CN1899644B - Methods and apparatus for improved administration of pharmaceutically active compounds - Google Patents
Methods and apparatus for improved administration of pharmaceutically active compounds Download PDFInfo
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Abstract
Methods and apparatus for improving administration of drugs through the use of heat and other physical means. The present invention relates to the use of heat and other physical means (100) in conjunction with specially designed dermal drug delivery systems (120), conventional commercial dermal drug delivery systems, or drugs delivered into a sub-skin depot site via injection and other methods to alter, mainly increase, the drug release rate from the dermal drug delivery systems or the depot sites to accommodate certain clinical needs.
Description
The application divides an application for one Chinese patent application 99813750.2 (PCT/US99/22698's).
Background of invention
Prior art
The percutaneous dosing of pharmaceutically active compounds comprises that directly putting on skin to pharmaceutically-active preparation manages reactive compound, and the medicine of absorption is taken away by blood flow.This dose regimen is known already in medical practice, and in the administration of pharmaceutically active compounds, to continue be a kind of important technology.For example; The United States Patent (USP) 4286592 that on JIUYUE 1st, 1981 licensed to Chandrasekaran has provided a kind of binder and has been used for the percutaneous dosing to user; The drug storing layer that it comprises impermeable supporting layer, contain medicine and carrier with contact adhered layer, paste binder on the skin through adhered layer.
This percutaneous dosing is compared with other practical technique, like injection, oral tablet or capsule, number of important advantages is arranged.That these advantages comprise is non-invasive (risk that therefore infects is little), avoid for the first time through metabolism (first pass metabolism) (when medicine oral and during through gastrointestinal absorption medicine at the metabolism of liver), do not have peak and the low ebb of drug level in patient's blood flow.Particularly, concentration peak of not regulating and low ebb are typical in injection and oral administration, and often produce ungracious side effect and/or more unsatisfied expectation effect.
Term used herein " transdermal drug delivery system " or " DDDS " are defined as a kind of article or device, and it is sent to the pharmaceutically active compounds that contains through dermal osmosis in the skin of the person, other target site in subcutaneous local organization, body circulation or the human body.In this application, term " DDDS ", except as otherwise noted, what refer to only is that the main drive of those drug osmotics is systems of drug level gradient.
Term used herein " skin " is defined as skin and the mucosa that comprises that horny layer covers.
Term used herein " medicine " is defined as and comprises any pharmaceutically active compounds, includes but not limited to those treatment diseases, wound, undesirable symptom and improvement or the chemical compound of keeping fit.
Term used herein " target area " is defined as the systemic blood circulation that comprises human body, the human region that the systemic blood circulation can reach, include but not limited to, muscle, brain, liver, kidney, or the like and press close to the tissue zone of administration position.
In DDDS, medicine is generally comprised within the preparation, and is for example moisture-alcohol gel, and can be included in the speed limit film between preparation and the skin, makes the variation of drug osmotic minimum.When DDDS put on skin, medicine began from preparation, to transfer out, and passed speed limit film (if existence) and transmit.Then medicine gets into skin, intravasation and subcutaneous tissue, and the body circulation of being brought into health by blood.At least before some DDDS uses in the speed limit film skin side of (if existence) or a certain amount of pharmaceutically active compounds arranged on the skin side.In these DDDS, get into skin at that part of medicine of speed limit hymeniderm side and need not pass through the speed limit film.For a lot of medicines, the medicine of skin absorbs is stored in the skin greatly or subcutaneous tissue interior (hereinafter referred to as " stored position ") progresses into later body circulation (hereinafter referred to as " storage effect ") again.Store effect according to think be part at least with use some DDDS after body circulation Chinese medicine postpone to occur, and medicine continues to get into the body circulation relevant after skin removes some DDDS.
In recent years, non-invasive androgen drug-supplying system caused gradually that people paid close attention to.Transdermal delivery system is a type in the androgen replacement therapy that can be used as of those development.The main target of testoterone supplementation is to return to healthy man normal range to serum testosterone concentration, and, if possible, substitute to simulate endocrine normal physiological rhythm pattern.More particularly, hope that this treatment can simulate raising naturally of testosterone concentration and reach peak value in the morning, then be reduced in gradually and reach the lowest point evening.The man of hypogonadism uses androgen transdermal delivery system of the present invention can reach above target.Other androgenic treatment of the present invention is used and is included but not limited to the disease of treating hypopituitarism, osteoporosis, menoxenia, refractory anemia, promotion anabolism and influenced by adolescence.
Male's hypopituitarism is that testosterone produces the not normal phenomenon below the normal range that is reduced to 3～10mg/ day.The symptom of this disease comprises the degeneration of hypofunction such as libido, sexual function, energy, emotion and secondary sex characteristics and health is become thin and bone density reduces.Available androgen replacement article comprise the testosterone of the long-acting testosterone ester of intramuscular injection and oral alkylating and esterification.But neither one can transmit testosterone with the mode of concentration in the blood plasma that produces the spontaneous hormonal normal physiological rhythm of simulation in these treatments.Recently, several kinds of percutaneous testosterone systems have been developed.These systems had the serum testosterone concentration of standard in 24 hours, and the circadian rhythm pattern that some are proximate, Healthy Youth man occurs is on one's body arranged.Although it is useful having confirmed these systems, they are not to be free from side effects.For example, about 53% man local skin reaction (contact dermatitis) occurs in the use location after using Androderm_ (a kind of testosterone sheet), need interrupt using this in some cases.
Term used herein " androgen Transcutaneous Therapeutic System " or " ATTS " are defined as through dermal osmosis and are sent to the intravital article of people, device or method to androgen.Design ATTS is used for androgen to use treatment or other purposes.Term " ATTS " in this application, except as otherwise noted, the main drive that only is meant those drug osmotics is the system of drug level gradient.
Term used herein " androgen " is broadly defined as and comprises any pharmaceutically active compounds that can regulate male secondary sex characters; It includes but not limited to the testosterone ester, for example propionic ester, phenylacetate, heptanoate, cipionate, methyltestosterone, FL, protobolin, 17-Alpha-Methyl nortestosterone, norethandrolone, dihydrotestosterone, adroyd, stanozolol, ethylestrenol.
In addition; Androgen comprises the pharmacological component that promotes growth, and for example the growth of the growing up of the growth of minimizing, armpit hair and the chaeta of the propagation of the thickening of the development of the increase of height, skeletal muscle, skin, sebaceous gland, subcutaneous fat, larynx, beard and male's shape bald head is initial.Androgen also can usually be described as acting on the medicine of hypophysis, testis or sebaceous gland, or has the medicine that nitrogen keeps anabolic action.
After DDDS is put on the skin; The concentration of destination organization or blood Chinese medicine is beginning gradually to raise and is reaching the concentration of required medical effect or be called " therapeutic dose " (arrive required time of therapeutic dose hereinafter referred to as " zero-time ") before, usually zero or near zero maintenance a period of time.Under the ideal situation, the concentration of destination organization or blood Chinese medicine should have a platform (promptly arriving a basicly stable state) on the concentration a little more than therapeutic dose, and keeps segment length's time at this platform.For given people or given DDDS, the relation of " concentration of destination organization or blood flow Chinese medicine and time " can not change under normal mode condition usually.
Typical case's DDDS Chinese medicine gets into the zero-time in physical target zone to be confirmed by following factor with medicine-feeding rate usually, comprising: the speed that medicine discharges from preparation, medicine pass the circulation of permeability that speed limit permeability of the membrane (if using speed limit film), medicine pass skin (particularly horny layer), medicine blood and other body fluid below the permeability of the storage of stored position and release, blood vessel wall, DDDS and in the surrounding tissue (comprising skin).Although these original factors that influence zero-time and medicine-feeding rate are known, none is designed in the process of drug administration, change the speed of administration existing DDDS.
Although DDDS effect aspect much is pretty good, medicine dermal delivery technology still has some serious deficiencies at present, comprising: 1) looking for a lot of situation zero-times does not conform to people's will ground; 2) in case DDDS is administered on the skin, and the speed that medicine gets into circulation of health body or target area is not easy to change, when reaching the stable state medicine-feeding rate, medicine-feeding rate is malleable not; 3) percutaneous permeability is too low makes a lot of medicines can not be used for transmitting eliminating from percutaneous because the dosage of medicine is not enough to reach therapeutic dose.In addition, the variations in temperature of skin and DDDS is according to thinking the skin absorbs that can change medicine.
It is known that elevated temperature can increase the percutaneous absorption of medicine.The United States Patent (USP) 4898592 that licenses to people such as Latzke February 6 nineteen ninety relates to a kind of equipment that is used to heat percutaneous absorbing activity material, and it comprises carrier and the support that contains percutaneous absorbing activity material.Support is that one or more layers polymeric layer stacks and processes, and selectively comprises heat-conduction component.These heat-conduction components are used to disperse the absorption of patient's body heat with the enhanced activity material.The United States Patent (USP) 4230105 that on October 28th, 1980 licensed to Harwood discloses a kind of binder that comprises medicine and pyrogen, preferably, mixes each other to strengthen the speed of medicine through the user skin absorbs.Separated drug layer and pyrogen layer are also disclosed.The United States Patent (USP) 4685911 that licensed to people such as Konno on August 11st, 1987 discloses a kind of heating element heater that comprises the pieces of skin and the selective usefulness of ingredient, is used for when body temp is not enough to melt the preparation of drug, melting it.
The field of another kind of administration comprises and is sent to controlled release/slow release form/preparation (" form/preparation ") in the skin or in the subcutaneous tissue (storage of these form/preparations hereinafter referred to as " stored position "), makes medicine discharge from the mode of stored position with controlled release/slow release.The modal technology that is administered into stored position to form/preparation is injection.Also can use other technology, for example implant form/preparation/force in the skin with hitting at a high speed.But, in case be administered into stored position to form/preparation, change medicine usually and from form/preparation, discharge and the speed that gets into health body circulation or target area is difficult at stored position, this speed is called " rate of release ".
Another administration field comprises subcutaneous or intramuscular injection.Under some clinical setting, after such injection, the acceleration drug absorption is advanced the circulation of body endosome or other target area is useful.
Though known elevated temperature can increase the percutaneous absorption of medicine, provide effectively, convenient and in check heating is difficult to improve percutaneous dosing.And, in some application or therapeutic treatment, in the administration process of transdermal drug delivery system; Use individual heating elements to increase the percutaneous absorption of medicine, in percutaneous dosing, have a lot of complicated factors, for example the serviceability temperature control element; Just need patient or care-giver to take extra step serviceability temperature control element; As obtain, store and prepare independently temperature control component, and adding and take off independently temperature control component, this makes that the administration of healing potion is complicated.
And along with the complicated increase of healing potion administration, the probability that patient or care-giver obey the use of doctor's advice temperature control component is tending towards reducing, and just possibly reduce the effectiveness of doctor's advice treatment.If doctor's advice is used the DDDS except the needs patient, need also that the patient buys, stores, preparation, medication and then take off independently heating element heater, the patient is owing to spent extra time and then feel inconvenient and select to abandon the temperature control component that doctor's advice is used.And use temperature control component independently to receive given temperature control component and want compatible restriction between the DDDS of serviceability temperature control element.When temperature control component independently is not when using DDDS specially to design, the shape of DDDS, preparation and structure possibly hinder effective use of independent temperature control element.
Yet, often be problematic and unsuccessful through attempting independently temperature control component and DDDS combination (not having careful design to consider) to solve the difficulty that is applied to the independent temperature control element on the DDDS simply.For example, through pharmaceutical preparation oxygen exposure or utilize other mechanism make himself the heating, can attempt to combine temperature control component and DDDS.But,, must make heating mechanism compatible fully each other with pharmaceutical preparation in order to accomplish this point.When using the exothermic oxidation reaction adstante febre; Mix with hydrogel based local anesthesia preparation if comprise the heating medium of iron powder, active carbon and water, it just can not suitably generate heat, because; Except other reason, the gel in the local anesthesia preparation will stop oxygen to get into the heating medium.
Other initial direct method that occurs has simply and is attached to heating plate on the tablet, and puts integrated sheet in the airtight container into.Albert Argaud has used the method in United States Patent (USP) 4963360.The patent of Argaud has provided the use of substrate, is the gelatin that keeps medicine in a side of substrate, and opposite side is designed to the composition of generation exothermic reaction when in air, exposing.Owing to do not have heat regulation mechanism in the patent of Argaud, absorb entering skin so can not control ingredient.Because overdose or dose are not enough, uncontrollable absorption can cause serious reaction in the patient.The side effect of these appearance has surpassed the interests that exothermic reaction produces.Except can not regulating the heating, other problem for example lacks any heat insulationly or any the design of conduction of heat in the health, also reduces the effectiveness and the concordance of exothermic reaction among the DDDS.
Because early stage doser is not provided for sealing the mechanism of the medicine layer of a relative side with skin, in case therefore gel is exposed to the rapid evaporation that just can produce ingredient in the air.And, firmly be not attached to the mechanism on the skin to sheet, also just can not guarantee suitable absorption.Can find that the contact area between medicine layer is limited during the sample that proposes referring to the patent of Argaud, and the contact area changes easily, this influences the absorbtivity of medicine.Another problem of Argaud sheet comes from the packing of this device, and the air in the packing can both contact with the heating medium with pharmaceutical preparation.This problem makes heating medium and pharmaceutical preparation in storage, produce mass exchange or transmission, and this causes that inefficacy or the two in pharmaceutical preparation and the medium that generates heat all lost efficacy.For example; If iron powder, active carbon, salt, wood flour and water that the heating medium has proper proportion; And pharmaceutical preparation is the form of hydrogel, and the heating medium will absorb water vapour from pharmaceutical preparation, thereby has changed the ratio of desirable water in heating medium and the pharmaceutical preparation simultaneously.This problem that is applied to the medicine generation of fentanyl and so on when it will be below than explaining in more detail.
Through following heated oxide sheet and the bonded instance of fentanyl DDDS, the difficulty that explanation is combined temperature control unit and DDDS.Through the heating element heater that has at the heating medium of the preceding paragraph described in falling, be attached on the medicine sheet of preparation with spirituosity and water, can attempt obtaining integrated, and be sealed in this integrated in the airtight container.Although airtight container separates integrated with external environment; Although and between heating element heater and pharmaceutical preparation, can place Obstruct membrane; Ethanol in the pharmaceutical preparation and water still can be moved in the space of airtight container with the form of steam, and are absorbed by the heating medium.Active carbon in the heating medium has the ability of strong absorption volatile substance.Therefore after a period of time, pharmaceutical preparation will be lost the ethanol and the water of significant amounts.
Ethanol and water play important effect in the percutaneous transmission of some drugs.At least one function of ethanol is to increase percutaneous permeability in the preparation, thereby can absorb the medicine of requirement.Water and ethanol also play the solvent of the medicine in the preparation; If temperature control equipment and the DDDS as above said that kind of a paragraph combine; Then will lose the ethanol and the water of significant amounts at lay up period; Can not resemble designed increase the permeability of skin, cause lower medicine skin absorbs.In addition, dissolubility and the concentration of medicine in preparation will change, and this will change the driving force of percutaneous penetration of drugs.As a result, from having than big difference, and can not predict very much through the drug absorption of skin graft and the speed of design.This will cause serious drug dose not enough or excessive.
And,, also will weaken the function of heater element if the heating medium has absorbed enough ethanol and water.In the heating medium that uses active carbon, active carbon has the tendency that from surrounding, absorbs moisture.If the water yield in the heating medium increases too much, the heating medium can not suitably generate heat.Therefore it is important will generating heat that medium and moisture separates.Protection heating medium makes it not to be exposed in the oxygen, also is no less important in case oxidation is reacted too early generation.
Therefore, even integrated is sealed up for safekeeping in airtight container, it also is very important in integrated, separating pharmaceutical preparation and heater element well.This separation not only should stop the material Transfer (i.e. infiltration) between pharmaceutical preparation and the heating element heater, and should prevent in the space of airtight container, to pass through the transmission or the exchange of steam.
The heater of heating human body skin has much in existing techniques.The heating element heater that uses in the heater has material impact for the combination property of design and heater.As the heating medium, the element that use can stand exothermic oxidation reaction has can be through the advantage of controlling the oxidation reaction component exposure in the oxygen around.For example, the heating hand warmer based on oxidation reaction can comprise the venting bags that contains the medium that generates heat.This mixture can comprise loose thin iron powder, active carbon, salt, water and alternative material such as wood powder, so that more porous is arranged in the medium.Hand warmer is stored in the airtight container usually.After it took out from container, the oxygen in the surrounding air flowed in the heating medium through venting bags, and the iron powder exothermic oxidation in the heating medium begins to produce heat.
In the device that is designed for warm hands or health, the common of heater do not made compactly, and the persistent period of heating-up temperature and heating is not designed to accurately controlled yet.GRABBER Wamers for example, Grand Rapid, the minimum temperature of MI49512 hand warmer and maximum temperature are respectively 40 ℃ and 69 ℃, about 20 grams of weight.But in some cases, the size of heater and the ability of control temperature and the persistent period of heat are important.
The device that United States Patent (USP) 5658583 discloses based on the oxidation reaction heating is used to strengthen the transdermal drug transmission.The electro-heat equipment that provides in this patent is the end of being processed by gas impermeable material and wall chamber that surround, thin, flexible all around, and has a lid, and its structure can make during the oxygen in the surrounding air enters the room with suitable data rate stream.The heating medium that can generate heat when being exposed to air is arranged in the chamber of thin flexibility.The typical case of heating medium forms active carbon, iron powder, sodium chloride, thin wood flour and the water that comprises proper proportion.
In much relevant application with medical treatment, for example strengthen percutaneous dosing and the controlled drug delivery system of regulating injection or implanting, heater must meet some standard of functionalization and practicability device.For example need device thin and compact usually.Persistent period of generating heat and temperature need accurately control and tool repeatability, so that the danger of the overdose or the amount of owing is reduced to minimum degree.In addition, hope can be placed heating medium as much as possible in the chamber usually, so that heater, even compact, can be in enough persistent period internal heat generations.And device needs aseptic and disposable use.The design of heating medium influences the potential application of heater.
The limitation of these designs can produce serious problem for some application, for example in the relevant application of a lot of medical treatment, and designs hour when the volume of chamber.
Therefore; Exploitation is used to improve the method and apparatus of the drug administration of DDDS; More particularly, make the use of DDDS more flexible, controlled and titratable (changing drug administration speed, quantity or cycle according to the biological agent of medicine) to adapt to various clinical needs better, have advantage.Exploitation makes the method and apparatus that can be used in percutaneous dosing because of the low medicine of still getting rid of at present outside percutaneous dosing of its dermal osmosis band also have advantage.Developing change with the mode that adapts to some clinical needs mainly is to increase the device of medicine from the absorption rate of stored position or injection point, also has advantage.
And exploitation improves the ATTS of androgen administration, to adapt to various clinical needs better and to be reduced to the method and apparatus of minimum level to side effect, also has advantage.For example, exploitation can have advantage to the drug-supplying system that skin temperature is elevated to the temperature desired scope.The temperature desired scope is to improve the androgen administration, but and not obvious increase because the overheated scope that causes the chance of skin injury.The scope that is elevated to doctor's advice to temperature equally also has advantage, and this can change in this scope or regulate as required.The controllability of temperature will make patient or care-giver control absorption rate preferably.And, in one in check period or in one required period, provide the temperature of rising also to have advantage.Exploitation makes patient or care-giver can freely select to want on the skin method and apparatus of the position of elevated temperature also to have advantage.
Provide a kind of handle convenience and wieldy integrated temperature control element and transdermal drug delivery combination of elements structure together also leading in the art; And this structure can prevent material Transfer unnecessary between temperature control component and the transdermal drug delivery system simultaneously; Isolate they and ambient oxygen and unnecessary solvent as required, and prevent from environment, unnecessarily to obtain or lose solvent.
Invention field
The present invention relates to the method and apparatus of administration, more particularly, the present invention relates to use controlled heat and other physical means to improve medicine percutaneous, mucosa and drug administration by injection.The invention still further relates to a kind of design and method of new manufacturing heater, said heater produces heat through oxidation reaction and carries out controlled heat.
The present invention's general introduction
The present invention relates to improve the distinct methods and the device of skin and mucosa delivery through controlled heating and other physical means.The invention still further relates to and use controlled heat and other physical means to change, mainly is to increase, and medicine is from the rate of release of stored position or injection position, to satisfy the method and apparatus of some clinical needs.
In DDDS uses; The absorption of medicine is confirmed by several factors usually, being comprised: diffusion coefficient, the medicine of drug molecule in pharmaceutical preparation passes the concentration, skin of dissolved substance in the infiltration coefficient, preparation of speed limit film (if in DDDS, using) permeability to capillary wall in the circulation of the permeability of medicine, medicine body fluid (comprising blood) in the storage of stored position and release, skin and/or in subcutaneous other tissue, the subcutaneous tissue.Like this, in order to handle the deficiency of present dermal drug medicine-feeding technology, just hope that control maybe can change these drug absorption factors.According to thinking very potential each the above-mentioned factor that influences of controlled heat/cooling.
Specifically, general elevated temperature can increase the permeability that diffusion coefficient and the medicine of medicine in preparation passes speed limit film and skin.Improve heating and also accelerate the flowing of blood and/or other body fluid in the tissue of DDDS below, this can take drug molecule in the body circulation to speed faster.In addition, elevated temperature also increases the permeability of capillary wall in the subcutaneous tissue.And elevated temperature can increase the dissolubility of most medicines in the preparation.Certainly, cooling also has opposite effect basically.Like this, the present invention uses controlled heat/cooling to influence each above-mentioned factor, absorbs to obtain controlled medicine percutaneous.
In order to deal with different clinical condition and the needs that satisfy different patients, the present invention also uses controlled heat/cooling with several kinds of novel modes, so that the dermal drug administration is more flexibly with more controlled.More broadly, the present invention provides novel being used for can begin, reduce, increase and stop heating like this to satisfy different needs at the method and apparatus of using DDDS process controlled heat/cooling (hereinafter referred to as " temperature control equipment ").
The effect that an alternative embodiment of the invention is based on medicine is confirmed to be used in the persistent period that DDDS goes up controlled heat, be used to obtain the extra drug of q.s and make not enough with administration and excessive relevant treatment inadequately and side effect be reduced to minimum degree.
According to concrete application and/or each patient's needs; The stopping of the zero hour through appropriate selection controlled heat, heating-up temperature, controlled heat can reach the control/operation of following absorption rate constantly: the 1) zero-time of shortening DDDS Chinese medicine under the situation of its stable state medicine-feeding rate of not obvious change; 2) during using DDDS, an amount of extra drug is provided in needs; 3) absorption rate of increase medicine in one period long duration of using DDDS or its whole persistent period.
At DDDS enough stable state medicine-feeding rates are provided, but under the slow excessively situation of zero-time, it is important shortening zero-time.Satisfy the baseline dosage of medicine in the administration of DDDS, but the patient needs extra medicine to be used under the situation of special time period in the special occasion of using DDDS, the extra drug that right quantity is provided is important.Increase drug absorption speed and be used for the patient that those need obtain high medicine-feeding rate from DDDS.
Above-mentioned first method can be through applying controlled heat in the zero-time of using DDDS; And design the heating and continuous long enough time so that in the health drug level in body circulation or other target area be elevated to about therapeutic dose, stop heating (gradually) afterwards soon and reach.Second method can be through using controlled heat when the needs extra drug, and or after the effect of the predetermined moment or required extra drug reaches, stop controlled heat and reach.Third party's method can reach through using controlled heat in the initial moment of using DDDS.At all in these three methods, the temperature of controlled heat need design the degree that increases of the described drug administration speed of control.
Because the permeability of skin is low, the zero-time of traditional DDDS is longer usually, and often is not hope length with having.Thereby another aspect of the present invention provides the method and apparatus that uses controlled heat to shorten the DDDS zero-time, preferably, does not change the stable state medicine-feeding rate in fact.The useful especially application of this one side of the present invention provides and is used to use traditional, available DDDS, the zero-time when using to shorten medical treatment, and do not need to design again DDDS or adjust its stable state medicine-feeding rate.
According to thinking, cause among the DDDS that major reason that drug absorption changes is that health by ambient temperature and/or people changes the DDDS that causes and near the variations in temperature of skin.Certainly, these variations in temperature can influence the factor that all these collectives confirm the final drug administration speed of DDDS potentially.Like this, provide the present invention of use controlled heat/refrigerative method and apparatus also can make skin and the variations in temperature that is applied to the DDDS on the skin be reduced to minimum degree.Also it is contemplated that and join a kind of heat-barrier material in the temperature control equipment; Not only help to be reduced to minimum degree to variations in temperature; Can also improve the temperature (through reducing heat loss) of DDDS and following surface skin thereof, their each aspects can both strengthen the absorption of dermal drug.
The invention still further relates to the method and apparatus that uses heat insulation means, the lid of for example being processed by heat-barrier material (such as the foam tape of closed pore) has adhesive edge; The size of lid is slightly larger than the zone of DDDS or injectable drug; When the DDDS of user and/or skin are exposed to (that is hot bath or shower or hot tub bath, the directly Exposure to Sunlight, of very high following time of temperature; Or the like), cover the DDDS/ injectable drug.
The key areas of modern anaesthesia is the anesthesia (hereinafter is designated as " PCA ") that the patient controls, and wherein, he gives oneself medicine of a dosage when the patient need to feel.The scope of dosage size and administration frequency is confirmed by care-giver (that is, doctor, nurse etc.) usually.In a lot of PCA situation, the patient accepts the medicine of reference speed rate, and when need feeling, obtains extra medicine pill.Technology of the present invention can be used for PCA, and wherein the patient obtains basic dose and obtains extra (" rescue ") dosage through heating percutaneous analgesic sheet through normal skin medicine sheet.Heating-up temperature and persistent period need be designed to such an extent that transmit the extra dose of appropriate quantity.
Through as injection, implant, squeeze into medicine/pharmaceutical preparation skin and be embedded into the method for skin and so on to medicine/pharmaceutical preparation with supersonic speed, can be sent to the medicine in the form of controlled release or slow release or the preparation repository/stored position in skin and/or the subcutaneous tissue.Controlled release/slow release form/preparation is discharged in surrounding tissue and/or the body circulation medicine gradually in one long period.For example, can subcutaneous injection slow release insulin (like the Ultralente_ insulin zinc of Eli Lilly company), so that insulin gets into the circulation of patient's body in longer a period of time.But,, just be difficult to usually change or the control drug release process in case controlled release/slow release form/preparation is administered into stored position.Apparatus and method of the present invention can be after controlled release/slow release form/preparation enters into repository/stored position; Controlled heat is with the release of increase medicine from controlled release/slow release form/preparation, or the control cooling is to reduce the release of medicine from controlled release/slow release form/preparation.For example, a lot of diabeticss not long ago needed extra insulin in dining, with the blood sugar concentration increase that suppresses to cause owing to having meal.But the rate of release of subcutaneous injection slow release insulin is more constant.
Use method and apparatus of the present invention; Diabetics can be injected the subcutaneous depot insulin in the morning; And on dining is ingested not long ago the skin of controlled heat dispensing at injection point, continue a period of time, thereby obtain extra insulin to suppress sugar part from food.Controlled heat is accelerated flowing of stored position peripheral blood and other body fluid, and according to thinking the rate of dissolution that can improve insulin.Certainly, it should be understood that can the given controlled release at repository/stored position/slow release form/preparation discharge the character that extra medicine depends on medicament forms/preparation along with the rising of temperature.But; Because heat is known or expectedly can accelerate the diffusion rate of medicine in their preparation; Increase the permeability of blood vessel wall; And the circulation of acceleration stored position ambient body fluid, wherein each all trends towards strengthening the release of medicine, estimates all to take place the release of thermoinducible extra drug for a lot of control that is positioned at subcutaneous stored position/prolong drug dosage form/preparation.
Important aspect of the present invention is; When being applied to the injectable drug preparation; Prolongation/controlled release formulation particularly; Similar with the mode that is applied to DDDS of top discussion, can suitably select moment of temperature and the beginning and the end controlled heat of controlled heat, to adapt to the needs of different treatments and individual patients.
A lot of biodegradable polymer can be used for making controlled release/slow releasing preparation.It should be noted that biodegradable lactic acid/hydroxyacetic acid polymer especially; Marcel Dekker publishing house publishes nineteen ninety-five that " in biomaterial and the encyclopaedical handbook of biological engineering the 29th Zhanghe the 33rd chapter description is arranged, this paper draws for referencial use in that people such as Donald L.Wise edit for this.An importance of the present invention is; As stated; Use the rate of release of controlled heat control/adjusting medicine from controlled release/slow releasing preparation; Controlled release/slow releasing preparation is made by above-mentioned polymer, and preferably, uses " the method making described in biomaterial and the biological engineering encyclopedia handbook.
Absorb very important medicine for rapid system, the present invention is useful.For example, it is generally acknowledged, successfully treat migraine, treat the concentration of migraine remedy (like dihydroergotamine) in the blood flow, in the certain hour that begins from migraine, must reach therapeutic dose.In this case, as stated, can use heater with normal medicine injection.Because heating can be accelerated the diffusion rate of medicine in their preparation usually, increase the permeability of blood vessel wall, and quicken the circulation of injection point ambient body fluid, medicine will get into the body circulation quickly.
Prior aspect of the present invention is the device that produces and provide controlled heat.These controlled heat generators generally comprise a heating part and a heat passage device to DDDS, skin and/or subcutaneous repository and stored position by the heating part generation.These devices that produce controlled heat generally also comprise a mechanism (for example belt, binding agent, or the like), are used for being fixed to DDDS and/or skin to this device.Preferably, fixed mechanism fixedly secures the device that produces controlled heat in position in use, but this device is relatively easily taken off.In addition, these devices that produce controlled heat also comprise the mechanism that ends heating.The bottom shape and the size that produce the device of controlled heat are generally specially made, can hold the DDDS that will use these devices.
The embodiment of device that produces controlled heat is shallow chamber, comprises air-locked sidewall, diapire and air-locked roof, has some zones to have limited and required air permeability (like, the hole of blocking with microporous membrane) on the roof.The heating medium is placed in the shallow chamber, preferably, it comprise iron powder, active carbon, salt, water and, the mixture of selective sawdust etc.The device that produces controlled heat preferably is kept in the container of hermetic seal, is using before from wherein taking out.After from the hermetic seal container, taking out, airborne oxygen (" ambient oxygen ") through on airtight roof, having an infiltrative zone of required air, gets in the heating medium, starts the oxidation reaction (being exothermic reaction) of heating.Air exposure district through selecting roof (for example; Covering the hole of selecting suitably big or small and quantity and/or selecting microporous membrane to cover the hole for concrete air permeability); And/or, can obtain required heating-up temperature and persistent period through selecting the heating medium composition of right quantity and/or ratio.
This embodiment that produces the device of controlled heat preferably includes the mechanism that is fixed to the device that produces controlled heat skin or is applied in the DDDS on the skin.For those application that need remove or end to heat, electro-heat equipment also should have a mechanism and remove or be used for ending heating from DDDS and/or skin making it easily.Be used for easily removing shallow chamber and do not comprise the layer of adhesive on the electro-heat equipment sidewall from the mechanism that skin is removed DDDS from DDDS; There is zone or the little zone (adhesiveness is less than the binding agent that is fixed to DDDS on the skin) of adhesiveness that does not have binding agent in the bottom, shallow chamber of electro-heat equipment, and the shape that does not have a little zone of binding agent or adhesiveness is similar with DDDS's.When this electro-heat equipment was applied to the DDDS on the skin, the binding agent of electro-heat equipment sidewall bottom adhered on the skin, does not have the little part of binding agent or adhesiveness on the top of DDDS, but did not have stickup or adhesive force not to stick on the DDDS doughtily.This just makes it possible under the situation of not disturbing DDDS, take off electro-heat equipment.
Although a kind of application of this electro-heat equipment is to combine DDDS to use; But it should be understood that; Electro-heat equipment also can directly be used for skin; To strengthen the release of medicine, perhaps quicken absorption subcutaneous or the intramuscular injection medicine from stored position or injection point or controlled release medicine implantation point (stored position).
The heating mechanism that the present invention is used to produce the device of controlled heat is not limited to the exothermic reaction mixture that preferred iron powder, active carbon, salt, water and selective sawdust etc. are formed, and also can comprise the heating unit of electricity consumption heating.Electric heating unit preferably, comprises the surface of two dimension, is used to transfer heat to DDDS and/or skin.Electric heating unit also can comprise temperature feedback system and be placed on the temperature sensor on DDDS or the skin.The temperature of temperature sensor monitors DDDS or skin, and being sent to controller based on the signal of telecommunication of measured temperature, controller is regulated the curtage of electric heating unit, makes the temperature at DDDS or skin place remain on desired level.Preferably, can use two-sided tape to be fixed on electric heating unit on the skin.
Heating mechanism also can comprise infrared ray generating unit and mechanism, leads infra-red radiation on DDDS or the skin.It also can have temperature feedback system and be placed on the temperature sensor on DDDS or the skin, is used to control the intensity of infra-red radiation, makes the temperature at DDDS or skin place remain on desired horizontal.
Heating mechanism also can comprise microwave generating unit and mechanism, is used for being directed to DDDS or skin to microwave radiation.Likewise, there are temperature feedback system and temperature sensor in heating mechanism, to regulate the intensity of microwave emission, the temperature maintenance on DDDS or the skin in desired horizontal.
Heating mechanism also can comprise the container that contains subcooled liquid, heating (" heat release ") during the subcooled liquid crystallization.Crystallization starts in container, for example start through bent sheet metal in subcooled liquid, and container is placed on DDDS or the skin, and it is heat passage on DDDS or skin that crystallization process discharges.But the heat that crystallization discharges can not remain on a constant level usually in long-time.So; This mechanism of generating heat is unfavorable in narrow scope, keeping the application of long period to a temperature that raises; But the situation for the duration of heat that only need lack is useful, for example for DDDS, benefits from and drops to zero-time minimum short heat time heating time.
Usually, although recognized that through adding heat gain drug absorption and rate of release be that DDDS has brought a lot of benefits, also need to increase also in some cases to reduce drug absorption and rate of release.It should be understood that the more thoroughly control for skin and control/prolong drug administration is that for the two provides heating or cooling body simultaneously, this will have advantage as required.Like this, the method for a novelty of the present invention is, is DDDS, skin and/or subcutaneous tissue, and perhaps pharmaceutical dosage form/the preparation in skin or the subcutaneous tissue is provided for heating or refrigerative method and apparatus, thereby can control the absorption and/or the release of medicine.Heating/cooling body comprises electrothermal module, and it plays heat pump, wherein, according to hope be the heating or the cooling, can be reversal of power.Cooling body comprises and similar heat absorption crystallization mechanism of above-mentioned heat release crystallization mechanism.
Certainly, it should be understood that in controlled release/slow release form/preparation entering skin or behind the subcutaneous tissue, use controlled heat and/or cooling control drug absorption and/or discharge to be applied to controlled release/slow release form/preparation with being equal to.But the physical mechanism except heating and/or cooling also can be used as identical purpose.Like this, novel part of the present invention is, provides and uses ultrasound wave, electric current and mechanical vibration to induce controlled release/slow release form/preparation to discharge the method and apparatus of extra drug, and wherein controlled release/slow release form/preparation has got in the body and responded these physics inducementes.
The present invention also provides an administration assembly, like transdermal delivery system, with temperature-controlling module, like heating plate, integrates formation " integrated DDDS sheet " or claims " integrated ".Administration assembly comprises the pharmaceutical preparation applicator and is fixed on the pharmaceutical preparation in the pharmaceutical preparation applicator.Barrier and/or compartment prevent the unnecessary material Transfer between temperature-controlling module and the medicine delivery components.Barrier and/or compartment also stop the mass exchange between drug administration and temperature-controlling module and external environment condition or absorb volatile material.Temperature-controlling module comprises temperature control component and can control and the temperature control of attemperation regulating element heating.
Administration assembly is similar with known transdermal drug delivery system, comprises the medicine that is scattered in the preparation, and preparation sticks to or is included on the medicines dressing device.The pharmaceutical preparation applicator can be any structure or the method in the transdermal drug delivery system, and it makes or causes that medicine or pharmaceutical preparation are delivered on patient's the skin, for example, are fixed on the gauze pad on the adhesive tape.The medicines dressing device comprises the speed limit film between pharmaceutical preparation and user skin, perhaps selectively makes the direct and contact skin of preparation.Physical barriers like air-locked medical package film, is the means that prevent between medicine delivery components and the temperature-controlling module to carry out through direct infiltration or vapor absorption mass exchange.Medicines dressing device with pharmaceutical preparation is fixed on the device that prevents to exchange.This medicine delivery components and temperature-controlling module integrate and form integrated.In addition, can be fixed on the medical adhesive tape layer other part of Obstruct membrane or integrated, thereby the means that are attached to integrated on the patient skin are provided.
From integrated DDDS sheet, absorb medicine usually by the several factors decision, comprising: the concentration, skin that diffusion coefficient, the medicine of drug molecule in pharmaceutical preparation passes dissolved substance in the infiltration coefficient, preparation of speed limit film (if use) to the permeability of medicine, in skin and/or in subcutaneous other tissue in the circulation, subcutaneous tissue of body fluid (comprising blood) permeability of capillary wall and drug absorption get into hypodermic stored position and from wherein release.According to thinking that controlled heat possibly influence above-mentioned each factor, like this, be worth and integrate temperature-controlling module and medicine delivery components easily.
The integrated DDDS sheet of the present invention can the very wide pharmaceutical preparation of the scope of application.Preparation itself can have a lot of forms, for example liquid, gel, cream, paste or solid.Usually, healing potion mixes or dissolves in the pharmaceutical preparation.Drug-supplying system attempt of the present invention uses percutaneous to transmit the medicine in the pharmaceutical preparation, includes but not limited to the medicine such as analgesic, androgen, anesthetis and anaesthetic.The structure of pharmaceutical preparation applicator can be controlled pharmaceutical preparation, so that the pharmaceutical preparation on the applicator can easily take out from storage bag and be applied on patient's the skin.
Temperature-controlling module has temperature control component and temperature control, and to allow the user attemperation, temperature control component can be heater element (for example a, heating plate).Heating plate is specially designed, to improve the efficient and the therapeutic effect of transdermal drug delivery system.A key character of heating plate is that it can be elevated to about 39 ℃～43 ℃ temperature to skin temperature apace.Heating plate can maintain skin temperature in this scope in longer a period of time.This not only provides the heating of self-consistentency, and can prevent to use other method the time because the overheated skin injury that causes.
An embodiment of heating plate is particularly useful for integrated.Heating plate comprises the shallow chamber that the end, frame wall and lid surround.The heating medium is arranged in shallow chamber, when it contacts with ambient oxygen, can generate heat.There is a lid this chamber, and it is processed by the impervious material of oxygen.Covering the zone has perforate, makes in the oxygen inlet chamber.User can optionally cover, part covers or open perforate, flows in the chamber and heating there with control air.
In addition, can live the part or all of zone of lid with membrane cover with certain air permeability.Like this, surrounding air is flowed in the chamber through lid with desired rate, the result causes the oxidation reaction of heating medium, on skin, produces required temperature.Oxygen also passes through the only end and the frame wall of chamber basically.Heating medium in the chamber generally comprises active carbon, iron powder, Yan Heshui.Also can add and improve the mobile material of air, like thin wood flour.Can normally work in order to guarantee heater element; Each component ratio in the present embodiment is very important; For example, according to typical proportion: active carbon: iron powder: thin wood flour: sodium chloride: water=5: 16: 3: 2: 6 (weight ratio), can produce quite good heating medium.
Utilize the heating plate of oxidation reaction heating to be kept in the airtight container.When taking out from container for integrated, the oxygen in the environment flows in the shallow chamber, causes the oxidation reaction of generating heat in the heating medium.The caloric value of unit interval is flowed into the speed decision of heating medium through lid by oxygen.Can use foraminous number and size further to control the caloric value of unit interval less than covering.
Effectively, as top concise and to the point description, just produce integrated transdermal drug delivery system sheet combining as the heating plate of temperature-controlling module and dermal drug delivery components.
Integrated heating plate design makes patient or care-giver use controlled heat more easily, is used for more effectively transdermal drug administration.In addition, the design of integrated heating plate can prevent to misuse or use irrelevantly controlled heat in the transdermal drug administration.Integrated heating plate provides more uniform heating for relevant pharmaceutical preparation.When the patient uses when having the drug-supplying system of independent temperature control element, user is laying temperature control element improperly just, has perhaps by mistake moved heating element heater, and this can cause the inhomogeneous heating of pharmaceutical preparation.Independently temperature control component need that patient or care-giver determine to use any heating element heater, when begin to heat, when finish to heat, which type of temperature range be fit to and the conduction of heat of independent temperature control element to or where transfer to and how do i.Actual operation can be because of patient and different Yin treatment.Patient and care-giver make erroneous decision and misuse independent heating elements the above-mentioned problem of listing easily.The incorrect use of temperature control component will cause unsuitable drug dose.Integrated heating component and medicine delivery components can reduce or eliminate the probability of misusing the independent temperature control element.
The preferred embodiment of integrated heating plate comprises a dish, and it is by to volatile liquid, and particularly water and ethanol have the material of good block to process, but needn't good block be arranged to oxygen.A shallow bin is arranged in the dish, and it can hold pharmaceutical preparation also can hold the pharmaceutical preparation applicator.Pharmaceutical preparation sticks on the pharmaceutical preparation applicator, and the pharmaceutical preparation applicator is fixed on a kind of film that volatile liquid is had a good barrier effect.Film is thermally sealed on the edge of dish, between dish and film, forms the airtight compartment that is limited bin.Pharmaceutical preparation is placed in the said compartment.Because the dish and the lid of chamber stop as solvent, when said compartment hermetic seal, it has stoped the transfer of material between pharmaceutical preparation and external environment condition.
The top of film is an adhesive tape, and its area is slightly larger than film.Binding agent one side of adhesive tape is to film, and the edge of adhesive tape extends beyond the edge of film.Edge that part of that adhesive tape extends beyond film is used for the skin that is fixed to user to integrated.Heating plate be fixed on adhesive tape above, and be positioned at the center of adhesive tape.Close the area that the inboard area that contains the heating plate of the medium that generates heat in hope ground equals or be slightly larger than the pharmaceutical preparation applicator basically, so that effective heating to be provided.In other words, when heating plate is fixed on envelope barrier and the medicines dressing device, heater element should be positioned at any medicine area directly over, basic so all pharmaceutical preparation (also comprising Obstruct membrane) is by as one man and equably heating.
In a preferred embodiment, the outermost edge of epiphragma is not sealed on the dish, and adhesive tape be placed on epiphragma above, its binding agent one side sticks on the epiphragma.The size of adhesive tape can be identical with epiphragma, perhaps preferably, is slightly larger than epiphragma.If adhesive tape is slightly larger than epiphragma, the part that adhesive tape extends beyond the epiphragma edge leans against on the dish.When the patient took off the adhesive tape use from coiling, adhesive tape can be peeled off from an end of dish.The part (but sticking on the adhesive tape) that epiphragma is not sealed on the dish is mentioned by adhesive tape.When continuing to peel off, whole epiphragma and adhere to superincumbent pharmaceutical preparation is mentioned by adhesive tape.Like this, the top of adhesive tape is a heating plate, and the below is pharmaceutical preparation, then adheres to integrated on the skin with this adhesive tape.The end of dish can fall in one so that begin to peel off.
Integrated is sealed in the airtight container.Preparation is sealed in the space between dish and the Obstruct membrane fully, therefore between preparation and heating medium or external environment condition, mass exchange can not take place.The heating medium also is sealed in the airtight container, so it is completely contained in the space of airtight container.Pharmaceutical preparation is isolated with temperature-controlling module and external environment condition fully like this.Isolate between temperature-controlling module and the pharmaceutical preparation.When being sealed in the airtight container for integrated, temperature-controlling module also and between the external environment condition is isolated.Like this, heating plate can integrate with administration assembly, and can be stored in together in the air-tightness chamber, for example by the pouch that all has the film of fine barrier effect to process to air and moisture.
In an embodiment of integrated DDDS sheet; The barrier that stops undesirable material Transfer between drug-supplying system assembly and the temperature-controlling module can comprise one or more chambeies or compartment; Medicine delivery components and temperature-controlling module are isolated therein, but still integrate on the structure.According to the concrete pharmaceutical preparation and the needs of temperature-controlling module, these chambeies can be air-locked materials.Same, stop that the device of material Transfer between drug administration and the temperature assembly comprises chamber or pouch, wherein storing integrated heating plate.As required, moisture, oxygen, light or other environmental factors can not see through chamber or pouch.
In another embodiment of integrated heating plate, the means of the heat loss that prevents not conform to hope are provided.The means that prevent not conform to the heat loss of hope are included in drug administration and the temperature-controlling module uses heat-barrier material.Other means that prevent not conform to the heat loss of hope comprise uses binding agent and other integrated DDDS sheet to fix and be sealed to the means on the user skin; Like this heat can not be from medicine delivery components and the loose edge of temperature-controlling module or the angle scatter and disappear, and integrated heating plate shape customized and appearance can be fit to the special part of user health better.
The means of the heat loss that prevents not conform to hope are provided in one embodiment of the invention.In some cases, it is difficult being fixed on the angle of sheet on the skin of user.The basic ovalize of integrated heating plate shown in Fig. 4.With rectangle or quadrate ratio, ellipse does not have the angle.Therefore, ellipse has been eliminated the angle, has realized preventing that heat scatters and disappears from loose angle, and the angle is to be difficult to fixed and to produce the heat loss that does not conform to hope.
An alternative embodiment of the invention is that heat generating component provides foam cap.Foam tape is stamped heat insulation performance, can drop to minimum degree to the heat loss through lid, and can prevent that the variation of ambient temperature from influencing the heating to the temperature control component of heating unfriendly.And, also designed the insulation cover that can completely cut off integrated heating plate exposed surface.
Often need heating medium and pharmaceutical preparation storing and/or sealing fully each other and be sealed in the external environment condition between the operating period.Although need complicated sealing be used to preserve pharmaceutical preparation and heating medium, also need provide and be convenient to above-mentioned two assemblies of using and using.The novel structure of the present invention can satisfy the isolation of assembly between preservation and/or operating period, also can conveniently use and use.
Temperature-controlling module of the present invention and medicine delivery components are preferably isolated.Use isolated temperature-controlling module and isolated medicine delivery components be for prevent or avoid and environment between and and the device other assembly between the reaction that does not conform to hope.For example, isolated temperature-controlling module can be the heat release medium that is encapsulated in the complete air-tightness environment, and has the barrier that does not conform to the material Transfer of hope between heating medium, environment and the medicine delivery components that can prevent in the temperature-controlling module.Same, isolated medicine delivery components can be encapsulated in the complete air-tightness chamber, and has and can prevent not conform between external environment condition, temperature-controlling module and the medicine delivery components material Transfer of hope or the barrier of exchange.Depend on the pharmaceutical preparation of heating medium and use, the required isolation of each assembly can be different.
Do not have careful design, attempt combines exothermic oxidation reaction with the transdermal drug administration will be impracticable and invalid combination.Because assembly is not isolated rightly and easily, some be row can not with invalid.Absorb through steam, heating oxygen response element can suffered a loss and/or make a mess of to the material in the pharmaceutical preparation.Between the storage life, the material of from pharmaceutical preparation, losing can cause that the function of pharmaceutical preparation is obviously different with desirable initial condition.And ungracious reaction also can take place with pharmaceutical preparation in the material of temperature control component, makes pharmaceutical preparation inefficacy or invalid.Other combines for manufacturing and use is difficulty or unpractical.
Brief description of the drawings
Although this description and claims particularly point out and clearly proposed to think content of the present invention,, will confirm advantage of the present invention more in conjunction with explanation of the present invention below the advantages.In the accompanying drawings:
Fig. 1 is the sectional view of temperature control equipment embodiment of the present invention;
Fig. 2 is the sectional view of another embodiment of temperature control equipment of the present invention;
Fig. 3 is the sectional view of transdermal drug delivery system embodiment of the present invention;
Fig. 4 is the temperature control equipment and the bonded sectional view of transdermal drug delivery system in Fig. 3 among Fig. 2 of the present invention;
Fig. 5 is the time of temperature control equipment of the present invention and the curve chart of temperature;
Fig. 6 is nine volunteers of the present invention heating and do not add average fentanyl concentration and the curve chart of time behind the DDDS that thermo-contact contained fentanyl in four hours;
Fig. 7 is the time of temperature control equipment of the present invention and the curve chart of temperature;
Fig. 8 is the sectional view of another embodiment of temperature control equipment of the present invention;
Fig. 9 is the sectional view of another embodiment of transdermal drug delivery system of the present invention;
Figure 10 is the temperature control equipment and the bonded sectional view of transdermal drug delivery system in Fig. 9 among Fig. 8 of the present invention;
Figure 11 is the sectional view of another embodiment of transdermal drug delivery system of the present invention;
Figure 12 is the temperature control equipment and the bonded sectional view of transdermal drug delivery system in Figure 11 among Fig. 8 of the present invention;
Figure 13 is the sectional view of another embodiment of temperature control equipment of the present invention, and three cap rocks are wherein arranged on oxygen activated thermoregulation mechanism chamber;
Figure 14 is the sectional view of temperature control equipment of the present invention among Figure 13, has wherein removed first cap rock;
Figure 15 is the vertical view of temperature control equipment of the present invention 15-15 along the line among Figure 14;
Figure 16 is the sectional view of temperature control equipment of the present invention among Figure 14, has wherein removed second cap rock;
Figure 17 is the vertical view of temperature control equipment of the present invention 17-17 along the line among Figure 16;
Figure 18 is the sectional view of temperature control equipment of the present invention among Figure 16, has wherein removed the 3rd cap rock;
Figure 19 is the vertical view of temperature control equipment of the present invention 19-19 along the line among Figure 18;
Figure 20 is the sectional view that the present invention has another embodiment of transdermal drug delivery system of speed limit film;
Figure 21 is the sectional view of electron temperature controlling organization of the present invention;
Figure 22 is the sectional view that the present invention includes the temperature control equipment that is full of the subcooled liquid flexible pouch;
Figure 23 is the sectional view that the present invention is applied directly to the temperature control equipment on the patient skin;
Figure 24 is the sectional view that the present invention is applied to the heat-barrier material of DDDS and injection or store medication point, and wherein heat-barrier material makes variations in temperature be reduced to minimum and/or raising DDDS and its temperature of surface skin down;
Figure 25 be an embodiment layering of integrated cut open perspective view;
Figure 26 is the exploded view of integrated of Fig. 1;
Cutaway view when Figure 27 is the sheet storage among Fig. 1;
Figure 28 is the top perspective of an embodiment of integrated of medicine delivery components;
Figure 29 is the cutaway view of heating plate.
The detailed description of above-mentioned embodiment
Fig. 1-2 9 shows different temperatures control or other device and transdermal drug delivery system.It should be understood that given diagrammatic sketch and following explanation and do not mean that it is diagram, and only be as Utopian representative to the actual view of any specific device, than possibly illustrating of other clearer with the present invention is described up hill and dale.Components identical is used identical numeral among each figure.
Temperature control equipment of the present invention 100 shown in Fig. 1 comprises the chamber that is surrounded by diapire 102, roof 104 and sidewall 106, it is characterized in that thermoregulation mechanism 108 is placed on wherein.Thermoregulation mechanism 108 comprises heating oxidation reaction mechanism, electric heating unit, heat release crystallization mechanism, heat absorption crystallization mechanism, heating/cooling body, cooling body, or the like.
Temperature control equipment of the present invention 100 shown in Fig. 2 comprises the thermoregulation mechanism 108 that is surrounded by diapire 102, roof 104 and sidewall 106.Diapire 102 is plastics preferably, and sidewall 106 is preferably processed by air-locked material of flexibility, for example air-locked closed-cell foam material.Temperature control equipment 100 diapires 102 a part or all comprise jointing material 112, be used to paste DDDS or patient's skin.Thermoregulation mechanism 108 preferably includes active carbon, iron powder, sodium chloride and the water of forming with proper proportion.Select ground at choice, can add sawdust during this forms so that air flows in this forms and/or forms for this reason provides one " body ".Roof 104 also is to be processed by air-locked material of flexibility preferably, wherein passes porose 114.Preferably, between roof 104 and thermoregulation mechanism 108, one deck ventilated membrane 116 is arranged, to regulate the air capacity that arrives thermoregulation mechanism 108 through hole 114.Ventilated membrane is perforated membrane (CoTran for example preferably
TMNo. 9711 microporous polyethylene films of board, the 3M company of Minn. Minneapolis produces).
Transdermal delivery system of the present invention 120 shown in Fig. 3 (below be designated as DDDS120) comprises the shell of being processed by flexible material 122.Shell 122 preferably includes sidewall 124 and roof 126, and pharmaceutical preparation 128 is arranged in the shell 122.Preferably, the bottom of DDDS sidewall 124 comprises that binding agent 132 is to stick on DDDS120 on patient's the skin.
Fig. 4 representes to paste the temperature control equipment 100 of Fig. 2 on the DDDS120 of Fig. 3.DDDS120 pastes on the part of patient skin 134.The area of thermoregulation mechanism 108 preferably is slightly larger than the area of pharmaceutical preparation 128.Temperature control equipment 100 and DDDS120 preferably are stored in the cabin that airtight container separates (perhaps being stored in the airtight container separately).
The different views that Figure 25-27 expression is integrated.Comprise temperature-controlling module 20 and medicine delivery components 4 for integrated 2.Be kept in the metal forming pouch 6 for integrated 2.
Medicine delivery components 4 also comprises dish 8, and pharmaceutical preparation bin 40 and basic and pharmaceutical preparation bin 40 the same big medicines dressing device bins 42 are wherein arranged.Dish 8 has the edge 44 that extends along its periphery.Pharmaceutical preparation 10 is placed in the formulation reservoir 40 of dish 8.Gauze 12 is placed in the applicator bin 42, and contacts with pharmaceutical preparation in being placed on formulation reservoir 40.Thin barrier film 16 can be fixed on dish 8 the edge 44 with unclamping and be fixed on the gauze 12.The thin barrier film 16 that is fixed on dish 8 the edge 44 defines a pharmaceutical preparation compartment.Adhesive tape 18 can be fixed on dish 8 the edge 44 and the top that is fixed on thin barrier film 16 with unclamping.Adhesive tape 18 is all wideer and long than thin film 16, gauze 12 and pharmaceutical preparation 10, makes adhesive tape 18 exceed the periphery of thin film 16, gauze 12 and pharmaceutical preparation 10.The binding agent of adhesive tape bottom side is used for the skin that is fixed on user to integrated, and is fixed on adhesive tape 18 on the dish 8.
Temperature-controlling module 20 also comprises sheet bin 52.The sheet bin is surrounded by medical tape base 22, foam tape frame 24 and foam with cover 28.The heating medium is placed in the sheet bin 52.On the lid 28 a plurality of holes 32 are arranged.Hole 32 can optionally be covered or opened by oxygen flow air-vent cap 54 or air flow rate restriction port lid 54.Port lid 54 enables perhaps to open the persistent period in hole through change, optionally adjustable cap 28 permeabilitys through covering or open some or whole holes 32.Hole 32 also can select the film (not shown) of air permeability to cover.
In a preferred embodiment, the device of isolation medicine delivery components is the chamber that is surrounded by thin barrier film 16 and dish 8.Other device of isolating the medicine delivery components comprises other alternative physical barriers.
Preferred embodiment shown in Fig. 3 has provided the means that are used for the isolated temperature Control Component and has comprised metal forming pouch 6.Other this assembly and the isolated means of external environment factor comprise other alternative physical barriers, are used for separating integrated chip module and environment.
The temperature-controlling module 20 that an embodiment shown in Fig. 2 provides comprises the hole 32 that is defined in the airtight lid 28, and hole 32 can optionally cover or open.The design of other control temperature means is relevant with the heating medium 34 in the temperature-controlling module 20.This alternative means comprise the electronic installation that is used for attemperation and other method that is used to control the heating that is produced by exothermic reaction (being that ambient oxygen is passed through frame wall entering heating medium).
In preferred embodiment shown in Figure 2, temperature control component is a heating medium 34, more specifically is the medium that can stand with the exothermic oxidation reaction of oxygen.Also can design other temperature control component, like electronic heating element and other heat-producing chemical reaction.
Should consider adhesive tape and membranous relative position and binding agent and thermosealed relative intensity so that sheet easily takes off and can by mistake not dismantle integrated 2 from dish.As shown in Figure 4, keep blow-by between preferred heat seal film 16 has an end 17 at least and coils, but be attached on the adhesive tape.This can take off heat seal film 16 with adhesive tape, rather than still is fixed on the dish 8.In the embodiment shown in fig. 4, find from being fit to apart from the narrow end 2mm termination heat seal band of film 16 approximately.
In actual experiment; Temperature control equipment 100 comprises sidewall 106, and it is by 1/4 inch thick rectangle foam tape (4 layers of No. 1,779 1/16 inch thick white foam band, 3M company; The company of Minn. Minneapolis; Minn. Minneapolis) surround, external dimensions is about 2.25 inches * 4 inches, wherein has inside dimension to be about 1.75 inches * 3.5 inches opening; Diapire 102; Comprise that size is about 2.25 inches * 4 inches the medical band of rectangle (the medical band of 1525L plastics; The 3M Company products; The Company products of Minn. Minneapolis, Minn. Minneapolis), it does not have a side of binding agent and the bottom connection of sidewall 106; Roof 104; Comprise 1/32 inch thick foam tape of rectangle (No. 9,773 1/32 inch filemot foam tape, 3M Company products, the Company products of Minn. Minneapolis; Minn. Minneapolis), 32 holes 114 (about 1/16 inch of diameter) are wherein arranged.Sidewall 106, diapire 102 and roof 104 surround a chamber.The hole 114 of roof 104 is covered by ventilated membrane 116, and ventilated membrane 116 comprises perforated membrane (No. 9711 CoTran
TMFilm, 3M company, the company of Minn. Minneapolis, Minn. Minneapolis), be positioned between roof 104 and the thermoregulation mechanism 108.The thermoregulation mechanism 108 that is placed in the chamber comprises that active carbon, iron powder, sawdust, sodium chloride and water are by weight being about 5: 21: 3: 2: 6 weight are about the mixture of 31 grams.
On volunteer's skin, tested temperature control equipment 100, wherein be placed on temperature probe between temperature control equipment 100 and the volunteer's skin and measure temperature.The result of temperature test is shown among Fig. 7 and the Biao D, can find out that temperature control equipment 100 can keep longer a period of time (at least 840 minutes) to the temperature of skin in narrow, being about in 41 ℃～44 ℃ the scope of raising.
Table D
| Time (minute) | Temperature (℃) |
| 0 | 31.9 |
| 1 | 32.2 |
| 2 | |
| 3 | 33.2 |
| 4 | 33.8 |
| 5 | 34.4 |
| 6 | 34.8 |
| 7 | 35.8 |
| 8 | 35.9 |
| 9 | 36.7 |
| 10 | 37.3 |
| 11 | 37.8 |
| 12 | 38.4 |
| 13 | 38.7 |
| 14 | 39.2 |
| 15 | 39.4 |
| 16 | 39.8 |
| 17 | 39.9 |
| 18 | 40.1 |
| 19 | 40.3 |
| 20 | 40.5 |
| 22 | 40.8 |
| 24 | 40.9 |
| 26 | 41 |
| 28 | 41.1 |
| 30 | 41.1 |
| 35 | 41 |
| 40 | 41 |
| 45 | 40.9 |
| 75 | 41.1 |
| 150 | 41.7 |
| 210 | 41.6 |
| 300 | 41.5 |
| 390 | 41.7 |
| 510 | 41.4 |
| 570 | 41.5 |
| 720 | 41.4 |
| 780 | 41.4 |
| 840 | 41.5 |
Above-mentioned experimental result and the description of heating plate is demonstrated heating plate here and have special advantages than technology formerly, and in some cases also has special advantages than the heating method of other temperature control equipment.Heating plate provides a kind of safe means, the temperature of the skin that can raise whereby.Because heater element is iron powder and the oxidation reaction between the oxygen of control, it is overheated and produce the chance of skin injury to have significantly reduced heater element.Use the quantity of the oxygen that the lid restriction of selectable air flow rate contacts with iron powder, the heating of exothermic reaction can maintain in the safe temperature range.And heater element can not contain dangerous chemical substance.Because reactant is the shape of powder, punctured if contain the chamber of reaction component, if mainly be that the situation of liquid is compared with reaction component, they are not easy to reveal.
The use of heating plate also is easily.Because the heating plate of design has the selectively penetrating barrier between oxidation reaction and ambient oxygen, so possibly change and regulate the temperature that raises by oxidation reaction heating in the chamber.The quantity and/or the size that cover the hole through change can be accomplished this point.One embodiment of the present of invention provide gas-pervious air-vent cap, are used for covering the pore that covers.User can optionally cover or open one or several hole, with the speed of quickening or reduction exothermic reaction, thereby regulates and control the heat that heater element produces.In addition, the surface area that ventilated membrane exposes has greatly determined the speed that oxygen contacts with heater element, for thermoregulation in narrow available temperature range, can cover the required part of exposed surface area.
Be exposed to the time in the oxygen and/or be placed on reactant quantity in the compartment through the conditioned reaction thing, can change the persistent period of heating through adjusting.The capacity that heating plate can be regulated makes heating plate can be applicable to many aspects, to satisfy patient or care-giver's needs.Heating plate another easily characteristic be that it uses oxygen activated heater element.Just can activate heating plate easily through being exposed to heating plate simply in the ambient oxygen, for example when heating plate takes out before use from the air-tightness pouch.Heating plate does not need electricity or other extra power just can generate heat, and therefore is easy to carry.
The unique distinction of heating plate is that also it provides the required solution cheaply of controlled heat in the transdermal drug administration.The making of heating plate is very complicated, and the design of heating plate sells and storage heating plate with profile easily.The element of making heating plate obtains with lower cost from the industrial source of goods of having set up easily.Heating plate also is eco-friendly.
Another novel characteristics of the present invention is that thermal insulation layer is provided in electro-heat equipment.Shown in figure 25, one embodiment of the present of invention are removed outside the surface that is used to transfer heat to heated target (being the transdermal drug sheet, the skin area below the heater), and heater element is on all directions and all be heat insulation between the surrounding air.Make between device 4 and the external environment condition heat insulationly in the device 4 around the thermal insulation layer 6 of heating medium 8, and make heating accumulate heat better in the medium 8.This means, compare, can reach identical heating-up temperature with low heating speed with the device that does not have thermal insulation layer.The present invention prolongs the heating dielectric heat persistent period to determined number, and this is in demand for the device that needs compact.If heater directly affacts on the skin,, also drop to the dangerous probability of scalded skin minimum through making the heating medium effectively but produce lower slightly heating-up temperature.
Fig. 8 illustrates temperature control equipment 150 another embodiment, comprises the thermoregulation mechanism 108 that is surrounded by diapire 102, roof 104 and sidewall 152.Following sidewall 152 stretches out diapire 102 1 segment distances and forms cavity 154.Diapire 102 is preferably processed by plastic tape, and sidewall 152 is preferably processed by air-locked material of flexibility, for example air-locked closed-cell foam material.The part of temperature control equipment 150 bottoms comprises jointing material 112 on the bottom of sidewall 152, and preferably comprises second jointing material 156 in the bottom of diapire 102, wherein, and the adhesive force specific adhesion material 112 of second jointing material 156 little.Likewise, thermoregulation mechanism 108 preferably includes active carbon, iron powder, sodium chloride, water and the selective sawdust of forming with proper proportion.Roof 104 also is to be processed wherein porose 114 by air-locked material of flexibility preferably.Preferably, between roof 104 and thermoregulation mechanism 108, one deck ventilated membrane 116 is arranged, to regulate the air capacity that arrives thermoregulation mechanism 108 through hole 114.
DDDS160 shown in Fig. 9 comprises the shell of being processed by flexible material 122.Shell 122 preferably comprises sidewall 124 and roof 126, is placed with pharmaceutical preparation 128 in the shell 122, and can comprises film 130, and film 130 can be the speed limit film.
Figure 10 representes the temperature control equipment 150 attached to the Fig. 8 on the DDDS160 of Fig. 9.DDDS160 is placed on the part of (or paste with binding agent, do not illustrate) patient skin 134, and temperature control equipment 150 is placed on the DDDS160, makes DDDS160 be arranged in cavity 154 (see figure 8)s.Jointing material 112 pastes on the skin 134 and temperature control equipment and is fixed on the appropriate location.If DDDS160 does not stick on the skin, temperature control equipment 150 is fixed on DDDS160 on the appropriate location.Preferably, paste DDDS160 on the skin 134 with the jointing material (not shown), temperature control equipment 150 is placed on the DDDS160.Stick on temperature control equipment 150 on the skin 134 with jointing material 112, paste temperature control equipment 150 on the DDDS160 with second jointing material 156 (adhesive force of second jointing material 156 is than all little of any stickup binding agent (not shown) of 134 of DDDS160 and skins and less than the adhesive force of the jointing material 112 of 134 of temperature control equipment 150 and skins).This arrangement can guarantee adhering to of 134 of temperature control equipment 150 and DDDS160 and skins, can also under the situation of not taking off DDDS160, take off temperature control equipment 150.
DDDS166 shown in Figure 11 comprises the shell of being processed by flexible material 123.Shell 123 preferably includes roof 125 and film 103, and this film can be the speed limit film, is placed with pharmaceutical preparation 128 in the shell 123.Figure 12 representes to paste the temperature control equipment 150 of Fig. 8 on the DDDS165 of Figure 11, is similar to the explanation of Figure 10.
Embodiment 1
Before applying sheet (0 hour) and apply sheet after gathered the venous samples can be used to detect serum testosterone concentration in 2,4,6,8,10 and 12 hours.After exhausting blood in 12 hours, take off chip system.Selected Androderm_ testosterone is the 5mg system through dermal system, and it has 24cm
2Total contact area and 15cm
2Medicament reservoir wherein contains the 24.3mg testosterone USP that is dissolved in the alcohol-based gel.Use radioimmunoassay to confirm serum testosterone concentration.Table B has provided 0,2,4,6,8 and 10 hour serum testosterone concentration.Can find; Use has the testosterone administration of the androgen testosterone of the auxiliary drug administration of controlled heat (CHADD sheet) through dermal system; Compare with independent use Androderm_ testosterone percutaneous system on chip, in person under inspection's blood, produced high significantly testosterone concentration.
Table B
Serum testosterone concentration
| Time (hour) | Testosterone concentration (ng/DL) Androderm_ sheet | Testosterone concentration (ng/DL) Androderm_ sheet+ |
| 0 | 340 | 325 |
| 2 | 456 | 722 |
| 4 | 402 | 961 |
| 6 | 567 | 1020 |
| 8 | 339 | 558 |
| 10 | 463 | 647 |
In being designed for the experimental study of the absorption whether drug-supplying system of confirming controlled heat can obviously strengthen testosterone; An adult volunteer accepted the Androderm_5mg sheet 12 hours on the first treatment arm, on the second treatment arm, accepted the Androderm_5mg sheet and added the activatory percutaneous dosing of CHADD controlled heat 12 hours.Each treatment arm all keeps three days time.The Androderm_ sheet is that the TheraTech company of Salt Lake City, Utah, United States produces.The CHADD sheet is the ZARS manufactured, and its function is similar with the heating plate that designs and generation table D (below) data are used.It is made up of 5 members: foam is with cover, microporous membrane, heating medium, foam tape bin and bottom adhesive tape layer, and the heating medium is contained in the foam tape bin.Except the heating medium, the 3M manufactured of Minn. Minneapolis the material of the CHADD sheet element that is useful on.
Therefore, can think that the raising temperature increases the permeability (with the ATTS120 ratio that does not have such heating arrangements) of skin, and causes the testosterone quickening that gets in the circulation of patient's body.This will make the serum testosterone reach required therapeutic dose quickly.Also think to add the permeability that heat energy strengthens hypodermic body fluid circulation and blood vessel wall, and make testosterone get into the subcutaneous tissue stored position with little time.As a result, the patient received male hormone compound quickly and received the treatment that improves (with the ATTS120 that does not heat not the testosterone of transmissibility q.s situation than).
It should be understood that androgenic concentration in the circulation of desirable increase body can reach through increasing androgen derivant that androgenic concentration that drug-supplying system sends and/or drug-supplying system send and/or different androgens.For example, in order to increase the concentration of testosterone in the body circulation, can send the testosterone enanthate through drug-supplying system.Like this, drug-supplying system androgen (in this situation, being the testosterone enanthate) has made things convenient for the increase of target androgen (testosterone) concentration in the body circulation.
1. whether obviously increase in the research of absorption of testosterone being designed for the heating of confirming the controlled heat drug-supplying system, in 12 hours time, gathered six adult volunteers' serum testosterone level.Then, the volunteer accepted the Andorderm_5mg sheet 12 hours on the first treatment arm.The volunteer has accepted the Andorderm_5mg sheet again and has added the activatory percutaneous dosing of CHADD controlled heat 12 hours on the second treatment arm.Each treatment arm all keeps three days time.The Androderm_ sheet is that the TheraTech company of Salt Lake City, Utah, United States produces.The CHADD sheet is the ZARS manufactured, and its function is similar with the heating plate that designs and generation table D (below) data are used.It is made up of 5 members: foam is with cover, microporous membrane, heating medium, foam tape bin and bottom adhesive tape layer, and the heating medium is contained in the foam tape bin.Except the heating medium, the 3M manufactured of Minn. Minneapolis the material of the CHADD sheet element that is useful on.Between CHADD sheet and Androderm_ sheet, put into gauze belt so that take off the CHADD sheet after using up.
On non-treatment arm, gathered the venous blood sample that is used to measure serum testosterone concentration, to obtain base-line data in 0,1,2,4,6,8,10 and 12 hour.Before executing sheet (0 hour) and execute sheet after gathered the venous samples can be used to detect serum testosterone concentration in 2,4,6,8,10 and 12 hours.After exhausting blood in 12 hours, take off chip system.Selected Androderm_ testosterone is the 5mg system through dermal system, and it has 24cm
2Total contact area and 15cm
2Medicament reservoir wherein contains the 24.3mg testosterone USP that is dissolved in the alcohol-based gel.Use radioimmunoassay to confirm serum testosterone concentration.Table B-1 has provided 0,1,2,4,6,8,10 and 12 hour serum testosterone concentration.As experimental study; This research shows; Use has the testosterone administration of the androgen testosterone of the auxiliary drug administration of controlled heat (CHADD sheet) through dermal system; Compare with independent use Androderm_ testosterone percutaneous system on chip, produced obvious high testosterone concentration in person under inspection's blood.
Table B-1
| CHADD-Androderm research 5/99 | |||||
| The 1# person under inspection | Serum testosterone concentration (ng/DL) | ||||
| Time (hr) | The nature baseline | Use Androderm separately | Androderm +CHADD | The Androderm baseline | |
| 0 | 500 | ?515 | 354 | 15 | -146 |
| 1 | 425 | ?442 | 566 | 17 | 141 |
| 2 | 464 | ?429 | 626 | -35 | 162 |
| 4 | 542 | ?687 | 967 | 145 | 425 |
| 6 | 567 | ?470 | 706 | -97 | 139 |
| 8 | 353 | ?498 | 735 | 145 | 382 |
| 10 | 315 | ?506 | 742 | 191 | 427 |
| 12 | 388 | ?614 | 727 | 226 | 339 |
| The 2# person under inspection | Serum testosterone concentration (ng/DL) | ||||
| Time (hr) | The nature baseline | Use Androderm separately | Androderm +CHADD | The Androderm baseline | |
| 0 | 299 | ?287 | 314 | -12 | 15 |
| 1 | 357 | ?314 | 400 | -43 | 43 |
| 2 | 335 | ?321 | 544 | -14 | 209 |
| 4 | 387 | ?459 | 1020 | 72 | 633 |
| 6 | 350 | ?561 | 641 | 211 | 291 |
| 8 | 397 | ?509 | 555 | 112 | 158 |
| 10 | 408 | ?519 | 536 | 111 | 128 |
| 12 | 335 | ?523 | 597 | 188 | 262 |
| The 3# person under inspection | Serum testosterone concentration (ng/DL) |
| Time (hr) | The nature baseline | Use Androderm separately | ?Androderm?+CHADD | The Androderm baseline | Androderm+ CHADD baseline |
| 0 | 360 | ?394 | ?414 | 34 | 54 |
| 1 | 319 | ?413 | ?530 | 94 | 211 |
| 2 | 271 | ?455 | ?666 | 184 | 395 |
| 4 | 362 | ?604 | ?878 | 242 | 516 |
| 6 | 389 | ?677 | ?590 | 288 | 201 |
| 8 | 234 | ?551 | ?597 | 317 | 363 |
| 10 | 295 | ?588 | ?542 | 293 | 247 |
| 12 | 327 | ?635 | ?658 | 308 | 331 |
| The 4# person under inspection | Serum testosterone concentration (ng/DL) | ||||
| Time (hr) | The nature baseline | Use Androderm separately | ?Androderm ?+CHADD | The Androderm baseline | Androderm+ CHADD baseline |
| 0 | 279 | ?272 | ?246 | ?-7 | -33 |
| 1 | 285 | ?241 | ?441 | ?-44 | 156 |
| 2 | 243 | ?341 | ?514 | ?98 | 271 |
| 4 | 214 | ?322 | ?592 | ?108 | 378 |
| 6 | 261 | ?394 | ?586 | ?133 | 325 |
| 8 | 268 | ?380 | ?587 | ?112 | 319 |
| 10 | 240 | ?393 | ?456 | ?153 | 216 |
| 12 | 205 | ?363 | ?477 | ?158 | 272 |
| The 5# person under inspection | Serum testosterone concentration (ng/DL) | ||||
| Time (hr) | The nature baseline | Use Androderm separately | ?Androderm ?+CHADD | The Androderm baseline | Androderm+ CHADD baseline |
| 0 | 373 | ?266 | ?434 | ?-107 | 61 |
| 1 | 370 | ?409 | ?567 | ?39 | 197 |
| 2 | 419 | ?502 | ?847 | ?83 | 428 |
| 4 | 314 | ?667 | ?1103 | ?353 | 789 |
| 6 | 364 | ?732 | ?790 | ?368 | 426 |
| 8 | 283 | ?749 | ?876 | 466 | 593 |
| 10 | 356 | ?650 | ?723 | 294 | 367 |
| 12 | 413 | ?619 | ?808 | 206 | 395 |
| The 6# person under inspection | Serum testosterone concentration (ng/DL) | ||||
| Time (hr) | The nature baseline | Use Androderm separately | ?Androderm ?+CHADD | The Androderm baseline | |
| 0 | 484 | ?484 | ?447 | 0 | -37 |
| 1 | 457 | ?518 | ?864 | 61 | 407 |
| 2 | 396 | ?523 | ?1057 | 127 | 661 |
| 4 | 385 | ?742 | ?857 | 357 | 472 |
| 6 | 395 | ?608 | ?1076 | 213 | 681 |
| 8 | 472 | ?708 | ?790 | 236 | 318 |
| 10 | 420 | ?528 | ?787 | 108 | 367 |
| 12 | 368 | ?580 | ?828 | 212 | 460 |
| On average | |||||
| On average | Serum testosterone concentration (ng/DL) | ||||
| Time (hr) | Average baselining | Use Androderm average separately | Androderm+CHADD is average | The Androderm baseline is average | Androderm+ CHADD baseline is average |
| 0 | 382.5 | ?369.67 | ?368.17 | -12.83 | -14.33 |
| 1 | 368.83 | ?389.5 | ?561.33 | 20.67 | 192.5 |
| 2 | 354.67 | ?428.5 | ?709 | 73.83 | 354.33 |
| 4 | 367.33 | ?580.17 | ?902.83 | 212.83 | 535.5 |
| 6 | 387.67 | ?573.67 | ?731.5 | 186 | 343.83 |
| 8 | 334.5 | ?565.83 | ?690 | 231.33 | 355.5 |
| 10 | 339 | ?530.67 | ?631 | 191.67 | 292 |
| 12 | 339.33 | ?555.67 | ?682.5 | 216.5 | 343.17 |
Fig. 8-12 shows another instance that uses the embodiment of the invention, and it is used for transdermal administration of nicotine to suppress the demand to nicotine, comprises that user is put into nicotine DDDS160,165 on the skin 134.After several hours, obtain the nicotine concentration of stable state in the user blood flow, this is enough to suppress the primary demand to nicotine.When user began to increase to the demand of nicotine, user was placed on temperature control equipment 150 above the DDDS160,165.Preferably, before exothermic reaction ran out of thermoregulation mechanism 108, temperature control equipment 150 heated 15 minutes at least.Accelerated nicotine and passed the transmission of skin, and accelerated flowing of blood in DDDS160, the 165 below tissues, thereby brought body into and circulate being stored in nicotine in DDDS160, the 165 below tissues with the speed accelerated.As a result, the concentration of nicotine increases with the urgent needs of treatment to nicotine fast in the user blood.After the heating, the nicotine absorption rate is got back to nicotine Css in the normal blood flow gradually.
Embodiment 3
Fig. 8-12 shows another instance that uses the embodiment of the invention; It is used for the percutaneous dosing of testosterone to increase and to optimize the drug administration amount; Comprise user DDDS160,165; Skin testosterone sheet once a day for example, the Androderm_ sheet as the TheraTech company of Salt Lake City, Utah, United States produces is put on the skin 134.Generally at night, like point in evenings 10, use DDDS160,165 on the skin 134.But if user can not obtain the testosterone of sufficient dosage at second day, user just is placed on temperature control equipment 150 above the DDDS160,165.DDDS160,165, the skin absorbs of the obvious testosterone of rising of skin 134 and subcutaneous tissue temperature.In addition, if DDDS160,165 has penetration enhancers, glycerin mono-fatty acid ester for example, heating also makes the skin that sees through of reinforcing agent accelerate, thereby makes its efficient higher.Final result is that user obtains enough testosterone from DDDS160,165.And when user was starved of high dose, user also can be placed on temperature control equipment 150 above the DDDS160,165 in the morning, so that from morning to night can both send higher testosterone.Can reduce the concentration of the penetration enhancers that uses among the DDDS160,165 through the absorption of controlled heat increase testosterone.In testosterone DDDS, need penetration enhancers usually in order to send enough testosterone, still, penetration enhancers can cause serious skin irritation, for example the glycerin mono-fatty acid ester in the Androderm_ sheet.
Embodiment 4
Certainly, it should be understood that DDDS160,165 and temperature control equipment 150 can be used for athletic injury.For example, people ancon in sporting accident or this type of incident is injured, and user can use the DDDS160,165 that contains analgesic, for example contains dexamethasone, wintergreen oil or this type of medicine among the DDDS160,165.The heat that temperature control equipment 150 produces drives more medicine and gets into ancon, and the blood flow increase that causes of heating make medicine get into ancon than the depths.
Embodiment 5
Another instance that use is shown in Fig. 8-12 embodiment of the invention comprises; When the diffusion coefficient of active component in the preparation 128 and/or pass too low so that its major decision of the infiltration coefficient of speed limit film 130 medicine from DDDS160,165, absorb when getting into the intravital total absorption rate of patient 150 administrations of serviceability temperature control device.As using DDDS160,165 instance, patient or care-giver are placed on DDDS160,165 on the patient skin 134.If use DDDS160, after 165 a period of times; Confirmed for this particular patient and the state of an illness thereof; Need higher drug level to treat his disease rightly in the blood flow, just be placed on temperature control equipment 150 above the DDDS160,165 with heating DDDS160,165.
Elevated temperature increases the diffusion coefficient of preparation active component among the DDDS160,165 and the infiltration coefficient that speed limit film 130 among the DDDS160,165 is passed in increase, this then increased active component and got into the intravital total speed of patient.Therefore increased the concentration of active component in the blood flow.As a result, the improved and appropriate effect of patient.
Embodiment 6
Another embodiment that use is shown in Fig. 8-12 embodiment of the invention comprises, and serviceability temperature control device 150 is to shorten the zero-time that medicine oozes out from DDDS160,165.For instance, patient or care-giver are placed on DDDS160,165 on patient's the skin 134, and are placed on temperature control equipment 150 on the DDDS160,165.Preferably, temperature control equipment 150 comprises active carbon, iron powder, sodium chloride and the water of sufficient amount in thermoregulation mechanism 108, to keep at least 4 hours exothermic reaction.
The heat that from temperature control equipment 150, discharges improves skin 134 and DDDS160,165 contact surface to about 60 ℃ temperature; The narrow temperature scope between about 36～46 ℃ preferably; More preferably between about 37～44 ℃; And in a period of time, keep this temperature (that is, about 4 hours).During this period of time, heat has been accelerated the speed that medicine discharges, the infiltration rate that passes skin 134 and sanguimotor speed from DDDS160,165, brings fentanyl in the body circulation into quickly.After exothermic reaction stops (about 4 hours), the absorption of blood flow Chinese medicine and concentration begin to be reduced to from the higher level that DDDS160,165 heat releases cause and normally (do not heat) level.The patient continues to use this system to certain time between 48 to 72 hours altogether.Compare with the DDDS160,165 of serviceability temperature control device 150 not; Medicine begins obviously to do sth. in advance in the time that blood flow occurs; Shortened zero-time, and in initial several hours of using blood flow Chinese medicine concentration apparently higher than the concentration that does not heat DDDS160,165 generations.Curative serum drug level varies with each individual.For example, some people's response is higher than the concentration of 0.2ng/ml.With reference to figure 6, reaching the required time of 0.2ng/ml concentration with heating system is 1/3rd (that is, about 70 minutes compare with about 210 minutes) with heating system not.
After a period of time; When the exothermic reaction of temperature control equipment 150 stops adstante febre gradually; The concentration of blood flow Chinese medicine begins to reach gradually its normal stable state drug level, if the competent time is arranged, in the DDDS160 that does not heat, 165, finally also will reach this concentration.The result; Temperature control equipment 150 is not having obviously to change the zero-time that obviously shortens the sheet Chinese medicine under the situation of stable state medicine-feeding rate; Thereby the significant advantage that the method provides is, can shorten in the DDDS160 of clinical use, 165 zero-time not having obviously to change under the situation of stable state medicine-feeding rate; Said stable state medicine-feeding rate is not only enough, and is that care-giver and patient are familiar with.
Embodiment 7
Another instance that use is shown in Fig. 8-12 embodiment of the invention comprises that also serviceability temperature control device 150 is to shorten the zero-time that medicine oozes out from DDDS160,165.For instance, before the treatment of pain program, local anesthetic, like the eutectic mixture of lignocaine and tetracaine, can be with DDDS160,165 administrations so that skin 134 lose sensibility and then carry out painful operation.Comparatively fast come into force at short notice and darker anaesthetic effect through being placed on temperature control equipment 150 can reach on the DDDS160,165; Wherein temperature control equipment 150 can be heated to skin in about 37 ℃～41 ℃ close limit; Preferably about 39 ℃～40 ℃, reach 30 minutes at least.Skin 134 lost sensibility in 30 minutes or short time, and these are more a lot of than the weak point that not have to heat.Depend on original skin temperature, do not heat about 60% of zero-time according to thinking that this heating will reduce zero-time.
Embodiment 8
Another embodiment that use is shown in Fig. 8-12 embodiment of the invention comprises that also serviceability temperature control device 150 increases the dissolubility of DDDS160,165 Chinese medicines.For example, preparation design the dissolubility of medicine in preparation that contain too low so that wherein major part be undissolved grain shape, but dissolubility increases with the rising of formulation temperature.
The patient is placed on this DDDS160,165 on the skin of oneself.If the medical compounds underdosage that the patient accepts from DDDS160,165, the patient just is placed on temperature control equipment 150 on the DDDS160,165.The heat that temperature control equipment 150 produces has improved the temperature of preparation among the DDDS160,165, and keeps the temperature of this rising in the suitable major part of DDDS160,165 application processes or all.The rising of formulation temperature has increased the dissolubility of preparation of Chinese medicine chemical compound.Therefore, more the multiple medicines compounds is dissolved in the preparation, just obtains the driving force of higher medical compounds transdermal penetration.As a result, more medical compounds gets in patient's body.
Although embodiment 1-10 has discussed the application of concrete medicine, should be understood that the present invention is not limited to any specific drugs.It should be understood that considerable drug kinds and specific drugs can use in the present invention.Drug kinds includes but not limited to: androgen, estrogen, on-steroidal anti-inflammatory agent, antihypertensive, analgesic, antidepressant, antibiotic, anticarcinogen, local anesthetic, Bendectin, infection medicine, contraceptive, antidiabetic drug, steroid, antiallergic agent, antimigraine, smoking deterent and appetrol.Specific medication includes but not limited to: testosterone, estradiol, nitroglycerin, clonidine, dexamethasone, wintergreen oil, tetracaine, lignocaine, fentanyl, sufentanil, Progesterone, insulin, vitamin A, vitamin C, vitamin E, prilocaine, marcaine, sumatriptan and dihydroergotamine.
Embodiment 9
Another instance that use is shown in Fig. 8-12 embodiment of the invention comprises that also serviceability temperature control device 150 maintains stable temperature to DDDS160,165.Some drugs has lower therapeutic index, and the meaning is the difference between therapeutic dose and can causes that the dosage of serious and/or undesirable side effect is little.Like this, the percutaneous dosing of these medicines possibly be dangerous (excessive) or invalid (amount of owing), particularly is exposed to the big individuality of variation of ambient temperature, the people who for example under the extreme weather situation, works for those skins.The variation of ambient temperature can cause the variation of skin temperature, and this can obviously change the final skin absorbs of medicine.Cover the DDDS160,165 that contains low therapeutic index medicine with temperature control equipment 150 and can in narrow temperature range, regulate skin temperature, and reduce the variation of medicine skin absorbs.Medicine or drug kinds that can be from the method; Comprise medicine but be not limited to: medicine and drug kinds such as on-steroidal anti-inflammatory agent, antihypertensive, analgesic, antidiabetic drug and antimigraine such as nicotine, nitroglycerin, clonidine, fentanyl, sufentanil and insulin.
Another embodiment of Figure 13-19 expression temperature control equipment 170.The temperature control equipment 170 that Figure 13 representes is similar with embodiment shown in Figure 8, but comprises the thermoregulation mechanism of being made up of a plurality of chambers 172 108, is separated by airtight wall 174 between the chamber 172.Thermoregulation mechanism 108 is surrounded by diapire 102, roof 104 and sidewall 152 basically.Once more, thermoregulation mechanism 108 comprises that preferably the ground component has active carbon, iron powder, sodium chloride, water and selective sawdust, is placed with this component in each chamber 172.Roof 104 also is flexible gas impermeable material preferably, wherein is installed with a plurality of holes 114, and preferably, there is delegation hole 114 each chamber 172.Between roof 104 and thermoregulation mechanism 108, be placed with ventilated membrane 116, to regulate the air capacity that reaches thermoregulation mechanism 108 through hole 114.Roof 104 has at least a lid to cover a plurality of holes 114 that are used to regulate air admission chamber 172.Shown in figure 13, three layers of lid are arranged on the roof 104.First cap rock 176 is attached on the roof 104, and opening 178 (seeing Figure 17) is arranged so that expose 2 in 3 holes 114.Second cap rock 182 is attached on first cap rock 176 and opening 184 (seeing Figure 15) is arranged so that expose 1 in 3 holes 114.Top cover 186 does not have opening, is attached on second cap rock 182.Like this, the patient has different selections to the percent that chamber 172 is exposed in the surrounding air.From 1/3rd Room, generate heat if desired, remove top cover 186, shown in Figure 14 and 15.If also need other heat after heating or first thermoregulation mechanism of 1/3rd 108 use up from 2/3rds Room if desired, the top cover 186 and second cap rock 182 all remove, shown in Figure 16 and 17.The other heat of needs also after if the heating of being had family if desired or first use up with second 1/3rd thermoregulation mechanism 108, top cover 186, second cap rock 182 and first cap rock 176 all remove, shown in Figure 18 and 19.Certainly, it should be understood that to use to have the cap rock arbitrary number metering-orifice, more or less, with the thermoregulation mechanism 108 that activates any requirement.
Thereby for instance, the patient can have a lot of selections when serviceability temperature control device 170, be used to suppress severe pain.When severe pain was shown effect, the patient was placed on analgesic drug product DDDS to temperature control equipment 170 and goes up and do by following each:
1) depends on the essential lid of how much removing of the required extra analgesic drug product of treatment severe pain, activate the chamber 172 of specific quantity or percent.Preferably, when no longer needing extra analgesic drug product, can also preferably stick lid again to end exothermic reaction.
2) chamber 172 of activation specific quantity or percent uses up the heat that can produce in those chambers 172, then activates other (unactivated) chamber 172.This has prolonged the heat time heating time of temperature control equipment 170.The length of total heat time heating time was confirmed by the typical persistent period of particular patient severe pain.
3) activate the severe pain of once showing effect with treatment in enough chambers 172, and keep heating plate in situ.When the severe pain of outbreak next time arrives, activate the not chamber 172 of usefulness.
Transdermal drug delivery system 190 shown in Figure 20 (hereinafter is designated as " DDDS190 ") has speed limit film 192.Similar among the structure of DDDS190 and Fig. 3.But DDDS190 comprises speed limit film 192, and it is between pharmaceutical preparation 128 and patient skin 134.
Usually, pharmaceutical preparation 128 Chinese medicines are starkly lower than the permeability that pharmaceutical preparation 128 Chinese medicines get into general patient skin through the permeability of speed limit film 192.The use of speed limit film 192 can make total infiltration reach minimum degree, and regulates and to give the quantity of patient's medicine, thereby avoids taking place overdose.Another aspect of the present invention is to use temperature sensitive speed limit film, and the infiltration rate that makes medicine pass through the speed limit film raises with temperature and obviously increases.Use this DDDS190; Said temperature control device 100 (Fig. 1 and 2), 150 (Fig. 8) and 170 (Figure 13) can be used to increase the drug administration speed of passing speed limit film 192, reach treatment severe pain, reduce zero-time, increase stable state medicine-feeding rate or other above-mentioned advantage.
Possible temperature control device is not limited to the exothermic reaction mixture, for example above-mentioned iron powder, active carbon, salt, water and sawdust.Figure 21 illustrates a kind of electron temperature controlling organization 200, comprises electrical heating elements 202, and it surrounds (similar like Fig. 8) by diapire 202, roof 104 and sidewall 152.Sidewall 152 preferably, extends a segment distance to define cavity 154 below diapire 102.Certainly, it should be understood that the electrical heating elements 202 unnecessary sidewalls 152 that formation cavity 154 is arranged.
Diapire 102 is preferably processed by the gas impermeable material of flexibility with sidewall 152, for example the foamed materials of air-locked closed pore.The part of temperature control equipment 200 bottoms is included in the jointing material 112 on the sidewall 152, and is preferably incorporated in second jointing material 156 of diapire 102 bottoms, and the adhesive force that it is characterized in that second jointing material 156 is preferably less than jointing material 112.Electrical heating elements 202 preferably comprises flexible resistance board, and it can generate heat when through line 206 and 208 electric current being provided.Electric current is preferably provided by battery 212, and battery 212 is attached on controlling organization 214 and the electrical switch 216.Battery 212, controlling organization 214 and electrical switch 216 are preferably on the top surface attached to roof 104.Through triggering electrical switch 216, electric current begins to flow to electrical heating elements 202 from battery 212, thereby makes electrical heating elements 202 work.Temperature sensor 218, critesistor for example is delivered to controlling organization 214 to signal (corresponding to the temperature of diapire 102 bottoms) preferably attached to the bottom of diapire 102, and through electric wire 222.Controlling organization 214 is regulated the electric current of electrical heating elements 202, so that electrical heating elements 202 is elevated to predeterminated level to the temperature of contact surface between diapire 102 and the DDDS (not shown) top apace.Controlling organization 214 can comprise following characteristic: 1) allow doctor or care-giver to set the mechanism of each of length for each patient, it makes the doctor can limit heating heating cycle, thus also limited based on the status of patient patient the quantity of receptible extra drug; 2) allow doctor or care-giver to set the mechanism of the shortest time between heating cycle, therefore limited the frequency of patient through the heat acquisition extra drug of increase; 3) allow doctor or care-giver to set the mechanism of predetermined temperature; And/or 4) mechanism of permission doctor or care-giver's controlled heat temperature curve for example improves heating-up temperature gradually or reduces temperature at preset time in the cycle.These characteristics might let those simple DDDS give doctor and/or patient the administration quantity of extra drug with various control selection probability was arranged on the time.
The instance of the present invention such as the embodiment shown in Figure 21 that uses comprises that serviceability temperature control device 200 shortens the zero-time of local anesthetic.This local anesthetic consists of: the tetracaine of about 14% (percentage by weight)/lignocaine eutectic mixture, and the polyvinyl alcohol of 8.6% (percentage by weight) (PVA), the sodium hydroxide of 0.17% (percetage by weight) (NaOH), all the other are water (H
2O).The local anesthetic of chip shape is placed on volunteer's left forearm; Temperature control device 200 is set to 41 ℃ of temperature of maintenance, is placed on above the local anesthetic.Local anesthetic is also placed on volunteer's the right forearm (at different time), and remains room temperature (about 24 ℃).The result lists in table D, and wherein when stinging skin with blunt object, the local anesthesia effect is weighed by pain score.Pain score defines as follows:
Mark
Effect
0 is invalid
1 between numbness and moderate numbness
2 moderate numbnesss
3 almost thorough numbnesss
4 thorough numbnesss, but not dark
5 thorough numbnesss and dark
Table D
| Time (minute) | The pain score of heating | The pain score that does not heat |
| 15 | 4 | 2 |
| 20 | 5 | 3 |
| 25 | 4 | |
| 30 | 5 |
Therefore, can find out that heating reduces thorough and gos deep into out of the count zero-time about 33%.
Embodiment 11
The instance that use is shown in Figure 23-24 embodiment of the invention comprises, uses the temperature control equipment 300 of ability heating and cooling.Thereby, can increase or reduce the absorption rate of DDDS pharmaceutical preparation as required.
For example, shown in figure 23, if when the intravital levels of drugs of patient need be regulated, just be placed on temperature control equipment 300 on the DDDS160.Heating makes drug absorption increase (as stated), and cooling then reduces drug absorption to prevent overdose.Temperature control equipment 300 shown in Figure 23 is can be used for heating also can be used for refrigerative electrothermal module.Temperature control equipment 300 is as small-sized heat pump; Wherein low-voltage dc power supply 304 provides electric current along a direction 306 in thermoelectric unit 310, and this is with first side 308 (preferably ceramic substrate) and chilling temperature control device 300 second sides 312 (preferably fin radiating structure) of heating and temperature control device 300.If current opposite in direction is then cooled off first side 308 and heating second side.
Shown in figure 24, use closed loop thermal controller 314 control temperature control equipments 300.Temperature controller 314 comprises positive direct-current node 316 and negative direct current node 318, is main circuit 320 power supplies.Main circuit 320 is sent to thermoelectric unit 310 to the signal of telecommunication 322 through voltage amplifier 324 and power amplifier 326.Main circuit 320 also comprises temperature sensor 328, and it receives temperature signal 330 from thermoelectric unit 310; Also comprise thermoregulation mechanism 332, it regulates the signal of telecommunication 332.
This treatment can be used multiple medicine and drug kinds.Said medicine includes but not limited to: nicotine, nitroglycerin, clonidine, dexamethasone, fentanyl, sufentanil and insulin.Said drug kinds includes but not limited to: androgen, on-steroidal anti-inflammatory agent, antihypertensive, analgesic, antidepressant, anticarcinogen, antidiabetic drug, steroid, antimigraine, antasthmatic and smoking deterent.
Certainly, it should be understood that above-mentioned heater can replace with the infrared heating device with feedback mechanism.Above-mentioned all control and the modification in the control may be used to this infrared heating device.Infrared Heating is that with the advantage that simple heating is compared the former permeates patient's skin under suitable wavelength darker.
Another aspect of the present invention is, uses heating and other physical means, and for example ultrasound wave, microwave, electric current and vibration improves the absorption of medicine from repository/stored position.The existence of this repository/stored position can be to obtain through the drug administration of pieces of skin or direct injection medicine or below implanting skin surface.
Have the type of preparation of response to be to above-mentioned physics inducement means:
Ultrasound wave: when using ultrasonic therapy, containing can ground grains on pharmaceutical preparation and the volume.
Microwave: the limited medicine of dissolubility in the body fluid around, but elevated temperature can obviously improve its dissolubility; Can be through increasing flowing/the obvious solid preparation of accelerating its etch/degradation rate of exchange of its ambient body fluid.
Electric current: the medicine that exists with ionic species in preparation and/or in the ambient body fluid.
Vibration: the limited medicine of dissolubility in body fluid; Can be through increasing flowing/the obvious solid preparation of accelerating its etch/degradation rate of exchange of its ambient body fluid.
Use is shown in the instance that stored position of Fig. 1 and 2 embodiment of the invention absorbs and comprises, patient or care-giver hit (the product similar products like of for example producing with Britain Powderject pharmaceuticals) through injection or other method such as supersonic speed and introduce the slow release insulin in his skin.In the slow release insulin preparation, most insulin molecules are crystal habits.After the injection, insulin comes out from the crystal habit slow release, because crystal dissolves slowly in the body fluid around.This provides and has discharged into body circulation baseline islets of langerhans.But needs of patients surpasses the extra insulin of baseline to suppress the sugar from food.Like this, before each the dining, the patient preferably is designed to one section preset time of controlled heat (promptly between about 15～60 minutes) to temperature control equipment 100, is placed on the skin of injection point, has injection slow release insulin preparation at the injection point place.The heating of temperature control equipment 100 has accelerated to prolong flowing of blood and other body fluid in the insulin preparation surrounding tissue, has improved the rate of dissolution of insulin and has brought insulin into the body circulation with speed faster.The duration of heat of temperature control equipment 100, preferably, design lasting long enough, to discharge the extra insulin of q.s, handle sugar from food.Like this, the patient has accepted to regulate from the suitable absorption of insulin of slow releasing preparation, and makes a choice between the physiology consequence that need before having meal, not take extra insulin pill and caused by the hyperglycemia from food.
Embodiment 13
The instance that use is shown in a stored position absorption of Fig. 1 and 2 embodiment of the invention comprises that patient or care-giver are expelled to the medicine that is mixed in the controlled release granule below the skin surface.Medicine is sneaked into controlled release drug-supplying system (Atrigel for example
TMThe product of the Atrix Laboratories company of Colorado Fort Collins); The polymer biodegradable, biocompatibility that is included in the biodegradable solvent (being N-methyl-2-pyrrolidone) [is a poly DL-lactide; Poly DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester, poly DL-lactide/6-caprolactone, polycaprolactone or their combination].In order to control patient's cancer pain, usually be expelled to controlled release formulation in the following 3cm of patient skin, in the preferred 1cm, in the preferred 0.3cm.
It should be understood that the homopolymer or the copolymer that can use any lactic acid or hydroxyacetic acid.Lactic acid or hydroxyacetic acid polymer are solids, it is characterized in that medicine and polymer all are dissolved in the biodegradable organic solvent.After the injection, biodegradable organic solvent diffuses out, and has stayed polymer with sedimentary, biodegradable particulate form, and it is keeping most of medicine.When polymer beads etch/degraded gradually, drug release gets into the body circulation.Release rate of drugs is by polymer beads etch/degradation rate decision in vivo.
Use diverse ways, stored position can sneaked into and be sent to active drug also, for example sneaks into medicine in the polymer of biodegradable, the biocompatibility that dissolves in solvent, and evaporating solvent obtains sneaking into the polymeric granule of active drug.The medicine size that comprises polymer beads should be enough little, to sneak into the suspension of (not dissolving in) liquid (preferably aqueous solution).Suspension is injected into the tissue of patient near skin surface.The liquid stored position that speeds away stays the polymer implant that contains active drug.Can accelerate the release of active drug with aforesaid way from the polymer implant.
Embodiment 14
Detected the influence of heating to the release of the medicine of sneaking into bio-compatible, biodegradable polymers matrix.Sneak into polymeric matrix (that is lactide/glycolide polymer) to anesthetics (that is lignocaine) and form anesthetics/polymeric blends.It is subcutaneous that anesthetics/polymeric blends is used for injection/implantation patient, and wherein, slowly erosion is when invading in vivo when polymeric matrix, and medicine discharges in the body gradually.
The making of anesthetics/polymeric blends is to be dissolved in the lactide/glycolide polymer of 1/10 gram (Medisorb level 8515DL, the Medisorb of Ohio, USA Cincinnati technology international corporation product) and 0.1g lignocaine base in the 2g acetone to form solution.In solution, slowly add about 5ml water (pH value is adjusted to 8), use the bar magnet agitating solution of atwirl polytetrafluorethylecoatings coatings simultaneously.Along with textured material attached on the bar magnet and fine grained be suspended in the solution, Medisorb lignocaine mixture precipitation comes out.Containing of about 0.5ml fine grain injection of solution go into 0.2mm the PTFE polytetrafluoroethylene filter (nalgene, 25mm).Normal saline is by 3M
TM3000 modular infusion pump were passed through the filter infusion about 7 days with the speed of 2ml/hr.This washed off do not sneak into the Medisorb matrix with the lignocaine of granule less than 0.2mm, and stay on the filter greater than lignocaine-polymer beads of 0.2mm.Because the hydrolysis granule slowly decomposes, therefore in saline, discharge lignocaine gradually through filter.
Tie up the port of export at filter to blunt pin tightly, thin plastic tube is tied up on blunt pin.Collect according to following steps from the solution that the terminal effusive filtration of thin plastic tube is intact:
Step 1: filter down in room temperature (about 24 ℃), be collected in the solution that has filtered in the vial about 1 hour;
Step 2: immerse filter in the water-bath of 36 ℃ (approximately), waited about 1 hour, collected the solution that finishes from the effusive filtration of light wall pipe about 1 hour;
Step 3: the temperature that improves water-bath waited about 1 hour to about 44 ℃, about 1 hour of the solution that collection has been filtered;
Step 4: from water-bath, take out filter, put about 0.5 hour, about 1 hour of the solution that collection has been filtered in room temperature (about 24 ℃);
Step 5: repeating step 4 after about 2 hours.
In whole experiment, saline passes through the filter infusion with the speed of 2ml/hr.Discard the solution that in non-acquisition time, flows out from thin plastic tube.Measure the concentration of lignocaine in the above-mentioned collection solution through HPLC (HPLC) method.
Lignocaine densitometer from collect sample has been calculated lignocaine rate of release from polymeric matrix under different temperatures.Rate of release is shown in following table E:
Table E
| Step | Temperature | Lignocaine rate of release (mcg/hour) |
| 1 | 24℃ | 0.36 |
| 2 | 36℃ | 0.61 |
| 3 | 44℃ | 1.59 |
| 4 | 24℃ | 0.47 |
| 5 | 24℃ | 0.38 |
In The above results, when the temperature of filter raise, the lignocaine rate of release was accelerated; When the temperature of filter reduced, the lignocaine rate of release slowed down.Although step 4 is identical with the temperature of 5 middle filtrators, the rate of release of lignocaine is lower than the value of step 4 in the step 5, and reaches the value of step 1.
Although do not measure the total amount of Medisorb and lignocaine in the filter, the relative difference of benefit caine rate of release shows under the different temperatures, and the rate of release of lignocaine from the Medisorb polymer increases with the rising of temperature.The result that the rate of release of lignocaine is lower than in step 5 in step 4 shows that temperature reduces the back rate of release and reduces gradually.
Because according to thinking degraded (hydrolysis) the controlled release speed of Medisorb polymer, these results show that the degradation rate of Medisorb polymer increases with the rising of temperature.This shows and can increase any Medisorb of sneaking into matrix (or other similar material) and be injected into intravital release rate of drugs through elevated temperature.Except increasing the particulate hydrolysis rate of Medisorb-lignocaine, heating also can increase the flow rate of stored position granule ambient body fluid in practical application, and it is more to cause drug absorption speed to increase.
For Medisorb (identical), also carried out other experiment with above-mentioned model.The heavy 0.1024g of first Medisorb sample (transparent bead) puts into the vial with 9.9024g 0.9% sodium chloride injection.With sealing film phonograph seal first vial, and put into stove and keep about 43 ℃ of temperature.Second heavy 0.1028g of Medisorb sample puts into the vial with 9.9167g 0.9% sodium chloride injection.With sealing film phonograph seal second vial, and put into stove and keep about 23 ℃ of temperature.
After 29 days, visible variation does not appear in the Medisorb (second sample) that remains on room temperature.But the Medisorb that is maintained at about 43 ℃ becomes the milky with smooth edge from transparent material.The Medisorb globule is also little than original size.This simple experiment shows that the degradation rate of Medisorb polymer is accelerated with the rising of temperature.
Another instance that use is shown in the stored position absorption of Fig. 1 and 2 embodiment of the invention comprises that patient or care-giver implant the solid members of being processed by material (as listed among the embodiment 16) biocompatible, biological etch (being plate, rod or similar) below the skin surface.As for example, can sneak into insulin in this type material.Implant the position in about 3cm under the diabetics skin to the solid members of insulin-containing, preferably within the 1cm, more preferably within the 0.3cm.The insulin of design from the rate of release of solid members enough in a long time (for example some months) the baseline insulin requirement is provided.Before each the dining, the patient preferably has the predetermined duration of heat to temperature control equipment 100, is placed on it and deposits on the skin points of solid members down.The heating of temperature control equipment 100 has improved the solid members blood on every side and the flow rate of other body fluid, has therefore accelerated the etch/decomposition of solid members, and is sent to extra insulin in the body circulation to suppress the sugar from food.After the predetermined lasting time end back of temperature control equipment 100 or patient were interrupted the heating of temperature control equipment 100, the etch/decomposition rate of solid members turned back to normal level gradually, and the rate of release of insulin is like this too.
And this system can be used for implanting the solid members that patient skin contains testosterone.Preferably, 100 persistent period of temperature control equipment of design very long (promptly about 6-10 hour).When the patient was starved of testosterone, the patient was placed on it to temperature control equipment 100 and deposits on the skin points of solid members down, can both in blood, obtain the testosterone level that raises in the time from the morning to the evening.
Although in embodiment 13-18, only disclose the sub-fraction medicine; But any medicine that is used for treating that meets following description all possibly benefit from the method: 1) treat the time domestic demand in the Changzhi and want medicine with the treatment of baseline rate administration (for example; Longer than one day, preferably than a girth); With 2) treat the time domestic demand in the Changzhi and want medicine treatment with the speed administration of increase in a period of time or several period.This treatment can be used multiple medicine and drug kinds.Said medicine includes but not limited to: nicotine, testosterone, estradiol, nitroglycerin, clonidine, dexamethasone, tetracaine, lignocaine, fentanyl, sufentanil, Progesterone, insulin, prilocaine, marcaine, sumatriptan and dihydroergotamine.Drug kinds includes but not limited to: androgen, estrogen, on-steroidal anti-inflammatory agent, antihypertensive, analgesic, antidepressant, antibiotic, anticarcinogen, local anesthetic, Bendectin, infection medicine, contraceptive, antidiabetic drug, steroid, antiallergic agent, antimigraine, smoking deterent, antasthmatic and appetrol.
Another instance that use is shown in the stored position absorption of Fig. 1 and 2 embodiment of the invention comprises that patient or care-giver imbed stored position to medicine.As an example; When the patient feels that the migrainous time closes on; The care-giver imbeds antimigraine for example pulverous dihydroergotamine, sumatriptan and Ergotamine through the method (device that for example utilizes Britain Powderject pharmaceuticals to make) of throwing medicine under skin stored position with high speed.Utilize the device of Powderject, drug powder is accelerated to speed and surpasses velocity of sound and throw skin into.Be applied to medicine to temperature control equipment 100 at once and imbed above the skin in zone, preferably continue about 1 hour.The heating of temperature control equipment 100 has been accelerated the flow rate of antimigraine drug ambient body fluid and has been brought antimigraine drug into the body circulation quickly.As a result, reached the treatment concentration of antimigraine drug in the blood and treated migraine in time earlier.
This technology also can be used for medicine with the administration of preventative baseline rate of release, for example antimigraine or nitroglycerin.Then, use medical cycle heating plate to discharge extra medicine when beginning.
Certainly, it should be understood that and to replace above-mentioned heater with infrared heating device with feedback mechanism or microwave heating equipment.Variation in above-mentioned all controls and the control all may be used on this device.
Embodiment 17
Particularly, and when controlled release formulation is the bigger shape of granule (, 25 μ m or bigger), the ultrasonic rate of release that can be used for increasing the pharmaceutical preparation of injection controlled release.Controlled release formulation is injected into the tissue in about 3cm under the patient skin, within the preferred 1cm, within the preferred 0.3cm.Granule etch/degradation rate decision drug release rate, and the medicine steady state release rates of design can be to the medicine of patient's delivery treatments amount.For analgesic drug product, steady state release rates is usually a little less than the requirement of treating the average patient postoperative pain.For the not enough particular patients ' of steady state release rates (because of its drug effect and/or pain level), to preparation, and become more tiny granule (this require granule can by ultrasonication) to ultrasonication to grain breakage.
This has increased the surface area that is exposed to the preparation in the ambient body fluid, thereby has increased the rate of release of surplus back administration.This method enables to carry out the administration of safe low rate of release preparation, and subsequently the patient of the higher medicine-feeding rate of needs is increased rate of release.Can be increased to suitable amount to rate of release through selecting hyperacoustic intensity, frequency and persistent period.The ultrasonic therapy of example and device see also the United States Patent (USP) 4,948,587 of granting people such as Kost on August 14th, 1998, and this paper income is drawn as a reference.
Particularly, when controlled release formulation exists with ionic species, on the part of patient body, produce the rate of release that electromotive force is used to increase the pharmaceutical preparation of injection controlled release in preparation and/or ambient body fluid.For example; In the controlled release injection of insulin is gone into diabetics skin; The normal rate of release of insulin from preparation is characterized in that by the granule rate of dissolution control that comprises insulin normal rate of release provides enough baseline insulin levels in patient's body.Shown in figure 26, the patient is placed on first electrode 262 on the skin 134 of injection point top of controlled release insulin preparation 264.Second electrode 266 be placed on position on the skin 134 near the injection point (that is, leaving several centimetres at least) of controlled release insulin preparation 264.Before each the dining, the level that increases insulin in his blood when needs of patients is when suppressing from food sugared, and the patient is connected to electric current-producing device 272 to first electrode 262 and second electrode 266 respectively with electric wire 268 and 270.Electric current-producing device 272 produces electromotive force between first electrode 262 and second electrode 266.Preferably, when using insulin, current intensity should be between about 0.2～0.4mA.Because on physiological pH value, the negative charge that the insulin molecule band is clean, first electrode 262 should have negative charge, to promote electronegative insulin away from the body fluid around the preparation and get into body circulation 254.This accelerates the release of insulin.Preferably, current's intensity and persistent period available current generator 272 change, to send the extra insulin of required therapeutic dose.
Particularly; When the dissolubility of controlled release formulation in body fluid has in limited time; When perhaps etch/the degradation rate of solid preparation can obviously be accelerated through the mobile and exchange that increases the solid preparation ambient body fluid, on controlled release pharmaceutical preparation injection point, produce the rate of release that vibration can be used for accelerating preparation.For example; In the controlled release injection of insulin is gone into diabetics skin; The normal rate of release of insulin from preparation is by comprising the control of the particulate etch of insulin/decomposition or rate of dissolution, and wherein normal rate of release provides enough baseline insulin levels in patient's body.Shown in figure 27, before each the dining, the patient is placed on vibration generating apparatus 282 on the skin 134 of injection point top of controlled release insulin preparation 264.Vibration generating apparatus 282 preferably, produces the vibration between about 20～400Hz.Body fluid (not shown) around the vibrational excitation controlled release insulin 264 is also accelerated its circulation.As a result, from controlled release insulin preparation 264, be discharged in the body circulation 254 at the not long ago more insulin of having meal.Preferably, the intensity of vibration and persistent period can use vibration generating apparatus 282 to change, to send the extra insulin of required therapeutic dose.
Although in embodiment 19-22, only provided several drugs; But any medicine that is used for treating that meets following description all possibly benefit from introducing the physical method of accelerating to discharge: 1) treat the time domestic demand in the Changzhi and want medicine with the treatment of baseline rate administration (for example; Longer than one day, preferably than a girth); 2) treat the time domestic demand in the Changzhi and want medicine treatment with the speed administration of increase in a period of time or several period; With 3) preparation that one or more physical methods that introduce to accelerate discharge are responded.This treatment can be used multiple medicine and drug kinds.Said medicine includes but not limited to: nicotine, testosterone, estradiol, nitroglycerin, clonidine, dexamethasone, tetracaine, lignocaine, fentanyl, sufentanil, Progesterone, insulin, prilocaine, marcaine, sumatriptan and dihydroergotamine.Said drug kinds includes but not limited to: androgen, estrogen, on-steroidal anti-inflammatory agent, antihypertensive, analgesic, antidepressant, antibiotic, anticarcinogen, local anesthetic, Bendectin, infection medicine, contraceptive, antidiabetic drug, steroid, antiallergic agent, antimigraine and smoking deterent.
Another embodiment of the present invention comprises, and uses temperature control equipments 300 similar with the device shown in Figure 23, can heating and cooling, thereby, can increase or reduce to inject the absorption rate of controlled release pharmaceutical preparation when needed.
For example; When controlled release pharmaceutical preparation is injected in the patient skin; The normal rate of release of insulin from preparation is by comprising the particulate etch of insulin/degradation rate control, and wherein, normal rate of release provides enough baseline insulin levels in patient's body.Shown in figure 28, if when the intravital levels of drugs of patient need be regulated, just be placed on temperature control equipment 300 on the skin 134 of injection point top of controlled release pharmaceutical preparation 302.Heating makes drug absorption increase (as stated), and cooling then reduces drug absorption to prevent overdose.Temperature control equipment 300 shown in Figure 23 is can be used for heating also can be used for refrigerative electrothermal module.Temperature control equipment 300 plays small-sized heat pump; Wherein, Low-voltage dc power supply 304 provides the electric current along a direction 306 in thermoelectric unit 310, make first side 308 (preferably ceramic substrate) and chilling temperature control device 300 second sides 312 (preferably fin radiating structure) of heating and temperature control device 300.If reverse the sense of current, will cool off first side 308 and heat second side 312.Shown in Figure 24 like the front, use closed loop thermal controller control temperature control equipment 300.
This treatment can be used multiple medicine and drug kinds.Said medicine includes but not limited to: nicotine, nitroglycerin, clonidine, dexamethasone, fentanyl, sufentanil and insulin.Said drug kinds includes but not limited to: androgen, on-steroidal anti-inflammatory agent, antihypertensive, analgesic, antidepressant, anticarcinogen, antidiabetic drug, steroid, antimigraine and smoking deterent.
Embodiment 21
Another embodiment of the present invention comprises: use temperature control equipment 300 shown in figure 23, perhaps any device that can cool off skin and contain the injectable liquids drug administration preparation of hot gel.
Hot gel and the different of conventional gel are that hot gel at room temperature (that is, about 20～25 ℃) is a liquid, and (that is, about 37 ℃) is gel under body temperature, but the viscosity of conventional gel generally descends with the rising of temperature.Therefore, when gel is in room temperature (liquid form), sneak into pharmaceutical preparation in the hot gel.Following hot gel/medicinal mixture can be easy to by the syringe suction and be expelled to the patient.In case get in patient's body, hot gel/medicinal mixture is rapidly solidificated into gel.Pass the gel dissolving then in time, be discharged into the circulation of patient's body to pharmaceutical preparation.
Use chiller, for example the temperature control equipment shown in Figure 23 can cool off the hot gel/medicinal mixture that has solidified subcutaneous, returns liquid to gel conversion.In liquid condition, pharmaceutical preparation diffusion rate and rate of release improve, thereby when needing, have increased the pharmaceutical preparation in the circulation of patient's body.
An instance of hot gel is the SmartHydrogel of GelScience/GelMed company exploitation
TM, it comprises two kinds of staggered-meshs of graft polymers at random.A kind of is polyacrylic acid, and it has bioadhesive and pH-response.Another kind of polymer is a triblock copolymer, and it comprises PPOX (" PPO ") and PEO (" PEO ") sections, and putting in order is PEO-PPO-PEO.
Another uses the instance of the hot gel of the present invention to be, before eating food extra insulin administration to diabetics.In order to form the insulin of gel, arrive the hot gel injection that contains insulin subcutaneous with continuous release baseline dosage.During dining, when needing insulin extra when sugared to absorb in the circulation, the patient can be placed on chiller on the skin of contiguous injection point, and is cooled to be lower than the gelling temp of hot gel/insulin mixture to injection point.Certainly, gel will become liquid and increase the needs that insulin level assimilates food with compensation in patient's body.This process can repeat repeatedly to disappear up to the hot gel of injecting/insulin mixture.The advantage of this drug-supplying system is, a diabetics only shot just can be at the time inner control insulin administration in several days even several weeks.
Shown in figure 29; Can merge to heat-barrier material on the temperature control equipment; This not only helps to be reduced to minimum degree to variations in temperature, also helps to increase DDDS and its temperature of side skin (through reducing heat loss) down, they each can both increase dermal drug and absorb.
Similar among structure shown in Figure 29 and Fig. 4, wherein, among Fig. 2 on the DDDS120 of temperature control equipment 100 attached to Fig. 3.DDDS120 is attached on the part of patient skin 134.Collet 350 abuts on the skin 134, encases the essential part of temperature control equipment 100 and DDDS120.
Figure 30 illustrates another by the collet 360 that heat-barrier material (like the closed-cell foam band) is processed, and its binding agent edge 362 is attached on the patient skin 134, and is more bigger and cover it than DDDS364.Collet 360 shown in Figure 31 covers heater 366 and DDDS364, and is attached on the patient skin 134.Collet 360 shown in Figure 32 covers the zone above injection/implantation controlled-release/sustained release pharmaceutical formulation 368 position skins 134.
Embodiment 23
Another application of the invention is for example heater recited above, with typical liquid medicine injection bonded.For some drugs, in they are injected into body after, improve to absorb get into body circulation speed and can treatment be provided the patient.For example, for the purpose of effectively, antimigraine drug, dihydroergotamine must in blood flow, in the certain hour that migraine begins, reach the valid density amount, otherwise medicine is with invalid.Usually can not change it after the medicine injection and get into the absorption of patient's body circulation.Like this, the characteristic of controlled heat of the present invention can be used to improve subcutaneous and the absorption rate intramuscular injection medicine.
For example, behind subcutaneous or intramuscular injection medicine,, describe among the for example top embodiment, have below being placed on the skin of injectable drug existence heating plate.The circulation of injectable drug ambient body fluid is accelerated in heating, improves the permeability of surrounding tissue blood vessel wall, therefore makes drug absorption get into body circulation faster.
This method for the medicine that is expelled to a health part of great use, these medicines can be heated device on skin or the skin external heat, and their effect absorption rate that can be enhanced, that get into body circulation or deep tissue is improved.These medicines can comprise: antimigraine, antihypertensive, analgesic, Bendectin, cardiovascular drug.Certain drugs comprises: dihydroergotamine, Ergotamine, sumatriptan, rizatriptan, zolmitriptan and other selective serotonin receptor subtype agonist, morphine and other anesthetis, atropine, nitroglycerin, fentanyl, sufentanil, alfentanil and pethidine.
Because accelerate to get into body circulation absorption rate can cause peak value usually in blood concentration, therefore this technology also is used to increase the peak value haemoconcentration of subcutaneous or intramuscular injection medicine.
Because system's absorption of subcutaneous or intramuscular injection needs just can work for a long time, so some medicine needs intravenous injection.But difficult operation of intravenous injection and danger are bigger.Use the present invention to bring up to the absorption rate of some medicine enough greatly, so that subcutaneous or intramuscular injection can provide enough absorption rates.Therefore, for some drugs, present technique also can be used subcutaneous or intramuscular injection replaces intravenous injection.
As special instance, when the patient feels migraine, subcutaneous injection sumatriptan or dihydroergotamine voluntarily.Then, he takes out heating plate from the airtight container of heating plate, and heating plate comprises the heating medium of being made up of iron powder, active carbon, water, sodium chloride and sawdust (similar with embodiment 1), and is placed on heating plate on the injection point.Heating plate soon is elevated to 39～43 ℃ of close limits with the skin under the heating plate very, and kept this temperature at least 15 minutes.Heating has improved near the body fluid cycle rate and the permeability of organizing the peripheral vessels wall the injectable drug simultaneously.As a result, medicine gets into the body circulation quickly and arrives application point, and the patient has controlled migrainous outbreak sooner and/or better.
In another example, for treating violent pain, the nurse injection of morphia in patient's muscular tissue.Then, as stated, the nurse is placed on heating plate on the injection point.As stated, improve morphine and absorbed entering body circulation speed.As a result, the patient has controlled pain sooner and/or better.
Another application of the invention is to use heater, and is for example recited above, to simulate circadian pattern.For example, testosterone or its derivant like testosterone enanthate and testosterone cipionate, can arrive in man's body to replace or to substitute the natural testis hormone of minimizing or disappearance in intramuscular injection.With the testosterone ratio, preferred testosterone enanthate and testosterone cipionate are because they are longer than the acting duration of testosterone.But, it should be understood that testosterone or its derivant; Like the testosterone ester; Can sneak into the controlled release polymeric matrix, for example the homopolymer of lactic acid or hydroxyacetic acid and copolymer, preferably poly DL-lactide; Poly DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester and poly DL-lactide/caprolactone), with the persistent period of prolongation effect.After the intramuscular injection, the testosterone enanthate is absorbed, is provided the action time that reached for 2～4 weeks gradually from the lipid of injection point is organized mutually.But healthy man's nature blood testosterone concentration is higher by day, lower at night.Therefore the blood testosterone concentration that obtains from injection testosterone derivant can not simulating nature circadian rhythm pattern.
As an example, patient or subcutaneous or intramuscular injection testosterone enanthate (if intramuscular injection, injection should be relatively near skin surface).Then, the patient is placed on heating plate on the injection point and (uses up up to all injection testosterone enanthate) every morning.Heating plate is brought up to a narrow scope to the temperature of injection point fast, and keeps one period desirable persistent period (promptly about 8 hours).Heating makes the release quickening of testosterone enanthate and/or improves from the conversion rates of testosterone enanthate to testosterone, therefore obtains high blood testosterone concentration.Before being placed on same position to new heating plate, take off the sheet that uses up earlier.Use this heating dispensing technology of being interrupted, blood testosterone concentration is low at night, and is high by day, therefore simulated natural circadian rhythm pattern.
Androderm_ sheet by the TheraTech manufactured is the androgen Transcutaneous Therapeutic System, and is similar with the ATTS among Figure 13 with Fig. 3.The Androderm_ sheet can provide testosterone 24 hours for patient's percutaneous.There is the pharmaceutical preparation bin in the Androderm_ system, and it is to surround through the circumference that is fixed to along it polyester vinyl vinyl acetate laminar films after circumferential microporous polyethylene film.These two kinds of films interfix, thereby between two films, form the pharmaceutical preparation bin.The pharmaceutical preparation that contains testosterone is placed in the bin.Microporous polyethylene film has permeability, when medicament reservoir is attached on the patient skin, can makes pharmaceutical preparation pass microporous membrane migration and absorbs skin.When storing, prevent that with the seal disc of EVAc film pharmaceutical preparation from passing microporous polyethylene film.Disk is as the physical barriers of pharmaceutical preparation migration.Disk is attached on the polyester film release liner.When the Androderm_ sheet stored, the binding agent of release liner protection microporous membrane bottom, disk prevented that pharmaceutical preparation from passing film.Before using the sheet administration, take down release liner and disk.
The subject matter of present commercially available ATTS sheet is skin irritation.Skin irritation is according to thinking it mainly is (for Androderm_, penetration enhancers is a monoolein) that is caused by the penetration enhancers in the preparation.For improving percutaneous permeability, need penetration enhancers, so that enough testosterone penetrate skin.Because controlled heat can obviously increase skin absorbs, can expect, use controlled heat can reduce the concentration of reinforcing agent in the preparation, reduce the time of contact between preparation and the skin, and/or use more demulcent penetration enhancers.Just because of this, can still send enough testosterone in the skin irritant while of reduction.In other words, use controlled heat to cause that enhanced some effect of percutaneous permeability is replaced by heating to penetration enhancers at least, and heating is the method for safer enhancing percutaneous permeability.
The rate of release of this testosterone sheet (ATTS) is normally substantially invariable with night by day.This is not the circadian rhythm pattern of nature.When using constant release rate or high or low ATTS, can use controlled heat to obtain the circadian rhythm pattern that this is not a nature.In the morning, user is placed on heating plate the skin area that has injection/implantation controlled release formulation below it.The etch rate that temperature raises and accelerates the mobile of preparation ambient body fluid and/or accelerate the preparation matrix causes the raising of androgen rate of release and therefore obtains high serum levels.Add thermal design and get the persistent period long enough, so that keep high rate of release by day.In the afternoon or evening, heating plate stops heating (or taking off), and rate of release turns back to the level that does not heat.User repeats these every day.Use this arrangement, other stable delivery formulations also can obtain the blood testosterone concentration map of simulating nature circadian rhythm pattern.
Embodiment 25
Fig. 8-12 shows another instance that uses the embodiment of the invention; It is used for the percutaneous dosing of testosterone to increase and to optimize the drug administration amount; Comprise that user is placed on ATTS160,165 on the skin 134; Once a day skin testosterone sheet for example, the Androderm_ that produces like the TheraTech company of Salt Lake City, Utah, United States.Generally,, be placed on ATTS160,165 on the skin 134 like point in evenings 10 at night.User is to be placed on temperature control equipment 150 on the ATTS160,165 in first thing of the next morning.Rising ATTS160,165, skin 134 and hypodermic temperature obviously improve the skin absorbs of testosterone, thus the medicine-feeding rate that obtains accelerating at administration time.In addition, among the ATTS160,165 penetration enhancers is arranged, for example glycerin mono-fatty acid ester.In testosterone ATTS160,165, need penetration enhancers to send enough testosterone usually, still, penetration enhancers like the glycerin mono-fatty acid ester that uses among the Androderm_, can produce serious skin irritation.When reducing the danger that stimulates, the increase that the testosterone that controlled heat produces absorbs can reduce the concentration of the penetration enhancers that uses among the ATTS160,165.Heating has also been accelerated reinforcing agent and has been oozed through skin, therefore makes it more effective.The final result of controlled heat is that by day, when needing most testosterone, user obtains enough testosterone from ATTS160,165.
Embodiment 26
Another instance that use is shown in the embodiment of the invention of Fig. 8-12 comprises that serviceability temperature control device 150 is used for improving the androgen medicine from ATTS160,165 absorption rate with reduce its zero-time.As an example, use commercially available testosterone sheet as ATTS160,165, Androderm_-50 for example, patient or care-giver are placed on ATTS160,165 on patient's the skin 134, and are placed on temperature control equipment 150 on the ATTS160,165.Preferably, temperature control equipment 150 comprises the heating medium of the q.s that is used for thermoregulation mechanism 108, to keep exothermic reaction at least 4 hours.
The heating of temperature control equipment 150 is heated to skin 134 and ATTS160,165 contact surface in about 38 ℃～45 ℃ narrow temperature scope, and preferably about 39 ℃～43 ℃, more preferably about 42 ℃, and keep this temperature a period of time (that is, about 4 hours).During this period, heating has improved speed, the infiltration rate that passes skin 134 and rate of blood circulation that testosterone discharges from ATTS160,165, brings testosterone into the body circulation quickly.Exothermic reaction stops back (about 4 hours), and testosterone absorbs under the higher level that begins to cause from ATTS160,165 heating with concentration and rolls back normally (not heating) level in the blood flow.The patient continues to use this system afterwards in 24 hours.Compare with the ATTS160,165 of serviceability temperature control device 150 not, testosterone occurs in blood flow obviously in advance, has shortened zero-time; And in initial several hours in the blood flow testosterone concentration apparently higher than not heating the result that ATTS160,165 produces.As a result, in initial several hours, reached high serum testosterone level (behind first thing dispensing temperature control equipment promptly doing in the morning 4～6 hours).
The above-mentioned preferred embodiment of the invention that specified; But it should be understood that; The present invention who is limited appended claims is not limited to by details special in the above-mentioned explanation, because do not departing under the spirit and scope of the invention, has its a lot of significantly modification.
Claims (24)
1. a transdermal drug delivery system comprises
The heating component that when contacting, can generate heat with oxygen;
Be fixed on the medicine delivery components on the said heating component; With
Prevent the device that material transmits between said heating component and said medicine delivery components,
Wherein said device comprises ground floor barrier material and second layer barrier material; The sealing at all edge of said ground floor and second layer barrier material is to form between them by moisture vapor transmission gas and alcoholic acid material airtight space that the medicine delivery components is sealed fully not basically; Said ground floor barrier material than said second layer barrier material more near heating component, and
Prevent the device that material transmits between said surrounding air and heating component.
2. the described system of claim 1 also comprises the device that prevents ungracious heat loss.
3. the described system of claim 1 is characterized in that said heating component comprises the heating medium that contains active carbon, ferrum and water.
4. the described system of claim 1 is characterized in that said heating component comprises:
The shallow chamber that the end of being processed by air-locked basically material and surrounding wall surround;
Lid with selected air permeability; With
Be put in the heating medium that comprises active carbon, ferrum and water in the said shallow chamber.
5. system as claimed in claim 4, the said lid with selected air permeability comprises the air-locked basically material layer of one deck, and the hole of the selected size of selected number is arranged in the said layer.
6. system as claimed in claim 5, the hole of the selected size of said selected number is had the membrane cover of selected air permeability and is lived.
7. the system of claim 1, said medicine delivery components are included in the basic pharmaceutical preparation in the two-dimentional matrix that is.
8. the system of claim 1, said medicine delivery components comprises the pharmaceutical preparation that is placed between counterdie and the speed limit film.
9. the system of claim 1, said medicine delivery components comprises the pharmaceutical preparation that is placed between counterdie and the non-speed limit film.
10. the system of claim 1, said medicine delivery components comprises the medicine that is selected from fentanyl, sufentanil, carfentanil, testosterone, lignocaine, tetracaine, prilocaine, Luo Pilu caine, marcaine, procaine, flurbiprofen, naproxen, ibuprofen and dexamethasone.
11. the system of claim 1, said medicine delivery components comprises the medicine that is selected from analgesic, anti-inflammatory agent, steroid, hormone, antiviral agents, antasthmatic, cardiovascular drug, antihypertensive, antidepressant and cox2 inhibitor.
12. the described system of claim 11, said hormone is androgen or estrogen.
13. the system of claim 1 also comprises the means of keeping apart medicine delivery components and environment.
14. the system of claim 1 is characterized in that said sealing can separate by hand.
15. the system of claim 1 also comprises the device of being convenient to the said sealing of strip off.
16. like each described system of claim 7-9, said second layer barrier material surrounds the bin that is used to deposit pharmaceutical preparation.
17. system as claimed in claim 16, said second layer barrier material has bigger rigidity than said ground floor material.
18. the system of claim 1, said ground floor barrier material comprises layer of aluminum.
19. the system of claim 1, said second layer barrier material is selected from the group that the aluminum by polyethylene, polypropylene, polystyrene, Merlon, polrvinyl chloride, Barex, Aclar, aluminum or coated polymer layer constitutes.
20. the system of claim 1, said transdermal drug delivery system also comprises the device that is fixed on the human body skin.
21. system as claimed in claim 20, the said device that is used for fixing comprises along the outer peripheral bonding zone of said transdermal drug delivery assembly.
22. the system of claim 1, preventing that said device that material transmits between said heating component and surrounding air from comprising can hold the said transdermal drug delivery system and the container of oxygen flow and moisture not basically.
23. the system of claim 22 prevents that the said device of heat loss is included in the heat-barrier material in the said heating component.
24. the system of claim 22 prevents that the said device of heat loss can basically all be sealed to all edges of said medicine delivery components on the human body skin, is exposed in the surrounding air to stop said skin and said medicine assembly.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/162,890 US6245347B1 (en) | 1995-07-28 | 1998-09-29 | Methods and apparatus for improved administration of pharmaceutically active compounds |
| US09/162,890 | 1998-09-29 | ||
| US09/317,313 US6726673B1 (en) | 1999-05-24 | 1999-05-24 | Methods and apparatus for improved administration of testosterone pharmaceuticals |
| US09/317,372 | 1999-05-24 | ||
| US09/317,313 | 1999-05-24 | ||
| US09/317,372 US6546281B1 (en) | 1995-07-28 | 1999-05-24 | Integrated apparatus for controlled heat aided dermal drug delivery |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99813750 Division CN1291703C (en) | 1998-09-29 | 1999-09-29 | Method and apparatus for improved administration of pharmaceutically active compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1899644A CN1899644A (en) | 2007-01-24 |
| CN1899644B true CN1899644B (en) | 2012-12-12 |
Family
ID=37655750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006100908271A Expired - Fee Related CN1899644B (en) | 1998-09-29 | 1999-09-29 | Methods and apparatus for improved administration of pharmaceutically active compounds |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1899644B (en) |
| HK (1) | HK1040610A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4934210B2 (en) * | 2010-03-05 | 2012-05-16 | オカモト株式会社 | Skin laminate |
| CN110314275B (en) * | 2019-07-09 | 2020-04-17 | 清华大学 | Degradable flexible medicine controlled release device |
| CN112556112B (en) * | 2020-11-26 | 2022-10-28 | 青岛海尔空调器有限总公司 | Air conditioner with sprayer and control method and device |
| CN112999200B (en) * | 2021-03-03 | 2024-04-09 | 北京昊澄生物科技有限公司 | Transdermal drug delivery layer |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4230105A (en) * | 1978-11-13 | 1980-10-28 | Merck & Co., Inc. | Transdermal delivery of drugs |
| US4685911A (en) * | 1984-02-21 | 1987-08-11 | Yamanouchi Pharmaceutical Co., Ltd. | Patch |
| US4898592A (en) * | 1986-08-23 | 1990-02-06 | Latzke Arno W | Means for the application of transdermally absorbable active substances |
| US5658583A (en) * | 1995-07-28 | 1997-08-19 | Zhang; Jie | Apparatus and methods for improved noninvasive dermal administration of pharmaceuticals |
-
1999
- 1999-09-29 CN CN2006100908271A patent/CN1899644B/en not_active Expired - Fee Related
-
2002
- 2002-03-26 HK HK02102320.5A patent/HK1040610A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4230105A (en) * | 1978-11-13 | 1980-10-28 | Merck & Co., Inc. | Transdermal delivery of drugs |
| US4685911A (en) * | 1984-02-21 | 1987-08-11 | Yamanouchi Pharmaceutical Co., Ltd. | Patch |
| US4898592A (en) * | 1986-08-23 | 1990-02-06 | Latzke Arno W | Means for the application of transdermally absorbable active substances |
| US5658583A (en) * | 1995-07-28 | 1997-08-19 | Zhang; Jie | Apparatus and methods for improved noninvasive dermal administration of pharmaceuticals |
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| Publication number | Publication date |
|---|---|
| CN1899644A (en) | 2007-01-24 |
| HK1040610A1 (en) | 2002-06-21 |
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