ratiowas used as a measure of dose efficiency. It is to be understoodthat the term "bioavailability" as used herein isproportional to the term "dose efficiency", the two termsare used interchangeably throughout the specification and claims.

According to preferred embodiments of the current invention, themicro-channels may be generated separately or simultaneously withthe application of a medical patch. Among the other applications,the system may include a medical patch comprising an adhesivecut-out template which is placed on the skin, and through which thecartridge is placed to treat the region of skin exposed through thetemplate. The dried or lyophilized medication, contained within aprinted patch or any other suitable patch according to embodimentsof the present invention, is attached to the template, which is tobe placed over the treated region of skin. In these applications,after removing a protective backing, the template portion of themedical patch is placed on the skin and secured by the adhesive. Anelectrode cartridge is then affixed to the handle, the user holdsthe handle so as to place the cartridge against the region of skininside the template, and the electrodes are energized to treat theskin. Subsequently, the cartridge is discarded. A protectivecovering is then removed from the medicated matrix by pulling on atab projecting from the covering, so as to concurrently lift andplace the medicated matrix over the treated region of skin. It isnoted that the integration of the template and the patch into asingle unit assists the user in accurately placing the medicatedpatch onto the treated area of skin. Utilizing the system of theinvention in this manner becomes advantageous for disinfectedapplications.

For still other applications, an integrated electrode/medicated padcartridge is used, to provide a practical apparatus as disclosed inInternational Patent Application WO 02/092163 which is assigned tothe assignee of the present patent application and incorporatedherein by reference and is also denoted MicroDerm. In theseapplications, the cartridge comprises an electrode array, acontrolled unit and a medicated pad. Accordingly, no template istypically required. The user places the electrodes against the skinand this contact is sufficient to initiate current flow or sparkformation within the electrode and the subsequent formation ofmicro-channels. An adhesive strip, coupled to the bottom of themedicated pad, comes in contact with and sticks to the skin whenthe electrodes are placed against the skin. A top cover on themedicated matrix is coupled to the electrode region of thecartridge, such that as the electrode region, fixed to the handle,is removed from the skin the top cover is pulled off the medicatedpad and the pad is concurrently folded over the treated region ofskin. This type of application eliminates the need for the user totouch any parts of the electrode cartridge or the medicated pad,thus substantially reducing or eliminating the likelihood of theuser contaminating the apparatus.

In a preferred embodiment, current may be applied to the skin inorder to ablate the stratum corneum by heating the cells. In onepreferred embodiment, spark generation, cessation of sparkgeneration, or a specific current level may be used as a form offeedback, which indicates that the desired depth has been reachedand current application should be terminated. For theseapplications, the electrodes are preferably shaped and/or supportedin a cartridge that is conducive to facilitating ablation of thestratum corneum and the epidermis to the desired depth, but notbeyond that depth. Alternatively, the current may be configured soas to ablate the stratum corneum without the generation of sparks.

The present invention incorporates methods and apparatus describedin International Patent Application WO 02/092163 entitled"Monopolar and bipolar current application for transdermaldrug delivery and analyte extraction," which is assigned tothe assignee of the present patent application and incorporatedherein by reference. For example, this application describesmaintaining the ablating electrodes either in contact with theskin, or up to a distance of about 500 microns therefrom. Theapplication further describes spark-induced ablation of the stratumcorneum by applying a field having a frequency between about 10 kHzand 4000 kHz, preferably between about 10 kHz and 500 kHz.

Alternatively or additionally, preferred embodiments of the presentinvention incorporate methods and apparatus described inInternational Patent Application WO 02/085451 entitled"Handheld apparatus and method for transdermal drug deliveryand analyte extraction," which is incorporated herein byreference.

Still further alternatively or additionally, preferred embodimentsof the present invention incorporate methods and apparatusdescribed in the above-cited U.S. Pat. No. 6,148,232 to Avrahami,which is assigned to the assignee of the present patent applicationand incorporated herein by reference.

In some preferred embodiments of the present invention, thecartridge supports an array of electrodes, preferably closelyspaced electrodes, which act together to produce a highmicro-channel density in an area of the skin under the cartridge.Typically, however, the overall area of micro-channels generated inthe stratum corneum is small compared to the total area covered bythe electrode array.

In further preferred embodiments of the present invention, aconcentric electrode set is formed by employing the skin contactsurface of the cartridge as a return path for the current passingfrom the electrode array to the skin. Preferably, the cartridge hasa relatively large contact surface area with the skin, resulting inrelatively low current densities in the skin near the cartridge,and thus no significant heating or substantial damage to the skinat the contact surface.

In proximity to each electrode in the electrode array, by contrast,the high-energy applied field typically induces very rapid heatingand ablation of the stratum corneum.

Claim 1 of 28 Claims
1. A printed patch comprising a non-adhesive liner and a driedpharmaceutical composition comprising parathyroid hormone (PTH) ora fragment thereof that can elevate calcium ions or decreasephosphorus in blood in a manner similar to that of PTH(1-34), withthe PTH or fragment being present on the non-adhesive liner,wherein the non-adhesive liner is made of a material that is notpermeable to PTH or the fragment thereof.
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