KR101291519B1 - Method for making a needle-free jet injection drug delivery device - Google Patents

Abstract

A method of making a spray injection drug delivery device, the drug delivery device having at least one drug reservoir and at least one injection nozzle, the method comprising the steps of identifying a drug to be delivered; Identifying the volume of drug needed to be delivered; Setting a reservoir diameter for the one or more drug reservoirs; Setting nozzle diameters for the one or more scanning nozzles; Identifying a tissue model for drug delivery; Identifying the penetration depth in the tissue model for drug delivery; Injecting the drug into the tissue model under variable pressure until the desired depth of penetration is achieved. It also includes identifying an optimal pressure range for the drug delivery device that achieves the desired penetration depth.

Injection injection drug delivery device, drug reservoir, nozzle, tissue model.

Description

METHOD FOR MAKING A NEEDLE-FREE JET INJECTION DRUG DELIVERY DEVICE}

1 is a perspective view of one embodiment of a micro-injection drug delivery device according to the present invention.

2 is an exploded view of the device of FIG. 1 in accordance with the present invention;

3 is a cross-sectional view of the device of FIG. 1 in a pre-launch configuration according to the present invention.

4 is a cross-sectional view of the device of FIG. 1 in a fired configuration in accordance with the present invention.

5 is a perspective view from the front end of another embodiment of a micro-injection drug delivery device particularly useful for applications such as ophthalmic use in accordance with the present invention.

6 is a perspective view of the distal side of the device of FIG. 5 in accordance with the present invention.

7A is a cross-sectional view of the device of FIG. 5 in accordance with the present invention.

FIG. 7B is a cross-sectional view of another embodiment of the apparatus of FIG. 7A having an LED focusing light in accordance with the present invention. FIG.

8 is a partial cross-sectional side view of another embodiment of a micro-injection drug delivery device particularly useful for applications such as nasal use in accordance with the present invention.

9 is an enlarged side view of the distal end of the device of FIG. 8 in accordance with the present invention;

10 illustrates the device of FIG. 8 for use for a nose application in accordance with the present invention.

FIG. 11 is a graph illustrating penetration depth versus pressure study for a microinjection drug delivery device having a 100 μl drug delivery volume and a nozzle diameter of 50 μm in accordance with the present invention.

[Description of Reference Numerals]

20: drug delivery device 24: housing

28: cap 30: nozzle plate

34: nozzle 38: reservoir

40: drug 44: piston

48: push rod 70: striker pin

The present invention relates generally to drug delivery and is particularly suitable for delivering the drug to sensitive areas of the human body, such as the eye, nasal passage way, mouth and other parts of the human body, with minimal needle trauma to the drug without tissue. Novel useful apparatus and method for delivering.

Despite the continuing advances in medical technology, conventional surgical and interventional interventions, especially in the treatment of various diseases such as heart disease, vascular disease, eye disease, cancer, pain, adverse reactions, orthopedic treatment and many other diseases and abnormalities There are a significant number of patients who are unable to implement therapy or are insufficient to treat a disease or condition. For many patients, only medical treatment with drugs or the like is available and viable.

Much progress has recently been made with regard to drug therapy, particularly cell or site-specific treatments known as "local" drug delivery. Unlike systematic administration of treatments, which typically consist of oral or intravenous injection, most of the effects of local drug delivery or cell or site-specific therapy are based on the ability to accurately and precisely deliver the therapeutic agent to a target location in the body.

Needle injection devices are the most commonly used means for local delivery or site-specific administration of reagents or solutions. Although many advances have been made in injection-based drug delivery / injection systems, these systems have significant drawbacks and drawbacks. One such disadvantage is that the use of needles or other penetrating means for injection into the target tissue area inevitably creates holes in the target area, resulting in tissue damage and trauma at the local tissue location.

Another disadvantage associated with this needle penetrating and injection approach is that it is very common for a significant amount of injectate to leak or exude again from the holes created by the needle or other penetrating member. Often, these leaked injections are systematically released or discarded throughout the body, resulting in a shortage of prescribed therapeutic or drug dosage from the patient. In addition, this requires more dosages, time and reagents to increase the cost of treatment and achieve the desired effect.

It is also known that needle injection or penetration into tissue can trauma or destroy tissue cells, resulting in an increased risk for trauma, pain, and discomfort at the local location and surrounding area after surgery of the patient. This is due in particular to the difficulty of precisely controlling the penetration of the needle during injection. The greater the number of injections or penetrations, the greater the destruction and cell trauma. Another disadvantage of needle-based injections is the location of each injection site, in particular when multiple injections are required, to avoid repeated delivery of the drug to the same injection hole or to prevent accidental delivery of the drug to a disease-free tissue. Cannot be tracked carefully.

Other known drug delivery devices and methods do not include needle-based drug delivery. Instead, devices such as indwelling catheters are used to release the therapeutic agent in a stable, controlled-release form. Devices of this type may present a greater risk of systematically releasing the drug. In addition, with these types of devices, it is more difficult to assess whether the actual administration of the target area is made. Therefore, this type of device has the disadvantages of being less effective, insecure and much more expensive than generally known needle injection approaches and techniques.

Another condition in which site-specific or local drug delivery is generally adopted is the treatment of peripheral vascular disease (such as deep vein thrombosis and embolism). One such treatment is venous lytic treatment, and dissolution of clots (thrombosis) in peripheral vascular structures (eg, femoral and iliac arteries and veins). Lysis therapy involves the systematic infusion of thrombolytics such as urokinase, streptokinase, reteplase, and Tissue Plasminogen Activator (tPA). Another more recently developed procedure involves delivering thrombolytics directly to thrombus sites through the use of indwelling infusion catheters. In order to effectively dissolve the thrombi, thrombolytics are typically infused for several hours, even one or more days, increasing the length of hospital stay required and the total procedure cost.

One general approach to removing needles in local drug delivery is to use conventional needleless injection syringes. Needleless injection technology was introduced about 40 years ago for use in the public immunization campaign. Today, more than 15 companies develop and manufacture injection syringes for intradermal and transdermal (subcutaneous and intramuscular) delivery of drugs. While these modern designs offer significant improvements in size, cost and convenience over time, the basic functionality remains unchanged. In principle, compressed gas is used to propel a medicament (liquid, liquid or dry powder) through a single orifice at a suitable high speed, allowing the drug to precipitate through or under the skin. Examples of known needleless injection syringes are assigned to -VioValve Technologies, Inc. of Willis et al., Disclosed in WO 00/35520 and US Pat. No. 6,406,455 B1. It is.

In addition, needleless injection has long been hyped up as a painless procedure, but clinical studies comparing conventional injection needles with conventional needles and syringes showed that 25ga. The pain score was equivalent to the pain score of the needle. For the most part this is due to the size of the scanning stream, ie the size of the nozzle orifice. All of the existing devices use nozzle orifices that are about 0.06 to 0.08 "in diameter. These conventional needleless injection syringes incorporate only a single injection chamber and are 0.006 to 0.008" or 150 to 200 microns (0.15 to 0.2 mm). It is known to spray the entirety of the drug contents through a single plastic nozzle having a typical orifice diameter of. Such injection syringes typically deliver a range of volumes as high as 0.100 to 0.500 cc (100 to 500 μl), even 1 cc (1,000 μl). There are some important constraints on current injection injection techniques. First, the injection time associated with such conventional needleless injection syringes is typically for a few seconds, which means that the patient may not have laceration if the patient moves (eg, falters) or if the syringe is shaken from the injection site during the injection. There is a risk of wearing it. Second, the pain felt is the same as with conventional needles and syringes. This is probably the single biggest reason why injection injection is not widely accepted. Third, injection syringes tend to deliver so-called "wet injections" where the drug leaks back through the injection site, resulting in concerns about the accuracy of the delivered dose.

The first two items, pain and wet injection, are the result of the nozzle orifice size (about 0.006 "in current injection syringes.) This size is sized for the convenience of the user and to minimize or eliminate any" leakage "of the drug being injected. Rather than any effort to optimize, it comes from the practical constraints of plastic injection molding for high volume commercial manufacturing The compromise of sub-optimal performance for this manufacturability would otherwise have been enjoyed by the market. After being unsupported, the product fell apart.

One particular form of conventional needleless injection is disclosed in US Pat. No. 6,716,190 B1 (of Glines et al.), Which is an apparatus for delivery and injection of therapeutic and diagnostic reagents to a target site in the body. And methods. This apparatus and method uses a complex system comprising an ampule body and a nozzle assembly having milled or machined channels in the end face of the ampoule body. These channels act as a manifold and are disposed perpendicular to the reservoir orifice. The reservoir orifice discharges or discharges the contents contained in the ampoule body into channels arranged at right angles, and the channels send the contents to a plurality of sprinkling orifices disposed at right angles to the channels. The sprinkling orifices are located perpendicular to the channels and are generally within the target opposing surface of the flat end. In addition to this particular batch of complexes, high delivery pressures are required in the range of about 1800 to 5000 psi, and in some applications about 1800 to 2300 psi for the contents in the ampoule. In addition, the spacing orifice has a diameter of about 0.1 to 0.3 mm (100 to 300 microns). Although such devices do not use needles, the negative consequences of using such devices and arrangements not only result in excessive trauma to the tissue at the delivery site, but also due to the high delivery pressure as well as the relatively large size of the spacing orifice. It is easy to cause unwanted and unnecessary pain and / or discomfort for the user or patient. Thus, devices and methods such as GLINS are particularly effective at delivering micro-drugs to the drug in sensitive areas of the human body, such as the eyes, nasal cavity and mouth, or other sensitive areas of the human body, particularly those that easily feel trauma, pain and discomfort. Inappropriate.

Thus, there are many sensitive areas and disease states of the human body that are very difficult to treat using local drug delivery. For example, there are myriad ophthalmic diseases in which the delivery of drugs and treatment to the disease site, ie the eye, is difficult for the patient to be often painful or psychologically uncomfortable. Related examples of these diseases that are very difficult to treat include Age-related Macular Degeneration (AMD), diabetic retinopathy, choroidal neovascularization (CNV), macular edema, uveitis, and the like. .

For this type of disease, systematic administration of the drug usually results in subtherapeutic drug concentrations in the eye and can have significant adverse effects. As a result, current treatments for eye diseases often involve the direct injection of drugs into the eye via conventional needles and syringes—which are painful and undesirable means of delivery to the patient. In addition, chronic treatment requires repeated injections, which can cause the formation of spots and scars in the eye, retinal detachment, and ophthalmitis.

As a result of these complications, alternative means of delivering drugs to the eye are being developed. Research areas for delivery include iontophoresis, drug-eluting ophthalmic implants, photodynamic therapy, and “sticky” eye drop. And each of these approaches has proven to have its own limitations.

For example, iontophoresis has practical limitations on the size of drug molecules delivered. For example, delivery of molecules having molecular weights above about 20,000 Daltons cannot be expected. In addition, many new compounds, especially some promising proteins, far exceed this size and range as large as 150,000 Daltons.

In addition, ophthalmic implants require surgical procedures for transplantation and explants-these procedures are expensive, painful and can cause eye injury. Implants have additional constraints on the amount and physical size of the drug loaded or loaded into the implant.

It is also known that photodynamic therapy is an unproven technology and its long-term effects are unknown and may be harmful to the retina. Alternatively, eye drops have long been considered as the most convenient (and therefore perceived as more acceptable) means of delivering drugs to the eye. Eye drops, however, are very quickly washed away from the eye and deliver only the minimum amount of drug contained.

As a result, "viscous" eye drops, tears that provide mucoadhesion, have been developed to prevent the "washing out" effect. However, the rapidity of cell reversal at the eye surface was believed to limit the effectiveness of these means of delivery. In addition, the delivery mechanism from eye drops is passive diffusion across the sclera. And passive diffusion cannot deliver a drug having a molecular weight greater than about 500 Daltons. Also, delivery is aimed at the systemic rather than the eye itself.

As a result, there are currently no substantially acceptable means of delivering active therapeutic agents to sensitive areas of the eye and other human bodies, particularly promising new polymers for the treatment of various eye diseases and diseases associated with other sensitive areas of the human body.

To date, not only provide actual needleless drug delivery regardless of the size of the drug molecule involved, but also provide actual needleless drug delivery with minimal trauma to the tissue, and sensitive areas of the human body such as the eye, nasal or mouth There are no known devices or methods suitable for delivering the drug.

To date, no device is known to provide actual needleless drug delivery, which is a microinjection device that is simple in design and construction, efficient, inexpensive and easy to manufacture.

The present invention is directed to new and useful devices and methods that are suitable for delivering drugs to sensitive areas of the human body, such as the eyes, nasal cavity, mouth and other areas of the human body, and deliver needles without needles to the tissue with minimal trauma.

Therefore, the present invention provides a housing;

One or more nozzles in a portion of the housing;

A drug source in said housing; And

A drug delivery device comprising an energy source providing a propulsion pressure of about 800 to 2,000 psi to propel the drug out of the housing through the one or more nozzles.

In addition, the drug is propelled through the one or more nozzles within a time range of about 10 to about 200 msec upon operation of the energy source. In addition, the one or more injection nozzles have a diameter in the range of about 10-50 μm.

The present invention also provides a delivery tube having a pressure chamber;

One or more nozzles in fluid communication with the pressure chamber and at the distal end of the delivery tube;

A drug source adjacent the one or more nozzles;

A handle of the tip of the singer delivery tube; And

And an energy source in the handle to provide a propulsion pressure of about 800 to 2,000 psi to propel the drug out of the delivery tube through the one or more nozzles.

Additionally, the present invention relates to a method of making a spray injection drug delivery device, wherein the drug delivery device has one or more drug reservoirs and one or more injection nozzles.

Identifying a drug to be delivered;

Identifying the volume of drug needed to be delivered;

Setting a reservoir diameter for the one or more drug reservoirs;

Setting nozzle diameters for the one or more scanning nozzles;

Identifying a tissue model for drug delivery;

Identifying the 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.

In addition, the method further includes identifying an optimal pressure range for the drug delivery device to achieve the desired penetration depth. The optimum pressure range for the device according to the invention is about 800 to 2,000 psi and the optimum pressure range at the tip of one or more injection nozzles for the device of the invention is about 4,000 to 25,000 psi.

The invention also relates to a method for delivering a drug to a tissue, the method comprising

Providing a drug delivery device having a drug contained in a portion of the device and at least one nozzle;

Identifying the site of delivery of the drug in or on the tissue;

Placing a portion of the device on or near this site; And

Delivering the drug from this site to tissue through one or more nozzles of the device under microspray propulsion at a propulsion pressure of about 800 to 2,000 psi.

The method further includes delivering the drug from this site to the tissue at a pressure at the tip of one or more nozzles in the range of about 4,000 to 25,000 psi.

The novel features of the invention are set forth in particular in the appended claims. However, the invention itself will be understood with reference to the following detailed description in conjunction with the accompanying drawings, together with further objects and advantages, both in structure and method of operation.

The present invention relates to a novel drug delivery device, a method of making the same and a method of using the same. 1 to 10, the present invention is a needle-free, needle-less micro-injection drug delivery device 20, 20a, 20b, a method of manufacturing the same, and a method of using the same. All are described in more detail below. The drug delivery device 20, 20a, 20b according to the present invention is a needleless injection injection device that delivers a drug, such as a liquid drug, to a patient by injecting a very fine stream of drug formulation at high speed. The drug delivery devices 20, 20a, 20b provide a means for drug administration that is less painful than known needle and syringe devices as well as known needleless injection devices. The drug delivery devices 20, 20a, 20b according to the present invention can be used in a variety of medical applications including transdermal, skin, eye, intranasal, oral and generally transmucosal drug delivery.

The terms "drug delivery device", "delivery device", "needle drug delivery device", "needle-free micro drug delivery device", "micro injection drug delivery device", "needle-free drug delivery device", "needle-free fine Terms including “injection drug delivery device”, “needle injection injection device”, “injection injection device”, “microinjection device”, “microinjection”, and any combination of any portion of these terms all refer to the same meaning And interchangeably in the present application.

The terms "active agent formulation" and "drug formulation (formulation)" mean drugs or active agents, optionally in combination with pharmaceutically acceptable carriers and additional inert additives. . The drug may be a solid, liquid, or semi-solid or semi-liquid or a combination thereof.

The terms “drug”, “agent”, “active agent”, “pharmaceutical ingredient” are used interchangeably herein and often include components, mixtures of substances, including drugs that provide some therapeutic or beneficial therapeutic agent, Means a compound, drug, reagent. These include pesticides, herbicides, germicides, biocides, algicides, rats, fungicides, pesticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, Antipreservatives, disinfectants, sterilizers, catalysts, chemical reactants, fermentants, foods, food additives, nutritional supplements, cosmetics, drugs, vitamins, contraceptives, fertilization inhibitors, fertilizers, microorganism damping agents and other beneficial to the environment Contains medications. As used herein, the terms include warm-blooded mammals, humans, primates; Birds; Livestock or farm animals such as cats, dogs, sheep, goats, cattle, horses, and pigs; Laboratory animals such as rats, rats, guinea pigs; Pisces; reptile; And any physiological or pharmaceutically active substance that produces localized or systemic effect (s) in animals, including zoos, wildlife, and the like. Active drugs that can be delivered include peripheral nerves, adrenergic receptors, choline receptors, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, synoptic sites, neuroeffector junctional sites, endocrine and hormonal systems Inorganic and organic compounds, including, but not limited to, drugs acting on the immune system, the reproductive system, the skeletal system, the otacoid system, the digestive and excretory system, the histamine system and the central nervous system. Suitable agents include, for example, proteins, enzymes, hormones, nucleotide polymers, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, hypnotics and sedatives, psychic energizers. Antiseptics, anti-convulsants, muscle relaxants, anti-Parkinson's agents, analgesics, anti-inflammatory agents, local anesthetics, muscle contractors, antibacterials, antimalarials, contraceptives, sympathetic agents, hormone preparations including polypeptides, physiology Proteins, diuretics, lipid modulators, anti-male agents, anti-parasites, neoplastics, anti-tumor agents, hypoglycemic agents, nutrients and supplements, growth supplements, fats, ophthalmic, anti -May be selected from anienteritis agent, electrolyte and diagnostic agent.

Examples of drugs or agents useful in the present invention include prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mecaxylamine hydrochloride, and procaine hydrochloride. procainamide hydrochloride, amphetamine sulfate, metaamphetamine hydrochloride, benzphetamine hydrochloride, benzphetamine hydrochloride, isoproteronol sulfate, phenmetrazine hydrochloride, betacholine chloride, methacholine chloride (methacholine chloride), pilocarpine hydrochloride, Atropine Sulfate, scopolamine bromide, Isopropamide iodide, tridihexethyl chloride, hydrochloric acid Phenformin hydrochloride, methylphenidate hydrochloride, theophylline cholin ate, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, maleic acid prochlorperazine maleate, anicindione, diphenadione, Erythrityl tetranitrate, digoxin, isofluororophate, acetazolamide, metazolamide, bendroflumethiazide, chloropropamide ( chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, metotrexate, acetyl sulfisoxazole , Hydrocortisone, hydrocortisone acetate, cortizone acetate, dexamethasone, beta metazone, triamcinolone (triamc) inolone), derivatives thereof such as methyltestosterone, 17-.beta.-estradiol, ethynyl estradiol, ethynyl estradiol 3-methyl ether, prednisolone, 17-.beta.-hydroxyprogesterone Acetate, 19-nol-progesterone, nogestelrel, norethindrone, noletchisterone, noletiederone, progesterone, nolgesterone, nolethinoderel, Indomethacin, naproxen, fenoprofen, sulindac, indopropene, nitroglycerin, isosorbide dinitrate, propranolol, timolol, Atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chloropromazine, methyldopa, dihydroxyphenylalanine, theophylline, gluconate Calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, phenoxybenzamine, Diltiazem, milnonone, captropril, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbuprofen, flubufen, flu Propene, tolmetin, alclofenac, mefenamic, flufenamic, definial, nimodipine, nirenedipine, nisoldipine, nicardidipine, felodipine, lidofrazine, thiafamil, gallo Famil, amlodipine, myoflavin, lysinopril, enalapril, captopril, ramipril, enalprarilat, famotidine, nicatidine, sucralfate, ethyntidine, tetratolol, minoxidil , Chlordiazepoxide, diazepam, amit Liptiline, and imipramine. Further examples include insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, lenin, prolactin, corticotrophin, thyroid hormone, follicle stimulating hormone, chorionic gonadotropin (chorionic gonadotrophin), gonadotropin releasing hormone, bovine somatotropin, porcine somatropin, oxytocin, vasopressin, prolactin, somatostatin, sopressstatin, lypressin, Pancreozymin, luteinizing hormone, LHRH, interferon, interleukin, human growth hormone, bovine growth hormone, growth hormones such as pig growth hormone, modification inhibitors such as prostaglandin, fertilization Accelerators, growth factors, human pancreatic hormone-releasing factors, vinca alkaloids (i.e. Antiproliferative / antimitosis including natural products such as vinblastine, vincristine, vinorelbine), paclitaxel, epidipodophyllotoxin (ie etoposide, teniposide) Antimitotic agents, antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracycline, mitoxantrone, bleomycin, plicamycin (mithramycin) ) And mitomycin, an enzyme (L-asparaginase that systematically metabolizes L-asparagine and removes cells that do not have the ability to synthesize asparagine by itself); Anti-platelet agents such as G (GP) II _b II _a inhibitors and vitronectin receptor antagonists; Nitrogen mustard (mechloretamine, cyclophosphamide and analogues, melphalan, chlorambucil), ethyleneimine and methylmelamine (hexamethylmelamine and thiotepa), alkyl sulfonate-busulfan, nirtosourea Antiproliferative / antimitotic alkylating agents such as (carmustine (BCNU) and analogs, streptozosin), trazene-dacarbazinin (DTIC); Folic acid analogs (methoxetrexate), pyrimidine analogs (fluorouracil, phloxuridine, cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine Antiproliferative / antimitotic metabolic antagonists such as}); Platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutetimide; Hormones (ie estrogens); Anti-coagulants (heparin, synthetic heparin salts and other thrombin inhibitors); Fibrinolytic agents (such as tissue plasminogen activators, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; Antimigratory; Secretion inhibitors (brevodine); Corticosteroids (cortisol, cortizone, fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone, triamcinolone, betamethazone, dexamethasone), non-steroidal agents (salicylic acid derivatives or aspirin) such as: Anti-inflammatory agents; Paraaminophenol derivatives, namely acetominophene; Indole and indene acetic acid (indomethacin, sulindac, etoalalac), heteroaryl acetic acid (tolmethine, diclofenac, ketorolac), arylpropionic acid (ibuprofen and derivatives), anthranilic acid (mephenamic acid, meclo) Phenolic acid), inol acid (pyoxycamp, tenoxycam, phenylbutazone, oxypentatazone), nabumethone, gold compounds (oranopine, orothioglucose, gold sodium thiomalate); (Cyclosporin, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil): immunosuppressants; Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) platelet-induced growth factor (PDGF), erythropoetin: angiogenic agent; Angiotensin receptor blockers; Nitric oxide donors; Anti-sense oligonucleotides and compounds thereof; Cell cycle inhibitors, mTOR inhibitors, growth factor signal transduction kinase inhibitors, chemical compounds, biological molecules, peptides and proteins, including but not limited to nucleic acids such as DNA and RNA, amino acids, peptides, proteins or compounds thereof.

One or more drugs or agents may be combined or mixed together and included in or used by the present invention, and the term "drug", "formulation" or "drug" or "pharmaceutical ingredient" may in no case be more than one The use of such drugs, agents, actives and / or pharmaceutical ingredients is not excluded.

One embodiment of the drug delivery device 20 according to the present invention is illustrated in FIGS. The drug delivery device 20 is a needleless injection injection device that is particularly useful for injecting drugs delivered under microspray propulsion at very high speed and very fine flow into various forms of human tissue, including organs. For example, the drug delivery device 20 according to the present invention is particularly useful for skin or transdermal delivery of a drug to a patient, i.e. without a needle, the drug is delivered to the blood flow and circulatory system of the patient through various layers of the skin or through layers of the skin. It is useful as a skin or transdermal drug delivery device for delivery. The drug delivery device 20 according to the present invention is not limited to skin and transdermal applications, but is directed to the use of other forms of tissue and other medical, therapeutic and diagnostic applications.

The drug delivery device 20 has a housing 24, a cap 28 at the tip 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 injection injection nozzles (also called "micro-nozzles"), are disposed in the nozzle plate 30. As shown in FIGS. 1-4, the injection nozzle 34 terminates as a small outward protrusion from the outer surface of the nozzle plate 30, so that the proper positioning of the injection nozzles 34 on the surface of the human tissue of the user. And provide tactile feedback to the user for alignment. As best seen in FIGS. 2-4, the housing 24 further includes one or more reservoirs 38 in fluid communication with and aligned with the one or more nozzles 34. Each reservoir 38 is longitudinally aligned in the housing 24, acting as a storage space or drug reservoir for the drug 40.

Each reservoir is shaped to receive a push rod 48 and a reservoir seal 54 attached or secured to the distal end of each push rod 48. The push rod 48 and reservoir seal 54 are aligned in the longitudinal direction directly to the respective reservoir 38, and the push rod 48 and reservoir seal are movable in each drug reservoir 38. Disposed (movable in the longitudinal direction). Each reservoir seal 54 is designed to prevent the drug 40 from leaking or exuding from the drug reservoir 38. Therefore, the reservoir seal 54 is movable in sealable contact with the inner wall of the drug reservoir 38.

The push rod 48 and reservoir seal 54 are slidably movable in the longitudinal direction in each reservoir 38. The piston 44 is integral with or fixed to the tip of each push rod 48 and acts as a driving platform for accumulating and exerting thrust on the push rod 48. The piston 44 is fixed as a single unit at the leading end of all the push rods 48 to actuate and move each push rod 48 simultaneously in each reservoir 38, or the piston 44 stores It may be individually fixed to the tip of each push rod 48 to selectively and individually actuate and move each push rod 48 within the portion 38.

In this example, the piston 44 has a cylindrical shape which is fixedly fitted in the inner wall of the housing 24 which is also cylindrical in shape and movably engages with the inner wall. The piston 44 has a circumferential space shaped to receive the O-ring seal 52, and the O-ring seal is shaped to movably engage and movably engage within the inner wall of the housing 24 together with the piston 44. . Seal 52 may be any type of seal that prevents gas, release contents, or other material from leaking or seeping through piston 44.

As shown in FIG. 3 (in the drug delivery device 20 in which the drug 40 is loaded and in pre-launch configuration), an energy source for releasing thrust force to the piston 44 is provided within the housing 24. 44, located at the tip side or above, for example, in one embodiment according to the present invention, a charge housing 60 is located at the tip side or upper portion of the housing 24. As shown in FIG. A flammable charge 64 is received in the charge housing 60. A primer 68 is positioned near the pyrophoric charge 64 to hold a small explosive charge that delivers ignition energy or pyrophoric energy to the pyrophoric charge 64 to ignite the pyrophoric charge 64 upon operation of the primer 68. do.

The striker pin 70 is positioned in the cap 28 to engage or contact the primer 68 to move with the primer 68 to actuate the primer 68 to initiate the explosive charge contained in the primer 68. The striker pin 70 is movably connected to an actuating member such as an actuated button 74 biased to be actuated by a spring 72. Thus, the actuation button is a striker in the cap 28 such that the striker pin 70 propels the primer 68 such that a sufficient downward force is exerted on the actuation button 74 by, for example, the thumb of the user or patient. The pin 70 is movably deflected.

As shown in FIG. 4 (fired configuration after the drug delivery device 20 is injected with the drug 40 under the microspray propulsion), by pressing the operation button 74, the striker pin 70 is a primer ( 68) to activate the primer 68, which in turn causes rapid burning of the flammable charge 64. This controlled explosion provides the propulsion force necessary for the piston 44 and the push rod 48 attached thereto to slide forward through the reservoir 38 so that the push rod 48 can be applied to the drug 40 by microspray propulsion. ) Is discharged through the injection nozzle 34.

Energy sources such as the flammable charge 64 or the compressed gas 36 (FIGS. 8 and 10) deliver sufficient propulsion pressure and energy in the range of about 800 to 2,000 psi to the main propulsion piston 44 and associated push rod 48. do. In turn, the energy and pressure at the tip of the micronozzle 34 ranges from about 4,000 to 25,000 psi, preferably about 8,000 to about 12,000 psi, and more preferably about 10,000 psi at each micronozzle tip. . The method further includes discharging the drug through the tip of the one or more nozzles in a pressure range of 8,000 to 12,000 psi, more preferably in a pressure range of 10,000 psi.

For all embodiments of the present invention, the same reference numerals are used to indicate the same or similar features and parts. Thus, Figures 5, 6, 7A and 7B illustrate another embodiment of the present invention that is particularly useful for ophthalmic applications such as delivering drug 40 to the eye 100 of a patient. Therefore, the nozzle plate 30a of the distal end of the housing 24 has a distal end 31 of a constant shape, which is a concave ring having a hole in the center. In this example, the distal end 31 of the constant contour is disposed circumferentially within the contour (concave region) formed by the distal end 31 of the constant contour and of the outer circumference (peripheral or outer edge) of the distal end 31 of the constant contour. It has a plurality of scanning nozzles 34 spaced apart from the outer edge by a predetermined distance away from the edge. Thus, in this example, the nozzle plate 30a having the contoured distal end 31 is shaped to receive the patient's eye 100, with the pupil of the eye 100 circumferentially facing the contoured distal end 31. It can be arranged in the center of the ring (open space). Therefore, if desired, the drug 40 can be delivered to the area of the eye 100 outside the pupil, such as the vitreous or sclera, under microspray propulsion, as well shown in FIG.

7B shows another embodiment of a delivery device 20a in which a light emitting diode (LED) cavity 76 is provided in the central portion (open space) of the circumferential ring of the distal end 31 of the contour of the nozzle plate 30a. To illustrate. The LED 80 delivers the focus light 88 (focusing LED light) under operational control from a switch 86 movably located in an outer portion of the housing 24 (in this example, near the tip of the housing 24). Disposed in the LED cavity 76 to disperse. The switch 86 acts as a power switch for operating the LED 80 projecting the focus light 88; That is, switch 86 acts as an "on" and "off" switch for LED 80 and light 88. For brevity, the contacts, leads, and wires that operatively connect the LED 80 to the switch 86 are not shown, but will be understood by those skilled in the art.

The focus light 88 is used to attract the patient's direct attention and to align and focus the pupil of the eye 100 and mentally relax the patient while the drug 40 is delivered to the eye 100 under microspray propulsion. It acts as the focus of the patient's attention in order to make it (basically, the patient's attention). Therefore, the LED 80 and the focus light 88 serve as a means of lowering the tension and anxiety of the patient, usually associated with drug injection, especially in sensitive areas such as the eye 100.

Alternatively, instead of the LED 80, a light emitting member (including self luminescence) or a member or feature having a luminescent coating such as a feature or a self luminescent coated dot is used as a focal point and the patient mentally It can be used to receive the drug 40 injected under microspray propulsion while directly attracting the patient's attention and the focus of the pupil of the eye 100 to act as a focal point that attracts the patient's attention. Tritium-coated dots are one example of a suitable substitute.

8-10 illustrate another embodiment of the present invention in which the drug delivery device 20b uses an elongated cylindrical tube as the delivery tube 25 having a pressure chamber 27. The handle 23 is connected to the delivery tube 25 at the tip of the delivery tube 25. The valve 33 is connected to the tip of the pressure chamber 27 and the delivery tube 25 and a source of compressed gas 36, such as compressed CO ₂ gas contained in the cartridge 36, is connected to the other end of the valve 33. And is accommodated in the handle 23. The cartridge 36 is a compact compressed gas cylinder containing a compressed gas such as CO ₂ that has the ability to achieve and deliver pressures as high as 2,000 psi. The valve 33 is, for example, a delivery tube from the cartridge 36 by an actuation button 74a disposed at a convenient position of the handle 23 which is easily accessible to the pad of the index finger of the patient or user's hand. The release of compressed gas into the pressure chamber 27 of 25 is controlled.

If desired, a detachably connected cover (not shown) is provided to the gas cartridge 36 to replace the cartridge 36 with a freshly filled (filled) gas cartridge 36 after its contents have been exhausted (empty). By being used with the handle 24 to provide direct access to, the drug delivery device 20b can be made into a multi-use device or a reusable device.

As shown in FIG. 9, the nozzle plate 30 and the nozzle 34 are located at the distal ends of the pressure chamber 27, the delivery tube 25, and the pressure chamber 27, for example the human tissue of the user, for example. , Tissue located within the nostril of the nose 110 (as shown in FIG. 10), or tissue located within the patient's mouth (oral application), such as the mouth ceiling or gum, or location within the patient's ear. It is disposed as a projection extending outward from the outer surface of the nozzle plate 30 to provide tactile feedback to the user 90 for proper positioning and alignment of the injection nozzle 34 to the surface. Therefore, the drug delivery device 20b is suitable for delivering the drug 40 to an area inaccessible to the human body of the patient due to the thin, long and low profile design.

The drug reservoir 38, the drug 40, the reservoir seal 54, the push rod 48, the piston 44 and the O-ring 52 have these features in the pressure chamber 27 and the delivery tube 25. It is arranged and functions in the same or similar manner as described for the embodiments of FIGS. 1-7B except that it is located in the pressure chamber 27 and the delivery tube 25 at the distal end.

The pressure chamber 27 causes compressed gas to be discharged from the cartridge 36 and directs the gas from the handle 23 to the piston 44 along the entire length of the delivery tube 25, which causes the reservoir 38 to flow. Through which the piston 44 and the attached push rod 48 provide the necessary driving force to slide forward, so that the push rod 48 discharges the drug 40 to the outside through the injection nozzle 34 by microspraying propulsion. Do it.

The drug delivery device 20 (FIGS. 1-4), the drug delivery device 20 a (FIGS. 5, 6, 7A, and 7B) and the drug delivery device 20b (FIGS. 8-10) are, for example, about External surface dimensions (for each of the embodiments of FIGS. 1-4 and 5, 6, 7A, and 7B) with a length of 2.00 "and a diameter of 0.600", very light weight, for example a few ounces A compact design with a weight of oriented. Ergonomically, it may be desirable to increase the size or significantly change the geometry, but the basic functionality remains exactly as shown in these figures.

Alternatively, the energy source releasing thrust force to the piston 44 is, for example, a compressed gas such as C0 ₂ releasably received in the gas cartridge 36 (FIG. 8). In addition, the energy source releasing thrust force to the piston 44 may be any form of energy source as long as it can deliver the drug under microspray propulsion in accordance with the requirements presented below and later herein. For example, the energy source must be able to release enough energy to propel the main propulsion piston 44 and associated push rod 48 to a propulsion pressure in the range of about 800 to 2,000 psi. In turn, the energy and pressure at the tip of the micronozzle 34 ranges from about 4,000 to 25,000 psi, preferably about 8,000 to 12,000 psi, and more preferably about 10,000 psi at each micronozzle tip. The method further includes discharging the drug through the tip of the one or more nozzles in a pressure range of 8,000 to 12,000 psi, more preferably in a pressure range of 10,000 psi.

Delivery under microspray propulsion by the drug delivery device 20 (FIGS. 1 to 4), 20 a; 5, 6, 7 a and 7 b, and 20 b; The volume of drug 40 that can be customized can be customized, modified, and modified to accommodate any form of drug delivery, any tissue form, and any form of medical application. The total volume of drug delivered is modified in accordance with the volume range of about 10 microliters (μl) or about 1 milliliter (ml) or less, depending on the configuration and design of the drug delivery device 20, 20a, 20b. Can be.

In addition, the diameter of the injection nozzle 34 (s) may vary and is in the range of about 10-50 μm or more, with the exception of which results in a very fine injection flow of the drug 40, which is impacted by injection. By minimizing the number of neuronal receptors, it reduces the trauma, pain and discomfort of the patient. One of the novelty and uniqueness of the drug delivery device 20 (FIGS. 1 to 4), 20a; 5, 6, 7a and 7b, and 20b; FIGS. 8 to 10 according to the present invention. Aspects are in using one or more separate drug reservoirs 38 that act as injection chambers, each reservoir in FIG. 3 (in a pre-launch configuration, before drug delivery device 20 delivers drug 40). Drug 40 as part of the total injection volume of the total dose of drug 40, as shown well). And each reservoir 38 has a scanning nozzle 34 designated for itself of a very small diameter. For example, the diameter of each nozzle 34 is in the range of about 10-50 μm or about 0.0004 ″ to 0.002 ″. Therefore, the drug delivery device 20 (FIGS. 1-4) 20a (FIGS. 5, 6, 7A, and 7B), 20b; 8-10 in accordance with the present invention is the entirety of the drug 40. The delivery volume is divided over several separate reservoirs 38 (for embodiments according to the invention having one or more injection reservoirs 38) and conventional injection syringes such as the injection syringes summarized above. As shown in FIG. 4 (shown in the fired configuration after drug delivery device 20 delivers drug 40 under microspray propulsion), it is contained within the patient's tissue at a higher rate than shown in FIG. Deliver each volume of drug.

Accordingly, the drug delivery device 20 (FIGS. 1 to 4), 20 a; 5, 6, 7 a, and 7 b, and 20 b; It dramatically reduces the time required to inject, which can be as short as 40 milliseconds (msec.). As for the requirements for delivery of 0.5 cc (or 0.5 ml) injection of drug 40, drug delivery devices 20 (FIGS. 1 to 4), 20 a; FIGS. 5, 6, 7 a and 7b). And injection time obtained by (20b; FIGS. 8-10) is in the range of about 10-200 msec (and in one example, in the range of about 40-100 msec for about 0.5 ml of a particular type of drug). A further feature of the present invention is that the drug delivery device 20 is compared to the conventionally known thinnest hypodermic needle (extrafine insulin needle with 31 gauge cannula having a diameter of 0.010 ") because the area of the injection flow is reduced by the square of the diameter. Nearly 100-fold reduction in the area of the skin or tissue affected by the injection by FIGS. 1 to 4), 20a; 5, 6, 7a and 7b), and 20b; 8 to 10 It is.

In one embodiment according to the present invention, the drug delivery devices 20 (FIGS. 1-4), 20a; 5, 6, 7a and 7b, and 20b; It is a one-use, pre-filled drug delivery device (designed for one time use as a single use unit, ie a one time use for only one patient) that does not require prior preparation or modification by the personnel or patient. Therefore, the drug delivery devices 20 (FIGS. 1 to 4), 20 a; 5, 6, 7 a and 7 b, and 20 b; 8 to 10 are ready for use by being manufactured and provided. have.

Alternatively, the drug delivery devices 20 (FIGS. 1-4), 20a; 5, 6, 7a and 7b, and 20b; FIGS. 8-10 may include a housing 24 or a handle. Reusable unit (eg, with a one-use, disposable internal assembly inserted into 23 and delivery tube 25 and pre-filled or reloaded by the patient or health care staff prior to administration and removed after use) (eg For example, the main housing 24, the cap 28 with the actuation button 74, the delivery tube 25, the handle 23 with the actuation button 74a are reused and re-sterilized if necessary). It is intended. In this case, the waste internal assembly may include a primer 68, a flammable charge 64, or a compressed gas cylinder 36, a drug reservoir push rod 48, a drug reservoir 38, and an injection nozzle 34. Include. Other components such as the reusable housing 24, the delivery tube 25, the handle 23, the cap 28 and the actuation buttons 74, 74a may be made of metal that can withstand re-sterilization and reuse if necessary. It is made of a suitable material such as an alloy.

Additionally, in all embodiments of the present invention, the injection nozzles 34 are in a single target point of tissue, for example, for receiving a specific target point in the tissue, ie, the entire injection volume of the drug 40, or in the tissue. Arrangement of the injection nozzles 34 (any desired pattern on the nozzle plates 30 and 30a), which are separated from the plane or constructed at different ballistic angles to provide the desired concentration of the drug 40 to a number of desired target points. May be).

Optimization of Microspray Promoting Drug Delivery and Manufacturing Methods

Characterize and measure the performance of drug delivery devices 20 (FIGS. 1-4), 20a; 5, 6, 7a and 7b, and 20b; 8-10 in accordance with the present invention. There are two mechanisms used to do this. The first mechanism is a predictive model based on the so-called Hagen-Pouiselle equation. This equation differs between the main members and components of the drug delivery devices 20 (FIGS. 1-4), 20a; 5, 6, 7a and 7b, and 20b; FIGS. 8-10. It was used to evaluate the design and method of use of the devices and the impact of the resulting propulsion required to operate the drug delivery device according to the performance criteria of the present invention. In addition, the actual force required to deliver the required amount of drug 40 under microspray propulsion has been measured experimentally, both in vitro and in vivo. For example, FIG. 11 is used to measure penetration depth versus pressure for micro-injection drug delivery devices 20, 20a, 20b having a nozzle diameter of 50 μm and a volume of 100 μl of drug delivered according to the present invention. It is a graph showing the results of one of the involvement in in vitro studies.

In the development and manufacture of the drug delivery devices 20, 20a, 20b according to the invention, not only the diameter of the individual drug reservoir 38, but also the diameter of the injection nozzle 34 and the drug 40 or medicament discharged ( The force / volume / length was adjusted based on the desired scan rate or flow rate of 40). In addition, the design of these components depends on the physical properties required by the constituent material for many of the critical members of the drug delivery device 20, 20a, 20b and the size of the main piston 44, the injection nozzle 34 used. ), Number of drug reservoirs 38, and duration of injection.

This relationship is modeled by the following Hagen-Poisel equation:

F = 8QμL (R ² / r ⁴ )

Where F = injection force

        Q = flow rate of the drug or injection

        μ = viscosity of drug or injection

        L = length of injection nozzle

        R = radius of drug reservoir

        r = radius of injection nozzle

To illustrate the utility of this equation, it is desirable to deliver 500 μl (1/2 cc) of aqueous drug (40; drug solution 40 having a viscosity μ of 1 cps) to the subcutaneous layer at a flow rate Q of 5 cc / sec. Assume that Also assume that a scanning microspray or nozzle diameter of 50 microns (0.002 ") or r = 25 microns (0.001") is used. While minimizing drug reservoir length is desired, it is also desired to minimize injection force. Therefore, shorter lengths are better, but smaller diameters mean smaller forces and longer lengths. Therefore, a convenient size is selected with respect to the reservoir length suitable for the portable microinjection drug delivery devices 20, 20a, 20b while attempting to minimize the injection force. As a result, a drug reservoir diameter of 0.072 "or R = 0.036" (0.914 mm) was selected. The length L of the scanning nozzle 34 is determined by manufacturing constraints (very small holes can only be made in a given material for a limited length). Therefore, an appropriate length L is assumed to be 0.050 "(1.27 mm). Therefore, the Hagen-Poisel equation can estimate the required scanning force for any given scan nozzle as follows:

Q = 5 cc / s

μ = 1 cps

L = 0.050 "= 0.127 cm

R = 0.036 "= 0.091 cm

r = 25 μm = 0.0025 cm

F = 8QμL (R ² / r ⁴ ) = 10,218,121 dyne or about 23 lbf

The number of drug reservoirs 38 is determined by dividing the total force exerted by the main propulsion piston 44 by the force required to propel each of the drug reservoir push rods 48, the push rod being in this example. At the same time they act as individual pistons (to be expressed as whole numbers). The actual pressure obtained by either the compressed gas cylinder 36 or the flammable charge 64 is limited to about 2,000 psi. As a result, given the main piston 44 diameter of 0.500 "and the resulting area x pi = 0.196 square inches of (0.250") ² , the maximum possible propulsion is 2,000 psi X 0.196 square inches or 392 lbf. With 392 lbf possible and 23 lbf required to propel each drug reservoir push rod 48, the maximum number of drug reservoirs 38 that can be applied (as a whole in whole) is 392 divided by 23, or a total of 17 reservoirs. (38).

The length of each drug reservoir 38 is calculated as a result of the volume requirement for each. For illustration, assume five storage units are used. Therefore, assuming a total of 500 microliters is required to be delivered through five reservoirs 38, each reservoir 38 delivers 100 microliters of drug 40. Given a reservoir diameter of 0.072 "(1.83 mm), each reservoir length is 100 microliters divided by the reservoir area (pi X (.914 mm) ² ), or 38.1 mm length (1.50").

The scanning flow rate Q is already determined at 5 cc / s (as described above). As a result, the total injection time was determined by the time required to inject the volume of drug 40 contained in each reservoir 38, which was 100 microliters or 1/10 cc. Therefore, the scan time is the inverse of 0.10cc times flow rate Q, or 20 milliseconds.

As a predictive model, the Hagen-Poisel equation is a useful tool for the prediction and preliminary analysis of the necessary design variables for the absence of drug delivery devices 20, 20a, 20b, but as predicted the experimental results differ from the predictive analysis. It was. In vivo testing comprising testing the drug delivery device according to the invention to a hairless guinea pig model and in vitro using testing using 2 mm thick ballistic gelatin for saturated Pluronic (F127) All of the tests involved the speed, microinjection propulsion required for the medicament 40 to be delivered through the injection nozzle 34 to the therapeutic dose, ie in this case the depth of penetration into tissue such as the skin required for subcutaneous administration. It is illustrated that pressurization to about 8,000 psi is required to achieve this.

For example, if drug reservoir 38 has a diameter of 0.072 ", the cross-sectional area of each drug reservoir 38 is (.036) ² times pi or 0.004 square inches. Force F is the pressure ( P) Since multiply area (A), the force required to propel push rod 48 to achieve 8,000 psi pressure in medicament 40 is 8,000 times 0.004 or 32 lbf, which is estimated by Hagen-Poisel 23 A little over lbf, but certainly the same size, most of the increase is explained by the friction between the sliding seal 54 and the O-ring 52.

Continue using the values used in the examples for the Hagen-Poisel equation, assuming that 500 microliters of medicament 40 are required at the total dose and five drug reservoirs 38 are used for the design. Each reservoir 38 contains 500/5 or 100 microliters of medication 40. If 32 lbf is required for a total of five drug reservoirs and each drug reservoir 38, this requires a total of 32 × 5 or 160 lbf to propel all drug reservoir push rods 48. Therefore, the main propulsion piston 44 must exert a force of 160 lbf.

Given a diameter of 0.500 "for the main propulsion piston 44 (this dimension may be large or small depending on the application and the actual ergonomic limitations of the physical size), the area of the piston 44 is (0.250") ² Times pi or 0.196 square inches. Therefore, the energy source must apply a pressure of F / A (160 / 0.196) or 816 psi to the main propulsion piston 44. This pressure requirement is within the performance specification of either the compact compressed gas source 36 or the flammable charge 64. The length of the drug reservoir 38 and the injection duration are maintained as given in the Hagen-Poisel example.

The main propulsion piston assembly 44 is connected to the flammable charge 64 (or alternatively the compressed gas source 36 shown in FIGS. 8 and 10) as shown in FIGS. 2, 3, 7A and 7B. It acts as an accumulator for the pressure created by it, distributing the pressure and delivering it as a driving force to the individual push rods 48. The push rod 48 is integral with the main propulsion piston 44 such that the total load applied to the piston 44 is transmitted proportionally to each push rod 48. If a larger size main piston diameter is required, this translates into a greater exerted force for any given engine pressure. For example, if the main piston diameter increased from 0.500 "to 0.600" in the previous examples, its combined force from a maximum engine pressure of 2,000 psi would be 2,000 psi X 0.283 square inches = 565 at 2,000 psi X 0.916 square inches = 392 lbf. increases in lbf This increase in effective propulsion allows the use of additional injection nozzles 34, which in turn reduces the volume of each nozzle 34, in turn reducing the duration of the injection time, and the like.

Finally, the geometry of the nozzle is defined by the desired diameter of the drug flow, the tensile / yield strength of the constituent material, and the practical constraints of producing very small orifices that are economically cost effective. While one objective of achieving a lightweight, compact, portable drug delivery device 20, 20a, 20b in terms of nozzle geometry is “smaller is better”, there are practical limitations in constructing such a nozzle 34.

In known conventional needleless drug syringes, these known devices are practical in mass injection molding with suitable thermoplastics (ie core pins smaller than this diameter are practical at high pressures and high shear forces required for injection molding in high volume manufacturing). And not) and have a relatively large orifice (about 0.006 "to 0.008").

As mentioned for the drug delivery devices 20, 20a, 20b according to the invention, the drug delivery devices 20, 20a, 20b have a significantly higher operating pressure than in the known conventional needleless injection syringes as described above. And nozzles 34 of 10 to 50 microns in size.

As a result, the drug delivery device 20, 20a, 20b according to the present invention has the advantage of a material having high tensile and burst strength properties for the components of the drug delivery device 20, 20a, 20b. Such materials include ceramics, various metals and alloys, high strength engineering thermoplastics (such as PEEK ^™ , Torlon ^™ , Ultem ^™ , etc.), and the like. The present invention therefore relates to the use of the most cost effective combination of these materials and to minimizing the number of parts, i.e. minimizing the number of parts and components required.

Since the material used needs to withstand a given injection pressure of more than 8,000 psi instantaneously at the nozzle tip, for example, by means of ultrasonic welding or bonding, the housing 24 (FIGS. 1-7B) or the delivery tube 25; It may be desirable to use individual nozzles 34 made of metal, alloy or ceramic (eg alumina or zirconia) in FIG. 8). Although the final nozzle orifice can be secondary molded, formed using laser drilling, ultrasonic drilling, wire EDM processing, or the like, all of these materials can be formed by injection molding. Although not currently considered practical, as micro-injection molding advances, it may be possible to mold any fully finished injection nozzle that is more suitable and more cost effective than current approaches involving secondary finishing operations. Nevertheless, injection molding of high strength materials in combination with laser drilling to produce accurate and repeatable injection nozzles 34 must meet the engineering and cost requirements associated with the present invention.

In another example according to the present invention, FIGS. 1-4 can be used to accelerate a large number of small drug 40 volumes at a suitable rate for delivery to tissue across the skin, for example, as part of a transdermal drug delivery procedure. Various diagrams of the drug delivery device 20 are illustrated. The design of the drug delivery device 20 requires a total of 30 injection nozzles 34, each of which has a diameter of 40 microns and a calculated drug volume of 30 μL per drug reservoir 38 or 30 ×. This example is used to illustrate the function of the drug delivery device 20, assuming a total drug volume of 3.3 = 100 μl. In addition, assuming that a speed of 200 m / s is required for delivery of the drug 40, the Hagen-Poisel equation for which the force required for each injection nozzle 34 yields a value of about 10 lbs per injection nozzle 34 Can be calculated from Given 30 injection nozzles 34, the total load force required is 30 × 10 = 300 lbf. Assuming that the surface area of the main piston 44 is one square inch, a pressure of 300 psi is required to achieve the required performance parameters. Again, this performance criterion can be achieved using a small compressed gas cylinder 36 (FIGS. 8 and 10) or a flammable charge 64 (FIGS. 2, 3, 7A and 7B). The advantage of a flammable charge is that the pressure profile can be controlled over the entire dispensing cycle, providing varying pressures at different times to optimize drug dispensing. In addition, as will be readily appreciated, there may be a number of suitable energy sources that may be used for the purpose of accelerating the drug 40 at a desired rate to achieve the microspray propulsion criteria according to the present invention, The examples are not meant to limit in any way the kind of energy source that can be used in the present invention.

As best illustrated in the graphs illustrated in FIG. 11, ex vivo studies provide microinjection drug delivery according to the present invention to determine the optimal range for optimal pressure range in psi versus penetration-depth in cm. For devices 20, 20a, 20b. The nozzle 34 diameter was about 50 microns and the volume of drug 40 delivered was about 100 μl. As clearly illustrated in FIG. 11, the delivery pressures for the micro-injection drug delivery device 20, 20a, 20b can be easily adjusted to target any selected tissue. Therefore, the micro-injection drug delivery device 20, 20a, 20b can be tailored in a manner that ensures that a particular drug can be delivered at a particular penetration depth in a particular tissue morphology based on the specific delivery pressure according to the graph of FIG. have. Thus, this tailored approach is also allowed for certain tissue layers targeted for drug delivery. For example, the transmucosal layer of tissue can be precisely targeted according to the algorithm illustrated in FIG. 11.

In addition, any number of drug reservoirs 38 and injection nozzles 34 may be used for the present invention (within practical limits). As illustrated above, it can be any one between more than 50 reservoirs 38 and nozzles 34 from one reservoir 38 and one nozzle 34.

Standard semiconductor processes can easily produce the scanning nozzles 34 similar to the manufacturing of nozzles used in inkjet printing. Therefore, the injection nozzles 34 may be a mass produced silicon device having an orifice diameter of 3 to 10 microns as an example. The scanning nozzles 34 may be cut into desired shapes after they are manufactured as dense arrays on a silicon wafer. Wafer patterns, ie, array shapes, can be made in any desired design. As a result, the micronozzle array can be produced in any desired pattern, such as, for example, a circular, elliptical or semicircular pattern, and with the actual density of any scanning nozzle 34 required. Typically, every effort is made to reduce the size of the scan nozzle 34 and maximize the number of scan nozzles 34 from which such wafers can be produced.

Micro-molding of thermoplastics is a novel technique that may also be useful for manufacturing the drug delivery devices 20, 20a, 20b according to the present invention. The advantages are significant. Silicon wafers have a flat structure, but not injection molded plastics. Therefore, the arrangement of the scanning nozzles 34 can be configured to be out of plane, for example, which offers a myriad of advantages in creating an arrangement intended to be positioned with a targeted concentration. Another important advantage is cost. Micronozzle arrangements molded from thermoplastics result in a few penny compared to a silicon device that can easily range from several dollars.

Other methods that may be used to construct the micronozzle 34 include microfabrication of orifices in place as part of the nozzle plate 30 or nozzle plate 30a having a distal end 31 (annular cup) of constant contour, glass. Forming or processing orifices in a metal, ceramic, or other suitable material and then assembling (eg, fitting) into some form of distal end 31 (annular cup). As with other major components of the drug delivery device 20, 20a, 20b according to the present invention, the design or manufacture of the micronozzle 34 is not limited to a particular embodiment.

Therefore, in general, the present invention relates to a method of making or making a drug delivery device 20, 20a, 20b according to the present invention. Thus, the method includes several important steps, such as identifying the drug to be delivered (which may be based on any desired treatment or disease state or condition targeted for treatment). In addition, the volume of drug to be delivered is also identified. In addition, important variables are determined for the features of the apparatus 20, 20a, 20b. This includes variables such as the diameter of one or more injection nozzles 34 and the diameter of one or more drug reservoirs 38 that are first set. In addition, tissue models for the disease or tissue form to be treated are identified. For example, the tissue model is any suitable in vitro or in vivo model that is acceptable for this purpose. Therefore, the tissue model may be based on a tissue model that is a material, such as synthetic, natural, mammalian (including any animal or human tissue), living tissue, preserved tissue, and the like.

Additionally, another important step includes identifying the depth of penetration in the tissue model for delivery of the drug. This includes targeting any desired or specific layer of tissue deemed suitable for microspray injection of drug 40. The drug 40 is then injected into the tissue model using a drug delivery device 20, 20a, 20b according to the present invention under variable pressure until the desired penetration depth or desired tissue layer is obtained. Is tested in

In using the method according to the invention, an optimum pressure range is identified for the drug delivery devices 20, 20a, 20b to achieve the desired penetration depth or the desired tissue layer. As summarized above, the optimum pressure range was found to be ≦ 2,000 psi at the main piston 44 and the optimum pressure range of ≦ 8,000 psi was identified for the area at the tip of the injection nozzle 34.

The method according to the invention also comprises the use of predictive modeling to predict the optimal pressure range required by determining the required injection force F. Determining the injection force (F) is achieved according to the formula: F = 8QμL (R ² / r ⁴ ), where Q = flow rate of the drug; μ = viscosity of drug; L = length of injection nozzle; R = radius of drug reservoir; r = radius of the scanning nozzle.

How to use

For transdermal or skin delivery, the drug delivery device 20 (FIGS. 1-4) is in its pre-launch configuration and is loaded with the total volume of drug 40 to be delivered and the drug delivery device 20 is conventionally The skin is pinched and placed firmly at right angles to any desired injection site (typically forearm, stomach or thigh). Because the injection nozzle 34 terminates as a small outward projection from the outer surface of the nozzle plate 30, the user may be prompted for proper positioning and alignment of the injection nozzle 34 on the surface of the user's human tissue at the desired injection site. Tactile feedback is provided.

As shown in FIG. 4, by pressing the actuation button 74, the striker pin 70 strikes the primer 68 to activate the primer 68, which in turn causes very rapid burning of the pyrotechnic charge 64. Cause This controlled explosion provides the propulsion force necessary to slide and advance the piston 44 and the attached push rods 48 through the reservoir 38 such that the push rods 48 are injected by microspray propulsion. Drugs 40 are discharged to the outside through the).

Although these examples described immediately above are for subcutaneous or skin delivery, the eye (the drug delivery device 20a), the mouth (the drug delivery device 20b), the nose (the drug delivery device 20b), the ear Other examples of drug delivery devices 20a, 20b used in applications such as the genus (drug delivery device 20b) and, more broadly, common transmucosal delivery (drug delivery devices 20, 20a, 20b). There is. Also, "transdermal" delivery means all forms of delivery, such as intradermal, subcutaneous, and intramuscular.

In another embodiment according to the invention, the drug delivery device 20a (FIGS. 5-7B) is particularly suitable for ophthalmic applications, and any drug 40 required for micro-injection in the eye (especially intrascleral or vitreous injection) I can deliver it. Such drugs known for this particular application generally include VEGF antagonists, cortical steroids, angiogenesis inhibitors. Indications treated by the drug delivery device 20a (FIGS. 5-7B) according to the present invention include, for example, diabetic retinopathy, ectopic degeneration, and other diseases related to neovascularization of the eye.

In this embodiment, the contoured distal end or cup 31 is disposed on or above the surface of the eye 100, with the open center portion of the cup 31 overlying the cornea. The micronozzles or injection nozzles 34 are configured spaced around the concentric rings of the distal end 31 of a certain shape such that they contact the sclera. In one embodiment according to the invention, the injection nozzle 31 is configured in a circular or elliptical pattern. However, it is contemplated by the present invention that the scan nozzles 34 are arranged or configured in any desired configuration or pattern.

As the actuation button 74 is pressed, the injection flow of drug 40 as shown in FIG. 5 penetrates deeply into the eye 100 through the sclera, resulting in aqueous fluid or vitreous or any portion of the eye 100. Deeply penetrates into the desired tissue layer. Preferably, the drug 40 injected under microspray propulsion is aimed towards the back of the eye 100 as now illustrated. As mentioned above, many drugs of current importance are administered by injection directly into the eye with conventional needles and syringes. As can be seen, it is a rather dangerous procedure and requires injections to be administered by a trained ophthalmologist. There is a significant risk to the patient with regard to the prior art and includes detachment of the detachment, wounds after repeated injections, and even blindness. In addition, the injection itself is anxious and requires the patient to be very still for a few seconds of the injection itself.

In the present invention, injection of the drug 40 into the eye 100 is extremely fast. For example, given the drug storage 38 having a volume of 20 microliters, the flow rate of the drug 40 injected under 100 m / s of microspray propulsion, the total injection is a drug delivery device according to the present invention. Using only 20a requires only about 10 msec. Assuming that the patient deliberately moves his or her eye 100 from one side to the other during the injection, and assumes that eye movement occurs at a rate of about 1 cm / s, the eye is about 1/10 during this time. Mm movement, and consequently, no movement when using the drug delivery device 20a according to the invention. Also, as a result, the present invention provides a safer and more comfortable means of administering drugs to the eye 100 for both doctors and patients.

As contemplated by the present invention, the drug delivery device 20a (FIGS. 5-7B) according to the present invention provides a number of advantages over conventional techniques or techniques. For example, the injection nozzle 34 may be designed to "target" the injection flow to certain areas of the eye 100 (eg, behind the eye 100). In addition, the penetration depth of drug 40 can be controlled without depending on the skill of the caregiver. In addition, the risk of injury to the eye 100 is a drug delivery device according to the present invention by minimizing the energy and tear (trauma) received by the eye 100 due to the extremely fast nature of the micro-injection of the drug into the tissue of the eye 100 5a; FIGS. 5-7b) (estimated to be as fast as about 10 msec during the injection of a small dose of drug 40).

In addition, the drug delivery device 20a has the ability to adjust the injection injection energy and the injection flow shape as a means of controlling the delivery depth of the drug to the eye. In addition, the design of the micronozzle shape allows control of the flow diameter, trajectory, cohesion, and focus. In addition, the flexibility of the design of the micronozzle arrangement allows to optimize the drug delivery profile for any drug, disease, or disease site in the eye. In addition, the drug delivery device 20a provides a means for administering the drug 40 very quickly to the eye 100 such that eye movement is not a risk factor.

Additionally, many of the drugs 40 currently preclinical and / or clinically investigated are efficacy drugs and require periodic administration of only a small dose to the eye 100. The drug delivery device 20a (FIGS. 5-7B) according to the present invention is a more controlled, repeatable, safe and convenient means of delivering such drug 40 to the eye 100 over all known devices and techniques currently available. To provide.

Another embodiment according to the invention is the nose application illustrated in FIG. 10. Accordingly, the drug delivery device 20b (FIGS. 8-10) is a particularly useful application for administering the CNS (central nervous system) drug 40 to the olfactory bulb of the patient's nose 110 via microinjection injection. Has

In this embodiment, a drug delivery device 20b (FIGS. 8-10) is used to provide direct injection of drug 40 into the CSF of the olfactory lobe into the submucosal space of the nose 110 under microspray propulsion. For this purpose, a dose of 20 mg or more of drug 40 can be injected extremely rapidly (<50 msec) into the submucosal space and the injection depth is accurately delivered to this area without any risk of drug 40 penetrating into an undesired location. Can be controlled as accurately as possible.

In another embodiment according to the invention, the drug delivery device 20b is also used for intraocular delivery of the drug 40 where the drug is targeted for applications such as treating a tumor, ie, for injection of a tumor. Under propulsion, it can be microsprayed into any desired area of the mouth, such as the transmucosal membrane, for targeted delivery of the drug 40.

In another embodiment according to the present invention, the drug delivery device 20b is used for intradermal delivery of the drug 40, such that the drug 40 can be used for example for abnormalities or abnormalities in the ear and various diseases that affect hearing. It can be microsprayed into the auditory canal or any desired part of the ear for treatment.

Additionally, in other embodiments of the present invention, the drug delivery device 20b is also useful for areas of the human body that are difficult to access, such as various canals, passages, cavities or inaccessible surfaces. An extended delivery tube 25 facilitates access to these injection sites for injecting the drug 40 under microspray propulsion into these difficult areas.

Therefore, as described above, the drug delivery device 20, 20a, 20b according to the present invention has many novel features and advantages. Some of these novel features and advantages include here extremely small injection nozzles (less than 0.002 "); multiple injection reservoirs and injection nozzles that minimize pain by minimizing each injection volume and injection time; for targeting shallower tissues. Variable pressure injections, including high pressure injections to reach low and deep tissues; the ability to spread over a wider surface area or to concentrate drug dosages into a defined area; large volumes of injections divided into smaller volumes of separate syringes (Which can achieve an injection volume greater than or equal to conventional injection syringes with faster delivery times); including total energy requirements, such as the total energy requirements possible with prior art devices, but in the present invention suffer much less from the patient. Efficient injection, which is a natural injection and involves the administration of drugs much faster; The ability to deliver drugs (i.e. different drugs may be housed in different drug reservoirs, which is not possible with existing drug delivery devices currently available); excipients during storage until injection time which improves the long term stability of drug 40 is summarized as the ability to separate excipients.

There is no known or conventional technique that provides the benefits that the present invention supports, including safety, ease of use, dose and depth of penetration accuracy, patient comfort and appreciation. Other advantages with respect to the present invention may be provided for accurate and targeted delivery of large and small molecules such as large proteins, cells or other physiological molecules and large molecules such as drugs. And another advantage is that the micro-injection drug delivery device according to the invention is extremely fast in drug delivery, i.e. less than about 10 ms of delivery, resulting in almost painless injection.

The present invention contemplates that reducing the nozzle orifice size significantly reduces pain in the patient. In addition, the present invention may make practical use of new injection injection techniques such as transmucosal delivery.

It is an advantage of the present invention that a plurality of nozzles can be used that ensure a squareness because they form a two-dimensional flat structure that can be arranged in an arrangement and have a space between each adjacent nozzle and can lie flat on the skin.

In addition, the present invention is well suited for delivering drugs to sensitive areas of the human body such as the eyes, nasal cavity, mouth, etc., and delivers drugs that are truly needle-free with minimal trauma to the tissue and are not related to the size of the drug molecules involved. Pass without a needle.

The drug delivery devices 20, 20a, 20b are simple and efficient design and construction, low cost and easy to manufacture. Thus, the micro-injection drug delivery device according to the invention has a suitable design which is very suitable for disposable devices for one patient if desired.

Since the foregoing description includes preferred embodiments of the invention, it will be understood that modifications and variations may be made in accordance with the principles of the invention disclosed herein without departing from the scope of the invention.

While the preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments have been provided for purposes of illustration only. Various modifications, changes and substitutions will now occur to those skilled in the art without departing from the invention. Accordingly, the invention is limited only by the spirit and scope of the appended claims.

Claims (17)

A method of making an injectable injection drug delivery device having at least one drug reservoir and at least one injection nozzle, the method comprising Identifying a drug to be delivered; Identifying a volume of drug to be delivered; Setting a reservoir diameter of the at least one drug reservoir; Setting a nozzle diameter of said at least one scanning nozzle; Identifying a tissue model excluding human tissue for delivery of the drug; Identifying the depth of penetration in the tissue model for delivery of the drug; Injecting the drug into the tissue model under variable pressure until the desired penetration depth is achieved; And Identifying an optimal pressure range of 800 to 2,000 psi for the drug delivery device to achieve the desired penetration depth; The tissue model is based on materials of synthetic, natural, non-human mammal, living tissue, or preserved tissue, Wherein said tissue model is an ex vivo tissue model or an in vivo tissue model. delete delete The method of claim 1, And confirming that the optimum pressure range at the tip of said at least one injection nozzle is between 4,000 and 25,000 psi. The method of claim 1, Using at least one material selected from the group consisting of ceramics, metals, metal alloys and thermoplastics for the components of the drug delivery device. 6. The method of claim 5, The method of claim 1 further comprising the step of making an orifice in the at least one injection nozzle by drilling. The method according to claim 6, The method of claim 1 further comprising the step of making an orifice in the at least one injection nozzle by laser drilling. The method according to claim 6, The method of claim 1 further comprising the step of making an orifice in the at least one injection nozzle by ultrasonic drilling. The method according to claim 6, The method of claim 1 further comprising the step of making an orifice in said at least one injection nozzle by wire processing. The method according to claim 6, Further comprising making an orifice in said at least one injection nozzle by molding or molding. The method of claim 1, A method of manufacturing an injectable injection drug delivery device further comprising the step of predicting the optimum pressure range required by determining the required injection force (F) by the following equation. F = 8QμL (R ² / r ⁴ ) Where Q = flow rate of the drug         μ = viscosity of drug         L = length of injection nozzle         R = radius of drug reservoir         r = radius of injection nozzle delete delete 5. The method of claim 4, And discharging said drug through the tip of said at least one nozzle in a pressure range of 8,000 to 12,000 psi. The method of claim 1, And discharging said drug through the tip of said at least one nozzle in a pressure range of 10,000 psi. delete The method of claim 1, And discharging the drug through the one or more nozzles within a time range of 10 msec to 200 msec upon operation of the energy source to provide a propelling pressure of 800 to 2,000 psi. .

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