• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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  • 优先权
    • 专利摘要:
    The present invention relates to a drug delivery device that absorbs fluid, useful for initial delayed delivery of the active pharmaceutical formulation into the fluid environment of use, an initial delay period for the initiation or activation of a device having a predetermined length of time. Delivery of the pharmaceutical formulation from the dispensing device continues until essentially all of the active pharmaceutical formulation is delivered as a result of the expansion of the swelling agent in the active drug delivery chamber.
    公开号:KR19990022177A
    申请号:KR1019970708656
    申请日:1996-05-29
    公开日:1999-03-25
    发明作者:리앙 씨. 동；패트릭 에스.엘. 웡；시홍 염；로렌스 쥐. 하멜；마이클 에이치. 디일리；크리스탈 폴록
    申请人:에드워드 엘.멘델；앨자 코포레이션；
    IPC主号:
    专利说明:

    Osmotic device with delayed activation of drug delivery and full drug release
    Oral delivery of therapeutically active agents is a convenient and cost effective method of delivery. The active agent may be released into the oral cavity or anywhere in the digestive tract. Delivery can be done with a pill, which can be intermittent, or it can be continuous.
    Osmotic dispensing devices for the delivery of therapeutically active agents are well known in the art. Such a device uses expansion means to deliver a medicament to the environment of use over a period of time, days or months. The expansion means act to absorb the liquid, expand it, and release the beneficial pharmaceutical formulation from the interior of the device in a controlled, generally constant manner. Osmotic expansion means are used to deliver a medicament over a period of time, controllably, generally relatively slowly.
    Also described is an osmotic device for prolonged and controlled delivery of one or more active agents if an initial delivery delay is desired. US Pat. No. 5,198,229, which is incorporated herein by reference, relates to an osmotic device for delivery of an active agent to the upper gastrointestinal tract. The dispensing device comprises a concentric housing, arranged slidably sandwiched between each other. The first expansion means absorbs the fluid when positioned in the stomach environment. This expansion means is inflated to push the septum layer, which in turn pushes out the active pharmaceutical formulation. The active agent is controlled through a small outlet and delivered to the gastric environment in a continuous manner. After all active agents have been delivered, the housing is separated, the buoyant chamber is exposed to the gastrointestinal environment, the density of the device increases, and the device sinks and exits from the stomach.
    US Pat. No. 5,312,388, which is incorporated herein by reference, discloses the use of a slidably fitted concentric housing in an osmotic device, for the purpose of delivering one or more active agents or for the individual dispensing of one active agent. It is described. In one particular embodiment, delayed delivery of the active agent is followed by initial rapid delivery of the particular active agent. The loading dose of the active agent is dispensed as soon as the device enters the environment of use. Persistent delivery is performed as a result of expansion means which absorb and expand the fluid to separate the concentric housings. Upon separation, the active agent contained in the housing is dispensed.
    US Pat. No. 5,312,390, which is incorporated herein by reference, describes osmotic devices useful for early delayed delivery of one active agent. Slidably fitted concentric housings are separated after absorption of fluid through the housing. The fluid passage means is exposed to the fluid environment and the active agent is released in a controlled and continuous manner through an outlet at the end of the housing opposite the fluid passage means.
    U. S. Patent No. 5,358, 502 describes osmotic devices using semipermeable membranes with agents which are sensitive to pH and dissolve at a given pH to release the contents of the device.
    As observed in the above referenced patents, osmotic devices have been described as providing an initial pulse of an active agent, providing a sustained delivery of the active agent, and providing delivery of one or more active agents. However, there remains a need for improved methods and systems for delivering one or more active agents in a reliable and reproducible manner.
    Summary of the Invention
    The inventors have observed that the device as described above will open in a predictable manner, but that the medicament contained in the device may not always be completely released into the environment of use following the desired delay period. Accordingly, the present invention relates to a fluid absorption dispensing device and a method for essentially complete delivery of an active agent to a fluid environment of use following an initially delayed delivery period of the agent.
    In one aspect, the present invention relates to a fluid absorption delivery device consisting of a first housing and a second housing. The housings are in a reversibly slidably fitted configuration with each other. The first housing contains an active drug delivery chamber having an active drug formulation and a first expanding agent. Active agent formulations include one or more active agents. The open end of the first housing provides for delivery of the active pharmaceutical formulation to the environment of use. The second housing contains an expansion chamber for separately separating the first and second housings of the device after exposure to the use environment. The expansion chamber includes a second expanding agent and optionally includes a piston. The first expanding agent in the first housing ensures an essentially complete release of the active pharmaceutical formulation into the environment of use.
    In another aspect, the invention relates to a fluid absorption delivery device consisting of a first housing and a closure to the housing. The housing contains the active pharmaceutical formulation and the first expanding agent. The active agent formulation includes one or more agents. The housing is arranged to provide a flow passage between the interior of the housing and the active pharmaceutical formulation. The closure includes a second expanding agent.
    The present invention further relates to an apparatus for dispensing an active pharmaceutical formulation into an environment of use following an initial delay period and comprising a housing having a closed end and an open end. The housing contains an active agent formulation comprising one or more active agents. The housing further contains an expanding agent. The device further includes a closure that seals the open end of the housing. The improved invention includes a fluid flow passage between the interior of the housing and the active pharmaceutical formulation.
    The present invention also relates to an apparatus for dispensing an active pharmaceutical formulation into an environment of use following an initial delay period, comprising a first impermeable housing and a second semipermeable housing. The first and second housings are reversibly slidably fitted in one another. The first housing contains an active agent formulation comprising one or more active agents. The first housing further contains a first expanding agent. The second housing contains a second expanding agent. The first housing is arranged to provide a flow passage between the interior of the first housing and the active pharmaceutical formulation.
    The present invention relates to delayed delivery of an active agent, followed by essentially complete delivery of the active agent. More specifically, it relates to osmotically activated devices for dispensing the active agent essentially completely after the initial delay period into the biological use environment.
    The drawings are not drawn to scale. Various embodiments of the invention are described to illustrate. Identical numbers indicate the same structure.
    1 is a side cross-sectional view of one embodiment of a delivery device of the present invention in a closed or manufactured form prior to being placed in a use environment.
    2 shows the expanded second expansion means and the first and second housings of the device separated to allow activation of the first expansion means to initiate delivery of the active pharmaceutical formulation to the environment, Fig. 1 is a device diagram in operation.
    FIG. 3 is a first housing diagram of the device of FIG. 1 in operation at the end of its useful life having an expanded first expansion means and an active pharmaceutical formulation delivered to the environment.
    4 is a side cross-sectional view of a further embodiment of the delivery device of the present invention in a closed or manufactured form prior to being placed in a use environment.
    5 is a side cross-sectional view of another further embodiment of the delivery device of the present invention in a closed or manufactured form prior to being placed in a use environment.
    6 is a side cross-sectional view of another embodiment of the device of the present invention in a closed form prior to being placed in a use environment.
    7 is a side cross-sectional view of another embodiment of the device of the present invention in a closed form prior to being placed in a use environment.
    8 is a graph showing the emission characteristics of the six inventive devices.
    The present invention provides a device useful for delivering an active pharmaceutical formulation to a use fluid environment. There is an initial delay period for the initiation or activation of the device, which lasts for a predetermined length of time, followed by essentially complete delivery of the active pharmaceutical formulation to the environment of use.
    Justice
    The old initial delay period is intended to range from about a few minutes to about 1 day, preferably from about 1 to 24 hours, in particular from about 2 to 15 hours and generally from about 2 to 7 hours. Delivery of the pharmaceutical formulation from the dispensing device, once started, continues until essentially all active pharmaceutical formulations have been dispensed. Essentially all active agent formulations are intended to be at least about 95% of the active agent formulation, and preferably at least about 97%, more commonly at least 98% of the active agent is delivered to the fluid environment of use. The active pharmaceutical formulation is preferably administered as a pill. That is, the dosage of the active agent in the device is released within a short period of less than 1 hour of initiation of delivery of the active agent formulation, usually within about 30 minutes, preferably within about 15 minutes.
    Semipermeable is intended to be a material that is permeable to fluids but impermeable to other components contained in the dispensing device and the environment of use. Impermeable means a material that is impermeable to the fluid as well as to other components contained within the dispensing device, wherein movement of such material into or out of the device has no impact on the device's functionality substantially during the delivery period. Very slow not to.
    The term active agent formulation is intended to mean any active agent in combination with any pharmaceutically acceptable carrier and additional inert ingredients. It is to be understood that one or more active agents can be introduced into the active agent in the device of the invention and that the use of the term agent or drug never excludes the use of two or more such agents or drugs. The agent may be in various forms, such as uncharged molecules, components of the molecular complex, or pharmacologically acceptable salts that do not cause inflammation. In addition, simple derivatives (eg, ethers, esters, amides, etc.) of a drug which can be easily hydrolyzed by body pH, enzymes or the like can be used.
    As used herein, the term active agent means a composition of a medicament, drug, compound, substance or mixture thereof that provides some biological, often beneficial effect. This includes insect repellents, herbicides, fungicides, biocides, insecticides, antiseptics, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, antiseptics, disinfectants, sterilizers, catalysts, chemical reactants, Fermenters, foods, food additives, nutritional products, cosmetics, drugs, vitamins, genital disinfectants, fertilizers, fertilizers, fertilizers, microbial dampers and other agents that benefit the environment of use. As used herein, the term includes constant temperature mammals, humans and primates; Birds; Livestock or breeding animals such as cats, dogs, sheep, goats, cattle, horses, and swine; Experimental animals such as mice, rats, and guinea pigs; Pisces; reptile; And any physiological or pharmacologically active substance that exhibits local or systemic effects or effects in animals, including zoo animals, wild animals, and the like. Active agents that can be delivered are peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, synopsis sites, synaptic sites of neurological effects, endocrine and hormone systems, immune system, reproductive system, skeletal system, otacoid Inorganic and organic compounds, including, without limitation, drugs acting on the digestive, digestive and embryonic, histamine and central nervous systems. Suitable active agents are, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, hypnotics and sedatives, psychostimulants, neurostabilizers, spasms, muscle relaxants, parkinsons Hormonal agents, analgesics, anti-inflammatory agents, local anesthetics, muscle contractors, microbial inhibitors, malaria inhibitors, contraceptives, sympathetic neurostimulants, polypeptides and proteins that can produce physiological effects, diuretics, lipid control agents, Androgen inhibitors, parasitic inhibitors, tumor agents, tumor inhibitors, hypoglycemic agents, nutritional and nutritional supplements, growth aids, fats, eye drops, enteritis inhibitors, electrolyte solutions and diagnostic reagents. Examples of active agents that are beneficial for use in the present invention include prochlorperazine edylate, ferrous sulfate, aminocaproic acid, mechaxylamine hydrochloride, procaineamide hydrochloride, amphetamine sulfate, metaamphetamine hydrochloride, benzpetamine Hydrochloride, isoproteronol sulfate, penmetrazine hydrochloride, betacol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodine, tridihexetyl chloride, Phenformin hydrochloride, methylphenidate hydrochloride, theophylline collinate, cephalexin hydrochloride, diphenidol, meclizin hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate, anicin Dion, Diphenadione Litrityl tetranitrate, digoxin, isofluromate, acetazolamide, metazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopuri Nol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone and betamethasone and derivatives thereof, triamcinoline, methyltestosterone, 17-β-estradiol, ethynyl estradiol , Ethynyl estradiol 3-methyl ether, prednisolone, 17-β-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, noethynedron, noestysterone, noethieredone, progesterone, norgesterone , Noretinodrel, aspirin, indomethacin, naproxen, phenopropene, sulindac, indopro Pen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, cimetidine, cloninidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluco Nate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, jomepyrak, ferrous lactate, vincamine, phenoxybenzamine, diltiazem, milnonone, captropril, mandol, quaan benz, hydrochlorthiazide , Lanitidine, flurbiprofen, fenbufen, fluprofen, tolmethine, alclofenac, mefenamic, flufenamic, difuninal, nimodipine, nirenedipine, nisoldipine, nicardidipine, felodipine , Lidofrazine, thiopamyl, galofamil, amlodipine, myopazine, ricinopril, enalapril, captopril, ramipril, enalapril, famotidine, nizatidine, sucralate, ethyntidine , Tetratolol, Noksi there may be mentioned pyridyl, chlor dia jepok seed, diazepam, amido trip motilin, and imipramine. Further examples include proteins and peptides, including insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid hormone and pituitary hormone, calcitonin, renin, prolactin, corticotropin, thyroid affinity hormone, follicle stimulating hormone, chorionic gonadotropin Ropin, gonadotropin releasing hormone, bovine somatotropin, swine somatropin, oxytocin, vasopressin, prolactin, somatostatin, ripressin, pancreozaman, progesterone, LHRH, interferon, interleukin, human growth Growth hormones such as hormones, bovine growth hormone and porcine growth hormone, fertilization inhibitors such as prostaglandins, fertilization promoters, growth factors, and human pancreatic hormone-releasing factors.
    As used herein, the term therapeutically effective amount or rate means the amount or rate of active agent required to affect the desired treatment, often a beneficial outcome.
    The dispensing device of the present invention provides for use in humans or other animals, for example. The environment of use is a fluid environment and may include a body cavity such as the stomach, the intestine, or the abdominal cavity or the vagina. One dispensing device or several dispensing devices may be administered to a patient during a treatment program.
    1 shows a cross-sectional side view, showing one embodiment of a delivery device according to the invention. The device is shown in a closed or formulated form prior to being placed in the use environment. The dispensing device 1 comprises a housing 8 and a closure 10. The housing 8 and closure 10 in this particular embodiment are shown as a first impermeable housing 12 and a second semipermeable housing 14. The first housing 12 and the second housing 14 are in an arrangement slidably fitted with each other. The first housing 12 surrounds and defines the active drug delivery chamber 16 and contains a first swelling agent 20 and an active drug formulation 22.
    The second housing 14 surrounds the expansion chamber 18 and contains a second expanding agent 30 and a movable impermeable partition 32. The partition 32 is located between the second inflator 30 and the open end 36 of the first housing 12, which allows delivery of the active pharmaceutical formulation to the environment of use when exposed to the environment.
    The first housing 12 and the second housing 14 are similar in size at their ends so that a frictional adaptation is formed between the housings. The friction generated is sufficient to hold the two housings together prior to activation of the second inflator 30, but is not large enough to prevent the two housings from sliding off once the expansion drive force is exerted. The end of the first housing 12 is fitted in the second housing 14. The edge 34 of the end of the first housing 12 provides a platform or ridge to the partition 32 border that accommodates the driving force of the second expander separating the two housings.
    In operation, the dispensing device 1 is positioned in the working fluid environment, and the second expander 30 begins to absorb the fluid from the environment through the second housing 14. The second expander 30 expands while exerting a driving force via the partition 34 on the edge 34 of the first housing 12 and the end wall of the formulation 22, thereby expanding the first housing 12 in a second manner. Begin to slidably separate from the housing 14. After separation of the first housing 12 and the second housing 14, the fluid enters the open end 36 of the first housing 12 from the environment of use, causing the first expander 20 to absorb the fluid. . As the first swelling agent 20 absorbs the fluid, it swells and pushes out the active pharmaceutical formulation 22. The drug formulation 22 is subsequently discharged from the active drug delivery chamber 16 into the environment of use. The expanding agent 20 continues to inflate and deliver the active agent until the expanding agent 20 reaches the open end 36 of the first housing 12. At a time within 1 hour, preferably within about 30 minutes, typically within about 15 minutes of separation of the two housings, essentially all of the active pharmaceutical formulation 22 is delivered.
    2 shows the dispensing device of FIG. 1 in operation after separation of the two housings of the device. The first housing 12 is separated from the second housing 14 by a driving force to inflate the second expander 30, which expands to the same size as the result of absorbing fluid from the environment. The open end 36 of the first housing 12 is exposed to the environment so that the active agent can be delivered.
    3 shows essentially the active drug delivery chamber 16 of the first housing 12 and the dispensing device 1 of FIG. 1 after all the active agent has been delivered to the environment. The first inflator 20 expands in size as a result of absorbing fluid from the open end 36 of the first housing 12 to push the active pharmaceutical formulation 22 out of the first housing 12.
    4 shows a further embodiment of a delivery device according to the invention in a side cross-sectional view. In this embodiment, the partition 32 shown in FIGS. 1-3 is removed and the swelling agent 30 is pushed directly against the active pharmaceutical formulation to achieve separation of the housings 12 and 14.
    5 shows another embodiment of a delivery device according to the invention in a side cross-sectional view. This embodiment is similar to the device described above. The third housing 40, consisting of the first compartment 42 and the second compartment 44, defines a second active drug delivery chamber 46. The active agent formulation 48 contained in the delivery chamber 46 may be the same as or different from the active agent formulation 22. The active agent itself may be the same or different. The housing may be made of a dissolving material, such as a gelatin capsule, such that the housing 40 can dissolve when the housing is introduced into the fluid environment and the active pharmaceutical formulation 48 can be released as a loading dose. The fluid is then absorbed through the housing 14 to effect separation of the housing 12 and the housing 14 and delivery of the active pharmaceutical formulation 22 as described above with respect to FIG. 1.
    6 shows a further embodiment of a delivery device according to the invention. This device is similar to the device of FIG. 1 in that it includes a first impermeable housing 12 and a second semipermeable housing 14. The first housing contains the first expanding agent 20 and the active pharmaceutical formulation 22. In this embodiment, the swelling agent 20 and the active pharmaceutical formulation 22 do not completely fill the first housing 12. The housing 12 is arranged to provide a fluid flow passage 24 between the inner wall of the housing 12 and the active pharmaceutical formulation 22 so that the housing 12 can be quickly released into the housing 12 after separation of the housing and rapid expansion of the expander 20. Promoting the introduction of the fluid and delivery of the active pharmaceutical formulation 22. FIG. 6 shows the flow passage between the inner wall of the housing 12 and both the active pharmaceutical formulation 22 and the first dilator 20, while the flow passage is a region between the active pharmaceutical formulation 22 and the housing 12. You can limit it.
    7 shows another embodiment of a delivery device according to the invention. In this embodiment, the housing 50 contains the swelling agent 54 and the active pharmaceutical formulation 56. Similar to the device of FIG. 6, the swelling agent 54 and the active pharmaceutical formulation 56 do not completely fill the housing 50. Instead, the fluid flow passage 58 that facilitates fluid introduction into the housing 50 and delivery of the active pharmaceutical formulation 56 may include both the interior of the housing 50 and the active pharmaceutical formulation 56 and the swelling agent 54. It is prescribed between. 7 shows a flow passage 58 between both the housing 50 and the active pharmaceutical formulation 56 and the swelling agent 54, but the flow passage is in the region between the active pharmaceutical formulation 56 and the housing 50. It may be limited. The second inflator in the form of a stopper 60 is a closure that closes the open end 62 of the housing 50. As soon as it is inserted into the working fluid environment, the stopper 60 swells and separates from the housing 50 to allow introduction of the fluid into the chamber.
    The first expanders 20 and 54 operate by absorbing fluid entering the fluid flow passages 24 and 58 via the open ends 36 and 62 of the housings 12 and 50, respectively. As such, the walls of the first housings 12 and 50 preferably comprise at least a portion of the housing in contact with the first inflator 20 and 54 made of an impermeable material. In this way, the first expanding agents 20 and 54 are not activated in a hurry. When the active agent or active agent dispensing form is sensitive to fluids from external fluids present in the environment of use, the first housings 12 and 50 must be substantially impermeable to introduction of external fluids. It is preferred to act as a means of substantially protecting the swelling agents 20 and 54 as well as the active pharmaceutical formulations 22 and 56.
    Since the second inflator 30 operates by absorbing external fluids while the housings 12 and 14 are kept plugged and connected, at least of the wall of the second housing 14 adjacent to the second inflator 30. At least some of them should be translucent.
    The walls of the housings 12, 14 and 50 optionally comprise further components, such as plasticizers, for example. Suitable impermeable and semipermeable compositions for use in the housings 12, 14, and 50 as well as suitable additives are known in the art, examples of which are described in US Pat. 4,874,388.
    The delivery devices of the present invention are nontoxic, biologically inert, nonallergenic and non-inflammatory to body tissues and maintain their physical and chemical properties; That is, the device does not corrode or decompose in the environment of use during the dispensing period. Within the scope of the present invention, the device should be insoluble only during the intended period of use and can subsequently be dissolved in the use environment. Therefore, the dispensing device is considered to be undisrupted by its environment, solubility mode at the site of use, or separately, only slightly soluble during the intended period of use, once its active agent content is removed and then dissolved or corroded. Will be.
    The first and second swelling agents 20, 30, 56 and 60 are nontoxic, nonallergenic and biologically inert. The first and second expanders in each device may be the same or different. In one embodiment, the swelling agent comprises an osmopolymer. Osmopolymers interact with water and biological liquids and swell or expand in equilibrium. Osmopolymers exhibit the ability to swell in a fluid and retain a significant portion of the fluid absorbed within the polymer structure. In another embodiment, the swelling agent includes an osmotic agent. Osmotic agents are also known as osmolally effective solutes and compounds. Osmotic agents that can be used for the purposes of the present invention include inorganic and organic compounds that exhibit an osmotic component across a semipermeable wall, ie a fluid permeable wall. In another embodiment, the swelling agent includes an osmotic agent dispersed in the osmopolymer. The expanding agent may be in tablet or layered form, or may be present in a plurality of tablets or layers. The osmotic agent or osmopolymer may be present in any suitable form such as particles, crystals, pellets, granules, porous hydrogels, elastin polymeric sponges and the like. Osmotic agents and osmopolymers are known in the art and are described, for example, in US Pat. Nos. 3,865,108, 4,002,173, 4,207,893, 4,327,725 and 4,612,008, which are incorporated herein by reference.
    The partition 32 includes a composition that is substantially impermeable to the passage of the fluid and restricts the passage of the sugar fluid in the swelling agent to the first housing. This works essentially to maintain the insertion and expansion layer of the active pharmaceutical formulation 22. In addition, the partition 32 ensures that the expansion drive force generated by the second expander 30 is applied directly to the first housing 12 to separate the first and second housings. Therefore, the partition 32 must be of sufficient strength, thickness and stiffness to transfer the driving force to the first housing 12. Representative impermeable materials useful as piston 32 are known in the art and are described, for example, in US Pat. No. 4,874,388, which is incorporated herein by reference.
    Active pharmaceutical formulations include the active pharmaceutical to be delivered as a liquid, solid, semisolid or heat sensitive composition, generally in the presence or absence of additional inactive ingredients in the carrier material. The active drug formulations may further comprise a dispensing form comprising the active agents capable of maintaining their physical placement and chemical insertion while housed in the dispensing device. These include purification of the presence or absence of density elements; Template tablets; sphere; Pellets and long tablets; capsule; Basic osmotic pumps such as those described in US Pat. No. 3,845,770; Small osmotic pumps such as those described in US Pat. Nos. 3,995,631, 4,034,756 and 4,111,202; And multi-chamber osmometers referred to as push-pull and push-melt osmotic pumps, such as those described in US Pat. Nos. 4,320,759 and 4,449,983, including, without limitation, Patents are incorporated herein by reference.
    Pharmaceutically acceptable carriers include one or more components, such as buffers, viscosity control mediators, surfactants, dyes, permeation enhancers, protease inhibitors, or other formulation ingredients and additives, as known in the art. You may also The carrier may contain one or more active agents. The active pharmaceutical formulation can be corroded or degraded and can exist, for example, in the form of a wax formulation, solid form or tablet. The formulation may dissolve immediately upon exposure to the fluid or it may be slowly corroded in the presence or absence of an excipient that controls corrosion.
    Active pharmaceutical formulations can be designed in a number of ways to provide specific drug delivery profiles. One embodiment may include a formulation containing a biologically acceptable solid surfactant that can be slowly dispersed in a fluid of the environment. In another embodiment, the formulation may contain fluid insoluble waxes and surfactants so that the formulation is susceptible to corrosion in the environment. In another embodiment, the formulation may be effervescent or may provide drug delivery in a finely dispersed form. This is accomplished by the addition of a solid basic compound capable of releasing carbon dioxide in the presence of an acid in the environment of use. Suitable basic compounds are described in US Pat. No. 4,265,874, which is incorporated herein by reference. In a further embodiment, the formulation may comprise an osmotic agent or solute, for example those described above as a reference to the expansion means, so that when the formulation comes into contact with the fluid of the environment, it dissolves immediately. In yet another embodiment, the pharmaceutical formulation may consist of a medicament and a heat sensitive composition. In this way, the formulation will exhibit solid-like properties at room temperature of 21 ° C. and within a few degrees of it, and may have a close melting point within 37 ° C. and several degrees of body temperature of the mammal. As used herein, the term thermal sensitivity refers to a solid, or solid-like property at temperatures below 31 ° C., and fluids, semisolids or dots when disturbed by heating to temperatures above 31 ° C., typically 31 ° C. to 45 ° C. Refers to the physicochemical properties of the pharmaceutical carrier composition, which is to be a composition. Materials suitable for use as active pharmaceutical carriers and excipients are known in the art and are described, for example, in US Pat. Nos. 4,595,583 and 4,874,388, which are incorporated herein by reference.
    The amount of active agent used in the delivery device will be that amount necessary to deliver a therapeutically effective amount of the agent that achieves the desired result at the delivery site. In practice, this will vary from 0.01 ng to 500 mg, depending on the particular agent, delivery site, depth of disease, and desired therapeutic effect.
    For proper delivery of the active agent, in some cases it may be desirable for the dispensing device to deliver the active agent to a particular use environment. Therefore, it may be necessary for the device to remain in a particular environment until such time that the pharmaceutical formulation is delivered, or alternatively for the device to pass through one particular environment to another environment before delivering the pharmaceutical formulation. In this case, additional elements are included in the device, or the device is designed in such a way as to provide this particular delivery. For example, when the environment of use is at the potential of the ruminant, the device may include a density element in the dispensing device so that it is weighed and remains within the potential for the dispensing period. Density elements are known in the art and are described, for example, in US Pat. No. 4,874,388, which is incorporated herein by reference. When the environment of use is a human stomach, it may be desirable for the device to have a low initial density, or include air, for example, in part of the compartment inside the device, which also contains the pharmaceutical formulation. In this way, the device will float on the surface of the gastric contents and will remain in the stomach until the device is open to release the formulation. On the other hand, it is desirable here to delay the release of the active agent, which may be inactivated by the gastric contents or by stimulating the mucous membrane of the stomach, which may result in nausea or bleeding, and thus is not intended for delivery into the stomach, The blood may be applied over at least a portion of the housing of the dispensing device consisting of a semipermeable membrane. The enteric skin will remain intact in the stomach, but once they reach the small intestine, it will dissolve quickly and then allow fluid to be absorbed to activate the dispensing device. Enteric coatings are known in the art and are discussed, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
    The total delay time preceding the separation of the two housings of the dispensing device and the total delivery time of the active drug formulation can be controlled by a number of means to provide precise onset of delivery at a specific time. For example, the rate of fluid absorption into each swelling agent, and the rate of swelling of the means, can be controlled by a particular choice of semipermeable membrane or porous screen. The rate of expansion of the expanding agent can also be controlled by the selection of the composition of the expanding agent. From the overlapping distance between the fitting portions of the first and second housings it is possible to determine the period of time required for the two housings to be separated. Combinations of such control means may be used. Such control means are known in the art and can be determined in the absence of excessive experimentation.
    A fluid flow passage 24 or 58 is formed between the active pharmaceutical formulation 22 and the housing 12 or 50, and the first swells 20 and 54, and the housings 12 and ( It can extend to the area between 50). The space occupied by the fluid flow passages is at least 5% of the cross sectional area inside the housing, generally about 5% to 75% of the cross sectional area inside, and often 20% to 60% of the cross sectional area inside.
    The delivery device of the present invention can be manufactured by standard manufacturing techniques. For example, in the manufacture of the apparatus of the present invention, the first housing 12 (container) and the second housing 14 (lid) may be molded or extrusion molded into desired shapes, respectively. Possible semipermeable materials from the second housing 14 that can be prepared are, for example, Hytrel® polyester elastomers (Du Pont), cellulose esters, cyclically enhanced ethylene-vinyl acetate copolymers, Semipermeable membranes made by mixing a rigid polymer with a water soluble low molecular weight compound, and other semipermeable membranes known in the art. Impermeable materials from good first housing 12 that can be prepared are, for example, polyethylene, polystyrene, ethylene-vinyl acetate copolymers, Hytrel® polyester elastomers (Du Pont) and the art of sugar Other impermeable materials known in the art. Alternatively, the two-part rigid gelatin capsules may be coated with one part using an impermeable material and the other part using a semipermeable material, such as a cellulose ester based polymer mixture. In a preferred embodiment of the invention, the device assembled in a closed arrangement is approximately the size and volume of a size 3 to size OO rigid gelatin capsule.
    The swelling agent 20 is made from an osmotic material and formed into a shape that will fit snugly within the container 12. The layers are compressed into tablets on a rotary two-layer tablet press. The swelling agent 30 is made from an osmotic material and the partition 32 is made from an impermeable material. Both are formed into shapes that will fit snugly in the lid 14 and are pressed onto two layers of tablet presses.
    Referring to Figure 1, the device is assembled as follows. The swelling agent 20 is inserted into the container 12 at its end opposite the open end 36 thereof. The active pharmaceutical formulation 22 is then placed on top of the swelling agent 20. The formulation may be, for example, in the form of a liquid, solid, semisolid, powder, or shaped tablet or tablets. The expander 30 and the partition 32 are positioned in the lid 14 so that the partition 32 is located close to the open end of the filled container 12, and the lid part is positioned at the end of the filled container 12. Position it over.
    The invention is illustrated by the following examples. They should not be construed as limitations of the scope of the invention. Variants and equivalents of these examples will be apparent to those skilled in the art as the disclosure, the figures, and the claims herein.
    Example 1
    A delivery device according to the invention for delivering progesterone into the colon for hormone replacement therapy was prepared as follows:
    100 mg of crospovidone XL-10 (International Specialty Products, Wayne NJ) powder was compressed into cylindrical tablets in a rotary compactor to form the first expanded layer portion of the device. One side of the tablet was convex to conform to the shape of the device, while the other side was flat.
    The second expanded layer portion of the device was formed from an osmotic layer and a barrier layer. The osmotic layer was formed as follows. Sodium chloride (NaCl) was sorted by size and screened at full speed using a Quardo grinder with a 21 mesh screen. This anhydrous component was added to the Glat fluid bed granulator ball with the other anhydrous components in the following proportions: 58.75 weight percent sodium carboxymethyl cellulose (NaCMC), 30 weight percent NaCl (prepared as described above), hydride 5.0 weight percent oxypropylmethyl cellulose E-5 (Aqualon), iron red oxide and 1.0 weight percent. The dry ingredients were mixed thoroughly for 10 minutes. 5.0 wt.% HPC-EF (Aqualon, Wilmington, DE) was dissolved in purified water and sprayed on the anhydrous ingredients until the ingredients were in the form of granules. Magnesium stearate (0.25 wt.%) Is added to the granules and the granules are thoroughly mixed for 5 minutes.
    The barrier layer portion of the portion of the second expanded layer of the device was formed as follows. 95% by weight of hydroxypropylmethyl cellulose E-5 (Aqualon) and 5.0% by weight of stearic acid were sized and screened using a 40 mesh screen. The screened material was added to the mixing vessel of a Hobart mixer and mixed for 10 minutes. Subsequently, ethanol was added until the wet mass formed during mixing. The wet mass was then screened through a 20 mesh screen and the wet granules were air dried for 12 hours. After drying, the granules were likewise passed through a 20 mesh screen.
    To form part of the second expanded layer of the device, 200 mg of osmotic layer granules and 50 mg of barrier layer granules were pressed together into a cylindrical bilayer tablet having convex osmotic layer face and flat barrier layer face in a rotary compactor. Tableting produced a clear and distinct interface between the two layers.
    The drug layer portion of the device contained 80 weight percent progesterone, 10 weight percent crospovidone XL-10 (International Specialty Products, Wayne NJ) and 9.5 weight percent polyoxyethylene 40 stearate (ICI America International, Wilmington, DE). During manufacture, each component was screened through a 40 mesh screen and the ingredients sorted by size were added to the mixing vessel in the appropriate proportions. The anhydrous ingredients were mixed thoroughly until a wet mass formed. The wet mass was then screened through a 20 mesh screen and the granules were oven dried at 40 ° C. for 24 hours. Magnesium stearate (0.5 wt.%) Was then added to the granules and the granules were thoroughly mixed for 5 minutes. 125 mg of drug layer granules containing 100 mg of progesterone were pressed together into a cylindrical bilayer tablet with flat top and bottom sides in a rotary compactor.
    The first housing (drug container), consisting of ethylene vinyl acetate copolymer (9 wt% vinyl acetate), having one closed end and one open end, was passed through a pelletized ethylene vinyl acetate copolymer (EVA) at 130 ° C. Prepared by placing in a discharger having a temperature and discharging the material into a container mold. The EVA was cooled in the mold and the finished vessel was then separated.
    Clear, size O gelatin capsules were used to form the second housing (engine part) of the device. A portion of the second expanded layer of the device was placed into the short compartment of the capsule and the convex end of the tablet was directed into the closed end of the capsule. Polyvinylpyrrolidone (PVP k29-32, International Specialty Products) was dissolved in methanol and sprayed on the capsules as 2 mg apicoat. 75 wt% cellulose acetate 398-10 (Eastman Chemical, Kingsport, NJ) and 25 wt% polyethylene glycol 3350 (Union Carbide, Danbury, CT) were dissolved in acetone / methanol (80/20 wt / wt) solution to 4 wt% Made to a solid solution. This solution was sprayed onto the coating to form 70 mg of a semipermeable membrane. The second housing was dried at 50 ° C. and 50% RH for 72 hours and then at 50 ° C. and ambient RH for 24 hours to anneal the coating and remove residual solvent.
    To assemble the delivery device, the first expanded layer portion of the device was placed into the first housing having the convex side of the tablet facing into the closed end of the housing. The drug layer was then placed on top of the first expanded layer. The open end of the first housing was fitted into the open end of the second housing and the two housings were squeezed until the first housing, a portion of the second expansion layer and the second housing fit snugly together.
    The opening time of the device is shown in FIG. 8. This system was placed for 2 hours in fluid above the artificial stomach (pH 4) and then for 22 hours in the fluid of the artificial small intestine. The opening time was determined to be the time interval when the osmotic lid was separated from the drug containing vessel. Progesterone concentrations were measured by HPLC after dissolution with ethanol. FIG. 8 shows the progesterone release profile of the six devices, with open time of 11 to 14 hours and delivery shown to be completed within 1 hour of open time.
    Example 2
    Tablets containing 100 mg of progesterone were placed in # 2 size gelatin capsules and dispensed using the device according to Example 1. The capsule will disintegrate immediately upon administration and deliver 100 mg of the initial progesterone and the remaining 100 mg will be dispensed after 13 hours.
    Example 3
    A delivery device according to the invention for delivering human growth hormone into the colon was prepared as follows:
    90 mg of Crospovidone XL-10 (International Specialty Products) powder was pressed into a cylindrical tablet in a rotary compactor to form part of the first expanded layer of the device. One side of the tablet was convex to conform to the shape of the device, while the other side was flat.
    A portion of the second expanded layer of the device was formed from the osmotic and barrier layers. An osmotic layer was formed as follows. Sodium chloride (NaCl) was sorted by size and screened at full speed using a Quardo grinder with a 21 mesh screen. This anhydrous component was added to the Glat fluid bed granulator ball with the other anhydrous components in the following proportions: 58.75 weight percent sodium carboxymethyl cellulose (NaCMC), 30 weight percent NaCl (prepared as described above), hydride 5.0 weight percent oxypropylmethyl cellulose E-5 (Aqualon), and 1.0 weight percent iron oxide. The dry ingredients were mixed thoroughly for 10 minutes. 5.0 wt.% HPC-EF (Aqualon) was dissolved in purified water and sprayed on the anhydrous ingredients until the ingredients were in the form of granules. Magnesium steareart (0.25 wt.%) Was then added to the granules and the granules were thoroughly mixed for 5 minutes.
    The barrier layer portion of the portion of the second expanded layer of the device was formed as follows. 95% by weight of hydroxypropylmethyl cellulose E-5 (Aqualon) and 5.0% by weight of stearic acid were sized and screened using a 40 mesh screen. The screened material was added to the mixing vessel of a Hobart mixer and mixed for 10 minutes. Ethanol was then slowly added during mixing until a wet mass formed. The wet mass was then screened through a 20 mesh screen and the wet granules were air dried for 12 hours. After drying, the granules were likewise passed through a 20 mesh screen.
    To form part of the second expanded layer of the device, 250 mg of osmotic layer granules and 50 mg of barrier layer granules were compressed together in a cylindrical bilayer tablet with convex osmotic layer face and flat barrier layer face in a rotary compactor. Tableting produced a clear and distinct interface between the two layers.
    Some of the drug layers of the device are 6.67% by weight recombinant human growth hormone (HGH) (ARES-Serono, Norwell, Mass.), 78.33% by weight sodium salicylate (Bryant Lab, Berkeley, Calif.) And corn oil (Spectrum Chemical, Gardena, CA) 15 weight percent. During manufacture, sodium salicylate and HGH were screened through 80 mesh screens respectively. The ingredients sorted by size were air mixed for 15 minutes. Corn oil was added dropwise and mixed until homogeneous. The oily mass was then screened through a 40 mesh screen to form granules. 216 mg of drug layer granules were then compressed into cylindrical tablets with flat top and bottom faces in a rotary compactor.
    The first housing (drug container), consisting of ethylene vinyl acetate copolymer (9 wt% vinyl acetate), having one closed end and one open end, was passed through a pelletized ethylene vinyl acetate copolymer (EVA) at 130 ° C. Prepared by placing in a discharger having a temperature and discharging the material into a container mold. The EVA was cooled in the mold and the finished vessel was separated.
    Clear, size O gelatin capsules were used to form the second housing (engine part) of the device. A portion of the second expanded layer of the device was placed into the short compartment of the capsule and the convex end of the tablet was directed into the closed end of the capsule. 90% by weight of cellulose acetate 398-10 (Eastman Chemical, Kingsport, NJ) and 10% by weight of polyethylene glycol 3350 (Union Carbide, Danbury, CT) were dissolved in acetone / methanol (80/20% by weight) solution to 4% by weight. Made to a solid solution. This solution was sprayed onto the coating to form 29 mg of a semipermeable membrane. The second housing was dried at 50 ° C. and 50% RH for 72 hours and then at 50 ° C. and ambient RH for 24 hours to anneal the coating and remove residual solvent.
    To assemble the delivery device, a portion of the first expansion layer of the device was placed into the first housing with the convex side of the tablet facing into the closed end of the housing. The drug layer was then placed on top of the first expanded layer. The open end of this first housing was fitted into the open end of the second housing, and the two housings were pressed together until the first housing, part of the second expansion layer and the second housing fit snugly together. The opening time of the system was measured as described in Example 1 and found to be about 6 hours. Dog delivery studies were performed by feeding the device to dogs. The system recovered from feces was analyzed for HGH formulations. The results of this study demonstrated that an average of 86% of the HGH formulation was delivered comparable to 62% for the system in the absence of the first expansion layer portion.
    Example 4
    A delivery device for delivering 125 mg of progesterone formulation into the colon for hormone replacement treatment according to the present invention was prepared as follows:
    The first housing (drug container), consisting of ethylene vinyl acetate copolymer (EVA, 9 wt% vinyl acetate), having one closed end and one open end, was subjected to pelletized ethylene vinyl acetate copolymer (EVA) at 130 ° C. Prepared by placing in an ejector having a keg temperature of, it was formed into a container having an ID of 0.762 cm and an OD of 0.876 cm. The expander tablets were then placed in the first housing. Tablets were prepared by pressing 125 mg of Crospovidone XL-10 (International Specialty Products, Wayne NJ) powder in a rotary compactor to a diameter of 0.556 cm and a length of 0.206 cm. The fluid flow passage between the tablet and the inner wall of the housing was measured at 0.206 cm. The active pharmaceutical formulation tablet was placed on top of the swelling tablet. 125 mg of the active pharmaceutical formulation tablet contained 80% by weight progesterone, 10% by weight crospovidone XL-10 (International Specialty Products, Wayne NJ) and 10% by weight polyoxyethylene 40 stearate (ICI America International, Wilmington, DE). . The formulations were prepared by screening ingredients through a 40 mesh screen, mixing with ethanol to form a wet mass, screening through a 20 mesh screen, and oven drying at 40 ° C. for 24 hours. Magnesium stearate (0.5% by weight) was added. The resulting active pharmaceutical formulation was compressed into a cylindrical tablet having a diameter of 0.556 cm and a length of 0.556 cm in a rotary compactor. The tablets were placed in the first housing, leaving a fluid flow passage between 0.206 cm of the active pharmaceutical formulation tablet and the inner wall of the first housing. The flow passage occupied 46% of the cross sectional area inside the housing.
    The second housing was formed from a transparent, size O gelatin capsule. The second expanded layer of the device was formed from the following anhydrous components: 58.75 wt% sodium carboxymethyl cellulose (NaCMC), 30 wt% NaCl, 5.0 wt% hydroxypropylmethyl cellulose E-5 (Aqualon, Wilmington, DE), And 1.0 wt% iron red oxide. After mixing for 10 minutes, granules were prepared by spraying 5.0% by weight HPC-EF (Aqualon, Wilmington, DE) dissolved in purified water onto the anhydrous ingredients. Magnesium steareart (0.25 wt.%) Was added and the second expanded layer granules were thoroughly mixed for 5 minutes. Impervious bulkheads were formed by screening 95% by weight of hydroxypropylmethyl cellulose E-5 (Aqualon) and 5.0% by weight stearic acid using a 40 mesh screen. The screened material was added to a Hobart mixer and mixed for 10 minutes. Ethanol was added until a wet mass formed. The wet mass was screened through a 20 mesh screen and air dried for 12 hours. The granules were then passed through a 20 mesh screen. 200 mg of expanded bed granules and 50 mg of septum bed granules were pressed together into a two-layer tablet in a rotary compactor. The tablets were placed into gelatin capsules with the expanded layer face down. Polyvinylpyrrolidone (PVP k29-32, International Specialty Products) was dissolved in methanol and sprayed on the capsules as 2 mg apicoat. 75% by weight of cellulose acetate 398-10 (Eastman Chemical, Kingsport, NJ) and 25% by weight of polyethylene glycol 3350 (Union Carbide, Danbury, CT) were dissolved in acetone / methanol (80/20% by weight) solution. This 4 wt% solid solution was sprayed onto the coat to form 70 mg of a semipermeable membrane. The second housing was dried at 50 ° C. and 50% RH for 72 hours and then at 50 ° C. and ambient RH for 24 hours. The open end of the second housing was aligned over the open end of the first housing and the two housings were pressed together.
    Example 5
    Eight devices were prepared as described in Example 1. The system was administered orally by placing the system deep into the dog's mouth pharynx so that the starved dog could swallow without damaging the system. Water was fed immediately after administration to ensure migration into the stomach of the system.
    Dogs were monitored at regular intervals during normal life. At each observation, the presence of the system was carefully examined in any excretion found in the cage. The time to recover the system was used to estimate the delivery time of the device. Table 1 shows the delivery times and amounts recovered from these eight devices.
    Rev #Carrying time (hours)Progesterone Residue% One24.5-24.70.9 224.5-24.70.3 324.5-24.73.9 448.8-50.50.0 5Not recalledN / A 626.7-28.20.0 726.7-28.20.7 826.7-28.20.1
    As can be seen in Table 1, although delivery times varied in each dog, the device delivered more than 95% of the active pharmaceutical formulation in a predictable manner. When a similar device was made with no fluid flow passageway between the housing and the active drug formulation, delivery could not be predicted because the amount of active drug formulation remaining in the device varied from 0 to 82%.
    The above description is shown for easy understanding only. Since modifications will be apparent to those skilled in the art, unnecessary limitations need not be understood from them.
    权利要求:
    Claims (14)
    [1" claim-type="Currently amended] (a) the first and second housings are reversibly slidably sandwiched between each other, the second housing comprising a first housing and a second housing which are semipermeable membranes;
    (b) the first housing contains an active agent formulation comprising one or more active agents and a first expanding agent;
    (c) the second housing contains a second expanding agent;
    A fluid absorption delivery device for dispensing the active pharmaceutical formulation into a use fluid environment after an initial, delayed controlled initiation of delivery.
    [2" claim-type="Currently amended] The device of claim 1, further comprising a fluid flow passage between the interior of the first housing and the active pharmaceutical formulation.
    [3" claim-type="Currently amended] A housing and a closure to the housing, the housing comprising an active pharmaceutical formulation comprising one or more active agents and a first dilatant, the housing being arranged to provide a fluid flow passage between the interior of the housing and the active pharmaceutical formulation, The closure comprises two expanding agents,
    A fluid absorption delivery device for dispensing the active pharmaceutical formulation into a use fluid environment after an initial, delayed controlled initiation of delivery.
    [4" claim-type="Currently amended] After an initial, controlled delayed initiation of delivery initiation, having a closed end and an open end, the housing containing an active pharmaceutical formulation comprising at least one active agent and an expanding agent, and a closure closing the open end of the housing, A fluid absorption delivery device for dispensing an active pharmaceutical formulation into a use fluid environment, the method comprising:
    Improved device comprising a fluid flow passage between the active pharmaceutical formulation and the interior of the housing.
    [5" claim-type="Currently amended] The device of claim 4, wherein the closure comprises a second expanding agent.
    [6" claim-type="Currently amended] The device of claim 1, 2, 3, or 4, wherein the first housing is impermeable.
    [7" claim-type="Currently amended] 6. The device of claim 1, 2, 3, or 5, wherein the first and second swelling agents are selected from the group consisting of osmotic agents, osmopolymers and mixtures thereof.
    [8" claim-type="Currently amended] The device of claim 1, wherein the device comprises a partition disposed between the second expanding agent and the active pharmaceutical formulation.
    [9" claim-type="Currently amended] The device of claim 1, 2, 3, or 4, wherein the active pharmaceutical formulation comprises progesterone.
    [10" claim-type="Currently amended] The device of claim 1, 2, 3, or 4, wherein the active pharmaceutical formulation comprises human growth hormone.
    [11" claim-type="Currently amended] The device of claim 1, 2, 3, or 4, wherein the active pharmaceutical formulation is selected from the group consisting of liquids, solids, semisolids, heat sensitive formulations, and mixtures thereof.
    [12" claim-type="Currently amended] 4. The apparatus of claim 1, 2 or 3, further comprising a third housing surrounding the first and second housings.
    [13" claim-type="Currently amended] The apparatus of claim 12, wherein the third housing defines a second active drug delivery chamber.
    [14" claim-type="Currently amended] The device of claim 1, 2, 3, or 4, further comprising enteric skin.
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    同族专利:
    公开号 | 公开日
    KR100428273B1|2004-07-31|
    AT221769T|2002-08-15|
    EP0828478A1|1998-03-18|
    WO1996038130A1|1996-12-05|
    ES2179946T3|2003-02-01|
    CN1186427A|1998-07-01|
    AU5883196A|1996-12-18|
    JP2002515016A|2002-05-21|
    CN1138527C|2004-02-18|
    DE69622857D1|2002-09-12|
    DE69622857T2|2003-06-18|
    EP0828478B1|2002-08-07|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1995-06-02|Priority to US45938795A
    1995-06-02|Priority to US08/459,387
    1995-06-02|Priority to US8/459,387
    1996-04-18|Priority to US60/015,567
    1996-04-18|Priority to US1556796P
    1996-05-29|Application filed by 에드워드 엘.멘델, 앨자 코포레이션
    1999-03-25|Publication of KR19990022177A
    2004-07-31|Application granted
    2004-07-31|Publication of KR100428273B1
    优先权:
    申请号 | 申请日 | 专利标题
    US45938795A| true| 1995-06-02|1995-06-02|
    US08/459,387|1995-06-02|
    US8/459,387|1995-06-02|
    US1556796P| true| 1996-04-18|1996-04-18|
    US60/015,567|1996-04-18|
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