MXPA06009041A

MXPA06009041A - Method for making a needle-free jet injection drug delivery device

Info

Publication number: MXPA06009041A
Application number: MXPA/A/2006/009041A
Authority: MX
Inventors: Scott J Gilbert
Original assignee: Johnson&Ampjohnson*
Priority date: 2005-08-10
Filing date: 2006-08-09
Publication date: 2008-09-02

Abstract

A method for making a jet injection drug delivery device wherein the drug delivery device has at least one drug reservoir and at least one injection nozzle includes the steps of:identifying a drug desired to be delivered;identifying a volume of the drug desired to be delivered;establishing a reservoir diameter for the at least one drug reservoir;establishing a nozzle diameter for the at least one injection nozzle;identifying a tissue model for delivery of the drug;identifying a penetration depth in the tissue model for the delivery of the drug;and injecting the drug into the tissue model under variable pressure until the desired penetration depth is achieved. The method also includes identifying an optimal pressure range for the drug delivery device that achieves the desired penetration depth.

Description

METHOD FOR MAKING A DRUG SUPPLY DEVICE THROUGH NO NEEDLE JET INJECTION FIELD AND BACKGROUND OF THE INVENTION The present invention relates, in general, to drug delivery and, in particular, to a new and useful device and method for delivering needleless drugs with minimal trauma to tissue and which are suitable for delivering drugs in sensitive areas of the body such as the eyes, nasal passages, mouth and other areas of the body. Despite continuous advances in medical technology, particularly in the treatment of various diseases such as heart disease, vascular disease, ophthalmic disease, cancer, pain, allergies, orthopedic repair and many other diseases and conditions, there is a significant number of patients for who conventional surgery and intervention therapies are not feasible or are insufficient to treat the disease or condition. For many patients, medical treatment with drugs and the like is the only feasible treatment available. There have been many recent advances in drug therapies, particularly with respect to cellular or site-specific therapeutic compounds also known as "local" drug delivery. Unlike the systemic administration of the therapeutic compounds, typically taken orally or given intravenously, much of the effectiveness of local delivery of cellular or site-specific therapeutic drugs or compounds is based on the ability to deliver in an accurate and Accurate the therapeutic compounds to the target site within the body. Needle injection devices are the most commonly used means for local delivery or site-specific administration of agents or solutions. Although there have been advances in needle / injection drug delivery systems, these systems have significant drawbacks and disadvantages. One of those disadvantages is that the use of a needle or other penetrating means to inject the target tissue area inevitably involves making a hole in the target site thus causing trauma and tissue injury at the local tissue site. Another disadvantage with this needle penetration and injection approach is that it is very common for a substantial amount of the injected substance to drain or exude from the hole created by the needle or penetration member. Often, this injected substance that leaks is systematically released throughout the body or is discarded by depriving the patient of the prescribed therapy or dosage amounts of the drug. This also results in increased treatment costs and requires more injections, time and agent to achieve the desired effect. In addition, it is known that needle injections or penetration into tissue can traumatize or destroy tissue cells and, as a result, increase a patient's risk of post-operative trauma, pain and discomfort at the local site and surrounding area. This is particularly due to the difficulty in accurately controlling the penetration of the needle during injection. The more injections or penetrations there are, the greater the cell destruction and tissue trauma that is likely to be experienced. A further disadvantage of needle-based injections, especially where multiple injections are required, is the inability to carefully track the location of each injection site to prevent accidental delivery of drug to non-diseased tissue or repeated delivery of the drug to the same hole. of injection. Other known drug delivery devices and methods do not involve needle-based drug delivery. Instead, devices such as catheters that remain in the interior are used to release the therapeutic agent in a constant controlled release manner. These types of devices could present a higher risk of agent release systematically. furtherWith these types of devices, it is more difficult to evaluate the actual dose of the target area that takes place. Therefore, these types of devices have the disadvantages of being less effective, possibly not as safe, and definitely more expensive than commonly known needle injection approaches and technology. Another condition in which the site or local specific drug supply is commonly used is in the treatment of peripheral vascular disease (such as deep vein thrombosis and embolism). One such treatment is venous lithic therapy, the dissolution of blood clots (thrombi) in the peripheral vasculature (eg, femoral and iliac arteries and veins). The lytic therapy involves the systemic infusion of thrombolytics, such as urokineses, streptokinase, reteplase and tPA. Other more recently developed procedures involve directly supplying the thrombolytics at the site of the thrombus by the use of infusion catheters that remain in the interior. In order to effectively lyse the thrombus, thrombolytics are typically delivered by infusion for many hours, even as many as a day or more, increasing the length of hospital stay and the overall cost of the procedure. A common approach to eliminating a needle in local drug delivery is to use conventional needleless injectors. Needle-free injection technology was introduced almost 40 years ago for use in mass immunization campaigns. Currently, more than fifteen companies develop and manufacture jet injectors for intradermal and transdermal (subcutaneous and intramuscular) drug delivery. And while these modern designs offer tremendous improvements in size, cost and convenience over their predecessors, the fundamental functionality has remained unchanged. Mainly, compressed gas is used to push a medication (either liquid or dry powder) through a single orifice at moderately high speed, allowing the medication to be deposited on or under the skin when piercing it. An example of a known needleless jet injector is described in WO 00/35520 and U.S. Pat. 6,406,455 Bl (Willis et al., Assigned to BioValve Technologies, Inc.). In addition, needleless jet injection has long been considered a painless procedure, but clinical studies comparing injection devices with a conventional needle and syringe have shown pain ratings equivalent to those of a gauge needle. 25. In large part, this is due to the size of the injection stream and, therefore, the size of the nozzle orifice. Existing devices all use a nozzle orifice of approximately 0.15 mm - 0.2 mm in diameter. It is known that these conventional needleless injectors incorporate only one injection chamber and inject the entire drug content through a single plastic nozzle having a typical orifice diameter of 150-200 microns (0.15 mm -0.2 mm). These jet injectors typically deliver volumes ranging from 0.100 cm3 (100 microliters) to 0.500 cm3 (500 microliters), and even as many as 1 cm3 (1,000 microliters). There are several significant limitations with current jet injection technology. First, the injection times associated with these conventional needleless injectors are typically several seconds in duration, which puts the patient at risk of laceration if he moves (e.g., backs off) or if the injector moves in a vibrating manner. of the injection site during an injection. Second, the perceived pain is equivalent to a conventional needle and syringe. This has perhaps been the only important reason why jet injection has not been widely accepted. Third, jet injectors are subject to supplying so-called "wet injections" where the medicine drains back from the injection site, a result that has given rise to concerns about the accuracy of the dose delivered. The first two points, pain and wet injections, are the result of the size of the nozzle orifice (approximately 0.15 mm in current jet injectors). This size resulted in more of the practical limitations of plastic injection molding for high volume commercial manufacture than of any effort in size optimization for user comfort and minimization or elimination of any "leakage" of the injected medicament. . This replacement of sub-optimal performance for manufacturing capacity has resulted in a marginalized product that has not enjoyed market acceptance that it might otherwise have. A particular type of conventional needleless jet is described in the US patent. No. 6,716,190 B1 (Glines et al.) Which teaches a device and methods for the delivery and injection of therapeutic and diagnostic agents to a target site within a body. This device and method uses a complex system comprising a nozzle assembly having an ampoule body and channels milled or machined within the distal surface of the ampoule body. These channels operate as a manifold and are arranged orthogonal to the reservoir orifice. The reservoir orifice ejects or expels the contents that are inside the body of the vial to the orthogonally arranged channels that channel the contents to a plurality of dispersion holes orthogonally disposed to the channels. The dispersion orifices are orthogonal to the channels and are located within the surface facing the target, generally flat distal. Not only is this particular arrangement complex, but it requires high supply pressures for the contents of the ampule in a range of about 126.54 to 351.5 kg / cm2, with some applications in a range of about 126.54 to 161.69 kg / cm2. In addition, the dispersion holes have a diameter of about 0.1 mm to about 0.3 mm (100 to 300 microns). Even when said device does not use a needle, the negative result involved with the use of said device and disposition is that it is likely to cause excessive trauma to the tissue at the delivery site as well as cause unwanted and unnecessary pain and / or discomfort to the tissue. end user or patient due to the high supply pressures required as well as the relatively high size of the dispersion orifices. Accordingly, the device and method of Glines et al. They are not suitable for microjet delivery of drugs especially in sensitive areas of the body such as the eyes, nasal passages and mouth or other sensitive areas of the body, especially those areas that are easily subject to trauma, pain and discomfort. Accordingly, there are a number of sensitive areas in the body and disease states that are extremely difficult to treat using local drug delivery. For example, there are a myriad of ophthalmic diseases that are difficult to treat and the delivery of the drug to the site of disease, i.e., the eyes, is often painful or psychologically uncomfortable for the patient. Relevant examples of these diseases that are extremely difficult to treat include age-related macular degeneration (AMD), diabetic retinopathy, choroidal neovascularization (CNV), macular edema, uveitis and the like. For these types of diseases, systemic drug administration commonly gives subtherapeutic drug concentrations in the eyes and can have significant adverse effects. Consequently, the current treatment for eye diseases often involves direct injection of the medicament into the eyes through a conventional syringe and needle - a painful and undesirable means of delivery to the patient. In addition, chronic treatment requires repeated injections that can result in plaque formations and scarring of the eyes, detachment of the retina and endophthalmitis. As a result of these complications, alternative means of drug delivery to the eyes are being developed. Research areas for delivery include iontophoresis, drug eluting eye implants, photodynamic therapy, "sticky" eye drops, and the like. In addition, it is well established that each of these approaches has its own limitations. For example, iontophoresis has a practical limit to the size of the drug molecule being delivered. One could not expect, for example, to supply molecules with a molecular weight above 20,000 Daltons. However, many new compounds, especially some promising proteins, are all above this size, which vary up to as much as 150,000 Daltons. In addition, eye implants require a surgical procedure for implantation and clarification procedures that are costly, painful, and can result in scarring of the eyes. Implants have the additional limitation of physical size and the amount of drug that can be loaded, or put into the implant. It is also known that photodynamic therapy is an unproven technology whose long-term effects are not understood and can be harmful to the retina. Alternatively, eye drops have long been considered the most convenient (and therefore perceived as the most acceptable) means of delivering drugs to the eyes. The eye drops, however, are washed out of the eyes very quickly and allow only a minimal supply of the contained drug. As a result, "sticky" eye drops, ie eye drops that provide adhesion of the mucosa, have been developed to avoid the "wash" effect, but the rapidity of cell turnover at the surface of the eye is believes that it is limiting in the effectiveness of this means of supply.In addition, the delivery mechanism of the eye drops is passive diffusion through the sclera.In addition, passive diffusion can not deliver drugs with a molecular weight greater than about Moreover, the supply is systemic rather than directed to the eye itself, consequently, there is currently no truly acceptable means of delivering active therapeutic agents to the eyes and other sensitive areas of the body, especially emerging macromolecules that show promise. in the treatment of a variety of ophthalmic diseases and diseases associated with these other sensitive areas of the body. date, there have been no known devices or methods that provide true drug delivery without a needle irrespective of the size of the drug molecules involved and that provide a true drug delivery without a needle with minimal trauma to tissue and that are adequate to deliver drugs in areas sensitive parts of the body such as the eyes, nasal passages or the mouth. To date, there have been no known devices that provide true needleless drug delivery where the devices are microjet delivery devices that are simple and efficient in design and construction, inexpensive and easy to manufacture.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to new and useful devices and methods for supplying needleless drugs with minimal tissue trauma and which are suitable for delivering drugs in sensitive areas of the body such as the eyes, nasal passages, mouth and other areas of the body . Therefore, the present invention is directed to a device for delivering a drug comprising: a housing; at least one nozzle in a portion of the housing; a drug source in the housing; an energy source for providing an impulse pressure of about 56.24 to about 140.6 kg / cm2 to propel the drug through at least one nozzle and out of the housing. In addition, the drug is driven through at least one nozzle within a time ranging from about 10 msec to about 200 msec under activation of the energy source. Moreover, at least one injection nozzle has a diameter ranging from about 10 μm to about 50 μm. In addition, the present invention is also directed to a device for delivering a drug comprising: a supply tube, the delivery tube having a pressure chamber therein; at least one nozzle at a distal end of the supply tube and in fluid communication with the pressure chamber; a drug source adjacent to at least one nozzle; a handle at a proximal end of the supply tube; and an energy source in the handle to provide an impulse pressure of about 56.24 to about 140.6 kg / cm2 to propel the drug through at least one nozzle and supply tube. In addition, the present invention is also directed to a method for making a drug delivery device by jet injection, wherein the drug delivery device has at least one drug reservoir and at least one injection nozzle, in wherein the method comprises the steps of: identifying a drug to be delivered; identify a volume of the drug to be delivered; establishing a reservoir diameter for at least one drug reservoir; establishing a nozzle diameter for at least one injection nozzle; identify a tissue model to deliver the drug; identify a penetration depth in the tissue model for drug delivery; and injecting the drug into the tissue model under variable pressure until the desired depth of penetration is achieved. Moreover, the method further comprises identifying an optimal pressure range for the drug delivery device that achieves the desired depth of penetration. An optimum pressure range for the device according to the present invention is from about 56.24 to about 140.6 kg / cm2 and an optimum pressure range at the tip of at least one injection nozzle for the device of the present invention is from about 281.2 to about 1757.5 kg / cm2. The present invention is also directed to a method for delivering a drug into the tissue comprising the steps of: providing a drug delivery device having at least one nozzle and a drug contained in a portion of the device; identify a site to deliver the drug in or on the tissue; place a portion of the device on or near the site; and delivering the drug into the tissue at the site through at least one nozzle of the device under microjet propulsion at a pulse pressure of about 56.24 to about 140.6 kg / cm2. The method further comprises delivering the drug into the tissue at the site with a tip pressure of at least one nozzle ranging from about 281.2 to about 1757.5 kg / cm2.

BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. The invention itself, however, in terms of organization and methods of operation, together with additional objects and advantages thereof; can be understood by reference to the following description, taken in conjunction with the accompanying drawings in which: Figure 1 is a perspective view of one embodiment of a microjet drug delivery device in accordance with the present invention; Figure 2 is an exploded view of the device of Figure 1 according to the present invention; Figure 3 is a cross-sectional view of the device of Figure 1 in a pre-triggered configuration in accordance with the present invention; Figure 4 is a cross-sectional view of the device of Figure 1 in a fired configuration in accordance with the present invention; Figure 5 is a proximal perspective view of another embodiment of a drug delivery device per microjet particularly useful for applications such as ocular use in accordance with the present invention; Figure 6 is a distal perspective view of the device of Figure 5 in accordance with the present invention; Figure 7A is a cross-sectional view of the device of Figure 5 in accordance with the present invention; Figure 7B is a cross-sectional view of an alternative embodiment of the device of Figure 7A having an LED focusing light in accordance with the present invention; Figure 8 is a partial cross-sectional side view of another embodiment of a drug delivery device per microjet particularly useful for applications such as nasal use in accordance with the present invention; Fig. 9 is an enlarged partial side view of the distal end of the device of Fig. 8 in accordance with the present invention; Figure 10 is an illustration of the device in Figure 8 during use for a nasal application in accordance with the present invention; and Figure 11 is a graph illustrating a penetration depth versus pressure study for the drug delivery device per microjet having a 50 μm diameter and nozzle and 100 μl drug delivery volume in accordance with the present invention.

DESCRIPTION OF THE PREFERRED MODALITIES The present invention addresses novel drug delivery devices, their methods of manufacture and their methods of use. As best shown in Figs. 1-10, the present invention is a needle-free (needle-free), 20a drug microjet device 20 delivery device. 20b, its manufacturing methods and its methods of use, which are all elaborated in more detail later. The drug delivery device 20, 20a and 20b, in accordance with the present invention is a needleless jet injection device that delivers drugs, such as liquid drug formulations, to a patient by injecting very fine streams of the formulations of high-speed drug The drug delivery device 20, 20a and 20b provides a less painful means of administering drugs than conventional needle and syringe devices as well as known needleless injection devices. The drug delivery device 20, 20a and 20b, in accordance with the present invention, can be used in a variety of medical applications, including transdermal, dermal, infraocular, intranasal, oral, and generally transmucosal drug delivery. The terms "drug delivery device", "delivery device", "needleless drug delivery device", "needleless microjet drug delivery device", "drug delivery device per microjet", "device Needleless Drug Delivery "," Needleless Microjet Drug Delivery Device ", "needleless jet injection device", "needle free jet injection device", "jet injection device", "microjet device" and "microjet", including various combinations of any parts of these terms, they all intend to have the same meaning and are used interchangeably here. The terms "active agent formulation" and "drug formulation" and "formulation" mean the drug or active agent optionally in combination with pharmaceutically acceptable carriers and additional inert ingredients. The formulation can be either solid, liquid or semi-solid or semi-liquid or combinations thereof. The terms "drug", "agent", active agent "and" pharmaceutical composition "are used interchangeably herein and refer to an agent, drug, compound, material composition or mixture thereof, including its formulation, which provides some therapeutic effect , often beneficial, this includes pesticides, herbicides, germicides, biocides, algicides, rodenticjdas, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, anti-preservatives, disinfectants, sterilization agents, catalysts , chemical reagents, fermentation agents, food, food supplements, nutrients, cosmetics, drugs, vitamins, sexual sterilizers, fertility inhibitors, fertility promoters, attenuators of microorganisms and other agents that benefit the environment of use. the terms also include any substance physiologically or pharmacologically and active that produces a localized or systemic effect or effects in animals, including warm-blooded mammals, humans and primates; birds; domestic or farm animals such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals such as mice, rats and guinea pigs; fishes; reptiles; zoo and wild animals; and similar. The active drug that can be supplied includes inorganic and organic compounds, including, without limitation, drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synaptic sites , neuroefector binding sites, endocrine and hormonal systems, the innmunological system, the reproductive system, the skeletal system, the autacoid systems, the food and excretory systems, the histamine system and the central nervous system. Suitable agents can be selected, for example, from proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, spheroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, analgesics, anti -inflammatories, local anesthetics, muscular contraction agents, antimicrobial agents, antimalarials, hormonal agents including contraceptives, sympathomimetics, polypeptides and proteins capable of inducing physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitic agents, neoplasms, antineoplastics, hypoglycemics, agents and nutritional supplements, growth supplements, fats, ophthalmic agents, antiteteritis agents, electrolytes and diagnostic agents. Examples of drugs or agents useful in this invention include prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mechaxylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride, benzfetamine hydrochloride, isoproteronol sulfate, phenmetrazine hydrochloride, betanecol, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexetil chloride, fenformin hydrochloride, methylphenidate hydrochloride, theophylline kohlrabi, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, maleate prochlorperazine, phenoxybenzamine, maleate of thiethylperazine, anisindione, diphenadione, erythritil tetranitrate, digoxin, soflurofato, acetazolamide, methazolamide, bendroflumetiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, hydrocortisone, aceta hydrocorticosterone, cortisone acetate, dexamethasone and its derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-beta-estradiol, ethinyl estradiol, ethinylestradiol 3-methyl ether, prednisolone, 17-beta-hydroxyprogesterone acetate, 19-nor- progesterone, norgestrel, norethindrone, norethisterone, noretiederone, progesterone, norgesterone, norethynodrel, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, phenoxybenzamine, diltiazem, milrinone, captropril, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen, tolmetin , alclofenac, mefenamic, flufenamic, difuninal, nimodipine, nitrendipine, nisoldipine, nicardipine, f elodipine, lidoflazine, thiaparil, gallopamil, amlodipine, myoflazine, lisinopril, enalapril, captopril, ramipril, enalaprilat, famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, arnitriptilin and imipramine. Further examples are proteins and peptides including, but not limited to, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone, follicle-stimulating hormone, chorionic gonadotropin, gonadotropin-releasing hormone, bovine somatotropin, somatropin porcine, oxytocin, vasopressin, prolactin, somatostatin, lyserin, pancreozimine, luteinizing hormone, LHRH, interferons, interleukins, growth hormones such as human growth hormone, bovine growth hormone and porcine growth hormone, fertility inhibitors such as prostaglandins, fertility promoters, growth factors, human pancreatic releasing factor, antiproliferative / antimitotic agents including natural products such as vinca alkaloids (ie, vinblastine, vincristine and vinorelbine), paclitaxel, epidipodophyllotoxins (ie, etoposide, teniposide), antibiotics (dactinomycin (a cynomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramycin) and mitomycin, enzymes (L-asparaginase that systematically metabolizes L-asparagine and deprives cells that do not have the ability to synthesize their own asparagine); antiplatelet agents such as inhibitors of G (GP) lllla and vitronectin receptor antagonists; antiproliferative / antimitotic alkylating agents such as nitrogenous mustards (mechlorethamine, cyclophosphamide and the like, melphalan, chlorambucil), ethyleneimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and the like, streptozocin), trazenos- Dacarbazinin (DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogues (fluorouracil, floxuridine and cytarabine), purine analogues and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine., cladribine.); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (ie, estrogen); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; anti-migratory; antisecretor (breveldin); antiinflammatories: such as adrenocortical steroids (cortisol, cortisone, hydrocortisone, prednisone, prednisolone, 6a-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, ie, aspirin; para-aminophenol derivatives; say, acetaminophen, indole and indenacetic acids (indomethacin, sulindac and etodalac), heteroaryl acetic acids (tolmetin, diclofenac and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam) , tenoxicam, phenylbutazone and oxifentatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold thiomalate sodium), immunosuppressants: (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil), angiogenic agents : vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), growth factor derived from platelets (PDGF), erythropoietin; angiotensin receptor blocker; nitric oxide donors; antisense oligonucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, kinase inhibitors of growth factor signal transduction, chemical compound, biological molecule, nucleic acids such as DNA and RNA, amino acids, peptide, protein or combinations thereof. It should be understood that more than one drug or agent can be combined or mixed together and incorporated into or used by the present invention, and that the use of the term "drug", "agent" or "drug" or "Pharmaceutical composition" in no way excludes the use of two or more of those drugs, agents, active agents and / or pharmaceutical compositions. One embodiment of the drug delivery device 20 in accordance with the present invention is illustrated in Figures 1-4. The drug delivery device 20 is a needleless jet injection device especially useful for injecting drug delivered under microjet thrust in very fine streams at high speed in various types of body tissue, including organs. By way of example, the drug delivery device 20 in accordance with the present invention is particularly useful for the dermal or transdermal delivery of drugs to a patient, i.e., as a dermal or transdermal drug delivery device for delivering drugs without a needle to the various layers of skin or through the layers of skin and to the bloodstream and circulatory system of the patient. While the drug delivery device 20, in accordance with the present invention, is not limited to dermal and transdermal applications, rather, it is intended to be used for other types of tissue and other medical, therapeutic and diagnostic applications. The drug delivery device 20 has a housing 24 and a cover 28 at a proximal end of the housing 24 and a nozzle plate 30 at the distal end of the housing 24. One or more nozzles 34 or a plurality of nozzles 34, which are Jet injection nozzles (also referred to as "micro-nozzles"), are disposed on the nozzle plate 30. As shown in FIGS. 1-4, the injection nozzles 34 terminate as small projecting projections from the outer surface of the nozzle plate 30 thus providing the user with tactile feedback for the proper location and arrangement of the injection nozzles 34 on the user's tissue surface. As best illustrated in Figures 2, 3 and 4, housing 24 further includes one or more reservoirs 38 aligned and in fluid communication with one or more nozzles 34. Each reservoir 38 is longitudinally disposed in housing 24 and serves as a reservoir. drug reservoir or storage space for the drug 40. Each reservoir is configured to receive a push bar 48 and a reservoir seal 54 attached or attached to the distal end of each push bar 48. The push bar 48 and seal of reservoir 54 are in direct longitudinal alignment with each reservoir 38 and push bar 48 and reservoir seal are movably (longitudinally movable) within each drug reservoir 38. Each reservoir seal 54 is designed to prevent the drug 40 leaches or drips from the drug reservoir 38. Therefore, the reservoir seal 54 is in movable sealable contact with the inner wall of the drug reservoir 38. The push bar 48 and the reservoir seal 54 are slidably movable longitudinally in each reservoir 38. The piston 44 is integral to or attached to the proximal end of each push bar 48 and serves as a pulse platform for accumulating and exerting a force of pushing the push rods 48. The piston 44 can be fixed as an individual unit to the proximal end of all the push rods 48 in order to operate and move each push rod 48 simultaneously within each reservoir 38 or the piston 44 it can be fixed to the proximal end of each push bar 48 individually in order to operate selectively and individually and move each push bar 48 within the reservoir 38. In this example, the piston 44 has a cylindrical shape configured to fit securely within and in movable hitch with the inner wall of the housing 24 which also has a cylindrical shape. The piston 44 has a circumferential space configured to receive an O-ring seal 52 which is also configured to fit securely within and in movable engagement with the inner wall of the housing 24 together with the piston 44. The seal 52 can be any type of seal whenever you prevent the gas, discharge content or other material is leach or penetrate beyond the piston 44. As best shown in Figure 3 (drug delivery device 20 loaded with the drug 40 and in its predisposed configuration), a power source to discharge A driving force to the piston 44 is located proximal to or greater than the piston 44 within the housing 24, for example, in an embodiment in accordance with the present invention, a load housing 60 located in the proximal or upper portion of the housing 24. The load pyrotechnic 64 is contained within the loading housing 60. A detonator 68 is located adjacent the pyrotechnic charge 64 to contain a small explosive charge that delivers pyrotechnic energy or ignition energy to the pyrotechnic charge 64 to ignite the pyrotechnic charge 64 upon activation of the detonator 68. A blow pin 70 is located in the cover 28 and movably engages or movably contacts with the toner 68 for activating the detonator 68 and initiating the explosive charge contained in the detonator 68. The hit pin 70 is movably connected to an activation element such as an activation button 74 that is movably deflected by the spring 72. Therefore, , the activation button is movably diverted to the strike pin 70 within the cover 28 to urge the strike pin 70 towards the detonator 70 under a sufficient downward force pressed on the activation button 74, for example, by the user's thumb or patient. As best shown in Figure 4 (drug delivery device 20 in its fired configuration after having injected drug 40 under microjet propulsion), by depressing the activation button 74, the hit pin 70 hits the detonator 68 thus activating the detonator 68, which in turn causes the extremely rapid combustion of a pyrotechnic charge 64. This controlled explosion provides the driving force necessary to slidably advance the piston 44 and the fixed thrust rods 48 through the reservoirs 48 that make that the push bars 48 are ejected by drug microjet propulsion 40 outwardly through the injection nozzles 34. The energy source, such as pyrotechnic charge 64 or compressed gas 36 (FIGS. 8 and 10) supplies sufficient energy and pulse pressure to maintain the pulse piston 44 and associated push rods 48 ranging from about 56.24 to about 140. 6 kg / cm2. In turn, the energy and pressure at the tips of the micro nozzles 34 vary from about 281.2 to about 1757.5 kg / cm2 at each microtitre tip, and preferably in the range from about 562.4 to about 843.6 kg / cm2 at each microtitre tip and most preferably at about 703 kg / cm2 in each microtitre tip. For all embodiments of the present invention, the same number of references are used to designate the same or similar features and parts. Accordingly, Figures 5, 6, 7A and 7B, illustrate another embodiment of the present invention that is particularly useful for ophthalmic and ocular applications such as drug delivery 40 to the eyes of a patient 100. Therefore, the nozzle 30a at the distal end of the housing 24 has a contoured distal end 31 which is a concave ring having an opening in a central portion thereof. In this example, the contoured distal end 31 has a plurality of injection nozzles 34 circumferentially disposed within the contour (concave region) defined by the contoured distal end 31 and spaced proximally at a distance away from the edge of the outer surface of the circumference outer (periphery or outer edge) of the contoured distal end 31. Accordingly, in this example, the nozzle plate 30a having a contoured distal end 31 is configured to receive an eye of a patient 100 wherein the pupil of the eye 100 can be located within the central portion (open space) of the circumferential ring of the contoured distal end 31. Therefore, if desired, the drug 40 can be delivered under microjet propulsion to areas of the eye 100 outside the pupil, such as the vitreous or sclera, as best shown in Figure 5. Figure 7B illustrates an alternative embodiment of the invention. drug delivery device 20a wherein a cavity of the light emitting diode (LED) 76 is provided in the central portion (open space) of the circumferential ring of the contoured distal end 31 of the nozzle plate 30a. An LED 80 is located in the LED cavity 76 to disperse a focus light (focus LED light) 88 under operational control from the switch 86 movably located in an outer portion of the housing 24 in this example near the proximal end of the housing 24). Switch 86 serves as a power switch for activating LED 80 to project focus light 88, i.e. switch 86 serves as an "on", "off" switch for LED 80 and light 88. For purposes of Briefly, the contacts, terminals and cables that operatively connect the LED 80 to the switch 86 are not shown, but are well understood and can be appreciated by an expert in the field. The focus light 88 is used to attract the direct attention of the patient, align and focus the pupil of the eye 100 and serves as a focal point of attention by the patient in order to mentally relax the patient (basically distract the patient) while the drug 40 is supplied to the eye 100 under microjet propulsion. Therefore, the LED 80 and the focus light 88 serve as a means to reduce the levels of stress in the patient and the anxiety normally associated with receiving a drug injection, particularly in a sensitive area such as the eye 100. Alternatively, instead of an LED 80, an element or feature that is luminescent (including self-luminescent) or an element or feature having a luminescent coating, such as a point having luminescent coating that is used as a focal point and can be used to attract the direct attention of the patient and focus of the pupil of the eye 100 to serve as a focal point of patient care in order to mentally relax the patient in anticipation of and while receiving the injected drug 40 under microjet propulsion. A point coated with tritium is one of these suitable substitutes as an example. Figures 8, 9 and 10 illustrate another embodiment of the present invention wherein the drug delivery device 20b uses an elongated cylindrical tube as a delivery tube 25 having a pressure chamber 27 therein. A handle 23 is connected to the supply tube 25 at a proximal portion of the supply tube 25. A valve 33 is connected to the proximal end of the supply tube 25 and pressure chamber 27 and a source of compressed gas 36, such as C02 gas compressed contained in a cartridge 36 and is connected to another end to the valve 33 and contained within the handle 23. The cartridge 36 is a miniature compressed gas cylinder containing a compressed gas such as C02 with the ability to achieve and supply pressures as high as 140.6 kg / cm2. The valve 33 regulates the release of compressed gas from the cartridge 23 into the pressure chamber 27 of the supply tube 25 by activating the button 74a located at a convenient location on the handle 23, for example, easily accessible with the index finger of the hand of the patient or user. If desired, a detachably connected cover (not shown) can be used with a handle 23 to provide direct access to the gas cartridge 36 to exchange the cartridge 36 after its contents are spent (when empty) with a gas cartridge newly loaded (complete) 36 thereby making the drug delivery device 20b a multi-use device or reusable device. As shown in Figure 9, the nozzle plate 30 and the nozzles 34 are located at the distal end of the supply tube 25 and pressure chamber 27 and are arranged as projections extending outward from the outer surface of the plate. of nozzle 30 to provide the user 90 with tactile feedback for proper location and alignment of the injection nozzles 34 on a tissue surface of the user's body, for example, on the tissue located within a nostril of the nose 110 (as shown in FIG. 10) or tissue located inside the mouth of the patient (buccal application), such as the gums or palate of the mouth, or a place inside the patient's ear, etc. Therefore, the drug delivery device 20b is suitable for delivering drug 40 to areas difficult to access from the patient's body due to the design of the elongate and low profile. The drug reservoirs 38, the drug 40, reservoir seals 54, push rods 48, piston 44 and O-ring 52 are arranged and operate in the same manner or in a manner similar to that described for the embodiments of FIGS. 7B, except that these features are located within the supply tube 25 and pressure chamber 27 at the distal end of the supply tube 25 and pressure chamber 27. The pressure chamber 27 allows the compressed gas to be released from the cartridge 36 and it channels the gas from the handle 23 to the piston 44 along the entire length of the supply pipe 25 which provides the driving force necessary to slidably advance the piston 44 and the fixed thrust rods 48 through the tanks 48. causing the push bars 48 to eject the drug 40 outwardly through the injection nozzles 34. The drug delivery device 20 (FIGS. 1-4), 20a (FIG. uras 5, 6, 7A and 7B) and 20b (Figures 8-10) are designed to be compact in design, for example, having exterior surface dimensions that measure approximately 5.08 cm in length and 1.52 cm in diameter (for the modes of Figures 1-4 and Figures 5, 6, 7A and 7B respectively), and of very light weight, for example weighing only a few grams. Ergonomically, it may be desirable to increase the size or change the geometry significantly, but the fundamental functionality remains exactly the same as that presented in these figures. Alternatively, the power source for discharging a pulse force to the piston 44 is compressed gas, such as C02 as an example, releasably housed in a gas cartridge 36 (Figure 8). Moreover, the energy source for discharging a pulse force to the piston 44 can be any type of energy force as long as it is capable of delivering drug under microjet propulsion in accordance with the requirements set forth below and later in the description. For example, the energy source must discharge sufficient broad energy in order to drive the main pulse piston 44 and associated thrust rods 48 at a pulse pressure ranging from about 56.24 to about 140.6 kg / cm2. In turn, the energy and force at the tips of the micro nozzles 34 vary from about 281.2 to about 1757.5 kg / cm2 at each microtitre tip and preferably at a range from about 561.4 to about 843.6 kg / cm2 at each microtitre tip, and most preferably at about 703 kg / cm2 in each microtitre tip. The volume of the drug 40 delivered under microjet thrust by the drug delivery device 20 (Figures 1-4) 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10), in accordance with the present invention , it is customized, adjustable and variable in order to accommodate the supply of any type of drug, any type of tissue and any type of medical application. The volumes of drug delivered can be adjusted according to a volume range that is from about 10 microliters (μl) or less to about 1 milliliter (mi) or more depending on the configuration or design of the drug delivery device 20, 20a and 20b. In addition, the diameter of the injection nozzle (s) 34 is variable and varies from about 10 (μm) to about 50 (μm) or more, giving exceptionally fine injection currents of drug 40 and minimizing the number of nerve receptors impacted by an injection thus reducing the trauma, pain and discomfort for the patient. One aspect of the novelty and uniqueness of the drug delivery device 20 (Figures 1-4) 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10), in accordance with the present invention is its use of one or more discrete drug reservoirs 38 that serve as injection chambers wherein each reservoir contains drug 40 as a portion of the total injection volume of the total dose for drug 40 as best shown in FIG. 3 (delivery device). drug 20 shown in its predispared configuration before delivering drug 40). In addition, each reservoir 38 has its own dedicated injection nozzle 34 of extremely small diameter. For example, the diameter of each nozzle 34 ranges from about 10 μm to about 50 microns. Therefore, the drug delivery device 20 (Figs. 1-4) 20a (Figs. 5, 6, 7a and 7B) and 20b (Figs. 8-10), in accordance with the present invention divides the total delivery volume for the drug 40 in and through multiple discrete reservoirs 38 (for those embodiments in accordance with the present invention having more than one injection reservoir 38), and supplying each volume of drug contained therein in the patient's tissue at higher speeds as best shown in Figure 4 (drug delivery device 20 shown in fired configuration after delivering drug 40 under microjet propulsion) than those injection rates achieved with conventional jet injectors such as those jet injectors delineated above. Accordingly, an advantage associated with drug delivery device 20 (Figs. 1-4), 20a (Figs. 5, 6, 7A and 7B) and 20b (Figs. 8-10) in accordance with the present invention is a drastic decrease in the time required to inject drug 40 where this time can be as short as 40 milliseconds (msec). Even for a requirement for the delivery of 0.5 cm3 (or 0.5 ml) drug injection 40, the injection time achieved by the drug delivery device 20 (figures 1-4), 20a (figures 5, 6, 7A and 7B) ) and 20b (Figures 8-10) ranges from about 10 msec to about 200 msec (and, in one example, ranges from about 40 msec to about 100 msec for about 0.5 mL of certain types of drugs). A further aspect of the present invention is that since the area of the jet stream decreases with the diameter frame, there is almost a 100-fold reduction in the area of skin or tissue affected by injection with a drug delivery device. 20 (figures 1-4), 20a (figures 5, 6, 7A and 7B) and 20b (figures 8-10) as compared to the known thinner conventional hypodermic needle (ultrafine insulin needle having a 31-gauge cannula) with a diameter of 0.6 mm). In one embodiment in accordance with the present invention, the drug delivery device 20 (Figure 1-4), 20a (Figure 5, 6, 7A and 7B) and 20b (Figure 8-10) is a drug delivery device. pre-filled, single-use (designed to be used once as a disposable unit, ie, a single use, once, by the patient) that does not require preparation or adjustment in advance by the patient's care provider. Therefore, the drug delivery device 20 (Figures 1-4), 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10) is ready to be used as manufactured and is provided. Alternatively, the drug delivery device 20 (Figs. 1-4), 20a (Figs. 5, 6, 7A and 7B) and 20b (Figs. 8-10) is also intended to be a reusable unit (e.g., the main housing 24). , lid 28 with activation button 74 and supply tube 25 and handle 23 with activation button 74a would be reused and resterilized if required) with a single use, disposable internal assembly that is either refilled or reloaded by the patient or provider of health care before administration, inserted into the housing 24 or handle 23 and supply tube 25 (for the drug delivery device 20b) and then removed and discarded after use. In this case, the disposable internal assembly comprises a detonator 68, pyrotechnic charge 64 (or compressed gas cylinder 36), push bars of the drug reservoir 48, drug reservoirs 38, injection nozzles 34. the reusable housing 24 and tube of supply 25 and handle 23 and other components such as cover 28 and activation buttons 74 and 74a are made of a suitable material such as metal or metal alloy capable of resisting reuse and sterilization again if necessary. Furthermore, in all embodiments of the present invention, the injection nozzles 34 may be in the form of an arrangement of injection nozzles 34 (in any desired pattern on the nozzle plate 30 and 30a) that are configured out of the plane or at different angles. of the trajectory, for example, in order to provide objective convergence of the drug 40 either to a particular target point in the tissue, i.e., a single target point in the tissue to receive the entire volume of injected drug 40 or a plurality of of desired target points in the fabric.

Optimization of Drug Delivery by Microjet Propulsion and Manufacturing Method There are two mechanisms that are used to characterize and measure the performance of the drug delivery device 20 (Figures 1-4), 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10) in accordance with the present invention. The first mechanism is a predictive model based on the so-called Hagen-Pouiselle equation. This equation was used to estimate the effects of different designs on the main elements and components of the drug delivery device 20 (figures 1-4), 20a (figures 5, 6, 7A and 7B) and 20b (figures 8-10) and its methods of use and the resulting driving forces required to operate the drug delivery device in accordance with the performance criteria of the present invention. In addition, the actual forces required for drug delivery amounts required under microjet propulsion were determined empirically through both in vitro and in vivo tests.

For example, Figure 11 is a graph depicting the findings of one of these relevant in vitro studies used to determine penetration depth versus pressure for the drug delivery device per microjet (20, 20a and 20b) having nozzle diameter. of 50 μm and volume of drug supplied of 100 μl according to the present invention. During the development and manufacture of the drug delivery device 20, 20a and 20b according to the present invention, there is a force / volume / length exchange based on the diameter of the individual drug reservoirs 38, as well as the diameters of the injection nozzles 34 and the desired injection rate or mass flow rate of drug 40 or drug formulation 40 ejected. In addition, the design of these components has implications for the duration of the injection, the number of drug reservoirs 38 and injection nozzles 34 that are used, the size of the main piston 44 and even the physical properties required by the construction materials for many of the key elements of the drug delivery device 20, 20a and 20b. This relation is modeled by the Hagen-Pouiselle equation as follows: F = 8QμL (R2 / r4) where: F = Injection force Q = Flow rate of the formulation or drug injectable material μ = viscosity of the formulation or injectable drug material L = Injection nozzle length R = Drug reservoir radius r = injection nozzle radius To demonstrate the utility of this equation, suppose you want to supply 500 microliters (1/2 cm3) of a formulation of aqueous drug 40 (a drug solution 40 with viscosity = 1 cps) to the subcutaneous layer of tissue at a flow rate Q of 5 cm3 / second. Also, suppose that a microtiter diameter or injection nozzle of 50 microns, or r = 25 microns, is being used. Although the length of the drug reservoir is to be minimized, it is also desired to minimize the injection force. Therefore, although the shorter length is better, the smaller diameter also means less force but a longer length. Therefore, a convenient size is selected with respect to a suitable reservoir length for a portable microjet device delivery device (20, 20a and 20b) while also attempting to minimize injection force. Consequently, drug deposits of 1.82 mm in diameter, or 0.914 mm of R. were selected.

L of the injection nozzle 34 is determined by construction constraints (a very small hole can only be made in a given material for a limited length). Therefore, it is assumed that an adequate length L is 1.27 mm. Therefore, the Hagen-Pouiselle equation can estimate the injection force required for any injection nozzle given as follows: Con: Q = 5 cm3 / sec μ = 1 cps L = 0.127 cm R = 0.091 cm r = 0.0025 cm F = 8QμL (R2 / r4) = 10, 218,121 dynes or approximately 10.44 kgf. The number of drug reservoirs 38 is determined by the total force that the main impulse piston 44 can exert divided by the force required to propel each of the reservoir thrust rods of 48 which act as individual pistons simultaneously in this example ( expressed as an integer). The practical pressure achieved either by the pyrotechnic charge 64 or a cylinder of compressed gas 36 is limited to approximately 140.6 kg / cm2. Consequently, given a main piston 44 of 1.27 cm and the resulting area of (0.635 cm) 2 times pi = 1.26 cm2, the maximum available impulse force is 140.6 kg / cm2 x 1.26 cm2 or 177.9 kg of force. With 10.44 kg of force required to drive each drug reservoir push bar 48 and 177.9 kg of available force, the maximum number of drug reservoirs 38 that can be accommodated (as an integer) is 177.9 divided by 10.44 or a total of seventeen (17) reservoirs 38. The length of each drug reservoir 38 is calculated as a result of the volume requirement for each. For example purposes, assume that five (5) deposits are used. Therefore, since it is required that a total of 500 microliters be delivered through the five (5) reservoirs 38, each reservoir 38 will supply 100 microliters of drug 40. Given a reservoir diameter of 1.83 mm, each reservoir length will be 100 microliters divided between the deposit area (pi x (.914 mm) 2) or 38.1 mm in length. In addition, the injection flow rate Q has already been defined as 5 + cm3 / sec (as delineated above). Consequently, the total injection time is determined by the time required to inject the volume of drug contained within each individual reservoir 38, which has been found to be 100 microliters or 1 / 10a of cm3. Therefore, the injection time is 0.1 Ocm3 by the reciprocal of the flow regime Q or 20 milliseconds. As a predictive model, the Hagen-Pouiselle equation is a useful tool for preliminary and predictive analysis of design parameters required for elements of the drug delivery device 20, 20a and 20b, but as would be expected, the empirical findings did not differ from the predictive analysis Both in in vitro tests that included the use of a 2 mm thick ballistic gelatin on a Pluronic solution (FI27) and in vivo tests that included testing of the drug delivery device according to the present invention in the The hairless guinea pig model demonstrated that the drug formulation 40 is required to be pressurized to approximately 140.6 kg / cm2 in order to achieve microjet propulsion, ie, the speeds necessary for the drug formulation 40 to be delivered through the injection nozzles 34 at a depth of penetration into the tissue, such as the skin, necessary for therapeutic administration, i.e., in this case, subcutaneous administration. Given, for example, that the drug reservoir 38 has a diameter of 1.8 mm, the cross-sectional area of each drug reservoir 38 is (0.914) 2 per pi or 0.018 cm 2. With the force F equal to the pressure P for the area A, the force necessary to drive the push bars 48 to achieve a pressure of 562.4 kg / cm2 in the drug formulation 40 is 8,000 times 0.004 or 14.52 kg of force. This was a moderate increase over the 10.44 kg of force predicted by Hagen-Pouiselle, but certainly along the same order of magnitude. Much of the increase is explained by the friction of the sliding reservoir seals 54 and O-ring 52. Continuing with the values used in the example for the Hagen-Pouiselle equation, assuming that 500 microliters of drug formulation 40 are required for total administration and five (5) drug reservoirs 38 are being used for the design, then each reservoir 38 contains 500/5 or 100 microliters of drug formulation 40. Within 14.52 kg of force required for each drug reservoir 38 and five total drug deposits, it was calculated that 14.52 x 5 or 72.64 kg of total force is needed to drive all the push bars of the drug reservoir 48. Therefore, the main driver piston 44 must exert a force of 72.64 kg. Given a diameter of 1.27 cm for the main impulse piston 44 (note that this dimension can be higher or lower depending on the application and practical ergonomic limitations of physical size), the piston area 44 is (0.635 cm) 2 by pi or 0.497 cm. Therefore, the power source must apply a pressure of F / A (72.64 / 0.497) or 57.36 kg / cm2 to the main drive piston 44. This pressure requirement is within the performance specifications either of a pyrotechnic load 64 or a source of compressed miniature gas 36. The lengths of the drug reservoir 38 and the injection duration will be the same as those given in the Hagen-Pouiselle example. The main drive piston assembly 44 acts as an accumulator for the pressure generated by the pyrotechnic charge 64 as shown in Figures 2, 3, 7A and 7B (or, alternatively, a source of compressed gas 36 as shown in the figures 8 and 10), distributing the pressure and translating it as a driving force to the individual push rods 48. The push rods 48 are integral to the main drive piston 44, whereby the total load applied to the piston 44 is transferred proportionally to each of the push bars 48. In the event that a larger size main piston diameter is required, this will result in a greater exerted force for any given machine pressure. For example, if the main piston diameter is increased in the above examples from 1.27 cm to 1.5 cm, then the resultant force of a maximum machine pressure of 140.6 kg / cm2 will increase from 140.6 kg / cm2 x 1.26 cm2 = 177.9 kg of force 140.6 kg / cm2 x 1.82 cm2 = 39.72 kg of force. This increase in effective driving force allows the use of additional injection nozzles 34, which, in turn, reduces the volume in each nozzle 34, which, in turn, reduces the duration of the injection time, etc. Finally, the geometry of the nozzle is determined by the desired diameter of the drug stream, the tensile strength / deformation of the construction materials, and the practical limitations of manufacturing a very small orifice at a cost of effective economy of scale. Although a goal of achieving a portable, compact, lightweight drug delivery device 20, 20a and 20b with respect to the nozzle geometry is "the smaller the better", there are practical limits to construct such nozzles 34. In the Known and conventional needleless drug injectors, these known devices have a relatively large orifice (approximately 0.15 mm-0.20 mm) because these are practical limits of high volume injection molding in suitable thermoplastics (i.e., smaller core pins) that this diameter are not practical at the high pressures and high shear stress required by injection molding in high volume production). As indicated for the drug delivery device 20, 20a and 20b according to the present invention, the drug delivery device 20, 20a and 20b uses nozzles 34 in the size of 50 microns and at a significantly higher operating pressure than that found with conventional known needleless jet injectors, such as those described above. Accordingly, the drug delivery device 20, 20a and 20b in accordance with the present invention takes advantage of materials having high tensile strength and bursting properties for the components of the drug delivery device 20, 20a and 20b. Such materials include ceramics, various metals, metal alloys, high strength engineering thermoplastics (such as PEEK ™, Torlon ™, Ultem ™, etc.), and others. Therefore, the present invention is also directed to the use of the most effective combination in terms of costs of said materials and to minimize the counting of parts, that is, to minimize the number of components and parts required. Since the material used will need to withstand an injection pressure given in excess of 562.4 kg / cm2 immediately at the tip of the nozzle, it is desirable to use discrete nozzles 34 made of metal, metal alloy or ceramic (e.g., alumina or zirconia) and assembling the housing 24 (Figures 1-7B) or supply tube 25 (Figure 8), for example, by bonding or ultrasonic welding. All these materials can be formed by injection molding, although the orifice of the final nozzle would be formed secondarily using laser drilling, ultrasonic drilling, wire EDM machining, or the like. Although not currently believed to be practical, developments in micro-injection molding can make the molding of fully finished integral injection nozzles fully feasible and more cost-effective than current approaches involving secondary finishing operations. However, injection molding in high strength materials coupled with laser drilling to produce accurate, repeatable injection nozzles 34 would satisfy the engineering and cost requirements associated with the present invention. In another example in accordance with the present invention, Figures 1-4 illustrate several views of the drug delivery device 20 that can be used to accelerate a multiplicity of small drug volumes 40 at a rate suitable for delivery in tissue, example, through the skin as part of a transdermal drug delivery procedure. Using this example to illustrate the function of the drug delivery device 20 under the assumption that the design of the drug delivery device 20 will require a total of thirty (30) injection nozzles 34 with each nozzle 34 having a diameter of 40 microns and a calculated drug volume of 3.3 μl per drug reservoir 38, or a total drug volume of 30 x 3.3 = 100 μl. In addition, given a required speed of 200 m / s to supply the drug 40, the force required for each injection nozzle 34 can be calculated from the Hagen-Poiseuilie equation which gives a value of approximately 4.54 kg per injection nozzle 34. Given thirty (30) injection nozzles 34, the total required force is 30 x 4.54 = 136.2 kg. Assuming that the surface area of the main piston 44 is 6.45 cm2, then 136.2 kg of pressure is needed to achieve the required performance parameters. Again, these performance criteria can be achieved using the miniature compressed gas cylinder 36 (figures 8 and 10) or the pyrotechnic charge 64 (figures 2, 3, 7A and 7B). The advantage of the pyrotechnic charge is that the pressure profile can be controlled throughout the supply cycle, providing variable pressures at different times to optimize the drug supply. Moreover, as can be readily appreciated, there may be a number of suitable energy sources that can be used for the purpose of accelerating the drug 40 at the speeds required to achieve microjet propulsion criteria in accordance with the present invention and the examples provided herein are in no way intended to limit the type of energy source that may be used in the present invention. As best illustrated in the graph depicted in figure 11, an in vitro study for the microjet drug delivery device (20, 20a and 20b) was conducted in accordance with the present invention in order to determine an optimal range for depth of penetration (in cm) versus an optimal range of pressure (in kg / cm2). The diameter of the nozzle 34 was a diameter of approximately 50 microns where the volume of drug 40 supplied was approximately 100 μl. As illustrated clearly in Figure 11, the delivery pressures for the drug delivery device per microjet (20, 20a and 20b) can be easily adjusted to objective and selected tissues. Therefore, the drug delivery device per microjet (20, 20a and 20b) is customized in a manner that ensures that any particular drug can be delivered at a particular depth of penetration into a particular tissue type based on a pressure of particular supply according to the graph of Figure 11. Accordingly, this customizable approach even allows particular layers of tissue to be used as a target for drug delivery. For example, the tissue submucouse layer can be used as an objective exactly according to the algorithm shown in Figure 11. In addition, any number of drug reservoirs 38 and injection nozzles 38 can be used for the present invention (within practical limits). As demonstrated above, these can be any from an individual reservoir 38 and an individual nozzle 34 to as many as fifty (50) or more reservoirs 38 and nozzles 34 respectively. Standard semiconductor processes can easily fabricate injection nozzles 34 similar to the manufacture of nozzles used in jet printing. Therefore, the injection nozzles 34 may be mass produced silicon devices having an orifice diameter of between 3 and 10 microns as an example. The injection nozzles 34 can be manufactured as dense arrangements on a silicon wafer and subsequently cut the desired geometry. The wafer patterns, and therefore the layout geometry, can be fabricated into any desired design. Accordingly, the arrangement of micro nozzles can be made in any desired pattern such as a circular, elliptical, or semi-circular pattern, for example, and with any practical density of injection nozzles 34 that is required. Typically, every effort would be made to reduce the size of the injection nozzles 34 and to maximize the number of injection nozzles 34 that said wafer can give. The micromolding of thermoplastics is an emerging technology that may also be useful for manufacturing the drug delivery device 20, 20a and 20b in accordance with the present invention. The advantages would be significant. Although silicon wafers are flat structures, injection molded plastics are not. Therefore, the injection nozzle arrangement 34 can be configured out of plane, for example, which would provide a tremendous benefit to create an arrangement that is intended to be located with objective convergence. An additional significant advantage is the cost. A disposition of micro nozzles molded in a thermoplastic would cost very little, compared to a silicon device that could easily swing in dollars. Other methods that could be used to construct the micro nozzles 34, include micromachining the holes in place as part of the nozzle plate 30 or nozzle plate 30a having a contoured distal end 31 (annular cup), machining or hole formation in glass, metal, ceramic, plastic or other suitable material and then assembled (eg, press fit) into the contoured distal end 31 (annular cup), etc. Like other important components of the drug delivery device 20, 20a and 20b according to the present invention, the design or manufacture of the micro nozzles 34 is not intended to be limited to a specific embodiment. Therefore, in general, the present invention is directed to a method for making or manufacturing a drug delivery device 20, 20a, and 20b in accordance with the present invention. Accordingly, this method comprises several key steps such as identifying a drug to be delivered (it can be based on any desired treatment or disease status or condition that is the purpose of the treatment). In addition, a volume of the drug to be delivered is also defined. Moreover, the key parameters for the characteristics of the device 20, 20a and 20b are determined. This includes parameters such as the diameter for one or more drug reservoirs 38 and the diameter for one or more injection nozzles 34 that are established in advance. In addition, a tissue model is identified for the type of tissue or disease that is to be treated. For example, the tissue model is any in vitro or in vivo model acceptable for this purpose. Therefore, the tissue model can be based on material, for example, tissue model that is synthetic, natural, mammalian (to include any animal or human tissue), living tissue, preserved tissue, etc.

In addition, other key steps include identifying a penetration depth in the tissue model for drug delivery. This includes targeting any desired or particular layer of the tissue that is considered appropriate for injection of microjet of drug 40. In addition, drug 40 is tested in the tissue model by injecting drug 40 into the tissue model using the device. drug delivery 20, 20a and 20b according to the present invention under variable pressure until the desired depth of penetration or desired tissue layer is achieved. By using the method according to the present invention, an optimum pressure range is identified for the drug delivery device 20, 20a and 20b which achieves the desired penetration depth or tissue layer desired. As outlined above, an optimum pressure range has been identified which is < 140.6 kg / cm2 in the main piston 44 and an optimum pressure range of < has been identified; 562.4 kg / cm2 for the area at the tip of the injection nozzle 34. The method according to the present invention also includes the use of predictive modeling to predict the optimum pressure range required in determining the required injection force (F) . The determination of the injection force (F) is achieved according to the formula: F = 8QμL (R2 / r4); wherein Q = drug flow rate; μ = drug viscosity; L = length of the injection nozzle; R = radius of the drug reservoir; and r = radius of the injection nozzle.

Methods of use For transdermal or dermal delivery, the drug delivery device 20 (Figures 1-4) is in its pre-triggered configuration and loaded with the total volume of drug 40 to be delivered where the delivery device of drug 20 is placed firmly against and perpendicular to any desired site of injection (typically the back of the arm, stomach or thigh) with the skin pierced in a conventional manner. Since the injection nozzles 34 terminate as small protrusions projecting from the outer surface nozzle plate 30, the user is provided with instantaneous tactile feedback for proper placement and alignment of the injection nozzles 34 on the tissue surface of the body of the user in the desired injection site. As best shown in Figure 4, by depressing the activation button 74, the strike pin 70 hits the detonator 68 thereby activating the detonator 68, which in turn causes extremely rapid combustion of the pyrotechnic charge 64. This explosion This control provides the necessary driving force to slidably advance the piston 44 and the fixed push rods 48 through the reservoirs 38 by causing the push rods 48 to eject the drug 40 from the injection nozzles by means of microjet jet propulsion. this example described immediately above is directed to subcutaneous or cutaneous delivery, there are other examples for the drug delivery device 20a and 20b which are used in applications such as intra-ocular delivery (drug delivery device 20a), intra-oral delivery ( drug delivery device 20b), intra-nasal (drug delivery device 20b), intra-aural (delivery device 20b) e drug 20b), and, more broadly, intra-mucosal delivery in general (drug delivery device 20, 20a and 20b). It should also be noted that the "transdermal" supply is intended to cover all forms of supply such as: intradermal, subcutaneous and intramuscular. In another embodiment in accordance with the present invention, the drug delivery device 20a (Figures 5, 6, 7A and 7B) is particularly well suited for ocular use and can deliver any drug 40 necessary for intra-ocular microinjection (especially intra-ocular injections). -scleral or intra-vitreai). Such known drugs for these particular applications include VEGF antagonists, corticosteroids and anti-angiogenic drugs in general. Indications treated by the drug delivery device 20a (Figures 5, 6, 7A and 7B) in accordance with the present invention include, for example, diabetic retinopathy, macular degeneration and other diseases involving neovascularization in the eyes. In this embodiment, the contoured distal end or cup 31 is placed above or on the surface of the eyes 100 with the central open portion of the cup 31 overlapping the cornea. The micro nozzles or injection nozzles 34 are spaced apart and configured around the concentric ring of the contoured distal end 31 such that they are in contact with the sclera. In an embodiment according to the present invention, the injection nozzles 31 are configured in a circular or elliptical pattern. However, the present invention contemplates that the injection nozzles 34 are arranged or configured in any desired configuration or pattern. By depressing the activation button 74, the drug injection stream 40, as shown in Figure 5, penetrates deeply into the eye 100 through the sclera, and into the aqueous humor or vitreous humor or any other layer of desired tissue of the eye portion 100. Preferably, the drug 40 injected under microjet propulsion is directed toward the back of the eye 100 as illustrated herein. As mentioned before, currently, many of the drugs of interest are administered by injecting directly into the eye with a conventional needle and syringe. As can be seen to a large extent, this is a somewhat risky procedure and requires that the injection be administered by a trained ophthalmologist. There are significant risks to the patient associated with these conventional techniques and include retinal detachment, scarring after repeated injections, and even blindness. In addition, the injection itself discourages the patient and requires that the patient be very still during the seconds that the injection itself lasts. In the present invention, injection of the drug 40 into the eye 100 is extremely rapid. For example, given a current velocity of the drug 40 injected under microjet propulsion of 100 m / sec for a drug reservoir 38 having a volume of 20 microliters, the complete injection only requires approximately 10 milliseconds using the drug delivery device. 20a in accordance with the present invention. Assuming that the patient would intentionally move the eye 100 from one side to the other during the injection, and assuming that eye movement occurred at a rate of approximately 1 cm / sec, the eye could only move to approximately 1 / 10th of an eye. millimeter in this period, a distance without consequence when the drug delivery device 20a is used in accordance with the present invention. Consequently, this invention also represents a safer and more convenient means of administering drugs to the eyes 100 for both the physician and the patient. As contemplated by the present invention, the drug delivery device 20a (Figures 5, 6, 7 A and 7B) in accordance with the present invention offers a number of advantages over conventional technology and techniques. For example, injection nozzles 34 can be designed to "direct" the injection stream in specific areas in the eye 100 (e.g., the back of the eye 100). In addition, the penetration depth of the drug 40 can be controlled without relying on the skill of the health care provider. Moreover, the risk of damage to the eyes 100 is minimized with the drug delivery device 20a (Figures 5, 6, 7 A and 7B) in accordance with the present invention by minimizing energy and tearing (trauma). to which the eye 100 is subjected due to the extremely rapid nature of the microjet propellant of the drug in eye tissue 100 (estimated to be as fast as approximately 10 milliseconds for the injection of small doses of drug 40). Even more, the drug delivery device 20a has the ability to modulate the jet injection energy and the geometry of the injection stream as a means to control the delivery depth of the drug in the eye. Also, the design of the geometry of the microboquilla allows the control of the diameter, trajectory, cohesion and focus of the current. In addition, the flexibility in the design of the micro-nozzle arrangement allows the optimization of the drug delivery profile for any given drug, disease or disease site within the eye. In addition, the drug delivery device 20a provides an extremely rapid means of administering drug 40 to the eyes 100 in such a way that the movement of the eyes does not present an element of risk. In addition, many drugs currently under clinical and / or clinical investigation are potent drugs and only require the periodic administration of small doses to the eye 100. The drug delivery device 20a (Figures 5, 6, 7A and 7B) in accordance with the present invention offers a more controlled, repeatable, safe and convenient means of delivering these drugs to the eye 100 on any known devices and techniques available to date.

Another embodiment in accordance with the present invention is an intranasal application depicted in Figure 10. Accordingly, the drug delivery device 20b (Figures 8-10) has particularly useful application in the administration of drugs for the CNS (system central nervous) 40 by injection of microjet to the olfactory bulb of the nose 110 of patient 90. In this embodiment, the drug delivery device 20b (FIGS. 8-10) is used to provide direct injection of drug 40 under microjet propulsion in the submucous space of the nose 110 to the CSF of the olfactory lobe. For this purpose, drug doses 40 of 20 mg or more can be injected extremely rapidly (< 50 milliseconds) into the submucosa space and the injection depth can be precisely controlled such that drug 40 is delivered accurately to this area without any penetration damage to an unwanted place. In another embodiment according to the present invention, the drug delivery device 20b is also used for the intra-oral delivery of drug 40 wherein the drug can be micro-injected into any desired area in the mouth such as intra-mucosa for applications such as tumor treatment, ie, targeted delivery of drug under microjet propulsion intended, for example, to treat a tumor. In yet another embodiment in accordance with the present invention, the drug delivery device 20b is used for the intra-aural delivery of drug 40 such that the drug 40 can be microinjected into any desired portion of the ear or ear canal to treat various diseases and conditions of the ears or those conditions that affect, for example, the ear. In addition, in other embodiments according to the present invention, the drug delivery device 20b is also useful for areas of the body that are difficult to access such as various channels, passages, cavities or hard-to-reach surfaces. The extended supply tube 25 facilitates access to these injection sites for injection of drug 40 under microjet propulsion to these difficult areas. Therefore, as described above, the drug delivery device 20, 20a and 20b according to the present invention has many novel features and advantages. Some of these features and novel advantages are summarized here for convenience such as extremely small injection nozzles (0.05 mm or smaller); multiple injection tanks and injection nozzles that reduce to the minimum each injection volume and injection time which results in customizable, variable pressure injections with less pain; which include high pressure injection to reach deep tissues and lower pressure to target shallower tissues; ability to concentrate the dose of drug to a confined area or expand it over a large surface area; high-volume injections divided into a small volume, discrete injectors (can achieve injection volumes equivalent to or greater than conventional jet injectors in faster delivery times; multiple medical applications (ie, transdermal, intra-ocular, intranasal, intra-oral , etc.), efficient operation to include total energy requirements equivalent to those total energy requirements available with the prior art devices, but with the present invention being much quicker to administer the drug and a much less painful injection for the patient, ability to deliver multiple drugs (ie, different drugs can be housed in different drug reservoirs that is not possible with currently known drug delivery devices), and ability to separate excipients during storage up to the time of delivery. the injection which improves the long-term stability of the drug 40. There is no known or existing technology that provides the advantages given by the present invention, including safety, ease of use, accuracy in both dose and depth of penetration, patient comfort and acceptance thereof. Other advantages associated with the present invention is that it can provide the targeted, targeted delivery of small molecules and similar large molecules to include macromolecules such as large proteins, cells or other biological molecules and drugs. In addition, another advantage is that the drug delivery device per microjet according to the present invention is extremely fast in its drug delivery, ie, delivery of approximately <; 10 msec that results in an almost pain-free injection. The present invention contemplates that a significant reduction in the size of the nozzle orifice will result in reduced pain to the patient. In addition, the present invention allows practical new uses of jet injection technology such as transmucosal delivery. An advantage of the present invention is that a plurality of nozzles can be used, arranged in an arrangement and having space between each adjacent nozzle, which defines a flat two-dimensional structure that can be laid flat on the skin and, therefore, ensures perpendicularity. Moreover, the present invention provides true delivery of needleless drugs irrespective of the size of the drug molecules involved and provides true needleless drug delivery with minimal tissue trauma and which are suitable for delivering drugs to sensitive body areas such as eyes, nasal passages, mouth, etc. In addition, the drug delivery device 20, 20a and 20b are simple and efficient in design and construction, low cost and easy to manufacture. Accordingly, the drug delivery device per microjet according to the present invention has an appropriate design that is extremely suitable for a disposable disposable device by the patient, if desired. While the above specification comprises preferred embodiments of the invention, it is understood that variations and modifications can be made here, in accordance with the principles of the invention described, without departing from the scope of the invention. Although preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will occur to one skilled in the art without departing from the invention. Accordingly, it is intended that the invention be limited only by the spirit and scope of the appended claims.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A method for making a drug delivery device by jet injection, wherein the drug delivery device has at least one drug reservoir and at least one injection nozzle, the method comprising the steps of: identifying a drug to be delivered; identify a volume of the drug to be delivered; establishing a reservoir diameter for at least one drug reservoir; establishing a nozzle diameter for at least one injection nozzle; identify a tissue model to deliver the drug; identify a penetration depth in the tissue model for drug delivery; and injecting the drug into the tissue model under variable pressure until the desired depth of penetration is achieved.

2. The method according to claim 1, further characterized in that it comprises identifying an optimal pressure range for the drug delivery device that achieves the desired depth of penetration.

3. The method according to claim 2, further characterized in that it comprises identifying an optimum pressure range of about 56.24 to about 140.6 kg / cm2.

4. - The method according to claim 2;. further characterized in that it comprises identifying an optimum pressure range of about 281.2 to about 1757.5 kg / cm2 at a tip of at least one injection nozzle.

5. The method according to claim 2, further characterized by comprising using one or more materials for components of the drug delivery device selected from the group comprising: ceramics, metals, metal alloys and thermoplastics.

6. The method according to claim 5, further characterized in that it comprises making a hole in at least one injection nozzle by drilling.

7. The method according to claim 6, further characterized in that it comprises making a hole in at least one injection nozzle by laser drilling.

8. The method according to claim 6, further characterized in that it comprises making a hole in at least one injection nozzle by ultrasonic drilling.

9. The method according to claim 6, further characterized in that it comprises making a hole in at least one injection nozzle by wire machining.

10. The method according to claim 6, further characterized in that it comprises making a hole in at least one injection nozzle by molding or forming.

11. The method according to claim 2, further characterized in that it comprises predicting the optimum pressure range required in determining the required injection force (F) in accordance with the formula: F = 8QμL (R2 / r4); wherein Q = drug flow rate; μ = drug viscosity; L = length of the injection nozzle; R = radius of the drug reservoir; and r = radius of the injection nozzle.

12. The method according to claim 2, further characterized in that it comprises the use of a tissue model that is in vitro.

13. The method according to claim 2, further characterized in that it comprises the use of a tissue model that is in vivo.

14. The method according to claim 4, further characterized in that it comprises driving the drug through a tip of at least one nozzle at a pressure ranging from about 562.4 kg / cm2 to about 843.6 kg / cm2.

15. The method according to claim 13, further characterized in that it comprises driving the drug through a tip of at least one nozzle at a pressure that varies to about 703 kg / cm2.

16. The method according to claim 1, further characterized in that it comprises driving the drug through at least one nozzle within a time ranging from about 10 msec to about 200 msec when activating the power source.