KR20000022467A - Drug delivery devices and process of manufacture - Google Patents

Abstract

PURPOSE: The invention provides a heat equilibration process for the manufacture of drug delivery devices which eliminates the need to preload the body contacting layer with a drug. CONSTITUTION: An improved method for manufacturing a drug delivery device has more than one layer containing a concentration of drug in excess of saturation which method comprises: forming a device comprising at least one layer initially containing drug in excess of saturation and at least one other layer initially free of drug in excess of saturation; subjecting the device to an elevated temperature for a predetermined period of time sufficient to cause a predetermined amount of a drug to migrate from the layer initially containing drug in excess of saturation into the other layers of the device that are initially free of drug in excess of saturation; and rapidly cooling the device to ambient conditions.

Description

Drug delivery device and manufacturing method

Transdermal delivery devices for the delivery of a wide variety of drugs have been known for some time. Typical devices range from simple ones as described in U.S. Pat. to be. Such rate control devices typically contain a support layer through which the drug cannot permeate, a drug reservoir that may contain a permeation accelerator or permeation promoter mixture in addition to the drug, a contact adhesive layer, and a rate control membrane located between the drug reservoir and the contact attachment. . The layers are typically laminated or heat sealed together to create a transdermal device.

In transdermal techniques, the initial amount of drug is kept above the concentration of the reservoir or its saturation concentration so that a single active supply of the drug is maintained so that delivery of the drug from the device remains constant over the intended delivery period. It is known to provide drug reservoirs. Saturated systems as described in US Pat. Nos. 4,379,454, 4,908,027, 5,004,610 and 5,344,656 are also known in the art.

In addition to providing a drug in a drug reservoir, it is also known to preload a contact attachment with a quantity of drug. For example, US Pat. Nos. 4,201,211, 4,588,580, and 4,832,953 describe transdermal drug delivery devices wherein the contact adhesive layer is made by a solvent containing a mixture of drug and an attachment. Typically, the preloaded amount corresponds to the amount needed to provide an initial loading dose that results in a concentration gradient through the skin and saturates the skin binding site underlying the device with the delivered drug. In addition, US Pat. No. 4,832,953 describes heating a laminate system containing a dispersant of a liquid in a non-aqueous base to prevent the formation of crystalline hydrates.

In addition, Cleary "Transdermal Delivery System: A Medical Rationale", Topical Drug Bioavailability, Bioequivalence, and Penetration, Plenum Press 1993, pp 17-68 provides additional background information on commercially available transdermal drug delivery systems. do. Govil, "Transdermal Drug Delivery Devices", Drug Delivery Devices, Marcel Dekker, Inc. 1998, pp 385-419; Chien "Transdermal Systemic Drug Delivery Recent Development and Future Prospects", S.T.P. Pharma Sciences, Vol. 1, No. 1, pp 5-23, 1991; And Cleary "Transdermal Drug Delivery", Skin Permeation Fundamentals and Application, pp 207-237, 1993, where a summary of appropriately completed factors related to percutaneous absorption of drugs can be found.

The transdermal route of delivering drugs parenterally provides many advantages, and transdermal systems for delivering a variety of drugs or other useful agents have been described. For example, steroids, including testosterone, have been studied for their suitability for transdermal delivery and prior art has described a transdermal drug delivery system for delivering testosterone. Conventional transdermal testosterone systems can generally be classified as scrotum or non-scrotum systems. Each has its advantages and disadvantages.

Scrotum systems as described in US Pat. Nos. 4,704,282, 4,725,439, and 4,867,982 have more limitations on the surface area available for drug delivery, while eliminating the need for the use of permeation promoters. Non-scrotum systems as described in US Pat. Nos. 5,152,997 and 5,164,990 are not limited in area of application, while many penetration promoters need to be used and are therefore susceptible to the accompanying problems, in particular stimuli. Irritation occurs as a skin response to topically applied materials, especially those that remain under confinement due to blisters or redness associated with unpleasant burns, pruritis and stinging sensations. In transdermal delivery devices it is desirable to minimize the number of possible irritants.

More specifically, US Pat. Nos. 4,704,282, 4,725,439, and 4,867,982 describe transdermal absorption of testosterone through woundless scrotum skin. These patents show that scrotum skin has a fivefold increase in permeability to testosterone compared to non-scrotum skin. Testosterone is provided in an ethylene vinyl acetate copolymer base and delivered through the scrotum skin without the use of permeation promoters.

U.S. Pat.Nos. 5,152,997 and 5,164,990 describe transdermal administration of testosterone through the woundless nonscrotum skin surface. The 5,164,990 patent requires ethanol carriers and additionally includes permeation promoters or permeation promoting mixtures such as glycerol monooleate and methyl laurate to deliver therapeutically effective amounts of testosterone through the nonscrotum skin.

In addition, US Pat. No. 5,223,262 describes a system for transdermal delivery of hydrophobic alkanol soluble activators to the skin at a constant rate using lower alkanol penetration accelerators. The system includes an overlying solvent reservoir containing a lower alkanol solvent and a drug reservoir containing an active agent in an aqueous alkanol. These two reservoirs are separated by the aromatic membrane as long as the alkanol solvent can permeate and the active agent and water cannot permeate substantially.

WO 96/35427 describes a transdermal therapeutic system for testosterone delivery containing an alcoholic carrier saturated with testosterone and without a penetration enhancer. The release rate of the active agent is controlled by the adhesive layer.

WO 97/10812 describes a method for producing a transdermal drug delivery system comprising a supersaturated drug reservoir which yields a higher drug flow. The method relates to heating the drug reservoir component to a predetermined temperature and thereafter cooling the drug reservoir component to provide a supersaturated reservoir containing only a single phase drug and reservoir material.

As mentioned above, it is often desirable to preload an adhesive having the drug amount in excess of the saturated concentration, which is done by premixing the drug to the adhesive. However, although the drug amount can be made in excess of the saturation amount initially added to the adhesive, the method of premixing the drug in the adhesive layer has considerable practical problems. The drug must be sent to the adhesive support mixed with the adhesive and then sent back to the manufacturing department which finally manufactures the device. This requires undesired transportation, time, and most importantly, this method requires special equipment in the part of the adhesive support that conforms to the control requirements for the manufacture of the drug delivery device.

Description of the invention

According to the invention, there is no need to premix the body contact layer of the drug delivery device with the drug during the production of the final product having a saturation excess with a suitable drug amount in the layer than the drug reservoir, such as the contact adhesive of the transdermal drug delivery device. .

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

Another aspect of the present invention provides an improved method of manufacturing a drug delivery device, such that a desired amount of drug can be provided in various layers of the drug delivery device and devices made therefrom.

Another aspect of the invention is to obviate the need to preload the contact adhesive of the transdermal drug delivery device with the drug in order to obtain a final product having a saturated excess of drug in the adhesive.

Another aspect of the present invention is to provide an improved therapeutic transdermal system for delivering testosterone through the woundless, non-scrotum skin to obtain therapeutically effective blood testosterone levels in a patient.

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

The present invention relates to an improved method of manufacturing a drug delivery device and a drug delivery device produced thereby. Improvements include thermal equilibrium methods that regulate the movement of drugs from the drug reservoir through adjacent layers of the device. Preferably, the method may improve control over the concentration of the drug in the body contact layer, such as the contact adhesive layer of the transdermal device, to better control the initial loading dose of the drug delivered by such device. This method is particularly applicable in the manufacture of transdermal drug delivery devices that include drug reservoirs that contain drugs above or above saturation.

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

2A is a cross-sectional view of one embodiment of a transdermal drug delivery device prior to thermal equilibrium.

2B is a cross-sectional view of one embodiment of a transdermal drug delivery device during thermal equilibrium.

2C is a cross-sectional view of one embodiment of a transdermal drug delivery device after thermal equilibrium.

3 shows the testosterone release rate from the system applied to various thermal equilibrium processes.

4 shows the effect of exposure time at 40 ° C. on the initial fentanyl release rate from the transdermal device.

As used herein, the term “drug” in its broadest sense produces several biological, useful, therapeutic, or other intended effects, such as, for example, promoting permeability to the organism to which it is applied. It is understood to mean any material intended to be.

As used herein, the term "saturated excess" refers to a condition in which the drug is present in both the solid phase that represents the excess and the dissolved phase saturated in the carrier.

As used herein, the term “load dose” refers to the amount of drug present in the body contact layer that is different from the drug reservoir, which is an excess of the adhesive layer or saturated concentration.

As used herein, the term "quick cooling" refers to a cooling method that occurs over a time shorter than the time the device is held at an elevated temperature and preferably has no resulting rebalance of the drug-containing layer. Says about.

As used herein, the term "significant portion" means at least 60% of the administration period.

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

As used herein, the term "transdermal" means using the skin, mucous membranes, and / or other body surfaces as a gateway to drug administration by topical application of the drug.

According to the present invention, drug delivery is initially controlled by the absence of a saturation excess of drug, the amount of which is effectively controlled by performing a thermal equilibrium process, where the device is subjected to an increased temperature for a period of time and then rapidly cooled to ambient conditions. It has been found that a predetermined amount of drug may be introduced into the layer of the device. This method moves a larger amount of drug initially to a layer that is free of saturated excess drug, such as the rate control membrane and the adhesive layer of the transdermal device, at a much faster rate than is possible by allowing the device to equilibrate at room temperature. You can. The method also allows for a rapid initial cooling of the saturated excess drug-free layer to ambient conditions to maintain a predetermined dose of drug which becomes a saturated excess. This method does not require mixing the drug with the body contact layer, such as the adhesive layer of the transdermal delivery device, at a site different from the location of the device manufacture to provide the desired loading capacity in the body contact layer.

The method of the invention selects an appropriate drug load in one layer of the device, typically a saturation excess in the drug reservoir, and selects a suitable concentration of the desired concentration within any particular layer of the final system by selecting the appropriate time and temperature to perform the thermal equilibrium process It can be applied to provide a drug. The temperature chosen for the equilibrium method should be below the temperature that results in the loss of the drug or other adverse effects such as undesirable phase changes in the components of the device, and should be chosen to maintain the drug above saturation in the layer at elevated temperatures. do. Temperatures useful in the present invention are about 30 ° C to 60 ° C, preferably 35 ° C to 45 ° C. Once the temperature is selected, the time may vary from about 8 hours to 3 weeks depending on the desired loading dose of the delivery drug. A preferred range of time useful in the practice of the present invention is about 1 to 10 days.

After the heating process, the device is rapidly cooled to ambient conditions. A cooling step is performed to supply the drug in saturated excess in the desired layer of the device. Preferably, the cooling process comprises applying the device to a temperature below the elevated temperature for less time than when applied to the heating process. Preferred temperatures for rapid cooling are those at ambient conditions and preferred cooling times are from 6 hours to 5 days, most preferably from 6 to 36 hours.

The present invention has found applicability to any type of drug delivery device utilizing a dose of drug in one layer of the drug delivery device. For example, drug delivery systems as described in US Pat. Nos. 3,854,480 and 3,938,515 can be used in the practice of the present invention to provide a loading dose of drug to an external polymeric membrane.

A preferred embodiment of the present invention relates to controlling the amount of drug that migrates to the contact adhesive of the transdermal drug delivery device. By controlling the amount of drug that moves from the drug reservoir to the contact adhesive, the initial loading dose of the delivered drug can be effectively controlled to achieve the desired infusion of the drug that saturates the skin binding site without the need for a drug directly loaded onto the adhesive directly. have.

Particularly preferred embodiments relate to transdermal drug delivery devices that administer drugs at a substantially constant rate throughout the intended dosing period, wherein the drug reservoir contains the drugs in saturated or saturated excess throughout the delivery period. According to this particularly preferred embodiment, the drug reservoir is initially fed with saturated excess drug and adhesive and the rate control membrane is initially drug free. During thermal equilibrium, the solubility of the drug in the reservoir and the other layers will be higher than the solubility in the ambient state, and the other layers will be saturated with this drug at this increased solubility level. After the thermal equilibrium process and cooling the device to ambient conditions, the decrease in solubility of the other layer results in precipitation of saturated excess drug which will then be in the other layer at the load capacity. The load of the initial drug in the reservoir is preferably selected such that the reservoir remains saturated with the drug throughout the entire process.

The practice of the present invention obviates the problem of preloading the drug directly onto the adhesive and provides the adhesive with more drug amount than is possible at equilibrium at standard conditions. In addition, providing a saturated or saturated excess of drug to the drug reservoir and the contact adhesive, respectively, helps prevent drug backing from the contact adhesive to the drug reservoir.

According to a particularly preferred embodiment, the inventors also found that sexual function through non-scrotic skin with lower frequency skin irritation from the device of the invention containing testosterone in its saturation concentration excess in its ethanol carrier without additional permeation promoter. It has been found that it can be effectively administered transdermally to this degraded male. The mean serum testosterone concentrations in men with reduced sexual function were approximately above the low borderline in the normal range of men (275-300 ng / dl) and the mean maximum testosterone concentrations were obtained approximately in the middle of the normal range of about 500-600 ng / dl. 5-6 mg of testosterone can be delivered transdermally over 24 hours. This is contrary to the contents of US Pat. Nos. 5,152,997 and 5,164,990, which proposed the need to provide testosterone in subsaturation with a permeation promoter in addition to ethanol to obtain effective testosterone concentrations by transdermal administration through non-scrotum skin. In addition, ethanol and testosterone are provided in a single reservoir, thereby simplifying the manufacture of the device.

Referring now to FIG. 1, a drug delivery device 10 comprising an aqueous gel reservoir 2 according to the present invention is shown. The delivery device 10 includes a support element 3 which acts as a protective cover of the device, to give structural support and to actually prevent the components in the device 10 from exiting the device. Apparatus 10 also includes a reservoir 2 containing the drug with or without the permeation accelerator, and its surface away from the rate control membrane 4 for controlling the release of the drug and / or permeation promoter from the support element 3, apparatus 10. Is pressing down. The outer edge of the support element 3 lies above the edge of the reservoir 2 and is joined along the peripheral length with the outer edge of the speed control membrane 4 in a fluid-tight arrangement. Such sealed reservoirs may be obtained by pressure, melting, adhesion, adhesive applied to the edges, or other methods known in the art. In this way, the reservoir 2 is contained entirely between the support element 3 and the speed control film 4. On the skin's proximal face of the speed control membrane 4 there is a peelable liner that is removed before the adhesive layer 5 and the device 10 are attached to the skin.

According to a particularly preferred embodiment, the drug reservoir 2 is initially provided with a drug load containing an excess of drug at or above the saturated concentration of the drug in this reservoir, such that after the thermal equilibrium according to the invention the reservoir is given a predetermined period of drug administration. Maintain saturation or above saturation throughout the actual portion of the. This provides that the system will contain enough drug to provide the desired amount of drug to the contact adhesive layer during thermal equilibrium and this reservoir will contain enough drug to achieve the desired serum concentration level for the intended dosing period. In addition, maintaining the drug reservoir in saturated or saturated excess provides a substantially constant rate of administration.

In order to carry out the thermal equilibrium method of the invention according to this particularly preferred embodiment, a drug delivery device having a drug reservoir containing the drug in saturated excess is subjected to elevated temperatures for a predetermined time. FIG. 2 (a) shows the drug delivery device 20 with excess drug 21 in the drug reservoir 22 as provided prior to thermal equilibrium. The apparatus 20 also includes a support 23, a speed control film 24, a contact adhesive 25, and a release liner 26. When the device 20 is heated to a predetermined temperature, the solubility of the drugs in all the layers increases. Therefore, as long as the drug reservoir layer remains saturated with the drug for a period of time, the drug is removed from the drug reservoir at adjacent speeds 24 and 25 of the device at an increased rate due to the equilibrium shift as shown in Figure 2 (b). Go to. Equilibrium shifting also allows higher amounts of drug to migrate to adjacent layers such as contact adhesive 25 due to the increased solubility of the drug in the adhesive at elevated temperatures. After a predetermined time, the device is removed from the elevated temperature and allowed to cool to ambient conditions. As shown in Figure 2 (c), as the temperature decreases, the solubility of the drug in the adhesive also decreases, leaving the amount of drug 21 in the contact adhesive at saturation excess at ambient conditions.

The amount of drug present in the therapeutic drug delivery device and necessary to obtain an effective treatment result may be based on the minimum required dose of drug for the particular indication to be treated; Solubility and permeability of the carrier and the adhesive layer; And the length of time that the device will be fixed to the skin. The minimum amount of drug is determined by the requirement that a sufficient amount of drug be present in the device to maintain the desired release rate over a given application period. The maximum amount for safety purposes is determined by the requirement that the amount of drug present should not produce a toxic effect. Typically, maximum concentrations are adverse effects on the characteristics of the delivery device such as harmful histological effects such as irritation, unacceptably high initial drug loading doses into the human body, or reductions in accuracy, loss of viscosity, or other properties. It is determined by the amount of drug that can be contained in the carrier without producing it.

The initial load of drug in the carrier determines the expiration date of the device (typically from 8 hours to 7 days). The invention may be used during such time periods, but certain preferred embodiments are particularly suitable for periods of administration up to about 24 hours. As discussed for particularly preferred embodiments, the drug is initially present in the carrier in saturated concentration or saturated excess. However, as long as the drug is continuously administered to the skin or mucosal site in an amount sufficient to provide the desired therapeutic rate and for time, the drug may be present at sub-saturation levels during use without departing from the present invention.

The support may be an air-tight or enclosed material, including but not limited to polyethylene, polyurethane, polyester or ethylene vinyl acetate film. Preferred are polyethylene terephthalate / ethylene vinyl acetate supports. When ethylene vinyl acetate is used as the support, it preferably has a vinyl acetate content of 33% or 40%.

Rate control membranes are known in the art for controlling the rate at which drugs enter and exit the delivery device and may be made of a permeable, semipermeable or porous material having a lower permeability to the permeation promoter than the drug reservoir 12. Suitable materials include, but are not limited to, polyethylene, polypropylene, polyvinyl acetate, ethylene n-butyl acetate and ethylene vinyl acetate copolymers. The rate control membrane also includes a significant amount of mineral oil or other diffusive medium as described in US Pat. No. 3,797,494.

The reservoir formulation can be an aqueous or non-aqueous substrate. Aqueous formulations usually contain water or water / ethanol and about 1 to 5% by weight of a gelling agent, for example hydrophobic polymers such as hydroxyethylcellulose or hydroxypropylcellulose. Conventional non-aqueous gels contain silicone fluid or mineral oil. Gels based on mineral oils also typically contain 1-2% by weight of a gelling agent such as colloidal silicon dioxide. The suitability of a particular gel depends on the compatibility of the permeation promoting mixture (if used) and its components added to the drug and any other ingredients in the formulation.

When using non-aqueous based formulations, the reservoir base is preferably composed of a hydrophobic polymer. Suitable polymeric bases are well known in the transdermal drug delivery technique, examples of which are described in the patents cited above. Conventional lamination systems consist essentially of polymeric membranes and / or bases such as ethylene vinyl acetate (EVA) copolymers, as described in US Pat. No. 4,144,317, and preferably have a vinyl acetate (VA) content of about 9% to about 60% or less and more preferably 9% to 40% VA. Polyisobutylene / oil polymers containing 4 to 25% high molecular weight polyisobutylene and 20 to 81% low molecular weight polyisobutylene together with a balance which is an oil such as mineral oil or polybutene are also used as base materials. Can be used.

Suitable adhesives are well known in the art, and polyisobutylene (PIB) adhesives containing mixtures of acrylate polymers containing silicone and / or mixtures and grafting copolymers thereof, low molecular weight and high molecular weight PIB, and the United States. And any amount of mineral oil or polybutene, styrene-butadiene copolymers, and tackifier (s) and styrene-isoprene copolymers, as described in patent 5,508,038.

Although any drug suitable for transdermal administration can be delivered in accordance with the present invention, there are certain drugs that are particularly suitable for administration from the device according to the present invention. In particular, testosterone and its esters used to treat men with reduced sexual function constitute a preferred drug for delivery in accordance with the present invention. Other preferred drugs include hormonal agents, in particular steroids, estrogens such as estradiol and esters thereof, metabolites such as nandrolone and esters thereof, progesterones such as progesterone and esters thereof, corticosteroids, and anesthetics do.

The surface area of the device of the present invention varies from about 5 cm ² to about 75 cm ² . However, conventional devices will have a surface area in the range of about 20 to 60 cm ² . Conventional transdermal devices according to the present invention are made into rectangular patches having generally oval or rounded corners of about 60 cm ² .

The drug delivery device of the present invention may also contain other permeation accelerators, stabilizers, dyes, diluents, pigments, carriers, inert fillers, antioxidants, excipients, gelling agents, anti-irritants, vasoconstrictors as is known in the art. have.

The device of the present invention may be designed to effectively deliver drugs for extended periods of up to 7 days or less at three to four hours. Seven days is the maximum time limit for applying a single device because the side effects of sealing the skin area increase over time and a standard cycle of skin peeling and replacement occurs within about seven days.

According to a particularly preferred embodiment for transdermal administration of testosterone, the drug reservoir contains a gelling agent such as 20 to 30 wt% testosterone, 68 to 80 wt% ethanol, and 1 to 2 wt% hydroxypropyl cellulose. , The speed control membrane contains ethylene vinyl acetate copolymer having a vinyl acetate content of 5 to 30% by weight, preferably 9 to 18%, and the adhesive has a ratio of high molecular weight PIB / low molecular weight PIB / mineral oil of 0.75 to 1.25 / 1 And a polyisobutylene mixture containing ˜1.5 / 1.5 to 2.5, most preferably 1 / 1.25 / 2.

The foregoing patents describe various materials that can be used to manufacture the various layers and components of the drug delivery device according to the present invention. Therefore, the present invention contemplates the use of materials other than those described in detail herein, including those that may be known to the art below and that may perform the necessary functions.

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

Example 1

A transdermal delivery system for the administration of testosterone through the nonscrotum skin is prepared as follows. A reservoir gel containing 26 wt% testosterone, 1-2 wt% hydroxypropyl cellulose, and the remaining 95% ethanol is prepared by mixing testosterone, 95% ethanol and adding hydroxypropyl cellulose with the mixing. Gel load is 21 mg testosterone / cm ² .

The contact adhesive composition is prepared by mixing polyisobutylene (MW 1200000), polyisobutylene (MW 35000) and light mineral oil in a weight ratio of 1: 1.25: 2. A 50 micron thick contact adhesive layer is placed over a 75 micron thick siliconized polyethylene terephthalate release liner film. The contact adhesive faces of the two layers of semi-assembled obtained are laminated to a 50 micron thick ethylene vinyl acetate (EVA) copolymer (9% vinyl acetate) film. The gelled testosterone-ethanol mixture is placed on an EVA membrane. A support element consisting of an EVA heat sealable coating and an aluminum treated polyethylene terephthalate is placed on the gel and heat sealed to the EVA copolymer using a rotary heat seal machine. The finished system is punched out of the laminate using a circular punch and placed in a sealed bag to prevent loss of volatile components.

The system is then applied at 35 ° C., 40 ° C., or 50 ° C. for 7 days and the release rate is tested at room temperature to compare with the system left at room temperature for 1 month to observe the effect of temperature on the load capacity.

After removing the laminate's release liner, the system is placed on a rod named Teflon. Then, a known volume of receptor solution (0.10% phenol / H ₂ O) is placed in a test tube and allowed to equilibrate at 35 ° C. The Teflon rod with the system attached is then placed in a 35 ° C. water bath. The mixing is carried out by an attachment to the motor which produces a constant vertical mixing.

At a given time interval, the entire receptor solution is removed from the test tube and replaced with an equal volume of fresh receptor solution previously equilibrated at 35 ° C. Receptor solutions are stored in capped vials at 4 ° C. until the testosterone content is determined by HPLC. From the drug concentration and the volume, permeation area and time interval of the receptor solution, the drug flow can be calculated as follows: (drug concentration x volume of receptor) / (area x time) = flow (μg / cm ² · hour) .

3 shows the effect of thermal equilibrium on the testosterone release rate. From the results shown in Figure 3, it can be seen that the temperature has the most significant effect on the release rate of testosterone during the initial delivery period of 0 to 2 hours corresponding to the delivery of the load capacity. The loading capacity for this system corresponds to the accumulation of testosterone release for approximately 0 to 2 hours. The effect of thermal equilibrium on the load capacity is shown in Table 1, as measured by the accumulated release of testosterone over a period of 0 to 2 hours. As shown in Table 1, the load capacity increases with the temperature of the thermal equilibrium process.

Effect of Thermal Equilibrium on Load Capacity of Testosterone group Accumulated release amount from 0 to 2 hours (㎍ / cm ² ) I 6.7 II 26.0 III 28.2 IV 46.8

Group I was stored for 1 month at room temperature.

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

A transdermal treatment system containing an aqueous ethanol gel is prepared according to the following procedure. Fentanyl substrate is added to 95% ethanol and stirred to dissolve the drug. Purified water is then added to produce a mixture containing 14.7 mg / g fentanyl in 30% ethanol-water solvent. 2% of hydroxyethyl cellulose gelling agent is slowly added to the solution with stirring and mixed until a smooth gel is obtained (approximately 1 hour). A fluorocarbon-diasylate treated polyester containing a release liner for the system by a solution in which a 0.05 mm thick contact adhesive layer was placed with an amine resistant silicone medical adhesive on a polyester film from a solution in trichlortrifluoroethane. Form on the film. A 0.05 mm thick speed control film containing EVA (9% VA) is laminated under pressure to the exposed adhesive. A support element is also provided which contains multiaminates of polyethylene, aluminum, polyester, and EVA and the aqueous gel has a support load and release liner / adhesive / rate in a rotary heat seal machine with a gel loading of 15 mg / cm ² . Put it in the pocket between the control membranes. A 10 cm ² sealed bag is die cut and immediately placed in the bag to prevent ethanol loss.

The effect of thermal equilibrium on the 10 cm ² system prepared according to the procedure was tested. The system is applied to regensens of various temperatures / hours and then left at 25 ° C. The accumulated release of fentanyl over a period of initial 0-2 hours to determine the release rate is measured using the method described in Example 1. The release rate is measured after storage at 25 ° C. for 2 months. The results are shown in Table 2.

Effect of Thermal Balance on Fentanyl Load Capacity group 0 to 2 hours of release (μg / hour) I 208.9 II 246.3 III 404.2 IV 445.1

Group I was placed in an oven at 30 ° C. for 7 days before storage at 25 ° C.

Group II was placed in an oven at 40 ° C. for 3 days before storage at 25 ° C.

Group III was placed in an oven at 51 ° C. for 1 day before storage at 25 ° C.

Group IV was placed in an oven at 60 ° C. for 1 day prior to storage at 25 ° C.

Table 2 shows that as the temperature of the thermal equilibrium process increases, the accumulated release of the drug increases during the initial 0-2 hour dosing period. This initial 0 to 2 hour delivery period roughly corresponds to the delivery of the load capacity. After 2 months of storage at room temperature, no detectable reverse migration of fentanyl from the adhesive to the drug reservoir was observed. From Table 2 it can be seen that the amount of fentanyl released (load capacity) increases with thermal equilibrium temperature for 0 to 2 hours.

Example 3

The effect of exposure time on the thermal equilibrium of elevated temperatures is studied. The system prepared according to Example 2 is left at 40 ° C. and release rates are taken at 0, 3, 7, and 14 day intervals. 4 shows the effect of storage at 40 ° C. on the initial release of fentanyl for 0 to 2 hours (load dose) after initiation of delivery. As shown in FIG. 4, the load capacity increases with exposure time.

Example 4

A 10 cm ² system is prepared according to Example 2. Some of these systems are applied at 40 ° C. for 4 days and the remaining systems are left at room temperature. In vitro release profiles using the method described in Example 1 are measured for each set of systems. The average loading capacity for this system, measured by the accumulated release of 0-2 hours, was determined to be 199.00 μg / hour for room temperature systems and 282.25 μg / hour for systems left at 40 ° C. for 4 days. The solid drug amount is observed in the drug reservoir gel of each system set prior to performing the release rate test, indicating that this drug reservoir contains the drug amount in a saturation excess. Solid drugs are observed in the drug reservoir gel of the system that is in thermal equilibrium when they are removed from the oven.

Although the above embodiment describes a method performed in a pocketed system, it is also possible to perform such a method before drilling and bagging the system in cases where care is not taken of the loss of volatile components. .

While the invention has been described in detail with particular reference to certain preferred embodiments thereof, it is understood that changes and variations can be made within the scope and spirit of the invention.

Claims (25)

An improved method of making a drug delivery device having one or more layers containing a concentration of drug in saturated excess, comprising: Forming a device comprising at least one layer initially containing a saturated excess of drug and at least one other layer initially free of saturated excess drug; Applying the device to an elevated temperature for a predetermined amount of time sufficient to allow a quantity of drug to migrate from the layer initially containing a saturated excess of drug to another layer of the device that is initially free of saturated excess drug; And Rapid cooling of the device to ambient conditions. The method of claim 1, wherein the drug load of the drug in the layer that initially contains a saturated excess of drug is sufficient to provide a saturated excess drug amount after a rapid cooling step to one or more of the other layers that are initially free of saturated excess drug. Further comprising selecting in amounts. 3. The method of claim 2, wherein the drug loading is selected such that the layer initially containing a saturated excess of drug contains a saturated excess of drug after rapid cooling. An improved method of making a transdermal drug delivery device comprising: (a) forming a drug reservoir over the support layer (the drug reservoir contains a drug load containing a saturated excess of drug); (b) forming a contact adhesive layer over the release liner (the contact adhesive is free of saturated excess drug); (c) placing a drug reservoir in a drug transport relationship on the adhesive layer to form a device; (d) subjecting the device to elevated temperature for a period of time to facilitate the movement of the drug from the drug reservoir to the contact adhesive; (e) Rapid cooling of the unit to ambient conditions. 5. The method of claim 4, further comprising selecting a drug load to provide a saturated excess drug amount to the adhesive after the rapid cooling step. 6. The method of claim 5, further comprising selecting a drug load to provide a saturated excess drug amount to the drug reservoir after the rapid cooling step. 5. The method of claim 4, further comprising selecting a temperature and time for the adhesive to contain a saturated excess drug amount after the rapid cooling step. The method of claim 7 wherein the selected temperature is 30 to 60 ° C. and the selected time is 12 hours to 20 days. The method of claim 8, wherein the selected temperature is 35 to 45 ° C. and the selected time is 1 to 10 days. The method of claim 4, wherein a speed control membrane is provided between the contact adhesive and the drug reservoir. The method of claim 4, wherein the drug reservoir contains ethanol. The method of claim 4 wherein the contact adhesive contains polyisobutylene and mineral oil. The method of claim 4 wherein the contact adhesive contains an acrylate adhesive. The process of claim 10 wherein the rate controlling membrane contains an ethylene vinyl acetate copolymer having a vinyl acetate content of 6 to 60%. Apparatus for transdermal administration of testosterone through an intact, nonscrotic skin comprising: a) support layer; b) a drug reservoir containing testosterone dispersed in the carrier in an amount in excess of the testosterone saturation concentration in the carrier in an amount; c) means for maintaining a device in a testosterone-delivery relationship in the woundless, nonscrotum skin, (Wherein testosterone is administered through the skin at a substantially constant rate throughout the practical portion of the dosing period). 16. The device of claim 15, wherein the means for maintaining the device in testosterone-delivery to the woundless, nonscrotum skin comprises a contact adhesive. 17. The device of claim 16, wherein said excess is sufficient to maintain testosterone at a level of saturation or saturation excess in the drug reservoir and contact adhesive throughout the actual portion of the administration period. 16. The device of claim 15, further comprising a speed control membrane on the skin proximal surface of the drug reservoir. The device of claim 15, wherein the carrier contains an aqueous gel. 20. The device of claim 19, wherein the carrier contains ethanol. 19. The device of claim 18, wherein the rate controlling membrane contains ethylene vinyl acetate copolymer having a vinyl acetate content of 5 to 30%. The apparatus of claim 21 wherein the vinyl acetate content is 9-18%. The apparatus of claim 16 wherein the adhesive contains a mixture of low molecular weight polyisobutylene and high molecular weight polyisobutylene. 24. The apparatus of claim 23 wherein the ratio of low molecular weight polyisobutylene to high molecular weight polyisobutylene is 1.25: 1. Apparatus for transdermal administration of testosterone through woundless, non-scrotic skin containing: a) support layer; b) a drug reservoir containing: a saturated or saturated excess of testosterone, comprising: i) 20-30% by weight of testosterone; ii) 68 to 80 weight percent lower alcohol carrier; And iii) 1-2 wt% gelling agent, c) speed control membrane on the skin proximal surface of the reservoir; d) means for maintaining a device in a testosterone-delivery relationship in the woundless, nonscrotum skin, (Wherein testosterone is administered through the skin at a substantially constant rate throughout the practical portion of the dosing period).