MXPA06004903A - Self-actuating applicator for microprojection array - Google Patents

Abstract

An applicator for applying a microprojection member to the stratum corneum of a patient having a housing, a piston moveable within the housing and a cap adapted to activate the applicator. The applicator is self-setting and auto-triggering, which allows the applicator to be used by patient's having neither the strength, nor the manual dexterity to pre-set and activate other types of applicator devices.

Description

SELF-ACTIVE APPLICATOR FOR A MICROPROJECTION SETTLEMENT CROSS REFERENCE TO RELATED REQUESTS This request claims the benefit of the provisional application in the United States with No. 60 / 516,182, filed on October 31, 2003.

FIELD OF THE INVENTION The present invention relates to an apparatus and method for applying a penetrating member to the skin by impaction, and more particularly, the invention relates to a self-isolating, self-firing device for reproducibly penetrating the corneal bone with a penis member. , as a micro projection arrangement, for ranstermic administration or sampling of an agent.

BACKGROUND OF THE INVENTION Active agents (or drugs) are more conveniently administered either orally or by injection. Unfortunately, many agents are completely ineffective or have a radically reduced efficacy when administered orally because they are not absorbed or are adversely absorbed before being cooled by blood and therefore do not possess the desired activity. In addition, agents orally administered orally do not effect as rapidly as the injected agents. On the other hand, the direct injection of an agent into the blood stream, while ensuring that there is no modification of the agent during administration, is a difficult, inconvenient, painful and uncomfortable procedure that sometimes results in poor compliance of the patient. First, in principle, the transdermal administration provides a method for the administration of active agents that would otherwise need to be administered via a hypodermic injection or intravenous infusion. The transdermal administration of the agent offers improvements in both of these areas. The transdermal administration, when compared with the oral administration, avoids the severe environments of the digestive tract, skips the gastrointestinal metabolism of drugs, reduces the first pass effects and avoids the possible deactivation by the digestive and liver enzymes. The word "transdermal", as used herein, refers to the administration of an active agent (e.g., a therapeutic agent, such as a drug or an immunological active agent, such as a vaccine) through the skin to a Iejido or sysiemic circulatory system without substantial cutting or penetration of the skin, such as cutting with a surgical knife or piercing the skin with a hypodermic needle.

The systems and distribution of transdermal agents generally depend on passive diffusion to administer the agent, whereas the distribution systems of active transdermal agents depend on an external source of energy, including electricity, (for example iontophoresis) and ultrasound (for example , phonophoresis), to distribute the agency. Systems of dissipation of passive transdermal agents, which are more common, typically include a reserve of agents that conies to a high concentration of the agent. The reserve is adapted to make contact with the skin, which allows the agent to diffuse through the skin and body tissues or into the patient's bloodstream. As is well known in the art, the transdermal flow of the agent depends on the condition of the skin, the size and physical / chemical properties of the agenie molecule, and the concentration gradient across the skin. Due to the low permeability of the skin to many active agents, the transdermal distribution has had limited applications. This low permeability is mainly attributed to the stratum corneum, the most superficial layer of skin, consisting of flat, dead cells filled with keratin fibers (ie, keratinocytes) surrounded by lipid bilayers. This highly ordered structure of lipid bilayers confers a relatively impermeable character to the strained cornea. A common method for increasing the diffusional flow of passive transdermal agent involves the previous treatment of the skin with, or co-distribution with the drug, a skin permeation enhancer.

An increase in permeability, when applied to a body surface through which the agency is distributed, improves the flow of the agency through it. However, the efficacy of these methods in increasing the transdermal protein flow has, in many instances, been limited. As established, the active transport systems use an external source of energy to help and, in most cases, improve the flow of the agent through the stratum corneum. One such improvement for the distribution of transdermal agent is referred to as "electro-transport". The electric transport uses an electric potential, which results in the application of an electric current to assist in the transportation of the agency to the surface of the body such as the skin. There have also been many techniques and systems developed to mechanically penetrate or disturb the most superficial layers of skin by creating pathways to the skin to improve the quality of the organism that is distributed transdermally. Early vaccination devices, known as reamers, generally include a plurality of tips or needles that were applied to the skin to scratch or make small cuts in the area of application. The vaccine was applied either topically on the skin, as described in United States Pat. No. 5,487,726, or as a wet liquid applied to the teeth of the reamer, as described in US Pat. Nos. 4,453,926, 4, 109.655 and 3, 136.314. There are, however, numerous disadvantages associated with reamers. A serious disadvantage in using a reamer to dispense an agent is the difficulty in determining the transdermal flow of the agent and the resulting dissipative dose. Also, thanks to the elastic and resistant nature of the skin to prevent and resist perforation, small piercing elements often do not uniformly penetrate the skin and / or are cleaned of a liquid layer of an agent when they penetrate the skin. Additionally, thanks to the self-healing procedure of the skin, the perforations or cuts made in the skin tend to close after the piercing elements of the stratum corneum are removed. Therefore, the elastic nature of the skin acts to remove the active agent and the liquid layer of active agent that has been applied to the small piercing elements to the penetration of these elements into the skin. In addition, the small cuts formed by the penetrating elements heal quickly after the device is removed, thus limiting the passage of the liquid agent solution through the passages created by the piercing elements and by limiting the transdermal flow. of said devices. Other systems and apparatuses employing small skin piercing elements to improve the transdermal distribution of drugs are described in U.S. Patent Nos. 5,879,326, 3,814,097, 5, 279.54, 5,250,023, 3,964,482, remitted No. 25,637, and PCT publications with numbers WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO 98/00193, WO 99/64580, WO 98/28037, WO 98/29298, and WO 98/29365; all incorporated here by reference in their entirety. The systems and apparatuses described employ perforating elements in various shapes, sizes and arrangements to perforate the most superficial layer, (ie, the stratum corneum) of the skin. The piercing elements described in these references generally extend perpendicularly from a thin, flat member, such as a bearing or a blade. The perforating elements in some of these devices are extremely small, some have a micro projection length of only about 25-400 microns and a micro projection thickness of only about 5-50 microns. These small perforation / cutting elements perform the corresponding small micro cuts / micro tears in the corneal bone to improve the transdermal distribution of the agent through them. The systems described typically include a reserve for maintaining the active agent and a distribution system that is adapted to transfer the agent from the reserve through the stratum corneum., such as by hollow teeth of the device itself. The device described in the PCT publication is illustrative. WO 93/17754, which has a reservoir of liquid agent. As described in U.S. Patent Application No. 10 / 045,842, which is fully incorporated by reference herein, it is also possible to make the active agent to be distributed cover the micro-projections or the micro-projection arrangement instead of be contained in a physical reservation. This eliminates the need for a separate physical reserve and develops a formulation of the agent or composition specifically for the reserve. When micro projection arrays are used to improve the distribution or sampling of the agent across the skin, a consistent, complete and repeatable penetration is desired. The manual application of skin patches, which have micro projections projected on their side that makes contact with the skin, often results in a significant variation in the depth of the peeling through the length and width of the patch. Additionally, the manual application results in large variations in the depth of penetration between applications due to the way in which the user applies the arrangement or a micro projection arrangement to the stratum corneum with an automatic device, which provides in a consistent and repeatable manner. , perforation of the corneal spine, not only on the length and width of the arrangement of micro projections, but also of an application of the arrangement of micro projections to the next one. Some applicators with spring loaded applicators for dispensing lancets for sampling body fluids (eg blood) are described in PCT publication No. WO 99/26539 and WO 97/42886. However, these devices are difficult to use because they require a two-handed preparation of the applicator device before application. In particular, known spring loaded lancet applicators require that either two sections of the device be pulled and pulled apart for preparation or require that a part of the device be pulled apart to prepare or require that part of the device be rotated. with respect to part of the device for preparation. In both of these movements, a two-hand preparation operation is required. Many patients who use these devices do not possess the strength or manual dexterity to prepare such applicator devices. In the United States application No. 09 / 976,763 another applicator with spring load is described, which is adapted to apply a micro projection arrangement. The applicator noted, includes a preparation mechanism that allows a one-handed preparation of the applicator. An inconvenience of the applicator is therefore that the applicator still requires a separate step of manually preparing the device before it is used. Therefore, it would be desirable to provide an applicator that eliminates the step of manually preparing the applicator prior to its use. It is therefore an object of the present invention to provide an applicator for applying a micro projection member or a micro projection array to a patient which substantially reduces or eliminates the disadvantages of the aforementioned drawbacks associated with the prior art applicator devices. It is another object of the present invention to provide a self-priming applicator that eliminates the step of manually preparing the applicator prior to use. It is another object of the present invention to provide a self-priming and self-firing applicator that is adapted to apply a micro projection member or a micro projection array to a patient. It is another object of the present invention to provide a self-priming and self-firing applicator that applies micro projection arrangements in a consistent and repeatable manner. It is another object of the present invention to provide a self-priming and self-firing device for applying a micro projection array that is compact in design. It is another object of the present invention to provide a self-priming and self-firing applicator for applying a micro projection array that requires minimal components and has an extended service life.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the foregoing objections and those which will be mentioned and will become apparent later, the applicator for applying a microprojection array to a patient in accordance with this invention comprises (i) a housing having a first and second end; (ii) a cap that is adapted to move from a primary position to a preparation position relative to the housing, the first end of the housing being adapted to receive the micro projection member; (Ii) a sliding plunger disposed within the housing for impaling the micro projection member confers the horn spout, the plunger being adapted to move from a preparation position to a swelling position in which the plunger extends from the end of the housing opposite the lid; (iv) an impact spring in communication with the cap and the plunger, the impaction spring being adapted to provide an impact force to the plunger and bias the plunger away from the first end of the housing toward an activation position proximate to the horn , wherein the impact spring is energized when the cap and the plunger are in the preparation position; (v) a preparation spring in communication with the lid and the housing, the preparation spring being adapted to provide a preparation force to the lid and bias the lid from the preparation position to the primary position, wherein the spring preparation is energized when the plunger is in the activation position; (vi) a first securing assembly in communication with the cap and the plunger, the first securing assembly being adapted to cooperate with the cap and the preparation spring to return the plunger to the primary position when the limpet moves from the position of preparation for the primary position; (vii) a second securing assembly in communication with the housing and the plunger to position the plunger in the preparation position; (vili) a release member in communication with the limpet, said release member being adapted to communicate with the second securing assembly when the cover is moved from the primary position to the repair position, wherein the impact spring is energizes and the release member disengages, wherein the plunger moves from the preparation position to the activation position and forces the micro projection member into the stratum corneum. Preferably, the impaction spring has an impaction (or stored) energy on the scale of approximately 0.0005 - 0.5 joules / cm2. More preferably, the impact spring 40 has an energy stored on the scale of approximately 0.01-0.3 joules / cm2. In one embodiment of the invention, the impact spring has an impact velocity on the scale of approximately 0.5-20 meters (m) / second, more preferably, on the scale of approximately 1.0 -10 m / second. In one embodiment of the invention, the plunger has a surface area in the range of about 0.1-20 cm2, more preferably, in the range of 1.0-10 cm2. In a preferred embodiment of the invention, the micro projection member includes at least one biologically active agent. According to another embodiment of the invention, the device for impacting the micro projection member against the stratum corneum of a patient comprises (i) a housing having a first and second exile, the housing includes a cover that is adapted to move from a primary position to a preparation position relative to the housing; (ii) a retainer adapted to engage the housing proximate the second end, the retainer being further adapted to receive and position the micro projection member; (ili) a housing having a first and second end; (iv) a cover that is adapted to move from a primary position to a preparation position relative to the housing, the first end of the housing being adapted to receive the micro projection member; (v) a slide plunger disposed within the housing for impacting the micro projection member with the stratum corneum, the plunger being adapted to move from a preparation position to an activation position; (vi) an impact spring in communication with the cap and the plunger, the Impact spring being adapted to provide an impact force to the plunger and bias the plunger away from the first end of the housing towards the activated position close to the stratum corneum , where the impact spring is energized when the cap and the plunger are in the preparation position; (vii) a preparation spring in communication with the lid and the housing, the preparation spring being adapted to provide a preparation force to the lid and bias the limpet from the preparation position to the primary position, wherein the spring preparation is energized when the plunger is in the activation position; (viii) a first securing assembly in communication with the cap and the plunger, the first securing assembly being adapted to cooperate with the cap and the preparation spring to return the plunger to the primary position when the cap moves from the position of preparation for the primary position; (ix) a second securing assembly in communication with the housing and the plunger to position the plunger in the preparation position; and (x) a release member in communication with the limpet, said release member being adapted to communicate with the second securing assembly when the lid moves from the primary position to the preparation position, wherein the impaction spring is energizes and the release member disengages, where the plunger ^ moves from the preparation position to the acivation position and forces the micro projection member into the stratum corneum. In accordance with another embodiment of the invention, there is a transdermal delivery system for distributing a biologically active agent to a patient comprising (i) a patch system, the patch system including a gel packet containing an agent formulation and a micro projection member having upper and lower surfaces, a plurality of openings extending from the micro projection member and a plurality of micro projections of penetration of the stratum corneum projecting from the lower surface of the micro projection member , the micro projection member being adapted to receive the gel pack wherein the agent formulation flows through the openings of the micro projection member, and (i) an applicator, the applicator including a housing having a first and second ends, the first end of the housing being adapted to receive the micro projection member, a a cap which is adapted to move from a primary position to a preparation position relative to the housing, a plunger slidably disposed within the housing for impaling the micro projection member cony the horn, the plunger being adapted to move from a preparation position to a pinning position, an impact spring in communication with the cap and the plunger, the impact spring being adapted to provide an impaction force to the plunger and biasing the plunger away from the first end of the housing toward a position of acivation proximate to the horn spiral, wherein the impaction spring is energized when the cap and the plunger are in a preparation position, a preparation spring in communication with the limpet and the housing, the preparation spring being adapted to provide a preparation force to the lid and skew the lid from a position of priming to the prime position ia, wherein the preparation spring is energized when the plunger is in the activation position, a first securing assembly in communication with the limpet and the plunger, the first securing assembly being adapted to cooperate with the limpet and the preparation spring to return the plunger to the primary position when the lid moves from a preparation position to the primary position, a second securing assembly in communication with the housing and plunger for positioning the plunger in the preparation position and a release member in communication with the cap, said release member being adapted to communicate with the second securing assembly when the cap moves from the primary position to the position of preparation, wherein the impact spring is energized and the release member is disengaged, wherein the piston moves from a preparation position to an activation position and forces the micro projection member to the corneal esyrate. Preferably, the applicator includes a retainer adapted to engage the housing of the applicator proximate the second end, the retainer being further adapted to receive and position the micro projection member. In a preferred embodiment, the agent formulation includes at least one biologically active agent. In one embodiment of the invention, the biologically active agent is selected from the group consisting of leutinizing hormone-releasing hormone (LHRH), LHRH analogs (such as goserellna, leuprolide, buserelin, tripriorelin, gonadorelin, and napfarelin, menotropins (urofollitropin ( FSH) and LH)), vasopressin, desmopressin, corticotropin (ACTH), ACTH analogues such as ACTH (1-24), calcitonin, parathyroid hormone (PTH), vasopressin, deamino vasopressin [Val4, D-Arg8] arginine, interferon alpha, interferon beta, interferon gamma, erythropoiephine (EPO), factor for stimulation of granulocyte macrophage colony (GM-CSF), factor for granulocyte colony stimulation (G-CSF), interleukin-10 (IL-) 10), glucagon, hormone for the release of growth hormone (GHRH), growth hormone releasing factor (GHRF), insulin, insultropine, calciumine, ocreotide, endorphin, TRN, NT-36 (chemical name: N- [ [(s) -4-oxo-2-azetidinyl] carbo nil] - L-histidyl-L-prolinamide), liprecin, pituitary hormone (eg, HGH, HMG, desmopressin acetate, etc.), follicle luteodles, aANF, growth factors such as growth factor-releasing factor ( GFRF), bMSH, GH, somatostaine, bradykinin, somairopropin, platelet-derived growth factor-releasing factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, corticofropin (ACTH), erythropoiefin, epoprosenol (platelet aggregation inhibitor) ), glucagon, HCG, hirulog, hyaluronidase, interferon, inerleucins, menotropins (urofollitropin (FSH) and LH), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, desmopressin, ANP, inhibitors of ANP elimination, antagonists of angiotensin II, antidyuric hormone agonists, bradykinin antagonists, ceredases, CSI's, peptide related to the calcitonin gene (CGRP), encephams, FAB fragments, peptide suppressors IgE, neurotrophic factors of IGF-1, colony of stimulating facies, parathyroid hormone and agonists, parathyroid hormone antagonists, prostaglandin antagonists, pentigelide, protein C, protein S, renin inhibitors, thymosin, alpha-1, thrombolytics, TNF, vasopressin antagonist analogs, alpha-1 (recombinant) anti-yrsin, TGF-beia, fondaparinux, ardeparin, dalteparin, defibrotide, enoxaparin, hirudin, nadroparin, reviparnin, tinzaparin, pentosan polysulfate, oligonudeotoids, and oligonucleotide derivatives, such as formivirsen, alendronic acid, clodronic acid, etidronic acid, ibandronic acid, ncadronic acid, pamidronic acid, risedronic acid, ududronic acid, zoledronic acid, argairoban, RWJ 445167, RWJ-671818, and mixtures thereof. In another embodiment of the invention, the biologically active agent is selected from the group consisting of antigens in the form of proteins, polysaccharides, oligosaccharides, lipoproteins, weakened or annihilated viruses such as cytomegalovirus, hepatifis B virus, hepatic virus C, human papillomavirus, rubella virus , and varicella zosir, weakened or annihilated bacteria such as bordella pertusis, clostridium tetani, corynebacteum diphtheriae, group A streptococcus, legionela pneumofilia, neisseria meningitis, pseudomonas aeruginosa, pneumonia streptococcus, treponema palidum, and vibrio cholera and mixtures thereof. In another embodiment, the agent formulation includes at least one additional pharmaceutical agent selected from the group consisting of pathway evidence modulators and vasoconstrictors.

BRIEF DESCRIPTION OF THE DRAWINGS The additional features and advantages will become apparent from the following more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, and in which similarly referenced characters generally refer to the same parts or elements throughout the drawings. You see, and in which: Figure 1 is a front cross-sectional view of an embodiment of the applicator illustrating an initial configuration or a primary position with a patch holder adhered to the applicator, in accordance with the invention; Figure 2 is a front cross-sectional view of the retainer illustrating a preparation position, in accordance with the invention; Figure 3 is a front cross-sectional view of the retainer illustrating an aclivation position with the plunger near the skin site, in accordance with the invention; Figure 4 is a lateral view of the transverse section of the applicator in the primary position shown in Figure 1; Figure 5 is a cross-sectional side view of the applicator in the preparation position shown in Figure 2; Figure 6 is a cross-sectional side view of the applicator in the musli-shaped position in Figure 3; Figure 7 is a front cross-sectional view of the patch holder which is adapted to cooperate with the applicator shown in Figures 1 through 6, in accordance with the invention; Figure 8 is a perspective view of the patch retainer shown in Figure 7; and Figure 9 is a partial perspective view of a modality of a micro projection arrangement.

DETAILED DESCRIPTION OF THE INVENTION Before describing the present invention in detail, it should be understood that this invention is not limited to particularly exemplified materials, methods or structures because these may of course vary. Therefore, although a number of materials and methods similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and methods are described herein. It should also be understood that the terminology used herein is for the purpose of describing the particular embodiments of the invention only and is not intended to be limiting. Unless defined otherwise, all the technical and scientific terms used herein have the same meaning as commonly understood by one having average experience in the art to which the invention pertains. In addition, all publications, patents and patent applications cited herein, whether subsequent or prior, are incorporated herein by reference in their entirety. Finally, as used in this specification and the appended claims, the singular forms "a", "an" and "the" / "she" include plural references unless the context clearly dictates otherwise. For example, the reference to "a micro projection" includes two or more of said micro projections and the like.

Definitions The term "transdermal", as used herein, means the distribution of an agent in and / or through the skin for local or systemic therapy. The term "transdermal flow", as used herein, means the fransdermal distribution rate. The term "biologically active agent", as used herein, refers to a composition of matter or mixture containing a drug that is pharmacologically effective when administered in a lerapeutically effective amount. Examples of such agents include, without limitation, leutinizing releasing hormone (LHRH), LHRH analogues (such as goserelin, leuprolide, buserelin, triptorelin, gonadorelin, and napfarelin, menof rape (urofollinopin (FSH) and LH)), vasopressin, desmopressin, corticofropin (ACTH), ACTH analogs such as ACTH (1-24), calcitonin, vasopressin, vasopressin deamino [Val4], D-Arg8] argillin, interferon alpha, interferon beta, interferon gamma, erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), interleukin-10 (IL-10), glucagon, growth hormone releasing factor (GHRF), insulin, insulinotropin, calcitonin, octreotide, endorphin, TRN, NT-36 (chemical name: N - [[(s) -4-oxo- 2-azeidinyl] carbonyl] -L-hisididyl-L-prolinamide), liprecin, aANF, bMSH, somatosilane, bradykinin, somalolopropin, platelet-derived growth factor-releasing factor, cimopapain, colecystokinin, chorionic gonadotropin, epoprosenol (inhibitor of platelet aggregation), glucagon, hirulog, inermers, interleukins, metropins (urofoliyropin (FSH) and LH), oxilocin, streptokinase, tissue plasminogen activator, urocinase, ANP, inhibitors for ANP elimination, angiotensin II antagonists, agonists antidiuretic hormone, a ntagonists bradykinin, inheritance, CSI's, peptide related to the calcitonin gene (CGRP), enkephalins, FAB fragments, suppressors of IgE peptide, IGF-1, neutrophil factors, colony esimulaje de faciores, paraíiroides hormone and agonists, parathyroid hormone antagonists, antagonists prostaglandin, penligetide, protein C, protein S, renin inhibitors, thymosin alfa-1, thrombolytics, TNF, vasopressin antagonist analogues, alpha-1 antitrypsin (recombinant), TGF-beta, fondaparinux, ardeparin, dalieparin, defibrotide, enoxaparin , hirudin, nadroparin, reviparin, tinzaparin, pentosan polysulfate, oligonucleotides and oligonucleotide derivatives, such as formivirsen, alendronic acid, clodronic acid, etidronic acid, bandronic acid, incadronic acid, pamidronic acid, risedronic acid, tiludronic acid, zoledronic acid , argatroban, RWJ445167, RWJ-671818, and mixtures thereof. The biologically active agents noted may also be in various forms, such as free bases, acids, charged or uncharged molecules, components of molecular complexes or non-irritant, pharmaceutically acceptable salts. In addition, simple derivatives of the acive agents (such as ether, esters, amides, etc.), which are easily hydrolysed with the body pH and enzymes, efe, can be used. The term "biologically active agent" as used herein, also refers to a composition of matter or mixture that contains a "vaccine" or other immunologically active agent or an agent that is capable of triggering the production of an immunologically active agent, and which is directly or indirectly immunologically effective when administered in an immunologically effective amount. The term "vaccine," as used herein, refers to conventional and / or commercially available vaccines, including, but not limited to, influenza vaccines, vaccines against Lyme disease, rabies vaccines, measles vaccines, mumps vaccine, smallpox vaccine, varicella vaccine, hepatic vaccine, osferin vaccine, diphtheria vaccine, recombinant protein vaccines, DNA vaccines and therapeutic cancer vaccines. The term "vaccine" therefore includes, without limitation, antigens in the form of proteins, polysaccharides, oligosaccharides, lipoproieins, weakened or annihilated viruses such as cytomegalovirus, hepatic virus B, hepatic virus C, human papilloma virus, rubella virus, and varicella, weakened or dead batteries such as bordella pertusis, clostridium tetani, corinebacterium dipgtgeriae, group A streptococci, legionella pneumofilia, neisseria, meningitis, pseudomonas aeruginosa, estretopcocos pneumoniae, treponema palidum, and vibrio cholera and mixtures thereof. It should be understood that more than one biologically active agent can be incorporated into a microprojection or microprojection agent or coating formulation, and that the use of the term "active agent" in no way excludes the use of two or more of said agents. The term "biologically effective amount" or "biologically effective cup" shall be used when the biologically active agent is a pharmaceutically active agent and refers to the quantity or cup of the pharmaceutical agent as necessary to effect the therapeutic effect., often beneficial. The term "biologically effective amount" or "biologically effective cup" should also be used when the biologically active agent is an immunologically active agent and refers to the amount or cup of the immunologically active agent necessary to stimulate or initiate the immune response, often beneficial, desired. The term "vasoconstrictor," as used herein, refers to a composition of matter or mixture that narrows the lumen of blood vessels and, therefore, reduces peripheral blood flow. Examples of suitable vasoconstrictors include, without limitation, amidefrin, cafaminol, cyclopentamine, deoxyapinephrine, epinephrine, felipresin, indanazoline, metizoline, midodrine, naphazoline, nordefrine, octodrin, orinpresin, oximeiazoline, phenylephrine, phenylenediamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline. , tuaminoheptane, thimazoline, vasopressin, xylometazoline and mixtures thereof. The terms "micro projections" and "micro protuberances", as used herein, refer to piercing elements that are adapted to pierce or cut through the stratum corneum in the underlying epidermal layer I, or the layers of epidermis or dermis, of the skin of a living animal, particularly a mammal and more particularly a human. In one embodiment of the invention, the micro projections have a projection length of less than 1000 microns. In another embodiment, the microprojections have a projection length of less than 500 microns, more preferably, less than 250 microns. The micro projections typically have a width and thickness of about 5 to 50 microns. The microprojections may be formed in different shapes such as needles, knives, pins, punches, and combinations thereof. The term "micro projection arrangement", as used herein, refers to a plurality of micro projections disposed in an array to pierce the stratum corneum. The arrangement of micro projections can be formed by engraving or punching a plurality of micro projections of a thin sheet and folding the micro projections out from the plane of the sheet to form a configuration, such as the mosière in Figure 5. The arrangement of The micro projection may also be formed in other known manners, such as by forming one or more strips having micro projections along an edge of each of the strips as described in US Pat. No. 6,050,988. References to the area of the sheet or member and references to some property by area of the sheet or member is reverencing to the area described by the outer circumference or edge of the sheet. As will be appreciated by one skilled in the art, the applicator of the present invention can be easily employed for a repeatable impact application of an array of micro projections to the stratum corneum in conjunction with a distribution or sampling of a transdermal therapeutic agent. Although the applicator 10 is described for use with certain types of micro projection arrangements, it should be understood that the applicator can also be used with other types of micro penetrating members of the corneal horn. As explained in detail here, the applicator of the invention is self-prepared and therefore eliminates the step of manually preparing the applicator before use. The applicator is also self-firing. The applicator can therefore be immediately used by patients who do not have the strength in the hands or manual dexterity to prepare other types of spring-loaded applicator devices. The applicator of the invention additionally employs a firing mechanism that is loaded outside the diameter of the impact spring that biases the plunger out of the device, allowing the use of smaller diameter springs made of smaller diameter wire, which can store a density of energy equal or higher with the same trip while weighing less. The reduced mass of the impaction spring also allows less force to be used to compress the spring to achieve a higher impact velocity. further, the impact spring and the preparation spring have different internal and external diameters and their positions in the applicator prevent the possibility of accidentally placing a spring in the wrong position. The plunger, the inner rate and the outer cup may also be marked so that they can only be assembled in a functional orientation. The plunger, inner cup and outer cup are also designed and configured to snap into each other to avoid the need for additional assembly steps, such as inserting screws, ultrasonic welding, adhesion by adhesives or solvents. The pressure inputs also make the applicator disassembly difficult, discouraging anyone from altering the mechanism. Referring now to Figures 1-3, the applicator 10 generally includes a housing 12, having an inner cup 14, and a plunger 30 movable within the housing 12. As illustrated in Figure 1, the housing 12 also includes a cup (10) to activate the plunger 10 to impact the stratum corneum with a patch 60 or a micro projection arrangement 64. The applicator 10 further includes an impact spring 40 which is positioned within the spring guide 22 that is extends inward from the upper part 23 of the outer cup 20. The impact spring 40 is also accepted in the spring seat of the plunger or recess 34. According to the invention, the impact spring 40 biases the plunger 30 downwards. (in the direction denoted by the arrow A) with respect to the housing of the applicator 12. As illustrated in Figure 2, the plunger 30 fills a lower surface or face 32, which, according to the invention, it may be superficially flat, slightly convex or shaped to a body surface (that is, a specific site of the skin). As described in detail herein, when the applicator 10 is acyivated, the lower surface 32 of the piston of the plunger 30 causes a micro projection array or a transdermal patch containing a micro projection array to impact and puncture the corneal bone. According to the invention, the face of the plunger 32 preferably has a surface area on the scale of approximately 0.1-20 cm2. More preferably, the face of the footplate 32 has a surface area on the scale of 1-10 cm 2. Referring again to Figure 1, the applicator 10 further includes a preparation spring 42 which is positioned around the impact spring. The preparation spring 42 is also seated in the spring seat 16 disposed close to the upper end of the inner cup 14. As described in detail here, the preparation spring 42 biases the outer lance 20 upwards (in the direction denoted by the arrow B) with respect to the inner lance 14 after activating the applicator 10. As illustrated in Figure 1, the inner cup 14 further includes a plunger stop 18, which has an upper surface 19 a and a lower surface 19 b that it holds the plunger 30 in a ready position and restricts the movement of the plunger 30 there further in an upward direction. Referring now to Figure 4 (which is another sectional view of the applicator 10 rotated approximately 90 ° with respect to the view shown in Figure 1) the plunger 30 includes at least one, more preferably, at least two locking members 36 (ie, the first securing assembly) which are disposed near the opposite end to the face of the plunger 32. According to the invention, the locking members 36 are adapted to make conjointly with the outer cup 20 in the handle of the blocking member 24 after the acivation of the applicator 10 (see Figure 6) and raising the plunger 30 to a preparation position, as illustrated in Figure 4. As illustrated in Figure 1, the plunger 30 also includes at minus one, more preferably, at least two, flexible release detents 38 (that is, second securing assembly). According to the invention, the release detents 38 are designed and adapted to communicate with (or be positioned in) the upper surface 19 a of the inner cup 14 of the piston seal 18. (See Figures 1 and 2). As described in detail below, the release detents 38 are further adapted to flex inwardly and, by extension, disengage from the retainer 18 when the collar 20, therefore, the spring guide 22 moves from the primary position to the rearward position. Preparation position (see Figure 2). Figures 1-6 further illustrate a patch retainer 50 operationally secured to the applicator 10. Referring now to Figures 7 and 8, the refiner 50 preferably has a substantially annular shape with a first end 52 that is configured to engage the inlet end. 15 of the inner cup 14. The second end or end of enira 54 of the retainer 50 provides a contact surface with the stratum corneum. Referring now to Figure 7, the retainer 50 includes a patch seat 56 that is adapted to receive the patch 60. Although the manner in which the patch 60 is mounted on the retainer 50 may vary (eg, the patch 60 can be positioned next to the entrance end 54 of the retainer 50), it is preferred that the patch 60 be mounted distally of the entrance end 54, as illustrated in Figure 8, to avoid inadvertent contact of the micro-projections of the patch with other objects (for example, the user's fingers). According to an example, the patch 60 is connected by fragile sections of patch base material to an annular ring of the patch material 62, which adheres to the patch seat 56. The patch 60 is separated from the retainer seat 56 by the downward force of the plunger 30. Alternatively, the patch 60 can be releasably adhered to the plunger 30 or positioned on the skin below the plunger 30. As indicated, two significant features of the applicator 10 are the locations of the impaction spring 40 and the spring of preparation 42, and the use of a small diameter and, by virtue of this, an impact spring 40 of low mass. As is well known in the art, the mass (m) of a spring is a function of the density of the spring material (p), the diameter of the wire (d) and the length of the wire (L); m = pLd2 / 4 The length of the wire (L), is a function of the average diameter of the spring (D), the length of the spring (s) and the step (P): As is also well known in the art, the hardness of the spring (k) is a function of the elasticity modulus of the material (E), the diameter of the wire (d), the average diameter of the spring (D), the length of the spring (s) and step (P): k = EPd4 / 8sD3 To maximize the hardness rate against impaction spring weight, the diameter of the wire, d, should be maximized and the average diameter of the spring should be minimized. In addition, the energy stored in the spring (PE) is a function of the hardness of the spring (k) and the amount of spring compression at the start (x0) and at the end (xi) of its trip: PE = k (x12) - x02) / 2 According to the relationships noted and one embodiment of the invention, the impact spring 40 has a stored or impact energy on the scale of approximately 0.005 - 0.5 joules / cm2, where the area (ie, in square centimeters) refers to the face of the plunger 32. More preferably, the impaction spring 40 has an energy stored on the scale of approximately 0.01-0.3 joules / cm2. According to the invention, in the illusive embodiment, the impact spring 40 has an impact velocity in the range of 0.5-20 m / second. More preferably, the impaction spring 40 has a speed in the range of 1-10 m / second. Referring now to Figures 1 to 9, the operation of the applicator 10 will be described in detail. Referring first to Figures 1 and 4, the applicator 10 is shown in a primary or cripple position with the patch 60 positioned on the retainer 50. As illustrated in Figure 1, in the primary position, the plunger 30 is positioned against the piston detent 18 and releasable flexible detents 38 are seated on upper surface 19 a of piston seal 18. Referring now to FIGURE 2 and FIGURE 4 (which is another transverse sectional view of applicator 10 rolled approximately 90 DEG. with respect to the view shown in Figure 2), when a user places the plunger 10 against a location on the skin 5 and exerts a downward force on the outer cup 20 (in a direction denoted by arrow B), the impact 40 and the impact springs 40 and preparation springs 42 are compressed (that is, they are energized) so that the spring guide 22 engages with the release detents 38, by flexing the release detents 38 towards the interior a direction denoted by the arrows R 1 and R 2) in which the release detents 38 disengage from the piston seal 18 and the piston 30 moves downward to a position of acivation and impacts the location of the skin 5 (this es, the stratum corneum) with patch 60 (see Figures 3 and 6). According to the invention, the force exerted on the lid 20 and, therefore, the site on the skin 5 (that is, the downward holding force) prior to the noticed activation is preferably less than 6.82 kilograms, more preferably , the retention force down is on the scale of approximately 910 grams-6.81 kilograms. Even more preferably, the downward reentering force is in the range of about 2.27 -4.55 kilograms, which substantially reduces and, in most instances, eliminates the retro-impact of the applicator 10. In accordance with the invention, the The retention force downward causes the stratum corneum to stretch at the entry end 54 of the retainer 50 such that the site of the skin 5 is under optimal tension at the time the patch 60 is hit with the site on the skin. In another preferred embodiment of the invention (not shown), the retainer 50 includes a flexible bias ring that is disposed at the inlet end 54 of the retainer 50 so that it also stretches the stratum corneum when the release force is applied to the applicator. 10. Referring now to Figures 3 and 6, when the plunger 30 is in an activation position (where the plunger 30 is proximate the inlet end 54 of the retainer 50), the plunger 30 repair 42 is compressed (or energized) and, therefore, biases the outer cup of the applicator 20 in an upward direction. The bias force provided by the preparation spring 42 moves the outer cup 20 and the plunger 30, which is in communication therewith (see Figure 6), back to the primary position illusive in Figures 1 and 6 when the force downwardly it is removed from the ex- terior cup 20. In another intended embodiment, not shown, the release detents 38 have an indian face communicating with the upper surface 19 a of the piston seal 18. According to this embodiment, when a user places the applicator against a site on the skin 5 and exerts a downward force, the impaction and preparation springs 42 are compressed and energized until a release force is reached, so that the release detents 38 disengage, (that is, they slide out of the piston seal 18) and the piston 30 moves downward to an activation position shown in Figures 3 and 6. The applicator 10 of the invention can be used with n a patch 60 which generally includes a micro projection array 64, a reservoir of agent, and a support. However, the applicator 10 can also be used with a micro projection arrangement without an agency reservation. In this case, the micro projection array is used as a pre-treatment member, which is followed by the application of an agent with a separate distribution of transdermal agent or sampling device, as described in the co-pending application. No. 60 / 514,387, which is incorporated by reference herein in its entirety. Alternatively, the micro projection array can incorporate the agent as a cover in the microprojections, for example, to distribute a vaccine intradermally, as described in US applications Nos. 10 / 674,626 and 60 / 514,433, which are incorporated by reference here in its entirety. The applicator 10 can also be used to impact other micro perforation elements against the corneal horn, for example those described in U.S. Patent No. 5,879,326 and in PCT publication WO 99/29364, which are similarly incorporated by reference herein in its entirety Referring now to Figure 9, a mode of a micro projection array 64 that can be employed within the scope of the present invention is shown. As illustrated in Figure 5, the micro projection array 64 includes a plurality of micro projections 68 extending down a surface of a sheet or plate 70. The microprojections 68 are preferably dimensioned and shaped to penetrate the Strange horn of the epidermis when a pressure is applied to the arrangement 64 (or to the patch 60).

The micro-projections 68 are further adapted to form microcuts in a body surface to increase the administration of a substance (e.g., a hydrogel formulation), through the body surface. The term "body surface", as used herein, generally refers to the skin of an animal or a human. The micro-projections 68 are generally formed from a single piece of sheet material and are sufficiently sharp and long to pierce the stratum corneum of the skin. In the illustrated embodiment, the sheet 70 is formed with an opening 69 between the micro projections 68 to improve the movement of the active directory through it. More details of the above-described micro projection arrangement and other micro projection arrangements and arrangements that may be employed within the scope of the invention are described in U.S. Pat. Nos. 6,322,808, 6,230,051 B1 and the co-pending application of United States No. 10 / 045,842, which are incorporated by reference herein in their entirety. As will be appreciated by one of ordinary skill in the art, the applicator of the present invention can be used in connection with a transdermal distribution of an agent, a sampling of transdermal analytes (eg, glucose), or both. Iransdermic distribution devices for use with the present invention include, but are not limited to, passive devices, devices activated by negative pressures, osmotic devices, and reverse electroreport devices.

From the above description, one of ordinary skill in the art can easily assess that the present invention, among other things, provides an effective and efficient method for distributing biologically active agents to a patient. As will be appreciated by one skilled in the art, the present invention provides many advantages such as: Self-preparation Self-activation A lower retention or release force compared to applicators of the prior art. Easy assembly Virtually resistant to improper handling Without departing from the spirit and scope of this invention, one skilled in the art can make various changes and modifications to the invention to adapt it to various uses and conditions. As such, these changes and modifications are properly, comparably, and are intended to be, within the full range of equivalence of the following claims.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. - A device for impacting a micro projection member against the corneal bone of a patient, comprising: a housing having first and second ends, said first eximere of said housing that is adapted to receive said micro projection member; a lid that is adapted to move from a primary position to a preparation position relative to said housing; a plunger slidably disposed within said housing for impacting said micro projection member against the corneum, said plunger being adapted to move from said preparation position to an activation position; an impact spring communicating with said cap and said plunger, said impact spring being adapted to provide an impact force to said plunger and biasing said plunger out of said first end of said housing toward an activation position proximate to the horn, wherein said impact spring is energized when said cap and said plunger are in said preparation position; a preparation spring communicating with said cover and said housing, said preparation spring being adapted to provide a preparation force to said cover and biasing said cover from said preparation position to said primary position, wherein said preparation spring it is energized when said piston is in said activation position; a first securing and communication assembly with said cap and said plunger, said first securing assembly being adapted to cooperate with said cap and said preparation spring for returning said plunger to said primary position when said cap moves from said preparatory position to said primary position; a second securing assembly in communication with said housing and said plunger for positioning said plunger in said preparation position; and a release member in communication with said cover, said release member being adapted to communicate with said second securing assembly when said cover moves from said primary position to said preparation position, wherein said impact spring is energized and said second securing assembly is disengaged, therefore said plunger moves from said preparation position to said activation position and forces said micro projection member into the corneal passage.

2. The device according to claim 1, further characterized in that said impaction spring has an energy stored in the scale of approximately 0.005-0.5 joules / cm2.

3. The device according to claim 2, further characterized in that said impaction spring has an energy stored in the scale of approximately 0.01-0.3 joules / cm2.

4. The device according to claim 1, further characterized in that said impact spring has an impact speed on the scale of approximately 0.5-20 m / second.

5. The device according to claim 4, further characterized in that said impact spring has an impact velocity in the range of approximately 1.0-10 m / second.

6. The device according to claim 1, further characterized in that said plunger includes a face, said face having a surface area in the scale of approximately 0.1-20 cm2.

7. The device according to claim 6, further characterized in that said face has a surface area in the scale of approximately 1.0-10cm2.

8. The device according to claim 1, further characterized in that said micro projection member includes a formulation of agent that has at least one biologically active agent.

9. The device according to claim 1, further characterized in that said second securing assembly is arranged on the outside of said impact spring.

10. The device according to claim 1, further characterized in that said preparation spring is arranged on the outside of said impact spring.

11. A device for impacting a micro projection member against the corneal esltrate of a patient, comprising: a housing having a first and second ends; a retainer adapted to engage said housing proximate said second end, said retainer being further adapted to receive and position said micro projection member; a lid that is adapted to move from a primary position to a preparation position relative to said housing; a plunger slidably disposed within said housing for impacting said micro projection member against the horn, said plunger being adapted to move from said preparation position to an activation position; an impact spring in communication with said cap and said plunger, said impaction spring being adapted to provide an impact force to said plunger and biasing said plunger away from said first end of said housing toward an activation position proximate to the horn run , wherein said impact spring is energized when said cap and said plunger are in said preparation position; a preparation spring communicating with said limpet and said housing, said preparation spring being adapted to provide a preparation force to said lid and biasing said lid from said preparation position to said primary position, wherein said preparation spring is energizes when said plunger is in said acclivation position; a first securing assembly in combination with said cap and said plunger, said first securing assembly being adapted to cooperate with said cap and said preparation spring for returning said piston to said primary position when said cap moves from said preparatory position to said primary position; a second securing assembly in communication with said housing and said plunger for positioning said plunger in said preparation position; and a release member in communication with said cover, said release member being adapted to communicate with said second securing assembly when said cover moves from said primary position to said preparation position, wherein said impact spring is energized and said second securing assembly is disengaged, wherein said plunger moves from said preparation position to said activation position and forces said micro projection member into the stratum corneum.

12. A system for the transdermal distribution for distributing a biologically active agent to a patient, comprising: a patch system, said patch system including a gel pack containing a hydrogel formulation and a micro projection member that has upper and lower surface, a plurality of openings that extend through said micro projection member and a plurality of stratum corneum perforating micro projections projecting from said lower surface of said micro projection member, said micro member projection that is adapted to receive said gel pack wherein said hydrogel formulation flows through said member of said apertures of the micro projection member; and an applicator, said applicator including a housing that has a first and second extrude, a lid that is adapted to move from a primary position to a preparation position relative to said housing, said first end of said housing that is adapted to receive said micro projection member, a plunger desirably disposed within said housing for impacting said micro projection member cony the stratum corneum, said plunger being adapted to move from said preparation position to an aclivation position proximate to the stratum corneum, a spring of impaction in communication with said limpet and said plunger, said impact spring being adapted to provide an impact force to said plunger and biasing said plunger out of said first end of said housing towards said activation position, wherein said spring impact is energized when said cap and said plunger are in said position of preparation, a preparation spring communicating with said lid and said housing, said preparation spring being adapted to provide a preparation force to said lid and biasing said lid of said preparation position to said primary position, wherein said preparation spring is energizes when said plunger is in said activation position, a first securing assembly in communication with said cap and said plunger, said first securing assembly being adapted to cooperate with said cap and said readiness spring to return said plunger to said primary position when said lid moves from said preparation position to said primary position, a second securing assembly in communication with said housing and said plunger for positioning said plunger in said preparation position, and a release member in communication with said lid, said member of liberation that is adapted to communicate with said second securing assembly when said limpet moves from said primary position to said preparation position, wherein said impact spring is energized and said second securing assembly is disengaged, wherein said piston moves from said preparatory position to said activation position and forcing said micro projection member in the corneal run.

13. The distribution system according to claim 12, further characterized in that said hydrogel formulation includes at least one biologically active agent.

14. The dispensing system according to claim 13, further characterized in that said biologically active agent is selected from the group consisting of hormone for the release of leutinizing hormone (LHRH), analogs of LHR, vasopressin, desmopressin, corticotropin (ACTH) ), ACTH analogues, calcilonin, vasopressin, parathyroid hormone (PTH), vasopressin, deamino vasopressin [Val4, D-Arg8] arginine, interferon alpha, interferon beta, gamma interferon, erythropoiein (EPO), macrophage colony stimulation factor granulocyte (GM-CSF), granulocyte colony stimulation factor (G-CSF), interleukin-10 (IL-10), glucagon, hormone for growth hormone release (GHRH), hormone release factor growth (GHRF), insulin, insulinotropin, calcitonin, octreotide, endorphin, TRN, N - [[(s) -4-oxo-2-azetidinium] carbonyl] -L-histidyl-L-prolinamide), liprecin, pituitary hormones , follicle luteioids, aA NF, growth factors, bMSH, GH, somaiosiaina, bradykinin, somalotropin, platelet-derived growth factor, asparaginase, bleomycin sulfate, chymopapain, colecisioquinine, chorionic gonadotropin, corticotropin (ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor) ), glucagon, HCG, hirulog, hyaluronidase, interferon, interleukins, menotropins (urofoliíropin a (FSH) and LH), oxylocin, srepiko kinase, tissue plaminogen activator, urocinase, vasopressin, desmopressin, ANP, ANP elimination inhibitors, antagonisms of angioinensin II, antidiuretic hormone agonists, bradykinin antagonists, ceredases, CSI's, peptide related to the calcitonin gene (CGRP), enkephalins, FAB fragments, IgE peptide suppressors, IGF-1, pneumophilic favors, colony stimulating factors, parathyroid hormone (PTH) and agonists, parathyroid hormone antagonists, prostaglandin antagonists, pentigetlda, protein C, protein S, renin inhibitors, Ilmoslna alfa-1, Irombolytics, TNF, vasopressin antagonist analogues, alpha-1 antitrypsin (recombinant), TGF-beía, fondaparinux, ardeparin, dalievirin, defibroide, enoxaparin, hirudin, nadroparin, reviparin, tinzaparin, pentosan polysulfate, oligonucleolides and oligonucleotide derivatives, alendronic acid, clodronic acid, etidronic acid, ibandronic acid, incadronic acid, pamidronic acid, risedronic acid, tiludronic acid, zoledronic acid, argatroban, RWJ445167, RWJ-671818, and mixtures thereof.

15. The distribution system according to claim 13, further characterized in that said biologically active agent is selected from a group consisting of antigens in the form of proteins such as polysaccharides, oligosaccharides, lipoproteins, viruses weakened or annihilated such as cytomegalovirus, Hepaitis virus B, virus C hepatiitis, human papillomavirus, rubella virus, and varicella, weakened or annihilated bacteria such as bordella pertussis, clostridium tetani, corinebacterium diphtheria, group A streptococcus, legionela pneumofilia, neiseria, meningitis, pseudomonas aeruginosa, estretopcocos neumoniae, treponema palidum, and vibrio cholerae and mixtures thereof.

16. The distribution system according to claim 12, further characterized in that said hydrogel formulation includes at least one path of evidence modulator.

17. The distribution system according to claim 12, further characterized in that said hydrogel formulation includes at least one vasoconstrictor.