• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention is a method for parenteral administration of a drug to a patient so that the drug is dispersed immediately once the drug is administered, the method comprising the following steps: Obtaining anhydrous solid drug composition consisting essentially of a drug and a pharmaceutically acceptable carrier of less than 50% by weight. and upon contact with the parenteral fluids is selected and formulated to be distributed into the patient's bloodstream according to the blood's blood profile of the drug corresponding to the blood's blood profile when the liquid formulation is administered. The method comprises the step of introducing the solid drug composition into the parenteral fluid of the patient.
    公开号:KR20030096434A
    申请号:KR1020017005475
    申请日:1995-08-31
    公开日:2003-12-31
    发明作者:롤랑드세리프-세이크
    申请人:디랩；
    IPC主号:
    专利说明:

    Delivery of Solid Drug Compositions
    [17] The present invention relates to parenteral administration of solid drug compositions.
    [18] Drugs are administered via the parenteral route of administration for a variety of reasons, for example by injecting a drug solution. For example, in the case of compounds that partially or completely degrade in the gastrointestinal tract, the method of infusion is used rather than oral administration. Infusion methods are also preferably used when a rapid response is required, i.e. when the time interval between the time when the drug is orally administered and the time when the drug acts at the target point is too long. In addition, in order to use drugs efficiently, continuous and controlled parenteral administration methods are required to achieve a predetermined effect. This form of prolonged parenteral administration can also be achieved by injecting a drug solution.
    [19] Continuous parenteral delivery of the drug involves the use of a mechanical perfusion device comprising a catheter and a needle or a polylactide polymer that allows the drug to be released over an extended period of time by acting to delay the release of the drug. It may also be achieved by a sustained release composition that typically contains the same carrier and drug. See, for example, US Pat. No. 3,773,919 to Boswell et al. And US Pat. No. 5,004,602 to Hutchinson.
    [20] The perfusion device includes a removable device driven by electrical power or mechanical power. Such devices generally have a fairly large size, often ranging in volume from 40 to 1000 cm 3. As a result, such a device causes physical discomfort for the patient. Electrically powered devices are designed to be reusable by exchanging the catheter and needle after each use, while devices powered by mechanical power are generally designed for single use.
    [21] Electrically actuated pumps include syringe pumps whose mechanical screws are adapted to push the plunger onto the syringe, and peristaltic pumps, wherein the rotating wheels pressurize the tubes to inject liquid drug solutions into the patient. Piezoelectric pumps are also used to inject small amounts of liquid drug solutions into patients. Removable pumps operated by mechanical power are operated by osmotic pressure, gas pressure or air pressure, or mechanical elastic force.
    [22] Although the method of administration of injecting a liquid drug solution clearly provides advantages, there are also many disadvantages associated with the use of liquid excipients in which the liquid solution used for infusion is inevitably used in large quantities. For example, in conventional infusion with syringes and needles, the drug to be administered must be dissolved or suspended in water or the corresponding therapeutically acceptable liquid excipient. However, even small amounts of active drug compounds often require a significant volume of liquid to suspend or dissolve them. For example, the weight ratio of drug to excipient may be 1: 100, or even 1: 1000. Such high doses can cause discomfort or severe pain in patients, especially those that require at least once a day for months or even lifetime, such as diabetics who need to inject insulin once or twice a day. This is especially true for patients. In addition, the drug is often deteriorated in stability when mixed with excipient solutions, and the preparation of infusion solutions using sterile solutions on the fly is inevitably exposed to the risk of contamination.
    [23] The present invention is based on the discovery that any drug can be formulated into an anhydrous solid composition that can deliver the drug immediately once injected into body fluids. This new drug composition can reduce the volume of a conventional liquid drug solution hundreds to thousands of times. That is, the present invention is a system for injecting a solid dosage form of a pill in the form of a single dose that is preloaded into a needle equipped with a disposable syringe type device or an externally removable pump device. It is characterized by a system that can address the disadvantages of liquid drug delivery systems for administration.
    [24] Syringe-like devices are inexpensive and can be fabricated using the elements used to make existing standard syringes. External pumps allow the solid drug composition to be slowly injected and can be made from many standard materials.
    [25] The system of the present invention, once used with a pre-loaded needle, whether a syringe-type device or an external pump, cannot reload the needle by a patient and can also be used to deliver a liquid drug formulation. It provides an additional benefit of no. Thus, it is much safer than standard liquid drug delivery syringes that can be transmitted by repeated use to spread diseases such as AIDS and hepatitis.
    [26] In addition, the system of the present invention does not need to formulate the drug composition on the fly, and does not require any special technique to properly inject the drug composition, that is, it does not require a procedure for finding a blood vessel and injecting the drug composition. have. Therefore, the expert does not need to administer the drug composition.
    [27] Generally, the present invention comprises (1) anhydrous solid drugs consisting essentially of drugs such as peptides or proteins, and less than 50% by weight of pharmaceutically acceptable carriers, such as water soluble, water miscible or biologically dispersed carriers. As a step of obtaining a composition, the drug and carrier are dispersed from the composition as soon as the drug contacts parenteral fluids and the patient according to the blood concentration profile of the drug corresponding to the blood profile of the drug when the liquid formulation is administered. Characterized in that the selection and formulation so as to be distributed in the blood stream; (2) introducing the solid drug composition into the parenteral fluid of an animal or human patient, wherein the drug is parenterally administered to the patient so that the drug is dispersed immediately once administered.
    [28] The solid drug compositions of the invention are designed for parenteral administration, for example, by intravenous, intramuscular, subcutaneous, intradermal, or intracapital routes. Preferably, the composition is administered by subcutaneous route.
    [29] The solid drug composition of the present invention may be formulated into a substantially non-porous cylinder in which the ratio of surface area to weight per mg of drug in the composition is at least 10 mm 2. This ratio can range from less than 30 mm 2 per mg for nonporous solid compositions, and less than about 100 mm 2 for porous solid drug compositions.
    [30] The drug can be, for example, insulin, progesterone-releasing hormone (LH-RH), somatostatin or growth hormone releasing factor (GRF) and their analogs with biological activity. The drug may also be a cytostatic compound, anesthetic compound, a hormone or a vaccine.
    [31] The solid drug composition of the present invention may be combined with a carrier such as a polymer such as cellulose, hyaluronic acid, polyalcohol such as mannitol, or sugars, or in a solid composition without the use of a carrier.
    [32] The present invention also provides a solid drug composition using a device comprising a hollow needle containing a solid drug composition and a microplunger that moves inside the needle and pushes the composition from the needle into the parenteral fluid of the patient. It provides a method for parenteral administration of the drug, characterized in that the injection to the patient.
    [33] According to another embodiment of the present invention, there is essentially a drug such as a peptide or protein and a pharmaceutically acceptable carrier, such as a water soluble, water miscible or biologically dispersed carrier, which is less than 50% or less than 10% by weight. An anhydrous solid drug composition is provided, wherein the solid drug composition is formed in the form of a solid cylinder having a surface area-to-weight ratio of at least 10 mm 2 per drug in the composition, and wherein the drug and the carrier are combined with the parenteral solution of the drug. It is characterized in that it is selected and formulated to be distributed in the bloodstream of the patient according to the blood concentration profile of the drug corresponding to the blood concentration profile of the drug when it is dispersed from the composition upon administration of the liquid formulation upon contact. The compositions of the present invention may also contain no carrier and / or may be formulated in the form of a cylinder having a diameter of, for example, less than 0.8 mm.
    [34] The drug can be, for example, insulin, progesterone-releasing hormone (LH-RH), somatostatin or growth hormone releasing factor (GRF) and their analogs with biological activity. The drug may also be a cytostatic compound, anesthetic compound, a hormone or a vaccine. The carrier formulated in the solid composition can be, for example, cellulose, hyaluronic acid, polyalcohol, or saccharide.
    [35] The present invention provides the following steps: preparing a drug in a non-solid form; Extruding the non-solid drug into the form of a long filament; Cutting the long filament to obtain a solid cylinder form having a ratio of surface area to weight per mg of drug of at least 10 mm 2; and solidifying the cylinder form to obtain a solid drug composition. It provides a method of manufacturing.
    [36] In particular, the drug of the non-solid form of the present invention is obtained by mixing a water-soluble carrier with a sufficient amount of solvent to form a gel, mixing the gel with the drug to homogenize and obtaining a non-solid mixture, and then extruding and cutting the obtained mixture. It is then prepared by removing the solvent from the obtained cylinder form to solidify. In another embodiment, the drug may be obtained in non-solid form by heating the drug below the melting point of the drug and then cooling and solidifying the cylinder.
    [37] According to another embodiment, the present invention provides an externally removable device for automatically controlling and administering a solid drug to a patient, including: a housing having a maximum external size of about 3.0 cm and a total thickness of about 0.5 cm; A plunger located within the housing; A dispensing tube attached to the housing and consisting essentially of the drug and less than 50% by weight of a pharmaceutically acceptable water soluble carrier; An actuator disposed inside the housing to move the plunger from the housing into the dispensing tube; A controller acting on the actuator to regulate the movement of the plunger that is passed through the housing and into the dispensing tube; And a power source arranged to power the actuator and the controller, wherein the plunger moves the solid drug composition out of the dispensing tube at a predetermined controlled rate.
    [38] In a specific embodiment, the controller includes an electric motor, the power source is a battery, the actuator includes two rotating wheels that contact the plunger and move the plunger into the dispensing tube, wherein the controller is controlled drug. Certain drug delivery profiles include programmed microcomputers or microchips to provide delivery rates. Furthermore, since the drug delivery tube is disposable after use, the main parts of the housing including the controller, motor, battery and circuit can be recycled.
    [39] The present invention also provides a method for automatically administering a drug to a patient in accordance with a predetermined drug delivery profile, the method comprising: (a) obtaining an externally removable device as described above; (b) loading the solid drug composition into a dispensing tube; (c) inserting a dispensing tube into the patient; (d) programming the controller to cause the actuator to move the plunger through the dispensing tube in accordance with a predetermined drug delivery profile; (e) energizing controllers and actuators such that the plunger moves within the dispensing tube to move the solid drug composition out of the dispensing tube, entering the patient's interior to deliver the drug to the patient's body fluid according to a predetermined drug profile. Characterized in that it comprises a step. In this way, the device can be attached to the patient.
    [40] As used herein, the term “analog” or “biologically active analog” refers to peptides, proteins or proteins that are present in nature, recombined, or synthesized with physiological or therapeutic activity. Polypeptides. In general, the terms refer to peptides, proteins or polypeptides that act as unmodified or exhibit a qualitatively similar agonist or antagonist as compared to peptides, proteins or polypeptides present in nature. All analogs are included.
    [41] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present invention, the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. In addition, the materials, methods, and examples are illustrative only and not intended to limit the invention.
    [42] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
    [1] 1A-1C are cross-sectional views of syringe type devices used to inject a solid drug composition.
    [2] 2A-2C are cross-sectional views of another embodiment of a syringe like device.
    [3] 3 is a cross-sectional view of an externally removable pump device for delivering a solid drug composition, showing a state divided into two main parts.
    [4] 4 is an enlarged view of the apparatus shown in FIG. 3.
    [5] 5 is a cross-sectional view of the device shown in FIG. 3.
    [6] 6 is a schematic side view in partial cross-sectional view of another embodiment of an externally removable pump for delivering a solid drug composition.
    [7] 7 is a schematic side view of another embodiment of an externally removable pump for delivering a solid drug composition.
    [8] FIG. 8 is a graph comparing plasma glucose concentrations in rats injected with bovine insulin in the form of several solid formulations versus standard liquid formulations.
    [9] 9 is a graph showing plasma glucose concentrations in mice injected with a standard liquid insulin solution.
    [10] 10 is a graph showing plasma glucose concentrations in mice injected with a solid composition comprising 90% human insulin and 10% hyaluronic acid.
    [11] FIG. 11 is a graph showing plasma glucose concentrations in mice injected with a solid composition comprising 100% pure human insulin.
    [12] 12A-12C are bar graphs showing the effect of solid compositions of somatostatin analogs (BIM 23014C), standard liquid solutions of BIM 23014C, and controls on gastric acid hypersecretion in rats.
    [13] FIG. 13 is a graph showing plasma concentrations in mice of subcutaneously injected synthetic anti-platelet activating factor (anti-PAF) (BN 50730).
    [14] FIG. 14 is a graph showing plasma concentrations in mice of synthetic anti-platelet activating factor (anti-PAF) (BN 50730) injected subcutaneously in liquid solution.
    [15] FIG. 15 is a graph showing percent platelet aggregation inhibition induced by 2.5 nM platelet activating factor (PAF) induced by solid and standard liquid formulations of ginkgolide B (BN 52021), a natural anti-PAF.
    [16] FIG. 16 is a graph showing the skin anesthesia effect of the solid and liquid formulations of tetracaine on rats compared to the control group.
    [43] The present invention relates to a delivery system for a solid pharmaceutical composition comprising a syringe-like or external pump device specifically designed for use with a novel anhydrous solid pharmaceutical composition. This syringe type device preferably dispenses the solid drug composition into a single dosage unit so that the drug can be delivered immediately. That is, the drug is dispersed into the body fluid from the composition upon contact with the body fluid and delivered according to the blood concentration profile of the drug corresponding to the blood concentration profile of the drug when the liquid formulation is administered.
    [44] This blood concentration profile can be determined by taking blood samples at specific time intervals, for example, 30 minutes from 5 hours after injecting the drug composition and measuring the concentration of drug in the blood for each sample. The two profiles are comparable compared to the results of a control injected in the form of a standard liquid formulation sampled at the same time interval, that is, the concentration of drug in the blood in both liquid and solid compositions Determine if the first peak is within 50% of each point after stabilization.
    [45] On the other hand, an external pump may be used to administer the solid drug composition as a separate dosage unit at predetermined time intervals for a long time, or to administer the solid drug composition as a continuous dosage unit that is gradually and continuously delivered over a day or several days. In each case, the drug is dispersed from the solid composition into the body fluid as soon as it is injected into the body. For example, small individual drug cylinders are delivered separately from each other, or long drug cylinders are slowly introduced into the body fluids.
    [46] Solid drug compositions
    [47] The solid drug composition contains one or more drugs and one or more carriers, and is preferably a small rod having a hardness that is rigid enough to be handled and to be inserted and injected into the patient's body from a delivery device. ) Or a cylinder. The shape and size of the cross section of these cylinders should be constant in the longitudinal direction and small enough to allow highly precise control of the amount of drug contained in the cylinder of a given length. These small cylinders are, for example, 0.1 to 5.0 cm in length and 0 to 0.8 mm in straight line.
    [48] The ratio of surface area to weight of the solid drug composition also plays a very important role in the rapid dispersal of the drug from the composition once the composition is introduced into the body fluids of the patient. For solid compositions that are substantially nonporous, this ratio should have a surface area of at least 10 mm 2 per mg of drug in the composition, and can reach 30 mm 2 per mg of drug. In the case of porous drug compositions, the surface area may be larger because the voids increase the total surface area. In this case, the ratio may be in the range of 100 mm 2 per mg of drug. These ratios can be achieved by preparing the solid drug composition by the method described below.
    [49] It is desirable to disperse the drug or drugs homogeneously throughout the solid drug composition cylinder. In addition, in the case of long term administration using a removable pump, the delivery profile can be changed by varying the concentration of the drug throughout the cylinder.
    [50] Drugs Suitable For Solid Drug Compositions
    [51] Some drugs can be formulated into solid cylinders on their own without the use of a carrier. For example, so-called "pro-drugs" polymerize from hybrid molecules of a crosslinkable drug, such as hybrid molecules with a drug and a crosslinking site, such as sugars or polyamino acids, such as polyarginine derivatives, and the like. . Examples of drugs that do not require the presence of carriers are peptides, e.g. SOMA tulrin R (SOMATULINE R) (BIM- 23014) , and such somatostatin analogs, are peptides such as LH-RH, or human insulin, such as a trip Sat relrin .
    [52] In general, the composition contains at least 50% by weight of the drug and less than 50% of the carrier, preferably less than 10% of the carrier. Typical solid drug compositions contain at least 90% of the drug or drugs depending on the properties of the carrier and the properties of the rod or cylinder to be produced.
    [53] Even when a carrier is required, the solid drug composition has the advantage of minimizing the total amount of carrier injected into the patient. For example, in conventional liquid formulations, insulin is usually administered in an amount of 40 to 100 I.U./ml, which typically corresponds to a dose of about 2 to 4 mg / ml. That is, the aqueous carrier accounts for 99.5 to 99.8% of the total administered weight injected, which corresponds to 500: 1 to 200: 1 in terms of weight ratio of carrier to insulin.
    [54] In addition, many liquid drug formulations contain organic solvents or other additives to change pH, for example for the purpose of forcing the drug to dissolve in solution. These solvents and additives are usually harmful to the patient, even when used in small amounts, and therefore it is advantageous to minimize their use. In addition, the carriers selected for use in the solid drug compositions of the present invention are inert and have no detrimental effect, since they do not require special physical properties and are used in very small amounts.
    [55] The present invention also does not include problems associated with the formulation and solubility of liquid drug solutions. Thus, even if the drug is incompatible or insoluble with standard liquid formulations, it is possible to combine one or more drugs in the drug compositions of the invention in various ways, for example simply dispersing the drug in particulate form in a carrier This is because they do not dissolve the drug but only disperse in the carrier to form a suspension or semi-solid dispersion. The homogeneous mixture obtained is solidified and the carrier used in the production process is removed. As a result, a drug that is insoluble or incompatible in the solution can be easily blended into the solid drug composition.
    [56] Another advantage of the present invention is the increased stability of the drug in the solid composition. Drug solutions are often difficult to keep stable for long periods of time. For example, drug solutions may absorb contaminants or precipitate active ingredients out of solution. Anhydrous solid drug compositions largely solve this problem. In addition, the solid composition is not affected by shear force or turbulence that degrades proteins or peptides in solution, and does not have problems such as crystallization, aggregation or coagulation associated with liquid formulations. That is, the drug (s) in the solid drug composition are stable for a longer time than the same drug in the liquid formulation.
    [57] Drugs that can be used in solid drug compositions include polypeptides such as growth hormone (GH), growth hormone releasing peptide (GHRP), growth hormone releasing factor (GRF), epidermal growth factor, interferon, insulin, somatostatin, bombesin, calcitonin , Calcitonin gene related peptide (CGRP), amylin, parathyroid hormone (PTH), parathyroid hormone-related peptide (PTHrp), gastrin, gastrin releasing peptide (GRP), black cell stimulating hormone (MSH), adreno Corticotropic hormone (ACTH), luteinizing hormone (LH), luteinizing hormone-releasing hormone (LH-RH), cytokinase, sorbine, cholecystokinin (CCK), glucagon, glucagon-type peptide (GLP), gastrin, Enkephalin, neuromedin, endothelin, substrate P, neuropeptide Y (NPY), peptide YY (PYY), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating polypeptide It includes de (PACAP), bradykinin, tee Trojan pin releasing hormone (TRH), taxol, or derivatives, fragments, analogs, work material or antagonists of these drugs. These examples are for illustrative purposes only and do not limit the invention.
    [58] Preferably the drugs are those used in the fields of inflammation, oncology, cardiology, hormonal therapy, gynecological medicine, immunology, metabolism or maturation. Examples of such drugs include insulin, adrenaline, xylocaine, morphine, corticoid compounds, enzymes, atropine, cytostatic compounds, anesthetic compounds, estrogens, androgens, interleukins, digitoxins, biotin, testosterone, heparin, ginkgolides Anti-platelet activating factor (anti-PAF), such as BN 52021 or BN 50730, Beaufour Ipsen, France), cyclosporin, penicillin, vitamins, somatriptan R or diazepam. The drug may also be a therapeutic vaccine.
    [59] Suitable carriers for solid drug compositions
    [60] The carrier is required to impart physical properties to the composition and to be able to deliver the drug immediately upon contact with the body fluid. In addition, the carrier should not affect the biological activity of the drug and should be able to support and maintain the chemical stability of the drug.
    [61] The drug composition may be prepared using a carrier homogeneously combined with a solid drug or drugs. The carrier must be water soluble or biodegradable. Suitable carriers include hyaluronic acid, gelatin, polyvinylpyrrolidone (PVP), surfactants, organic solvents, polysaccharides (e.g., hydroxypropyl methylcellulose (HPMC), carboxy methylcellulose (CMC) and hydroxy ethylcellulose ( Cellulose such as HEC), saccharides such as textulose, mannose, sorbitol or glucose, and starch, collagen and the like.
    [62] How to Make a Solid Drug Cylinder
    [63] One method of mixing the drug with the carrier and loading the resulting drug composition for infusion through the needle of the delivery device is as follows. Carrier, for example hyaluronic acid, cellulose, PVP, or other such as mentioned above or known in the art, in water, for example in a container such as a 10 ml syringe with one end closed. Put it in. For example, a spatula is used to mix the two components to produce a homogeneous mixture such as a gel. For example, after about 24 hours once the gel has reached a stable structural equilibrium, it is mixed with the desired drug (s) in another container, for example 2 ml syringe. For example, the gel / drug mixture is kneaded well using a spatula to make it homogeneous. If the final solid composition does not contain a carrier, the drug is kneaded with water alone or with another carrier which will later evaporate.
    [64] The mixture is then transferred to an extrusion chamber, for example a stainless steel syringe, having an extrusion nozzle such as a needle with an internal diameter of 0.3 to 0.8 mm in the syringe. The gel / drug mixture (or water / drug mixture) is extruded and the cylinder with the correct length suitable for administration is completely dried in vacuo, for example at room temperature for 24 hours. Alternatively, the cylinder may be extruded in the form of a longer rod and then cut into shorter cylinders of the exact length required for administration.
    [65] Solid drug cylinders may also be made using other standard methods, such as fusion extrusion or wet or dry spinning. All of these techniques involve passing a non-solid mass of material through a small hole of a particular shape capable of producing a long cylinder or rod having a predetermined cross section.
    [66] The cylinder or rod can be dried or solidified directly, or it can be solidified after stretching. The material is made into a non-solid state by heating or addition of a solvent and then reduced again to a solid state by cooling or removing a solvent such as evaporation, cooling drying or vacuum drying.
    [67] The cylinders are then evaluated to determine the correct mass fraction of the drug, ie the dosage per cylinder length. Five cylinders are taken from each batch, and all drugs are removed from each cylinder by, for example, dissolved in a suitable solvent such as an aqueous 0.1% acetic acid solution and then measured by standard HPLC. For example, if the drug is insulin, a chromatographic column of 25 μm 25 × 0.46 cm of Chromasil-C8 may be used. The mobile phase is an isocratic mixture (pH 2.3) of 0.1% triethylamine and acetonitrile dissolved in 0.2 M Na 2 SO 4 . Various drugs are detected by UV of 220 nm. Sample solvent is 0.05N HCL and 0.2 mM cetyl-trimethylammonium bromide (Sigma).
    [68] Prior to use, uniformity is evaluated by calculating the weight / length ratio of the cylinder. Ten cylinders are weighed and the length is measured to obtain an average value. Only allowed if relative standard deviation (RSD) is less than 1%. Since this RSD corresponds to (length / reduction ratio ÷ standard deviation of the mean) × 100, it can be a measure of unity of weight / length ratio.
    [69] As a quality control measure, the batches of the cylinders are tested for their tendency to break or break into small debris upon application of firability, ie breaking force. This means that a ball mill with a steel or agate ball of 7 mm diameter, for example in a specific amount, for example 1 to 10 mg, is found to have the same size cylinder (MIXER MILL type MM-2, RETSCH, Germany In a 5 ml Teflon R grinding cup. The cup is shaken horizontally for 5 minutes at 20% of the machine's total operating force. The material obtained is sieved through a sieve having a predetermined mesh size (400 microns). The proportion of material passing through the sieve is a measure of the crushability or strength of the cylinder, and the acceptable range of crushability is determined as a function of the delivery device to be used, the length and diameter of the solid drug cylinder, and the injection route.
    [70] Once the cylinder is acceptable, the dosage is determined by measuring its length and weight. The cylinder is cut to the correct length corresponding to the desired dosage unit. Weigh again using microbalance (Mettler UMT 2) before dosing. The cylinder is now ready to be loaded into a hollow needle.
    [71] Pre-loading the drug composition into the hollow needle can be done through the back end of the needle. The tip of the needle is first sealed with an inert biomaterial layer such as gelatin or hyaluronic acid. The rear end of the needle is preferably in the form of a funnel to facilitate insertion of a solid drug cylinder and a microplunger which will be used to push the cylinder out of the needle and into the patient.
    [72] In one preferred embodiment, the back end of the needle is attached to a sterile plastic or glass cylinder from which the solid drug cylinder is extruded and dried. When dry, the cylinder falls into the needle by gravity. The preloaded needle is then ready to be attached to a syringe type or external pump delivery means as described below. This sterile plastic or glass cylinder also helps to prevent the device from dispensing the solid drug composition incorrectly.
    [73] Syringe-like Delivery Device
    [74] Syringe delivery devices for delivering solid drug cylinders, including hollow syringe barrels, needles, and microplungers and piston assemblies, can be readily manufactured using existing techniques. The needle may be for a standard hollow needle, for example a hypodermic syringe. The microplunger, which pushes the drug cylinder out of the needle and injects it into the patient, may be a stainless steel shaft such as that used in chromatography syringes, for example, Hamilton syringes. Pistons or guides that slide over the microplunger are inexpensive and simple plastic fittings, which are smaller and lighter than 1 ml syringes and can be repeated for many different preloaded needles.
    [75] 1A-1C show an infusion apparatus 10 comprising a hollow needle 1 pre-loaded with a single dose of solid drug composition 2 having the form of a cylinder to be injected. The diameter of the needle varies, for example 0.45 mm, 0.6 mm or 0.8 mm, and may be a diameter between 0 and 2 mm. The needle 1 is fitted to the sleeve 3, which causes the needle to be connected to the nozzle 6 at the end of the syringe barrel 5.
    [76] Microplunger 4 fits into the hollow channel of needle 1 and is in contact with drug 2. The microplunger may for example be made of stainless steel or plastic. Since the drug composition is solid, the periphery of the microplunger 4 does not need to be waterproof sealed, and the microplunger preferably has a diameter of 0.01 to 0.02 mm smaller than the inner diameter of the needle. For example, in the case of a 0.45 mm needle, the inner diameter of the needle is 0.27 mm, and the preferred diameter of the microplunger is 0.25 mm. In addition, the microplunger is preferably not sealed so that a significant amount of air does not enter the body fluid when the drug cylinder is injected into the body fluid.
    [77] Barrel 5 has two small flanges 7 at its distal end. Plunger stick 8 moves inside barrel 5 to push microplunger 4 into needle 1 and eject drug cylinder 2 to the outside. The device also includes a rubber plunger 9, which has a protective film 13 made of aluminum or paper on its side which, in use, comes into contact with the micro plunger 4 and the air passage 11. During assembly of the device according to the invention, the air present between the end of the microplunger 4 and the drug cylinder 2 is discharged from the space present between the microplunger 4 and the needle 1. As shown in FIG. 1B, during preservation, the loaded needle 1 is protected by a cap 12 and the barrel 5 is sealed by a protective film 13 'of aluminum or paper, which protective film 13' is positioned at the flange 7 position. Seal the barrel.
    [78] As shown in FIG. 1C, the protective film 13 'is removed or torn and the plunger stick 8 is inserted into the barrel 5, pushed over the plunger stick 8 to be in contact with the plunger 9 and the micro plunger 4 is in contact with the needle 1 so that the drug cylinder 2 Drug cylinder 2 is dispensed from needle 1 by causing it to be discharged from the end of needle 1. The length of the plunger stick and micro plunger is chosen so that when the micro plunger is inserted to the highest depth in the needle, the micro plunger does not come out of the tip of the needle or more than a few millimeters.
    [79] By adjusting the microplunger 4 and the plunger 9 to different positions or having different lengths, different amounts of drug can be loaded using the same microsyringe. In a preferred embodiment, the drug composition is pre-loaded into the needle.
    [80] 2A-2C show another infusion device 20 wherein the hollow drug cylinder 2 to be injected comprises a hollow needle 1 pre-loaded in a single dose. The tip of the needle 1 is sealed by the protective film 1 ', which may be immersed in the HPMC 2% gel or cover the entire needle using a cap as shown in FIG. 1B. The other end of needle 1 is conical and is fixed in guide member 23. Microplunger 4 has its one end fitted in contact with the drug cylinder in the hollow channel of needle 1 and the other end fitted with head 25. Guide member 23 has a grip portion 26 to be grasped by a user. The two extensions 27 located in the grip area 26 are designed to receive and fix the head 25 of the microplunger 4 and to prevent accidental movement, so the drug cylinder is released before the needle is inserted into the patient. To be safe. A slight pressure on the extension 27 causes the head 25 to move along the guide member 23 to push the microplunger 4 into the hollow channel of the needle 1 and thereby release the drug cylinder.
    [81] External Wearable Pump
    [82] 3-7 show several embodiments of an externally detachable pump for delivering a solid drug composition, for example for a prolonged period of days to weeks.
    [83] FIG. 3 shows an externally detachable pump 30 divided into a permanent housing portion 32 and a disposable housingportion 34, which are heat resistant, chemically inert and rigid materials such as polyvinyl It can be made or molded from chloride, polycarbonate, Teflon R , polysulfone R (AMOCO), or stainless steel. The central plunger 36 passes through the device to deliver the drug composition loaded in the needle 38 to the patient in a precisely controlled manner. The needle 38 is connected to a dispensing tube 40 made of metal, for example, and may include a guide tab 42 used to insert the needle into the patient. The guide tab 42 is preferably made of flexible plastic or rubber, attached to the dispensing tube 40 or molded integrally. Dispensing tube 40 is attached to outlet guide tube 50 via connector 51.
    [84] Both housing sections can be made transparent so that the plunger 36 can move properly through the device. The outer size of the housing is preferably about 3 cm in diameter and 0.5 cm in height. Permanent site 32 and disposable site 34 are preferably attached to each other by friction.
    [85] 4 and 5, the one-time housing portion 34 has three openings. The opening 44 allows for attachment of the plunger guide tube 46 and the opening 48 for attachment of the plunger discharge guide tube 50. These two hollow tubes 46 and 50 allow the plunger 36 to pass through the disposable portion 34 while simultaneously protecting and guiding the plunger. The cap 47 is coupled to the guide tube 46 to restrict the plunger 36 from moving inside the device. The opening 45 moves the wheel 56 (and the shaft 56 'and wheel holder 57) on the side of the lever 61 against the force of the spring 60. It forms part of a clip system that serves to connect the permanent portion 32 of the housing to the disposable portion 34, whereby the plunger 36 can be seated between the wheels 56 and 58.
    [86] An adhesive may be applied to the outer surface of the one-time housing site 34 to attach the device 30 to the patient's skin. This adhesive does not have to be too strong because the device is very light, but it should be easy to remove the device without inconvenience to the patient. The externally removable pump 30 can be connected to a strap that allows the device to be attached to the patient (for example, this purpose can be achieved by attaching the strap to the disposable housing buoy 34).
    [87] The permanent housing portion 32 includes an opening 33, which allows for easy removal of the battery 52 without affecting other parts of the housing. The permanent housing portion 32 includes an actuator assembly 54 for moving the plunger 36 through the discharge guide tube 50. Actuator 54 includes two wheels 56 and 58. These wheels are attached to the actuator by wheel holders 57 and 59, respectively. The wheel holder 59 is fixed to the support 53, which in turn is fixed to the substrate 53 ′ of the actuator assembly 54.
    [88] The wheels rotate in the opposite direction, causing the plunger 36 to move through the housing between the wheels and convert the rotary motion into a translational motion. Preferably, the distance between the two wheels is slightly smaller than the plunger diameter. The wheels are preferably made of stainless steel or plastic. These wheels may be cogwheels or wheels or rollers with smooth surfaces, eg rubber or plastic and without cogs, in the latter case they can only touch and move the plunger through the discharge guide tube 50. Just do it. The pressure the wheel exerts on the plunger is controlled by a spring 60 that pushes the two wheels in opposite directions. The wheel 56 is attached to the wheel holder 57 by the shaft 56 '. The wheel 58 is connected to the wheel holder 59 and the electric motor 62 by a shaft 58 '.
    [89] The plunger 36 is preferably made of a material having suitable rigidity, for example stainless steel or plastic, and includes a tip 35 in contact with the microplunger 37, which is also made of stainless steel and moves within the needle 38. The plunger may have a smooth surface or may have cogs or ridges to interact with the gear wheels 56 and 58. Preferably, the microplunger 37 may have a diameter slightly smaller than the inner diameter of the needle 38 (eg 0.3 to 0.8 mm) and a length slightly longer than the needle 38 (eg 3 cm). Preferably the plunger 36 is disposable. The new plunger can be loaded into the plunger guide tube 46 and the discharge guide tube 50 via wheels 56 and 58.
    [90] In this embodiment the power source for driving the device is an electric motor 62 driven by a battery 52 such as, for example, a 1.5V battery. The motor rotates the shaft 58 'coupled to the wheel 58, whereby the wheel 58 again rotates the second wheel 56 in the opposite direction. The motor may be a low-cost one-stage watch motor or movement type, typically less than 2 cm x 3 mm. In the case of a watch motor, power is transmitted to the actuator wheels by the hour or minute hand shaft.
    [91] Suitable watch movements include F.E. 7930, 6220 and 6230 (France-Ebauches, SA) (size 6¾ mm or 8 mm), Ronda Harvey 375 1.5V motor (10½ mm), Ronda 313 (11½ mm), and ISA 1198 (11½ mm) do. Other usable motors include continuous current motors, for example Maxon DC motors (2.8 to 12 mm in diameter) or Arsape AM 15-24 or AM 10-20 motors, or stepper motors, for example Arsape single-phase stepper motors P130. -S130 or P141, or an MMT two-phase stepper motor or the like. Other types of motors, for example spring-driven memory alloy-driven mechanical motors, electromagnetic motors, osmotic or electrochemically driven motors, also convert the drive force into a force that allows the plunger to move within the housing. I just need to be.
    [92] When using a watch motor, the translation speed of the plunger is determined by the diameter of the wheel 58 and its position on the hour or minute hand shaft. The speed of the wheel can also be adjusted by adding another wheel with a different radius between the axis 58 'and the wheel 58. If no watch motor is used, a separate transmission can be added to adjust the translation speed of the plunger. In addition, when using the watch motor, the patient can adjust the translation speed of the plunger by manual operation by rotating the external pin to rotate the hour and minute hands. For example, an external pin is an external pin used to reset the hour and minute hands of a clock. Thus, the patient can inject the drug immediately if necessary, for example, to eliminate pain.
    [93] The motor may also include a regulating mechanism such as an integrated circuit or microprocessor or associated circuit that is preprogrammed to regulate the motor and have the desired transfer profile. Such microchips and microprocessors and their associated circuits are known in the art and can be easily adapted to regulate electric motors for use in the devices of the present invention. Examples of such electrical control mechanisms include those disclosed in US Pat. Nos. 5,049,141 and 4,265,241. The power supply of such a circuit may be battery 52 or an additional separate battery.
    [94] The plunger discharge guide tube 50 is connected to the dispensing tube 40 by a connector 51, which may be molded integrally with the dispensing tube 40, preferably directly. Connector 51 is preferably made from silicone or TYGON R. The outer diameter of the discharge guide tube 50 is about the same as the inner diameter of the connector 51, which enables a strong frictional seal when the connector 51 is attached to the discharge guide tube 50. The dispensing tube 40 preferably forms part of the hollow metallic tube of the needle 38, or the needle 38 may be a separate part inserted into the dispensing tube 40. The needle is preferably a hypodermic needle or a butterfly needle.
    [95] Dispensing tube 40 and needle 38 are loaded with the solid drug composition. In a preferred embodiment, the solid drug composition is pre-loaded in the needle and tube by the above-described technique or other standard loading technique, and the composition is located between the tip of the needle and the connector 51. The inner diameter of the needle (eg 0.27 mm) should be slightly larger than the solid drug (eg 0.25 mm) and the microplunger 37 (eg 0.25 mm) which pushes the drug through the tube 40 into the needle 38.
    [96] In order to keep the tube and housing water-sealed, the interior of the dispensing tube 40 and, if necessary, the entire housing may be filled with biocompatible oil. Examples of suitable oils include silicone oil, Dow Corning 344 medical solution, Miglyol 812 Dynamit oil, castor oil, isopropyl myristate, ethyl oleate or olive oil for injection. These oils, for example, prevent the entry of aqueous liquids, such as body fluids or water, into the housing via dispensing tubes or needles when the patient bathes or showers.
    [97] In another embodiment, the motor includes an actuator of a mechanism that rotates the screw. Referring to the figure of FIG. 6, plunger 36 is attached to nut 70, which moves along screw 72 and rod 74 as screw 72 rotates by motor 76. The plunger 36 is stabilized by the plunger guide 78 connected to the rod 74.
    [98] The figure of FIG. 7 shows another embodiment in which the actuator is a pulley. In this embodiment, the bobbin 80 is attached to the motor 82 by the axis 84. The filament or wire 86 is connected to bobbin 80, passes through pulley 88 and is connected to plunger 66. As bobbin 80 is rotated by motor 82 in the direction of arrow 80 ', plunger 36 is pushed towards pulley 88, thereby pushing the drug composition out of the needle (not shown).
    [99] Examples of Solid Drug Compositions
    [100] Example 1: 100% human insulin
    [101] 81.52 mg of water was added to 81.86 mg of insulin. The mixture was kneaded with a spatula in a 1 ml plastic syringe and placed in a stainless steel syringe with an internal diameter of 2.3 mm with a needle having an internal diameter of 0.3 mm. The mixture was extruded through a syringe using a Harvard syringe pump. The obtained extruded rod was cut into a 1.5 cm long cylinder and collected on a glass slide. The cylinder was dried under vacuum for 24 hours. The resulting cylinder contains 0.470 mg (12.69 I.U.) of insulin / cm (19.035 I.U. in total). The cylinder was loaded into a needle having an inner diameter of 0.5 mm and a length of 15 mm.
    [102] Recombinant human insulin (RHI) is water soluble whereas bovine pancreatic insulin (BPI) is zinc insulin that is insoluble in water and usually prepared in a form dissolved in 16% glycerol. RHI and BPI provide about 26 to 28 insulin units (IU), respectively, depending on the purity of the insulin. Thus, a 10 IU solid drug cylinder may be 0.5 mg, 1.0 cm in length, and 0.3 mm in diameter. A 20 IU cylinder would be 1 mg, 2 cm x 0.3 mm. The 40 IU cylinder would be 2 mg, 4 cm x 0.3 mm.
    [103] Multiple doses of solid insulin may be compared to standard liquid injectable formulations made from 0.5 ml physiological serum or 16% glycerol formulation to contain the same amount of IU. FIG. 8 is an experiment conducted in vivo using non-diabetic Sprague-Dawley rats, and a liquid formulation control group containing the same dose (0.6 IU) of insulin (BPI). The hypoglycemic action of the insulin drug cylinder of the present invention is shown. Solid drug cylinders (eg, □) are as effective as liquid insulin preparation controls (■) in the strength and rapidity of their effects on glucose plasma concentrations in rats. This confirms the possibility of using solid drug compositions in place of standard liquid formulations.
    [104] In insulin therapy, solid drug delivery devices offer several distinct advantages; Patients need to carry small caps or blister-packs of micro-syringe needles pre-loaded with different doses of insulin (eg 10 IU, 20 IU, 40 IU) and small reusable delivery devices. Without any preparation, the patient can connect his chosen pre-loaded needle to the device and self-administer the appropriate dose of insulin in a manner that is relatively painless on its own. The solid drug composition is stable for a longer time than any other liquid formulation at room temperature.
    [105] Example 2 90% human insulin, 10% hyaluronic acid
    [106] 0.75 g of sodium hyaluronate and 9.25 g of water were mixed to make a gel. 0.11496 g of the gel obtained was mixed with 0.17761 g of insulin. The mixture was kneaded and extruded. The resulting extruded rods were cut to 1.5 cm in length and collected on a glass slide. The resulting 1.5 cm cylinder was dried under vacuum for 24 hours, which contained 0.514 mg (13.87 I.U.) insulin / cm (10 wt% hyaluronic acid and 90 wt% insulin). Thus, each cylinder contains 1.5 cm x 13.87 IU / cm = 20.8 IU.
    [107] Experiments using rats injected with insulin (0.6 IU) of various preparations showed that the effect of commercially available insulin solution (Humulina regular) on plasma glucose concentration (FIG. 9) was 90% insulin / 10 in solid drug form. % Hyaluronic acid composition FIG. 10) and 100% insulin (FIG. 11).
    [108] Example 3: 90% bovine insulin, 10% hyaluronic acid
    [109] The same protocol as in Example 2 was carried out by preparing a gel by mixing 0.75 g of sodium hyaluronate and 9.25 g of water. 0.30936 g of the gel obtained was mixed with 0.20848 g of bovine insulin. The mixture was extruded and cut. The 1.5 cm long cylinder contains a total of 22.17 IU of insulin / cm (10 wt% hyaluronic acid and 90 wt% bovine insulin).
    [110] FIG. 8 shows plasma glucose concentrations in mice administered 90% bovine insulin and 10% hyaluronic acid at a dose (◇) of 0.6 IU per mouse. This result shows that plasma glucose concentration is affected at substantially the same level as that of the insulin solution control (■) and the 100% insulin solid preparation (□).
    [111] Example 4: 97% bovine insulin, 3% carboxymethylcellulose
    [112] The same protocol was followed by preparing a gel by mixing 0.3 g of carboxy methylcellulose (CMC) and 9.7 g of water. 0.15964 g of the gel obtained was mixed with 0.14129 g of bovine insulin. The mixture was extruded and cut. A cylinder 1.5 cm long contains a total of 26.58 insulin (3% CMC and 97% bovine insulin).
    [113] The action of this bovine zinc insulin solid preparation (○) was compared with other bovine insulin preparations (FIG. 8). The results show that the 97% BPI / 3% CMC preparation had a glucose concentration reducing effect at substantially the same level as that of the insulin solution control (■) and the 100% insulin solid preparation (□).
    [114] Example 5: 100% SOMATULINE R(BIM-23014C)
    [115] The same protocol was carried out by mixing the gel with 175.43 mg of water and 75.34 mg of the acetate salt of somatostatin analogue SOMATULINE R (BIM-23014C, Biomeasure, Milford MA) to prepare a gel. The mixture was extruded and cut through a 2.3 mm syringe (0.5 mm inner diameter of the needle). The 3.6 cm long cylinder had a total capacity of 0.624 mg / cm. The cylinder was loaded into a 0.8 mm outer diameter needle.
    [116] In experiments with mice, BIM-23014C was gastric fluid for 100% BIM-23014C preparation (dose 50 μg / rat), liquid BIM-23014C solution (50 μg / ml, 1 ml dose per rat) and physiological serum control. The effect on secretion was determined. The results show that in terms of acid concentration (FIG. 12A), reduction of acid (FIG. 12B) and volume of acid (FIG. 12C), the solid drug formulation and the liquid solution formulation all exhibit substantially the same action.
    [117] Example 6: 10% hyaluronate, 5% POLOXAMER 188, 85% BIM-23014C)
    [118] The protocol described above was carried out by mixing 0.4065 g of sodium hyaluronic acid salt, 0.2157 g of POLOXAMER R 188 and 7.215 g of water to prepare a gel. 0.280 g of the obtained gel was based on 0.120 g of SOMATULINE R acetate salt. The mixture was weighed, kneaded and extruded. The resulting extruded rods were cut and collected on glass slides and dried under vacuum for 24 hours. This 3.6 cm cylinder contains 0.648 mg of SOMATULINE R / cm (10% of sodium hyaluronate sodium salt, 5% POLOXAME R 188, 85% SOMATULINE R acetate). Thus, each cylinder contains 3.6 cm x 0.648 mg / cm = 2.33 mg of SOMATULINE R.
    [119] Example 7: 80% BIM-23014C, 20% mannitol
    [120] The above protocol was carried out by preparing a solution by mixing 1.00 g of mannitol and 9.0 g of water. 0.14122 g of the obtained solution was added to 0.0605 g of SOMATULINE R acetate salt. The mixture was weighed, kneaded and extruded. The resulting extruded rods were cut and collected on glass slides and dried under vacuum for 24 hours. The resulting 3.6 cm cylinder contained 1.22 mg of SOMATULINE R / cm (20% mannitol, 80% SOMATULINE R acetate). Thus, each cylinder contains 3.6 cm x 1.220 mg / cm = 4.39 mg SOMATULINE R.
    [121] Example 8: 90% BIM-23014C, 10% mannitol
    [122] The above protocol was carried out by preparing a solution by mixing 1.0096 g of sorbitol and 19.0053 g of water. 0.14 g of the obtained solutionRTo 0.06094 g of acetate salt was added. The mixture was weighed, kneaded and extruded. The resulting extruded rods were cut and collected on a slide-slide and dried under vacuum for 24 hours. The resulting 3.6 cm cylinder was 0.644 mg SOMATULINER/ Cm (10 wt% mannitol, 90% SOMATULINERAcetate). Thus, each cylinder had a SOMATULINE of 3.6 cm x 0.644 mg / cm = 2.31 mg.RIt includes.
    [123] Example 9: 84% BIM-23014C, 16% polysorbate 80
    [124] The above protocol was carried out by preparing a solution by mixing 0.8 g of POLYSORBATE 80 and 9.2 g of water. 0.14079 g of the obtained solution was added to 0.06 g of SOMATULINE R acetate salt. The mixture was weighed, kneaded and extruded. The resulting extruded rods were cut and collected on glass slides and dried under vacuum for 24 hours. The resulting 3.6 cm cylinder contained 0.6459 mg of SOMATULINE R / cm (16% by weight polysorbate 80 and 85% SOMATULINE R acetate). Thus, each cylinder contains a SOMATULINE R of 3.6 cm x 0.6459 mg / cm = 2.3 mg.
    [125] Example 10: 84% BIM-23014C, 16% polyvinylpyrrolidone (PVP)
    [126] The above protocol was carried out by preparing a gel by mixing 0.64 g of PVP and 7.37 g of water. 142 mg of the obtained gel was added to 64 mg of SOMATULINE R acetate salt. The mixture was weighed, kneaded and extruded. The resulting extruded rods were cut and collected on a slide-slide and dried under vacuum for 24 hours. The resulting 3.6 cm cylinder contained 0.6207 mg of SOMATULINE R / cm (14 wt% PVT, 86% SOMATULINE R acetate). Thus, each cylinder contains 3.6 cm x 0.6207 mg / cm = 2.23 mg of SOMATULINE R.
    [127] Example 11 85% BIM-23014C, 15% Hyaluronic Acid Sodium Salt
    [128] The above protocol was carried out by mixing 1.0 g of sodium hyaluronate and 9.0 g of water. 0.24417 g of the obtained gel was added to 0.13864 g of SOMATULINE R acetate salt. The mixture was extruded and cut through a 2.3 mm syringe (0.3 mm inner diameter of the needle). The resulting 3.6 cm cylinder contained 0.993 mg / cm (15 wt% hyaluronic acid, 85% BIM-23014). Thus, each 3.6 cm cylinder contains 3.57 mg of SOMATULINE R.
    [129] Example 12: 95.7% BIM-23014C, 4.3% Carboxy Methylcellulose
    [130] The above protocol was implemented by mixing 0.3 g CMC and 9.7 g water. 0.2095 g of the obtained gel was added to 0.13992 g of BIM-23014. The mixture was extruded and cut through a 2.3 mm syringe (0.3 mm inner diameter of the needle). The resulting 3.6 cm cylinder contained 0.929 mg / cm (4.3 wt% CMC, 95.7 wt% BIM-23014). Thus, each 3.6 cm cylinder contains 3.34 mg of SOMATULINE R.
    [131] Example 13: 100% anti-platelet activating factor
    [132] 4,7,8,10-tetra-1-methyl-6- (2-chlorophenyl) -9- (4-methoxyphenyl-thiocar, which is 86 mg of water and synthetic anti-platelet activating factor (anti-PAF) Barmoyl) -pyrido- [4 ', 3',-4,5] thieno [3,2-f] -1,2,4-triazolo [4,3-a] 1,4-diazepine The above protocol was carried out by mixing with 114 mg (BN 50730) or Ginkgolide B (BN 52021), a natural anti-PAF. The mixture was extruded and cut through a 2.3 mm syringe (0.3 mm inner diameter of the needle). The cylinder obtained had a dose of 1.0 mg / cm.
    [133] These cylinders were subcutaneously administered to rabbits at a dose of 2.0 mg / kg and compared with BN 50730 mixed with propylene glycol. For this insoluble compound, the solid preparation had an immediate effect on plasma. As shown in Fig. 13, when 20% BN 50730 paste dissolved in 80% propylene glycol was injected subcutaneously into rabbits (n = 5) at a dose of 4.0 mg, plasma was reduced for 48 to 96 hours except for one rabbit. Approximately constant concentration of about 10 mg / ml was maintained. The single rabbit showed peak concentrations at 6 and 24 hours and then decreased in concentration for 36 to 96 hours. The concentration of 10 mg / ml is sufficient to exhibit a pharmacological effect.
    [134] On the other hand, as shown in Fig. 14, when a 0.2% solution of BN 50730 dissolved in propylene glycol was administered at a dose of 4.0 mg, the concentration in plasma rapidly decreased from 24 hours. The exception was for only one rabbit 0, which was re-administered at 36 hours, with concentrations changing over 72 hours.
    [135] In ex vivo rabbit testing, the biological action of BN 52021, ie, the inhibition of platelet aggregation induced by PAF, was determined in solution form (NaCl at pH 8.75, dose 0.5 mL / kg) and in solid form (drug). The same dosage for Mggliol 812) was comparable and commenced at the same time. As shown in FIG. 15, at a concentration of 2.5 nM PAF, the anti-PAF drug BN 52021 in liquid solution showed the first platelet aggregation inhibition peak in about 30 minutes, which is later in time compared to the solid form of the drug. However, the solid BN 52021 composition showed a higher overall platelet aggregation inhibitory effect than the liquid formulation after 1 hour. Both formulations showed a significant inhibitory effect after 24 hours.
    [136] Example 14 93% BN 52021, 7% hyaluronate
    [137] The above protocol was implemented by mixing 0.75 g sodium hyaluronic acid salt and 9.25 g water. 0.18912 g of the obtained gel was added to 0.1885 g of BN 52021. The mixture was extruded and cut through a 2.3 mm syringe (0.3 mm inner diameter of the needle). The resulting 2.3 cm cylinder contained 0.678 mg / cm BN 52021 (7% by weight hyaluronic acid, 93% BN 52021) for a total of 1.56 mg per cylinder.
    [138] Example 15: 98% BN 52021, 2% Carboxy Methylcellulose
    [139] The above protocol was implemented by mixing 0.3 g CMC and 9.7 g water. 0.09347 g of the obtained gel was added to 0.12076 g of BN 52021. The mixture was extruded and cut through a 2.3 mm syringe (0.3 mm inner diameter of the needle). The resulting 2.3 cm cylinder contained 0.998 mg / cm BN 52021 (2 wt% CMC, 98% BN 52021) for a total of 2.29 mg per cylinder.
    [140] Example 16 100% Tetracaine HCL
    [141] The protocol described above was implemented by mixing 169.86 mg of tetracaine HCL, 92.94 mg of water, as a local anesthetic. The mixture was extruded and cut through a 2.3 mm syringe (0.5 mm inner diameter of the needle). The obtained cylinder was loaded with a needle having an outer diameter of 0.8 mm, and the anesthetic effect was compared with respect to the control solution formulation.
    [142] The effect of the solid formulation was tested using a rabbit model of skin contraction caused by punch stimulation (10 punches for 10 seconds). Four male New Zealand rabbits were given tetracaine (3.0 mg / 0.2 ml) in solution form (● in Fig. 16), tetracaine in powder form (3.04 mg) (□ in Fig. 16), and physiological saline (○ in Fig. 16). ) Was injected subcutaneously into a circle set at a random point on each rabbit's back (shaved hair).
    [143] Skin contractions for punch stimulation can occur before and after compound injection at various time intervals: every 5 minutes (0-30 minutes), every 10 minutes (30-120 minutes), and every 15 minutes (120-345 minutes). It was performed under blinded conditions. The average inhibition rate (± S.E.M.) of skin response by various treatment methods is shown in FIG. 16, which shows no substantial pharmacological difference in the action profile induced by tetracaine in solution and powder form. This test with powdered drugs reflects the blood flow characteristics of the solid drug cylinder of this soluble drug.
    [144] Another embodiment
    [145] While the present invention has been described in connection with the detailed description, it is to be understood that the above description is merely illustrative of the invention and is not intended to limit the scope of the invention as defined by the appended claims. Other aspects, advantages and variations that fall within the scope of the invention will be apparent to those skilled in the art.
    [146] The system of the present invention, once used with a pre-loaded needle, whether a syringe-type device or an external pump, cannot reload the needle by a patient and can also be used to deliver a liquid drug formulation. It provides an additional benefit of no. Thus, it is much safer than standard liquid drug delivery syringes that can be transmitted by repeated use to spread diseases such as AIDS and hepatitis.
    [147] In addition, the system of the present invention does not need to formulate the drug composition on the fly, and does not require any special technique to properly inject the drug composition, that is, it does not require a procedure for finding a blood vessel and injecting the drug composition. have. Therefore, the expert does not need to administer the drug composition.
    权利要求:
    Claims (12)
    [1" claim-type="Currently amended] Anhydrous solid drug compostion consisting essentially of a drug and a pharmaceutically acceptable carrier of less than 50% by weight,
    The solid drug composition is formed in the form of a solid cylinder having a surface area to weight ratio of at least 10 mm per 1 mg of the drug in the composition, and the drug and the carrier are dispersed from the composition as soon as the drug comes into contact with the parenteral liquid to form a liquid formulation. Anhydrous solid drug composition, characterized in that selected and formulated to be distributed in the bloodstream of the patient according to the blood concentration profile of the drug corresponding to the blood concentration profile of the drug at the time of administration.
    [2" claim-type="Currently amended] The composition of claim 1 consisting essentially of the drug and no carrier.
    [3" claim-type="Currently amended] The composition of claim 1 wherein the cylinder has a diameter of less than 0.8 mm.
    [4" claim-type="Currently amended] The composition of claim 1, wherein the drug is a peptide, polypeptide or protein.
    [5" claim-type="Currently amended] The method of claim 1, wherein the drug is insulin, progesterone-releasing hormone (LH-RH). Somatostatin, growth hormone releasing factor (GRF), and their analogues.
    [6" claim-type="Currently amended] The composition of claim 1, wherein the drug is selected from the group consisting of cytostatic compounds, anesthetic compounds, and hormones.
    [7" claim-type="Currently amended] The composition of claim 1 wherein the drug is a vaccine.
    [8" claim-type="Currently amended] The composition of claim 1, wherein the carrier is cellulose, hyaluronic acid, polyalcohol, or saccharide.
    [9" claim-type="Currently amended] The composition of claim 1, consisting essentially of the drug, a water-soluble pharmaceutically acceptable carrier of less than 10% by weight.
    [10" claim-type="Currently amended] Next steps
    Preparing a drug in a non-solid form;
    Extruding the non-solid drug into the form of a long filament;
    Cutting the long filaments to obtain a solid cylinder form having a surface area-to-weight ratio of at least 10 mm per drug;
    Solidifying the cylindrical form to obtain a solid drug composition, wherein the drug is dispersed from the composition upon contact with parenteral fluids when the drug is administered to a patient.
    [11" claim-type="Currently amended] The method of claim 10,
    The non-solid form of the drug is obtained by mixing a water-soluble carrier with a sufficient amount of solvent to form a gel, mixing the gel with the drug to obtain a homogeneous and non-solid mixture, and then extruding and cutting the obtained mixture, and then It is prepared by removing the solvent from the cylinder form to solidify.
    [12" claim-type="Currently amended] The method of claim 10,
    The non-solid form of the drug is a carrier, the drug is mixed to form a mixture and the mixture is heated to a temperature above the melting point of the carrier to produce a non-solid form, and the cylinder is at a temperature below the melting point of the carrier. Cooling to solidify the production method.
    类似技术:
    公开号 | 公开日 | 专利标题
    US10159714B2|2018-12-25|Compositions, devices and methods of use thereof for the treatment of cancers
    US10441528B2|2019-10-15|Devices, formulations, and methods for delivery of multiple beneficial agents
    US9682127B2|2017-06-20|Osmotic delivery device comprising an insulinotropic peptide and uses thereof
    JP2018168195A|2018-11-01|Rapid establishment and/or termination of substantial steady-state drug delivery
    US10252039B2|2019-04-09|Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
    JP5964602B2|2016-08-03|Intradermal injection method
    US20170119854A1|2017-05-04|Highly concentrated drug particles, formulations, suspensions and uses thereof
    US20170319662A1|2017-11-09|Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles
    AU2016250444B2|2018-12-20|Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
    ES2719595T3|2019-07-11|Method and device for transdermal administration of parathyroid hormone using a microprojection matrix
    Lam et al.2000|Sustained release of recombinant human insulin-like growth factor-I for treatment of diabetes
    ES2250437T3|2006-04-16|intradermal administration of substances.
    DE60127822T2|2007-12-27|Compressed microparticles for dry injection
    DK1824460T3|2015-01-19|Stabilized polymeric delivery system
    US6395292B2|2002-05-28|Sustained delivery of an active agent using an implantable system
    DE60028818T2|2006-11-30|Apparatus for administering a controlled-dose therapeutic substance in endoluminal treatments
    EP1281416B1|2006-03-01|Medicinal implant, device and method for loading and delivering implants containing drugs and cells
    DE69816980T2|2004-07-22|Implantable diffusion delivery system
    KR100722607B1|2007-05-28|A process of preparing microspheres for sustained release having improved dispersibility and syringeability
    EP1335661B1|2009-05-06|Production of microspheres
    US6214370B1|2001-04-10|Method and device for administering analgesics
    US8372424B2|2013-02-12|Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles
    AU2010212478B2|2011-06-23|Non-aqueous single phase vehicles and formulations utilizing such vehicles
    JP2013009976A|2013-01-17|Delivery of viscous formulations by needle-free injection
    AU2004233869B2|2010-08-12|Solid drug formulation and device for storage and controlled delivery thereof
    同族专利:
    公开号 | 公开日
    CN1212830C|2005-08-03|
    PT1498150E|2008-02-19|
    EP1498150B1|2007-11-14|
    US5582591A|1996-12-10|
    DE69535645T2|2008-10-30|
    KR100491424B1|2005-05-24|
    DE69535645D1|2007-12-27|
    ZA9507356B|1996-04-02|
    AT280599T|2004-11-15|
    JPH10508293A|1998-08-18|
    EP0778767A2|1997-06-18|
    US5616123A|1997-04-01|
    ES2230431T3|2005-05-01|
    CA2198916A1|1996-03-14|
    EP1270032A1|2003-01-02|
    AT378082T|2007-11-15|
    AU712916B2|1999-11-18|
    WO1996007397A2|1996-03-14|
    DE69529415D1|2003-02-20|
    DE69533709D1|2004-12-02|
    ES2295745T3|2008-04-16|
    EP0778767B1|2003-01-15|
    CN1165477A|1997-11-19|
    DK778767T3|
    DK0778767T3|2003-04-07|
    CA2198916C|2008-07-22|
    DE69529415T2|2003-11-13|
    DE69533709T2|2005-10-20|
    BR9508688A|1997-10-28|
    JP4072867B2|2008-04-09|
    WO1996007397A3|1996-08-15|
    EP1270032B1|2004-10-27|
    DK1270032T3|2005-01-31|
    AU3398195A|1996-03-27|
    AT230977T|2003-02-15|
    EP1498150A1|2005-01-19|
    HK1067870A1|2008-04-11|
    ES2188669T3|2003-07-01|
    PT1270032E|2005-02-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1994-09-02|Priority to US08/300,713
    1994-09-02|Priority to US08/300,713
    1994-10-04|Priority to US31746594A
    1994-10-04|Priority to US08/317,465
    1995-08-31|Application filed by 디랩
    1995-08-31|Priority to PCT/IB1995/000778
    2003-12-31|Publication of KR20030096434A
    2005-05-24|Application granted
    2005-05-24|Publication of KR100491424B1
    优先权:
    申请号 | 申请日 | 专利标题
    US08/300,713|US5582591A|1994-09-02|1994-09-02|Delivery of solid drug compositions|
    US08/300,713|1994-09-02|
    US31746594A| true| 1994-10-04|1994-10-04|
    US08/317,465|1994-10-04|
    PCT/IB1995/000778|WO1996007397A2|1994-09-02|1995-08-31|Delivery of solid drug compositions|
    [返回顶部]