CN102641548B - Saturating mucosal drug conveyer device and method including chemical permeation reinforcing agent - Google Patents
Saturating mucosal drug conveyer device and method including chemical permeation reinforcing agent Download PDFInfo
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Abstract
It is disclosed saturating mucosal drug conveyer device and the method including chemical permeation reinforcing agent.Mucosal drug conveyer device can include that being configured to intracavity inserts thoroughly, and the shell of the mankind or animal subjects is inserted in such as intravaginal；Accommodating the medicament distribution part of at least one medicine, this medicament distribution is partially configured to is distributed medicine from shell by positive displacement；With penetration enhancer distribution portion, it is configured to when intracavity inserts the mankind or animal subjects, strengthens material in release seclected time or generation permeability, destroys at least one region of the mucosal barriers of adjacent shells.Operable described device to strengthen the mucosal barriers region of material damage by medicine from shell distribution to being saturated property.
Description
Technical field
Each embodiment disclosed herein relates to implantable medical device, more particularly relates to the apparatus and method to patient's saturating mucosa conveying medicine.
Background technology
Mucosal drug conveying (transmucosal drug thoroughly
Delivery) it is an interesting field, because may be by avoiding first pass metabolism effect (first-pass metabolism
Effect) and with high relative bioavailability general action medicine is carried, may be to position of interest localized delivery of therapeutic agent, and route of administration is convenient.Some of mucosal drug conveying may include oral cavity, nose, vagina and rectal delivery in position thoroughly.
There is the challenge that many and saturating mucosal drug conveying is relevant, mucosa conveying includes the macromole of some aminoacid sequence particularly thoroughly.The enzyme being present in the fluid secreted by mucosal tissue decomposes some aminoacid.The type of the enzyme presented by mucosal tissue changes according to the position of mucosal tissue.The enzyme being present in vaginal fluid includes nuclease (nuclease), lysozyme (lysozyme), esterase (esterase), G-Px (guaiacol peroxidase), aldolase (aldolase) and beta-glucuronidase (β-glucuronidase).It addition, aminopeptidase (aminopeptidase), beta-glucuronidase, phosphate (phosphatase), lactic acid dehydrogenase, esterase and 5 type phosphodiesterases are combined with the apical cell's layer along vaginal mucosal surfaces.The existence of these enzymes, particularly aminopeptidase is a factor of the bioavailability reducing vaginal application albumen and peptide medicine.
Other mucosal tissue presents other enzyme that can decompose some drugs.Such as, gastrointestinal tract present mixed function oxidase system, alcoholdehydrogenase, monoamine oxidase, MAO, reductase,p-nitro-anisol demethylase, ethoxy coumarin-o-ethoxyresorufin O-deethylase (ethoxycournarin-o-deethylase), Epoxide hydrolase, UDP-glucoronosyl/transferring enzyme, thiokinase, glutathione-S-transferase, glycine transferring enzyme, acetyltransferase and calechol-O-transmethylase.These enzymes reduce albumen and the bioavailability of peptide medicine being applied to this type of mucosal tissue.
Additionally, most of mucosal tissues constantly secrete the water fluid of thickness.The liquid of this thickness proposes other challenge to the conveying of saturating mucosal drug.First, the liquid acquisition of thickness and the intrusion of exotic of slowing down, thus allow in it enzymatic and other defense mechanism have time to decompose and/or kill exotic.Secondly, along with it is discharged from tissue, the fluid liquid of thickness constantly cleans and washs mucosal tissue surfaces.Therefore, conventional application technique is used may to waste substantial amounts of medicine.
In the case of intravaginal drug carries as, the film of vaginal mucosa can be regarded two continuous print barrier layers, aqueous barrier layer and mucosa film barrier layer.Mucosal inner layer is glycogenesis (glycogenated) and the stratified squamous epithelium of non-keratinization (nonkeratinized).Human vagina epithelium is made up of about 25 cellular layers, depends on Maturity and position.Similar with other stratified epithelium of great majority, human vagina epithelium contains (tight junction) (TJ) system of combining closely, and it is positioned at uppermost cellular layer.Territory, apical cell surface is separated by these TJ with territory, basal cell surface, and the saturating mucosa for water-soluble substances carries the barrier layer providing primary.It it is not only the epithelium in vagina and the TJ topical that hinders medicine during these are present in all mucosas of health just.
Therefor it is required that provide the apparatus and method improving saturating mucosal drug transfer efficiency.
Summary of the invention
In one aspect, it is provided that the intracavitary unit carried for saturating mucosal drug.Mucosal drug conveyer device can include that being configured to intracavity inserts the shell of the mankind or animal subjects thoroughly；Accommodating the medicine-distribution portion of at least one medicine, this medicine-distribution portion is configured to pass positive displacement and is distributed from shell by medicine；With penetration enhancer-distribution portion, it is configured to release or produces permeability enhancing material, when inserting the mankind or animal subjects, destroying at least one region of the mucosal barriers of adjacent shells in seclected time.Medicine is strengthened the mucosal barriers region of material damage by operable described device from shell distribution to being saturated property.
In yet another aspect, it is provided that the method carrying medicine via mucosal tissue from inner cavity.The method can include inserting in inner chamber delivery device；Strengthen material from the release of described device or generation permeability, make permeability strengthen material contact mucosal tissue region；With by positive displacement method, medicine is distributed from described device so that medicine is transported to strengthen, with permeability, the mucosal tissue region that material contacts.
On the other hand, it is provided that the intravaginal device carried for saturating mucosal drug.This device can include that being configured to intravaginal inserts the shell of the mankind or animal subjects；Accommodating the pill dispenser of medicine, this pill dispenser is had one or more nozzle and is suitable for the positive displacement component distributed from shell by medicine via the one or more nozzle by positive displacement；With penetration enhancer allotter, it is configured to release or produces permeability enhancing material, when the mankind or animal subjects are inserted in intravaginal, destroying at least one region of the mucosal barriers of adjacent shells in seclected time.Medicine is strengthened the mucosal barriers region of material damage by operable described device from shell distribution to being saturated property.
Accompanying drawing explanation
Fig. 1 is profile, it is illustrated that the placement in anatomical lumens of the mucosal drug conveyer device is described.
Fig. 2 is profile, it is illustrated that illustrate that the delivery device conveying permeability from placing in the lumen strengthens material.
Fig. 3 is profile, it is illustrated that illustrate after conveying permeability strengthens material, from the delivery device conveying medicine placed in the lumen.
Fig. 4 is profile, it is illustrated that illustrates to have penetration enhancers and produces the placement in the lumen of the saturating mucosal drug conveyer device of ability.
Fig. 5 is end-view, it is illustrated that the saturating mucosal drug conveyer device of explanatory diagram 4.
Fig. 6 is profile, it is illustrated that after illustrating to produce penetration enhancers, carries medicine from the device of Fig. 4.
Fig. 7 is profile, it is illustrated that the alternate embodiment of mucosal drug conveyer device is described.
Fig. 8 is profile, it is illustrated that illustrate to carry medicine from the saturating mucosal drug conveyer device of Fig. 7.
Detailed description of the invention
The saturating mucosal drug conveyer device inserting (intralumenal deployment) for intracavity is provided.As used herein, term " intracavity " represents to be placed on have in the body cavity of mucosal tissue wall, passage, pipeline etc..This term includes but not limited to (such as rectum) position in intravaginal, intrauterine and gastrointestinal tract.Device generally at least keeps during potion or more multiple doses carrying in inserting or placing of intracavity.The device inserted can reclaim as required from inner chamber, including such as carrying between single dosage, after carrying some dose drugs, or after completing the treatment of a series of multiple dose.This device can be inserted until medicine payload is consumed.
In some embodiments, saturating mucosal drug conveyer device includes that (i) is configured to allow to insert the shell of inner chamber, and (ii) is one or more for accommodating medicine and the storeroom of permeability enhancing material.In certain embodiments, medicine and permeability enhancing material are contained in independent storeroom.Described mucosal drug conveyer device can also include for medicine and permeability are strengthened dispensed materials entrance inner chamber or the distribution portion of mucosal tissue wall.Described delivery device can also include for controlling medicine and/or permeability enhancing material from the release of described device or the integrated control module of conveying.
In yet another aspect, it is provided that the method carried for saturating mucosal drug.The method includes the interior intracavity that delivery device is placed or is embedded in patient or the mankind or animal subjects.Inner chamber can be such as vagina, cervix uteri, uterus or part gastrointestinal tract, such as rectum.
After delivery device is placed on inner chamber, described delivery device can produce or discharge permeability on inner chamber or mucosa sidewall on one's own initiative and strengthen material.Then medicament distribution to being saturated property can be strengthened the mucosal tissue region of material damage by described delivery device.Permeability strengthens the application of material and can advantageously improve medicine transfer rate and/or can thus improve the efficiency of the transmucosal administration of medicine without degraded through the amount of mucosal barriers.
In some embodiments, permeability strengthens material and medicine accommodates in independent storage storeroom in a device.Such as, as illustrated in Figure 1, it is provided that mucosal drug conveyer device 10 thoroughly, it has the shell 16 including penetration enhancer storeroom 18, drug storage room 20 and control module 34.Shell 16 is configurable to be placed in the inner chamber 12 with mucosal tissue 14.Shell 16 includes that the permeability being contained in penetration enhancer storeroom 18 for distribution strengthens the penetration enhancer allotter of material, and the pill dispenser of the medicine being contained in drug storage room 20 for distribution.
Penetration enhancer allotter can include that nozzle 26 and actuator (actuator) 22, nozzle 26 and actuator 22 are configured to axially distribute permeability enhancing material (i.e. leave shell 16 end and enter inner chamber 12) from shell 16 jointly.Pill dispenser can also include nozzle 28 and actuator 24, nozzle 28 and actuator 24 to be jointly configured to from shell 16 and axially distribute medicine.Although this example illustrates axially distributes layout, but this device can also be configured to be radially injected permeability strengthens material and medicine (i.e. the sidewall of shell 16 is left in the direction towards mucosal tissue 14).Such as, in an alternate embodiment, nozzle 26 and 28 can be arranged on one or more sides of the shell of mucosal tissue 14.
Control module 34 includes power supply 32, such as battery, and controller 30.Controller 30 is configurable to by controlling actuator 22 and actuator 24, independently controlled conveying medicine and the opportunity of penetration enhancer and order.It is possible, as will be seen in more detail below, various actuator mechanisms may be used for actuator 22 and 24, come via positive displacement method (positive displacement
Process) penetration enhancer and medicine are distributed from shell.
In some embodiments, permeability strengthens material and produces outside shell, and medicine accommodates in independent storage storeroom in a device.Such as, as illustrated in Figure 4, it is provided that mucosal drug conveyer device thoroughly, it has the shell 36 including drug storage room 56, pump storage tank 58 and control module 50.The array of electrochemical element 38 is provided outside shell 36, for when shell 36 is inserted in inner chamber 12, produces permeability in one or more periods and strengthen material.As illustrated in Figure 5, the array of electrochemical element 38 can be arranged around the longitudinal side wall of shell 36.Or, electrochemical element array can be provided within shell 36, strengthen material for producing permeability within shell 36.Each electrochemical element 38 can include pair of electrodes 60 and second pair of electrode 62.It is described more particularly below use electrochemical element 38 and produces permeability enhancing material (H2O2) mechanism.
The array of the distributing nozzle 40 being in fluid communication with drug storage room 56 can be provided, for medicine being delivered into mucosal tissue 14 in the side of shell 36.In other embodiments, one or more distributing nozzle can be set at the end of shell 36, axially to distribute medicine.In such an implementation, one or more electrochemical element can be set at the end of shell 36 or adjacent end, strengthen material for producing permeability near medicine delivery site.
Can be in pump storage tank 58 or adjacent pump storage tank 58 provides internal gas-volume displacement pump, to drive the medicine accommodated in distribution drug storage room 56 via positive displacement method.In one embodiment, pump can include contacting the water in pump storage tank 58 or the negative electrode 44 of aqueous solution and anode 46.Passage 42 can be provided, to allow the aqueous secretions from mucosal tissue 14 to enter passage 42 Contact cathod 44 and anode 46 in shell 36.In other embodiments, it is convenient to omit the passage 42 being in fluid communication with the inner space of inner chamber, and electrolyte can be provided on device.Such as, pump storage tank 58 can include the solion of such as sodium nitrite.Or, pump storage tank 58 can accommodate deionized water, and solid electrolyte can be provided to replace passage 42 so that solid electrolyte contacts the negative electrode 44 towards passage 42 and the surface of anode 46.The mechanism using negative electrode 44 and anode 46 to produce gas in pump storage tank 58 is described more fully below.
Control module 50 includes power supply 54, such as battery, and controller 52.Controller 52 is configurable to by applying electromotive force, independently controlled conveying medicine and the opportunity of penetration enhancer and order to electrochemical element 38 and negative electrode 44 and anode 46.It is possible, as will be seen in more detail below, other actuator mechanism various can be used to be distributed from shell by medicine via positive displacement method.
Shell is typically configured to and promotes delivery device the inserting of intracavity in mucosa.In some embodiments, described device can be placed in the lumen by inserting inner chamber via outside body orifice (exterior body orifice).Therefore, in some embodiments, shell is formed and is sized to, and to allow and to put into the insertion of described device via outside body orifice, i.e. inserts in predetermined inner chamber.Specifically, shell can insert for vagina, cervix uteri, uterus or rectum and place with molding be sized to.The configuration constituent material of crust of the device, size, shape and surface character and further feature, make described device can insert in mucosa inner chamber, securely rest in inner chamber during device works, and generally maybe reclaim from inner chamber when additionally needing and removing after device works.Apparatus structure, based on specific intracavity position and the mankind or animal anatomy factor, is inserted with the minimum discomfort to patient.
Shell can include the one or more storerooms arranged in the enclosure, is used for accommodating medicine and/or permeability strengthens material.This shell can also include for distributing medicine and/or the allotter of permeability enhancing material, and for controlling medicine and/or the release of permeability enhancing material and the control module of conveying.Allotter can include strengthening the nozzle that material passes therethrough for distributing medicine and/or permeability.These nozzles could be arranged to axial (i.e. the leaving the end of shell) relative to shell, with relative to the radial direction of shell (i.e. leaving the sidewall of shell), or strengthens material with a combination thereof injection of medicine and/or permeability.Medicine and permeability strengthen material and can be contained in independent shell.Independent storage can advantageously facilitate the simplification of compounding pharmaceutical, because some common-formulation there may be the compatibility and/or the difficulty of solvent selection.
Shell can be formed by any biocompatible materials.It addition, sheathing material can tolerate the Degradation in inner chamber environment.The suitably example of material includes rustless steel, titanium and some polymer.The material forming shell can include coating, to improve biocompatibility and/or the operation of device.
Provide a mean for positive displacement by medicine pill dispenser of actively distribution from delivery device.Medicine can be stored in the storeroom of described device, and distributes in inner chamber or mucosal tissue via one or more nozzles in seclected time.This pill dispenser can be set so that medicine to strengthen to being saturated property the mucosal barriers region of material damage from shell distribution.
Pill dispenser can use various positive displacement component for distributing medicine from described device, and described positive displacement includes mechanical displacement, Permeation Swelling displacement, gas-volume displacement, electrostatic-sensing extruding, Piezoelectric Driving or heat/magnetic induction phase transformation.Driving that actively displacement component can include being combined with hydrostatic head dispenses valve.As used herein, term " positive displacement " refers to any method under by the power provided inside delivery device from delivery device distribution medicine.Therefore, this term does not indicates that the chemical diffusion that medicine is passive from described device.
In some embodiments, in medicament storage storeroom in the enclosure, and by the mechanical displacement element of such as piston or spring leaf, via one or more distributing nozzles from shell actively distribution.Such as, in the implementation of figure 1, integrated control module 34 electrically or mechanically can will can be delivered to actuator 22 selectively, advances the piston of actuator 22 through drug storage room 20 and to distribute medicine via distributing nozzle 28.
In some embodiments, by gas-volume displacement distribution medicine.Such as, as illustrated in Figure 4, described device can include the aqueous or pump storage tank 58 of aqueous solution.Pair of electrodes (negative electrode 44 and anode 46) can be provided in pump storage tank 58, be used for producing gas, such as oxygen.Passage 42 can be provided in-between the electrodes, to allow to exchange proton and electronics from the water in inner chamber 12 with the water in pump storage tank 58 or aqueous solution.In other embodiments, it is convenient to omit the passage 42 being in fluid communication with the inner space of inner chamber, and electrolyte can be provided on device.Such as, pump storage tank 58 can include the solion of such as sodium nitrite.Or, pump storage tank 58 can accommodate deionized water, and solid electrolyte can be provided to replace passage 42 so that solid electrolyte contacts the negative electrode 44 towards passage 42 and the surface of anode 46.
The electromotive force of about 1.0 V or bigger can be applied, to produce O at anode to electrode2.Reaction at anode is described by formula 1.In water, reduction reaction occurring at electronegative negative electrode, the electronics from negative electrode is endowed hydrogen cation, forms hydrogen, as shown in Equation 2.The pressure applied by the oxygen produced and hydrogen causes piston 48 to advance in drug storage room 56, thus causes medicine to distribute in inner chamber 12 or mucosal tissue 14 via distributing nozzle 40.The integrated control module 50 that can be provided by load (on-board) on device in shell 36 controls the generation of oxygen and hydrogen.Control module 50 can include power supply 54, such as battery, and controller 52, and this controller 52 is programmed to provide electromotive force in seclected time to negative electrode 44 and anode 46:
2H2O
(l) → O2 (g)
+ 4H+ (aq) + 4e-
Formula 1
2H+
(aq) + 2e- → H2 (g)
Formula 2.
Other positive displacement component be may be better understood with reference to Fig. 7 and 8.In these examples, by the medicine accommodated in the expansion distribution drug storage room 56 of parts 64.Parts 64 can be such as swellable material (such as swellable gel) or expansible storeroom.In some embodiments, medicine is distributed by Permeation Swelling displacement.It is optionally possible to provide valve 66, to control water entrance storeroom or swellable material selectively.Water from inner chamber 12 can be introduced into storeroom or swellable material, causes storeroom or swellable material volumetric expansion.The expansion of storeroom or swellable material can cause medicine to distribute into inner chamber from device with the volume of the medicine of receiving in displacement shell.The driving of valve 66 can be controlled by integrated control module 50.
In other embodiments, can be by the expansive force distribution medicine provided by sensing phase transformation.Such as, can include accommodating can the inflatable storage tank of phase-change material for parts 64.Can phase-change material can be when being heated or stand electromagnetic field, by experience from any liquid or solid of solid or liquid to gas phase transformation.When material is converted into gas, this material expands and advances through drug storage room 56, is distributed by medicine from device.The driving of phase transformation can be controlled by load control module 50.
In other embodiments, can be extruded by electrostatic induction or use piezo-activator, from the positive displacement of shell and distribution medicine.For example, it is possible to install dielectric elastomeric actuator or piezo-activator so that the change delivered in the voltage of actuator or electric current causes actuator that the medicine in drug storage room is applied extruding force.This extruding force can cause medicine to distribute from device.The driving of actuator can be controlled by load control module.
In other embodiments, it is possible to use hydrostatic head and actuatable valve door realize the positive displacement of medicine.Valve can work the most in an analog fashion, for amplitude modulation dosed administration (amplitude-modulated
Dosing), or it can work in a digital manner, for frequency/duty cycle modulation dosed administration (frequency/duty-cycle modulated
dosing).Can be by medicine device for loading will provide static pressure head under stress, or can be by device supercharging after by medicine device for loading.
Various medicines can be administered by delivery device.Medicine can be albumen or peptide.nullSuch as，In some embodiments，Described delivery device can be used to be administered hormone or steroid，Include but not limited to follicle stimulating hormone、Parathyroid hormone、Metakentrin、Gonadotropin releasing hormone (GnRH)、Estradiol、Progesterone、Melatonin、Serotonin、Thyroxine、3、Epinephrine、Noradrenaline、Dopamine、Miao Shi pipe inhibitive factor、Adiponectin、Thyroliberin、Proangiotensin、Angiotensin、Vassopressin、Anterior chamber-natriuretic peptide、Calcitonin、Cholecystokinin、Corticotropin releasing hormone、Erythropoietin、Gastrin、Growth hormone releasing factor、Glucagon、Growth hormone-releasing hormone、Human chorionic gonadotropin、Human placental lactogen、Growth hormone、Inhibin、Insulin、Insulin-like growth factor、Leptine、Melanotropin、Orexin、Oxytocin、Prolactin antagonist、Relaxin、Secretin、Somatoliberin、Thrombopoietin、Thyrotropin、Throtropin releasing hormone、Hydrocortisone、Aldosterone、Testosterone、Dehydroepiandrosterone、Androstenedione、Dihydrotestosterone、Estrone、Estriol、Calitriol、Calcium glycol、Prostaglandin、Leukotriene、Prostacyclin、Thromboxane、Prolactin releasing hormone (PRH)、Lipotropin、Brain natriuretic peptide、Neuropeptide tyrosine、Histamine、Endothelin、Enkephalin、Feritin and pancreatic polypeptide.
In some embodiments, delivery device may be used for being administered in cell communicating the cytokine signaling molecule used or immunomodulator.These molecules generally include protein, peptide or glycoprotein.Cytokine signaling molecule includes such as four race's alpha-helix bundles, including IL-2 subtribe (such as erythropoietin (EPO) and thrombopoietin (THPO)), interferon (IFN) subtribe and IL-10 subtribe.Cytokine signaling molecule also includes IL-1, IL-18 and IL-17 race.
In some embodiments, delivery device may be used for being administered pain therapy medicine, includes but not limited to corticosteroid, opioid, antidepressant, anticonvulsant (spasmolytic medicine), non-steroidal anti-inflammatory medicine, COX2 inhibitor (such as rofecoxib (rofecoxib) and celecoxib (celecoxib)), tricyclics (such as amitriptyline), carbamazepine, gabapentin (gabapentin) and Pregabalin (pregabalin), codeine, oxycodone, hydrocodone, heroin and Pethidine.
In some embodiments, delivery device may be used for being administered cardiovascular drugs.B-type natriuretic peptide (BNP), anterior chamber's natriuretic peptide (ANP), anterior chamber's natriuretic factor (ANF), anterior chamber's natriuretic hormone (ANH) and atrial natriuretic peptide can be included with the example of the cardiovascular drugs that described device is administered.The cardiovascular drugs can being administered by described device also includes such as arrhythmia reagent, and such as I type (sodium channel blockers), including quinidine, lignocaine, phenytoin, Propafenone；II type (Beta receptor blockers), including metoprolol；Type III (potassium channel blocker), including atlansil, dofetilide (dofetilide), Su Teluo；IV type (chronic calcium channel blocker), including diltiazem, verapamil；V-type (cardiac glycoside), including adenosine and digoxin.Other cardiovascular drugs can being administered by described device includes ACE inhibitor, such as captopril, enalapril, perindopril, ramipril；Angiotensin ii receptor antagonist, such as Candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan；Beta receptor blockers；And calcium channel blocker.
Medicine can be prepared as required together with one or more pharmaceutical acceptable excipients, to promote medicine to store in said device and to discharge from described device.In one embodiment, medicine can be the form of liquid solution or suspension.Medicine can be the form of microgranule or nano-particle.Solvent or carrier can be aqueous or organic.
Penetration enhancer allotter for strengthening material from shell distribution permeability can be provided.Permeability strengthens material and can store in said device, or it can be produced by this device.As used herein, when relating to penetration enhancer or permeability strengthens material, term " allotter " and " distribution portion " represent release, produce or discharge and produce penetration enhancer or the device part of permeability enhancing material or parts.
In one embodiment, permeability strengthens material and is stored in storeroom, and then by diffusion or active method, such as actively displacement method is distributed from described device.Any one of the example of aforementioned positive displacement mechanism, includes but not limited to that mechanical displacement, Permeation Swelling displacement, gas-volume displacement, electrostatic induction extruding, Piezoelectric Driving, heat/magnetic induction phase transformation or driving of being combined with hydrostatic head dispense valve and can be used for strengthening material from storeroom distribution permeability.
In some embodiments, permeability strengthen material by described device within shell or outside produce.In certain embodiments, permeability enhancing material produces in vivo.Such as, shell can include for producing hydrogen peroxide (H2O2) and dispense into the external dispenser into mucosal tissue.Water, electricity and oxygen can be used to produce hydrogen peroxide.Water can be provided in a device, or water can be obtained by the environment from inner chamber.Can be powered by load power source.By being dissolved in by oxygen in described device in the fluid accommodated, provide air by trapping or to described device, or by being electrochemically generated, it is provided that for the oxygen of reaction.
As illustrated in Figure 4, can be at the outside array providing electrochemical element 38 of shell 36.Each electrochemical element 38 can include two groups of electrodes separated and PEM.Pair of electrodes can be set so that anode stretches into inner chamber 12 from shell 36.The electromotive force of about 1.0 V or bigger can be applied, to produce O from water present in inner chamber 12 at anode to this electrode2.Reaction at anode is described by formula 1.Can arrange second pair of electrode, it can be adjacent with pair of electrodes so that negative electrode stretches into inner chamber 12 from shell 36.The electromotive force of about 1.6 V to about 2.0 V can be applied, to produce H at negative electrode to this electrode2O2.Reaction at negative electrode is described by formula 3:
O2
+ 2H+ (aq) + 2e- → H2O2 (aq)
Formula 3.
H can be controlled by the integrated control module 50 loading offer in shell 36 on such devices2O2Generation.Control module 50 can include power supply 54, such as battery, and controller 52, and this controller 52 is programmed to activate electrochemical element 38 in one or more seclected times.
Various permeability can be provided to strengthen material.Term " permeability enhancing material " represents the material promoting conveying medicine through mucosal tissue.This term includes chemical intensifier, and when putting on mucosal tissue, it gives organizes permeability higher to medicine and enzyme inhibitor, prevents medicine by mucosal tissue enzymatic degradation.Chemical intensifier includes such as dimethyl sulfoxide (DMSO), hydrogen peroxide (H2O2), propylene glycol, oleic acid, hexadecanol, benzalkonium chloride, SDS, isopropyl myristate, Tween 80, dimethyl sulfoxide, dimethylformamide, dimethyl acetylamide, sodium lauroyl sarcosine, sorbitan monolaurate, methyl sulfonyl methane, azone, terpenes, lecithin rely on this type of material of saline solution (such as PBS and NaCl) of phospholipase C, triacylglycerol hydrolytic enzyme, acid phosphatase, phospholipase A2 and concentration.
Enzyme inhibitor includes reversible inhibitor and irreversible inhibitor.Reversible inhibitor includes such as protease inhibitor and antiretroviral, such as Saquinavir (saquinavir), ritonavir (ritonavir), indinavir (indinavir), viracept see nelfinaivr (nelfinavir), amprenavir (amprenavir), Lopinavir (lopinavir), atazanavir (atazanavir), Fosamprenavir (fosamprenavir), tipranavir (tipranavir) and DRV (darunavir).Irreversible inhibitor includes such as diisopropyl fluorophosphate (DFP) (DFP), alpha-difluoromethyl ornithine (DFMO), trypanosomicide thioketone (trypanothione) reductase, methotrexate, allopurinol and acyclovir.
There is provided and strengthen material and medicine and deliver into the control module of mucosal tissue for controlling permeability.Can load on delivery device in shell and control module is provided.Control module can include power supply and controller.Power supply can be any mechanically or electrically energy, such as battery or fuel cell.Controller can be programmable, or it can be previously programmed, to strengthen material and medicine according to preassigned process conveying permeability.
In some embodiments, control module may further include one or more for analyzing around described device or the sensor of inner cavity environment.It is, for example possible to use sensor detects the existence of inner chamber Chinese medicine-digestive enzyme.In such an implementation, controller can be further configured to reduce at detection medicine-digestive enzyme or detect after other control environment condition of medicine conveying, distributes medicine.
In some embodiments, control module may further include the wireless receiver for receiving wireless control signal from separate, independent dispensing device.In certain embodiments, described device can be inserted in inner chamber by patient or doctor, and subsequently, patient or doctor can use dispensing device to send control signal to drive the release of penetration enhancer and medicine to the device placed.Additionally, in some embodiments, control module receptor and dispensing device can be for sending and receive the transceiver of control signal and out of Memory each other.Therefore, in certain embodiments, control module transceiver can send the data relevant with device work, such as about the dosage being administered, dosed administration process, storeroom Chinese medicine or penetration enhancing substance residue level and the data of remaining battery power, and the data relevant with inner chamber environment, the data such as being detected by integrated sensor or measuring.In some embodiments, control module can also be wireless power.
In various embodiments, described device is configurable to for radio operation, such as after inserting in the mankind or animal subjects.In this case, described device includes suitable remote measurement parts as known in the art.Such as, the distribution of penetration enhancing substance and/or the driving of generation and/or medicament distribution can be completed by the remote-operated controller that the such as mankind or animal subjects are external.Generally, use first coil by electromagnetic energy and coupling/corresponding second coil-induced coupling, it is achieved remote measurement (i.e. sends and receives).The means realizing this point are set up for a long time, including various modulation schemes, such as sending amplitude or the frequency modulation(PFM) of the data about carrier frequency.The selection of carrier frequency and modulation scheme will depend upon which position and the desire bandwidth of device, together with other factors.Other data telemetry system as known in the art can also be used.In another case, device is configured to remote power-feeding or charging.Such as, described device can include for receiving the transducer of energy being wirelessly transmitted to device, for the energy of reception guides or transforms into the circuit of the form that can be used or store, and if storage, storage device, such as rechargeable battery or capacitor.In another case, described device is wireless power and controlled in wireless simultaneously.
The method using intracavitary unit for the conveying of saturating mucosal drug is provided.The method includes being placed in patient bore delivery device.Patient can be the mankind or other mammal (such as cow, horse, pig or Canis familiaris L.).Described method includes various medical treatment and veterinary's therapy, and zootechnical use.Inner chamber can be such as vagina, cervix uteri, uterus, bladder or rectum.Described device may adapt to contact substantially any mucosal tissue surfaces.Described device can be placed in the lumen by this device is inserted inner chamber via the outer aperture of patient.In some embodiments, described device can be the form that can be taken orally, for carrying medicine by gastrointestinal tract mucous tissue.
After delivery device is placed on mucosa inner chamber, delivery device can produce or discharge permeability on inner chamber or mucosa sidewall on one's own initiative and strengthen material.Permeability strengthens the generation of material or discharges and can be driven in seclected time by integrated control module.Then medicament distribution to being saturated property can be strengthened the mucosal tissue region of material damage by delivery device.The method of this administration and order can advantageously be reduced or avoided the degraded of medicine, particularly protein drug, and otherwise in the case of not permeating potentiation, it may be degraded at mucomembranous surface.Medicine can also be driven in another seclected time by control module from the release of described device after permeability enhancing material has discharged or destroyed mucosal tissue.
As illustrated in Figure 1, saturating mucosal drug conveyer device 10 can be placed in inner chamber 12.Delivery device 10 can be in position by the friction engagement between mucosal tissue 14 and shell 16.As illustrated in Figure 2, permeability strengthens material and may then pass through the driving of actuator 22, distributes from storeroom 18 via nozzle 26.The driving of actuator 22 can be controlled by control module 34.As illustrated in Figure 3, at penetration enhancers by hindering enzymatic activity or giving mucosal tissue 14 permeability higher to medicine, after having destroyed mucosal tissue, medicine is distributed from storeroom 20 via nozzle 28 by the driving of actuator 24.The driving of actuator 24 can also be controlled by control module 34.Then described device can remove from inner chamber.
With reference to Fig. 4, in the embodiment that penetration enhancing substance is produced by described device wherein, first control module 50 can drive the array of electrochemical element 38, produces penetration enhancing substance.After producing penetration enhancing substance, control module 50 can drive the conveying of medicine by applying electromotive force to negative electrode 44 and anode 46.As illustrated in Figure 6, when producing gas in pump storage tank 58, piston 48 advances through drug storage room 56, causes medicament distribution to pass nozzle 40.Then described device can remove from inner chamber.
With reference to Fig. 7, using wherein in the embodiment of swellable material or expansible storeroom, first penetration enhancers is produced by described device or distributes.Such as, control module 50 can apply electromotive force to each electrochemical element 38, to produce penetration enhancing substance.Then valve 66 can be driven, to allow water to enter in swellable material or inflatable storage tank 64.Or, control module 50 can drive the phase transformation inducing the material in inflatable storage tank 64.Such as, control module 50 can drive heating element heater to carry out heating phase-change material, or can produce electromagnetic field with drive circuit.As illustrated in Figure 8, the expansion of swellable material or inflatable storage tank 64 promotes medicine leave nozzle 40 and enter mucosal tissue 14.
Described delivery device and method may be used for various medical treatment and treatment use.In some embodiments, described delivery device may be used for treating the infertility of female subject.For example, it is possible to described delivery device is placed in the vagina (or uterus, or the other parts of birth canal) of female subject.Then described delivery device can distribute and/or produce permeability in the lumen and strengthen material.Thereafter, described delivery device can carry follicle stimulating hormone, to promote that female subject is ovulated.In some embodiments, described delivery device is configurable to suitably order, in due course between, with to treat the appropriate amount of infertility, carry multiple hormone either individually or in combination, including follicle stimulating hormone, metakentrin, gonadotropin releasing hormone.Described device can also distribute estradiol, to regulate the natural hormone generation of female subject.Suitable dosed administration process and amount can be determined by reproduction field of pharmacology technical staff.
In another embodiment, described delivery device may be used for treating the insulin dependent diabetes mellitus (IDDM) (type i diabetes) of experimenter.Described delivery device can be placed in experimenter's inner chamber.Then described delivery device can distribute and/or produce permeability in the lumen and strengthen material.Thereafter, described delivery device can carry insulin (Humulin R, Novolin R), isophane insulin (Humulin N, Novolin N), insulin lispro (Humalog), insulin aspart (NovoLog), insulin glulisine (Lantus) or insulin detemir (Levemir) in one or more seclected times to patient.
In another embodiment, described delivery device may be used for treating the diabetes (type ii diabetes) of experimenter.Described delivery device can be placed in experimenter's inner chamber.Then described delivery device can distribute and/or produce permeability in the lumen and strengthen material.Thereafter, described delivery device can carry Exenatide (exenatide) in one or more seclected times to patient.
In another embodiment, described delivery device may be used for treating breast or the ovarian cancer of experimenter.Described delivery device can be placed in experimenter's inner chamber, such as in the vagina of female subject.Then described delivery device can distribute and/or produce permeability in the lumen and strengthen material.Thereafter, described delivery device can carry formulation for paclitaxel (abraxane) (or other to treatment or controls the cancer medicable medicine of tool) in one or more seclected times to patient.
In another embodiment, described delivery device may be used for treating the HIV/AIDS of experimenter.Described delivery device can be placed in experimenter's inner chamber.Then described delivery device can distribute and/or produce permeability in the lumen and strengthen material.Thereafter, described delivery device can carry Abacavir (Abacavir) (ABC) or cidofovir (Cidofovir) (or other to treatment or controls the HIV/AIDS medicable medicine of tool) in one or more seclected times to patient.Described device can be used for treating other sexually transmitted disease (STD).
In another embodiment, described delivery device may be used for treating the genital herpes of experimenter.Described delivery device can be placed in experimenter's inner chamber, such as in the vagina of female subject.Then described delivery device can distribute and/or produce permeability in the lumen and strengthen material.Thereafter, delivery device can carry acyclovir (acyclovir), famciclovir (famciclovir) or valaciclovir (valacyclovir) (or other to treatment or controls the genital herpes medicable medicine of tool) in one or more seclected times to patient.
In another embodiment, described delivery device may be used for treating the diabetes insipidus of experimenter.Described delivery device can be placed in experimenter's inner chamber.Then described delivery device can distribute and/or produce permeability in the lumen and strengthen material.Thereafter, described delivery device can carry Desmopressin (desmopressin) (or other to treatment or controls the diabetes insipidus medicable medicine of tool) in one or more seclected times to patient.
In another embodiment, described delivery device may be used for treating the osteoporosis of experimenter.Described delivery device can be placed in experimenter's inner chamber, such as in the vagina of female subject.Then described delivery device can distribute and/or produce permeability in the lumen and strengthen material.Thereafter, described delivery device can carry her this phosphate (ibandronate), calcitonin or parathyroid hormone (or other to treatment or controls osteoporosis and have medicable medicine) in one or more seclected times to patient.
Thus, it is disclosed embodiments below.
The intracavitary unit that scheme 1. carries for saturating mucosal drug, including:
It is configured to intracavity and inserts the shell of the mankind or animal subjects；
Accommodating the medicine-distribution portion of at least one medicine, this medicine-distribution portion is configured to pass positive displacement and distributes medicine from shell；With
Penetration enhancer-distribution portion, it is configured to when intracavity is inserted in the mankind or animal subjects, strengthens material in release seclected time or generation permeability and destroys at least one region of the mucosal barriers being adjacent to shell,
The most operable described device to strengthen the mucosal barriers region of material damage by medicine from shell distribution to being saturated property.
The device of scheme 2. scheme 1, wherein this device is configured to produce in vivo penetration enhancing substance.
The device of scheme 3. scheme 1, wherein permeates enhancing-distribution portion and includes electrochemical element.
The device of scheme 4. scheme 1, wherein penetration enhancing substance includes hydrogen peroxide.
The device of scheme 5. scheme 1, its housing is arranged to intravaginal and inserts.
The device of scheme 6. scheme 1, wherein permeability enhancing material is stored in first storeroom, and medicament storage is strengthening in separate second storeroom of material with permeability.
The device of scheme 7. scheme 1, wherein medicine includes albumen or peptide.
The device of scheme 8. scheme 1, wherein medicine includes hormone or steroid.
The device of scheme 9. scheme 1, farther includes when being inserted in inner chamber by this device, is suitable for receiving energy or the receptor of control signal from dispensing device.
The device of scheme 10. scheme 1, farther includes to be configured to order and operates medicine-distribution portion and the controller of permeability-reinforcing agent distribution portion.
The device of scheme 11. scheme 1, wherein medicament distribution part include for by medicine from the positive displacement component of shell actively distribution, this positive displacement component selected from mechanical displacement element, Permeation Swelling displacement component, gas-volume displacement element, magnetic induction phase-change element, thermoinduction phase-change element, piezo-activator, electrostatic induction extrusion element, there is driving of hydrostatic head dispense valve and combinations thereof.
The device of scheme 12. scheme 1; wherein permeability enhancing material includes chemical intensifier, and this chemical intensifier is selected from DMSO, hydrogen peroxide, propylene glycol, oleic acid, hexadecanol, benzalkonium chloride, SDS, isopropyl myristate, Tween 80, dimethyl sulfoxide, dimethylformamide, dimethyl acetylamide, sodium lauroyl sarcosine, sorbitan monolaurate, methyl sulfonyl methane, azone, terpenes, lecithin saline solution relying on phospholipase C, triacylglycerol hydrolytic enzyme, acid phosphatase, phospholipase A2, concentration and combinations thereof.
The device of scheme 13. scheme 1, wherein permeability enhancing material includes enzyme inhibitor, and this enzyme inhibitor is selected from protease inhibitor, antiretroviral, diisopropyl fluorophosphate (DFP) (DFP), alpha-difluoromethyl ornithine (DFMO), trypanosomicide thioketone reductase, methotrexate, allopurinol, acyclovir and combinations thereof.
The device of scheme 14. scheme 1, wherein penetration enhancer-distribution portion include for by medicine from the positive displacement component of shell actively distribution, this positive displacement component selected from mechanical displacement element, Permeation Swelling displacement component, gas-volume displacement element, magnetic induction phase-change element, thermoinduction phase-change element, piezo-activator, electrostatic induction extrusion element, there is driving of hydrostatic head dispense valve and combinations thereof.
Scheme 15. is used for the method to the mankind or animal subjects local saturating mucosa conveying medicine, including:
Delivery device is inserted in mucosal tissue inner chamber；
Permeability enhancing material is produced so that permeability strengthens material contact mucosal tissue region from the release of described device or with this device；With
Medicine is distributed from described delivery device so that medicine is transported to strengthen, with permeability, the mucosal tissue region that material contacts by positive displacement method.
The method of scheme 16. scheme 15, wherein said delivery device is placed into the mankind or the vagina of animal subjects, uterus or internal rectum.
The method of scheme 17. scheme 15, wherein medicine includes albumen or peptide.
The method of scheme 18. scheme 15, wherein actively displacement method includes that mechanical displacement, Permeation Swelling displacement, gas-volume displacement, magnetic induction phase transformation, thermoinduction phase transformation, Piezoelectric Driving, electrostatic induction extrude, via driving the hydrostatic head displacement or a combination thereof dispensed valve.
The method of scheme 19. scheme 15, wherein penetration enhancing substance includes hydrogen peroxide.
The method of scheme 20. scheme 15; wherein permeability enhancing material includes chemical intensifier, and this chemical intensifier is selected from DMSO, hydrogen peroxide, propylene glycol, oleic acid, hexadecanol, benzalkonium chloride, SDS, isopropyl myristate, Tween 80, dimethyl sulfoxide, dimethylformamide, dimethyl acetylamide, sodium lauroyl sarcosine, sorbitan monolaurate, methyl sulfonyl methane, azone, terpenes, lecithin saline solution relying on phospholipase C, triacylglycerol hydrolytic enzyme, acid phosphatase, phospholipase A2, concentration and combinations thereof.
The method of scheme 21. scheme 15, wherein permeability enhancing material includes enzyme inhibitor, and this enzyme inhibitor is selected from protease inhibitor, antiretroviral, diisopropyl fluorophosphate (DFP) (DFP), alpha-difluoromethyl ornithine (DFMO), trypanosomicide thioketone reductase, methotrexate, allopurinol, acyclovir and combinations thereof.
The intravaginal device that scheme 22. carries for saturating mucosal drug, including:
It is configured to intravaginal and inserts the shell of the mankind or animal subjects；
Accommodating the pill dispenser of medicine, this pill dispenser has one or more nozzle and positive displacement component, and this positive displacement component is suitable for distributing medicine via one or more nozzles from shell by positive displacement；With
Penetration enhancer allotter, it is configured to when intravaginal is inserted in the mankind or animal subjects, strengthens material in release seclected time or generation permeability, destroys at least one region of the mucosal barriers being adjacent to shell,
The most operable described device to strengthen the mucosal barriers region of material damage by medicine from shell distribution to being saturated property.
The device of scheme 23. scheme 22, wherein penetration enhancers allotter includes one or more electrochemical element being configured to produce hydrogen peroxide in vivo.
The device of scheme 24. scheme 22, farther includes to be configured to control positive displacement component and the controller of penetration enhancer dispenser drive.
The device of scheme 25. scheme 22, wherein actively displacement component is selected from mechanical displacement element, Permeation Swelling displacement component, gas-volume displacement element, magnetic induction phase-change element, thermoinduction phase-change element and combinations thereof.
The device of scheme 26. scheme 21, wherein medicine includes albumen or peptide.
Scheme 27. medical treatment device, including:
It is configured to intracavity and inserts the shell of the mankind or animal subjects；With
Penetration enhancer-distribution portion, it is configured to when intracavity is inserted in the mankind or animal subjects, at release seclected time or generation hydrogen peroxide, destroys at least one region of the mucosal barriers being adjacent to shell.
Claims (4)
1. for the intracavitary unit of saturating mucosal drug conveying, including:
It is configured to intracavity and inserts the shell of the mankind or animal subjects；
Accommodating the medicine-distribution portion of at least one medicine, this medicine-distribution portion is configured to pass positive displacement and distributes medicine from shell；With
Penetration enhancer-distribution portion, it is configured to when being inserted in the mankind or animal subjects by this device intracavity, hydrogen peroxide is produced in seclected time, destroy at least one region of the mucosal barriers being adjacent to shell, wherein penetration enhancer-distribution portion includes one or more electrochemical element being configured to produce hydrogen peroxide in vivo
The most operable described device is to distribute medicine to by the mucosal barriers region of hydrogen peroxide destroying from shell.
2. the device of claim 1, its housing is arranged to intravaginal and inserts.
3. for the intravaginal device of saturating mucosal drug conveying, including:
It is configured to intravaginal and inserts the shell of the mankind or animal subjects；
Accommodating the pill dispenser of medicine, this pill dispenser has one or more nozzle and positive displacement component, and this positive displacement component is suitable for distributing medicine via one or more nozzles from shell by positive displacement；With
Penetration enhancer allotter, it is configured to when this device intravaginal being inserted in the mankind or animal subjects, hydrogen peroxide is produced in seclected time, destroy at least one region of the mucosal barriers being adjacent to shell, wherein penetration enhancer allotter includes one or more electrochemical element being configured to produce hydrogen peroxide in vivo
The most operable described device is to distribute medicine to by the mucosal barriers region of hydrogen peroxide destroying from shell.
4. medical treatment device, including:
It is configured to intracavity and inserts the shell of the mankind or animal subjects；With
Penetration enhancer-distribution portion, it is configured to when being inserted in the mankind or animal subjects by this device intracavity, hydrogen peroxide is produced in seclected time, destroying at least one region of the mucosal barriers being adjacent to shell, wherein penetration enhancer-distribution portion includes one or more electrochemical element being configured to produce hydrogen peroxide in vivo.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110040477.9A CN102641548B (en) | 2011-02-18 | 2011-02-18 | Saturating mucosal drug conveyer device and method including chemical permeation reinforcing agent |
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| CN201110040477.9A CN102641548B (en) | 2011-02-18 | 2011-02-18 | Saturating mucosal drug conveyer device and method including chemical permeation reinforcing agent |
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| CN102641548B true CN102641548B (en) | 2016-08-03 |
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| US9005108B2 (en) * | 2012-09-27 | 2015-04-14 | Palo Alto Research Center Incorporated | Multiple reservoir drug delivery device and methods |
| EP3272333A1 (en) | 2016-07-22 | 2018-01-24 | Chemo Research, S.L. | Vaginal composition comprising a combination of estrogen and vitamin d |
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| NZ337318A (en) * | 1999-08-18 | 2002-07-26 | Interag | Dispensing apparatus for dispensing same or different materials for at least two reservoirs |
| WO2004022033A1 (en) * | 2002-09-04 | 2004-03-18 | Microchips, Inc. | Method and device for the controlled delivery of parathyroid hormone |
| US7998060B2 (en) * | 2004-04-19 | 2011-08-16 | The Invention Science Fund I, Llc | Lumen-traveling delivery device |
| US20110009692A1 (en) * | 2007-12-26 | 2011-01-13 | Yossi Gross | Nitric oxide generation to treat female sexual dysfunction |
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