CN1237107A - Drug delivery devices and process of manufacture - Google Patents

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

Drug delivery device and manufacturing method thereof

The scope of the invention

The present invention relates to an improved method for manufacturing a drug delivery device, and to a drug delivery device produced by this method. The improved method is one that utilizes the principle of thermal equilibrium to control the migration of drug from a drug reservoir through adjacent layers of the device. Preferably, the method provides improved control of drug concentration in a body contacting layer such as a pressure sensitive adhesive layer in a transdermal delivery device, thereby enabling more effective control of the initial drug loading dose released from the device . The present invention has particular utility in the manufacture of transdermal drug delivery devices comprising drug reservoirs at or above saturating concentrations.

Background of the invention

Transdermal drug delivery devices for the delivery of various drugs have been known for some time. Typical devices range from simple monolithic devices such as those disclosed in U.S. Patent No. 4,758,434 to devices including layered adhesives ( in-line adhesive) and controlled immediate-release drug film devices. Such controlled-release rate devices typically comprise a drug-impermeable backing layer, a drug reservoir containing a penetration enhancer or mixture of penetration enhancers in addition to the drug, a pressure-sensitive adhesive The drug layer and the controlled immediate release drug film are placed between the drug reservoir and the pressure sensitive adhesive layer. The above layers are usually laminated or heat sealed together to form a transdermal delivery device.

In order to maintain the unit activity of the drug source so that the drug is released from the device substantially constant over the expected release period, it is necessary to provide a drug reservoir with an initial concentration of drug at or above saturation, which It is well known in the art of transdermal drug delivery. However, unsaturated drug delivery systems, such as those disclosed in US Pat.

In addition to providing the drug from a drug depot, it is also known to preload the pressure sensitive adhesive with a quantity of the drug. For example, US Pat. Nos. 4,201,211, 4,588,580 and 4,832,953 disclose transdermal drug delivery devices, wherein the pressure-sensitive adhesive layer is made by solvent casting a mixture of drug and adhesive. Generally speaking, the amount of pre-added drug is equivalent to the initial loading dose required to produce a certain concentration gradient through the skin, and under this initial loading dose, the drug can be saturated at the position where the drug is pasted on the skin. Furthermore, US Patent 4,832,953 discloses the use of heating a lamination system comprising a dispersion of a liquid in a non-aqueous matrix in order to prevent the formation of crystalline hydrates.

In addition, Cleary in "Transdermal Delivery System: A Medical Rationale", Topical Drug Bioavailability Bioequivalence and Penetration (Topical Drug Bioavailability Bioequivalence and Penetration), Plenum Press, 1993 , PP 17-68 provides additional background information on commercially available transdermal drug delivery systems. Govil in "Transdermal Drug Delivery Devices", drug delivery devices (Drug Delivery Devices), Marcel Dekker, Inc. 1988, pp385-419; Chien in "Transdermal Drug Delivery Devices recent development and future prospects (Transdermal Systemic Drug Delivery Recent Development and Future Prospects)", S.T.P.Pharma Sciences, Vol.1, No.1, PP5-23, 1991; and Cleary in "Transdermal Drug Delivery", Skin Penetration Characteristics and Application (Skin Permeation Fundamentals and Application), pp 207-237, 1993 have given a relatively comprehensive overview of the factors that affect drug absorption through the skin.

Transdermal drug delivery for parenteral release has many advantages and transdermal delivery systems have been described for the release of various drugs or other beneficial excipients. For example, the suitability of steroids including testosterone for transdermal administration has been studied, and transdermal delivery systems for testosterone have been disclosed in the prior art. Existing testosterone transdermal drug delivery systems can generally be classified into scrotal systems or non-scrotal systems. Each system has its own advantages and disadvantages.

Scrotal systems such as those disclosed in US Pat. Nos. 4,704,282, 4,725,439 and 4,867,982 are relatively limited in terms of available drug release surfaces, but on the other hand, such systems do not require the use of penetration enhancers. Non-scrotal systems such as those disclosed in US Pat. Nos. 5,152,997, and 5,164,990 are not limited by the area of use, but require the use of multiple penetration enhancers, and thus tend to cause problems related thereto, especially irritation. Skin irritation when the skin reacts to the substance applied, especially blistering or redness with unpleasant burning, itching, and stinging when the skin is kept closed . It is therefore desirable that the amount of potentially irritating substances in transdermal drug delivery devices be kept to a minimum.

More specifically, US Patent Nos. 4,704,282, 4,725,439 and 4,867,982 disclose transdermal administration of testosterone via atraumatic scrotal skin administration. These patents describe that the penetration of testosterone by scrotal skin is six times that of non-scrotal skin. Testosterone is maintained in an ethylene vinyl acetate copolymer matrix and administered through the scrotal skin without the use of penetration enhancers.

US Patent Nos. 5,152,997 and 5,164,990 disclose a transdermal delivery system for testosterone via non-invasive, non-scrotal skin surface administration. The 5,164,990 patent requires an alcohol carrier and also contains a penetration enhancer or mixture of penetration enhancers such as glyceryl monooleate and methyl laurate to deliver a therapeutic amount of testosterone through non-scrotal skin.

In addition, US Patent No. 5,223,262 discloses a transdermal drug delivery system utilizing a lower alkanol penetration enhancer to deliver a hydrophobic alkanol-soluble active agent to the skin at a constant rate. The system includes a solvent depot comprising a lower alkanol solvent and a drug depot comprising an active agent dissolved in an aqueous alkanol. The two reservoirs are separated by a membrane permeable to the alkanol solvent but substantially impermeable to active agent and water.

WO 96/35427 discloses a transdermal therapeutic system for the release of testosterone comprising an alcohol carrier saturated with testosterone but without any penetration enhancer. The release rate of the active agent is regulated by the adhesive layer.

WO 97/10812 discloses a method for the manufacture of transdermal drug delivery systems containing supersaturated drug depots to obtain higher drug flux. The method includes heating the drug depot composition to a predetermined temperature and then cooling the drug depot composition to form a supersaturated drug depot comprising only a single drug phase and depot material.

As noted above, it is often desirable to preload the adhesive with drug in excess of saturation concentration, and this has been accomplished by premixing the drug into the adhesive. However, the method of pre-mixing the drug into the adhesive layer, although it is possible to initially add the drug in an amount exceeding the saturation concentration to the adhesive, has considerable practical problems. The drug must first be sent to the adhesive supply to be mixed with the adhesive and then sent back to the manufacturing site where the device is finally manufactured. This adds unnecessary shipping operations which are time consuming and, or most notably, this approach requires the adhesive supply site to install specific equipment consistent with regulatory requirements for manufacturing drug delivery devices.

Disclosure of the invention

According to the present invention, we no longer need the step of pre-mixing the body contact layer in the drug delivery device with the drug, and in the final product, in addition to the drug reservoir, other layers (such as the compressive layer in the transdermal drug delivery device) Sensitive adhesive layer) still contains an appropriate amount of drug beyond the saturation concentration.

Accordingly, one aspect of the present invention is to provide an improved method of providing a drug delivery device with a loaded dose.

Another aspect of the present invention is to provide an improved method of manufacturing a drug delivery device whereby a desired amount of drug can be provided from the layers of the drug delivery device, and a device made by the method.

Yet another aspect of the present invention is that it is no longer necessary to preload the pressure sensitive adhesive layer of the transdermal delivery device with drug in order to obtain a final product having an amount of drug in the adhesive layer that exceeds the saturation concentration.

Yet another aspect of the present invention is to provide an improved testosterone transdermal therapeutic system for administration through atraumatic, non-scrotal skin to achieve therapeutically effective levels of testosterone in the patient's blood.

These and other objects and advantages of the invention will be apparent from the following description and with reference to the accompanying drawings.

Brief description of the drawings

Fig. 1 is a sectional view of one embodiment of the transdermal drug delivery system according to the present invention.

Figure 2(a) is a cross-sectional view of one embodiment of a transdermal delivery device prior to thermal equilibration.

Figure 2(b) is a cross-sectional view of one embodiment of a transdermal delivery device during thermal equilibration.

Figure 2(c) is a cross-sectional view of one embodiment of a transdermal delivery device after thermal equilibration.

Figure 3 is a graphical representation of the release rate of testosterone as the system goes through different thermal equilibration processes.

Figure 4 illustrates the effect of thermal equilibration time on the initial release rate of fentanyl from a transdermal delivery device at 40°C.

Detailed Description of the Invention

The term "drug" as used herein refers in a broad sense to any material used to produce some biological, beneficial, therapeutic or other desired effect (such as a penetration-promoting effect) on a target (such as an organism).

The term "supersaturated concentration" used herein refers to a state in which the drug is in a saturated dissolved phase in the carrier and at the same time an excess solid phase exists.

As used herein, the term "loading dose" refers to the amount of drug in an adhesive or other body contacting layer (as opposed to a depot containing drug at a concentration above saturation).

As used herein, the term "rapid cooling" refers to a cooling process in which the device is cooled for a shorter period of time than the time the device is maintained at elevated temperature, and preferably refers to a process in which the drug-containing layers do not subsequently undergo a re-equilibration process Such a period of time.

As used herein, the term "substantially" refers to at least 60% of the administration cycles.

As used herein, the term "therapeutically effective" refers to the amount or rate of administration of drug required to produce the desired therapeutic effect.

As used herein, the term "transdermal" refers to the use of the skin, mucous membranes and/or other body surfaces as an entry point for topical application.

In accordance with the present invention, it has been found that a predetermined amount of drug can be introduced into the layers of the drug delivery device that initially do not contain more than a saturating concentration of drug, and that the predetermined amount can be obtained by subjecting the device to an elevated temperature for a predetermined period of time, followed by rapid cooling. The thermal equilibrium process to ambient temperature is effectively controlled. This method allows more drug to be loaded at a much faster rate than a transdermal delivery device that is only equilibrated at room temperature (such as a controlled immediate release drug in a transdermal delivery device) at a much faster rate. film and adhesive layer) migration. The method also allows layers initially free of supersaturation drug to retain a predetermined amount of supersaturation drug after rapid cooling to ambient temperature. This method eliminates the need to incorporate the drug into the body contacting layer (such as the adhesive layer in a transdermal drug delivery device) at a location other than where the drug delivery device is manufactured in order to ensure the desired loading dose in the body contacting layer middle.

The method of the present invention can be implemented by selecting an appropriate drug loading amount exceeding the saturation concentration in one layer of the drug delivery device (usually a drug reservoir), and selecting an appropriate time and temperature for the thermal equilibrium process, so that the final drug delivery system Any particular layer in any given layer contains the desired concentration of any drug. The temperature chosen for the equilibration process must be below that which would cause degradation of the drug or produce other deleterious effects such as an undesired phase change of the components in the device, and should also be chosen so that the drug in the layer is At least it is still saturated. Suitable temperatures for use in the present invention are from about 30° to 60°C, preferably from 35° to 45°C. Once the temperature is selected, the time selected can vary from about 8 hours to 3 weeks depending on the desired drug loading to be released. A preferred time frame suitable for practicing the present invention is between about 1-10 days.

After the heating process, the device was rapidly cooled to ambient temperature conditions. The cooling step is carried out so that the required layers in the device have a concentration above saturation of the drug. The cooling process preferably includes subjecting the device to a lower than elevated temperature for a period of time that is shorter than the time the device is subjected to the heating process. Rapid cooling is preferably carried out at ambient conditions, with a preferred cooling time of 6 hours to 5 days, and most preferably 6 to 36 hours.

The present invention finds application in any type of drug delivery device employing one of the layers to carry a dose of drug. For example, drug delivery systems as disclosed in US Pat. Nos. 3,854,480 and 3,938,515 may be used in the practice of the present invention to have a drug loading dose on its outer polymeric membrane.

Preferred embodiments of the present invention relate to controlling the amount of drug that migrates into a pressure sensitive adhesive layer in a transdermal delivery device. By controlling the amount of drug that migrates from the drug depot into the pressure-sensitive adhesive layer, the initial drug loading dose released can be effectively controlled to achieve the drug input required to saturate the drug concentration at the skin bond without requiring The drug is pre-dosed directly in the adhesive.

A particularly preferred embodiment relates to a transdermal delivery device that provides a substantially constant release rate throughout the intended delivery period, wherein the drug reservoir contains a saturating concentration or a supersaturation concentration of the drug throughout the delivery period. According to this particularly preferred embodiment, the drug depot initially holds a supersaturation concentration of drug, and neither the adhesive nor the immediate release drug membrane initially contains drug. During thermal equilibration, the solubility of the drug in the depot and other layers increases compared to ambient conditions, and the drug concentration in the other layers saturates at this increased solubility level. After the device has been subjected to a thermal equilibration process and cooled to ambient temperature, the decrease in drug solubility in the other layers will prompt the precipitation of drug above the saturation concentration, which is then retained in the other layers as a loading dose. The initial drug loading in the drug depot is optimized so that the depot remains saturated throughout the thermal equilibrium.

The practice of the present invention avoids the problems caused by pre-dosing the drug directly in the adhesive layer and ensures that the drug content in the adhesive layer is higher than it would be if the equilibrium were reached under conventional conditions. In addition, having the drug depot and the pressure-sensitive adhesive each have a saturating concentration or more of the drug will help prevent backflow of the drug from the pressure-sensitive adhesive to the drug depot.

According to this particularly preferred embodiment, the inventors have also found that the use of a less irritating effect of the present invention containing testosterone in an ethanol vehicle at a supersaturation concentration, but without an auxiliary penetration enhancer A device that effectively transdermally administers testosterone through the non-scrotal skin to hypogonadal men. Transdermal administration can release about 5-6 mg of testosterone within 24 hours, so that the average testosterone concentration in the serum of men with hypogonadism can reach the lower limit of the normal range for men (275-300 ng /dl), that is, the average maximum testosterone concentration reaches the middle of the normal range, about 500-600 ng/dl. This is different from that proposed in U.S. Patent Nos. 5,152,997 and 5,164,990. These two patents propose that in order to achieve an effective concentration of testosterone released through a non-scrotal skin transdermal drug delivery device, it is necessary to provide a penetration-promoting drug in addition to ethanol. The concentration of the agent is lower than the saturation level of testosterone. Furthermore, ethanol and testosterone are stored in a single reservoir, thus simplifying the manufacture of the device.

Referring to Figure 1, there is shown a drug delivery device 10 comprising a hydrogel reservoir 2 according to the present invention. The drug delivery device 10 includes a backing layer 3 that acts as a protective cover for the device, imparts structural support and substantially prevents components of the device 10 from escaping the device. The device 10 also includes a drug depot 2 with or without a penetration enhancer and supports a surface of the depot 2 away from the backing layer 3 for controlling the passage of the drug and/or penetration enhancer from the device. The rapid-release drug film released in 10. The outer edge of the backing layer 3 covers the edge of the reservoir 2 and is joined together with the outer edge of the rapid-release drug film 4 along the periphery in a liquid-tight structure. Sealing of the reservoir can be accomplished by pressing, fusing, gluing, applying adhesive to the edges, or other methods known in the art. In this way, the reservoir 2 is entirely accommodated between the backing layer 3 and the immediate-release drug film 4 . On the skin-proximal side of the IR membrane 4 is an adhesive layer 5 and a release liner 6 which should be removed before the device 10 is applied to the skin.

According to a particularly preferred embodiment, the drug depot 2 is initially filled with an excess drug load that exceeds the saturation concentration of the drug in the depot, so that after the thermal equilibration step is carried out according to the invention, the depot is maintained throughout the predetermined dosing cycle. It remains saturated or above saturation for part of the time. This ensures that the system will contain enough drug to supply the required drug loading of the pressure sensitive adhesive during thermal equilibration, and that the drug depot will contain enough drug to meet the desired dosing cycle. Required serum concentration levels are required. In addition, maintaining a drug depot at or above a saturating concentration provides a substantially constant rate of drug delivery.

In order to carry out the thermal equilibration process of the present invention according to this particularly preferred embodiment, a drug delivery device having a drug reservoir containing drug in excess of the saturation concentration is subjected to high temperature treatment for a predetermined period of time. Figure 2(a) illustrates the drug delivery device 20 with an excess of drug 21 in the drug reservoir 22 prior to thermal equilibration. The device 20 also includes a backing layer 23 , an immediate drug release film 24 , a pressure sensitive adhesive 25 and a release liner 26 . When the device 20 is heated to a predetermined temperature, the solubility of the drug in all layers increases. Thus, as long as the drug concentration in the drug reservoir layer remains saturated for a predetermined period of time, the drug will migrate at an accelerated rate from the drug reservoir to adjacent layers 24 and 25 in the device due to the shift in equilibrium (Fig. 2(b)). Balanced migration also enables more drug to migrate into adjacent layers such as the pressure sensitive adhesive layer 25 due to the increased solubility of the drug in the adhesive at elevated temperatures. After a predetermined period of time, the device is removed from the source of high temperature and allowed to cool to ambient temperature conditions. When the temperature drops, the solubility of the drug in the adhesive layer also decreases, so that the concentration of the drug 21 in the pressure-sensitive adhesive layer reaches a supersaturation level under ambient conditions, as shown in Figure 2(c) Show.

The amount of drug to be administered in a therapeutic delivery device for effective treatment depends on many factors, such as the minimum necessary drug dose for the specific indication being treated, the solubility and permeability of the drug in the carrier and adhesive layer , and how long the device remains on the skin. The minimum dose of drug is determined by the requirement that there be sufficient drug in the device to maintain the desired rate of drug release for the specified time of use. The maximum dose for safety reasons is determined by the requirement that the amount of the drug will not produce toxic side effects. In general, the highest concentration of a drug is determined by the amount of drug that is acceptable to the body without adverse effects on tissues such as irritation, unacceptably high initial drug loading into the body, or is to adversely affect the characteristics of the drug delivery device, such as stickiness, decrease in viscosity or deteriorate other properties.

The amount of drug initially loaded in the carrier determines the effective service life of the device, and the general service life is 8 hours to 7 days. However, the present invention is applicable to periods of use for which certain preferred embodiments are particularly useful for administration periods of up to about 24 hours. As discussed for particularly preferred embodiments, the initial concentration of drug in the carrier is saturated or supersaturated. However, without departing from the spirit of the present invention, as long as a certain amount of medicine can be continuously supplied to the skin or mucous membrane within a certain period of time, and enough to ensure the required treatment rate, the drug concentration during use Can also be below saturation level.

The backing material can be a breathable or occlusive material including, but not limited to, polyethylene, polyurethane, polyester or ethylene vinyl acetate films. Backings made of polyethylene terephthalate/ethylene vinyl acetate are preferred. If ethylene vinyl acetate is used as the backing layer, a vinyl acetate content of 33% or 40% is preferred.

Immediate-release drug membranes can be made of permeable, semi-permeable or microporous materials that are well known in the art to control the rate at which agents enter and leave the drug delivery device and to permeate penetration enhancers. The rate is lower than the permeability of the drug depot 12 to the penetration enhancer. Suitable materials include, but are not limited to, polyethylene, polypropylene, polyvinyl acetate, ethylene n-butyl acetate, and ethylene vinyl acetate copolymers. As disclosed in US Patent No. 3,797,494, the immediate release drug film may also contain an amount of mineral oil or other diffusion medium.

Depot formulations can be water-based or non-water-based. Water-based formulations generally comprise water or water/ethanol and about 1 to 5% by weight of a gelling agent, an example of which is a hydrophilic polymer such as hydroxyethylcellulose or hydroxypropylcellulose. Typical non-aqueous gels are composed of silicone fluids or mineral oil. Mineral oil based gels also typically contain 1-2% by weight of a gelling agent such as colloidal silicon dioxide. The solubility of a particular gel will depend upon the compatibility of its components with the drug and penetration enhancer mixture, in addition to any other components of the formulation, if employed.

When non-aqueous based formulations are employed, the reservoir matrix is preferably composed of a hydrophobic polymer. Suitable polymer matrices are well known in the art of transdermal drug delivery, examples of which are listed in the aforementioned patents. A typical lamination system consists essentially of a polymer film and/or a polymer matrix (such as ethylene vinyl acetate (EVA) copolymer), such as those polymers disclosed in the lamination system of U.S. Patent 4,144,317, polymerized The vinyl acetate (VA) content in the product is preferably from about 9% up to 60%, more preferably from about 9% to 40% VA. Polyisobutylene/oil polymers containing 4-25% high molecular weight polyisobutene and 20-81% low molecular weight polyisobutene with the balance being an oil such as mineral oil or polybutene can also be used as matrix material.

Suitable adhesives are well known in the art and include, but are not limited to, polysiloxane and/or acrylate polymers (including blends and graft copolymers thereof), including low and high molecular weight PIB Mixture and optional amount of mineral oil or polybutylene polyisobutylene (PIB) adhesives, (such as those polyisobutylene adhesives disclosed in U.S. Patent No. 5,508,038), styrene-butadiene copolymers, and tackifier-containing styrene-isoprene copolymer.

While any drug suitable for transdermal delivery may be administered in accordance with the present invention, certain drugs are particularly suitable for delivery with the delivery device of the present invention. Testosterone and its esters are a preferred drug suitable for administration by the drug delivery device of the present invention, especially for the treatment of men with hypogonadism. Other preferred drugs include hormones, especially steroids, estrogens such as estradiol and its esters, anabolic agents such as nandrolone (19-nor-17β-hydroxy-3-one-androst-4-ene) and its esters, progestogens such as progesterone and its esters, corticosteroids, and anesthetics.

The surface area of the devices of the present invention can vary from about 5 ^cm2 to about 75 ^cm2 . However, one common device has a surface area in the range of about 20-60 ^cm2 . A typical transdermal delivery device according to the present invention is manufactured in the shape of a generally oval or rounded rectangular patch of about 60 ^cm2 .

The drug delivery device of the present invention may also contain other penetration enhancers, stabilizers, dyes, diluents, pigments, carriers, inert fillers, antioxidants, excipients, gelling agents, anti-irritants as known in the art , a vasoconstrictor.

The drug delivery device of the present invention can be designed to effectively release the drug over a duration of several hours up to 7 days or longer. In general, the maximum duration of use of a single device is 7 days, as the adverse effects of skin occlusion increase with prolonged use, and the normal cycle of shedding and renewal of skin cells is about 7 days.

According to a particularly preferred embodiment of testosterone transdermal administration, the drug depot comprises 20-30 (weight)% testosterone, 68-80 (weight)% ethanol, and 1-2 (weight)% gelling agent ( such as hydroxypropyl cellulose), the immediate release drug film comprises an ethylene vinyl acetate copolymer having a vinyl acetate content of 5-30% by weight, preferably 9-18%, and the binder comprises a high molecular weight PIB/low molecular weight PIB/mineral oil in a ratio of 0.75-1.25/1-1.5/1.5-2.5, most preferably 1/1.25/2 polyisobutylene mixture

The aforementioned patents describe a wide variety of materials that can be used to manufacture the layers and components of the drug delivery device of the present invention. Accordingly, the present invention contemplates the use of materials other than those specifically disclosed in the above-mentioned patents, including those that will be hereinafter understood in the art and can play a significant role.

The following examples are given to illustrate the practice of the invention and not to limit it in any way.

Example 1

The steps of preparing the testosterone transdermal drug delivery device for non-scrotal skin drug delivery are as follows. Testosterone, 95% ethanol and hydroxypropyl cellulose are mixed to make a depot containing 26 (weight)% testosterone, 1-2 (weight)% hydroxypropyl cellulose and all the other 95% ethanol gel. The gel loading was 21 mg testosterone/ ^cm2 .

Mix polyisobutylene (MW1200000), polyisobutylene (MW35000) and light mineral oil in a weight ratio of 1:1.25:2 to prepare a pressure-sensitive adhesive composition. The pressure sensitive adhesive was cast on a 75 micron thick siliconized polyethylene terephthalate release liner to form a 50 micron thick pressure sensitive adhesive layer. The pressure-sensitive adhesive side of the thus obtained two-ply monocomponent was laminated to a 50 micron thick film of ethylene vinyl acetate (EVA) copolymer (containing 9% vinyl acetate). The gelled testosterone-ethanol mixture was placed on the EVA membrane. A backing layer consisting of aluminized polyethylene terephthalate containing an EVA heat seal coating was placed over the gel and heat sealed to the EVA copolymer using a rotary heat sealer. The laminate was punched into a finished drug delivery system using round punches and placed in sealed bags to prevent loss of volatile components.

Then, the system was treated at 35°C, 40°C or 50°C for 7 days and the drug release rate was measured at room temperature. Release rates were compared.

Remove the release liner from the laminated system and stick the system on ^Teflon® , then place a known volume of receptor solution (0.10% phenol/water) in the test tube and allow to cool at 35°C down to balance. The Teflon rod with the drug delivery system attached was then placed in a 35°C water bath. Mixing is performed with a motor that produces constant vertical mixing.

At specified time intervals, remove the entire receptor solution from the test tube and add an equal volume of new receptor solution previously equilibrated at 35°C. The receptor solution was stored in a covered glass bottle at 4°C until the testosterone content was determined by HPLC. From the drug concentration and volume of the receptor solution, permeation area and interval time, the drug flux can be calculated according to the following formula: (drug concentration × receptor volume) / (area × time) = drug flux (μg/ ^cm2 . Hour)

Figure 3 shows the effect of heat balance on the rate of testosterone release. As can be seen from the results shown in Figure 3, the temperature has the most significant impact on the release rate of testosterone in the release period starting from 0-2 hours, and the release rate corresponds to the release of the loading dose. The system is loaded with a dose approximately equivalent to the cumulative release of testosterone over a 0-2 hour period. The effect of thermal equilibrium on the loading dose (as measured by cumulative release of testosterone over a 0-2 hour period) is presented in Table 1. As shown in Table 1, the loading amount increases with the temperature increase in the thermal equilibrium process.

Table 1 Effect of heat balance on testosterone loading dose group Cumulative release in 0-2 hours (μg/cm ² ) I 6.7 II 26.0 III 28.2 IV 46.8

Group Ⅰ stored at room temperature for 1 month

Group II was placed in an oven at 35°C for 7 days

Group III was placed in an oven at 40°C for 7 days

Group IV was placed in an oven at 50°C for 7 days

Example 2

Follow the steps below to prepare a transdermal therapeutic system comprising an aqueous ethanol gel. The fentanyl base was added to 95% ethanol and stirred until the drug was dissolved. Purified water was then added to obtain a mixture containing 14.7 mg/g of fentanyl in a 30% ethanol water solvent, 2% hydroxyethyl cellulose gelling agent was slowly added to the solution with stirring and mixed until a uniform gel ( takes about 1 hour). A trichlorotrifluoroethane solution of an amine-resistant polysiloxane medical adhesive was cast on a fluorocarbon-diacrylate-treated polyester film as a system release liner by solution casting. A 0.05 mm thick pressure sensitive adhesive layer was formed. A 0.05 mm thick immediate release drug film composed of EVA (containing 9% VA) was pressure laminated on the adhesive surface. The backing layer is constructed of multiple layers of polyethylene, aluminum, polyester, and EVA, and the aqueous gel is sealed into the backing layer and the release liner on a rotary heat sealer at a gel loading of 15 mg/ ^cm2 /Adhesive/Controlled release drug film between. The packaged devices were die cut to ^a 10 cm size and immediately sealed in pockets to avoid loss of ethanol.

The effect of thermal equilibrium was tested on a 10 ^cm2 system made according to the above procedure. The systems were processed at different temperature/time combinations and then held at 25°C. Using the procedure for determining the drug release rate described in Example 1, the cumulative release of fentanyl in the initial 0-2 hour period was measured. The drug release rate after storage for two months at 25°C was measured, and the results are listed in Table 2.

Table 2 The influence of heat balance on the loading dose of fentanyl group 0-2 hour release (μg/hr) I 208.9 II 246.3 III 404.2 IV 445.1 Group Ⅰ, placed in an oven at 30°C for 7 days before storage at 25°C. Group II, put in a 40°C oven for 3 days before storage at 25°C. For group III, put them in an oven at 51°C for 1 day before storing at 25°C. For Group IV, put them in an oven at 60°C for 1 day before storing at 25°C.

The results in Table 2 show that in the first 0-2 hours of the administration period, the cumulative release of the drug increases with the increase of the heat equilibrium processing temperature. The cumulative release of drug during the initial 0-2 hour release period is approximately equivalent to the release of the loading dose. After 2 months of storage at room temperature, no return of fentanyl from the adhesive layer to the drug depot was detected. As can be seen from Table 2, the release amount (loading dose) of fentanyl in the 0-2 hour period increases as the thermal equilibrium temperature increases.

Example 3

The effect of thermal equilibrium time on drug release rate during high temperature thermal equilibrium was studied. The system prepared according to Example 2 was maintained at 40°C and the drug release rate was measured at intervals of 0, 3, 7 and 14 days. Figure 4 shows the effect of incubation time at 40°C on the initial released amount of fentanyl (loading dose) within a period of 0-2 hours after the start of drug release. As seen in Figure 4, the loading dose increased with increasing incubation time.

Example 4

A 10 cm ² system was prepared according to the steps in Example 2. Some of the systems were incubated at 40° C. for 4 days, while the rest were kept at room temperature. The in vitro drug release profile of each group of samples was measured using the procedure described in Example 1. The average loading dose for these systems, measured as cumulative release over 0-2 hours, was 199.00 micrograms/hour for the system maintained at room temperature and 282.25 micrograms/hour for the system incubated at 40°C for 4 days. Before the drug release rate test, solid drug was observed in the drug depot gel of each system, which indicated that the drug depot contained more than saturated drug amount. Solid drug was still observed in the drug depot gel in the thermal equilibrium system when the thermal equilibrium system was removed from the oven.

Although the above embodiments have introduced the manufacturing process of the sealed bag system, for the completion of the manufacturing process, the bagging system is completed before the system is die-cut or when the loss of volatile components is not involved, the system is die-cut Back pocketing is all possible.

The invention has been described in detail with specific reference to several preferred embodiments of the invention, but it will be understood that various changes and changes can be made within the spirit and scope of the invention.

Claims (25)

1. An improved method for the manufacture of a drug delivery device having more than one layer containing a drug in excess of the saturation concentration, the method comprising: forming a device comprising at least one layer initially containing a drug at a supersaturation concentration and at least one other layer initially not containing a drug at a supersaturation concentration; subjecting the device to an elevated temperature for a predetermined period of time sufficient to cause a predetermined amount of drug to migrate from said layer initially containing a drug at a greater than saturation concentration to another layer not initially containing a drug at a greater than saturation concentration; and The unit was allowed to cool rapidly to ambient temperature conditions. 2. The method of claim 1 further comprising selecting the drug loading for the layer initially containing an amount of drug at a concentration above saturation so that after the rapid cooling step it is ensured that at least The drug content in one layer exceeds the saturation concentration. 3. The method of claim 2, wherein the drug loading is selected such that the layer initially containing drug at a supersaturation concentration continues to contain the drug at a supersaturation concentration after the rapid cooling step. 4. An improved method for manufacturing a transdermal drug delivery device, the method comprising: (a) forming a drug depot on the backing layer, the drug depot containing a drug loading exceeding the saturation concentration of the drug; (b), forming a pressure-sensitive adhesive layer on the release liner film, and the pressure-sensitive adhesive does not contain drugs with a concentration exceeding saturation; (c) placing a drug depot on said adhesive layer in drug migration relationship to form the device; (d) subjecting the device to an elevated temperature for a predetermined period of time to accelerate migration of the drug from the drug depot to the pressure sensitive adhesive layer; and (e) Rapid cooling of the device to ambient temperature conditions. 5. A method according to claim 4 further comprising selecting the drug loading to ensure that the drug content in the adhesive layer exceeds the saturation concentration after the rapid cooling step. 6. A method according to claim 5 further comprising selecting the drug loading to ensure that the drug content in the drug depot exceeds the saturation concentration after the rapid cooling step. 7. A method according to claim 4 further comprising selecting the temperature and time to ensure that the drug content in the adhesive layer exceeds the saturation concentration after the rapid cooling step. 8. A method according to claim 7, wherein the selected temperature is between 30°C and 60°C and the selected time is between 12 hours and 20 days. 9. A method according to claim 8, wherein the selected temperature is between 35°C and 45°C and the selected time is between 1-10 days. 10. A method according to claim 4, wherein an immediate release drug film is interposed between the pressure sensitive adhesive and the drug reservoir. 11. A method according to claim 4, wherein the drug depot comprises ethanol. 12. A method according to claim 4, wherein the pressure sensitive adhesive comprises polyisobutylene and mineral oil. 13. A method according to claim 4, wherein the pressure sensitive adhesive comprises an acrylate adhesive. 14. A method according to claim 10, wherein the immediate release drug film comprises ethylene vinyl acetate copolymer having a vinyl acetate content of 6-60%. 15. A device for administering testosterone through the non-invasive, non-scrotal skin, comprising: (a), a backing layer; (b), a drug depot, which contains testosterone dispersed in a carrier, and the testosterone content in the carrier exceeds the saturation concentration; (c) elements for maintaining the transfer of testosterone in the device in relation to atraumatic, non-scrotal skin, Wherein the testosterone is administered through the skin at a substantially constant rate throughout most of the administration cycle. 16. A device according to claim 15, wherein the means for maintaining the testosterone in the device in migratory relationship with atraumatic, non-scrotal skin is a pressure sensitive adhesive. 17. A device according to claim 16, wherein said excess is sufficient to maintain the concentration of testosterone in the drug depot and pressure sensitive adhesive at or above saturation throughout a substantial portion of the dosing cycle. concentration. 18. A device according to claim 15 further comprising an immediate release drug membrane on the skin proximal side of the drug reservoir. 19. A device according to claim 15, wherein the carrier comprises an aqueous gel. 20. A device according to claim 19, wherein the carrier comprises ethanol. 21. A device according to claim 18, wherein the immediate release drug membrane comprises an ethylene vinyl acetate copolymer having a vinyl acetate content of 5-30%. 22. A device according to claim 21, wherein the vinyl acetate content is 9-18%. 23. A device according to claim 16, wherein the adhesive comprises a blend of low molecular weight polyisobutylene and high molecular weight polyisobutylene. 24. A device according to claim 23, wherein the ratio of low molecular weight polyisobutene to high molecular weight polyisobutene is 1.25:1. 25. A transdermal drug delivery device for testosterone administered through non-invasive, non-scrotal skin, the device comprising: (a), a backing layer; (b), a drug depot whose testosterone content reaches a saturation concentration or exceeds a saturation concentration, the drug depot comprising: i) 20-30 (weight)% testosterone; ii) 68-80% by weight lower alcohol carrier; and iii) 1-2 (weight)% gelling agent, c), a controlled rapid release drug film placed on the side of the drug storage near the skin, d) the elements used to maintain the transfer of testosterone in the device to atraumatic, non-scrotal skin, Wherein the testosterone is administered through the skin at a substantially constant rate throughout most of the administration cycle.

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