CN101745177A - Disposable drug delivery device with own power - Google Patents

Abstract

The invention relates to a disposable drug delivery device with own power, which consists of a micro-needle, a drug storage chamber, an air pressure chamber, an activating device and a piston, wherein the drug storage chamber contains drugs for infusion, and a liquid channel is arranged between the drug storage chamber and the micro-needle; the air pressure chamber contains a liquid medium, and a gas channel is arranged between the air pressure chamber and the drug storage chamber; the activating device is used for starting up the chemical reaction in the air pressure chamber, and the piston is usually positioned in the drug storage chamber, makes one-way movement as the pressure in the air pressure chamber increases, and plays a role of separating the drug liquid in the drug storage chamber from chemical reagents and products in the air pressure chamber. The invention also relates to a shape and a use method of the device.

Description

Disposable use also has the doser of self power

Technical field

The present invention relates to a kind of doser and using method thereof.Particularly, this device is for disposable use and have the doser of self power.This device can effectively be controlled medicine-feeding rate, prolongs administration time.

Background technology

Drug administration by injection is the most reliable a kind of route of administration, for a lot of macromolecular drugs, and the route of administration that drug administration by injection is normally unique.Yet drug administration by injection is faced with needs of patients professional training, patient's feared state of mind, safety, a series of problems such as cross infection, and therefore, changing route of administration is a research field of receiving extensive concern.

Micropin is a kind of transdermal machinery, and it can only penetrate horny layer and form administration channel, does not stimulate subcutaneous pain nerve (document 1,2 sees reference) simultaneously.Micropin injection or micropin fusion are a kind of Wicresoft route of administration, for the subcutaneous injection administration provides a kind of attractive mode of sending.Chang Gui subcutaneous injection administration relatively, micropin is injected that common drug effect equates even is higher sometimes, can overcome the problem that most of drug administration by injection faces simultaneously, for example, its Wicresoft's effect can directly solve patient's compliance issues, and the micropin syringe needle has higher safety.

McAllister etc. utilize the long glass empty micropin of 900um to there not being hair rat input insulin (document 3 sees reference).Experimental result has shown the effect that blood glucose descends insulin dose is relied on, under the 10psi infusion pressure, and rat insulin injection solution 30 minutes, blood sugar level is stable to descend; Under the 14psi infusion pressure, rat blood sugar was lower than basic value 70% in sustainable 5 hours.

Davis etc. also are used for empty micropin array not having hair diabetes rat experiment (document 4 sees reference).Insulin enters in the rat body by the long 4x4 metal hollow pin array of 500um, and administration is glucose level decline 47% in the rat body after 4 hours, observes the corresponding rising of insulin level in the experimental animals simultaneously.

Empty micropin itself is less, and it is limited to thrust skin depth, belongs to intradermal administration on the stricti jurise.For a lot of vaccine kinds, intradermal administration can improve immunological effect, reduces antigen dose (document 5,6 sees reference), and therefore, micropin provides a kind of attractive vaccine delivery mode.

Although carry the theory of medicine just to propose [U.S. Patent number 3,964,482] as far back as the seventies in 20th century by micropin, the technology barriers of micropin administration are still its large-scale production and the commercial major obstacle of using.For example, the micropin administration faces usually because the micropin volume is small and the skin shallow-layer thrusts the leakage that causes, and simultaneously, microneedle devices causes the extruding of skin peptide tissue, further increases the resistance of liquid input of knowing clearly, thereby has reduced medicine-feeding rate (document 7 sees reference).

For example, Davis etc. studies have shown that the micropin of 1080 μ m length only can enter skin surface 100-300 μ m, and this moment, maximum input rate was 15 μ L/hr, and by this rate calculations, the medication amount that input can reach drug effect needs some hrs.Therefore, effectively micropin drug administration by injection system should be able to provide slowly, the stable administration that reaches the long period.

The motive force (see reference document 8) of thermal expansion bead as the micropin drug-supplying system adopted in trials such as Roxhed, and observed this device prototype insulin administration speed is at 2-4 μ L/hr.The medicine-feeding rate of this device is determined by the quantity and the external energy of bead.It should be noted that the author observes, when medicine-feeding rate reaches 60 μ L/hr the dyestuff leakage can take place, this conforms to the result of study of Davis.Restricted except medicine-feeding rate, therefore this device need limit the size and the ease of use of device by outside energy.

At above problem, people such as Good have reported a kind of portable water activation Micropump, and microsphere substrate (the document 9 sees reference) hydrophilic material of volumetric expansion or expansion bead were as administration power after its principle was based on and absorbs water.The expansion rate of this material makes us surprised, and its expansion rate of the gel of some porous surface can reach 1: 1000.The defective of this medication is that the volumetric expansion speed of material is too fast, is difficult to regulate.According to the report of Good, the volumetric expansion of this material can be finished at chance water several seconds, and its speed can be up to 17 μ L/min/mg.This is useful for micro-fluidic system, but is not suitable for the micropin injecting systems of slow administration.

People such as Good have also reported the example (document 10 sees reference) of another kind of Micropump according to the effervescent generated reactive gas.This reaction is to adopt some common reagent such as carbonate or bicarbonate and acid to react, and the carbon dioxide of release can generation pressure in airtight system.Experimental results show that reaction rate can reduce when using less sour of oarse-grained solid reactant or dissolubility.Even these parameters are all fixed, medicine-feeding rate is still in a few minutes and just can finishes, and is still too fast for micropin administration model.

With micro pump and micropin combination is a good medication.Having reported in a lot of patents or the application for patent adopts manual compressing, spring or alternate manner to come administration.These patents comprise: United States Patent (USP) 3964482,52500: 23,5957895,6503231,6656147,6743211,6780171,6623457,6960193,6939324,7047070,6808506,7083592,7115108,7156838,7250037,7410476,7429258; US patent application 20080215015; PCT patent WO03/022330, WO02/002179, WO03/024507, WO04/033021, WO06/054280, WO06/132602; Chinese patent CN02812823.0; And european patent application book EP1925333.

The character of micropin drug-supplying system be can be slow and lasting administration.In some applications, its medicine-feeding rate is normally with dozens of minutes, several hours even meter over these days, and the portable device that those have been in the news is to reach.

Now existing many drug-supplying systems still exist defective, and therefore a kind of Wicresoft, portable, self-powered, cheap, easy operating, simple and flexible, device that be easy to control and sustainable administration need be provided.

Summary of the invention

This invention may be summarized to be the doser of a kind of Wicresoft, disposable use, self-powered patch form.Device comprises micropin; And the drug storage chamber that fluid path is arranged between the micropin wherein contains the medicine that is useful on infusion; Air-pressure chamber with drug storage chamber has gas to communicate wherein is equipped with liquid medium; Indoor chemical reaction activator appliance is provided with the first and second two positions, when activator appliance when primary importance moves to the second position, reaction begins to start; A piston also is housed in the drug storage chamber, when pressure in the air-pressure chamber increases, can unidirectionally moves, and medicine and chemical reactant/product are separated.In some implementations, this device is disposable.

This invention provides a kind of medication for objective body simultaneously, comprises concrete dosing step: will install on the skin that directly sticks to objective body; The activating reaction active device starts chemical reaction; To install to stick for a long time and on objective body skin, in medicine enters body, produce drug effect.Its medicine-feeding rate depends primarily on the chemical reaction rate in the air-pressure chamber, i.e. the speed of pressure generation.In certain embodiments, normally effervescent reaction of chemical reaction.The present invention can be by with the embedding of effervescent reactant or be wrapped in the slow-release material with control and promote speed.Perhaps with effervescent reaction and another rate-limiting reaction, for example the hydrolysis of anhydride combines and promotes speed with control.

Simultaneously, the present invention specifically comprises doser, medicine for objective body provides a medicine box; and other compositions, for example operation instructions prevent the protector that micropin damages; the partition apparatus that stops reaction to start adheres to adhered layer on the skin and the processing bag after using with device.

Concrete summary of the invention is as follows:

A kind of doser of giving the objective body medication is characterized in that this device comprises:

A) micropin;

B) be closed in drug storage chamber in the device, fluid path arranged between drug storage chamber and the micropin and contain the medicine of being sent;

C) be closed in air-pressure chamber in the device, the gas passage arranged between air-pressure chamber and the drug storage chamber and contain liquid medium;

D) be used for starting the active device of air-pressure chamber chemical reaction, active device is designed to the primary importance and the second position, when active device when primary importance moves to the second position, the chemical reaction in the air-pressure chamber is activated;

E) be positioned at the piston of drug storage chamber, piston is unidirectional to be moved along with pressure in the air-pressure chamber increases, and plays the medicinal liquid separated in the drug storage chamber and the effect of chemical reactant in the air-pressure chamber and product.

F) comprise a removable protector that invests the device outside, in order to prevent the syringe needle injury.

G) comprise an adhered layer that is positioned at bottom of device, be used to stick in the objective body skin surface.

A ventilated membrane is arranged between drug storage chamber among the present invention and the air-pressure chamber, be used to prevent that liquid reaction medium from entering drug storage chamber.

Drug storage chamber among the present invention is cylindric.

Drug storage chamber height among the present invention and internal diameter ratio are between 2: 1 to 1000: 1.

Between drug storage chamber among the present invention and the air-pressure chamber jointing is arranged.

Drug storage chamber among the present invention comprises one and be used for pouring into the inlet that needs the infusion medicinal liquid in drug storage chamber.

Active device among the present invention can be selected from following enumerating the device: push the combination that pin device, wrench device, battery are done valving, heater and the above device of power.

Active device among the present invention comprises an active device and cuts off, and is used to guarantee that active device remains on primary importance, prevents that active device from moving to the second position by primary importance.

Comprise a solid reaction combination that is arranged in doser air pressure inside chamber among the present invention; The solid reaction combination contains: invest solid reactant and the diaphragm seal that is used to prevent that solid reactant from contacting with liquid medium on the solid support thing.

Air-pressure chamber among the present invention comprises first chamber that contains liquid medium and second chamber that contains reactant.

When active device was positioned at primary importance, first chamber and second chamber in the air-pressure chamber were separated fully; When active device is positioned at the second position, set up fluid passage between first chamber and second chamber.

Air-pressure chamber among the present invention comprises indicator, is used for monitoring that the air-pressure chamber chemical reaction is initial, process and/or performance.

Indicator among the present invention is a colour reagent.

Colour reagent among the present invention is the pH indicating dye.

Drug storage chamber among the present invention comprises a transparent window, is used for monitoring the situation of movement of piston at drug storage chamber.

Chemical reaction in the air-pressure chamber among the present invention is the effervescent reaction.

Effervescent reaction among the present invention produces carbon dioxide.

Carbon dioxide among the present invention is generated by the acid plus carbonate reaction.

Carbonate among the present invention comprises carbonic acid functional group, bicarbonate functional group, the perhaps combination of two kinds of functional groups.

Acid among the present invention is selected from one or more the mixture in acetic acid, malic acid, citric acid, butanoic acid, n-caproic acid, ascorbic acid, tartaric acid, sad, capric acid, lauric acid, benzoic acid, phenylacetic acid, benzoyl-glycine, aspirin and the salicylic acid.

Acid among the present invention is by the combination of ester hydrolysis, anhydride hydrolysis, the hydrolysis of poly anhydride or above hydrolysis.

Anhydride hydrolysis reaction among the present invention is regulated by reducing the anhydride surface area.

Anhydride hydrolysis among the present invention comprises the combination of phthalic anhydride hydrolysis, poly sebacic polyanhydride hydrolysis, succinic anhydrides hydrolysis or above hydrolysis.

Effervescent reaction rate among the present invention is regulated by the rate of dissolution that reduces solid reactant.

By the rate of dissolution that controlled release matrix reduces solid reactant is gone in solid reactant embedding or parcel.

Controlled release matrix among the present invention contains one or more in ethyl cellulose, glycerol acetate and the hydroxypropyl cellulose.

A kind of doser of giving the objective body medication is characterized in that, the doser at least two kinds of medicines of patient's while infusion comprises:

A) first and second micropin;

B) the inner drug storage chamber of first device has fluid passage between first drug storage chamber and first micropin, contains the first kind of medicine that is useful on infusion;

C) second drug storage chamber that device is inner has fluid passage between second drug storage chamber and second micropin, contains the second kind of medicine that is useful on infusion;

D) the inner air-pressure chamber of first device has gas passage between first air-pressure chamber and first drug storage chamber, contains first kind of liquid medium;

E) second air-pressure chamber that device is inner has gas passage between second air-pressure chamber and second drug storage chamber, contains second kind of liquid medium;

F) active device is used for starting first chemical reaction in first air-pressure chamber and second chemical reaction in second air-pressure chamber; Active device has the primary importance and the second position, and when primary importance moved to the second position, the chemical reaction in first air-pressure chamber and second air-pressure chamber was activated with active device;

G) first drug storage chamber and second drug storage chamber have a piston respectively, piston is under the pressure effect of first air-pressure chamber and the increase of second air-pressure chamber, unidirectional respectively moving completely cuts off chemical reactant and/or product in the medicine in first fluid reservoir and second drug storage chamber and first air-pressure chamber and second air-pressure chamber.

Second kind of medicine in first kind of medicine in first drug storage chamber among the present invention and second drug storage chamber can be identical or different.

Second kind of liquid medium in first kind of liquid medium in first air-pressure chamber among the present invention and second air-pressure chamber can be identical or different.

Second chemical reaction in first chemical reaction in first air-pressure chamber among the present invention and second air-pressure chamber can be identical or different.

Doser of the present invention comprises first kind of solid reactant combination that is arranged in inner first air-pressure chamber of device; First kind of solid reactant combination contains: invest first kind of solid reactant on the solid support thing, be used to first diaphragm seal that prevents that first kind of solid reactant from contacting with first kind of liquid medium.

Doser of the present invention comprises second kind of solid reactant combination that is arranged in inner second air-pressure chamber of device; Second kind of solid reactant combination contains: invest second kind of solid reactant on the solid support thing, be used to second diaphragm seal that prevents that second kind of solid reactant from contacting with second kind of liquid medium.

The first kind of solid reactant that is arranged in inner first air-pressure chamber of device in the doser of the present invention can be identical or different with the second kind of solid reactant that is arranged in inner second air-pressure chamber of device.

Doser of the present invention only can once use.

The using method that among the present invention is the doser of a kind of medicine of patient's infusion comprises:

A) device is sticked on the objective body skin surface;

B) by active device is moved to the second position from primary importance, start the chemical reaction in the air-pressure chamber;

C) simultaneously, assurance device is pasted on the objective body skin surface all the time, in treatment effective dose of medicine thing input objective body body.

The using method that among the present invention is the doser of at least two kinds of medicines of patient's while infusion comprises:

A) device is sticked on the objective body skin surface;

B), start first chemical reaction in first air-pressure chamber and second chemical reaction in second air-pressure chamber by active device is moved to the second position from primary importance;

C) simultaneously, assurance device is pasted on the objective body skin surface all the time, in two kinds of medicine input objective body bodies of treatment effective dose.

The using method of doser comprises device is sticked on before the objective body skin surface among the present invention, removes protector.

Among the present invention the using method of doser further comprise active device moved to the second position from primary importance before, remove active device and cut off.

Selectable infusion of drug approach in the doser using method of the present invention comprises: Intradermal infusion, h inf, intramuscular infusion and venoclysis.

There is medicine box doser outside among the present invention.

Comprise a protector in the doser medicine box among the present invention, be used to prevent unexpected syringe needle injury.

Comprise an active device in the doser medicine box among the present invention and cut off, be used to prevent that doser from being activated by accident.

Comprise an adhered layer in the doser medicine box among the present invention, be used for doser is pasted on the objective body skin surface.

Description of drawings

Fig. 1 is that the present invention is to push the external structure sketch map of bolt as the device design of active device.。Figure 1A is shown as this device unused state, and Figure 1B is shown as this device and removes protector and active device partition, and Fig. 1 C is shown as this device and is in state of activation.

Fig. 2 is the bottom view of device design shown in Figure 1.Fig. 2 A is shown as this device and does not remove protector, and Fig. 2 B is shown as this device and removes protector.

Fig. 3 is the decomposition chart of device design shown in Figure 1.

Fig. 4 is the component drawings of device design Chinese medicine bank shown in Figure 1.

Fig. 5 is the external structure sketch map of the another kind of alternative device design of the present invention.This device comprises a twisting active device.

Fig. 6 is the decomposition chart of device design shown in Figure 5.

Fig. 7 is the sketch map of the twisting active device of iris type.

Fig. 8 is the twisting active device sketch map in semi-open chamber.

Fig. 9 is that standard-sized sheet is put passage twisting active device sketch map.

Figure 10 is the vertical view of the another kind of alternative device design of the present invention.This device comprises one and pushes bolt as active device.Figure 10 A is shown as this device unused state, and Figure 10 B is shown as this device and removes the Tip protection subsides and push safety, and Figure 10 C is shown as this device and is in state of activation.

Figure 11 is the decomposition chart of device design shown in Figure 10.

Figure 12 is the vertical view of the another kind of alternative device design of the present invention.This device comprises a twisting active device.

Figure 13 is the decomposition chart of device design shown in Figure 12.

Figure 14 is the cut-away view of twisting active device and associated components thereof.

Figure 15 has shown the speed of utilizing doser of the present invention to import liquid in the S.D. rat model, and this device is embedded in the reactant benzoic acid in the film with different controlled release characteristics.

Figure 16 has shown the promotion speed of utilizing doser of the present invention liquid in the S.D. rat model, and this device adopts phthalic anhydride, succinic anhydrides, poly sebacic polyanhydride hydrolysis to produce reaction substrate.

Figure 17 has shown the promotion speed of utilizing doser of the present invention liquid in the S.D. rat model, and this device adopts bulk or Powdered phthalic anhydride hydrolysis as reaction substrate.

The rat blood sugar level relatively after Figure 18 had shown S.D. rat fast infusion (" SC ") or utilized doser control speed infusion (" Device ") insulin of the present invention.Control animals does not have infusion of insulin (" Blank ")

Figure 19 has shown and has utilized volume of insulin that doser of the present invention gives the input of S.D. rat curve over time.

Invention is described

As discussed above, the invention provides a kind of doser of nonrecoverable patch form and by this device, according to the using method of patient's needs infusion predetermined dose of medication. This device has self power, and the adhered layer by bottom of device can attach to skin surface. After device appropriately was fixed on the objective body surface and is activated, device can start reaction by the mixing of chemical reactant, and the gas of generation injects patient with the medicine in the drug storage chamber by one or more micropins as power. The control gas production rate can be regulated medicine-feeding rate, makes administration time extend to dozens of minutes, several hours even longer. Show that when the air-pressure chamber change color gas begins to produce, the simultaneously variation by the air-pressure chamber color can indicate the administration progress, can judge by the position of piston whether administration is finished.

Can better understanding be arranged to the present invention by accompanying drawing 1-14. Enumerated several for illustrating but unrestriced device design drawing among the figure.

Shown in Fig. 1-4, doser 100 represents to press bolt as active device, only activates by this step and the startup drug release process. Fig. 1 presses bolt as the top view of the doser 100 of active device, and Figure 1A represents this and installs 100 unactivated states. Tip protection pastes 112 and plays the effect of protecting syringe needle, and baffle 102 plays the effect that bolt active device 101 is pressed of pressing that stops. Among Figure 1B, protector 112 and baffle 102 are removed. Next, Fig. 1 C display unit bolt that is pressed activates. Fig. 2 is the bottom view of (Fig. 2 B) after doser 100 has protector in protector 112 (Fig. 2 A) and the same device to be removed. Fig. 3 is the stereogram that doser 100 element are described. Fig. 4 shows the composition in storage medicine pond 100.

The doser 100 that Fig. 1-4 shows is a kind of paster dosers. When device was not activated, protector 112 covered device 100 bottom surfaces, prevents that medicine from overflowing and needlestick injuries. In case protector 112 is removed, the adhered layer 111 of bottom of device and syringe needle 110d expose, and device 100 is pasted on the objective body skin surface, and syringe needle 110d transdermal top layer enters intracutaneous.

Simultaneously, doser 100 can be packed in the soft fabric adhesive tape, as adhesive bandage, makes this device feel more comfortable, and profile and conventional pad pasting are more near (not shown).

As shown in Figure 3, device 100 is to press bolt 101 as active device. Before activating, as activator appliance press bolt 101 by 102 lockings of removable partition, prevent unexpected the activation. Be removed when pressing bolt partition 102, press bolt 101 and be pressed, device is activated. Press that bolt 101 promotes to comprise encapsulant 106, solid piece 107, is attached to the solid reactant 108 of solid piece 107, the reactant aggregate of diaphragm seal 109, device is activated. Encapsulant 106 is used for solid reactant 108 is separated with liquid reactants 116. Solid reactant 108 is attached to solid piece 107, and encapsulant 106 separates with the liquid reactants (not shown) with the solid reactant 108 that diaphragm seal 109 is used for being stored in the air-pressure chamber 115. Liquid medium is preferably water or water buffer solution, is beneficial to effectively to promote the chemical reaction in the air-pressure chamber. Air-pressure chamber 115 is connected by joint 116 with drug storage chamber 110. Hydrophobic permeable membrane 118 is used for reactant liquor is separated in air-pressure chamber. Be pressed when pressing bolt 101, press bolt puncture through seal material 106 and diaphragm seal 109, solid reactant 108 contacts with liquid medium, pressing creation reaction beginning.

As shown in Figure 4, drug storage chamber parts 110 are by the drug storage chamber 110a of tubulose, the micropin 110d that is connected with drug storage chamber 110a, and piston 1 10b and dress liquid mouth 110c consist of. Dress liquid mouth 110c is for drug storage chamber 110a that pre-infusion liquid is packed into. Generated reactive gas in the air-pressure chamber 115 forms motive force, pushing piston 110b, and then force the liquid among the drug storage chamber 110a to pass through in the micropin 110d target approach body skin.

Except the structure member of above introduction, device 100 also comprises top 103 and bottom 113. Top enclosure 103 links to each other the air-tightness of assurance device inside with device internal part 105 respectively with bottom enclosure 113 with 111. Shown in Fig. 2 B, opening 114 and opening corresponding to dress liquid mouth 110c that micropin 110d comes in and goes out contained in bottom 113.

The administration state of doser 100 is to be monitored by following step:

Initial administration is that the color change of the air-pressure chamber 115 that causes by indicator is indicated. For example the pH indicating dye is encapsulated with solid reactant 108, when the reaction beginning, solid reactant contacts with liquid medium, and the pH indicating dye also contacts with liquid medium simultaneously. Because liquid medium is generally neutrality or original state slightly is alkalescence, the pH indicating dye contacts with liquid medium and causes color change (for example obvious purple). Along with solid reactant and liquid medium reaction, pH reduces gradually in the air-pressure chamber, and the pH indicating dye can present another kind of color (for example changing yellow into by purple), the process that the indication medicine is progressively inputted. Empty as drug storage chamber 110a, piston 110b is pushed to the place near micropin 110d, and can be observed visually piston 110b this moment by amplifying observation window 104. Whether finish for the ease of visually observing the conveying of doser herb liquid, piston 110b can be fabricated to colour. In sum, can by visually observing from initially finishing to administration, install whole administration process.

Protector 112 is used for protecting syringe needle, guarantees that syringe needle is in germ-free condition before device uses. When administration is finished, protector 112 can be pasted back original position, prevents unexpected syringe needle injury and abuse. This device is positioned as disposable use, and power set lost efficacy and can't reuse after using.

Shown in Fig. 5-9, doser 200 as active device, starts drug release process with the twisting activator appliance. Fig. 5 twists activator appliance as the top view of the doser 200 of active device, and Fig. 6 is the exploded view that doser 200 each element are described.

The doser 200 that Fig. 5-9 shows is a kind of paster dosers. Similar with device 100, when device was not activated, protector 212 covered device 200 bottoms, prevents that medicine from overflowing and needlestick injuries. During use, Tip protection pastes 212 and is removed, and device is pasted on the objective body skin surface, and syringe needle sees through objective body skin and enters intracutaneous.

As shown in Figure 6, device 200 is different from device 100. The air-pressure chamber of device 200 is connected by joint 215 with drug storage chamber 207. Air-pressure chamber is divided into 210 and 211 two chambers. Liquid medium is closed in the chamber 211 by hydrophobic permeable membrane 208. Liquid medium is preferably water or water buffer solution, is beneficial to effectively to promote the chemical reaction in the air-pressure chamber. May contain one or more in the liquid medium and be dissolved in wherein reactant. When device is not activated, twist activator appliance 206 and play the effect that cuts off chamber 210 and 211. By reversing activator appliance 206 with coupling spanner 201. Be rotated to appropriate angle when 206, produce a large passage in air-pressure chamber, 210 and 211 chambers are connected, be stored in 210 with 211 chambers in solid reactant contact with liquid medium, reaction is activated.

Pressing the bolt activator appliance is in active device with the main difference that twists activator appliance. As shown in Figure 6, when device is not activated, twist activator appliance 206 and cut off chambers 210 and 211. In case reverse activator appliance 206 with coupling spanner 201, between chamber 210 and 211, can produce a large passage.

A kind of twisting activator appliance 217 that Fig. 7 shows is by shim 218 split cavities 210 and 211. The twisting device need to be turned round and turn 90 degrees to finish activation.

Fig. 8 is another kind of selectable twisting activator appliance 219, contains a semi-open chamber 220 that stores one or more solid reactant (not shown)s. When device was not activated, liquid medium and/or other reactants in the reactant in the chamber 220 and the air-pressure chamber 210/211 did not come in contact, and reactant is in closed state. Twist activator appliance 219 with coupling spanner 201, the reactant in the chamber 220 is contacted with liquid medium and/or other reactants in the vapour-pressure type 210/211.

Fig. 9 is the schematic diagram of the twisting activator appliance 206 that shows of Fig. 6. Different from the twisting activator appliance 219 that shows among Fig. 8, do not contain any reactant in the 206 Full-open passages 221 that comprise. When twisting activator appliance 206 with coupling spanner 201, passage 221 plays the effect that is communicated with air- pressure chamber chamber 210 and 211.

Drug storage chamber parts 207 are similar to drug storage chamber parts 110 above shown in Figure 4. Chemical reaction in the air-pressure chamber 210/211 produces gas, forms motive force, and pushing piston is mobile in drug storage chamber, and then forces the liquid in the drug storage chamber to pass through in the micropin target approach body skin. Visually observe the administration state by amplifying observation window 202, this mechanism with device 100 is consistent.

Except the structure member of above introduction, device 200 also comprises air-pressure chamber diaphragm seal 205, device top 204 and bottom 214. Top enclosure 204 links to each other the air-tightness of assurance device inside with device internal part 203 respectively with bottom enclosure 214 with 216. Opening 213 and opening 209 corresponding to dress liquid mouth 110c that micropin 110d comes in and goes out contained in bottom 214.

Shown in Figure 10-11, a kind of alternative doser 300 represents to press bolt as active device, activates and the startup drug release process by this step. Figure 10 presses bolt 301 as the top view of the doser 300 of active device. When device is not activated (Figure 10 A), micropin 310 protected subsides 311 cover. Protector 311 plays the effect of protection syringe needle 310, prevents that medicine from overflowing and needlestick injuries. Baffle 302 plays the effect that bolt is pressed by accident of pressing that stops. Figure 10 B shows that protector 311 and baffle 302 are removed, and the adhered layer of bottom of device 312 and micropin 310 expose, and install 300 Pastings in the objective body skin surface. Figure 10 C shows, the device bolt 301 that is pressed activates, and syringe needle 310 enters intracutaneous through skin. Figure 11 is to press bolt 301 as the exploded view of device 300 element of active device in order to explanation.

As mentioned above, device 300 was cut off 302 lockings as the bolt 301 of pressing of activator appliance by removable activation before activating, prevent unexpected the activation. When protector 311 with activate and cut off 302 and be removed, press press bolt 301 after, device 300 is activated. Diaphragm seal 305 is used for separating with solid reactant 306 being stored in the liquid medium (not shown) that is positioned at top 304 in the air-pressure chamber. When press press bolt 301 after, diaphragm seal 305 breaks. Air-pressure chamber and drug storage chamber tunicle 307 separate. Liquid medium is preferably water or water buffer solution, is beneficial to effectively to promote the chemical reaction in the air-pressure chamber. May contain one or more in the liquid medium and be dissolved in wherein reactant. Chemical reaction in the air-pressure chamber produces gas, forms motive force, promotes diaphragm 307, and then forces the liquid in the drug storage chamber 312 to pass through in the micropin 310 target approach body bodies. In some implementation, film 307 may adopt soft material, caves in along with pressure in the air-pressure chamber increases, and then promotes liquid; In other implementations, film 307 also may adopt hard material to form piston, moves towards syringe needle 310 directions under the air-pressure chamber pressure-acting.

Except the structure member of above introduction, device 300 also comprises presses bolt diaphragm seal 303, bottom of device 308 and the opening 309 that is used for micropin 310 discrepancy.

The initial administration process of this device is to indicate by the color change of air-pressure chamber. PH indicating dye and solid reactant 306 combinations, when the reaction beginning, solid reactant contacts with liquid medium, and the pH indicating dye also contacts with liquid medium simultaneously. Because liquid medium is generally neutrality or original state slightly is alkalescence, the pH indicating dye contacts with liquid medium and causes color change (for example obvious purple). Along with solid reactant and liquid medium reaction, pH reduces gradually in the air-pressure chamber, and the pH indicating dye can present another kind of color (for example changing yellow into by purple), the process that the indication medicine is progressively inputted. Therefore, administration process is to indicate by the variation of air-pressure chamber indicating agent color.

As mentioned above, protector 311 is used for protecting syringe needle 310, guarantees that syringe needle is in germ-free condition before device uses. When administration is finished, protector 311 can be pasted back original position, prevents unexpected syringe needle injury and abuse. This device is positioned as disposable use, and power set lost efficacy and can't reuse after using.

Shown in Figure 12-14, a kind of alternative doser 400 represents to twist activator appliance 403 as active device, activates and the startup drug release process by this step. Figure 12 twists activator appliance 403 as the top view of the doser 400 of active device. Figure 13 is the exploded view that doser 400 each element are described. Figure 14 is the interior view of twisting activator appliance 403 and dependency structure.

The doser 400 that Figure 12-14 shows is a kind of sheet dosers. When device was not activated, protector 408 covered 400 bottom surfaces, prevents that medicine from overflowing and the generation of syringe needle injury accident. In case protector 400 is removed, the adhered layer 405 of bottom of device and syringe needle 407 expose. After device is activated, install 400 Pastings in the objective body skin surface, syringe needle 407 passes objective body skin and enters intracutaneous. As shown in figure 13, bottom of device 405 contains the opening 406 that is useful on micropin 407 discrepancy.

As shown in figure 14, contain semi-open chamber 411 in the twisting activator appliance 403, be used for storing one or more solid reactants. Before activating, sealed 410 protection of cavity 411 openings do not contact the cavity content with the liquid medium (not shown) that is stored in air-pressure chamber top 402. Liquid medium is preferably water or water buffer solution, is beneficial to effectively to promote the chemical reaction in the air-pressure chamber. May comprise one or more in the liquid medium and be dissolved in wherein reactant. Use coupling spanner 401 twisting activator appliances 403, the solid reactant that is stored in the chamber 411 begins to contact with liquid phase reactor thing in the air-pressure chamber, and device is activated. Air-pressure chamber and drug storage chamber 409 tunicles 404 are separated. Chemical reaction in air-pressure chamber produces gas, forms motive force, promotes diaphragm 404, and then forces the liquid in the drug storage chamber 409 to pass through in the micropin 407 target approach body bodies. Film 404 may adopt soft material, along with pressure in the air-pressure chamber increases and caves in, also may adopt hard syringe piston material, moves towards syringe needle 407 directions under pressure.

The initial administration process of this device is to indicate by the color change of air-pressure chamber. The solid reactant of pH indicating dye in being stored in twisting activator appliance 403 cavitys 411 is combined. When the reaction beginning, solid reactant contacts with liquid medium, and the pH indicating dye also contacts with liquid medium simultaneously. Because liquid medium is generally neutrality or original state slightly is alkalescence, the pH indicating dye contacts with liquid medium and causes color change (for example obvious purple). Along with solid reactant and liquid medium reaction, pH reduces gradually in the air-pressure chamber, and the pH indicating dye can present another kind of color (for example changing yellow into by purple), the process that the indication medicine is progressively inputted. Therefore, administration process is to indicate by the variation of air-pressure chamber indicating agent color.

As mentioned above, protector 408 is to protect syringe needle to be in germ-free condition before device uses. When administration is finished, protector 408 can be pasted back original position, prevents unexpected syringe needle injury and prevents abuse, and this device is positioned as the i.e. throwing type that once uses.

1 micropin:

The micropin part includes an empty micropin that is connected with drug storage chamber at least. During administration, micropin part and skin contact, transdermal top layer.

Similar to hypodermic needle, this doser contains a micropin at least. In some applications, this device can contain microneedle array, and this array may contain 2,3,4,5 or more micropins, is used for increasing absorption area in same administration time, improves medicine-feeding rate and administration volume.

The length of micropin is determined by the use approach. For hypodermic injection or infusion, micropin length can be greater than 3-5mm. For intracutaneous injection or infusion, micropin length is less than 2mm, or less than 1mm, or less than 0.5mm. The length of micropin and shape without limits, first-selected small gauge needle, 31G-36G syringe needle for example, minute hand pain and tissue damage are less relatively.

Micropin can be made by various materials, comprises plastic material and the natural or artificial macromolecular materials such as stainless steel, silica, glass, titanium, Merlon or Crude oil ester. Certainly, more than enumerate kind and incomplete, the material of other suitable micropin manufacturings also can use.

2 drug storage chambers:

Need the liquid medicine storage of infusion in specific cavity, this cavity and micropin partly have fluid passage, and gas passage is arranged between the air-pressure chamber. In some implementations, drug storage chamber and driving force compartment are separated by removable, gastight film or piston, and under pressure, film or piston move along drug storage chamber, and the liquid that promotes in the drug storage chamber enters in the patient body by micropin.

In some implementations, drug storage chamber is designed to column or tubulose; In some implementations, drug storage chamber and micropin contact portion are designed to taper to reduce dead volume.

In some implementations, drug storage chamber length is obviously greater than its internal diameter. In some implementations, drug storage chamber is designed to tubular structure, and pipe range and bore ratio are between 2: 1 to 1000: 1, more preferably between 10: 1 to 500: 1. The length of drug storage chamber and diameter mainly depend on the volume that needs the infusion liquid. Be less than or equal to 1 drug storage chamber with the L/D ratio value and compare, promote the liquid of same volume, the piston of tubulose drug storage chamber need to move more multiple spurs from, so the tubulose drug storage chamber is more accurately controlled aspect the liquid infusion rates. Simultaneously, the tubulose drug storage chamber needs less motive force owing to reduced the contact area of piston and drug liquid tube. The drug storage chamber internal diameter is less, and the liquid infusion rates is more accurate. In some implementations, between the 5mm, more preferably 1mm is between the 3mm at 0.2mm for the drug storage chamber internal diameter. In some implementations, drug storage chamber volume scope between the 10ml, can satisfy the demand of most injectable drugs at 10 μ L.

In some implementations, utilize this device, by increasing drug storage chamber and thrust unit, make apparatus of the present invention also can be used as the infusion of larger volume liquid. This device can be used for making the doser of the portable controllable type large volume liquid of clinical use, for example intravenous infusion device.

In some implementations, drug storage chamber and driving force compartment are separated by hydrophobic permeable membrane. When hydrophobic permeable membrane prevents that reactant liquor from entering drug storage chamber, allow gas to enter drug storage chamber, ventilative speed depends on the structure of film. The gas permeation rate of hydrophobic permeable membrane depends on the physicochemical characteristic of film, for example structure, aperture and surface chemistry. Material for the manufacture of this type film comprises plastic polymer, for example fluoropolymer polymer (DuPont

), polyethylene, polypropylene. Hydrophobic permeable membrane can be used to regulate the pressure from the air-pressure chamber to the drug storage chamber so that liquid can be steadily at the uniform velocity conveying.

In some implementations, in same doser, a plurality of drug storage chambers can be installed independently, while two or more medicines of infusion, and do not need various medicines are mixed. These two or more drug storage chambers can link to each other with same air-pressure chamber, obtain similar motive force. Perhaps, depend on different infusion requirements, in same device, two or more independent air-pressure chambers can be respectively link to each other with independent drug storage chamber. For example, pramlintide usually is administered for treating diabetes with insulin combination, and present patient need to distinguish insulin injection and pramlintide when using. In this device, adopt the design of binary drug storage chamber, just can pass through an independent operation, simultaneously insulin injection and pramlintide.

3 motive forces:

In some implementations, the motive force of apparatus of the present invention is to realize by the chemical reaction that produces gas, for example effervesce reaction. As previously mentioned, drug storage chamber links to each other with the pressing creation chamber, guarantees that by piston or film reactant is not excessive. The pressing creation chamber generally comprises two separating parts, stores respectively effervesce reactant and/or liquid reaction medium. When starting, active device can cause the effervesce reaction to start.

Carbonate and acid reaction are adopted in traditional effervesce reaction. The preferred subcarbonate of carbonate or bicarbonate. Common acid comprises, but be not limited to acetic acid, malic acid, citric acid, butyric acid, n-caproic acid, ascorbic acid, tartaric acid, sad, capric acid, laurate, benzoic acid, phenylacetic acid, benzoyl-glycine, acetylsalicylic acid, salicylic acid, and the mixture of various acid etc.

Effervescent system is everlasting and is used for promoting the mixing of drug-eluting or each component in the delivery system, and the reaction time General Requirements is very short. The present invention produces pressure by generate carbon dioxide in chamber, and then pushing piston or film, and liquid partly is transmitted by syringe needle.

Because the micropin injection needs the stable inject time that continues, traditional quick effervesce reaction also is not suitable for. As reports such as Davis, even by employing bulky grain reactant, the benzoic acid of low solubility, this reaction is still too fast, is not suitable for the micropin injection.

In below discussing, the invention provides the mode in the prolongation reaction time that can be used for the micropin injection.

In some implementations, can be by gas production rate be controlled in the embedding of effervescent system component or the mode that is wrapped in the controlled release matrix. The effervesce reactant can be separately or is jointly carried out embedding. By controlled release matrix, the effervesce reactant is released rear participation effervesce reaction with speed stably, and then produces the pressure that continues.

Material for generation of sustained release matrix comprises the hydrophilic and hydrophobic compound that is generally used in controlled release or the sustained release preparation, comprise biodegradable and biological non-degradable material, include but not limited to: polymethyl methacrylate, PET, poly-disiloxane, polytetrafluoroethylene (PTFE), polyethylene, polyurethane, polyesters is acid polyethylene for example, PLA, the copolymer of PLA/glycolic, polycaprolactone, PEE kind polyester list block or segmented copolymer, polydioxanone for example, Merlon, polyesteramide, polyester-acrylic-amino resin, poe, poly-acid anhydrides, Polyalkylcyanoacrylanano, polyaminoacid, poly-phosphine cyanogen, polyphosphate, poly-polysaccharide, cellulose, starch, alginic acid, hyaluronic acid, chitin, shitosan, protein, collagen, gelatin, Polyhydroxyalkanoates polyhydroxy antibiotic, poly-(gamma-glutamic acid), polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, strange polymer especially, CAP, cellulose acetate, polyvinyl acetate O-phthalic base acid esters, the hydroxypropyl methylcellulose titanate, pectin, glucan, cyclodextrin, guar gum, synanthrin, chondroitin sulfate, carob, beeswax etc., and the derivative of these compounds, all kinds of salt, single block or segmented copolymer.

The matrix that above material forms is the compound that includes of sustained release progressively. Can be a few minutes, several hours, several days, a few week or several months release time, depends on the composition of matrix.

Usually, the polymer hydrophilicity that forms matrix is stronger, discharges sooner, and release time is shorter, and hydrophobic polymer ethyl cellulose for example can provide longer release dynamics of duration. By regulating polymer composition and ratio in the matrix, can obtain the release characteristics that needs. For example, contain 35% ethyl cellulose, 20% glycerine, 10% hydroxypropyl cellulose and 40% benzoic release matrix, the lasting product that can produce about 60 minutes is pressed the time, by comparison, contain 35% ethyl cellulose, 35%PEG-400,12% glycerol acetate and 18% benzoic release matrix, can produce greater than 12 hours lasting product and press the time.

Above release matrix can be various forms: membranaceous, sheet, discoid, spherical, graininess, capsule shape, bar-shaped, pellets, Powdered, perhaps other any forms. In order to guarantee the uniformity of matrix, can contain plasticizer in the matrix; In order to guarantee the stability of matrix, can contain stabilizing agent in the matrix; In order to regulate the rate of release of embedding compound, can contain excipient in the matrix.

In some implementations, can regulate by the solubility of effervesce reactant the speed of pressing creation. For example, insoluble carbonate, for example calcium salt, magnesium salts or zinc salt are rarely used in effervesce reaction, yet, utilizing the poor character of above compound water soluble, insoluble carbonate can sustained release carbonic acid, thereby prolong the reaction time.

In some implementations, the speed that can regulate pressing creation by the reaction that produces the effervesce reactant. More than the purpose of reaction is to generate the required reaction substrate of one or more effervesce reactions, therefore, by regulating the speed that produces the effervesce reaction substrate, finally limits the speed of the effervesce reaction of pressing creation.

In some implementations, the ester hydrolysis can form pure and mild acid as the reaction that produces the effervesce reactant. According to the kind and the reaction condition that consist of ester, the difference of the hydrolysis rate of all kinds of esters can reach 10¹⁵Doubly. Therefore can be by kind and the speed of hydrolysising condition control acid reaction generation, further the controlled pressure generating rate of selecting ester.

In some implementations, acid anhydrides or the hydrolysis of poly acid anhydrides are as the reaction that produces the effervesce reactant, and the acid of formation can participate in the effervesce reaction. Acid anhydrides forms acid with the hydroxy functional group reaction in water or alcohol, finally become the required reactant of effervescent system. According to the kind of the structure of acid anhydrides and the acid that generates, the hydrolysis rate of acid anhydrides has very large difference. By the hydrolysis rate of control acid anhydrides, but the controlled pressure generating rate.

Simultaneously, the acid anhydrides hydrolysis rate is also relevant with the concentration of the surface area of anhydride reaction thing and bicarbonate ion. Anhydride reaction thing surface area is larger, and hydrolysis rate is faster, and the infusion rates of generation is also faster, and in like manner, anhydride reaction thing surface area is less, and hydrolysis rate is slower, and the reaction time is longer, and then infusion rates is also slower.

The poly acid anhydrides is usually as the Biodegradable controlled release matrix in the preparation. The link key that the poly acid anhydrides has hydrophobic center and can be hydrolyzed, therefore, the hydrolytic process of poly acid anhydrides is a kind of process of surface erosion. Poly acid anhydrides controlled release matrix has the zero order kinetics feature usually, can guarantee to react with constant speed to produce acid. In the present invention, the hydrolysis of acid anhydrides or poly acid anhydrides continues to produce acid, then with the effervesce reactant reaction. The hydrolysis rate of acid anhydrides or poly acid anhydrides depends on the kind of acid, do not wait from a few days to a few weeks, therefore, the reaction of acid anhydrides or poly acid anhydrides hydrolysate and effervescent system, sustainable stable lasting pressure.

4 active devices

The built-in pressure-driven doser that the present invention produces by the effervesce reaction. In implementation, active device makes liquid medium contact with the effervescent system reactant. Liquid medium can be water or acid solution or carbonate solution.

In certain embodiments, liquid medium and effervescent system are separated by film. This film can be by the material damage by external force, for example the needle-like pressure lock.

In certain embodiments, liquid medium can be finished by the twisting activator appliance with contacting of effervescent system. As in the design of the second device, the twisting activator appliance is connected two independent reative cells.

The present invention orientates cheap, portable, disposable, self-powered doser as. Generally speaking, using outer drive is not a kind of preferred design, but it may be noted that by battery activated device herein and belong to the scope of the invention as active device yet. For example, the valve of doing power with battery can be used as active device; In addition, the method by electric energy thawing diaphragm seal also can be used as active device. Unite and use various dissimilar activator appliances discussed above also to belong to the scope of the invention.

5 indicator

Among the present invention, pressure produces the sign administration and starts, and is to be monitored by the chromogenic reaction of mixing in the device. Mode as chromogenic reaction has a lot, and wherein the pH indicator is a kind of good selection. For example, can will mix with acid reactant matrix responsive phenol red of pH value, when reaction starts, liquid phase medium or carbon acid solution pH value partial neutral or alkalescence contacts with indicator, and indicator makes solution demonstration aubergine at once, show that the pressure generation is reacted to begin.

Along with acidic materials discharge from matrix gradually, consume carbonate and produce carbon dioxide, reactant liquor pH reduces in the reative cell. Along with pH reduces, solution colour becomes yellow by aubergine gradually, shows progress and the performance of reaction. On the other hand, it is constant that solution colour keeps reddish violet in the assumed response chamber, may need to consider that pressing creation reaction inexpectancy carries out, and infusion of drug is incomplete.

In concrete operations, can monitor the administration performance by the perusal position of piston.At last, device also may be equipped with a translucent shell on micropin next door, so that patient or doctor can directly see position of piston, fully whether the monitoring medicine in infusion such as the patient's body.

6 pistons:

As mentioned above, piston is to press material to separate medicine and product as physical barriers, simultaneously as promoting the unidirectional mobile device of medicinal liquid.

In certain embodiments, piston can be spherical, guarantees its air-tightness when mobile in drug liquid tube.Piston also can be made by colored materials, carries the indicator of finishing as medicinal liquid.In further embodiments, piston can be the flexibility or rigidity film.The material of making as piston must be chemical inertness and when mobile resistance less.In certain embodiments, piston can be made by pottery or polymer, for example fluoropolymer polymer (DuPont

) and some non-adhesive materials.

7 device administration covering scopes:

In specific embodiment, the medicine in the device comprises that all can be by the medicine of drug administration by injection.Be meant that further those need the medicine of percutaneous dosing or are easy to the medicine of first pass metabolism or cause tangible gastrointestinal tract or the medicine of liver side effect or be difficult for absorbed medicine or needs change the medicine of pharmacokinetics feature.

In specific embodiment, medicine can comprise some small-molecule drugs, as androgen, and estrogen, testosterone, nitroglycerin, nicotine, antihypertensive, A Xiluowei, alprazolam, aspirin, aldosterone, atenolol, azithromycin, azidothymidine AZT, penicillin, bacitracin, benzylpenicillin, caffeine, candoxatril, captopril, carbamazepine, chloromycetin, cimetidine, clonidine, cephamycin, Ciclosporin A, haloperidol, desipramine, dexamethasone, danazol, diazepam, voltaren see diclofenac, diltiazem, ketorolac, amycin, epinephrine, enalapril maleate, Abboticine, clindamycin, famotidine, felodipine, fluorouracil, flurbiprofen, hydrochlorothiazide, furosemide, norepinephrine, ibuprofen, imipramine, Itraconazole, labetalol, lisinopril, methotrexate, metoprolol, nadolol, naloxone, nortriptyline, omeprazole, phenytoin, piroxicam, prazosin, prostaglandin, macrolide, medrat, Progesterone, medroxyprogesterone, monobactam, aztreonam, propranolol, quinidine, ranitidine, scopolamine, tenidap, terfenadine, trovafloxacin, valproic acid, vinblastine, Ziprasidone, rapamycin, ketoconazole, steroid, prednisone, triamcinolone, ketoprofen, naproxen, Nifedipine, prostaglandin, Alprostadil, misoprostol, riboflavin, levodopa, furosemide, fentanyl, lignocaine, selegiline, tetracaine, rotigotine, methylphenidate, estradiol-, nortriptyline, Propranolol, potassium nitrate, megestrol, buprenorphine, morphine, meglumine antimony, lisuride, granisetron, BUP, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl, benzene (uncle) butylamine, tulobuterol, atenolol, cimetidine, ranitidine, terbutaline, the L-DOPA, madopar, phenylalanine, phenazone, and their salt, congener and derivant.

In specific embodiment, medicine generally includes some macromolecular drugs such as protein, polypeptide, saccharide, nucleotide, lipid, carbohydrate and their complex.

In specific embodiment, protein drug can be antifibrin-ferment, albumin, α-1 proteolytic enzyme, antihmemophilic globulin, coagulation factor, antibody, anti-CD 20 antibodies, anti-CD 52 antibody, the anti-CD 33 immunotoxin, the DNA enzyme, erythropoietin, the IX factor, the VII factor, the VIII factor, follicle stimulating hormone, granulocyte colony-stimulating factor G-CSF, the G-CSF of grafting PEG, α or beta galactosidase, glucagon, glucocerebrosidase, granulocyte-macrophage colony-stimulating factor, chorionic-gonadotropin hormone, hepatitis B antigen, hbs antigen, hepatitis B core antigen, the hepatitis B envelope antigen, hepatitis C antigen, hirudin, anti-HER-2 antibody, AIA, anti-IL-2 receptor antibody, insulin, insulin Glargine, Insulin Aspart, insulin lispro, interferon, the interferon of grafting PEG, α or α 2a or α 2b interferon, β or β-1a or β-1b interferon, interferon gamma, interleukin II, interleukin 11, interleukin 12, LH Luteinizing hormone, Nesiritide, Osteogenic Protein-1, BMP-2, the Lyme vaccine, platelet-derived somatomedin, antiplatelet antibody, anti-sarcoma virus antibody (annti-RSV), growth hormone, D2E7, the anti-tumor necrosis factor receptor fusion protein, tissue plasminogen activator, TNK-tPA, thyrotropin, fibrinolytic enzyme, thrombus dissolving enzyme, ADA Adenosine deaminase, the ADA Adenosine deaminase of PEGization, anistreplase, asparaginase, Collagenase, streptokinase, saccharase, urokinase, press down the phthalein enzyme, Botulinum toxin, fibroblast growth factor, endothelial cell growth factor (ECGF), snake venom etc.Said albumen comprises from modes such as gene recombinaton, chemosynthesis or biological extraction and obtaining.Albumen comprises the analog of mutant, modification or derivant etc. simultaneously.Proteic initial source can be human or other species.

In some specific embodiments, can use peptide class of the present invention comprises: thyroliberin (ACTH), the angiogenesis inhibitor polypeptide, adamtsostatin, adiponectin, adipokinetic hormone, fat connects plain, fat triglyceride fat (fat) enzyme, adrenomedullin, the agouti associated protein, the alarin vasoactive peptide, allatostatin, amelogenin, calcitonin, dextrin, amyloid, angiogenin, angiotensin, cause the peptide of becoming thin, the antiinflammatory peptide, the diuresis factor, antimicrobial peptide, apelin, peptide antibiotics, the RGD peptide, atrial natriuretic peptide, atriopeptin, auriculin, autocrine motility factor, Magainin, bombinakinin, Kallidin I, brain natriuretic peptide, Brain Derived Neurotrophic Factor, frog antibacterial peptide, the C peptide, caspase is restrained the factor, pancreas [gland] peptide, buccalin, bursin, C type natriuretic peptide, the calcitonin related peptides, the calcitonin receptor kassinin kinin, calmodulin, CART, cartilostatin, casomokinin, a cheese deltorphin delta, catestatin, cathepsin, attacin, cerebellin, chemerin, chelocystokinin, chromograin, ciliary neurotrophic factor, conotoxin peptide, aconopressin, conotoxin, and Copeptin, CASH, corticotropin-releasing factor, the cortex chalone, coupling factor, sozin, delta EEG, dermorphin, vassopressin, the desamino vassopressin, diuretic hormone, dynorphin, endokinin, interior morphine peptide, endorphins, endostatin, Endothelin, enkephalin, enterostatin, exendin, Exenatide, the erythropoiesis peptide, epithelium growth factor, fat directed peptide, galanin, gastric inhibitory polypeptide, Gastrin., gastrin releasing peptide, growth hormone-releasing peptide, glucagon, glucagon like peptide, the Agifutol derivant, deltorphin delta outside the glutenin source, somatotropin releasing factor, granulocyte-macrophage colony-stimulating factor is restrained peptide, growth hormone peptide, the guanylin peptide, the HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) peptide, helodemine, tachykinin, hepatitis c virus peptide, the hepatitis B phallotoxins, the HSV peptide, the herpesvirus peptide, hirudin, HIRULOG, insulin like growth factor, hydrin, melanotropin, kassinin, keratinocyte growth factor, kinetensin, kininogen, the kiss peptide, kyotorphin, the laminin peptide, the Leptin peptide, leucokinin, leucopyrokinin, leupeptin, gonadotropin releasing hormone, lymphokines, melanin-concentrating hormone and inhibitor thereof, melanotropin discharges inhibitor, the melanotropin intensifier, morphine is regulated neuropeptide, MSH, neoendorphin, nesfatin, neurokinin, neuromedin, neuropeptide tyrosine, neurotensin, neurotrophic factor, nociceptin, the fat element of restraining, opiate receptor antagonist, aricine, salmon calcitonin see calcimar, oxytocin, pancreastatin, peptide YY, physalaemin sample peptide, secretin, Somat, the seminal fluid activating peptide, the P material, syndyphalin, thrombin is responsive plain, thymopoietin, thymosin, throtropin releasing hormone, transforming growth factor, tuftsin, tumor necrosis factor or related peptides, usrechistachykinin, 17-hydroxy-11-dehydrocorticosterone, the urotensin antagonist, valorphin, vasotocin, vasoactive intestinal peptide, peptide antibiotics, xenopsin or related peptides, said peptide class comprises from gene recombinaton, mode such as chemosynthesis or biological extraction obtains.Peptide comprises the analog of mutant, modification or derivant etc. roughly the same the time.The source can be human or other species.

The bioactive macromolecule that relates in the invention comprises from adenovirus, anthrax, tuberculin, Botulinum toxin, cholera, diphtheria toxoid, diphtheria and tetanus toxoid, diph-tet and pertussis, haemophilus B, hepatitis A, hepatitis B virus, influenza, encephalitis, measles, parotitis, rubella, meningococcus, pestilence, pertussis, streptococcus pneumoniae, poliomyelitis, rabies virus, rotavirus, rubella, variola, tetanus toxoid, typhoid fever, chickenpox, yellow fever, the vaccine that extracts in bacterial antigen and the compound substance.

In certain embodiments, bioactive macromolecule comprises from chamber dirt mice, animal scurf, mycete, pollen, hogweed, rubber, wasp, the deutero-allergen of insecticide, reaches the allergen of selecting the compound substance.

Bioactive macromolecule mentioned above generally all exists with molecule family, comprises having the natural molecular structure and the chemical compound of sequence, and through the analog of structure or sequence modification, and through chemistry or the outside analog of modifying of biological method.

For example, " GLP-1 promoter " its scope of mentioning before this comprises the complex that activates people GLP-1 receptor wholly or in part.The glucagon-like peptide 1 (GLP-1) that L-cell in the intestinal discharges can increase the insulin response behind oral glucose or the fat.GLP-1 peptide and its variant, analog and derivant are the same.For example the GLP-1 peptide comprises natural glucagon like peptide, blocks, and extends sudden change or other mutational variety.Analog comprises ZP10A or BIM-51077, GLP-1 or with the analog of polyethylene glycol polymeric, the analog that GLP-1 or itself and albumin merge, or with chemically combined analog such as liraglutide, CJC-1131.Equally, extendin-4 (having another name called exenatide) is a GLP-1 promoter, and it and it analog all belongs to this scope.Exenatide, exenatide analog (United States Patent (USP) 7,329,646 have reported) and long-acting conjugated body such as CJC-1134 belong to glucagon like peptide and/or its derivant.It is unlikely to get rid of all analog, and present invention also is not limited to above-mentioned these that mention.

8 pharmaceutical formulations are formed:

In specific embodiment, the medicine in apparatus of the present invention is a liquid dosage form.Aqueous solution, non-aqueous solution, suspension, Emulsion, gel and emulsifiable paste all are the pharmaceutical dosage forms that is suitable for; Can produce the suitable selection that consists of that continues release of active agent.

Solution and suspension generally are by water (for example sterilized water or apirogen water), or water and biocompatible mutual solvent (for example ethanol, propylene glycol or Polyethylene Glycol such as PEG 400) are prepared.

The adjuvant that may also comprise other in solution and the suspension, antiseptic (as benzalkonium chloride) for example, solubilizing agent/surfactant (as Tween 80, sorbester p17, benzalkonium chloride), buffer agent, isoosmotic adjusting agent (as sodium chloride), and thickening agent.May also contain suspending agent (as microcrystalline Cellulose and sodium carboxymethyl cellulose) in the suspension.

Comprise medicine and adjuvant in the aqueous suspension, adjuvant commonly used has: suspending agent, carboxymethyl hydroxylated cellulose for example, methylcellulose, hydroxypropyl cellulose, sodium alginate, polyvidon, tragakanta, arabic gum; Dispersant or wetting agent, be generally natural phospholipid, as lecithin, alkylene oxide fatty acid condensation substance (Myrj 45), oxirane and long-chain fatty alcohol condensation substance, the condensation substance (octadecanoic acid ester of polyethylene glycol) of oxirane and fatty acid hexose alcohol ester, or the condensation substance of oxirane and the own dextran sulfate sodium of fatty acid (polyethylene sorbester p17).May also contain one or more antiseptic (as ethyl, n-propyl group, p-hydroxybenzoate) and coloring agent in the aqueous suspension.

Oil suspension is that medicine is suspended in vegetable oil (as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami, Oleum Cocois, liquid Paraffin).Oil suspension also contains thickening agent, as Cera Flava, and paraffin or hexadecanol.Can add a kind of antioxidant such as vitamin C in addition.

Drug component among the present invention also may be O/W.The oil phase composition can be a vegetable oil, and for example olive oil and Oleum Arachidis hypogaeae semen can be mineral oil, and for example liquid paraffin also can be above-mentioned miscella.The emulsifying agent that is fit to can be natural gum, and for example arabic gum or tragacanth gum can be natural phospholipid, for example soybean phospholipid, lecithin, esters, or isolating ester in the fatty acid can be hexitan, for example span can be the condensation substance of ester and oxirane, for example tween.Also can contain sweeting agent and spice in the emulsifying agent.

9 usings method:

The invention provides and a kind of doser is attached to patient skin surface, start active device and device is maintained skin surface and enter intravital medication fully up to the effective dose of medicine thing, this device can be attached on the skin with hands or with device fitting.

In some specific embodiments, this doser can be used for Intradermal, and is subcutaneous, muscle, the injection of vein or other approach or transfusion.For example, venous transfusion needs special-purpose infusion set usually, to the also constraint to some extent of action of objective body.By enlarging the volume of drug storage chamber and air-pressure chamber, this device can be used as portable venous transfusion device, and transfusion volume and infusion rate can be regulated.Objective body utilizes this device, can be free movable during infusing.

The problem that micropin faces when using mainly is the compression to skin histology, has greatly limited medicine-feeding rate.Bounce back slightly after micropin thrusts and to alleviate this problem.At some specific embodiment, micropin tilts to enter skin with certain angle can alleviate elastic force, and the angle of inclination is big more, and tissue bounce-back resistance is more little.Go into the pin angle by enlarging, can increase side tension force, reduce direct resistance, solve the problem of micropin administration.

Although this device desire reaches the purpose of Wicresoft by using micropin, also can adopt other types such as intravenous needle, scalp acupuncture with the prolongation administration time, thereby improve effect of drugs.For example, when coming control of diabetes patient's basic blood sugar level, need stable medicine-feeding rate and long administration time by replenishing basal insulin.Utilize the device that small gauge needle is housed among the present invention, can finish the administration process of insulin solutions easily.Although than micropin, injury subcutaneous or the intramuscular injection syringe needle increases to some extent, but consider other remarkable advantages, for example can reduce risk of hypoglycemia by controlled rate of release, improve aspects such as drug effect, comprehensively more factors is selected and is not only limited to and micropin when selecting syringe needle.

10 medicine boxs:

The invention provides a kind of medicine box that contains doser.Doser in some medicine box can the preliminary filling medicine.And other solids or freeze-dried drug can be contained in one independently in the container, before administration by the liquid medium dissolving and rapidly in the injection device.

Except doser and medicine, this medicine box also comprises some other components, for example operation instructions; prevent the protector that micropin damages; stop the activator appliance of reaction unit accidental activation to cut off, device is adhered to adhesion layer on the skin and the processing bag after using.In some specific embodiments, medicine box includes nonrecoverable doser for once using adnexa.

11 definition:

Unless otherwise specified, all technology mentioned among the present invention and scientific terminology implication are defined as those of ordinary skill the routine of this term are understood.Mentioned all patents among the present invention, application for patent (deliver or do not deliver), other publications are all mentioned in citing document.If the patent that the description among the present invention and the present invention quote, application, the application for patent of having delivered, the opposite or contradiction of other publications is as the criterion with the description among the present invention.

Unless special statement, all technology used herein are understood consistent with those of ordinary skill to the routine of this term with scientific terminology.The patent of all references, the patent application of delivering or not delivering and other documents quote in full at this.If the application's the definition that is proposed and patent, the patent application of quoting and to deliver definition in the document inconsistent or ambiguity arranged are as the criterion with the application's definition.

At this document quoted or article and do not mean that approval these documents or article are the industry common recognitions of being correlated with, perhaps approve the content of these documents or article and a few days ago.

" one " of Shi Yonging comprises one or more when not declaring especially herein.

" objective body " used herein refers generally to mammal, including, but not limited to experimental animal (as mice, rat, Cavia porcellus, primates etc.), house pet (as Canis familiaris L., cat etc.), physical culture animal (as horse etc.), farm-animals (as pig, cattle, goat, sheep etc.) or people.In the enforcement of being inclined to use, objective body is behaved.

" coupled " is meant directly or indirectly and by intermediate two mechanical fittings is connected as used herein.This connection can be that the intermediate by two accessories or any number forms a complete intermediate whole or two accessories and any number and interconnects and finish.This connection can be permanent, also can be dismountable.

" connection " of Shi Yonging herein is meant the connection, contact, combination, coupled, crosslinked etc. of physics or machinery, and each assembly that is in " connection " can not separate under the influence of no external force or energy each other.Equally, " disassembled connection " mean that machinery or physical connection can be disassembled or discharge.

" fluid path " between two or more accessories of Shi Yonging is meant direct or indirect connection herein, and this connection can allow that fluid flows between each accessory.

" gas passage " between two or more accessories of Shi Yonging is meant direct or indirect connection herein, and this connection can be allowed gas but is not that liquid flows between each accessory.

" liquid medium " used herein generally is meant fluid, the water slurry that the emulsion that include but not limited to aqueous solution, physiological water solution, is made of oil and water or this non-solubility salt are formed.

" basic sealing " or " preventing substantially " used herein are meant that employed medicine can separate with chemical reaction substrate (solid, liquid or gas) among the present invention, and can the safety and the effectiveness of medicine not impacted.

" disposable apparatus " of Shi Yonging is meant that this device is designed to disposable use herein, such as a process single operation process on a patient.

The each side of inventing among the application is many to be expressed by scope of data.The expression way of this scope just for the sake of simplicity and conveniently rather than means limitation of the scope of the invention.Equally, the statement of scope littler scope in the scope and the scope that comprises the numeral of limited range have also been comprised.By way of example, scope 1 to 6 comprised simultaneously as 1 to 3,1 to 4,1 to 5,2 to 4,2 to 6 etc. among a small circle, and the numeral that has also comprised limited range is as 1,2,3,4,, 5,6 etc.This statement scope is much all to be suitable for.

The specific embodiment

Ensuing experimental section only is used as illustrational purpose, but not description of this invention scope limits.Although all adopt air pressure in the following experiment as motive force, also can be by changing chemicals, mechanical force, electricity and/or biological method generation motive force.

Embodiment 1 uses controlled release matrix that rat is continued infusion

For sustained release speed, prolong drug release time, the effervescent reactant can wrap up in the controlled release matrix, and then the effervescent reactant progressively is provided.The effect of this controlled release matrix is mentioned in this device notion.

Have in the infusion tube of 31G syringe needle and be full of 470 microliters of water, be connected with 1 milliliter of syringe that solid acid (6 milligrams of benzoic acid that link to each other with syringe piston or contain the benzoic controlled release matrix of equivalent) is housed.The phthalic anhydride granule is in advance through the processing of sieving of 80 mesh sieves, or is single sheet.Syringe needle inserts male, the SD subcutaneous rat of 200 gram left and right sides body weight, the prior lumbar injection 1ml 20% urethane anesthesia of SD rat.Suck the 0.2ml saturated sodium bicarbonate solution in the syringe, by making the reaction of sodium bicarbonate solution and sour contact activation, the beginning subcutaneous injection.By surplus solution quantitative determination medicine-feeding rate in the monitoring different time infusion tube.

During the preparation controlled release matrix, according to the prescription of controlled release matrix, with benzoic acid, ethyl cellulose, acetin and hydroxypropyl cellulose are dissolved in the ethanol fully, and above solution is poured in the culture dish, form film matrix after the solvent evaporates.Matrix components and corresponding injection used time of 100 microliters of water all are listed in the table 1.Figure 15 showed three kinds of components time-volume infused relation.

Table 1 controlled release matrix-infusion rates effect relatively

Title	Matrix formulations	??T 100(min)
			Benzoic acid	Benzoic acid	??2
F1 substrate	58% ethyl cellulose, 20% acetin, 10% hydroxypropyl cellulose, 12% benzoic acid	??190
			F2 substrate	35% ethyl cellulose, 20% acetin, 35% hydroxypropyl cellulose, 10% benzoic acid	??18

Result of study shows that benzoic infusion rates is very in minutes just finished and injected.The effervescent reactant is embedded in the controlled release matrix, and infusion rates obviously slows down, and obtains inject time prolonging.By adjusting the constituent content in the controlled release matrix, infusion rates can be adjusted to dozens of minutes to several hrs.

The lasting infusion experiment of embodiment 2 acid anhydride-based hydrolysis

Experimental result shows that medicine-feeding rate depends on the chemical property of effervescent reactant.The anhydride hydrolysis provides a kind of lasting chemical reaction that discharges acid, the invention describes a kind of device notion that influences the infusion time by the anhydride hydrolysis.

During animal experiment, have in the infusion tube of 31G syringe needle and be full of 470 microliters of water, be connected with 1 milliliter of syringe that anhydride reaction thing (5.4 milligrams of succinic acid that link to each other with syringe piston are done or 8 milligrams of phthalic anhydrides) is housed.Syringe needle inserts male, the SD subcutaneous rat of 200 gram left and right sides body weight, the prior lumbar injection 1ml 20% urethane anesthesia of SD rat.Suck the 0.2ml saturated sodium bicarbonate solution in the syringe, by making the reaction of sodium bicarbonate solution and sour contact start, the beginning subcutaneous injection.Surplus solution amount in the monitoring different time infusion tube.

Anhydride is seen Figure 16 to the influence of infusion velocity, and the corresponding time of infusion 100 microliters of water is listed in the table 2.

Table 2 anhydride is for the influence of infusion velocity

The reactant title	??T 100(min)
		Succinic anhydride	??5
Phthalic anhydride	??120
		Poly sebacic polyanhydride	??720

This result of study shows, uses different anhydride can regulate infusion rates.Use succinic anhydride, the infusion time has only a few minutes, and phthalic anhydride and poly sebacic polyanhydride can be with the infusion time lengthening by several hours even several days.

The long-pending infusion rates of embodiment 3 acid anhydride-based reaction-ure surfaces is regulated experiment

Experiment can reach the purpose that prolongs the infusion time by reducing the particulate surface area of anhydride in the contrive equipment.

During animal experiment, have in the infusion tube of 31G syringe needle and be full of 470 microliters of water, be connected with 1 milliliter of syringe that anhydride reaction thing (8 milligrams of phthalic anhydrides that link to each other with syringe piston) is housed.The phthalic anhydride granule is in advance through the processing of sieving of 80 mesh sieves, or is single sheet.Syringe needle inserts male, the SD subcutaneous rat of 200 gram left and right sides body weight, the prior lumbar injection 1ml 20% urethane anesthesia of SD rat.Suck the 0.2ml saturated sodium bicarbonate solution in the syringe, by making the reaction of sodium bicarbonate solution and sour contact activation, the beginning subcutaneous injection.By surplus solution quantitative determination infusion rates in the monitoring different time infusion tube.

Anhydride is seen Figure 17 to the influence of infusion rates, and table 3 has shown the corresponding time of anhydride infusion 100 microliters of water.

Table 3 anhydride surface area is to the influence of infusion rates

The reactant title	?T 100(min)
		Phthalic anhydride (powder)	?40
Phthalic anhydride (lamellar)	?120

Sodium bicarbonate and phthalic anhydride powdered reaction, surface area is bigger, and the infusion time is then short; When using the less phthalic anhydride preparation of surface area, administration time prolongs.This result of study shows, for identical anhydride reaction thing, can regulate infusion rates by the surface area of control anhydride.

The test of embodiment 4 rat model infusion of insulin

This experiment has been described and has been utilized apparatus of the present invention, successfully controls the biological activity insulin in the intravital input rate of rat.

During animal experiment, SD rat about 10 male body weight 200 restrain, fasting is divided into 3 groups after 4 hours, 4 of device experiment group (" Device " group) animals, to have respectively in the infusion tube of 31G syringe needle and charge into the hydrochloric acid that 100 microlitres contain the 0.01N of 0.6 units of insulin in advance, be connected with 1 milliliter of syringe that 8 milligrams of Powdered phthalic anhydride things are housed, it is subcutaneous that syringe needle inserts the SD rat back, and rat is adopted the anesthesia of lumbar injection 1ml 20% urethane in advance.Sucking 0.2ml concentration in the syringe is the sodium bicarbonate solution of 30 mg/ml, makes the reaction of sodium bicarbonate solution and sour contact start, the beginning h inf, by surplus solution amount in the monitoring different time infusion tube with the mensuration infusion rates.

3 animals of subcutaneous injection group (" SC " group), every the animal in anesthesia back is 0.2 milliliter of 0.01N hydrochloric acid solution that contains 0.6 units of insulin of subcutaneous injection respectively.Blank group (" Blank ") 3 animals are only anaesthetized not administration.Different time before on-test and after the administration, each treated animal tail vein is got blood, adopts Johson ﹠ Johnson's ONETOUCH ULTRA blood-sugar detecting instrument and corresponding reagent paper to measure blood glucose.

Figure 18 shown and respectively organized the time dependent curve of rat blood sugar, Figure 19 then shown utilize this device in rat model in time and the change in volume of input insulin.Result of study shows, utilizes apparatus of the present invention can control the infusion rates of insulin medicament, finishes the infusion of 100 microlitre insulin solutions in 40-60 minute, and the insulin of input can significantly reduce the blood glucose of rat.Compare with subcutaneous injection and to have close bioavailability, thereby shown the feasibility of apparatus of the present invention.

List of references

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United States Patent (USP) 3964482,5250023,5957895,6503231,6656147,6743211,6780171,6623457,6960193,6939324,7047070,6808506,7083592,7115108,7156838,7250037,7410476,7429258; U.S. Patent application 20080215015; PCT patent WO03/022330, WO02/002179, WO03/024507, WO04/033021, WO06/054280, WO06/132602; Chinese patent CN02812823.0; European patent application EP 1925333.

Claims (43)

1. doser of giving the objective body medication is characterized in that this device comprises:

A) micropin;

B) be closed in drug storage chamber in the device, fluid path arranged between drug storage chamber and the micropin and contain the medicine of being sent;

C) be closed in air-pressure chamber in the device, the gas passage arranged between air-pressure chamber and the drug storage chamber and contain liquid medium;

D) be used for starting the active device of air-pressure chamber chemical reaction, active device is designed to the primary importance and the second position, when active device when primary importance moves to the second position, the chemical reaction in the air-pressure chamber is activated;

E) be positioned at the piston of drug storage chamber, piston is unidirectional to be moved along with pressure in the air-pressure chamber increases, and plays the medicinal liquid separated in the drug storage chamber and the effect of chemical reactant in the air-pressure chamber and product.

F) comprise a removable protector that invests the device outside, in order to prevent the syringe needle injury.

G) comprise an adhered layer that is positioned at bottom of device, be used to stick in the objective body skin surface.

2. doser according to claim 1 is characterized in that, a ventilated membrane is arranged between drug storage chamber and the air-pressure chamber, is used to prevent that liquid reaction medium from entering drug storage chamber.

3. doser according to claim 1 is characterized in that, drug storage chamber is cylindric.

4. doser according to claim 3 is characterized in that, drug storage chamber height and internal diameter ratio are between 2: 1 to 1000: 1.

5. doser according to claim 1 is characterized in that, between drug storage chamber and the air-pressure chamber jointing is arranged.

6. doser according to claim 1 is characterized in that, drug storage chamber comprises one and be used for pouring into the inlet that needs the infusion medicinal liquid in drug storage chamber.

7. doser according to claim 1 is characterized in that, active device can be selected from following enumerating the device: push the combination that pin device, wrench device, battery are done valving, heater and the above device of power.

8. doser according to claim 1 is characterized in that, active device comprises an active device and cuts off, and is used to guarantee that active device remains on primary importance, prevents that active device from moving to the second position by primary importance.

9. doser according to claim 1 is characterized in that, comprises a solid reaction combination that is arranged in doser air pressure inside chamber; The solid reaction combination contains: invest solid reactant and the diaphragm seal that is used to prevent that solid reactant from contacting with liquid medium on the solid support thing.

10. doser according to claim 1 is characterized in that, air-pressure chamber comprises first chamber that contains liquid medium and second chamber that contains reactant.

11. doser according to claim 10 is characterized in that, when active device was positioned at primary importance, first chamber and second chamber in the air-pressure chamber were separated fully; When active device is positioned at the second position, set up fluid passage between first chamber and second chamber.

12. doser according to claim 1 is characterized in that air-pressure chamber comprises indicator, is used for monitoring that the air-pressure chamber chemical reaction is initial, process and/or performance.

13. doser according to claim 12 is characterized in that, indicator is a colour reagent.

14. doser according to claim 13 is characterized in that, colour reagent is the pH indicating dye.

15. doser according to claim 1 is characterized in that, drug storage chamber comprises a transparent window, is used for monitoring the situation of movement of piston at drug storage chamber.

16. doser according to claim 1 is characterized in that, the chemical reaction in the air-pressure chamber is the effervescent reaction.

17. doser according to claim 16 is characterized in that, the effervescent reaction produces carbon dioxide.

18. doser according to claim 17 is characterized in that, carbon dioxide is generated by the acid plus carbonate reaction.

19. doser according to claim 18 is characterized in that, carbonate comprises carbonic acid functional group, bicarbonate functional group, the perhaps combination of two kinds of functional groups.

20. according to claim 18 or 19 described dosers, it is characterized in that acid is selected from one or more the mixture in acetic acid, malic acid, citric acid, butanoic acid, n-caproic acid, ascorbic acid, tartaric acid, sad, capric acid, lauric acid, benzoic acid, phenylacetic acid, benzoyl-glycine, aspirin and the salicylic acid.

21., it is characterized in that acid is by the combination of ester hydrolysis, anhydride hydrolysis, the hydrolysis of poly anhydride or above hydrolysis according to the described doser of claim 18-20.

22. doser according to claim 21 is characterized in that, the anhydride hydrolysis reaction is regulated by reducing the anhydride surface area.

23., it is characterized in that the anhydride hydrolysis comprises the combination of phthalic anhydride hydrolysis, poly sebacic polyanhydride hydrolysis, succinic anhydrides hydrolysis or above hydrolysis according to claim 21 or 22 described dosers.

24., it is characterized in that chemical reaction rate is regulated by the rate of dissolution that reduces solid reactant according to the described doser of claim 10-23.

25. doser according to claim 24 is characterized in that, by the rate of dissolution that controlled release matrix reduces solid reactant is gone in solid reactant embedding or parcel.

26. doser according to claim 25 is characterized in that, controlled release matrix contains one or more in ethyl cellulose, glycerol acetate and the hydroxypropyl cellulose.

27. a doser of giving the objective body medication is characterized in that, the doser at least two kinds of medicines of patient's while infusion comprises:

A) first and second micropin;

B) the inner drug storage chamber of first device has fluid passage between first drug storage chamber and first micropin, contains the first kind of medicine that is useful on infusion;

C) second drug storage chamber that device is inner has fluid passage between second drug storage chamber and second micropin, contains the second kind of medicine that is useful on infusion;

D) the inner air-pressure chamber of first device has gas passage between first air-pressure chamber and first drug storage chamber, contains first kind of liquid medium;

E) second air-pressure chamber that device is inner has gas passage between second air-pressure chamber and second drug storage chamber, contains second kind of liquid medium;

F) active device is used for starting first chemical reaction in first air-pressure chamber and second chemical reaction in second air-pressure chamber; Active device has the primary importance and the second position, and when primary importance moved to the second position, the chemical reaction in first air-pressure chamber and second air-pressure chamber was activated with active device;

G) first drug storage chamber and second drug storage chamber have a piston respectively, piston is under the pressure effect of first air-pressure chamber and the increase of second air-pressure chamber, unidirectional respectively moving completely cuts off chemical reactant and/or product in the medicine in first fluid reservoir and second drug storage chamber and first air-pressure chamber and second air-pressure chamber.

28. doser according to claim 27 is characterized in that, wherein second kind of medicine in first kind of medicine in first drug storage chamber and second drug storage chamber can be identical or different.

29., it is characterized in that wherein second kind of liquid medium in first kind of liquid medium in first air-pressure chamber and second air-pressure chamber can be identical or different according to claim 27 or 28 described dosers.

30., it is characterized in that wherein second kind of chemical reaction in first kind of chemical reaction in first air-pressure chamber and second air-pressure chamber can be identical or different according to the described doser of claim 27-29.

31. according to the described doser of claim 27-30, it is characterized in that, further comprise first kind of solid reactant combination that is arranged in inner first air-pressure chamber of device; First kind of solid reactant combination contains: invest first kind of solid reactant on the solid support thing, be used to first diaphragm seal that prevents that first kind of solid reactant from contacting with first kind of liquid medium.

32. doser according to claim 31 is characterized in that, further comprises second kind of solid reactant combination that is arranged in inner second air-pressure chamber of device; Second kind of solid reactant combination contains: invest second kind of solid reactant on the solid support thing, be used to second diaphragm seal that prevents that second kind of solid reactant from contacting with second kind of liquid medium.

33. doser according to claim 32 is characterized in that, wherein second kind of solid reactant in first kind of solid reactant in first air-pressure chamber and second air-pressure chamber can be identical or different.

34., it is characterized in that this device only can once use according to claim 1 or 27 described dosers.

35. the using method of doser according to claim 1 is characterized in that,

A) device is sticked on the objective body skin surface;

B) by active device is moved to the second position from primary importance, start the chemical reaction in the air-pressure chamber;

C) simultaneously, assurance device is pasted on the objective body skin surface all the time, in treatment effective dose of medicine thing input objective body body.

36. the using method of doser according to claim 27 is characterized in that,

A) device is sticked on the objective body skin surface;

B), start first chemical reaction in first air-pressure chamber and second chemical reaction in second air-pressure chamber by active device is moved to the second position from primary importance;

C) simultaneously, assurance device is pasted on the objective body skin surface all the time, in two kinds of medicine input objective body bodies of treatment effective dose.

37. the using method according to claim 35 or 36 described dosers is characterized in that, device is sticked on before the objective body skin surface, removes protector.

38. the using method according to the described doser of claim 35-37 is characterized in that, further comprises, active device is moved to the second position from primary importance before, remove active device and cut off.

39. the using method according to the described doser of claim 35-38 is characterized in that, selectable infusion of drug approach comprises: Intradermal infusion, h inf, intramuscular infusion and venoclysis.

40., it is characterized in that there is medicine box the doser outside according to claim 1 or 27 described dosers.

41. according to the described doser medicine box of claim 40, it is characterized in that comprising in the medicine box protector, be used to prevent unexpected syringe needle injury.

42. according to claim 40 or 41 described doser medicine boxs, it is characterized in that comprising in the medicine box active device and cut off, be used to prevent that doser from being activated by accident.

43., it is characterized in that according to the described doser medicine box of claim 40-42, comprise an adhered layer in the medicine box, be used for doser is pasted on the objective body skin surface.

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