KR100483913B1 - Drug delivery device - Google Patents

Abstract

The present invention relates to an improved method of making a transdermal drug delivery device and a device made therefrom. The present invention provides a method of thermal equilibrium to produce a drug delivery device that eliminates the need to prefill the drug in the body contact layer. The method is particularly applicable to the manufacture of transdermal drug delivery devices comprising a drug reservoir containing a saturated excess of drug.

Description

Medication delivery device

The present invention relates to an improved method of manufacturing a drug delivery device and a drug delivery device produced thereby. The improved methods 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.

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 certain amount 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 prefilled amount corresponds to the amount necessary to provide an initial fill dose that results in a concentration gradient through the skin and saturates the skin binding site that is to be placed under the device with the delivered drug. In addition, US Pat. No. 4,832,953 describes heating a laminate system containing a dispersion of liquid in a non-aqueous matrix 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", STP 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 appropriate complete summaries of 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, such as those described in US Pat. Nos. 5,152,997 and 5,164,990, are not limited in area of application, while it is necessary to use a large number of permeation promoters 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 irritating substances.

More specifically, US Pat. Nos. 4,704,282, 4,725,439, and 4,867,982 describe transdermal administration of testosterone through woundless scrotum skin. These patents show that scrotum skin has a five-fold increase in testosterone permeability compared to non-scrotum skin. Testosterone is provided in an ethylene vinyl acetate copolymer matrix and is 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 a therapeutically effective amount of testosterone through the nonscrotum skin.

U.S. Patent 5,223,262 also 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 a one way membrane that can penetrate the alkanol solvent and that the active agent and water are practically impermeable.

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 includes heating the drug reservoir component to a predetermined temperature and then cooling the drug reservoir component to provide a supersaturated reservoir to contain only the drug and reservoir material of the single phase.

As mentioned above, it is often desirable to pre-fill the adhesive with an excess amount of drug in saturation concentration, which has been done by premixing the drug into the adhesive. However, even if a saturated excess drug amount can be initially added to the adhesive, the method of premixing the drug in the adhesive layer has significant practical problems.

The drug must be sent to an adhesive feeder that is mixed with the adhesive, and then finally the device is returned to the manufacturing unit to be manufactured. This requires undesired transportation, time, and most importantly, this method requires special equipment at the site of the adhesive feeder that follows the regulatory requirements for the manufacture of the drug delivery device.

Disclosure of the Invention

The present invention eliminates the need to premix the body contact layer of the drug delivery device with the drug during the manufacture of the final product having a saturated excess of suitable amount of drug in the layer in addition to the drug reservoir, such as the contact adhesive of the transdermal drug delivery device. did.

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

Yet another aspect of the present invention is to provide an improved method for manufacturing a drug delivery device and a device made therefrom that allows a desired amount of drug to be provided to the various layers of the drug delivery device.

Another aspect of the invention is to obviate the need to prefill the contact adhesive of the transdermal drug delivery device with the drug in order to obtain a final product with 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 woundless, non-scrotum skin to obtain a therapeutically effective blood concentration of testosterone in a patient.

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

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.

The term "drug" as used herein is, in its broadest sense, any substance intended to produce some biological, useful, therapeutic, or other intended effect, such as, for example, promoting permeability to the organism to which it is applied. It is considered to mean.

As used herein, the term "saturated excess" refers to the state in which the drug is present in both phases, the solid phase indicating the excess and the dissolved phase saturated in the carrier.

As used herein, the term "loading dose" refers to the amount of drug present in the body contact layer or adhesive layer other than the drug reservoir above the saturation concentration.

As used herein, the term "quick cooling" refers to a cooling process that occurs over a time shorter than the time the device is held at elevated temperature, and preferably refers to a cooling process for a time without subsequent re-equilibration of the drug containing layer. .

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

As used herein, the term "therapeutically effective" refers to the amount of drug or rate of drug administration necessary 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 allows a larger amount of drug to be initially added 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 simply by allowing the device to equilibrate at room temperature. You can move it. The method also allows the drug-free layer initially to rapidly cool to ambient after the saturated excess drug-free layer to retain a predetermined amount of drug that becomes a saturated excess. This method does not require mixing the drug with a body contact layer, such as an adhesive layer of a transdermal delivery device, at a site different from the location of device manufacture to provide the desired fill capacity in the body contact layer.

The method of the invention selects an appropriate drug charge in one layer of the device, typically a saturation excess, and selects an appropriate time and temperature for carrying out the thermal equilibrium process to select any desired concentration in any particular layer of the final system. 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 is selected to keep the drug above saturation in the layer at elevated temperatures. Should be. 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 fill 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 filled doses of drug to the outer 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 moving from the drug reservoir to the contact adhesive, the initial filling dose of the delivered drug can be effectively controlled to achieve the desired infusion of the drug that saturates the skin binding site without having to be prefilled directly with the drug adhesive. .

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 supplied with a saturated excess of drug, and an 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 the saturated excess of drug that will then be in the other layer at the filling capacity. The filling 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 prefilling the drug directly with 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 backflow 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. In males with reduced sexual function, the mean serum testosterone concentrations are above 5 lower limit of the normal range of men (275-300 ng / dl) and the mean maximum testosterone concentrations are approximately 5 to obtain a mean-normal range of about 500-600 ng / dl. To 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, there is shown a drug delivery device 10 comprising an aqueous gel reservoir 2 according to the present invention. The delivery device 10 includes a backing number 3 that serves as a protective cover of the device, giving structural support and substantially preventing components in the device 10 from exiting the device. The device 10 also includes a reservoir 2 containing the drug with or without the permeation accelerator, and on its surface remote from the support element 3 a rate controlling membrane 4 for controlling the release of the drug and / or permeation promoter from the device 10. Have 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 can be obtained by pressing, melting, attaching, adhesive applied to the edges, or other methods known in the art. In this way, the reservoir 2 is entirely contained between the support element 3 and the speed control film 4. On the skin's proximal surface of the speed control film 4 is an adhesive layer 5, and a peelable liner that is removed before attaching the device 10 to the skin.

According to a particularly preferred embodiment, the drug reservoir 2 is initially provided with a drug filling containing an excess of drug above the saturation concentration of the drug in this reservoir, so 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 allows the system to contain sufficient drug to provide the desired amount of drug to the contact adhesive layer during thermal equilibrium, and the reservoir contains sufficient 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. 2 (a) shows a drug delivery device 20 with excess drug 21 in the drug reservoir 22, 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 rates 24 and 25 at an increased rate due to the equilibrium shift as shown in FIG. 2 (b). Go to. Equilibrium shifting also allows higher amounts of drug to migrate into adjacent layers, such as contact adhesive 25, due to the increased solubility of the drug in the adhesive at elevated temperatures.

After a certain time, the device is removed from the elevated temperature and allowed to cool to ambient conditions. As shown in Fig. 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 time for which 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 filling 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.

Initial filling of the drug in the carrier determines the expiration date of the device (usually from 8 hours to 7 days). The present invention may be used during such time periods, but certain preferred embodiments are particularly suitable for periods of administration up to about 24 hours. Drugs as discussed for particularly preferred embodiments are 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 hours, the drug may be present at sub-saturation levels during use without departing from the present invention.

The support may be a breathable or hermetic 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 may 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 hydrophilic 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 drug and the added permeation promoting mixture (if used) with the components of the gel, in addition to any other ingredients in the formulation.

When using non-aqueous based formulations, the reservoir matrix is preferably composed of a hydrophobic polymer. Suitable polymeric matrices are well known in transdermal drug delivery techniques, examples of which are described in the patents cited above. Conventional lamination systems consist essentially of polymeric membranes and / or matrices 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 about 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, oils such as mineral oils or polybutenes, are also known as matrix materials. Can be used as

Suitable adhesives are well known in the art and include polyisobutylene (PIB) containing silicone and / or acrylate polymers, mixtures thereof and grafting copolymers thereof, mixtures of low molecular weight and high molecular weight PIB with any amount of mineral oil ) Adhesives, and polybutenes, styrene-butadiene copolymers, and styrene-isoprene copolymers (which contain tackifier (s)) as described in US Pat. No. 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 may vary 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 known in the art. have.

The device of the present invention may be designed to effectively deliver drugs up to an extended period of time from three to four days to seven days or longer. 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% by weight testosterone, 68 to 80% by weight ethanol, and 1 to 2% by weight 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 required 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 mixing. The gel charge 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 cast 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 filling capacity.

After removing the laminate's release liner, the system is placed on a rod named Teflon. Thereafter, 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 flux of the drug can be calculated as follows:

(Drug concentration x volume of receptor) / (area x time) = flow (μg / cm ² · time).

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

TABLE 1

Influence of thermal equilibrium on the charge capacity of testosterone

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-diacrylate treated poly containing a release liner for the system by a solution of casting a amine resistant silicone medical adhesive onto a polyester film from a solution in trichlortrifluoroethane, a 0.05 mm thick contact adhesive layer. Form on ester 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 is supplied with a support element and release liner / adhesive / velocity in a rotary heat seal machine with a gel fill of 15 mg / cm ² . It is pouched between control films. A 10 cm ² sealed pouch is die cut and immediately pouched to prevent loss of ethanol.

The effect of thermal equilibrium on the 10 cm ² system prepared according to the procedure was tested. The system is applied to regensens at various temperatures / hours and then held at 25 ° C. To test the release rate, the cumulative release of fentanyl over a period of initial 0-2 hours 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.

TABLE 2

Effect of Thermal Equilibrium on Fentanyl Filling Capacity

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 before storage at 25 ° C.

Table 2 shows that as the temperature of the thermal equilibrium process increases, the cumulative 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 a filling 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 (charge capacity) increases with thermal equilibrium temperature during 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 (charge capacity) after initiation of delivery. As shown in FIG. 4, the charge 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 fill capacity for this system, measured by cumulative 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 (8)

As a transdermal administration device of testosterone through woundless nonscrotum skin over a period of administration: a) support layer 3; b) a drug reservoir (2,21) containing a carrier and testosterone dispersed in saturated excess thereof; And c) an adhesive contact (5,25) on the skin proximal surface of the drug reservoir for maintaining the device upon administration of testosterone in relation to woundless nonscrotum skin, wherein the contact adhesive is saturated in the contact adhesive at the beginning of the administration period. Additionally contains excessively dispersed testosterone) Wherein said saturated excess in the drug reservoir is sufficient to maintain testosterone at a saturated or saturated excess level in the drug reservoir over a substantial portion of the administration period. The device of claim 1, further comprising a speed control membrane (4,24) on the skin proximal surface of the drug reservoir. The device of claim 1, wherein the carrier contains an aqueous gel. 4. The device of claim 3, wherein the carrier contains ethanol. The device of claim 2 wherein the rate controlling membrane contains an ethylene vinyl acetate copolymer having a vinyl acetate content of 5 to 30%. 6. The device of claim 5 wherein the vinyl acetate content is 9-18%. The device of claim 1 wherein the adhesive contains a mixture of low molecular weight polyisobutylene and high molecular weight polyisobutylene. 8. The device of claim 7, wherein the ratio of low molecular weight polyisobutylene to high molecular weight polyisobutylene is 1.25: 1.