CN1237107A - Drug delivery devices and process of manufacture - Google Patents
Drug delivery devices and process of manufacture Download PDFInfo
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- CN1237107A CN1237107A CN 97196068 CN97196068A CN1237107A CN 1237107 A CN1237107 A CN 1237107A CN 97196068 CN97196068 CN 97196068 CN 97196068 A CN97196068 A CN 97196068A CN 1237107 A CN1237107 A CN 1237107A
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Abstract
An improved process for manufacturing transdermal drug delivery devices and devices made therefrom. The invention provides a heat euqilibration process for the manufacture of drug delivery devices which eliminates the need to preload the body contacting layer with a drug. The method has particular application in the manufacture of transdermal drug delivery devices including a drug reservoir comprising drug in excess of saturation.
Description
Scope of the present invention
The present invention relates to a kind of modification method that is used to make doser, and relate to the doser that method thus makes.The method of this improvement is that a kind of heat balance principle that utilizes is controlled medicine from the method for drug depot through the drug migration of each adjacent layer of this device.Preferably, this method can be improved the control to body contacting layer (as the pressure sensitive adhesive layer in the transdermal delivery device) Chinese medicine concentration, and the initial drug that can more effectively control device release thus thus loads dosage.The present invention comprises having special purposes aspect the transdermal delivery device of the drug depot that contains saturated concentration or surpass saturated concentration in manufacturing.
Background of the present invention
For a period of time, well-known for the transdermal delivery device of various drug releases.Typical devices comprises from simple monolithic devices (as be disclosed in the United States Patent (USP) 4758434 device) to being disclosed in United States Patent (USP) 3598122,3598123,3742951,4031894,4060084, the device that comprises stratification binding agent (in-line adhesive) and control rapid release medicine film in 4144317,4201211 and 4379454.The controlled device of this rate of releasing drug comprises the not backing layer of transdermal of one deck usually, one is removed the drug depot that the pastille beyond the region of objective existence also contains a kind of penetration enhancers or penetration enhancers mixture, a pressure sensitive adhesive layer and place drug depot and pressure sensitive adhesive layer between control rapid release medicine film.Above-mentioned each layer normally made transdermal delivery device through lamination or heat seal together.
In order to keep the units activity of drug source, and when medicine is discharged from this device, can in desired deenergized period, keep constant basically, thereby a kind of medicine initial concentration need be provided is saturated or surpass saturated drug depot, this is technical at transdermal administration to be well-known.But unsaturated drug-supplying system, as be disclosed in United States Patent (USP) 4379454,4908027, the unsaturated drug-supplying system in 5004610 and 5344656 also is known technically.
Except being provided the medicine by drug depot, adding a certain amount of medicine in contact adhesive in advance also is as you know.For example, United States Patent (USP) 4201211,4588580 and 4832953 disclosed transdermal delivery devices, wherein pressure sensitive adhesive layer is to carry out solvent cast by the mixture to medicine and binding agent to make.Generally come opinion, the medication amount that adds in advance is equivalent to medicine can produce the required original upload dosage that provides of finite concentration gradient through skin, and can make medicine above-mentioned to saturated in the position of skin adhesive doser under this original upload dosage.In addition, United States Patent (USP) 4832953 discloses and has adopted heating for the formation that prevents the crystalline state hydrate and comprise the method for lamination system of the dispersion of a kind of liquid in a kind of non-water base body.
In addition, Cleary is at " transdermal drug delivery system: pharmacy principle (Transdermal DeliverySystem:A Medical Rationale) ", the biological suitability of medicine, bioequivalence and osmosis introduction (Topical Drug Bioavailability Bioequivalence andPenetration), Plenum Press, 1993, other background information about commercially available transdermal drug delivery system is provided among the PP17-68.Govil is at " transdermal delivery device (Transdermal DrugDelivery Devices) ", doser (Drug Delivery Devices), Marcel Dekker, Inc.1988, pp385-419; Chien is at " transdermal system administration immediate development and vision of the future (Transdermal Systemic Drug Delivery Recent Development andFuture Prospects) ", S.T.P.Pharma Sciences, Vol.1, No.1, PP5-23,1991; With Cleary at " transdermal administration (Transdermal Drug Delievery) ", dermal osmosis feature and application (Skin Permeation Fundamentals andApplication), pp 207-237, in 1993 all to influencing the comprehensively general introduction of contrasting of factor that medicine absorbs through skin.
The transdermal administration mode that non-intestinal discharges has many advantages, and the transdermal drug delivery system that can be used for various medicines or other useful adjuvant release is described.For example, the transdermal administration suitability of the steroid that comprises testosterone is studied, and disclosed the transdermal drug delivery system that is used for testosterone in the prior art.Existing testosterone transdermal drug delivery system generally can be divided into scrotum system or non-scrotum system.Every kind of system each has its merits and demerits.
Is more limited such as the scrotum system that is disclosed in United States Patent (USP) 4704282,4725439 and 4867982 for available drug release surface, and but then, this system does not need to adopt penetration enhancers.Such as the non-scrotum system that is disclosed in United States Patent (USP) 5152997 and 5164990, though do not utilized the restriction of area, need to adopt multiple penetration enhancers, therefore cause relevant therewith problem, especially zest problem easily.When skin responds to institute's application matter, can produce zest to skin, especially remain on skin under the encapsulation situations and can take place with undesirable calcination, itch and the foaming or the rubescent phenomenon of sensation of pricking.Therefore wish in the transdermal delivery device that the quantity that may produce irritating material should remain on floor level.
More particularly, United States Patent (USP) 4704282,4725439 and 4867982 discloses the testosterone transdermal administration by the administration of not damaged skin of scrotum.It is six times of non-skin of scrotum penetrance to the penetrance of testosterone that these patents have been introduced skin of scrotum.Testosterone remains in the ethylene vinyl acetate copolymer substrate and passes through the skin of scrotum administration, and needn't adopt penetration enhancers.
United States Patent (USP) 5152997 and 5164990 discloses the testosterone transdermal drug delivery system by not damaged, the surface administration of non-skin of scrotum.5164990 patents need a kind of alcohol carrier but also need comprise a kind of penetration enhancers or penetration enhancers mixture (as glycerin mono-fatty acid ester and methyl laurate) to discharge the testosterone of effective in cure amount by non-skin of scrotum.
In addition, United States Patent (USP) 5223262 discloses a kind of transdermal drug delivery system that utilizes a kind of low-level chain triacontanol penetration enhancers to discharge the soluble activating agent of hydrophobicity alkanol to skin with constant rate of speed.This system comprises that a solvent storage storehouse that contains the lower alkane alcoholic solvent and one contain the drug depot that is dissolved in the activating agent in the aqueous alkanol.This two storages storehouse is with a kind of alkanol solvent thoroughly but the film of not saturating basically activating agent and water separates.
WO96/35427 discloses a kind of transdermal therapeutic system that discharges testosterone, and this system comprises a kind of through the saturated alcohol carrier of testosterone, but does not contain any penetration enhancers.The rate of release of activating agent is adjusted by adhesive phase.
WO 97/10812 discloses to be used for making and can obtain the higher drug flux, contains the method for the transdermal drug delivery system of oversaturated drug depot.This method comprises that the drug depot component is heated to predetermined temperature also then cools off the drug depot component to form the supersaturation drug depot, and this storage storehouse only contains single medicine phase and storage library material.
As mentioned above, wish in binding agent, to add in advance medicine usually, and realized by medicine is sneaked in the binding agent in advance above saturated concentration.Yet, medicine is sneaked into method in the adhesive phase in advance, though can will be added at the very start in the binding agent, there is considerable practical problem above the medication amount of saturated concentration.At first medicine must be delivered to binding agent activity so that mix, then send back to the manufacturing site location of last this device of manufacturing again with binding agent.So just increased unnecessary shipment operation time of having spent more expense again and or the most worth put forward be: this method requires binding agent supply place to install and the corresponding to particular device of management expectancy of making doser.
Disclosure of the present invention
According to the present invention, we have no longer needed step that the body contacting layer in the doser and medicine are pre-mixed, and in the final products that make except that drug depot, other layer (as the pressure sensitive adhesive layer in the transdermal delivery device) still contains the medicine that surpasses saturated concentration of appropriate amount.
Therefore, one aspect of the present invention provides a kind of doser that makes and contains a kind of modification method that loads dosage.
Another aspect of the present invention provides a kind of modification method of making doser, can provide required medication amount by each layer in the doser with this, and the device that provides method thus to make.
Another aspect of the present invention is when obtaining to have the final products above the saturated concentration medication amount in adhesive phase, no longer needs the pre-loaded medicine of pressure sensitive adhesive layer in transdermal delivery device.
Of the present invention also have an aspect to provide a kind ofly to be used for through not damaged, non-skin of scrotum administration, and the testosterone transdermal therapeutic system of improvement is so that the testosterone content in the blood samples of patients reaches the level with curative effect.
According to following explanation and with reference to accompanying drawing, these and other objects of the present invention and advantage are conspicuous.
Brief description of drawings
Fig. 1 is the sectional view according to an embodiment of transdermal drug delivery system of the present invention.
Fig. 2 (a) is the sectional view of an embodiment before thermal balance of transdermal delivery device.
Fig. 2 (b) is the sectional view of an embodiment during thermal balance of transdermal delivery device.
Fig. 2 (c) is the sectional view of an embodiment behind thermal balance of transdermal delivery device.
Fig. 3 illustrates the rate of release of system's testosterone when different thermal balance process.
When Fig. 4 illustrated 40 ℃, heat balance time was to the influence of fentanyl initial release speed in the transdermal delivery device.
Detailed description of the present invention
The noun " medicine " that this paper adopts refers to effective object (such as organism) is produced certain any material biological, useful, curative or other Expected Results (as promoting to penetrate effect) in broad terms.
The noun that this paper adopts " surpasses saturated concentration " and refers to medicine and be a kind of state when representing in addition that excessive solid phase exists in the saturated dissolving phase in carrier.
The noun " loading dosage " that this paper adopts refers to the medication amount in adhesive or other body contacting layer (rather than contain above saturated concentration drug depot).
The time that the noun that this paper adopts " fast cooling " experiences when referring to this device cooling the time of this device continuous high temperature be short cooling procedure, and preferably finger contains such a period of time that the rebalancing process can then not occur each layer of medicine in this process.
The noun " major part " that this paper adopts refers to at least 60% administration cycle.
The noun that this paper adopts " has result for the treatment of " and refers to can produce expects result for the treatment of required medication amount or medicine-feeding rate.
The noun " transdermal " that this paper adopts is meant and utilizes skin, mucosa and/or other body surface administration inlet as the local drug of topical application.
According to the present invention, have been found that, the medicine of scheduled volume can be imported in each layer that does not contain when initial in the doser above the saturated concentration medicine, and this scheduled volume can stand the high temperature of one period scheduled time by making this device, and the thermal balance process that is quickly cooled to ambient temperature is then controlled effectively.This method can just at room temperature reach each layer (as controlling rapid release medicine film and adhesive phase in the transdermal delivery device) that does not contain above the saturated concentration medicine when equilibrated transdermal delivery device has more medicine with faster speed initial and move.This method also can make and not contain the medicine that surpasses saturated concentration that still can keep scheduled volume above each layer of saturated concentration medicine after being quickly cooled to ambient temperature when initial.This method can be sneaked into medicine in the body contacting layer (as the adhesive phase in the transdermal delivery device) in other place beyond the place of making this doser in order to guarantee required loading dosage is arranged in body contacting layer.
Select the suitable drug load that surpasses saturated concentration by in one deck of doser, (being generally drug depot), and appropriate time and the temperature selecting to carry out the thermal balance process just can implement the inventive method, so that make the desired concn that contains any medicine in any certain layer in the final drug-supplying system.The selected temperature of equilibrium process must be lower than can cause that drug degradation maybe can produce the temperature of other illeffects (not wishing the phase change that takes place as each component in the device), and the selection of temperature also should make the medicine in this layer at high temperature at least still be in saturation.Be applicable to that temperature of the present invention is about 30 °-60 ℃, is preferably 35 °-45 ℃.In case temperature is selected, the selected time can load dosage with the medicine of required release and not wait between about 8 hours-3 weeks.Be applicable to that implementing preferred time range of the present invention is between about 1-10 days.
After heating process, this device is cooled to ambient temperature conditions rapidly.Implementing cooling step will make in this device desired each layer that medicine above saturated concentration is arranged.Cooling procedure preferably includes that to make this device stand one be low temperature a period of time than high temperature, and it is short to stand time of heating process than this device during this period of time.Preferably implement cooling fast under environmental condition, be 6 hours-5 days preferred cool time, and most preferably be 6-36 hour.
The present invention can obtain to use adopting one deck wherein to load in the doser of any kind of drug dose.For example, just can be used for implementing the present invention as disclosed drug-supplying system in United States Patent (USP) 3854480 and 3938515 makes its outer polymer film have medicine loading dosage.
The preferred embodiment of the invention relates to the control drug migration and goes into the dose in the pressure sensitive adhesive layer in the transdermal delivery device.Migrate into dose the pressure sensitive adhesive layer by control from drug depot, just the initial drug of sustained release loads dosage effectively, is saturated required medicine input and does not need medicine directly is added in the binding agent in advance with the drug level that reaches the adhering skin place.
With the transdermal delivery device of substantially constant rate of release administration, wherein drug depot contained saturated concentration or surpasses the medicine of saturated concentration during whole release in a particularly preferred embodiment related to during whole expection administration.According to this particularly preferred embodiment, just have medicine when drug depot is initial above saturated concentration, and binding agent and control rapid release medicine film composite medicine not when initial.During implementing thermal balance, the dissolubility of medicine in storage storehouse and other each layer increases under environmental condition, and the drug level in other each layer can reach capacity on the dissolubility level of this raising.This device is through the thermal balance process and after being cooled to ambient temperature, and the reduction of other each layer Chinese medicine dissolubility can impel the medicine above saturated concentration to produce precipitation, so these drug precipitation are retained in other each layer as a kind of loading dosage.Initial drug heap(ed) capacity in drug depot is that therefore storing the storehouse all keeps saturation in whole thermal balance process through preferred.
Enforcement of the present invention has avoided in advance medicine directly being added in caused variety of issue in the adhesive phase, and can guarantee that the medicament contg in adhesive phase is higher than the content that may have when normal condition is issued to balance.In addition, make drug depot and contact adhesive have saturated concentration separately or surpass the medicine of saturated concentration, can help to stop medicine to backflow to drug depot from contact adhesive.
According to this particularly preferred embodiment, the inventor also finds, employing to skin irritation influence lower, contain the testosterone that in the ethanol carrier, reaches above saturated concentration, but the apparatus of the present invention that do not contain auxiliary penetration enhancers, can be with testosterone with transdermal means effectively by of the man administration of non-skin of scrotum to the gonad inadequacy.But transdermal administration discharges about 5-6 milligram testosterone in 24 hours, thereby average testosterone concentration in man's serum of gonad inadequacy is reached be higher than man's lower bound of normal range (275-300 nanogram/decilitre), the highest promptly average testosterone concentration reaches the intermediate value of normal range, about 500-600 nanogram/decilitre.This with United States Patent (USP) 5152997 and 5164990 proposed different, these two pieces of patents propose to reach valid density for the testosterone that the transdermal delivery device that makes through non-skin of scrotum discharges, and need provide the testosterone that the concentration that also contains penetration enhancers except that ethanol is lower than degree of saturation.And ethanol and testosterone are stored in the single storage storehouse, have therefore simplified the manufacturing of this device.
Referring to Fig. 1, the figure illustrates the doser 10 that comprises an aqueous gel storage storehouse 2 according to of the present invention.Doser 10 comprise one lid, that give structural support and can prevent the overflow backing layer 3 of this device of each composition in this device 10 basically as this unit protection.Device 10 also comprise contain with penetration enhancers or do not have the drug depot 2 of penetration enhancers and support storage storehouse 2 away from a surface of backing layer 3, be used for controlling medicine and/or penetration enhancers from installing the control rapid release medicine film 4 that discharges 10.The outward flange of backing layer 3 covers the edge in storage storehouse 2 and is bonded together in the liquid sealing structure mode along periphery with the outer rim of controlling rapid release medicine film 4.Can adopt pressurization, fusion method, Method for bonding, be coated on the edge binding agent or the sealing in technical known other method enforcement storage storehouse.In such a way, storage storehouse 2 whole being accommodated between backing layer 3 and the control rapid release medicine film 4.In nearly skin one side of control rapid release medicine film 4 is an adhesive phase 5 and the antiseized lining form 6 that should remove before device 10 is attached to skin.
According to particularly preferred embodiment, drug depot 2 is filled with the overdose of medicine thing heap(ed) capacity that surpasses storage storehouse Chinese medicine saturated concentration when initial, therefore, after the invention process thermal balance step, the storage storehouse still keeps saturated or is higher than saturated state in the most of the time in whole predetermined administration cycle.This has just guaranteed that this system can contain enough medicine supply contact adhesive required medicines during thermal balance and load dosage, and has guaranteed that this drug depot can contain enough medicines to satisfy the requirement of the serum level that can reach required in the administration cycle of expection.In addition, drug depot keeps saturated concentration or surpasses the confession medicine speed that saturated concentration can provide substantial constant.
Contain above the doser of the drug depot of saturated concentration medicine high-temperature process in order to implement thermal balance process of the present invention according to this particularly preferred embodiment, can to make to have through one period scheduled time.Before Fig. 2 (a) illustrates thermal balance, the doser 20 of excess drug 21 arranged in the drug depot 22.This device 20 also comprises backing layer 23, control rapid release medicine film 24, contact adhesive 25 and antiseized lining form 26.When device 20 was heated to predetermined temperature, the dissolubility of medicine in all layers will rise.Therefore, as long as the maintenance of the drug level in medicine storing layer saturation in the predetermined time cycle, because equilibrated mobile, medicine will move (shown in Fig. 2 (b)) from the adjacent layer 24 and 25 of drug depot to device with the speed of quickening so.Equilibrated move also can make each layer that more medicine moves into contiguous as pressure sensitive adhesive layer 25, this be during owing to high temperature medicine in binding agent due to the dissolubility increase.Behind preset time, allow this device leave high temperature source and allow it be cooled to ambient temperature conditions.When temperature descended, the dissolubility of medicine in adhesive phase also decreased, and the concentration of medicine 21 in pressure sensitive adhesive layer was issued to above degree of saturation, shown in Fig. 2 (c) in environmental condition.
For reaching the effect of effective treatment, the consumption of medicine in the therapeutic doser is decided by many factors, for example, and the minimum necessary drug dose of the concrete indication of being treated, dissolubility and the permeability of medicine in carrier and adhesive phase, and this device sticks on the time on the skin.The lowest dose level of medicine is according in specified service time, for keeping desirable rate of releasing drug, must have in this device that this requirement of enough medication amount determines.Can not produce this requirement of toxic and side effects for the maximal dose of security consideration according to content of medicines determines.In general, the maximum concentration of medicine is by not determining the medication amount that the situation download physical ability that tissue has a negative impact is accepted, these adverse effect factors load just like zest, unacceptable high initial drug that dosage enters in the body or the feature of doser are had adverse influence, as cohesiveness, viscosity degradation or make other performance depreciation.
The medication amount of original upload has just determined the effective life of this device in the carrier, and the general operating period is 8 hours-7 days.But, the present invention can be used for such operating period, and promptly the administration cycle of some preferred embodiment particularly suitable reaches about 24 hours operating period.According to the discussion to particularly preferred embodiment, the initial concentration of medicine in carrier is saturated or surpasses saturated.Yet, under the prerequisite of spirit of the present invention,, can supply medicine to skin or mucosa position continuously with the medicine of some as long as within a certain period of time, and be enough to guarantee required treatment rate, then drug level also can be lower than degree of saturation during use.
Back lining materials can be gas-pervious or inaccessible material, and this class material comprises (but not limited) polyethylene, polyurethane, polyester or ethylene vinyl acetate films.Backing by polyethylene terephthalate/ethylene vinyl acetate system is preferred.If adopt ethylene vinyl acetate as backing layer, then the vinyl acetate ester content is 33% or 40% to be preferred.
Control rapid release medicine film can be made by infiltrative, semipermeable or poromerics, these materials are to be used for controlling medicament as everyone knows into and out of doser speed technically, and the permeability of penetration enhancers are lower than the permeability of 12 pairs of penetration enhancers of drug depot.The material that is suitable for comprises (but not limited) polyethylene, polypropylene, polyvinyl acetate, ethylene n-butyl acetate and ethylene vinyl acetate copolymer.Disclosed as United States Patent (USP) 3797494, control rapid release medicine film also can comprise a certain amount of mineral oil or other dispersive medium.
Storage storehouse prescription can be water base or non-water base.Water-based formulation generally comprises water or water/ethanol and about 1 to 5 (weight) % gellant, and one of them example is hydrophilic polymer such as hydroxyethyl-cellulose or hydroxypropyl cellulose.Typical non-aqueous gel is made of siloxanes liquid or mineral oil.The mineral oil based gel also contains 1-2 (weight) % gellant such as colloidal silica usually.The dissolubility of concrete gel any other component (if employing), also depends on the compatibility of its component and medicine and penetration enhancers mixture in prescription.
When adopting non-water-based formulation, storage storehouse matrix preferably is made of hydrophobic polymer.The polymeric matrix that is suitable for is well-known in the transdermal administration technical field, and the example has been listed in the above-mentioned patent.A kind of typical laminating system mainly is made up of polymeric film and/or polymeric matrix (as ethylene vinyl acetate (EVA) copolymer), such as those polymer in the United States Patent (USP) 4144317 disclosed laminating systems, vinylacetate in the polymer (VA) content is preferably about 9% to up to 60%, more preferably about 9%-40%VA.Polyisobutylene/the oil polymer that contains 4-25% high molecular weight polyisobutylene and 20-81% low-molecular-weight polyisobutylene and surplus and be a kind of oil (as mineral oil or polybutene) also can be used as matrix material.
The binding agent that is suitable for is well-known technically, comprise (but not limited) polysiloxanes and/or acrylate polymer (comprising its mixture and graft copolymer), the mixture and the mineral oil of optional amount or polyisobutylene (PIB) binding agent of polybutene that comprise low-molecular-weight and high molecular PIB, (as those disclosed polyisobutylene adhesives in the United States Patent (USP) 5508038), SB and the styrene-isoprene copolymer that contains viscosifier.
Though any medicine of transdermal administration that is applicable to all can carry out administration by the present invention, some drugs is specially adapted to carry out administration with doser of the present invention.Testosterone and ester thereof are a kind of preferred agents that is applicable to doser administration of the present invention, particularly are applicable to gonad inadequacy's man's treatment.Other preferred medicine comprises hormone, particularly steroid, estrogen such as estradiol and ester thereof, anabolic agent such as nandrolone (19-nor--17 beta-hydroxies-3-ketone-androstane-4-alkene) and ester thereof, progestogens such as Progesterone and ester thereof, corticosteroid and anesthetis.
The surface area of apparatus of the present invention can be at about 5 centimetres
2-Yue 75 centimetres
2Not etc.But, a kind of surface area of usual means is at about 20-60 centimetre
2In.A kind of typical transdermal delivery device according to the present invention is by about 60 centimetres
2, be generally that rectangle plaster shape oval or the band fillet makes.
Doser of the present invention also can comprise other penetration enhancers as technically known, stabilizing agent, dyestuff, diluent, pigment, carrier, inert filler, antioxidant, excipient, gellant, counter-stimulus, vasoconstrictor.
Doser of the present invention can be designed at several hours to the device that reached 7 days or can both discharge effectively in longer persistent period medicine.In general, the long life of single assembly is 7 days, because the adverse effect that occlusion of skin produced can increase with the prolongation of operating period, and the normal cycle that comes off and upgrade of Skin Cell is about 7 days.
Particularly preferred embodiment according to the testosterone transdermal administration, drug depot comprises 20-30 (weight) % testosterone, 68-80 (weight) % ethanol, and 1-2 (weight) % gellant (as hydroxypropyl cellulose), it is 5-30 (weight) % that control rapid release medicine film comprises vinyl acetate content, be preferably the ethylene vinyl acetate copolymer of 9-18%, and binding agent comprises a kind of high molecular PIB/ low-molecular-weight PIB/ mineral oil, its ratio is 0.75-1.25/1-1.5/1.5-2.5, most preferably is 1/1.25/2 polyisobutylene mixture
Above-mentioned patent description can be used for making the wide variety of materials of each layer and each component in the doser of the present invention.Therefore, the present invention consider to adopt comprise that those can understand hereinafter technically and can play an important role, and with above-mentioned patent in the concrete different material of those disclosed.
The following example be used for explanation implement of the present invention, rather than limitation of the present invention by any way.
Embodiment 1
Preparation is as follows through the step of the testosterone transdermal delivery device of non-skin of scrotum administration.With testosterone, 95% ethanol and add hydroxypropyl cellulose and contain 26 (weight) % testosterone through being mixed and made into, 1-2 (weight) % hydroxypropyl cellulose and all the other are 95% alcoholic acid storage storehouse gel.The gel heap(ed) capacity be 21 milligrams of testosterone/centimetre
2
With polyisobutylene (MW1200000), polyisobutylene (MW35000) and light mineral oil mutually are mixed and made into contact adhesive composition with weight ratio at 1: 1.25: 2.This contact adhesive is prolonged into the pressure sensitive adhesive layer of 50 micron thickness at the antiseized lining form of the silication polyethylene terephthalate upper reaches of 75 micron thickness.Pressure-sensitive adhesion face one side of the two-layer unimodule that obtains thus is laminated on ethylene vinyl acetate (EVA) copolymer (the containing 9% vinylacetate) film of 50 micron thickness.Testosterone-the alcohol mixture of gelation is placed on the EVA film.To cover by the backing layer that the polyethylene terephthalate of aluminizing that contains EVA heat-sealing coating constitutes and also adopt the rotation heat sealing machine that it is heat sealed on the EVA copolymer on the gel.The employing round punch strikes out the finished product drug-supplying system with laminate and is placed in the sealing bag to prevent the loss of volatile component.
Then, system was being handled respectively under 35 ℃, 40 ℃ or 50 ℃ 7 days and measuring rate of releasing drug under room temperature, in order to observe temperature to loading the influence of dosage, with measurement result with at room temperature keep the rate of releasing drug of 1 month system to compare.
Remove the antiseized lining form in the lamination system, then this system is sticked on Teflon
Fall, the receptor solution (0.10% phenol/water) with a kind of known volume places test tube and makes it be issued to balance at 35 ℃ then.The Teflon rod that will be stained with drug-supplying system is then put into 35 ℃ of water-baths.Can produce constant vertical blended motor with one implements to mix.
By designated time intervals, from test tube, take out whole receptor solutions and add the novel receptor solution that equal-volume is crossed 35 ℃ of balances in advance.Receptor solution stored in 4 ℃ the glass bottle with cover, until measuring testosterone content with HPLC.From the drug level of receptor solution and volume, see through area and blanking time, can be calculated as follows drug flux: (drug level * receptor volume)/(area * time)=drug flux (microgram/centimetre
2Hour)
Fig. 3 shows the influence of thermal balance to the testosterone rate of release.By result shown in Figure 3 as can be seen, 0-2 hour the beginning deenergized period in temperature the most remarkable to the influence of the rate of release of testosterone, rate of release with the loading dosage release corresponding.The loading dosage of this system is the accumulation burst size of testosterone during 0-2 hour approximately quite.Thermal balance is listed in table 1 to the influence that loads dosage (the accumulation burst size according to testosterone in the 0-2 hours period is measured).As shown in table 1, loading dosage increases with the temperature rising of thermal balance process.
Table 1 thermal balance loads the influence of dosage to testosterone
| Group | 0-2 hour accumulation burst size (μ g/cm 2) |
| ????Ⅰ | ?????6.7 |
| ????Ⅱ | ????26.0 |
| ????Ⅲ | ????28.2 |
| ????Ⅳ | ????46.8 |
The I group was at room temperature stored 1 month
The II group was put 7 days in 35 ℃ of baking ovens
The III group was put 7 days in 40 ℃ of baking ovens
The IV group was put 7 days in 50 ℃ of baking ovens
Comprise aqueous ethanol Gel Transdermal therapy system according to the following step preparation.In 95% ethanol, add the fentanyl base fluid and be stirred to and make medicine dissolution.Add pure water then to obtain containing in 30% ethanol water solvent mixture of 14.7 milligrams/gram fentanyl, become even gel (approximately needing 1 hour) by stirring to add 2% hydroxyethyl-cellulose gellant and be mixed to this solution lentamente.With solution casting method with the trichorotrifluoroethane solution casting of anti-amine agent polysiloxanes adhesive of medical as the antiseized lining form of system on the polyester film that fluorine carbon-diacrylate was handled to form the pressure sensitive adhesive layer of 0.05 millimeters thick.0.05 the control rapid release medicine film that is made of EVA (containing 9%VA) of millimeters thick is pressed on the adhesive surface through pressure level.Backing layer is made of multiwalled polyethylene, aluminum, polyester and EVA, and is rotating on the heat sealing machine with 15 milligrams/centimetre
2The gel heap(ed) capacity, aqueous gel is enclosed between backing layer and the release liner/binding agent/control rapid release medicine film.Packaged device is die-cut to 10 centimetres
2Size is also enclosed in the pocket immediately to avoid alcoholic acid loss.
Thermal balance is to 10 centimetres of making according to above-mentioned steps
2The influence of system is tested.System is handled with different temperature/time combination, keep 25 ℃ then.Adopt embodiment 1 described mensuration rate of releasing drug step, measure the accumulation burst size of fentanyl in the beginning 0-2 hours period.Measure the rate of releasing drug of storing down after two months at 25 ℃, the results are shown in table 2.
Table 2 thermal balance loads the influence of dosage to fentanyl
The I group was put 7 days in 30 ℃ of baking ovens before 25 ℃ of storages.The II group was put 3 days in 40 ℃ of baking ovens before 25 ℃ of storages.The III group was put 1 day in 51 ℃ of baking ovens before 25 ℃ of storages.The IV group was put 1 day in 60 ℃ of baking ovens before 25 ℃ of storages.
| Group | 0-2 hour burst size (μ g/hr) |
| ????Ⅰ | ????208.9 |
| ????Ⅱ | ????246.3 |
| ????Ⅲ | ????404.2 |
| ????Ⅳ | ????445.1 |
Table 2 result shows that in 0-2 hour the administration cycle of beginning, the accumulation burst size of medicine increases with the rising of thermal balance processing temperature.This initial 0-2 in hour deenergized period the accumulation burst size of medicine be equivalent to load the burst size of dosage approximately.After at room temperature storing 2 months, do not detect fentanyl turns back to drug depot from adhesive phase phenomenon.Can see that from table 2 burst size of fentanyl in the 0-2 hours period (loading dosage) raises with thermal equilibrium temperature to be increased.
Embodiment 3
Studied in the elevated temperature heat equilibrium process heat balance time to the influence of rate of releasing drug.The system that makes according to embodiment 2 remains on 40 ℃ and with 0,3,7 and 14 days measuring space rate of releasing drug.Fig. 4 shows the influence of the initial release amount (loading dosage) of fentanyl in the 0-2 hours period after 40 ℃ of following temperature retention times begin release.As Fig. 4 finding, loading dosage increases with temperature retention time.
Embodiment 4
Though the foregoing description by the agency of about the manufacturing process of seal bag system, but for finishing manufacturing process, finish the pack system or do not relating under the situation of volatile ingredient loss before system is die-cut, the pack of die-cut back all is possible in the system that finishes.
Specifically with reference to several preferred embodiments of the present invention the present invention has been done detailed explanation, but can carry out various modifications and changes within the spirit and scope of the present invention, this is understandable.
Claims (25)
1, a kind of be used for making have the modification method that the above medicament contg of one deck surpasses the doser of saturated concentration, this method comprises:
Form and contain above saturated concentration when one deck is initial at least and do not contain device when another layer is initial at least a kind of comprising above the saturated concentration medicine;
Make this device stand high-temperature process one preset time, contain other layer migration that does not contain when initial above the saturated concentration medicine with the medicine that is enough to make scheduled volume when initial above the described course of saturated concentration medicine; And
Make this device be quickly cooled to ambient temperature conditions.
2, the method for claim 1 also comprises this layer selection drug load that contains when initial above the saturated concentration medication amount, so that do not contain above the medicament contg in the one deck at least in other each layer of saturated concentration medicine above saturated concentration when initial guaranteeing behind cooling step fast.
3, the method for claim 2, wherein the selection of drug load should make and contain when initial above this layer of saturated concentration medicine at the medicine that still contains behind cooling step fast above saturated concentration.
4, a kind of modification method that is used to make transdermal delivery device, this method comprises:
(a), on backing layer, form a drug depot, this drug depot contains the drug load above the saturated concentration medicine;
(b), on antiseized lining form, form a pressure sensitive adhesive layer, do not contain in the described contact adhesive above the saturated concentration medicine;
(c), drug depot is placed on the described adhesive phase that has the drug migration relation to form this device;
(d), make this device through one section preset time of high-temperature process, to accelerate medicine from the migration of drug depot to pressure sensitive adhesive layer; With
(e), cooling off this fast installs to ambient temperature conditions.
5, a kind of method according to claim 4 also comprises the selection drug load, so that can guarantee that behind quick cooling step the medicament contg in the adhesive phase surpasses saturated concentration.
6, a kind of method according to claim 5 also comprises the selection drug load, so that can guarantee that behind quick cooling step the medicament contg in the drug depot surpasses saturated concentration.
7, a kind of method according to claim 4 also comprises the selection temperature and time, so that can guarantee that behind quick cooling step adhesive phase Chinese medicine content surpasses saturated concentration.
8, according to a kind of method of claim 7, wherein selected temperature is between 30 ℃ and 60 ℃, and the selected time is between 12 hours and 20 days.
9, a kind of method according to Claim 8, wherein selected temperature is between 35 ℃ and 45 ℃, and the selected time is between 1-10 days.
10,, wherein be equipped with a kind of control rapid release medicine film between contact adhesive and the drug depot according to a kind of method of claim 4.
11, according to a kind of method of claim 4, wherein drug depot contains ethanol.
12, according to a kind of method of claim 4, wherein contact adhesive comprises polyisobutylene and mineral oil.
13, according to a kind of method of claim 4, wherein contact adhesive comprises acrylic ester adhesive.
14,, wherein control rapid release medicine film and comprise the ethylene vinyl acetate copolymer that vinyl acetate content is 6-60% according to a kind of method of claim 10.
15, a kind of testosterone transdermal delivery device through not damaged, non-skin of scrotum administration, this device comprises:
(a), a backing layer;
(b), a drug depot, contain the testosterone that is dispersed in the carrier in this storage storehouse, testosterone content surpasses saturated concentration in the carrier;
(c), be used for keeping the key element of testosterone and not damaged in this device, non-skin of scrotum transition relationship,
Wherein testosterone in the most of the time in whole administration cycle with substantially invariable speed administration through skin.
16, according to a kind of device of claim 15, wherein being used for keeping the key element of testosterone and not damaged in this device, non-skin of scrotum transition relationship is contact adhesive.
17, according to a kind of device of claim 16, wherein said excessive be to be enough to make the concentration of testosterone in drug depot and contact adhesive in the most of the time in whole administration cycle, to remain on saturated or to surpass saturated concentration.
18, close skin one side that also is included in drug depot according to a kind of device of claim 15 has a control rapid release medicine film.
19, according to a kind of device of claim 15, wherein carrier comprises a kind of aqueous gel.
20, according to a kind of device of claim 19, wherein carrier comprises ethanol.
21,, wherein control rapid release medicine film and comprise the ethylene vinyl acetate copolymer that a kind of vinyl acetate content is 5-30% according to a kind of device of claim 18.
22, according to a kind of device of claim 21, wherein vinyl acetate content is 9-18%.
23, according to a kind of device of claim 16, wherein binding agent comprises the blend of low-molecular-weight polyisobutylene and high molecular weight polyisobutylene.
24, according to a kind of device of claim 23, wherein the ratio of low-molecular-weight polyisobutylene and high molecular weight polyisobutylene is 1.25: 1.
25, a kind of testosterone transdermal delivery device through not damaged, non-skin of scrotum administration, this device comprises:
(a), a backing layer;
(b), a testosterone content reaches saturated concentration or surpasses the drug depot of saturated concentration, this drug depot comprises:
ⅰ) 20 1 30 (weight) % testosterone;
ⅱ) 68-80 (weight) % lower alcohol carrier; And
ⅲ) 1-2 (weight) % gellant,
C), one place drug depot near the control rapid release medicine film of skin one side,
D), be used for keeping the key element of testosterone and not damaged in this device, non-skin of scrotum transition relationship,
Wherein testosterone in the most of the time in whole administration cycle with substantially invariable speed administration through skin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97196068 CN1256947C (en) | 1997-07-03 | 1997-07-03 | Drug delivery devices and process of manufacture |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97196068 CN1256947C (en) | 1997-07-03 | 1997-07-03 | Drug delivery devices and process of manufacture |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1237107A true CN1237107A (en) | 1999-12-01 |
| CN1256947C CN1256947C (en) | 2006-05-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 97196068 Expired - Fee Related CN1256947C (en) | 1997-07-03 | 1997-07-03 | Drug delivery devices and process of manufacture |
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| Country | Link |
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| CN (1) | CN1256947C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103919755A (en) * | 2013-01-15 | 2014-07-16 | 江苏康倍得药业有限公司 | Tulobuterol transdermal patch and preparation method thereof |
| CN103933018A (en) * | 2013-01-18 | 2014-07-23 | 江苏康倍得药业有限公司 | Transdermal drug delivery system |
-
1997
- 1997-07-03 CN CN 97196068 patent/CN1256947C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103919755A (en) * | 2013-01-15 | 2014-07-16 | 江苏康倍得药业有限公司 | Tulobuterol transdermal patch and preparation method thereof |
| CN103919755B (en) * | 2013-01-15 | 2019-10-18 | 江苏康倍得药业股份有限公司 | Tulobuterol transdermal patch and preparation method thereof |
| CN103933018A (en) * | 2013-01-18 | 2014-07-23 | 江苏康倍得药业有限公司 | Transdermal drug delivery system |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1256947C (en) | 2006-05-24 |
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