MXPA06009040A - Drug delivery device for buccal and aural applications and other areas of the body difficult to access - Google Patents
Drug delivery device for buccal and aural applications and other areas of the body difficult to accessInfo
- Publication number
- MXPA06009040A MXPA06009040A MXPA/A/2006/009040A MXPA06009040A MXPA06009040A MX PA06009040 A MXPA06009040 A MX PA06009040A MX PA06009040 A MXPA06009040 A MX PA06009040A MX PA06009040 A MXPA06009040 A MX PA06009040A
- Authority
- MX
- Mexico
- Prior art keywords
- drug
- further characterized
- nozzle
- injection
- delivery device
- Prior art date
Links
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Abstract
A device for delivering a drug includes a delivery tube wherein the delivery tube has a pressure chamber therein and at least one nozzle at a distal end of the delivery tube and in fluid communication with the pressure chamber. A source of drug is adjacent the at least one nozzle and a handle is located at a proximal end of the delivery tube. An energy source is located in the handle for providing a driving pressure of up to about 2,000 psi within the delivery tube for driving the drug through the at least one nozzle and out o f the delivery tube. The delivery device is particularly useful for delivering drug under microje t propulsion to the mouth, ear and other areas of the body that are difficult to access.
Description
DEVICE FOR THE SUPPLY OF DRUG FOR BUCCAL AND AURAL APPLICATIONS AND OTHER AREAS OF THE BODY OF DIFFICULT
ACCESS
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates, in general, to the delivery of drugs, and in particular to a new and useful device and method for the free delivery of needles of drugs with minimal tissue trauma and which are suitable for delivering drugs in the sensitive areas of the body, such as the eye, the nasal passages, the 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 whom 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 the specific therapeutics of cells or site, also known as "local" drug delivery. Unlike the sisthemic administration of therapeutics, typically taken orally or given intravenously, much of the effectiveness of the local delivery of the drug or the specific therapies of the cells or of the site is based on the ability to accurately and accurately deliver therapeutics to the objective site within the body. Needle injection devices are the most commonly used means for local delivery or site-specific administration of the agents or solutions. Although there have been advances in needle-based drug delivery / injection systems, these systems have significant defects and disadvantages. One such disadvantage is that the use of a needle or other means of penetration to inject the selected tissue area is that it inevitably involves making a hole in the target site, causing trauma and injury to the tissue at the local tissue site. Another disadvantage with this penetration and needle injection procedure is that it is very common for a substantial amount of the injected to leak out or exude from the hole created by the needle or penetration member. Frequently, this injected leak is released systemically through the body or is wasted, depriving the patient of prescribed therapy or adulterated amounts of the drug. This also results in increased treatment costs and requires more injections, time and an agent in order to achieve the desired effect.
In addition, it is known that needle injections or tissue penetration can traumatize or destroy tissue cells and, as a result, increase the patient's risk of postoperative trauma, pain and discomfort at the local site and the surrounding area. This is particularly due to the difficulty of precisely controlling the penetration of the needle during injection. The more injections or penetrations, the greater the destruction of the cells and the tissue trauma that is likely to be experienced. Yet another disadvantage of needle-based injections, especially where multiple injections are required, is the inability to carefully track the location of each site of the injection, to avoid accidental delivery of a drug to a tissue that is not diseased or repeat the supply of the drug in the same orifice of the injection. Other known drug delivery devices and methods do not involve delivery of the drug based on a needle. Instead, devices such as interior catheters are used to release the therapeutic agent in a stationary manner, controlled release. These types of devices may present a higher risk of releasing the agent systemically. Furthermore, with these types of devices, it is more difficult to assess the dosage of the target area that takes place. Thus, these types of devices have the disadvantage of being less effective, possibly not as safe, and definitely more expensive than commonly known needle injection techniques and procedures.
Another condition in which the specific site or site supply is commonly employed is in the treatment of peripheral vascular disease (such as thrombosis and deep vein embolisms). One such treatment is lithic venous therapy, the dissolution of blood clots (thrombi) in the peripheral vasculature (for example, femoral and iliac arteries and veins). The lytic therapy involves the systemic infusion of thrombolytics, such as urokinase, streptokinase, reteplase and tPA. Other more recently developed procedures involve directly supplying the thrombolytics at the site of the thrombus through the use of internal infusion catheters. In order to effectively lyse the thrombus, thrombolytics are typically infused over many hours, even as much as a day or more, increasing the necessary length of hospital stay and the total cost of the procedure. A common procedure for removing a needle in a local drug delivery system is the use of conventional, needle-free jet injectors. Needle-free jet 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 the intradermal and transdermal (subcutaneous and intramuscular) delivery of drugs. And while these modern designs offer tremendous improvements in size, cost and convenience over predecessors, the fundamental functionality has remained unchanged. Mainly, compressed gas is used to drive a medication (either liquid or dry powder) through a single orifice at a moderately high speed, allowing the medication to settle on or under the skin, when drilling through it. . An example of a known needle-free jet injector is described in WO 00/35520 and U.S. Pat. 6,406,455 B1 (Willis et al., Assigned to BioValve Technologies, Inc.). In addition, needle-free jet injection has been promoted as a painless procedure, but clinical studies comparing jet injection devices with conventional needle and syringe have shown that pain scores are equivalent to a needle with a caliber of 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 to 0.2 mm (0.006"to 0.008") in diameter. These conventional needle-free jet injectors are known to incorporate only one injection chamber and to inject the entire contents of the drug through a single plastic nozzle having a typical orifice diameter of 0.006"-0.008" or 150-200. microns (0.15 mm - 0.2 mm). These jet injectors typically provide volumes ranging from 0.100 ce (100 microliters) to 0.500 ce (500 microliters), and even as much as 1 ce (1,000 microliters). There are several significant limitations with current jet injection technology. First, the injection times associated with these conventional needle-free jet injectors are typically several seconds long, which puts the patient at risk of cementation if they must be moved (e.g., shuddering) or if the injector should be shaken. of the injection site during an injection. Second, the perceived pain is equivalent to a conventional needle and syringe. Perhaps this is the only big reason why jet injection has not been accepted more widely. Third, jet injectors are prone to supplying so-called "wet injections", where the drug leaks out through the site of injection, a result that has raised concerns regarding 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 (0.006") in the current jet injectors.) This size resulted more from the practical limitations of plastic injection molding for the high volume of commercial manufacturing than of any effort to optimize the size for the comfort of the user and the minimization or elimination of any "leakage" of the injected medicament.This trade of suboptimal performance by manufacturing capacity has resulted in a marginalized product that has not enjoyed market acceptance that it might otherwise have.A particular type of conventional needle free jet is described in 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 an objective site within the body. It illustrates a complex system using a nozzle assembly having an ampule body and channels machined or machined within the distal surface of the body of the ampule. These channels operate as a distributor and are arranged orthogonal to a hole in the tank. The orifice of the reservoir expels or expels the contents within the body of the ampule to the orthogonally arranged channels, which channel the contents to a plurality of scattering orifices arranged orthogonally to the channels. The dispersion holes are orthogonal to the channels and located within the surface facing the generally planar distal objective. This particular arrangement is not only complex, but requires high supply pressures for the content in the ampule in the range of about 126.55 to 351.53 kgf / cm2 (1800 to 5000 psi), with some applications in the range of about 126.55 to 161.70 kgf / cm2 (1800 to 2300 psi). In addition, the dispersion holes have a diameter of about 0.1 mm to about 0.3 mm (100 to 300 microns). Although such a device does not use a needle, the negative result involved with the use of such a device and arrangements is that it probably causes excessive trauma to the tissue at the delivery site, as well as causing unwanted and unnecessary pain and / or discomfort to the user. end or patient due to the high supply pressures required, as well as the relatively large size of the dispersion holes. Accordingly, the device and method of Glines et al., Are not suitable for microjet delivery of drugs, especially in sensitive areas of the body, such as the eye, nasal passages and mouth or other sensitive areas of the body, especially those areas that are easily susceptible to trauma, pain and discomfort. Consequently, there are several sensitive areas in the body and disease states that are extremely difficult to treat using the local drug supply. For example, there is a myriad of ophthalmic diseases that are difficult to treat and the delivery of the drug to the site of the disease, i.e., the eye, 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, the systèmic administration of the drug commonly provides subtherapeutic drug concentrations in the eye, and may have significant adverse effects. Accordingly, a current treatment for eye diseases often involves direct injection of the medicament into the eye via a conventional needle and syringe, a painful and undesirable means to deliver to the patient. In addition, chronic treatment requires repeated injections that can result in plaque and scar formation in the eye, detachment of the retina and endophthalmitis.
As a result of these complications, alternative means of drug to the eye are being developed. Research areas for delivery include iontophoresis, eye implants that elute the drug, photodynamic therapy, "sticky" eye drops and the like. And, it is well established for each of these procedures that have their own limitations. For example, iontophoresis has a practical limit to the size of the molecule being delivered. For example, it can not be expected to deliver molecules with a molecular weight above 20,000 Daltons. Even, many new compounds, especially some promising proteins, are above this size, varying to as large as 150,000 Daltons. In addition, eye implants require a surgical procedure for implantation and explantation, procedures that are costly, painful, and can result in scarring to the eye. The implants have the additional limitation of the physical size and the amount of the drug that can be loaded or put on the implant. It is also known that photodynamic therapy is an unproven technology whose long-term effects have not been understood and can be harmful to the retina. Alternatively, eye drops have long been considered the most convenient (and therefore perceived as most acceptable) means of drug delivery to the eyes. The eye drops, however, are washed very quickly from the eye, and provide only a minimal supply of the contained drug. As a result, "sticky" eye drops have been developed, that is, eye drops that provide adhesion to the mucosa, to avoid the "wash" effect. But it is believed that the rapidity of cell turnover in the surface of the eye, limits the effectiveness of this means of supply. In addition, the delivery mechanism for eye drops is passive diffusion through the sclera. And, passive diffusion can not deliver drugs with a molecular weight greater than about 500 Daltons. Furthermore, the supply is systemic rather than directed to the eye itself. Accordingly, there is currently no truly acceptable means to deliver therapeutic agents active to the eye and other sensitive areas of the body, especially the 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. . To date, there have been no known devices or methods that provide a true needle-free supply of drugs regardless of the size of the drug molecules involved, as well as providing a true needles-free supply of drugs with minimal tissue trauma. , and that are suitable for delivering drugs in sensitive areas of the body such as the eye, nasal passages or mouth.
To date, there have been no known devices that provide a true needle free supply of drugs, wherein the devices are microjet delivery devices that are simple and efficient in design and construction, low cost and easy to manufacture.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to new and useful devices and methods for the free delivery of needles of drugs with minimal trauma to tissue, and which are suitable for delivering drugs in sensitive areas of the body such as the eye, nasal passages, mouth and other areas of the body. Thus, 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 source of the drug in the housing; a power source for providing an operating pressure of about 56.24 (800) to about 140.61 kgf / cm2 (2,000 psi) to drive the drug through at least one nozzle and out of the housing.
In addition, the drug is operated through at least one nozzle within a time ranging from about 10 milliseconds to about 200 milliseconds after activation of the energy source. In addition, the 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 has 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 source of the drug adjacent to the mouthpiece; a handle at a proximal end of the supply tube; and an energy source in the handle to provide an operating pressure of about 56.24 (800) to about 140.61 kgf / cm2 (2,000 psi) to drive the drug through at least one nozzle and out of the supply tube. In addition, the present invention is also directed to 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, wherein the The method comprises the steps of: identifying a desired drug to be delivered;
identify a volume of the desired drug to be delivered; establishing a diameter of the reservoir for at least one drug reservoir; establishing a nozzle diameter for at least one injection nozzle; identify a tissue model for drug delivery; 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 reached. In addition, the method further comprises identifying an optimal pressure range for the drug delivery device, which reaches the desired depth of penetration. An optimum pressure range for the device according to the present invention is from about 56.24 (800) to about 140.61 kgf / cm2 (2,000 psi) and an optimum pressure range at the tip of at least one injection nozzle for the device of the present invention is from about 281.22 (4,000) to about 1757.67 kgf / cm2 (25,000 psi). The present invention is also directed to a method for delivering a drug in the tissue, comprising the steps of: providing a drug delivery device having at least one nozzle and a drug contained in the portion of the device;
identify a site for the delivery of 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 the propulsion of the microjet at an operating pressure of about 56.24 (800) to about 140.61 kgf / cm2 (2,000 psi). 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 281.22 (4,000) to about 1757.67 kgf / cm2 (25,000 psi).
BRIEF DESCRIPTION OF THE DRAWINGS
The novel features of the invention are set forth with particularity in the appended claims. The invention itself, however, both with the organization and with the methods of operation, together with the objects and additional advantages thereof, can be understood with 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 according to 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 predispared configuration according to the present invention; Figure 4 is a cross-sectional view of the device of Figure 1 in a fired configuration according to the present invention; Figure 5 is a perspective, perspective view of another embodiment of a microjet drug delivery device particularly useful for applications such as ocular use according to the present invention; Figure 6 is a distal perspective view of the device of Figure 5, according to the present invention; Figure 7A is a cross-sectional view of the device of Figure 5, according to the present invention; Figure 7B is a cross-sectional view of an alternate embodiment of the device of Figure 7A, having an LED focusing light according to the present invention; Figure 8 is a partial cross-sectional side view of another embodiment of a microjet drug delivery device particularly useful for applications such as nasal use according to the present invention;
Figure 9 is an enlarged partial side view of the distal end of the device of Figure 8, in accordance with the present invention; Figure 10 is an illustration of the device in Figure 8, in use for a nasal application in accordance with the present invention; and Figure 11 is a graph describing a study of penetration depth versus pressure for the microjet drug delivery device, which has a nozzle diameter of 50 μm and a volume of drug delivered of 100 μl, according to the present invention.
DESCRIPTION OF THE PREFERRED MODALITIES
The present invention is directed to novel drug delivery devices, their methods of manufacture and their methods of use. As best shown in Figures 1-10, the present invention is a needle-free micro needle device delivery device (without needles) 20, 20a and 20b, its manufacturing methods and its methods of use which are all elaborated with great detail below. The drug delivery device 20, 20a and 20b, according to the present invention, is a needle-free jet injection device that delivers drugs, such as liquid drug formulations, to a patient and injecting very fine streams of formulations of the drug at high speed. The drug delivery device 20, 20a and 20b provides a less painful means of drug delivery than conventional needle and syringe devices, as well as injection devices without known needles. The drug delivery device 20, 20a and 20b, according to the present invention, can be used in a variety of medical applications, including the delivery of the transdermal, dermal, intraocular, intranasal, oral and generally transmucosal drug. The terms "drug delivery device", "delivery device", "needle-free drug delivery device", "needle-free microjet drug delivery device", "microjet drug delivery device", "Needle-free drug delivery device", "Needle-free microjet drug delivery device", "Needle-free jet injection device", "Needle-free jet injection device", "Jet injection device" , "microjet device" and "microjet", including various combinations of any part of these terms, are intended to have all the same meaning and are used interchangeably herein. The terms "active agent formulation" and "drug formulation", and "formulation", are intended to be the drug or the active agent optionally in combination with pharmaceutically acceptable carriers and additional inert ingredients. The formulation can be solid, liquid 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, composition of interest or mixture thereof, including its formulation, which provides some therapeutic effect, often beneficial. This includes plagiarides, heroics, germicides, biocides, algicides, rodenticides, fungicides, insecticides, antioxidants,. plant growth promoters, plant growth inhibitors, preservatives, anti-preservatives, disinfectants, sterilizing agents, catalysts, chemical reagents, fermentation agents, foods, food supplements, nutrients, cosmetics, drugs, vitamins, sexual sterilants, inhibitors of fertility, promoters of fertility, attenuators of microorganisms and other agents that benefit the environment of use. As used herein, the terms further include any psychologically and pharmacologically active substance that produces a localized or systemic effect or effects in animals, including warm-blooded mammals, humans and primates.; birds; domestic animals 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 the similar. The active drug that can be supplied includes inorganic and organic compounds including, but not limited to, drugs that act in peripheral media, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, blood circulatory system, sites synoptics, sites of the neuroeffector junction, endocrine and hormonal systems, the immune system, the reproductive system, the skeletal system, the autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents can be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, spheroids, hypnotics and sedatives, psychotic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, analgesics, anti-inflammatories , local anesthetics, muscle contractants, antimicrobials, antipaludism, hormonal agents including contraceptives, sympathomimetics, polypeptides and proteins capable of causing physiological effects, diuretics, agents that regulate lipids, antiandrogenic, antiparasitic, neoplastic, antineoplastic, hypoglycemic agents, 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 edsylate, ferrous sulfate, aminocaproic acid, mechaxylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride, benzfetamine hydrochloride, isoproteronol sulfate, phenmetrazine hydrochloride, chloride of betanecol, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridhexetyl chloride, fenfounin hydrochloride, methylphenidate hydrochloride, theophylline kohlrabi, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, maleate of prochlorperazine, phenoxybenzamine, maleate of tietilperazine, anisindione, diphenadione, tetranitrate of erythritil, digoxin, isoflurofato, acetazolamide, methazolamide, bendroflumetiazide, chlorpropamida, tolazamide, cloiniadinone acetate, fenaglycodol, allopurinol, aspirin with aluminum, methotrexate, acetyl sulfisoxazole, hydroco rtisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone and its derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-beta-estradiol, ethinyl estradiol, 3-methyl ether of ethinyl estradiol, prednisolone, 17-beta-hydroxyprogesterone acetate, 19 -nor- progesterone, norgestrel, norethindrone, norethisterone, noretiederona, progesterone, norgesterone, norethynodrel, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate of sosorbida, 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, meinhrone, captropril, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen , fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuninal, nimodipine, nitrendi pineapple, nisoldipine, nicardipine, felodipine, lidoflacin, tiapamil, gallopamil, amlodipine, myoflacine, lisinopril, enalapril, captopril, ramipril, enalaprilat, famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, amitriptyline and imipramine. Additional examples are proteins and peptides that include, non-exclusively, insulin, colchicine, glucagon, hormone that stimulates the thyroid, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone, follicle-stimulating hormone, chorionic gonadotropin, gonadotropin-releasing hormone , bovine somatotropin, porcine somatropin, oxytocin, vasopressin, prolactin, somatostatin, lyserin, pancreozimine, luteinizing hormone, LHRH, interferons, interleukin, growth hormones such as human growth hormone, bovine growth hormone and porcine growth hormone, inhibitors of fertility such as prostaglandins, fertility promoters, growth factors, human pancreatic hormone releasing factor, antiproliferative / antifungal agents that include natural products such as vinca alkaloids (ie vinblastine, vinocrine and vinorelbine), paclitaxel, epidipodophyllotoxins (ie, etoposide, t eniphoside), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin) and mitomycin, enzymes (L-asparaginase that metabolizes L-asparagine systemically and derives cells that do not have the ability to synthesize their own asparagine); antiplatelet agents, such as G (GP) llbllla inhibitors and vitronectin receptor antagonists; antiproliferative / antifungal alkylating agents such as nitrogenous mustards (mechlorethamine, cyclophosphamide and analogues, melphalan, chlorambucil), ethylene imines and methylmelamines (hexamethylmelamine and totepa), alkyl sulfonates-busulfane, nitrosoureas (carmustine (BCNU) and the like, streptozocin), trazenos-dacarbazinine (DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogues (fluorouracil, floxuridine and cytarabine), purine analogs 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; antisecretory (breveldine); anti-inflammatories: such as adrenocortical exteriors (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, triamcinolone, betamethasone and dexamethasone), non-spheroidal agents (salicylic acid derivatives, ie, aspirin; para-aminophenol derivatives, ie , acetaminophen, indole and indacetic acids (indomethacin, sulindac and ethodalac), heteroaryl acetic acids (tolmetin, diclofenac and keto-trolac), arylpropionic acids (ibuprofen and derivatives), antacid acids (mefenamic acid and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone and oxifentatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, sodium gold thiomalate), immunosuppressants (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil), angiogenic agents: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), growth factor Platelet Derived (PDGF), Erythropoietin, Angiotensin Receptor Blocker; nitric oxide donors; antisense oligonucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, kinase inhibitors of the translation of the growth factor signal, chemical compounds, biological molecules, nucleic acids such as DNA and RNA, amino acids, peptides, proteins and combinations thereof. It will be understood that more than one drug or agent can be combined or mixed together or incorporated into or utilized by the present invention, and that the use of the term "drug", "agent", "drug" or
"Pharmaceutical composition", in no way excludes the use of two or more such drugs, agents, active agents and / or pharmaceutical compositions. One embodiment of the drug delivery device 20 according to the present invention is illustrated in Figures 1-4. The drug delivery device 20 is a needle-free jet injection device, especially useful for injecting a drug delivered under the propulsion of the microjet in very fine streams at high speed in various types of body tissue, to include the organs. By way of example, the drug delivery device 20 according to 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 into the bloodstream of the patient and the circulatory system. Although the drug delivery device 20 according to the present invention is not limited to dermal and transdermal applications, but instead intended to be used for other types of tissues 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 they are jet injection nozzles (also referred to as "micro nozzles"), they are arranged in the nozzle plate 30. As shown in Figures 1-4, the injection nozzles 34 end up as small protuberances outward from the outer surface of the nozzle plate 30, thereby providing the user with a tactile feedback of the proper positioning and alignment of the injection nozzles 34 on the tissue surface of the wearer's body. As best illustrated in Figures 2, 3 and 4, the housing 24 further includes one or more reservoirs 38 aligned with, and in fluid communication with, one or more nozzles 34. Each reservoir 38 is longitudinally arranged in the housing 24 and serves as a reservoir of the drug or a storage space for the drug 40. Each reservoir is formed to receive a push rod 48 and a reservoir seal 54 attached or fixed to the distal end of each push rod 48. The push rod 48 and the reservoir seal 54 are in direct longitudinal alignment with each reservoir 38 and push rod 48 and the reservoir seal is movably located (longitudinally movable) within each drug reservoir 38. Each reservoir seal 54 is designed to prevent the drug 40 from being filtered or leaking from the drug reservoir 38. Thus, the reservoir seal 54 is in a mobile sealable contact with the inner wall of the drug reservoir. or 38. The push rod 48 and the reservoir seal 54 move longitudinally slidable in each reservoir 38. The piston 44 is integral to or fixed to the proximal end of each push rod 48 and serves as a drive platform for accumulating and exerting a driving force on the push rods 48. The piston 44 can be fixed as a single unit to the proximal end of all the push rods 48, in order to operate and move each push rod 48 simultaneously with each reservoir 38 or piston 44 to be fixed to the proximal end of each push rod 48 individually, in order to operate and move selectively and individually each push rod 48 within reservoir 38. In this example, the piston 44 has a cylindrical shape for securely fitting within and in movable engagement with the inner wall of the housing 24, which is also of a cylindrical shape. The piston 44 has a circumferential space formed to receive an O-ring seal 52 which is also formed to fit securely in 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, the contents of the discharge or other matter leaks beyond the piston 44. As best seen in Figure 3 (the drug delivery device 20 loaded with the drug 40 and in its predispair configuration), a power source for unloading a driving force to the piston 44, is located proximal or superior to the piston 44 within the housing 24, for example, in an embodiment according to the present invention, a load housing 60 located in the proximal or upper portion of the housing 24 The pyrotechnic charge 64 is contained within the housing of the charge 60. A bait 68 is located adjacent the pyrotechnic charge 64 to hold a small explosive charge that supplies the pyrotechnic energy or the ignition energy to the pyrotechnic charge 64 to ignite the pyrotechnic charge 64 after the activation of the bait 68. A hammer needle 70 is located in the lid 28 and movably engages or comes in contact with with the bait 68 to activate the bait 68 and initiate the explosive charge contained in the bait 68. The hammer needle 70 is movably connected to an activation element, such as an activation button 74 that deviates in a manner moved by the spring 72. Thus, the activation button is deflected movably towards the firing pin needle 70 inside the cover 28 to drive the firing pin 70 in the bait 70 after a sufficient downward force pressed on the firing button 70. activation 74, for example, by the user's or patient's thumb.
As best seen in Figure 4 (drug delivery device 20 in its fired configuration after the drug 40 has been injected under the propulsion of the microjet), after pressing the activation button 74, the hammer needle 70 hits the bait 68 , thereby activating the bait 68, which, in turn, causes the extremely rapid combustion of a pyrotechnic charge 64. This controlled explosion causes the driving force necessary to slidably advance the piston 44 and the push rods. fixed 48 through the reservoirs 48, causing the push rods 48 to eject the drug 40 through the injection nozzles by means of microjet jet propulsion 34. The power source, such as the pyrotechnic charge 64 or compressed gas 36 (FIGS. 8 and 10), provides sufficient power and driving pressure to drive mainly the piston 44 and the associated push rods 48, which varies in approximate a. 56.24 (800) to approximately 140.61 kgf / cm2 (2,000 psi). In turn, the pressure energy at the tips of the micro nozzles 34, varies from about 281.22 (4,000) to about 1757.67 kgf / cm2 (25,000 psi) at each tip of the microtitre, and preferably at a range of about 562.45 (8,000) to about 843.68 kgf / cm2 (12,000 psi) in each pint of the microtip, and more preferably to about 703.07 kgf / cm2 (10,000 psi) at each tip of the microtip. For all embodiments of the present invention, the same reference numbers 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, which is particularly useful for ophthalmic and ocular applications such as delivering the drug 40 to the eye of a patient 100. Thus, the plaque of the nozzle 30a at a 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 arranged circumferentially within the contour (concave region) defined by the contoured distal end 31, and spaced proximally a distance away from the edge of the outer surface of the outer circumference (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 formed to receive the eye of a patient 100, wherein the pupil of the eye 100 may be located within the central portion (open space) of the circumferential ring of the contoured distal end 31. Thus, if desired, the drug 40 may be delivered using microjet propulsion to the areas of the eye 100 outside the pupil, such as the vitreous or sclera, as best shown in Figure 5. Figure 7B describes an alternate modality of the 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 placed in the cavity of the LED 76 to disperse a focusing light (focus LED light) 88 under the operational control of the switch 86 movably placed in an outer portion of the housing 24 (in this example, near the end). proximal of accommodation 24). The switch 86 serves as a power switch to activate the LED 80 to project a focus light 88, i.e. the switch 86 serves as an "On", "Off" switch for the LED 80 and the light 88. Briefly, the contacts, conductors and wires that operatively connect the LED 80 to the switch 86 are not shown, but are well understood and can be well appreciated by someone having a level of ordinary experience in this field. The focus light 88 is used to attract the patient's direct attention, aligning and focusing the pupil of the eye 100 and serving as a focal point of patient care in order to make the patient mentally relax (basically distract the patient), while the drug 40 is supplied to the eye 100 under the propulsion of the microjet. Thus, the LED 80 and the focus light 88 serve as a means to decrease the patient's stress levels and the anxiety normally associated with receiving a drug injection, particularly, in a sensitive area such as the eye 100. Alternately, instead of an LED 80, an element or feature that is luminescent (including autoluminescent) or a characteristic element having a luminescent element, such as a point having a self-luminescent coating that is used as a focal point and can be used to attract the Direct patient care and focusing the pupil of the eye 100 to serve as a focal point of patient care, in order to make the patient mentally relax in advance of, and while receiving the injected drug 40 under the propulsion of the microjet. 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 utilizes 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 the pressure chamber 27 and a source of compressed gas 36, such as gas Compressed CO2, contained within a cartridge 36 and connected at another end of the valve 33 and contained within the handle 23. The cartridge 36 is a compressed miniature gas cylinder containing a compressed gas such as C02 with the capacity of achieve and deliver pressures as high as 140.61 kgf / cm2 (2,000 psi). The valve 33 regulates the release of compressed gas from the cartridge 23 in the pressure chamber 27 of the delivery tube 25 by the activation button 74a located at a convenient location on the handle 23, for example, easily accessible with the pad of the index finger of the patient or the user's hand. If desired, a cover releasably connected (not shown), can be used with the handle 23 in order to provide direct access to the gas cartridge 36 to exchange the cartridge 36 after the issuance of its contents (when empty) with a freshly loaded gas cartridge 36 (full), thereby making the drug delivery device 20b a multipurpose device or a 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 the pressure chamber 27, and are arranged as protuberances extending outward from the outer surface of the nozzle plate 30 to provide the user 90 with a tactile feedback of the proper positioning and alignment of the injection nozzles 34 on the tissue surface of the user's body, for example, in the tissue located within a nose of the nose 110 (as shown in Figure 10) or tissue located within the patient's mouth (mouth application), such as the gums or palate of the mouth, or a location within the patient's ear, etc. Thus, the drug delivery device 20b is suitable for delivering the drug 40 to areas difficult to access from the body of a patient, due to an elongated and low profile design. The reservoirs of the drug 38, the drug 40, the reservoir seals 54, the push rods 48, the piston 44 and the O-ring 52 are placed and operate in the same manner or in a manner similar to that described for the embodiments of Figures 1-7B, except that these features are located within the supply tube 25 and the pressure chamber 27 at the distal end of the supply tube 25 and the pressure chamber 27. The pressure chamber 27 allows the compressed gas to be released from the cartridge 36. and channels the gas from the handle 23 to the piston 44 along the entire supply tube 25, which provides the driving force necessary to slidably advance the piston 44 and the fixed push rods 48 through the reservoirs. 48, causing the push rods 48 to eject the drug 40 via injection nozzles by propellant from the microchip 34. The drug delivery device 20 (Figures 1-4), 20a
(Figures 5, 6, 7A and 7B) and 20b (Figures 8-10), intended to be compact in design, for example, having exterior surface dimensions that measure approximately 5.08 centimeters (2.00") long and 1.524 centimeters ( 0.600") in diameter (for the embodiments of Figures 1-4 and Figures 5, 6, 7A and 7B, respectively), and very light in weight, for example, weighing only several grams (ounces). Ergonomically, it may be desirable to increase the size or significantly change the geometry, but the underlying functionality remains exactly the same as that presented in these figures. Alternatively, the power source for discharging a driving force to the piston 44 is compressed gas, such as CO2 as an example, releasably housed in a cartridge gas 36 (Figure 8). In addition, the energy source for discharging a driving force to the piston 44 can be any type of energy force, as long as it is capable of delivering the drug under propulsion of the microjet according to the requirements set out below and subsequently in this description. For example, the power source must discharge ample sufficient energy in order to drive mainly the piston 44 and the push rods 48 associated with an actuating pressure ranging from about 56.24 (800) to about 140.61 kgf / cm2 (2,000 psi). In turn, the energy and force at the tips of the microscrews 34, varies from about 281.22 (4,000) to about 1757.67 kgf / cm2 (25,000 psi) at each tip of the microtip, and preferably at a range of about 562.45 (8,000) to about 843.68 kgf / cm2 (12,000 psi) at each tip of the microtip, and more preferably at about 703.07 kgf / cm2 (10,000 psi) at each tip of the microtip. The volume of the drug 40 delivered under the propulsion of the microjet 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, is adjustable to the extent, 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 total volumes of the drug delivered can be adjusted according to a volume range that is from about 10 microliters (μl) or less to about 1 milliliter (ml) or greater, depending on the configuration or design of the drug delivery device 20, 20a and 20b. In addition, the diameter of the injection nozzle 34 is variable and varies from about 10 (μm) to about 50 (μm) or greater, providing exceptionally fine injection currents of drug 40, reducing the number of nerve receptors impacted by an injection, thus reducing 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) according to the present invention, is its use of one or more discrete drug reservoirs 38 that serve as injection chambers, wherein each reservoir contains the drug 40 as a portion of the total injection volume of the total dosage for the drug 40 as best shown in Figure 3 ( drug delivery device 20 shown in its predisposed configuration prior to delivering the drug 40). And 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 μm or from about 0.0004"to about 0.002". Thus, the drug delivery device 20 (Figures 1-4), 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10) according to the present invention, divide the total supply volume for the drug 40 in and multiple deposits 38 discrete, transverse (for those embodiments according to the present invention having more than one injection reservoir 38), and supplies each volume of the drug contained therein in the patient's tissue at higher speeds, as best shown in the Figure 4 (drug delivery device 20 shown in the fired configuration after the drug 40 is delivered under microjet propulsion) than those injection speeds achieved by conventional jet injectors such as those previously disclosed jet injectors. Accordingly, an advantage associated with the drug delivery device 20 (Figures 1-4), 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10) according to the present invention, is a decrease dramatic in the time required to inject the drug 40, where this time can be as short as 40 milliseconds (msec.). even for in requirement for the supply of an injection of 0.5 cc (or 0.5 ml) of the drug 40, the injection time reached 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 milliseconds to about 200 milliseconds (and, in one example, ranges from about 40 milliseconds to about 100 milliseconds, to about 0.5 milliliters of certain types of drugs). A further aspect of the present invention is that since the area of the jet stream decreases with the square of the diameter, there is approximately a 100-fold reduction in the area of the skin or tissue affected by the injection with the delivery device of drug 20 (Figures 1-4), 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10) compared to the known thinner conventional hypodermic needle (ultrafine insulin needle having a 31-gauge cannula) , with a diameter of 0.254 millimeters (0.010").) In an embodiment according to the present invention, the drug delivery device 20 (Figures 1-4), 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10) is a single-use pre-filled drug delivery device (designed for one-time use as a disposable unit, that is, once, a single patient uses it once), which does not require any Preparation in advance or adjustment by the care provider of health or the patient. Thus, 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 provided. Alternatively, the drug delivery device 20 (Figures 1-4), 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10), is also intended to be a reusable unit (eg, the housing main 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, a disposable internal assembly that is pre-loaded or recharged by the patient or the health care provider prior to administration, inserted into the housing 24 or the handle 23 and the delivery tube 25 (for the drug delivery device 20b), and then removed and discarded after use . In this case, the disposable internal assembly comprises the bait 68, the pyrotechnic charge 64 (or the compressed gas cylinder 36), the push rods of the drug reservoir 48, the drug reservoirs 38, the injection nozzles 34. The reusable housing 24 and supply tube 25 and handle 23 and other components such as cover 28 and activation buttons 74 and 74a are made of an appropriate material such as metal or a metal alloy capable of withstanding reuse and reuse. resterilization if needed. Further, in all embodiments of the present invention, the injection nozzles 34 may be in the form of an array of injection nozzles 34 (in any desired pattern on the nozzle plate 30 and 30a) that is configured out of plane or at different trajectory angles, for example, in order to provide the selected convergence of the drug 40 to a particular target point in the tissue, i.e., a single target point in the tissue to receive all of the injected volume of the drug 40 or a plurality of desired target points. in the tissue.
Optimization of Microjet Propulsion Drug Delivery 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) according to the present invention. The first mechanism is a predictive model based on the equation called Hagen-Pouiselle. This equation was used to estimate the events of different designs in the elements and main 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 resultant driving forces that are required to operate the drug delivery device in accordance with the performance criteria of the present invention. In addition, the actual forces required to deliver the required amounts of the drug 40 under the propulsion of the microjet were determined empirically through 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 the depth of penetration versus the pressure for the microjet device delivery device (20, 20a and 20b), which has a nozzle diameter of 50 μm and a volume of drug delivered of 100 μl, according to the present invention. In the development and manufacture of the drug delivery device 20, 20a and 20b according to the present invention, there is a trade-off between force / volume / length, based on the diameter of the individual deposits of the drug 38, as well as the diameters of the injection nozzles 34 and the desired injection velocity or the mass flow rate of the ejected drug 40 or the drug formulation 40. In addition, the design of these components has implications for the duration of the injection, the number of deposits of the drug 38 and the injection nozzles 34 that are used, the size of the main piston 44 and even the physical properties necessary for 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 drug formulation or injected μ = viscosity of the drug formulation or injected L = Length of the injection nozzle R = Radius of the drug reservoir r = radius of the injection nozzle To demonstrate the utility of this equation, suppose that it is desirable to supply 500 microliters (1/2 cc) of a formulation of an aqueous drug 40 (a solution of the drug 40 with a viscosity μ = 1 cps) to the subcutaneous layer of the tissue at a flow rate Q of 5 cc / second. Also, suppose that a diameter of the microjet or injection nozzle of 50 microns (0.002"), or r = 25 microns (0.001") is being used. Although we want to minimize the length of the drug reservoir, we also want to minimize the injection force. Thus, although a shorter length is better, a smaller diameter also means less strength but a longer length. Thus, a convenient size is selected with respect to the length of the reservoir suitable for hand holding the microjet drug delivery device (20, 20a and 20b), while also attempting to minimize the injection force. Consequently, a diameter of 1,828 millimeters (0.072") of the drug deposits was selected, or R = 0.036" (0.914 mm). The length L of the injection nozzle 34 was determined by manufacturing constraints (a very small orifice can only be made in a given material for a limited length). Consequently, it was assumed that an adequate length L is 0.050"(1.27 mm). Thus, the Hagen-Pouiselle equation can estimate the injection force required for any injection nozzle given as follows:
With: Q = 5 cc / second μ = 1 cps L = 0.050"= 0.127 cm R = 0.036" = 0.091 cm r = 25 μm = 0.0025 cm
F = 8QμL (R2 / r4) = 10,218,121 dynes or approximately 23 lbf.
The number of deposits of the drug 38 is determined by the total force that the main actuation piston 44 can exert, divided by the force required to drive each of the push rods 48 of the drug reservoir, which act as individual pistons simultaneously in this example (expressed as a complete integer). The practical pressure achieved by the pyrotechnic charge 64 or a cylinder of compressed gas 36 is limited to approximately 140.61 kgf / cm2 (2,000 psi). Consequently, given a diameter of the main piston 44 of 1.27 millimeters (0.500") and the resulting area of (0.250") 2 times pi = 1.264 square centimeters (0.196 square inches), the maximum available driving force is 140.61 kgf / cm2 (2,000 psi) x 1,264 square centimeters (0.196 square inches) or 177.97 kilograms (392 pounds) of force. With 10.44 kilograms (23 pounds) of force required to drive each push rod 48 of the drug reservoir and 177.97 kilograms (392 pounds) available, the maximum number of drug reservoirs 38 that can be accommodated (as a whole integer) is 392 divided by 23 or a total of seventeen (17) deposits 38. The length of each drug deposit 38 is calculated as a result of the volume requirement for each. For example purposes, assume that five (5) deposits are used. Thus, since it is required that a total of 500 microliters be supplied through five (5) reservoirs 38, each reservoir 38 will supply 100 microliters of the drug 40. Given a reservoir diameter of 0.072"(1.83 mm), each length of the tank will be 100 microliters divided between the tank area (pi x (.914mm) 2) or 38.1 mm long (1.50"). And, the flow velocity of the Q injection has already been defined as 5 cc / second (as discussed above). Accordingly, the total injection time is determined by the time required to inject the volume of the drug contained within each individual reservoir 38, which we have found to be 100 microliters or 1 / 10th of a ce. Thus, the injection time is 0.10 times the reciprocal of the flow velocity Q or 20 milliseconds. As a predictive model, the Hagen-Pouiselle equation is a useful tool for the preliminary analysis and prediction of the design parameters required for the elements of the drug delivery device 20, 20a and 20b, but as would be expected, the findings Empiricals differ from predictive analyzes. Both in vitro tests that included the use of 2 mm thick ballistic gelatin on a saturated Pluronic acid solution (F127) and in vivo tests that included testing the drug delivery device according to the present invention on the guinea pig model without hair, demonstrated that drug formulation 40 is required to pressurize to approximately 562.45 kgf / cm2 (8,000 psi) in order to achieve microjet propulsion, i.e., the speeds needed for 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, ie, in this case, subcutaneous administration. Given, for example, that the drug reservoirs 38 have a diameter of 1.83 millimeters (0.072"), the cross-sectional area of each drug reservoir 38 is (0.036) 2 times pi or 0.0258 square centimeters (0.004 square inches). With the force F equal to the pressure P times the area A, the force necessary to drive the push rods 48 to reach a pressure of 562.45 kgf / cm2 (8,000 psi) in the formulation of the drug 40 is 8,000 times 0.004 or 14.53 kilograms (thirty-two (32) pounds) of strength This was a modest increase over the 10.44 kilograms (23 pounds) of strength predicted by Hagen-Pouiselle, but certainly of the same order of magnitude. Much of the increase is explained by the friction of the seals of the sliding reservoir 54 and the O-ring 52. Continuing with the values used in the examples for the Hagen-Pouiselle equation, assuming that 500 microliters of the drug formulation 40 is required for the total administration and five (5) deposits of the drug 38 are used for the design, each reservoir 38 then contains 500/5 or 100 microliters of drug formulation 40. With 14.53 kilograms (thirty-two (32) pounds) of force required for each drug reservoir 38 and the five total drug reservoirs, it was calculated that 32 x 5 or 72.64 kilograms (160 pounds) of total force is required to drive all push rods 48 of the drug reservoir. Thus, the main drive piston 44 must exert a force of 72.64 kilograms (160 pounds). Given a diameter of 1.27 cm (0.500") for the main drive piston 44 (note that this dimension may be higher or lower depending on the application and practical ergonomic limitations of a physical size), the area of the piston 44 is (0.635 cm) 2 (0.250") 2 times pi or 0.49 cm (0.196") Thus, the energy source must apply a pressure of F / A 72.64 / 0.49 or 148.24 kgf / cm2 ((160 / 0.196) or 816 psi) to the main drive piston 44. This pressure requirement is within the performance specifications of a pyrotechnic charge 64 or a miniature compressed gas source 36. The lengths of the drug reservoirs 38 and the duration of the injection will remain the same as those given in the Hagen-Pouiselle example The assembly of the main drive piston 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 fu compressed gas er 36 as shown in Figures 8 and 10), which distributes the pressure and transfers it as a driving force to the individual push rods 48. The push rods 48 are integral with the main drive piston 44, so that the total load applied to the piston 44 is proportionally transferred to each of the push rods 48. In the event that a larger size of the Main piston diameter, this will translate to a greater exerted force for any given engine pressure. For example, if the diameter of the main piston increases in our previous examples of 1.27 cm to 1.52 cm (0.500"to 0.600"), then the resultant force of a maximum engine pressure of 140.6 kgf / cm2 (2,000 psi) will increase of 140.6 kgf / cm2 x 1.264 square cm = 177.72 kg (2,000 psi x 0.196 square inches = 392 pounds) of force at 140.6 kgf / cm2 x 1825 square cm = 256.59 kg (2,000 psi x 0.283 square inches = 565 pounds) 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 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 building materials, and the practical limitations of manufacturing a very small orifice at an economy of effective scale in costs. Although an objective of achieving a light weight, compact, portable drug delivery device 20, 20a and 20b with respect to the geometry of the nozzle is "the smaller the better", there are practical limits for the construction of such nozzles 34. In conventional and known needle-free drug injectors, these known devices have a relatively large orifice (approximately 0.15 mm - 0.20 mm (0.006"- 0.008")) because these are practical limits of high volume injection molding in the right thermoplastics (ie, core bolts smaller than this diameter are not practical at high pressures and the 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 10 to 50 microns and operating pressures significantly higher than those found with jet needle free injectors. , known, conventional, such as those previously described in the above. Accordingly, the drug delivery device 20, 20a and 20b according to the present invention takes advantage of the materials having properties of high tensile strength and abrupt increases for the components of the drug delivery device 20, 20a and 20b. Such materials include ceramics, various metals and metal alloys, high strength engineering thermoplastics (such as PEEK ™, Torlon ™, Ultem ™, etc.), and others. Thus, the present invention is also directed to use the most cost-effective combination of such 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 562.45 kgf / cm2 (8,000 psi) immediately at the tip of the nozzle, it is desirable to use discrete nozzles 34 made of metal, a metal alloy or ceramic (e.g. , alumina or zirconia) and mount to the housing 24 (Figures 1 - 7B) or the supply tube 25 (Figure 8) by means of ultrasonic welding or welding, for example. 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 currently not thought to be practical, the development in microinjection molding can make injection molding completely finished, integral, completely feasible and more cost effective than current procedures involving secondary finishing operations. However, injection molding in high strength materials together with laser drilling to produce precise, repeatable injection nozzles 34 would meet the engineering and cost requirements associated with the present invention. In another example according to the present invention, Figures 1-4 describe various views of the drug delivery device 20 that can be used to accelerate a multiplicity of small volumes of drug 40 at a delivery rate suitable for delivery in a tissue. , for 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 volume of the drug of 3.31 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 / second for drug delivery 40, the force required for each injection nozzle 34 can be calculated from the Hagen-Poiseuille equation, providing a value of approximately 4.54 kg (10 Ib.) Per injection nozzle 34. Given thirty (30) injection nozzles 34, the total loading force required is 30 x 4.54 = 136.2 kgf (30 x 10 = 300 lbf). Assuming that the surface area of the main piston is of (6.4516 square cm (1 square inch), then the pressure of 136.2 kgf (300 psi) is needed to reach the required performance parameters. 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 distribution cycle, providing several pressures at different times to optimize drug delivery. In addition, as can be readily appreciated, there may be several suitable energy sources that can be used for the purpose of accelerating the drug 40 at the required rates, in order to achieve the microjet propulsion criteria in accordance with the present invention, and Examples provided herein are in no way intended to limit the kind of energy source that may be used in the present invention. As best seen in the graph depicted in Figure 11, an in vitro study was performed for the microjet device delivery device (20, 20a and 20b) according to the present invention, in order to determine an optimal range for the penetration depth (in cm) versus an optimal pressure range (in kgf / cm2 (psi)). The diameter of the nozzle 34 was approximately 50 microns in diameter, where the volume of the drug 40 supplied was approximately 100 μl. As clearly illustrated in Figure 11, the delivery pressures for the microjet drug delivery device (20, 20a and 20b) can be easily adjusted to target any selected tissue. Thus, the microjet drug delivery device (20, 20a and 20b) is tailored in a manner that ensures that any particular drug can be delivered at a particular depth of penetration, in a particular tissue type, based on a Particular supply pressure according to the graph of Figure 11. Accordingly, this tailoring procedure even allows the particular tissue layers to be selected for drug delivery. For example, the submucosal layer of the tissue can be accurately selected according to the algorithm described in Figure 11. In addition, any number of reservoirs of the drug 38 and injection nozzles 38 can be used for the present invention (within practical limits). ). As demonstrated above, this can be anywhere from a single tank 38 and a single nozzle 34 as many as fifty (50) or more tanks 38 and nozzles 34, respectively. Standard semiconductor processes can easily manufacture injection nozzles 34 similar to the manufacture of the nozzles used in inkjet printing. Thus, the injection nozzles 34 may be mass produced silicone devices having an orifice diameter of between 3 and 10 microns, as an example. The injection nozzles 34 can be fabricated in dense arrays on a silicone wafer and subsequently cut to the desired geometry. The patterns of the wafer, and therefore the geometry of the arrangement can be fabricated into any desired design. Accordingly, the microboot arrangement can be manufactured in any desired pattern such as a circular, elliptical or semicircular pattern, for example, and with any practical density of the injection nozzles 34 that is required. Typically, any effort could be made to reduce the size of the injection nozzles 34 and to maximize the number of injection nozzles 34 that such a wafer can provide. The micromolding of thermoplastics is an emerging technology that may also be useful for the manufacture of the drug delivery device 20, 20a and 20b according to the present invention. The advantages would be significant. While silicone wafers are flat structures, injection molded plastics do not. Thus, the arrangement of the injection nozzles 34 can be configured out of the plane, for example, which would provide a tremendous benefit to create an array that pretends to be placed with a selected convergence. An additional significant advantage is the cost. A microbolet arrangement molded into a thermoplastic would cost pennies, compared to a silicone device that could easily be in the range of dollars. Other methods that can be used to construct the micro nozzles 34, includes micromachining the holes in the plate, as part of the nozzle plate 30 or the nozzle plate 30a having a contoured distal end 31 (annular cup), machining or forming the holes in glass, metal, ceramic, plastic, or other suitable material and then mounting it (eg press fit) on the contoured distal end 31 (annular cup), etc. Like the other major components of the drug delivery device 20, 20a and 20b according to the present invention, the manufacturing design of the microtubes 34 is not intended to be limited to a specific embodiment. Thus, in general, the present invention is directed to a method for making or manufacturing a drug delivery device 20, 20a and 20b according to the present invention. Accordingly, this method comprises several key steps such as identifying a desired drug to be delivered (it can be based on any treatment or disease status or condition that is selected for treatment). In addition, a volume of the desired drug to be delivered is also identified. In addition, 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 of the drug reservoirs 38 and a diameter for one or more of the injection nozzles 34, which is established in advance. In addition, a tissue model is identified for the type of tissue or disease to be treated. For example, the tissue model is any suitable in vitro or in vivo model acceptable for this purpose. Thus, the tissue model can be based on the material, for example, the 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 depth of penetration into the tissue model for drug delivery. This includes selecting any desired or particular tissue layer that is considered appropriate for microjet injection of the drug 40. And the drug 40 is tested in the tissue model by injecting the drug 40 into the tissue model, using the delivery device of the tissue. drug 20, 20a and 20b according to the present invention, under varying pressure until the desired depth of penetration or the 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 depth of penetration or the desired tissue layer. As discussed previously, an optimum pressure range has been identified as < 140.61 kgf / cm2 (2,000 psi) in the main piston 44 and an optimum pressure range of < 562.45 kgf / cm2 (8,000 psi) has been identified for the area at the tip of the injection nozzle 34. The method according to the present invention also includes using predictive modeling to predict the optimum pressure range required to determine the force of required injection (F). The determination of the injection force (F) is determined according to the formula: F = 8QμL (R2 / r4); wherein Q = drug flow rate; μ = viscosity of the drug; L = nozzle injection length; R = radius of the drug deposit; and r = injection nozzle radius.
Methods of use For transdermal or dermal delivery, the drug delivery device 20 (Figures 1-4) is in its triggered preconfiguration and is loaded with the total volume of the drug 40 to be delivered, wherein the drug delivery device 20 is placed firmly against and perpendicular to any desired injection site (typically, the back of the arm, stomach or thigh) with the skin punctured in a conventional manner. Since the injection nozzles 34 terminate as small protrusions outwardly from the outer surface of the nozzle plate 30, the user is provided with instantaneous tactile feedback for proper positioning and alignment of the injection nozzles 34 on the tissue surface of the body of the user, at the desired site of the injection. As best shown in Figure 4, after pressing the activation button 74, the hammer needle 70 hits the bait 68, thereby activating the bait 68, which, in turn, causes extremely rapid combustion of the load pyrotechnic 64. This controlled explosion provides the driving force necessary to slidably advance the piston 44 and the fixed push rods 48 through the reservoirs 38, causing the push rods 48 to eject the drug by the microjet drive. 40 through the injection nozzles 34. Although this example described immediately above is directed to a subcutaneous or cutaneous delivery, there are other examples for the drug delivery device 20a and 20b that are used in applications such as intraocular (delivery device of drug 20a), intraoral (drug delivery device 20b), intranasal (drug delivery device 20b), intraaural (d) drug delivery device 20b), and more broadly, intramucosal delivery in general (drug delivery devices 20, 20a and 20b). It should be noted that the "transdermal" delivery is intended to mean all forms of delivery such as intradermal, subcutaneous and intramuscular. In another embodiment according to 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 necessary for intraocular microinjection (especially intrascleral injections). or intravitreal). Such drugs known for these particular applications include VEGF antagonists., corticosteroids, and antiangiogenic drugs in general. The indications treated by the drug delivery device 20a (Figures 5, 6, 7A and 7B) according to the present invention include, for example, diabetic retinopathy, macular degeneration and other diseases involving neovascularization in the eye. In this embodiment, the contoured distal end or cup 31 is placed on or on the surface of the eye 100 with the open center portion of the cup 31 superimposed on the cornea. The micro nozzles or the injection nozzles 34 are separated and configured around the concentric ring of the contoured distal end 31, so 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, it is contemplated by the present invention that the injection nozzles 34 are arranged or configured in any desired configuration or pattern. After depression of the activation button 74, the drug injection stream 40, as shown in Figure 5, penetrates deep into the eye 100 through the sclera, and into the aqueous humor or the vitreous or any layer of tissue of the portion of the eye 100. Preferably, the drug injected under the propulsion of the microjet is directed towards the back of the eye 100, as described herein. As mentioned above, at present, many of the drugs of interest are administered by injecting directly into the eye with a conventional needle and syringe. As is greatly appreciated, this is a somewhat risky procedure and requires that the injection be administered by a trained ophthalmologist. There are significant risks for the patient, associated with these conventional techniques and include retinal detachment, healing after repeated injections and even blindness. In addition, the injection itself is distracting to the patient and requires that the patient be very still during the several seconds of the injection itself. In the present invention, injection of the drug 40 into the eye 100 is extremely rapid. For example, given a current velocity of the injected drug 40 under microjet jet propulsion of 100 m / second for a drug reservoir 38 having a volume of 20 microliters, the entire injection only requires approximately 10 milliseconds using the drug delivery 20a according to the present invention. Assuming that the patient intentionally moves his eyes 100 from one side to another during the injection, and assuming that eye movement occurs at a rate of approximately 1 cm / second, the eye would only move 1/10 of a millimeter in this period of time, a distance without consequence when the drug delivery device 20a is used according to the present invention. Accordingly, this invention also represents a safer, more convenient means of administering drug to the eye 100 for both the physician and the patient. As contemplated by the present invention, the drug delivery device 20a (Figures 5, 6, 7A and 7B) according to the present invention offers several advantages over conventional techniques and technology. 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 physician. In addition, the risk of injury to the eye 100 is minimized with the drug delivery device 20a (Figures 5, 6, 7A 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 propulsion of the microjet of the drug into the tissue of the eye 100 (estimated as fast as approximately 10 milliseconds for the injection of small doses of drug 40). further, the drug delivery device 20a has the ability to modulate the energy of the jet injection and the geometry of the injection stream, as a means to control the depth of delivery of the drug into the eye. Also, the geometry design of the microcephalus allows the control of the diameter of the current, the trajectory, the cohesion and the focus. In addition, the flexibility in the design of the microboot arrangement allows optimization of the drug delivery profile for any given drug, disease, or site of disease within the eye. In addition, the drug delivery device 20a provides an extremely rapid means of administering the drug 40 to the eye 100, so that the movement of the eye does not present an element of risk. In addition, many drugs currently under preclinical 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 with respect to any known devices and techniques available to date. Another embodiment according to the present invention is an intranasal application described in Figure 10. Accordingly, the drug delivery device 20b (Figures 8-10) has a particularly useful application in the administration of drugs for the CNS (system central nervous) 40 via microjet injection into the olfactory bulb of nose 110 of patient 90. In this embodiment, the drug delivery device 20b
(Figures 8-10) is used to provide a direct injection of the drug 40 under the propulsion of the microjet in the submucosal space of the nose 110 to the CSF of the olfactory lobe. For this purpose, doses of drug 40 of 20 mg or more, extremely fast (<50 milliseconds) can be injected into the submucosal space and the depth of the injection can be controlled precisely, so that the drug 40 is delivered in a Accurate to this area without any harm to penetrate to an unwanted location. In another embodiment according to the present invention, the drug delivery device 20b is also used for the intraoral delivery of the drug 40, wherein the drug can be microinjected in any desired area in the mouth, such as intramucosal, for applications such as treatments of tumors, ie, the selected delivery of the drug 40 under the propulsion of the microjet for the purpose of treating a tumor, for example. In yet another embodiment according to the present invention, the drug delivery device 20b is used for the intraaural delivery of the drug 40, so that the drug 40 can be microinjected into any desired portion of the ear or ear canal to treat several diseases and conditions of hearing or those conditions that affect hearing, for example. 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 delivery tube 25 facilitates easy access to these sites from drug injection 40 under the propulsion of the microjet to these difficult areas. Thus, 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 (0.005"(0.002") or smaller), multiple injection reservoirs and injection nozzles that minimize each injection volume and injection time resulting in less pain, adjustable, variable injection pressures to include high pressure injection to reach deep tissue and lower pressure to target shallower tissues, ability to concentrate drug dose in a confined area or disperse it over a larger surface area, high volume injections divided into a smaller volume, discrete injectors (can reach injection volumes equivalent to, or greater than, conventional jet injectors at faster delivery times, multiple medical applications ( that is, transdermal, intraocular, intranasal, intra-oral, etc.) Efficient operation to include the 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 injection much less painful to the patient; ability to deliver multiple drugs (ie, different drugs can be housed in different drug reservoirs, which is not possible with the known drug delivery devices currently available); and ability to separate the excipients during storage until the time of injection, which improves the long-term stability of the drug 40. There is no known or existing technology that provides the advantages provided by the present invention, including safety, ease of use, precision in the dose and depth of penetration, patient comfort and acceptance. Other advantages associated with the present invention is that it can provide the precise, targeted delivery of small molecules and similar large molecules, to include macromolecules such as large proteins, cells or other biological molecules and drugs. And, another advantage is that the microjet drug delivery device according to the present invention is extremely fast in its delivery of the drug, ie, approximately a supply of < 10 msec, which 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 for new practical uses of jet injection technology, such as transmucosal delivery. It is an advantage of the present invention that a plurality of nozzles can be employed, placed in an array and having space between each adjacent nozzle, defining a flat two-dimensional structure that can be placed flat on the skin and thus, ensure perpendicularity. In addition, the present invention provides a true needle-free drug supply, regardless of the size of the molecules of the drug involved, as well as providing true needle-free drug delivery, with minimal trauma to the tissue and that is adequate to deliver drugs in sensitive areas of the body, such as the eye, nasal passages, mouth, etc. And the drug delivery device 20, 20a and 20b is simple and efficient in design and construction, low cost and easy to manufacture. Accordingly, the microjet drug delivery device according to the present invention has an appropriate design that is extremely suitable for a disposable single-use device for a single patient, if desired. To the extent that the above specification comprises the preferred embodiments of the invention, it will be understood that variations and modifications may be made thereto, in accordance with the inventive principles described, without departing from the scope of the invention. Although the 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 now occur to those 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 (28)
1. - A device for delivering a drug comprising: a supply tube, the supply tube has 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 source of the drug adjacent to the mouthpiece; a handle at a proximal end of the supply tube; and an energy source in the handle to provide an operating pressure of about 56.24 (800) to about 140.61 kgf / cm2 (2,000 psi) to drive the drug through at least one nozzle and out of the supply tube.
2. The device according to claim 1, further characterized in that the drug is operated through at least one nozzle in the course of time varying from about 10 milliseconds to about 200 milliseconds after activation of the energy source.
3. The device according to claim 2, further characterized in that the at least one injection nozzle has a diameter ranging from about 10 μm to about 50 μm.
4. - The device according to claim 3, further characterized in that it comprises an activation element on the handle to activate the energy source.
5. The device according to claim 4, further characterized in that it comprises at least one reservoir at the distal end of the supply tube for contacting the drug within the supply tube, the at least one reservoir in fluid communication with the at least one nozzle
6. The device according to claim 5, further characterized in that the at least one reservoir contains a volume of drug ranging from about 10 μl to about 1 ml.
7. The device according to claim 6, further characterized in that it comprises a piston in the pressure chamber for driving the drug through at least one nozzle.
8. The device according to claim 7, further characterized in that it comprises at least one push rod connected to the piston and located mobile in the at least one tank to drive the drug through at least one nozzle.
9. The device according to claim 8, further characterized in that the drug is operated through a tip of the at least one nozzle at a pressure ranging from about 281.22 (4,000) to about 1757.67 kgf / cm2 (25,000 psi) ).
10. - The device according to claim 9, further characterized in that it comprises a seal in the supply tube located in a portion of the piston.
11. The device according to claim 10, further characterized in that the seal comprises an O-ring seal.
12. The device according to claim 10, further characterized in that it comprises a seal of the reservoir at a distal end of at least one push rod.
13. The device according to claim 4, further characterized in that it comprises a valve between the power source and the supply pipe to regulate the pressure inside the pressure chamber of the supply pipe.
14. The device according to claim 13, further characterized in that the energy source is a compressed gas.
15. The device according to claim 14, further characterized in that the compressed gas is contained in a cartridge.
16. The device according to claim 4, further characterized by comprising a disposable cover connected to the handle to access the power source.
17. The device according to claim 4, further characterized in that it comprises a nozzle plate at a distal end of the supply tube and at least one nozzle arranged within the nozzle plate.
18. The device according to claim 4, further characterized in that at least one nozzle extends from the nozzle plate as an outward projection on the distal tip of at least one nozzle.
19. The device according to claim 4, further characterized in that the energy source comprises a pyrotechnic charge.
20. The device according to claim 19, further characterized in that it comprises a bait on the handle for driving the pyrotechnic charge.
21. The device according to claim 20, further characterized in that it comprises a firing pin needle operably connected to the activation element for activating the bait.
22. The device according to claim 17, further characterized in that the at least one nozzle is arranged to deliver the drug at a target point.
23. The device according to claim 22, further characterized in that the at least one nozzle comprises a plurality of nozzles arranged at a distal end of the housing.
24. - The device according to claim 23, further characterized in that the plurality of nozzles is arranged to deliver the drug at a target point.
25. The device according to claim 4, further characterized in that the device is a disposable device for single use in a single patient.
26. The device according to claim 4, further characterized in that the device is a reusable device.
27. The device according to claim 9, further characterized in that the drug is operated through a tip of at least one nozzle at a pressure ranging from about 562.45 (8,000) to about 843.68 kgf / cm2 (12,000 psi) .
28. The device according to claim 27, further characterized in that the drug is operated through a tip of at least one nozzle at a pressure that varies by approximately 703.07 kgf / cm2 (10,000 psi).
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US11200772 | 2005-08-10 |
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MXPA06009040A true MXPA06009040A (en) | 2008-09-02 |
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