CN1777452A - Apparatus and methods for repetitive microjet drug delivery - Google Patents
Apparatus and methods for repetitive microjet drug delivery Download PDFInfo
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- CN1777452A CN1777452A CN 200480010719 CN200480010719A CN1777452A CN 1777452 A CN1777452 A CN 1777452A CN 200480010719 CN200480010719 CN 200480010719 CN 200480010719 A CN200480010719 A CN 200480010719A CN 1777452 A CN1777452 A CN 1777452A
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Abstract
An active, transdermal delivery (100) system includes a support structure (128) and a fluid reservoir (102) within the support structure configured to contain a fluid (108) to be delivered transdermally. There is also at least one exit orifice (104) defined in the support structure that is in communication with the fluid reservoir. The orifice has a diameter of between about 1 micrometer and 500 micrometers. Furthermore, a repeatable activation means is disposed within the support structure and is in cooperation with the exit orifice for ejection of fluid in response to an activation signal.
Description
PRIORITY CLAIM
The application requires to enjoy the provisional application No.60/463 that is submitted on April 21st, 2003,905, submit in the provisional application No.60/483 on June 30th, 2003,604 and submit in the provisional application No.60/492 on August 05th, 2003,342 priority, above provisional application are all incorporated this paper into by complete quoting.
Invention field
Generally speaking, the present invention relates to medicine and send the field.More specifically, the invention provides the apparatus and method of utilizing repeatedly miniature sprayer to continue transdermal delivery of drugs.
Background technology
Traditionally, the main method that medicine is delivered to human body is an oral ingestion of pills.In case swallow, medicine passes through the absorption of gastrointestinal (GI) road in theory and enters and carries out systemic delivery in the blood flow.Yet most drug candidate may be very promising medicine, does not perhaps have the suitable solubility that absorbs through the GI road, is perhaps destroyed by the digestive secretion thing before absorbing.As for the medicine that is absorbed by the GI road, its major part is inactivation through liver metabolism and before perceiving its fully favourable effect.And current pharmaceuticals industry changes towards more high-molecular weight biopharmaceutical type drugs.Follow this transformation, will the more effectively medicine of oral delivery occur.
The other method that medicine is sent is a transdermal delivery.Transdermal drug delivery is that drug substance directly passes sending of skin barrier.Transdermal drug delivery has occurred about 20 years.Transdermal delivery has lot of advantages with respect to the other drug delivering method, comprises avoiding first pass metabolism and keeping constant system dosage level, avoids using the peak value that delivery method experienced and the low ebb of pill, injection, lung and through mucous membrane.In addition, transdermal drug delivery is a drug administration carrier very easily for the patient, and can realize high levels of patient compliance.
Though it is very effective that proof is fit to the application of transdermal delivery, the selection medicine that seldom has drug candidate to be turned materially to be used for transdermal delivery.The tradition transdermal drug delivery depends on medicine and sees through skin.In the use, only there is small amount of drug in fact to pass through the passive absorption of skin with treatment level.At present, approximately 10 kinds of medicines only being arranged is the transdermal formats that can buy.In addition, current macromolecular drug has much larger than the quality of the transdermal drug of tradition success and have limited dissolubility in double-layer of lipoid, so the transdermal of this class medicine is used more limited.
The percutaneous major obstacle of drug diffusion is the outermost layer of skin, i.e. horny layer.Horny layer is made of the dense packing keratinocyte that is surrounded by the high-sequential double-layer of lipoid (being full of the flat dead cells of keratin fiber), forms effective permeability barrier.What directly be in the horny layer below is epidermis.Epidermis is enriched with immune cell, therefore, the target that the medicine that is used for the treatment of is sent at or relate to immune system.Under the epidermis corium.Corium has abundant capillary network, therefore becomes the attractive target that system's medicine is sent, and this is that the medicine of capillary network enters blood circulation fast and system sends in health everywhere because enter.
Designed enhancing and passed the whole bag of tricks of cuticular transdermal drug delivery, comprised utilizing strengthening property medicament or stimulus object such as chemical drugs, voltage charge, ultrasound wave, heat treatment, microneedle and laser ancillary technique.For example, referring to U.S. Patent No. 6,352,506 and 6,216,033.Yet, the development of these methods and accept extensively and be subjected to skin irritation, and the complexity of device itself and the obstruction of expense incompatible with pharmaceutical formulation.In addition, these technology do not provide time dependence dosage delivery capability, and this ability is most important for the many curative drugs that comprise insulin.
Another mechanism that medicine is sent is to use needleless injection or high-speed jet injectors.High-speed jet injectors is as existing a lot of years of the succedaneum of hypodermic syringe.For example, referring to U.S. Patent No. 2,380,534,4,596,556,5,520,639,5,630,796 and 5,993,412.Jet injector sprays as jet with solution high-speed mobile to be injected and with solution, penetrate horny layer and with solution deposition in the corium and subcutaneous area of skin.
Though traditional high-speed jets can carry medicine to pass horny layer, the shortcoming of this mechanism is that it sends a large amount of delivering compositions for the treatment of in a jet injection.As a result, some medicines are usually pushing back from through hole by sending under the pressure that is produced in a large number.And, once send the systemic drug concentration that can not keep the continued treatment level.Also have,, cause the patient usually to experience skin irritation, pain, swelling and other and be similar to undesirable effect with the hypodermic syringe injection because a high amount of drug sends.
Therefore, expect very much to continue the low invasive technique of the compositions of the constant treatment level of transdermal delivery to the patient.
Summary of the invention
The invention provides initiatively fluid delivery system, generally comprise supporting structure with at least one outlet opening.The outlet opening diameter is about 1 μ m-500 μ m.Described fluid delivery system also has design and is used for comprising the fluidic fluid container of waiting to be delivered to tissue.The structure of described fluid container and size are suitable for being communicated with outlet opening.Actuating device (repetitive activation mean) responsive actuation signal (activation signal) comes jet fluid with fluid container and outlet opening collaborative work repeatedly.
In alternative embodiment, fluid container and repeatedly actuating device be placed in the supporting structure.Supporting structure can be suitable for contacting skin surface, and outlet opening is near skin surface.Supporting structure also can comprise the nozzle that limits described hole.The structure of described nozzle and size make fluid therefrom quicken to leave
According to another embodiment of the present invention, fluid delivery system comprises the controller that is communicated with actuating device repeatedly.Controller is designed to generate actuated signal.Described controller can be a microprocessor, the medelling application program that its control able to programme is sent from fluid delivery system (patterned administration regime).The medelling application program preferably occurs in and is no less than about 500ms and in no more than about 10 days time.
The nozzle of fluid delivery system can be configured to before the nozzle ejection fluid, and fluid is kept from the distance of organizing basic fixed.This fixed range preferably before jet fluid, makes fluid be not more than about 5000 μ m apart from tissue.
According to another embodiment, fluid delivery system comprises the outlet opening array that is limited in the supporting structure and is communicated with fluid container.Fluid container can comprise that design is used for the storage capsule of store fluid.Fluid container also can comprise the pressure exerting arrangement to pressurized with fluid stored in the storage capsule.In addition, storage capsule can be divided at least two storage capsules by reservoir divider.
According to an embodiment, there are at least two outlet openings that are limited in the supporting structure.First outlet opening is communicated with first storage capsule that stores first fluid, thereby first fluid can be sprayed by first outlet opening.Also have at least one second outlet opening to be communicated with, thereby second fluid can be sprayed by second outlet opening with storage second fluidic at least one second storage capsule.
According to alternate embodiment, reservoir divider can comprise the reservoir divider disruption mechanism of destruction reservoir divider before the material that structure and size be suitable in applying container being comprised.For example, reservoir divider disruption mechanism can be a piezoelectric device.
In another embodiment, fluid delivery system comprises the pick off whether testing conditions satisfies.Also comprise control unit, its design is used for producing actuated signal to activate actuating device repeatedly when the condition from pick off received satisfies or do not satisfy signal.Pick off can be away from supporting structure, implant in patient's body, be positioned at supporting structure inside etc.In addition, pick off can be experienced patient's biological sign, such as temperature, pressure, chemicals or molecular concentration etc.
In another alternate embodiment, fluid delivery device comprises that structure and size are suitable for the antagonist reservoir with the fluid container collaborative work, thereby when the integrity of two containers is impaired, antagonist reservoir can make the antagonist of fluid inactivation with regard to release.
In a preferred embodiment, fluid delivery system comprises the driving force of supplying actuated signal and the power supply of the driving force of actuating device repeatedly.
According to an embodiment, actuating device is to produce the piezoelectric device that pressure changes in fluid repeatedly.According to another embodiment, actuating device is to produce the phase change mechanism that pressure changes in fluid repeatedly.In yet another embodiment, actuating device is to produce the electromagnetic mechanism that pressure changes in fluid repeatedly.In an embodiment again, actuating device is to produce the high-pressure hydraulic mechanism that pressure changes in fluid repeatedly.According to another embodiment, actuating device comprises a plurality of explosive mechanisms repeatedly, all can produce pressure in described each explosive mechanisms of explosive mechanisms explosion time in fluid and change.
According to a preferred embodiment, actuating device produces the pulse width that the persistent period is not less than about 5ns and no more than about 10 μ s repeatedly.The frequency of actuating device and cycle of operation and the unitary control of fluid jet length-controlled system repeatedly.
In a preferred embodiment, this system also comprises the connection user interface of actuating device repeatedly.This user-interface design is used for responding operating user interface to cause actuated signal.
In the use of the embodiment of fluid delivery system, fluid will pass epidermal tissue's transdermal delivery.
Fluid delivery system preferably includes and is used to store the fluidic delivery curves that is delivered to tissue and sends historical memorizer.
In an alternate embodiment of the present invention, fluid comprises the analyte that is delivered to tissue and is used to diagnose biological aspect subsequently.
According to the embodiment that comprises phase change mechanism of the present invention, described system also comprises the flexible membrane that fluid container is separated into first Room and second Room, and wherein first Room comprises the actuation fluid that is communicated with described phase change mechanism, and second Room comprises treats delivery of fluids.In yet another embodiment, actuation fluid be positioned near the phase change mechanism and this actuation fluid with treat the delivery of fluids unmixing.
According to one embodiment of the invention, the common structure of fluid ejection chamber, at least one outlet opening and actuating device and size are fit to the fluid that consecutive periods sprays the about 800nl of about 1pl-repeatedly.
Description of drawings
In order to understand feature of the present invention and purpose better, should and read relevant drawings with reference to following detailed description, wherein:
Fig. 1 is the sketch map of an embodiment of cassette reuse indication means according to an embodiment of the invention;
Fig. 2 A is the sketch map according to an embodiment of the cassette reuse indication means with array of microjets of the present invention;
Fig. 2 B is the sketch map according to another embodiment of the cassette reuse indication means with array of microjets of the present invention;
Fig. 3 is the sketch map according to another embodiment of cassette reuse indication means of the present invention;
Fig. 4 is the sketch map according to another embodiment of cassette reuse indication means of the present invention;
Fig. 5 is the sketch map according to another embodiment of cassette reuse indication means of the present invention;
Fig. 6 is the sketch map according to another embodiment of cassette reuse indication means of the present invention;
Fig. 7 is the sketch map according to another embodiment of cassette reuse indication means of the present invention;
Fig. 8 is the sketch map according to another embodiment of cassette reuse indication means of the present invention;
Fig. 9 is according to the sketch map of another embodiment of the cassette reuse indication means with array of microjets of the present invention;
Figure 10 is the sketch map according to an embodiment of the cassette reuse indication means with piezoelectric device of the present invention;
Figure 11 is the sketch map according to an embodiment of the cassette reuse indication means with piezoelectric device of the present invention;
Figure 12 is the sketch map according to an embodiment of the cassette reuse indication means with piezoelectric device array of the present invention;
Figure 13 is the sketch map according to an embodiment of the cassette reuse indication means with phase change mechanism of the present invention;
Figure 14 is the sketch map according to an embodiment of the cassette reuse indication means with phase change mechanism array of the present invention;
Figure 15 is the sketch map according to an embodiment of the cassette reuse indication means with the array of microjets that is activated by phase change mechanism of the present invention;
Figure 16 is the sketch map according to an embodiment of the cassette reuse indication means with electromagnetism micro ejector of the present invention;
Figure 17 is the sketch map according to an embodiment of the cassette reuse indication means with spring micro-injection mechanism of the present invention;
Figure 18 is the sketch map according to an embodiment of assembled two piece slider of the present invention;
Figure 19 is the sketch map according to another embodiment of assembled two piece slider of the present invention;
Figure 20 is the sketch map according to another embodiment of assembled two piece slider of the present invention;
Figure 21 is the sketch map according to another embodiment of assembled two piece slider of the present invention;
Figure 22 A is the sketch map that is shown in the assembled two piece slider of Figure 21;
Figure 22 B is the sketch map according to the another embodiment of assembled two piece slider of the present invention;
Figure 23 is the sketch map according to an embodiment of the microprocessor of cassette reuse indication means of the present invention;
Figure 24 is the sketch map according to another embodiment of cassette reuse indication means of the present invention;
Figure 25 is the sketch map according to the another embodiment of cassette reuse indication means of the present invention;
Figure 26 is the 3-D view according to an embodiment of the component layer of cassette reuse indication means of the present invention;
Figure 27 is to use the flow chart of embodiment of the method for transdermal microjet device of the present invention.
The specific embodiment
Now will be in detail with reference to the preferred embodiments of the invention, embodiment is shown in the drawings.Describe the present invention though will get in touch preferred embodiment, should be appreciated that this is not is that the present invention is limited to these embodiments.On the contrary, the present invention attempts to cover various replacement schemes, change and equivalent, and it can be included in the essence of the present invention and scope that is defined by the following claims.
Referring now to the cassette reuse indication means 100 that is shown in Fig. 1, medicament reservoir 102 is communicated with micro ejector 104 fluids of being controlled by microprocessor 106.Microprocessor 106 is able to programme to activate micro ejector 104, drives material jet 101 and sprays to biological barrier 130 from micro ejector 104.In order to quote conveniently, the surfaces A of cassette reuse indication means 100 be towards or near the surface of the cassette reuse indication means 100 of biological barrier 130, surperficial B is away from biological barrier 130.This is oriented in and is consistent in the whole description and regularly uses so that the reader determines direction.
In addition, cassette reuse indication means 100 can activate repeatedly.For clarity sake, can activate repeatedly be defined as repeatedly, sequential activation and need not between activation cycles and non-activation cycles, to remove, charging or supplementary device otherwise again.For example, concrete medicament administration pattern can be the medicine that continues per hour to send in 5 days specified quantitative.In this example, cassette reuse indication means can activate following power repeatedly and produce mechanism, and the microinjection agent of injection aequum is to send the medicine of scheduled volume at first hour.When finishing first hour use, described device will be waited for until next hour, use the medicine of scheduled volume more for the second time.Described device will continue this mode subsequently in whole 5 day time.In addition, according to an embodiment, microprocessor 106 is simple electronic component or the control units according to predetermined or pre-programmed timing sequence generating signal.Signal timing can be successive, but is not limited to continuous timing (sequential timing).Activate micro ejector by control unit subsequently, propelling fluid sprays and the generation signal towards biological barrier.
According to another embodiment, shown in Fig. 2 A and 2B, cassette reuse indication means 200 comprises the microprocessor 206 of control micro ejector 204 arrays.The material permeance that micro ejector 204 arrays can be sent volume more than the single micro ejector 104 of Fig. 1 is the biological barrier of high surface area more.In addition, micro ejector 204 arrays can be sent multiple material and/or see through the pattern delivered substance that biological barrier 130 is used to optimize predetermined substance.Preferably, shown in Fig. 1,2A and 2B, transdermal microjet device provides and is no less than about 500ms and no more than about 10 days substance delivery persistent period.
For succinct and clear for the purpose of, below the assembly of single transdermal microjet device 100 shown in Figure 1 will be mainly described in explanation in detail.With reference to the array implement scheme shown in Fig. 2 A and 2B, yet, should be appreciated that the explanation of assembly can be applicable to each embodiment equally, and be not limited to use the embodiment of single micro ejector.
According to preferred embodiment, container 102 can pressurize so that the injected material 108 that is wherein comprised extrudes container 102.Scheme also can utilize pump 132 that injected material 108 is initiatively pumped container 102 as an alternative.
According to an embodiment, as shown in Figure 3, can apply compression stress and produce to piston 304 by spring 302 injected material in the container 102 108 pressurization.Spring 302 is set to that an end props up the inwall of container 102 and the other end props up piston 304.When container 102 was full of injected material 108, compression spring 302 was exerted pressure 302 pairs of pistons 304 of spring.When injected material 108 is following be described in detail in use discharge in transdermal microjet device 100 processes and container 102 in injected material 108 volumes when reducing, spring 302 makes piston 304 move, thus the swept volume of minimizing container 102.Thereby injected material 108 remains under the pressurized state and discharges from container 102.It should be understood by one skilled in the art that the size that to select spring 302 and ratio satisfying conditions such as special container volume, injected material density, injected material viscosity, thereby all the volumetrical injected material 108 in the container 102 are produced required pressure.Scheme as an alternative, the pressurization of container 102 can be used for the gases at high pressure of driven plunger 304 by design and finish.Therefore, gases at high pressure provide the power of driven plunger, thereby reduce the swept volume of container 102, keep injected material 108 to be under the enough pressure.
In yet another embodiment, as shown in Figure 4, container 102 can contain the balloon-type air bag 306 that is made of expandable elastomeric-type material.When charging into injected material 108, this balloon-type air bag 306 expands.The power that expansible balloon-type air bag 306 produces along the direction of arrow is discharged air bag 306 with injected material 108.Scheme as an alternative, container 102 can be made of the elastomeric-type material itself, and it expands when filling and produces power with the content amount discharge container of container 102.
In a preferred embodiment, container 102 can be separated into more than one interior chamber, shown in Figure 105.Under many circumstances, if storing with powder morphology or other form, drug component has the long pot-life.Therefore, it is favourable the component of container 102 being kept in the chamber of separation.Accordingly, the reservoir divider 320 of Fig. 5 is separated little chamber that two or more are separated mutually 324 and 326 with container.Therefore, two or more injectate components preservation of can dispersing.Fig. 5 illustrates two chambers, but it should be understood by one skilled in the art that container 102 can be separated into a plurality of chambers with equal volume or have not isometric a plurality of chambers, each chamber can be at one time or different time mix, be formed for the multistage injected material that different administration is used at interval the time.
According to a preferred embodiment, container 102 has the volume that is not less than about 100 μ l and is not more than about 500ml.In an alternate embodiment, the volume of preferred container 102 is not less than about 150 μ l and is not more than about 1ml.In an embodiment again, the volume of preferred container 102 is not less than about 200 μ l and is not more than about 750 μ l.
Destroy mechanism 322 and be placed in a ball in the vessel.In the use, when shaking or operate cassette reuse indication means 100, described ball is motion and bump reservoir divider 320 in container independently, thereby destroys reservoir divider 320 and make the different component that is contained in vessel 324 and 326 mix.Along with the destruction of reservoir divider 320, described ball can promote the mixing of drug component, thereby guarantees before using suitably hybrid injection thing.
According to an above-mentioned replacement scheme, destroying mechanism 322 can be the mechanism that is controlled by microprocessor 106.This destruction mechanism 322 for example can be a piezoelectric device.According to a such embodiment, the microprocessor 106 voltage supplies of control from the power supply to the piezoelectric rupture mechanism are sent.When using alternating current, piezoelectric rupture mechanism produces the mechanical pressure ripple in fluid media (medium), as ultrasound wave.This mechanical pressure ripple is used for destroying reservoir divider.
According to such embodiment, container can be separated into a plurality of containers.Microprocessor 106 can be controlled reservoir divider 320 destructive timings and order, so that specific reservoir divider is destroyed, is used for blended component thereby discharge.Like this, current using only arranged, promptly mixed when the part component of predose, and the component of surplus is retained in the discrete container with stable discrete form.As a result, cassette reuse indication means 100 can comprise the treatment chemical compound discretely, and it can effectively be preserved for a long time, and the medicine repeatedly that continues period is sent.
The destruction mechanism 322 of microprocessor control for example can be the electric pulse that is produced by microprocessor 106.Each independent reservoir divider 320 can comprise electrode, and it makes independent reservoir divider destroy when activating, mix subsequently thereby allow to use component.Scheme as an alternative, destroy mechanism 322 for example can by jab, physical damage reservoir divider 320 such as distortion, vibration wave, blast.Destroying mechanism and can be can be damaged or destroy any mechanism of impermeable reservoir divider integrity.
Usually in medical applications, patient's treatment need break away from the medicine that doctor formula just may be illegal.Some this medicine can addiction and the individual earnestly seeks to use outside prescription.Can store a certain amount of this drug component of using of continuing repeatedly because transdermal microjet device 100 comprises, can imagine that therefore some individual can manage to take out drug component and illegal use from container 102.Therefore, comprise that in transdermal microjet device 100 shown in Figure 6 antagonist reservoir 350 is favourable.Antagonist reservoir 350 links to each other with container 102, and preferably comprises the antagonist 352 that the drug component that is contained in the container 102 is an injected material 108.
Antagonist reservoir 350 is designed to when utilizing the mode that is enough to extraction injected material 108 from container 102 to operate or intervening transdermal microjet device 100 destroyed easily, therefrom discharges antagonist 352.When antagonist reservoir 350 is destroyed, antagonist 352 will be released, thereby make injected material 108 ingredient inactivations.
Antagonist reservoir 350 for example can be to be provided with to come around container 102 and the container that is made of the easier ruined material of container 102.Scheme as an alternative, as shown in Figure 7, antagonist reservoir 350 for example can be the net that spreads all over container 102 of similar bag shaped structure, and design has destruction region 354, so that destruction region 354 response physical operations and destroying before container 102 destroys, thereby discharge antagonist to injected material 108 and make injected material 108 lose efficacy.
In yet another embodiment, as shown in Figure 8, antagonist reservoir 350 for example can be a plurality of microspheres 356.A plurality of microspheres 356 preferably become destruction when excessive operation container 102, thereby discharge antagonist.
Refer again to Fig. 1, container 102 is communicated with micro ejector 104 fluids by feed pipe 110.Feed pipe 110 can be pipe, chamber, the groove (being specified in down) in the floor of shell 128, thereby when described layer is assembled, form passage between container 102 and micro ejector 104, perhaps another configuration forms and make the mechanism that injected material 108 shifts between container 102 and micro ejector 104.
In a preferred embodiment, feed pipe 110 comprises the pressure regulator 116 of regulating pressure in the feed pipe 110.As mentioned above, injected material 108 can be kept at than under the pressure in the container 102 that required pressure is higher in the nozzle 114.Therefore, pressure regulator 116 functions are for regulating the downstream pressure in the feed pipe 110, so that the pressure of the injected material 108 at nozzle 114 places remains on suitable level.It should be understood by one skilled in the art that described proper level is to make injected material 108 be full of nozzle 114 but do not exceed injected material 108 is remained on power in the nozzle 114, described in more detail when nozzle 114 being described herein.
The micro ejector 104 of Fig. 1 will be described now, yet, should be appreciated that described description can be equal in the micro ejector 204 that is applied to one group of embodiment shown in Fig. 2 A and 2B.Micro ejector 104 generally comprises power and produces mechanism 118, chamber 120 and nozzle 114.
The power of Fig. 1 produces mechanism 118 and generally is positioned at cassette reuse indication means 100, thereby power produces mechanism 118 towards the A of cassette reuse indication means 100 side.Generally, each micro ejector 104 can comprise that discrete power produces mechanism 118, shown in figure l.Scheme as an alternative, one group of micro ejector 360a-360e can produce mechanism 118 by a power and activate, as shown in Figure 9.In the use, power generation mechanism 118 generally is used for changing the pressure in the chamber 120, thereby the injected material 108 in the chamber 120 is quickened towards nozzle 114.After power produced mechanism's actuating, the injected material 108 of acceleration ejected from nozzle 114, produced the jet of injectate that therefrom ejects.In a preferred embodiment, jet of injectate comprises the injected material that is no less than about 1pl and no more than about 800nl.In a preferred embodiment, jet of injectate comprises the injected material that is no less than about 100pl and no more than about 1nl.According to a preferred embodiment, power produces mechanism and produce pulse width or pressure variation with the speed that is not less than about 5ns and is not more than about 10 μ s in the chamber.In an alternate embodiment, pulse width is not less than about 0.5 μ s and is not more than about 5 μ s.In another alternate embodiment, pulse width is not less than about 1 μ s and is not more than about 3 μ s.In a preferred embodiment, power produces mechanism's per second and produces no more than about 100 pulses.In a preferred embodiment, the per second generation of power generation mechanism is no less than about 5 pulses and per second produces no more than about 15 pulses.
According to an embodiment, it is piezoelectric devices 400 that power produces mechanism 118, as shown in figure 10.Piezoelectricity is dielectric crystal, and when described crystal was applied mechanical stress, it produced voltage, and perhaps on the other hand, when described crystal was applied voltage, it produced mechanical stress.Piezo-electric device is well-known, and piezoelectric operated is conspicuous for those of ordinary skills.Piezoelectric device 400 is against the distally B of micro ejector 104.The wall B far away of micro ejector 104 is designed to bear the mechanical force that is produced by piezoelectric device 400, so that when piezoelectric device 400 produced mechanical stress, described wall was not crooked.As a result, the mechanical stress of piezoelectric device 400 or distortion concentrate on the proximal direction A towards nozzle 114.Piezoelectric device 400 is designed to piston, produces pressure along proximal direction A in injected material 108 and change in the mechanically deform process, thereby generate the jet of injectate 402 that sprays from nozzle 114.
Below the microprocessor 106 of Xiang Shuing is connected to piezoelectric device 400 by circuit 124, as shown in figure 10.In the use, when planning or needing administration of injectate 108, following more detailed description, the voltage of microprocessor 106 control stores in power supply 122 is to the supply of piezoelectric device 400.Response voltage, piezoelectric device 400 are subjected to mechanical stress and are out of shape and generation pressure variation in chamber 120 (Fig. 1).
According to embodiment shown in Figure 11, a piezoelectric device 410 can activate a plurality of nozzles 412.When using from the injected material 108 in the container 102, the volume of injected material 108 reduces.Respond the minimizing of described volume, the voltage that is applied on the piezoelectric device 410 increases, so that piezoelectric device 410 produces bigger physical deformation.The bigger physical deformation of piezoelectric device 410 is relevant with the injected material 108 volumes minimizing in the container 102, thereby producing the same relatively pressure in container 102 changes, cause constant jet power from the injected material of nozzle 114, thus constant and predictably apply and delivery of injectate.
According to the embodiment with piezoelectric micromotor ejector array 420, as shown in figure 12, circuit 424 can be bonded to each micro ejector 420 independently.Therefore, microprocessor 206 can be controlled the timing and the order of each piezoelectric device 420 distortion discretely.As a result, the mode of administration of injected material 208 can be controlled, depends on the application effect of required injected material type as the insulin of treatment diabetes thereby optimize.Can change mode of administration and optimize absorption/diffusion, the stimulation of biological barrier is minimized, make to be suitable for particular patient etc., so that patient's compliance, efficacy of drugs and effective percentage are optimized to systemic circulation system.
According to an alternate embodiment, it can be phase change mechanism 430 that power produces mechanism, as shown in figure 13.Phase change mechanism 430 comprises two electrodes 432 and 434.Electrode 432 and 434 passes the far-end of micro ejector 104 and inserts chamber 120.Chamber 120 is the totally-enclosed chambers that comprise actuating fluid (activation fluid) 436.The distally of chamber 120 and lateral layout are used for bearing the power that phase change mechanism 430 is produced, and the near-end of chamber 120 is flexible membranes 438.Flexible membrane 438 is impermeable for the actuating fluid in the chamber 120 436 with the injected material 108 that is included in the nozzle 114 preferably, so that described two kinds of components are not mixed.
Actuating fluid 436 is to be easy to decompose when setting up charge difference on electrode 432 and 434 and the fluid of vaporization fast.Actuating fluid 436 is the conductive ion fluid normally, includes but not limited to brine fluids, also can adopt the aqueous solution of other salt, as aqueous metal halide, i.e. potassium chloride, calcium chloride etc.In addition, also can be with the low boiling dielectric substance as actuating fluid 436, as fluorocarbon.
According to an alternate embodiment, actuating fluid 436 can be an injected material.Therefore, when whole chamber 120 and nozzle 114 were full of the fluid of final injection after phase change mechanism activates, flexible membrane 438 can be optional.
Because the specified rate fluid volumes rolls up when fluid is transformed into gas form, so the fluidic vaporization of specified rate will greatly increase chamber pressure in the chamber of fixed volume.Afterwards, flexible membrane 438 is out of shape on proximal direction, thereby reduces the volume of nozzle 114.As a result, injected material 108 is stressed and ejection from nozzle 114 on proximal direction, following detailed description.
In an alternate embodiment, the actuating fluid 436 of Figure 13 can keep separating with injected material 108 with physical property by the chemistry of actuating fluid, does not therefore need film.Thereby actuating fluid can be immiscible with injected material 108, so that described two kinds of fluids do not mix.Therefore, do not need flexible membrane.
According to another embodiment, as shown in figure 15, single phase change mechanism 450 can activate a plurality of nozzles 452.Phase change mechanism 450 comprises at least two electrodes 454 and 456.Around electrode 454 and 456 are the actuating fluids with closing volume 458 that contained by flexible membrane 460.During administration of injectate 108, the volume of the injected material 108 in the container 462 reduces.Therefore, in order to produce the constant jet power that injected material is sprayed from nozzle 452, phase change mechanism 450 produces corresponding increasing power, and described power makes the displacement of flexible membrane 460 increasing.Therefore, a plurality of nozzles 452 can be irrelevant by the amount of the injected material in the container 462 that a phase change mechanism 450 drives and is included in injected material jet power repeatedly.
Phase change mechanism of the present invention is generally worked being not less than about 500V and not being higher than under the high voltage of about 10kV.Phase change mechanism is preferably worked being not less than about 1kV and not being higher than under the voltage of about 6kV.In an alternate embodiment, this phase change mechanism is preferably worked being not less than about 3kV and not being higher than under the voltage of about 6kV.Potential pulse is no less than about 5ns and no more than about 10 μ s.In an alternate embodiment, potential pulse is no less than about 0.5 μ s and no more than about 5 μ s.In another alternate embodiment, potential pulse is no less than about 1 μ s and no more than about 3 μ s.
According to another embodiment, it can be electromagnet actuation mechanism 500 that power produces mechanism 118 (Fig. 1), as solenoid, as shown in figure 16.Electromagnet actuation mechanism 500 functions are the information of response from following microprocessor 106, so that piston 502 moves along the near-end A direction shown in the arrow among the figure in chamber 120, injected material 108 is moved and the jet 504 of jet injection thing 108 is applied to the patient thereby order about.Those of ordinary skills should understand electromagnet actuation mechanism 500, thereby are not described in detail.
According to another embodiment, it can be the spring mechanism 510 of operated piston 512 as shown in figure 17 that power produces mechanism 118 (Fig. 1).According to this embodiment, the near-end of chamber 120 can be opened, and does not have film that nozzle Room 114 and chamber 120 are separated.Chamber 120 and nozzle 114 all are filled with injected material 108.Therefore, the power that is produced in the injected material 108 of chamber 120 is amplified by the injected material 108 of nozzle 114, causes injected material 108 discharging jet 514 from nozzle 114, as detailed below.
In another embodiment of the present invention, it can be gases at high pressure that power produces mechanism 118 (Fig. 1), when it activated, and driven plunger, thus from nozzle 114, replace injected material 108.According to this embodiment, the motion of microprocessor 106 (Fig. 1) control gases at high pressure, thereby produce the jet of injected material 108 so that under above-mentioned suitable time and/or order administration of injectate 108.
In another embodiment, power generation mechanism 118 (Fig. 1) can be an explosive mechanisms.Described explosive mechanisms for example can comprise excite and produce the chemical mixture of blast when the incendiary source of service voltage or other type.Thereafter, blast produces the pressure variation and adjacent biological tissue is displaced and entered to injected material from nozzle 114 in chamber 120.
The chamber 120 of Fig. 1 preferably is made of the polydimethylsiloxane that is known as PDMS or silicone rubber, but also can use other polymer, pottery or metal material.The diameter of chamber 120 is not less than about 0.1 μ m and is not more than about 500 μ m.More preferably, the diameter of chamber 120 is not less than about 0.5 μ m and is not more than about 100 μ m.Most preferably, the diameter of chamber 120 is not less than about 1 μ m and is not more than about 10 μ m.
With reference to Fig. 1, chamber 120 is communicated with nozzle 114 fluids as ejector 104.Because power produces mechanism 118 and produce pressure variation and/or volume-variation in chamber 120 and nozzle 114, jet injection thing 108 from nozzle 114, chamber 120 and nozzle 114 must be stored injected material 108 again, so that prepare to carry out subsequent action, thereby produce micro-injection repeatedly.Power produces after mechanism's 118 actuatings, and at cassette reuse indication means 100 duration of works, chamber 120 refills the injected material 108 from container 102.
As mentioned above, one embodiment of the invention utilize feed pipe 110 to keep container 102 to be connected with nozzle 114 fluids.Equally, as mentioned above, container 102 can be pressurized or be comprised pump 132, enters nozzle 114 so that injected material 108 is discharged feed pipes 110, thereby is refilling nozzle 114 and chamber 120 after each jet injection thing 108.Scheme as an alternative, feed pipe 110 can be coupled with and empty in the chamber 120, rather than in the nozzle 114.
In a preferred embodiment, feed pipe 110 in the chamber 120 and/or the opening diameter of nozzle 114 junctions basically less than the opening of nozzle 114, thereby can ignore injected material 108 in opposite direction to the inflow of feed pipe 110.Equally, deflection plate 134 can be arranged, as shown in Figure 1, be positioned at the opening top that feed pipe 110 enters nozzle 114, its position makes during driving microjet 104, injected material 108 deflections and do not enter feed pipe 110 in opposite direction.According to another embodiment, valve 112 (Fig. 1) can be positioned at feed pipe 110 in conjunction with nozzle 114 places, makes that injected material 108 does not enter feed pipe 110 in opposite direction during driving microjet 104.
According to an alternate embodiment, if container 102 does not pressurize, then injected material 108 refills nozzle 114 and chamber 120 by capillarity.
In an alternate embodiment, Fig. 9, the remote extension of chamber 120 have the opening that enters container 102 to container 102, or have semipermeable membrane between chamber 120 and container 102.Because power produce mechanism 118 in injected material 108, produces be enough to will injection 108 ejection from micro ejector 104 pressure differentials, injected material is passed through opening 182 inlet chambers 120, so that the pressure in the chamber 120 equates with pressure in the container 102.
According to another embodiment, shown in Figure 11 and 15, the container that is used for containing injected material also can be used as the chamber.
Figure 18 illustrates the rough structure of nozzle 114.The far-end of nozzle 114 is connected with chamber 120, and the near-end of nozzle 114 is configured to interact with biological barrier 130.In the use, produces pressure change in chamber 120 because power produces mechanism 118 (Fig. 1), this pressure variation causes injected material 108 in chamber 120 and the nozzle 114 with pattern jetting nozzle 114.Nozzle 114 preferably is being reduced into the small cross sections diameter gradually on the direction of the proximal openings 602 of nozzle 114.Because nozzle 114 is with dwindling gradually near near-end, the initial volume of the injected material 108 of acceleration is greater than the volume of nozzle 114, so injected material 108 must accelerate to bigger speed.When arriving the opening of nozzle 114, the injected material of acceleration sprays from nozzle 114 as fluid jet.It should be understood by one skilled in the art that: can change jet size, chamber volume, injected material viscosity etc., so that the jetting stream of injected material carries the power of scheduled volume, make the jet of injected material penetrate biological barrier 130 and injected material is deposited in the adjacent tissue of desired depth.
According to the nozzle of Figure 18, nozzle 114 disposes half blunt near-end, herein nozzle 114 abut biological barrier 130 gently.Injected material 108 in the nozzle 114 is also had a common boundary with biological barrier 130.Therefore, when actuation force produced mechanism 118, the injected material of amount of application transmitted by injected material in the nozzle 114 108 and the initiation layer that passes adjacent biological barrier 130.
According to an embodiment, as shown in figure 19, the near-end 604 of nozzle 114 can comprise the coating of repelling injected material 108, and it is made of the institutes such as compositions that repel injected material 108.For example, if injected material 108 is hydroaropic substances, then the near-end 604 of nozzle 114 can apply lyophobic dust or be made of lyophobic dust, thereby repels injected material 108, makes it the impassive near-end 604 that enters nozzle 114.In this embodiment, at the quiescent phase of described device, injected material 108 keeps setpoint distance h with the surface of biological barrier 130.Therefore, if injected material 108 has stimulating organism barrier 130 or biological barrier 130 is produced the trend of other negative effect when contact biological barrier 130, then will make such event minimization.In addition, according to this embodiment, can predict and send the administration of injectate 108 of more accurate amount, this is because injected material can not see through biological barrier 130 diffusions or enter in the biological barrier 130, unless advance stream as jet during using.
Scheme as an alternative, the near-end of nozzle 114 can have convergent/divergent configuration 606, as shown in figure 20.According to this embodiment, the position of injected material 108 can be defined as the meniscus of injected material 608 is remained on apart from biological barrier 130 optimal distance h places.Determine height h and be set the distance that the administered jet for permission injected material 108 between the meniscus of injected material 608 and the biological barrier 130 penetrates, thereby penetrate biological barrier 130 1 setpoint distances.According to an embodiment, height h can be not less than about 0 μ m and be not more than about 5000 μ m for distance biological barrier surface.According to another representative configuration, for example, the about 10 μ m-15 μ m of cutin bed thickness, the epidermal thickness under the horny layer is about 50 μ m-100 μ m.Therefore, if epidermis is the target area of injected injectate, then height h can be set at the distance that causes injected material to see through being not less than 10 μ m and be not more than 500 μ m.In an alternate embodiment, the degree of depth that injected material sees through is for to be not less than about 25 μ m and to be not more than about 100 μ m under the surface of biological barrier.
According to one embodiment of the invention, as shown in figure 21, nozzle 114 is from shell 128 outstanding segment distance h.Between the operating period, the proximal end face A of shell 128 can be against biological barrier 130, shown in Figure 22 A, makes nozzle 114 be positioned at automatically on the preferential direction with respect to biological barrier 130.In addition, when transdermal microjet device 100 during against biological barrier 130, nozzle 114 applies tension force from the outstanding of shell 128 proximal surface A to biological barrier 130.Making biological barrier 130 bear tension force and preload promotes to see through biological barrier 130 from the jetting stream of micro ejector 104.Preload is eliminated or is reduced elasticity from biological barrier 130.Therefore, can calculate the actual accurate amount that sees through the injected material of biological barrier 130, and can utilize described device to send the required thing of exact dose.As a result, between nozzle 114 and biological barrier 130, apply known and constant contact pressure.Thereby the user only needs the proximal lateral A of shell 128 is touched biological barrier 130, and nozzle 114 will be in the appropriate location to optimize using of injected material.
According to an alternate embodiment, shown in Figure 22 B, the position of giving prominence to nozzle 114 near-ends outside shell 128 can form in the initiation layer that enters biological barrier 130 or see through this layer.In the use, the first some jet injection things that produced by micro ejector 104 generate the hole 190 that sees through or enter biological barrier 130, and the external force that makes transdermal microjet device 100 touch biological barrier 130 causes nozzle 114 proximal tip to navigate in the hole 190 that is generated by the jet injection thing.Therefore, after nozzle 114 proximal tip being inserted or seen through biological barrier 130, the injected material 108 in the nozzle 114 can passively diffuse into biological barrier 130.
According to another embodiment, wherein said device disposes array of microjets 204 and nozzle array 214, and for example shown in Fig. 2 A, multiple injectate substances can be sent by different spray nozzles.According to this embodiment, each micro ejector 204 all can be communicated with different vessels, or different micro ejector group 204 can be communicated with different vessels, thereby some micro ejectors can be injected specific injected material, and other micro ejector is injected another injected material.
According to another embodiment, for example shown in Fig. 2 B with array of microjets 204.Each micro ejector can be discrete delivery unit 242.Therefore, each delivery unit 242 can be activated by microprocessor 206 separately.In addition, microprocessor 206 is able to programme, and particular injectate in being included in delivery unit runs out of, and activates the operation of next delivery unit subsequently with delivery unit 242 of once-through operation, all has been consumed until the injected material of each delivery unit.
Preferred microprocessor 106 is described now.As shown in figure 23, microprocessor 106 bus 710 that comprises central processing unit (CPU) 700, memorizer 702, user interface 704, communications interface circuitry 706, random-access memory (ram) 708 and be connected these assemblies.Microprocessor 106 is able to programme and store the data that relate to particular injectate mode of administration, patient demand, micro-injection actuation patterns, container incorporation time and/or condition, dosage requirement etc. in memorizer 702.CPU700 compiling and carrying out is stored in and is used for the data of administration of injectate 108 in the memorizer 702.Thereby memorizer 702 also comprises actuating time and the order of controlling micro ejector 104 and controls the actuation sequence 716 that injected material is used.In the use, depend on that above-mentioned which kind of power produces mechanism 118 and is incorporated in the particular of cassette reuse indication means 100, the voltage of microprocessor 106 control piezoelectric devices, cause the voltage of activation fluid vaporization, the motions of control electromagnet, gases at high pressure etc. are with the actuating of control micro ejector 104.In entire description, microprocessor 106 relates to the actuating of controlling micro ejector.Those of ordinary skills should understand the power supply of the power generation mechanism of microprocessor control micro ejector.For example, micro ejector can starting switch, and as transistor, this causes energy to flow to power from power supply producing mechanism, thereby actuation force produces mechanism.But for convenience of the reader, the microprocessor control that this process will be called micro ejector activates.
According to another embodiment, the memorizer of microprocessor 106 702 keeps injected material delivering amounts, time of application, use the record of quantity etc., is used for futures analysis and assessment, to improve the therapeutic scheme to the patient.
In an alternate embodiment, microprocessor 106 can also comprise user interface 704.User interface device 704 can be button, switch or other mechanism, and it can be activated with using at any booster injection preset time thing by the user.For example, can settle to start button 136, so that this button can be communicated with microprocessor 106 by starting button communication link 138.Therefore,, then can trigger to start button 136 if determine need be in the injected material of delivery treatments dosage preset time arbitrarily for patient or administration person, thus the injected material of walking around the application program of programming and sending required predetermined close.This can help the embodiment that described device is used to send analgesic, because can send outside the scheme predetermined the needs of analgesic.Yet, relevant with user interface device 704, microprocessor 106 can pre-programmed for having security feature so that the user only triggers user interface device 704 so repeatedly in preset time, thereby make that the patient can excessive or abuse of injection thing.The number of times that the patient can trigger user interface device 704 can wait according to the seriousness of material that injected material comprised, patient age, weight in patients, patient's disease to be regulated.
According to another embodiment, microprocessor 106 has communications interface circuitry 706, with another computer system communication.Doctor, research worker etc. can be passed through computer, handheld computer, wireless connections equipment etc. and pass through interface alternation with microprocessor 106, and obtain about information such as frequency of administration, each dosage of sending at interval, the variation of dosage delivered, total dosage delivered.In addition, doctor or research worker data 718 of preserving in can download memory 702 or improve application program or actuation sequence 716.Can be used for alternately the treatment specified disease is further understood with microprocessor 106, develop new, better therapeutant and scheme.
In an alternate embodiment, as shown in figure 24, microprocessor 106 is communicated with biosensor 750.Biosensor 750 can be implanted in user's body or can be external the user.Biosensor 750 is preferably the pick off of the biological sign that induction injected material design is used for handling, check, change, treat, replenishing etc.Biosensor 750 is by can being that lead connects or the communication device 706 of wireless connections etc. is communicated with microprocessor 106.The biosensor 750 preferred measurement results that receive biological sign also transfer to microprocessor 106 with this measurement result by communication device 706.Microprocessor 106 reads the measurement result that biosensor 750 receives, these signs of response in certain predefined parameter scope, and microprocessor 106 will activate micro ejector 104, to user's inject injectate, with the induced sign of treatment.
According to another embodiment, device 100 can comprise condition sensor 133, Fig. 1.Condition sensor 133 is preferably designed for induction installation 100 and whether contacts or otherwise be in the position of relative biological barrier 130, so that install the injection that 100 actuating will cause injected material.Remove or otherwise leave the position if install 100 from biological barrier 130, the actuating of micro ejector 104 was lost efficacy and can not caused injected material to be administered in patient's body.Whether therefore, the condition sensor 133 that is communicated with microprocessor 106 can provide feedback, to indicate micro ejector 104 should activate or to forbid activating before device 100 resets.In addition, condition sensor 133 warning devices that can comprise buzzer or other type activates to remind patient or the described device of the personnel that cure mainly and offed normal and be limited.Condition sensor for example can be temperature sensor, pressure transducer etc.In an alternate embodiment, pick off 133 can be configured to respond to by power and produce the pressure that mechanism produces, thereby for microprocessor provides feedback mechanism, so that monitoring force produces the functional of mechanism.
Refer again to Fig. 1, cassette reuse indication means 100 also comprises power supply 122.Power supply 122 can be a battery, as NiCd, NiMH, LiMnO
2Battery, disposable battery, rechargeable battery etc.Preferred light weight, small size, long continuous capability, cheapness and disposable battery comprise power supply 122.Yet in an alternate embodiment, power supply 122 can be another power supply that can accept form, to provide voltage to power generation mechanism 118 and microprocessor 106.
According to an alternate embodiment, as shown in figure 25, transdermal microjet device 800 comprises external container 802.External container 802 is designed to the indent container of adjoining nozzles 804.Therefore, external container 802 can be full of the material that passes biological barrier 830 to be transferred.The material that passes biological barrier 830 to be transferred can be delivered to the outside cabin from container 808 by feed pipe 810.During use, transdermal microjet device 800 is positioned at abut biological barrier 830 places and activates micro ejector 812, as mentioned above.When activating, micro ejector 812 sprayed solution jets, thus penetrate biological barrier 830 and form hole 814.When transdermal microjet device 800 moves with respect to biological barrier 830, allow the material in the external container 802 passive diffusion to see through by the hole that jet produced 814 from micro ejector 812.In addition, can in the material that passes biological barrier 830 to be transferred, add material with the auxiliary permeability that increases biological barrier 830.
Scheme as an alternative, transdermal microjet device 800 as shown in figure 25, can be used for taking a sample, collect body fluid, see through the diagnostic data etc. that biological barrier 830 is gathered biological specimens.In this structure, activate micro ejector 812, as mentioned above, and usually with the brine type injection of solution in biological barrier 830, yet those of ordinary skills should understand and can use any being suitable for to play 812 injections and enter the solution of biological barrier 830 by micro-injection.After being expelled to biological barrier 830, biofluid diffuses out from the hole 814 that injection jet produced.Subsequently, can collect and take a sample or analyze this biofluid.In an alternate embodiment, micro ejector 812 can comprise the analyte that is used for being expelled in the biological tissue.After the injection of analytes, can detect or measure described analyte by optics or fluorescent technique commonly used.It should be understood by one skilled in the art that and to use many other chemistry, biochemistry and/or biological diagnosis technology.
According to a preferred embodiment of the invention, transdermal microjet device is designed to drug delivery patch 900, for example as shown in figure 26.Drug delivery patch 900 preferably constitutes described material such as polydimethylsiloxane (PDMS), polyethylene, poly terephthalic acid diethylester (PET), fluoropolymer polymer etc. by biocompatible and lamination 902,904,906 and 908 drug inert.
In an alternate embodiment, shown in Figure 11-15, power produces the assembly that mechanism 410 and 450 can be designed as microprocessor layer 908 respectively, so that described device kept when abandoning administration patch, thereby raises the efficiency and saves cost for the terminal use.
Described lamination preferred combination together.Described lamination can utilize chemical bond, thermal etc. to combine.In addition, wish that form with high-efficiency and economic makes up described subsides and after using inclusions it abandoned.
Lamination 902,904 and 906 preferably is made of flexible, biocompatible, drug inert, so that drug delivery patch 900 can be applicable to human body and meets human body contour outline.In addition, because transdermal drug delivery patch 900 is flexible, the activity that all can limited subscriber.According to an alternate embodiment, transdermal drug delivery patch 900 can be made of the material of inflexibility.Therefore, transdermal drug delivery patch 900 does not meet the profile of application site.
According to an alternate embodiment, transdermal microjet device 100 can be designed as the applicator of hand-held or robot medicine that hold, that be used for the treatment of biological disturbance, damage, disease, disease etc., treatment solution, saline solution etc.Scheme as an alternative, transdermal microjet device can be designed as implantable device, and it connects intracorporeal organ, tumor, biological barrier such as cerebral dura mater and pia mater encephali etc. by the interface.In addition, transdermal microjet device can be designed as the device that long term implantable continues controlled drug release.Described implantable device can be in the external controlled in wireless of accepting of implantation position, with the reprogramming therapeutic scheme.Said apparatus can also be used to substituting the intravenous drug delivery system.In this embodiment, described device can be used to transdermal delivery of drugs to epidermis.Described device can place on the patient skin, and container for example can be the supply of traditional intravenous (IV) drug drip.In a large amount of IV drug delivery applications, medicine diffuses to vein from epidermis in the very short time that can tolerate.In addition, when patients needing sustained intravenous treatments, often occur and conduit implant site complications associated with arterial system.Equally, catheter insertion site is to infect the predominating path that enters human body.Reduced infection according to this embodiment application the present invention and be derived from the complication of traditional intravenous drug delivery system with other.
Therefore because the present invention is directed to the apparatus and method of mechanical delivery of drugs to biological tissue, described device can be applicable to different medicines such as physicochemical properties such as partition coefficient, dissolubility, electric charge, molecular weight.Yet those of ordinary skills should understand can be to the injected material substance to increase the permeability of skin.This material can be a surfactant etc.
Figure 27 illustrates the method as drug delivery device with the present invention.According to shown in method, described method starts from the diagnose medical conditions in the step 1002 and the relevant selection of the required treatment of this disease.In case selected Therapeutic Method, then prepared injected material 108.The material that this injected material is to use transdermal microjet device 100 of the present invention to use.Described injected material can be medicine, antibiotic, analgesic, placebo, saline etc.Then, in step 1006, described injected material is written in the container 102 of transdermal microjet device 100.Subsequently, in step 1008, microprocessor 106 is programmed according to preferred dosage regimen and selected Therapeutic Method to concrete disease.Then, if microprocessor 106 separates with the administration unit of transdermal microjet device 100, then in step 1010, these two assemblies are linked together.Microprocessor 106 can be pin leads connection, wireless connections etc. with being connected of administration unit.In step 1012, described device is applied to biological tissue to be treated.The biological tissue that described device connects can be a tissue to be treated, as with as described in device directly apply to tumor with the treatment tumor, or biological tissue can be that injected material must see through the barrier that could arrive tissue to be treated.For the latter for instance, if the required application of described device is to patient's systemic medicine delivery, then skin can be barrier to be passed through.Therefore, attach the device to or contact this biological tissue, thereby and described device inject injectate see through described this injected material of barrier systemic delivery.
Injected material is being administered in the process of biological tissue, record is used relevant data with injected material in step 1014.Generally the data that can be recorded comprise the time of at every turn using, each amount of application etc.In a embodiment as selection, described device can comprise pick off, as the biosensor of the monitoring and the biological activity of record patient, described biological activity such as patient's temperature, blood pressure, pulse, blood sugar level or other this type of biology and/or chemical state.Then, if the doctor or the research worker of responsible biological tissue of being treated are ready that the real-time and/or random time recorded data during they can carry out electronic reciprocal and receive administration of injectate with described device is shown in step 1016.In step 1018, doctor or research worker also can be by changing application program with microprocessor 106 electronic reciprocals during injected material is used.Then, in step 1020, allow administration of injectate to realize application program.
If finish injected material use after disease be eased, then in step 1024, stop described method.But, if finish injected material use after disease be not eased, then in step 1026, microprocessor 106 and administration unit are disconnected, abandon administration unit, and keep microprocessor.The new injected material of preparation in step 1004, and continue described Therapeutic Method as previously mentioned.New injected material can be the identical injected material of using before of another consumption, maybe can use different injected material compositionss.
Below provide the exemplary illustration of the step execution of Figure 27.For example, the common execution in step 1002 of administration person or doctor is determined the therapeutic scheme that the patient is required.Step 1004,1006 and 1008 can be carried out during device is made usually, thereby prepares before being transported to retail trader such as pharmacy and the sealing administration unit.The step 1010 that connects control unit and administration unit can be carried out by any one party such as patient, pharmacists, doctors, is similar to step 1012.Can described device be put on the patient by any one party such as patient, pharmacists, doctors.Generally, in step 1013A, device put on to begin to activate after the patient and use, and can in step 1013B, trigger the startup button, thereby carry out sending of required injected material by any one party such as patient, pharmacists, doctors.The step 1018 of the step 1016 of retrieve data step and change application program is carried out by doctor or the technical staff under physician guidance usually.When finishing the using of administration unit, the patient usually disconnects administration unit and control unit, step 1026, and the administration unit that uses up is replaced by new administration unit, step 1010, but doctor or other Medical Technologist can carry out this step.The narration that those of ordinary skills should understand step operation of the present invention is for indicative purpose, and does not mean that restriction.The present invention can by patient, administration person, during manufacture or above combination carry out, as long as it is fit to concrete situation, proof effectively and convenient and help medical treatment of conditions.
Claims (41)
1. Zhu Dong fluid delivery system comprises
Supporting structure;
Be limited at least one outlet opening in the supporting structure, described hole has the diameter of the about 500 μ m of about 1 μ m-;
Fluid container, it is configured to comprise waits to be delivered to the fluid of tissue and is communicated with described at least one outlet opening;
Actuating device repeatedly, its responsive actuation signal and described fluid container and described at least one outlet opening collaborative work and jet fluid.
2. the delivery system of claim 1, wherein said fluid container and described actuating device repeatedly are in the described supporting structure.
3. the delivery system of claim 1-2, wherein said supporting structure is suitable for contacting skin surface, with described at least one outlet opening in abutting connection with skin surface.
4. the delivery system of claim 1-3, wherein said supporting structure comprises the nozzle that limits described hole, the structure of described nozzle and size are fit to make fluid therefrom to quicken to leave.
5. the delivery system of claim 1-4 also comprises the controller that is communicated with described actuating device repeatedly, and described controller can produce actuated signal.
6. the delivery system of claim 5, wherein said controller is the microprocessor of control model application program able to programme.
7. the delivery system of claim 6, wherein said medelling application program occurs in and is no less than in about 500ms and the no more than about 10 days time durations.
8. the delivery system of claim 4, wherein before spraying, described nozzle is configured to keep fluid away from the distance of organizing basic fixed.
9. the delivery system of claim 8 wherein separated fluidic described fixed range and is not more than about 5000 μ m for the distance tissue before fluid jet.
10. the delivery system of claim 1-9 also comprises the outlet opening array, and described array is limited in the supporting structure and with described fluid container and is communicated with.
11. the delivery system of claim 1-10, wherein said fluid container comprises the hold-up vessel that is configured to fluid storage.
12. the delivery system of claim 11 also comprises the pressing mechanism to the pressurization of the fluid storage in the hold-up vessel.
13. the delivery system of claim 11, wherein said hold-up vessel is separated at least two hold-up vessels by reservoir divider.
14. the delivery system of claim 13, also comprise at least two outlet openings that are limited in the described supporting structure, wherein first outlet opening is communicated with first hold-up vessel of storing first fluid, so that first fluid can spray by first outlet opening, at least one second outlet opening is communicated with storage second fluidic at least one second hold-up vessel, so that second fluid can spray by second outlet opening.
15. the delivery system of claim 13 also comprises reservoir divider disruption mechanism, its structure and size are destroyed described reservoir divider before being adapted at using the material that is included in the container.
16. the delivery system of claim 15, wherein said reservoir divider disruption mechanism is a piezoelectric device.
17. the delivery system of claim 1-16 also comprises:
Pick off, whether it is used for sensed conditions and satisfies; With
Control unit, it is configured to produce actuated signal and activate actuating device repeatedly when the condition from pick off of receiving satisfies signal.
18. the delivery system of claim 1-16 also comprises:
Control unit, it is configured to produce actuated signal and activates actuating device repeatedly; With
Pick off, whether it is used for sensed conditions satisfied, if satisfy, do not produce actuated signal thereby then send a signal to control unit, thereby do not activate actuating device repeatedly.
19. the delivery system of claim 17-18, wherein said sensing station is away from described supporting structure.
20. the delivery system of claim 17-18, wherein said pick off is implanted in patient's body.
21. the delivery system of claim 17-18, wherein said pick off can be responded to patient's biological sign.
22. the delivery system of claim 17-18, wherein said pick off is connected with described supporting structure, so that described pick off is determined and used relevant condition.
23. the delivery system of claim 17-22, wherein said pick off is temperature sensor, is used for determining whether described supporting structure is positioned near the tissue.
24. the delivery system of claim 17-22, wherein said pick off is a pressure transducer, is used to provide the monitoring functional feedback mechanism of actuating device repeatedly.
25. the delivery system of claim 1-24, also comprise antagonist reservoir, its structure and size are fit to be communicated with described fluid container, the integrity of two kinds of containers is collaborative, thereby when the integrity of fluid container is impaired, the integrity of antagonist reservoir is also impaired, thereby discharges the antagonist component that can make described fluid inactivation from antagonist reservoir.
26. the delivery system of claim 1-25 also comprises power supply, it provides driving force and provides driving force for actuating device repeatedly for actuated signal.
27. the delivery system of claim 1-26, wherein said actuating device repeatedly are to produce the piezoelectric device that pressure changes in fluid.
28. the delivery system of claim 1-26, wherein said actuating device repeatedly are to produce the phase change mechanism that pressure changes in fluid.
29. the delivery system of claim 1-26, wherein said actuating device repeatedly are to produce the electromagnetic mechanism that pressure changes in fluid.
30. the delivery system of claim 1-26, wherein said actuating device repeatedly are to produce the high-pressure hydraulic mechanism that pressure changes in fluid.
31. the delivery system of claim 1-26, wherein said actuating device repeatedly comprises a plurality of explosive mechanisms, described explosive mechanisms explosion time, and each explosive mechanisms all can produce pressure and change in fluid.
32. the delivery system of claim 1-31 also comprises the user interface that is communicated with described actuating device repeatedly, described user interface is configured to respond the operation of described user interface and causes actuated signal.
33. the delivery system of claim 1-32, wherein said fluid passes epithelial tissue with transdermal and sends.
34. the delivery system of claim 1-33, wherein said actuating device repeatedly produces the pulse width that is no less than about 5ns and no more than about 10 μ s.
35. the delivery system of claim 1-34, wherein the time span of the frequency of actuating device and duty cycle and fluid jet is controlled by control unit repeatedly.
36. the delivery system of claim 1-35 also comprises memorizer, its storage delivers a fluid to the delivery curves of tissue and sends history.
37. the delivery system of claim 1-36, wherein said fluid comprises analyte, and it is used for being delivered to tissue and diagnoses biological disease subsequently.
38. the delivery system of claim 28 also comprises the flexible membrane that fluid container is separated into first Room and second Room, wherein said first Room comprises the actuating fluid that is communicated with described phase change mechanism, and described second Room comprises fluid to be sent.
39. the delivery system of claim 28 also comprises near the actuating fluid that is positioned at the phase change mechanism, described actuating fluid with treat that delivery of fluids is miscible.
40. the active fluid delivery system comprises:
Supporting structure;
Fluid ejection chamber in the supporting structure;
At least one outlet opening, it is limited in the supporting structure and with fluid ejection chamber and is communicated with; With
Be positioned at the indoor actuating device of fluid jet;
The common structure of wherein said fluid ejection chamber, at least one outlet opening and actuating device and size are fit to the fluid that consecutive periods sprays the about 800nl of about 1pl-repeatedly.
41. the delivery system of claim 40 also comprises controller, it is communicated with actuating device, so that actuated signal is passed to actuating device.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46390503P | 2003-04-21 | 2003-04-21 | |
| US60/463,905 | 2003-04-21 | ||
| US60/483,604 | 2003-06-30 | ||
| US60/492,342 | 2003-08-05 |
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| Publication Number | Publication Date |
|---|---|
| CN1777452A true CN1777452A (en) | 2006-05-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480010719 Pending CN1777452A (en) | 2003-04-21 | 2004-04-21 | Apparatus and methods for repetitive microjet drug delivery |
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| Country | Link |
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| CN (1) | CN1777452A (en) |
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