CN102641548A - Device and method for delivering transmucosal drugs including chemical penetration enhancer - Google Patents
Device and method for delivering transmucosal drugs including chemical penetration enhancer Download PDFInfo
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- CN102641548A CN102641548A CN2011100404779A CN201110040477A CN102641548A CN 102641548 A CN102641548 A CN 102641548A CN 2011100404779 A CN2011100404779 A CN 2011100404779A CN 201110040477 A CN201110040477 A CN 201110040477A CN 102641548 A CN102641548 A CN 102641548A
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Abstract
The invention discloses a device and method for delivering transmucosal drugs including chemical penetration enhancer. The mucosal drug delivery device can comprise a shell, a drug distribution part and a permeability enhancer distribution part, wherein the shell is configured with a human or animal subject which is used for intralumenal deployment such as vagina deployment; the drug distribution part is used for containing at least one drug and is configured to distribute the drugs from the shell by virtue of a positive displacement process; and the permeability enhancer distribution part is configured to release or generate penetration enhancing substances in selected time to damage at least one region of a mucosa blocking layer between adjacent shells when the human or animal subject is subjected to the intralumenal deployment. The device can be operated to distribute the drugs to the mucosa blocking layer region damaged by the penetration enhancing substances from the shell.
Description
Technical field
Each embodiment disclosed herein relates to implantable medical device, relates more specifically to be used for passing through the apparatus and method that mucosa is carried medicine to the patient.
Background technology
Passing through mucosal drug conveying (transmucosal drug delivery) is an interesting field; Because possibly carry the general action medicine with high relative bioavailability through avoiding first pass metabolism effect (first-pass metabolism effect); Maybe be to the position localized delivery of therapeutic agent of being concerned about, and route of administration is convenient.Some possibility positions of passing through the mucosal drug conveying comprise oral cavity, nose, vagina and rectally approach.
Exist and manyly carry relevant challenge, particularly pass through mucosa and carry the macromole that comprises some aminoacid sequence with passing through mucosal drug.Be present in by the enzyme in the mucosal tissue secreted fluid and decompose some aminoacid.The type of the enzyme that is appeared by mucosal tissue changes according to the position of mucosal tissue.Be present in enzyme in the vaginal fluid and comprise nuclease (nuclease), lysozyme (lysozyme), esterase (esterase), G-Px (guaiacol peroxidase), aldolase (aldolase) and beta-glucuronidase (β-glucuronidase).In addition, aminopeptidase (aminopeptidase), beta-glucuronidase, phosphate (phosphatase), lactic acid dehydrogenase, esterase and 5 type phosphodiesterases combine with apical cell's layer along vaginal mucosa surface.The existence of these enzymes, particularly aminopeptidase is a factor that reduces vaginal albumen and peptide bioavailability of medicament.
Other mucosal tissue presents other enzyme that can decompose some drugs.For example, gastrointestinal tract appear 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-glucuronyl transferase, thiokinase, glutathione-S-transferase, glycine transferring enzyme, acetyltransferase and calechol-
O-transmethylase.These enzymes reduce albumen and the peptide bioavailability of medicament that is applied to this type of mucosal tissue.
In addition, most of mucosal tissues are constantly secreted heavy-gravity water fluid.This heavy-gravity liquid is carried the other challenge of proposition to passing through mucosal drug.At first, the intrusion of the interception of heavy-gravity liquid and the exotic that slows down allows its intrinsic enzymatic and other defense mechanism to decompose if having time thus and/or kills exotic.Secondly, along with it is discharged from tissue, heavy-gravity fluid liquid is cleaning and washing mucosal tissue surfaces constantly.Therefore, use conventional application technique possibly waste a large amount of medicines.
Under the situation that intravaginal drug is carried, can regard the film of vaginal mucosa as two successive barrier layers, aqueous barrier layer and mucosa film barrier layer.The mucosa internal layer is glycogenesis (glycogenated) and the stratified squamous epithelium of keratinization (nonkeratinized) not.The human vagina epithelium is made up of about 25 cellular layers, depends on Maturity and position.Similar with other stratified epithelium of great majority, the human vagina epithelium contains (tight junction) (TJ) system that combines closely, and it is positioned at uppermost cellular layer.These TJ separate territory, apical cell surface with territory, basal cell surface, and carry primary barrier layer is provided for the mucosa that passes through of water-soluble substances.These are present in all mucosas of health and are not only the topical that epithelium and TJ in the vagina have hindered medicine just.
Therefore, providing of needing improves the apparatus and method of passing through the mucosal drug transfer efficiency.
Summary of the invention
In one aspect, be provided for the intracavitary unit that mucosal drug is carried.Pass through the mucosal drug conveyer device and can comprise that configuration is used for the shell that intracavity is inserted the mankind or animal subjects; Medicine-distribution portion of holding at least a medicine, this medicine-distribution portion are configured to through positive displacement medicine distributed from shell; With permeability reinforcing agent-distribution portion, it is configured to discharge or produce the permeability enhancing substance, when inserting the mankind or animal subjects, destroys at least one zone on the mucosa barrier layer of adjacent shells in seclected time.Can operate said device is dispensed to medicine by the destructive mucosa barrier region of permeability enhancing substance from shell.
In yet another aspect, provide from inner chamber inside via the method for mucosal tissue conveying medicine.This method can comprise to be inserted delivery device in the inner chamber; Discharge or generation permeability enhancing substance from said device, make permeability enhancing substance contact mucosal tissue zone; With medicine is distributed the mucosal tissue zone that makes medicine be transported to contact through positive displacement method with the permeability enhancing substance from said device.
On the other hand, be provided for the intravaginal device that mucosal drug is carried.This device can comprise that configuration is used for the shell that the mankind or animal subjects are inserted in intravaginal; The pill dispenser that holds medicine, this pill dispenser have one or more nozzles and the positive displacement component that is suitable for medicine being distributed from shell via said one or more nozzles through positive displacement; With permeability reinforcing agent allotter, it is configured to discharge or produce the permeability enhancing substance, when the mankind or animal subjects are inserted in intravaginal, destroys at least one zone on the mucosa barrier layer of adjacent shells in seclected time.Can operate said device is dispensed to medicine by the destructive mucosa barrier region of permeability enhancing substance from shell.
Description of drawings
Fig. 1 is a profile, illustrates the placement of mucosal drug conveyer device in organizing inner chamber.
Fig. 2 is a profile, and the delivery device that illustrates from be placed on inner chamber is carried the permeability enhancing substance.
Fig. 3 is a profile, illustrates after carrying the permeability enhancing substance, and the delivery device from be placed on inner chamber is carried medicine.
Fig. 4 is a profile, illustrates to have the placement of mucosal drug conveyer device in inner chamber thoroughly that penetration enhancers produces ability.
Fig. 5 is an end-view, illustrates the mucosal drug conveyer device thoroughly of Fig. 4.
Fig. 6 is a profile, illustrates to produce after the penetration enhancers, from the device of Fig. 4, carries medicine.
Fig. 7 is a profile, illustrates the alternate embodiment of mucosal drug conveyer device.
Fig. 8 is a profile, illustrates from the mucosal drug conveyer device that passes through of Fig. 7 and carries medicine.
The specific embodiment
Be provided for intracavity and insert the mucosal drug conveyer device thoroughly of (intralumenal deployment).As in this use, term " intracavity " expression is placed in body cavity with mucosal tissue wall, passage, the pipeline etc.This term includes but not limited to (for example rectum) position in intravaginal, intrauterine and the gastrointestinal tract.Device is being carried at least potion usually or is more being kept during the multi-agent medicine in inserting or placing of intracavity.The device of inserting can reclaim from inner chamber as required, comprises for example carrying between the independent dosage, after carrying some dose drugs, perhaps after accomplishing a series of multiple dose treatments.Can insert this device is consumed up to the medicine payload.
In some embodiments, pass through the mucosal drug conveyer device and comprise that (i) is configured to allow to insert the shell of inner chamber and (ii) one or more storeroom that is used to hold medicine and permeability enhancing substance.In certain embodiments, medicine and permeability enhancing substance are contained in independently in the storeroom.Said mucosal drug conveyer device also can comprise and be used for medicine and permeability enhancing substance are distributed the distribution portion that gets into inner chamber or mucosal tissue wall.Said delivery device also can comprise and is used to control the integrated control module that medicine and/or permeability enhancing substance discharge or carry from said device.
In yet another aspect, be provided for the method that mucosal drug is carried.This method comprises places or inserts the interior intracavity in patient or the mankind or animal subjects with delivery device.Inner chamber can be for example vagina, cervix uteri, uterus or part gastrointestinal tract, for example rectum.
Delivery device is placed on after the inner chamber, and said delivery device can produce or discharge the permeability enhancing substance on one's own initiative on inner chamber or mucosa sidewall.Said delivery device then can be with medicament distribution to regional by the destructive mucosal tissue of permeability enhancing substance.The amount that the application of permeability enhancing substance can advantageously improve the medicine transfer rate and/or can pass the mucosa barrier layer without degraded improves the efficient of the transmucosal administration of medicine thus.
In some embodiments, permeability enhancing substance and medicine are contained in the independently storage storeroom in the device.For example, as illustrated among Fig. 1, mucosal drug conveyer device 10 can be provided, it has the shell 16 that comprises permeability reinforcing agent storeroom 18, drug storage chamber 20 and control module 34.Shell 16 can be configured to be placed in the inner chamber 12 with mucosal tissue 14.Shell 16 comprises permeability reinforcing agent allotter that is used for distributing the permeability enhancing substance that is contained in permeability reinforcing agent storeroom 18 and the pill dispenser that is used for distributing the medicine that is contained in drug storage chamber 20.
Permeability reinforcing agent allotter can comprise nozzle 26 and actuator (actuator) 22, and nozzle 26 is configured to axially to distribute permeability enhancing substance (promptly leaving the shell 16 terminal inner chambers 12 that get into) from shell 16 with actuator 22 jointly.Pill dispenser also can comprise nozzle 28 and actuator 24, and nozzle 28 is configured to axially distribute medicine from shell 16 with actuator 24 jointly.Though this instance illustrates axial distribution layout, this device also can be configured to radially to inject permeability enhancing substance and medicine (promptly leaving the sidewall of shell 16 towards the direction of mucosal tissue 14).For example, in alternate embodiment, nozzle 26 and 28 can be arranged on one or more sides of the shell of mucosal tissue 14.
In some embodiments, the permeability enhancing substance produces outside shell, and medicine is contained in the independently storage storeroom in the device.For example, as illustrated among Fig. 4, the mucosal drug conveyer device can be provided, it has the shell 36 that comprises drug storage chamber 56, pump storage tank 58 and control module 50.The array of electrochemical element 38 is provided outside shell 36, is used for when shell 36 is inserted inner chamber 12, produce the permeability enhancing substance in one or more periods.As illustrated among Fig. 5, the array of electrochemical element 38 can be around the longitudinal side wall setting of shell 36.Perhaps, can the electrochemical element array be provided within shell 36, be used within shell 36, producing the permeability enhancing substance.Each electrochemical element 38 can comprise first counter electrode 60 and second counter electrode 62.Below describe in more detail and use electrochemical element 38 to produce permeability enhancing substance (H
2O
2) mechanism.
The array of the distributing nozzle 40 that is communicated with drug storage chamber 56 fluids can be provided in the side of shell 36, be used for drug conveying is got into mucosal tissue 14.In other embodiments, one or more distributing nozzles can be set, with axial distribution medicine at the end of shell 36.In this embodiment, can one or more electrochemical elements be set in the end or the adjacent end of shell 36, be used near the drug conveying position, producing the permeability enhancing substance.
Can be in pump storage tank 58 or adjacent pump storage tank 58 internal gas-volume displacement pump is provided, distribute the medicine that holds in the drug storage chamber 56 to drive via positive displacement method.In one embodiment, pump can comprise water or the negative electrode 44 and anode 46 of aqueous solution in the contact pump storage tank 58.Passage 42 can be provided, to allow from the aqueous secretions admission passage 42 of mucosal tissue 14 and to contact negative electrode 44 and anode 46 in shell 36.In other embodiments, can omit the passage 42 that is communicated with the inner space fluid of inner chamber, and can on device, electrolyte be provided.For example, pump storage tank 58 can comprise the for example solion of sodium nitrite.Perhaps, pump storage tank 58 can hold deionized water, and can provide solid electrolyte to replace passage 42, makes the solid electrolyte contact towards the negative electrode 44 of passage 42 and the surface of anode 46.The mechanism of using negative electrode 44 and anode 46 in pump storage tank 58, to produce gas is described hereinafter in more detail.
Shell is configured to promote delivery device the inserting of intracavity in mucosa usually.In some embodiments, said device can be placed in the inner chamber through inserting inner chamber via outside body orifice (exterior body orifice).Therefore, in some embodiments, shell is by molding and be processed into certain size, said device is inserted and puts into via outside body orifice with permission, promptly inserts in the predetermined inner chamber.Particularly, shell can molding and is processed into certain size, is used for vagina, cervix uteri, uterus or rectum and inserts and place.The constituent material of inking device shell, size, shape and surface character and other characteristic; Make said device can insert in the mucosa inner chamber; Rest in the inner chamber safely at the device duration of work, and after device work or in the time need removing in addition, from inner chamber, reclaim usually.Apparatus structure is inserted with the minimum discomfort to the patient based on specific intracavity position and the mankind or animal anatomy factor.
Shell can comprise setting one or more storerooms in the enclosure, is used to hold medicine and/or permeability enhancing substance.This shell also can comprise and be used to distribute the allotter of medicine and/or permeability enhancing substance and be used to control the release of medicine and/or permeability enhancing substance and the control module of conveying.Allotter can comprise and is used to the nozzle that distributes medicine and/or permeability enhancing substance therefrom to pass through.These nozzles can be set to axial (promptly leaving the end of shell) with respect to shell, with respect to shell radially (promptly leave the sidewall of shell), or inject medicine and/or permeability enhancing substance with its combination.Medicine and permeability enhancing substance can be contained in independently in the shell.Independently storage can advantageously promote the simplification of compounding pharmaceutical, because the difficulty that some common-formulation possibly exist the compatibility and/or solvent to select.
Shell can be formed by any biocompatible materials.In addition, sheathing material can tolerate the Degradation in the inner chamber environment.The instance of suitable material comprises rustless steel, titanium and some polymer.The material that forms shell can comprise coating, to improve the biocompatibility and/or the operation of device.
Be provided for through positive displacement the medicine pill dispenser that active distributes from delivery device.Medicine can be stored in the storeroom of said device, and distributes in entering inner chamber or the mucosal tissue via one or more nozzles in seclected time.This pill dispenser can be set so that medicine is dispensed to by the destructive mucosa barrier region of permeability enhancing substance from shell.
Pill dispenser can use various positive displacement components to be used for distributing medicine from said device, and said positive displacement comprises mechanical displacement, the displacement of infiltration swelling, gas-volume displacement, static-induction extruding, Piezoelectric Driving or heat/magnetic induction phase transformation.Actively displacement component can comprise and the bonded distribution valve that drives of hydrostatic head.As in this use, term " actively displacement " general reference is distributed any method of medicine from delivery device under the power that is provided by delivery device inside.Therefore, medicine passive chemical diffusion from said device do not represented in this term.
In some embodiments, in the medicament storage storeroom in the enclosure, and the mechanical displacement element through piston for example or spring leaf, initiatively distribute from shell via one or more distributing nozzles.For example, in the embodiment of Fig. 1, integrated control module 34 can be delivered to actuator 22 selectively with electricity or mechanical energy, advances the piston of actuator 22 to pass drug storage chamber 20 and distribute medicine via distributing nozzle 28.
In some embodiments, distribute medicine through gas-volume displacement.For example, as illustrated among Fig. 4, said device can comprise the pump storage tank 58 of moisture or aqueous solution.Pair of electrodes (negative electrode 44 and anode 46) can be provided in pump storage tank 58, be used to produce gas, for example oxygen.Passage 42 can be provided, to allow from the water in water in the inner chamber 12 and the pump storage tank 58 or aqueous solution exchange proton and electronics between electrode.In other embodiments, can omit the passage 42 that is communicated with the inner space fluid of inner chamber, and can on device, electrolyte be provided.For example, pump storage tank 58 can comprise the for example solion of sodium nitrite.Perhaps, pump storage tank 58 can hold deionized water, and can provide solid electrolyte to replace passage 42, makes the solid electrolyte contact towards the negative electrode 44 of passage 42 and the surface of anode 46.
Can apply about 1.0 V or bigger electromotive force to electrode, to produce O at anode
2The reaction at anode place is described by formula 1.In water, reduction reaction takes place at electronegative negative electrode place, be endowed hydrogen cation from the electronics of negative electrode, form hydrogen, shown in formula 2.Cause by oxygen that produces and hydrogen applied pressure that piston 48 advances and get in the drug storage chamber 56, cause that thus medicine distributes in entering inner chambers 12 or the mucosal tissue 14 via distributing nozzle 40.Can control the generation of oxygen and hydrogen by the integrated control module 50 that the last load (on-board) of device in the shell 36 provides.Control module 50 can comprise power supply 54, and for example battery and controller 52, this controller 52 are programmed to negative electrode 44 and anode 46 electromotive force is provided in seclected time:
2H
2O (
l) → O
2(
g)+4H
+(
Aq)+4e
-Formula 1
2H
+(
Aq)+2e
-→ H
2(
g) formula 2.
Can understand other positive displacement component better with reference to figure 7 and 8.In these instances, the medicine that holds in the expansion distribution drug storage chamber 56 through parts 64.Parts 64 can be for example swellable material (for example swellable gel) or expansible storeroom.In some embodiments, distribute medicine through the displacement of infiltration swelling.Randomly, valve 66 can be provided, get into storeroom or swellable material to control water selectively.Water from inner chamber 12 can be introduced into storeroom or swellable material, causes storeroom or swellable material volumetric expansion.The volume of the medicine that the expansion of storeroom or swellable material is held in can the displacement shell causes that medicine distributes from device to get into inner chamber.Can be through the driving of integrated control module 50 by-pass valve controls 66.
In other embodiments, can distribute medicine through the expansive force that provides by the induction phase transformation.For example, but parts 64 can comprise the inflatable storage tank that holds phase-change material.But phase-change material can be for when being heated or stand electromagnetic field, with any liquid or solid of experience from solid or the phase transformation of liquid to gas.When material was converted into gas, this material expanded and advances and pass drug storage chamber 56, and medicine is distributed from device.Can be through the driving of load control module 50 control phase transformations.
In other embodiments, can or use piezo-activator through the electrostatic induction extruding, from positive displacement of shell and distribution medicine.For example, dielectric elastic actuator or piezo-activator can be installed, make voltage or the variation in the electric current of delivering to actuator cause that actuator applies extruding force to the medicine in the drug storage chamber.This extruding force can cause that medicine distributes from device.Can be through the driving of load control module control actuator.
In other embodiments, can use hydrostatic head and actuatable valve door to realize the positive displacement of medicine.Valve can be for example with analog form work; Be used for which amplitude modulation dosed administration (amplitude-modulated dosing); Perhaps it can be used for frequency/duty cycle modulation dosed administration (frequency/duty-cycle modulated dosing) with digital form work.Can through under pressure with in the medicine device for loading static pressure head being provided, will install supercharging after perhaps can be in the medicine device for loading.
Various medicines can be by the delivery device administration.Medicine can be albumen or peptide.For example; In some embodiments; Said delivery device can be used for administration hormone or steroid, includes but not limited to follicle stimulating hormone, parathyroid hormone, metakentrin, gonadotropin releasing hormone (GnRH), estradiol, Progesterone, melatonin, serotonin, thyroxine, 3, epinephrine, noradrenaline, dopamine, Miu 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 somatomedin, 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 can be used for CYTOKINES signaling molecule or the immunomodulator that the administration cell communicating uses.These molecules generally include protein, peptide or glycoprotein.The CYTOKINES signaling molecule comprises for example four family's alpha-helix bundles, comprises IL-2 subtribe (for example erythropoietin (EPO) and thrombopoietin (THPO)), interferon (IFN) subtribe and IL-10 subtribe.The CYTOKINES signaling molecule also comprises IL-1, IL-18 and IL-17 family.
In some embodiments; Delivery device can be used for administration pain therapy medicament, includes but not limited to corticosteroid, opioid, antidepressant, anticonvulsant (spasmolytic medicine), non-steroidal anti-inflammatory medicine, COX2 inhibitor (for example rofecoxib (rofecoxib) and celecoxib (celecoxib)), tricyclics (for example amitriptyline), carbamazepine, gabapentin (gabapentin) and lyrica (pregabalin), codeine, oxycodone, hydrocodone, heroin and Pethidine.
In some embodiments, delivery device can be used for the administration cardiovascular drugs.Can comprise 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 with the instance of the cardiovascular drugs of said device administration.Can also be comprised for example arrhythmia reagent by the cardiovascular drugs of said device administration, for example I type (sodium channel blockers) comprises quinidine, lignocaine, phenytoin, Propafenone; II type (Beta receptor blockers) comprises metoprolol; III type (potassium channel blocker) comprises atlansil, dofetilide (dofetilide), Su Teluo; IV type (chronic calcium channel blocker) comprises diltiazem, verapamil; V-type (cardiac glycoside) comprises adenosine and digoxin.Can comprise ACE inhibitor by other cardiovascular drugs of said device administration, for example captopril, enalapril, perindopril, ramipril; Angiotensin ii receptor antagonist, for example Candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan; Beta receptor blockers; And calcium channel blocker.
Medicine can be prepared with one or more pharmaceutical acceptable excipients as required, in said device, store and from said device release to promote medicine.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.
Can be provided for distributing the permeability reinforcing agent allotter of permeability enhancing substance from shell.The permeability enhancing substance can be stored in the said device, and perhaps it can be produced by this device.As in this use, when relating to permeability reinforcing agent or permeability enhancing substance, term " allotter " and " distribution portion " expression discharge, produce or discharge and produce the device part or the parts of permeability reinforcing agent or permeability enhancing substance.
In one embodiment, the permeability enhancing substance is stored in the storeroom, and then through diffusion or active method, for example actively displacement method is distributed from said device.Any of the instance of aforementioned positive displacement mechanism includes but not limited to mechanical displacement, infiltration swelling displacement, gas-volume displacement, electrostatic induction extruding, Piezoelectric Driving, heat/magnetic induction phase transformation or distributes valve also can be used for distributing the permeability enhancing substance from storeroom with bonded driving of hydrostatic head.
In some embodiments, the permeability enhancing substance by said device within the shell or outside produce.In certain embodiments, the permeability enhancing substance produces in vivo.For example, shell can comprise and is used to produce hydrogen peroxide (H
2O
2) and it distribute is got into the exterior portions orchestration of mucosal tissue.Can make water, electricity and oxygen produce hydrogen peroxide.Water can be provided in device, perhaps can obtain water by the environment from inner chamber.Can supply power by load power source.Through oxygen being dissolved in the fluid that holds in the said device, to said device air being provided through capturing perhaps, or generating the oxygen that can be provided for reacting through electrochemistry.
As illustrated among Fig. 4, the array of electrochemical element 38 can be provided in the outside of shell 36.Each electrochemical element 38 can comprise two groups of isolating electrodes and PEM.First counter electrode can be set, make anode stretch into the inner chamber 12 from shell 36.Can apply about 1.0 V or bigger electromotive force to this electrode, to produce O in the water that from inner chamber 12, exists at anode
2The reaction at anode place is described by formula 1.Second counter electrode can be set, and it can be adjacent with first counter electrode, makes negative electrode stretch into the inner chamber 12 from shell 36.Can apply the electromotive force of about 1.6 V to this electrode, to produce H at negative electrode to about 2.0 V
2O
2The reaction at negative electrode place is described by formula 3:
O
2+ 2H
+(
Aq)+2e
-→ H
2O
2(
Aq) formula 3.
Can be by the integrated control module 50 control H that load provides on said device in the shell 36
2O
2 Generation.Control module 50 can comprise power supply 54, and for example battery and controller 52, this controller 52 are programmed to activate in one or more seclected times electrochemical element 38.
Various permeability enhancing substances can be provided.Term " permeability enhancing substance " expression promotes to carry medicine to pass the material of mucosal tissue.This term comprises chemical intensifier, and when putting on mucosal tissue, it gives tissue to medicine and the higher permeability of enzyme inhibitor, prevents that medicine is by the mucosal tissue enzymatic degradation.Chemical intensifier comprises such as dimethyl sulfoxide (DMSO), hydrogen peroxide (H
2O
2), propylene glycol, oleic acid, hexadecanol, benzalkonium chloride, SDS, isopropyl myristate, Tween 80, dimethyl sulfoxide, dimethyl formamide, dimethyl acetylamide, sodium lauroyl sarcosine, sorbitan monolaurate, methyl sulfonyl methane, azone, terpenes, lecithin rely on this type of material of phospholipase C, triacylglycerol hydrolytic enzyme, acid phosphatase, phospholipase A2 and spissated saline solution (for example PBS and NaCl).
Enzyme inhibitor comprises reversible inhibitor and irreversible inhibitor.Reversible inhibitor comprises for example protease inhibitor and antiretroviral, for example Saquinavir (saquinavir), ritonavir (ritonavir), indinavir (indinavir), viracept see nelfinaivr (nelfinavir), VX-478 (amprenavir), Lopinavir (lopinavir), atazanavir (atazanavir), Fu Shanawei (fosamprenavir), tipranavir (tipranavir) and ground Rui Nawei (darunavir).Irreversible inhibitor comprises for example diisopropyl fluorophosphate (DFP) (DFP), alpha-difluoromethyl ornithine (DFMO), trypanosomicide thioketone (trypanothione) reductase, methotrexate, allopurinol and acyclovir.
Be provided for controlling the control module of permeability enhancing substance and drug conveying entering mucosal tissue.Can be in shell on delivery device load control module is provided.Control module can comprise power supply and controller.Power supply can be any machinery or electric energy, for example battery or fuel cell.Controller can be programmable, and perhaps it can be by programming in advance, to carry permeability enhancing substance and medicine according to preassigned process.
In some embodiments, control module may further include and one or morely is used to analyze around the said device or the pick off of inner chamber internal medium.For example, can use pick off to detect the existence of inner chamber Chinese medicine-digestive enzyme.In this embodiment, controller can further be configured to detection of drugs-digestive enzyme reduce or detect be used for other control environment condition of drug conveying after, distribute medicine.
In some embodiments, control module may further include be used for from separate, independently dispensing device receives the wireless receiver of wireless control signal.In certain embodiments, said device can be inserted in the inner chamber by patient or doctor, and subsequently, patient or doctor can use dispensing device to transmit control signal to the device of having placed and drive the release of permeability reinforcing agent and medicine.In addition, 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; The control module transceiver can send the data relevant with device work; For example remain the data of level and remaining battery power about dosage, dosed administration process, storeroom Chinese medicine or the infiltration enhancing substance of administration, and the data relevant with the inner chamber environment, for example detect or data measured by integrated sensor.What in some embodiments, control module also can be for wireless power.
In various embodiments, said device can be configured to be used for radio operation, for example in inserting the mankind or animal subjects after.In this case, said device comprises suitable remote measurement parts as known in the art.For example, the driving of the distribution of infiltration enhancing substance and/or generation and/or medicament distribution can be accomplished by the for example mankind or the external remote-operated controller of animal subjects.Usually, use first coil, realize remote measurement (promptly send and receive) electromagnetic energy and coupling/corresponding second coil-induced coupling.The means of realization this point are set up for a long time, comprise various modulation schemes, for example are used to send amplitude or the frequency modulation(PFM) about the data of carrier frequency.The selection of carrier frequency and modulation scheme will be depended on the position and the required bandwidth of device, together with other factors.Also can use other data telemetry system as known in the art.Under another kind of situation, device is configured to remote power-feeding or charging.For example; Said device can comprise the transducer that is used to receive the energy that is wirelessly transmitted to device, if be used for the energy guiding that receives or circuit that transforms into the form that can be used or store and storage; Storage device, for example rechargeable battery or capacitor.Under another kind of situation, said device is wireless power and controlled in wireless simultaneously.
Provide and use intracavitary unit to be used for the method that mucosal drug is carried.This method comprises delivery device is placed in patient's inner chamber.The patient can be human or other mammal (for example cow, horse, pig or Canis familiaris L.).Said method comprises various medical treatment and veterinary's therapy, and zootechnical use.Inner chamber can be for example vagina, cervix uteri, uterus, bladder or rectum.Said device can be suitable for any basically mucosal tissue surfaces of contact.Said device can be placed in the inner chamber through this device is inserted inner chamber via patient's outer aperture.In some embodiments, said device can be the form that can be taken orally, and is used for carrying medicine through gastrointestinal tract mucous tissue.
Delivery device is placed on after the mucosa inner chamber, and delivery device can produce or discharge the permeability enhancing substance on one's own initiative on inner chamber or mucosa sidewall.The generation of permeability enhancing substance or release can be driven in seclected time by integrated control module.Delivery device then can be with medicament distribution to regional by the destructive mucosal tissue of permeability enhancing substance.The method of this administration and the degraded that can advantageously reduce or avoid medicine, particularly protein drug in proper order, otherwise under the situation of not permeating potentiation, it possibly degraded at the mucomembranous surface place.Medicine also can be driven in another seclected time by control module after the permeability enhancing substance has discharged or destroyed mucosal tissue from the release of said device.
As illustrated among Fig. 1, pass through mucosal drug conveyer device 10 and can be placed in the inner chamber 12.Delivery device 10 can be through the friction engagement fix in position between mucosal tissue 14 and the shell 16.As illustrated among Fig. 2, the permeability enhancing substance can distribute from storeroom 18 via nozzle 26 through the driving of actuator 22 then.Can be through the driving of control module 34 control actuators 22.As illustrated among Fig. 3,, destroyed after the mucosal tissue through hindering enzymatic activity or giving mucosal tissue 14 pairs of higher permeabilitys of medicine at penetration enhancers, medicine distributes from storeroom 20 via nozzle 28 through the driving of actuator 24.Also can be through the driving of control module 34 control actuators 24.Said device can shift out from inner chamber then.
With reference to figure 4, to permeate therein in the embodiment of enhancing substance by said device generation, control module 50 can at first drive the array of electrochemical element 38, produces the infiltration enhancing substance.Produce after the infiltration enhancing substance, control module 50 can be through applying the conveying that electromotive force comes drives medication to negative electrode 44 and anode 46.As illustrated among Fig. 6, when producing gas in the pump storage tank 58, piston 48 advances and passes drug storage chamber 56, causes that medicament distribution passes nozzle 40.Said device can shift out from inner chamber then.
With reference to figure 7, use therein in the embodiment of swellable material or expansible storeroom, penetration enhancers is at first produced by said device or distributes.For example, control module 50 can apply electromotive force to each electrochemical element 38, to produce the infiltration enhancing substance.Can drive valve 66 then, get in swellable material or the inflatable storage tank 64 to allow water.Perhaps, control module 50 can drive the phase transformation of inducing the material in the inflatable storage tank 64.For example, control module 50 can drive heating element heater and come heating phase-change material, perhaps can generate an electromagnetic field by drive circuit.As illustrated among Fig. 8, the expansion of swellable material or inflatable storage tank 64 promotes medicine and leaves nozzle 40 and get into mucosal tissue 14.
Said delivery device and method can be used for various medical treatment and use with treatment.In some embodiments, said delivery device can be used to treat the infertility of female subject.For example, can said delivery device be placed in the vagina (or uterus, or other part of birth canal) of female subject.Said delivery device can distribute and/or produce the permeability enhancing substance then in inner chamber.Thereafter, said delivery device can be carried follicle stimulating hormone, to promote the female subject ovulation.In some embodiments; Said delivery device can be configured to suitable order, in due course between and with the treatment infertility appropriate amount; Carry multiple hormone individually or in combination, comprise follicle stimulating hormone, metakentrin, gonadotropin releasing hormone.Said device also can distribute estradiol, produces with the natural hormone of regulating female subject.Can confirm suitable dosed administration process and amount by reproduction field of pharmacology technical staff.
In another embodiment, said delivery device can be used to treat experimenter's insulin dependent diabetes mellitus (IDDM) (type i diabetes).Said delivery device can be placed in experimenter's inner chamber.Said delivery device can distribute and/or produce the permeability enhancing substance then in inner chamber.Thereafter, said delivery device can be carried insulin (Humulin R, Novolin R), isophane insulin (Humulin N, Novolin N), insulin lispro (Humalog), insulin aspart (NovoLog), Ge Luxin insulin (Lantus) or insulin detemir (Levemir) to the patient in one or more seclected times.
In another embodiment, said delivery device can be used to treat experimenter's diabetes (type ii diabetes).Said delivery device can be placed in experimenter's inner chamber.Said delivery device can distribute and/or produce the permeability enhancing substance then in inner chamber.Thereafter, said delivery device can be carried Exenatide (exenatide) to the patient in one or more seclected times.
In another embodiment, said delivery device can be used to treat experimenter's breast or ovarian cancer.Said delivery device can be placed in experimenter's inner chamber, for example in the vagina of female subject.Said delivery device can distribute and/or produce the permeability enhancing substance then in inner chamber.Thereafter, said delivery device can be carried formulation for paclitaxel (abraxane) (or other is to the medicine of treating or the control cancer has curative effect) to the patient in one or more seclected times.
In another embodiment, said delivery device can be used to treat experimenter's HIV/AIDS.Said delivery device can be placed in experimenter's inner chamber.Said delivery device can distribute and/or produce the permeability enhancing substance then in inner chamber.Thereafter, said delivery device can carry Abacavir (Abacavir) (ABC) or GS-504 (Cidofovir) (or other is to treatment or medicine with curative effect of control HIV/AIDS) to the patient in one or more seclected times.Said device also can be used to treat other sexually transmitted disease (STD).
In another embodiment, said delivery device can be used to treat experimenter's genital herpes.Said delivery device can be placed in experimenter's inner chamber, for example in the vagina of female subject.Said delivery device can distribute and/or produce the permeability enhancing substance then in inner chamber.Thereafter, delivery device can be carried acyclovir (acyclovir), famciclovir (famciclovir) or valaciclovir (valacyclovir) (or other is to the medicine of treating or the control genital herpes has curative effect) to the patient in one or more seclected times.
In another embodiment, said delivery device can be used to treat experimenter's diabetes insipidus.Said delivery device can be placed in experimenter's inner chamber.Said delivery device can distribute and/or produce the permeability enhancing substance then in inner chamber.Thereafter, said delivery device can be carried Desmopressin (desmopressin) (or other is to the medicine of treating or the control diabetes insipidus has curative effect) to the patient in one or more seclected times.
In another embodiment, said delivery device can be used to treat experimenter's osteoporosis.Said delivery device can be placed in experimenter's inner chamber, for example in the vagina of female subject.Said delivery device can distribute and/or produce the permeability enhancing substance then in inner chamber.Thereafter, said delivery device can be carried her this phosphate (ibandronate), calcitonin or parathyroid hormone (or other medicine that treatment or control osteoporosis are had curative effect) to the patient in one or more seclected times.
Thus, at this following embodiment is disclosed.
Scheme 1. is used for the intracavitary unit that mucosal drug is carried, and comprising:
Configuration is used for the shell that intracavity is inserted the mankind or animal subjects;
Medicine-distribution portion of holding at least a medicine, this medicine-distribution portion are configured to distribute medicine through positive displacement from shell; With
Permeability reinforcing agent-distribution portion, it is configured to when intracavity is inserted in the mankind or the animal subjects, and discharge or produce at least one zone that the permeability enhancing substance destroys the mucosa barrier layer that is adjacent to shell in seclected time,
Wherein can operate said device so that medicine is dispensed to by the destructive mucosa barrier region of permeability enhancing substance from shell.
The device of scheme 2. schemes 1, wherein this device is configured to produce in vivo the infiltration enhancing substance.
The device of scheme 3. schemes 1, wherein infiltration enhancing-distribution portion comprises electrochemical element.
The device of scheme 4. schemes 1 wherein permeates enhancing substance and comprises hydrogen peroxide.
The device of scheme 5. schemes 1, wherein shell is arranged to intravaginal and inserts.
The device of scheme 6. schemes 1, wherein the permeability enhancing substance is stored in first storeroom, and medicament storage is in second storeroom that separates with the permeability enhancing substance.
The device of scheme 7. schemes 1, wherein medicine comprises albumen or peptide.
The device of scheme 8. schemes 1, wherein medicine comprises hormone or steroid.
The device of scheme 9. schemes 1 further comprises when inserting this device in the inner chamber, is suitable for from the receptor of dispensing device received energy or control signal.
The device of scheme 10. schemes 1 further comprises the controller that is configured to operation in tandem medicine-distribution portion and permeability-reinforcing agent distribution portion.
The device of scheme 11. schemes 1; Wherein medicament distribution partly comprises and is used for positive displacement component that medicine is initiatively distributed from shell, and this positive displacement component is selected from mechanical displacement element, infiltration swelling displacement component, gas-volume displacement element, magnetic induction phase-change element, thermoinduction phase-change element, piezo-activator, electrostatic induction extrusion element, has the driven distribution valve and the combination thereof of hydrostatic head.
The device of scheme 12. schemes 1; Wherein the permeability enhancing substance comprises 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, dimethyl formamide, dimethyl acetylamide, sodium lauroyl sarcosine, sorbitan monolaurate, methyl sulfonyl methane, azone, terpenes, lecithin dependence phospholipase C, triacylglycerol hydrolytic enzyme, acid phosphatase, phospholipase A2, spissated saline solution and combination thereof.
The device of scheme 13. schemes 1; Wherein the permeability enhancing substance comprises 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 combination thereof.
The device of scheme 14. schemes 1; Wherein permeability reinforcing agent-distribution portion comprises and is used for positive displacement component that medicine is initiatively distributed from shell, and this positive displacement component is selected from mechanical displacement element, infiltration swelling displacement component, gas-volume displacement element, magnetic induction phase-change element, thermoinduction phase-change element, piezo-activator, electrostatic induction extrusion element, has the driven distribution valve and the combination thereof of hydrostatic head.
Scheme 15. is used for comprising to the mankind or the local method of passing through mucosa conveying medicine of animal subjects:
Go into the medicine conveyer device in that the mucosal tissue inner chamber is mid-;
Produce the permeability enhancing substance from said device release or with this device, make that permeability enhancing substance contact mucosal tissue is regional; With
Distribute medicine through positive displacement method from said delivery device, the mucosal tissue that makes medicine be transported to contact with the permeability enhancing substance is regional.
The method of scheme 16. schemes 15, wherein said delivery device are inserted vagina, uterus or the internal rectum of the mankind or animal subjects.
The method of scheme 17. schemes 15, wherein medicine comprises albumen or peptide.
The method of scheme 18. schemes 15, wherein actively displacement method comprise mechanical displacement, the displacement of infiltration swelling, gas-volume displacement, magnetic induction phase transformation, thermoinduction phase transformation, Piezoelectric Driving, electrostatic induction extruding, via driving hydrostatic head displacement or its combination that distributes valve.
The method of scheme 19. schemes 15 is wherein permeated enhancing substance and is comprised hydrogen peroxide.
The method of scheme 20. schemes 15; Wherein the permeability enhancing substance comprises 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, dimethyl formamide, dimethyl acetylamide, sodium lauroyl sarcosine, sorbitan monolaurate, methyl sulfonyl methane, azone, terpenes, lecithin dependence phospholipase C, triacylglycerol hydrolytic enzyme, acid phosphatase, phospholipase A2, spissated saline solution and combination thereof.
The method of scheme 21. schemes 15; Wherein the permeability enhancing substance comprises 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 combination thereof.
Configuration is used for the shell that the mankind or animal subjects are inserted in intravaginal;
The pill dispenser that holds medicine, this pill dispenser have one or more nozzles and positive displacement component, and this positive displacement component is suitable for distributing medicine via one or more nozzles from shell through positive displacement; With
Permeability reinforcing agent allotter, it is configured to when intravaginal is inserted in the mankind or the animal subjects, discharges or generation permeability enhancing substance in seclected time, destroys at least one zone on the mucosa barrier layer that is adjacent to shell,
Wherein can operate said device so that medicine is dispensed to by the destructive mucosa barrier region of permeability enhancing substance from shell.
The device of scheme 23. schemes 22, wherein the penetration enhancers allotter comprises one or more electrochemical elements that are configured to produce in vivo hydrogen peroxide.
The device of scheme 24. schemes 22 further comprises the controller that is configured to control positive displacement component and permeability reinforcing agent dispenser drive.
The device of scheme 25. schemes 22, wherein actively displacement component is selected from mechanical displacement element, infiltration swelling displacement component, gas-volume displacement element, magnetic induction phase-change element, thermoinduction phase-change element and combination thereof.
The device of scheme 26. schemes 21, wherein medicine comprises albumen or peptide.
Scheme 27. medical treatment devices comprise:
Configuration is used for the shell that intracavity is inserted the mankind or animal subjects; With
Permeability reinforcing agent-distribution portion, it is configured to when intracavity is inserted in the mankind or the animal subjects, discharges or the generation hydrogen peroxide in seclected time, destroys at least one zone on the mucosa barrier layer that is adjacent to shell.
Claims (4)
1. be used for the intracavitary unit that mucosal drug is carried, comprise:
Configuration is used for the shell that intracavity is inserted the mankind or animal subjects;
Medicine-distribution portion of holding at least a medicine, this medicine-distribution portion are configured to distribute medicine through positive displacement from shell; With
Permeability reinforcing agent-distribution portion, it is configured to when intracavity is inserted in the mankind or the animal subjects, discharges or generation permeability enhancing substance in seclected time, destroys at least one zone on the mucosa barrier layer that is adjacent to shell,
Wherein can operate said device so that medicine is dispensed to by the destructive mucosa barrier region of permeability enhancing substance from shell.
2. the device of claim 1, wherein shell is arranged to intravaginal and inserts.
3. be used for the intravaginal device that mucosal drug is carried, comprise:
Configuration is used for the shell that the mankind or animal subjects are inserted in intravaginal;
The pill dispenser that holds medicine, this pill dispenser have one or more nozzles and positive displacement component, and this positive displacement component is suitable for distributing medicine via one or more nozzles from shell through positive displacement; With
Permeability reinforcing agent allotter, it is configured to when intravaginal is inserted in the mankind or the animal subjects, discharges or generation permeability enhancing substance in seclected time, destroys at least one zone on the mucosa barrier layer that is adjacent to shell,
Wherein can operate said device so that medicine is dispensed to by the destructive mucosa barrier region of permeability enhancing substance from shell.
4. medical treatment device comprises:
Configuration is used for the shell that intracavity is inserted the mankind or animal subjects; With
Permeability reinforcing agent-distribution portion, it is configured to when intracavity is inserted in the mankind or the animal subjects, discharges or the generation hydrogen peroxide in seclected time, destroys at least one zone on the mucosa barrier layer that is adjacent to shell.
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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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| 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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| US20040082937A1 (en) * | 2002-09-04 | 2004-04-29 | Dennis Ausiello | Method and device for the controlled delivery of parathyroid hormone |
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| WO2009081411A2 (en) * | 2007-12-26 | 2009-07-02 | Rainbow Medical | Nitric oxide generation to treat female sexual dysfunction |
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| WO2001012101A1 (en) * | 1999-08-18 | 2001-02-22 | Interag | Multiple material dispensing |
| US20040082937A1 (en) * | 2002-09-04 | 2004-04-29 | Dennis Ausiello | Method and device for the controlled delivery of parathyroid hormone |
| US20070225634A1 (en) * | 2004-04-19 | 2007-09-27 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Lumen-traveling delivery device |
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| CN105769305A (en) * | 2012-09-27 | 2016-07-20 | 帕洛阿尔托研究中心公司 | Drug Delivery Device With Multiple Reservoirs |
| CN105769305B (en) * | 2012-09-27 | 2019-12-31 | 帕洛阿尔托研究中心公司 | Multi-container drug delivery device |
| EP3272333A1 (en) | 2016-07-22 | 2018-01-24 | Chemo Research, S.L. | Vaginal composition comprising a combination of estrogen and vitamin d |
| WO2018015503A1 (en) | 2016-07-22 | 2018-01-25 | Chemo Research S.L. | Vaginal composition comprising a combination of estrogen and vitamin d |
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| CN102641548B (en) | 2016-08-03 |
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