DE3546830C2 - Device for delivering fentanyl across the skin - Google Patents

Abstract

System for transdermal delivery of fentanyl (I), or its analgesically active derivs., comprises (1) a reservoir contg. enough (I) to provide analgesia within 4hr. of application to the intact human skin and to deliver (I) at a rate sufficient to maintain analgesia for not less than 12hr, this reservoir having a surface of predetermined area in contact with the skin, and (2) a device for keeping this surface on the skin

Description

Fentanyl and its analgesic derivatives (hereinafter only referred to as "derivatives") such as sulfentanyl, carfentanyl, Lofentanyl and alfentanyl have long been considered extraordinarily effective anesthetics and analgesics known. Fentanyl is described in U.S. Patent 3,164,600 and its Application is approved by the United States FDA. When using Fentanyl usually as a citrate either as an injection or as an infusion or continuous infusion to produce a Administered anesthesia or analgesia.

The principle of transdermal administration of drugs for administration of a wide variety of drugs is known. It is referred to US Pat. Nos. 3,598,122, 4,144,317,  4,201,211, 4,262,003 and 4,379,454, which are representative are for various transdermal delivery systems for Medicines, which systems are capable of controlled quantities on medicines given to patients for extended periods of time Range from a few hours to a few days.

Fentanyl and its derivatives are very potent, fast metabolizable drugs with a relative narrow therapeutic index, which is extremely undesirable Side effects of overdose leads, in particular a respiratory depression that when unchecked remains leading to death. They are also relatively expensive and easily lead to abuse. It has been shown that these characteristics are numerous and sometimes contradictory Requirements for a practical transdermal delivery device to lead. For example, it would be desirable that the active ingredient is removed from the device for at least 24 hours delivered at a substantially constant speed while at the same time the amount of active ingredient both in the not yet used as well as in the used System should be kept to a minimum. Another example of conflicting requirements is that the accuracy with which the system the Release rate controls, relatively high should be to ensure that no excessive amounts of Medicaments are delivered if the  Skin of a patient is damaged or an unusual one has high permeability. On the other hand, the release speed per unit area of the system not so low are chosen that the beginning of the analgesic effect Delayed over 5 hours or equivalent Doses of systems of a reasonable size not achieved can be.

In A. S. Michaels et. al., AIChE Journal 21 (5), pp. 985 to 996 (1975) are measurement data for the penetration of various drugs, including Fentanyl, contained by cadaver skin, and in Y.W. Chien, Novel Drug Delivery Systems - Fundamentals, Development Concepts, Biomedical Assessments, New York, Marcel Dekker, Inc. (1982), ch. 5, transdermal Control - Release Drug Administration, pp. 168-170 are theoretical Considerations made. After Michaels et. al. is of special medical Significance of the conclusion that of active substances with large water and Oil solubility, a considerable major permeability can be expected. So far they have sufficient potency, they can therefore in therapeutically effective extent over a relatively small area of skin be administered (p 986). Because of these considerations were for the Experiments on cadaver skin (p. 992) selected 10 active substances, the one wide range of chemical structure / molecular weight properties and oil / water solubility. The corresponding data is in Table 2 on page 993. These data are not known by fentanyl a suitable drug for transdermal administration; they lay considerably worse than nitroglycerin.

The object of the invention is therefore a transdermal therapeutic To provide delivery system that is suitable fentanyl or its derivatives at a substantially constant rate Over an extended period give analgesia to effect. Here is the delivery rate be limited and the duration of administration of fentanyl or its derivatives are accurately determined to the bloodstream and the amount of drug remaining in the system is very low his. At the same time the analgesic effect should be in proportion enter a short time.

The invention relates to a transdermal Delivery system for delivery of fentanyl and / or its analgesic derivatives according to the claims.

In the accompanying drawings is

Figure 1 is a cross-section through a schematic perspektifische view of an embodiment of a transdermal delivery system of the invention prior to application to the skin.

Fig. 2 is a cross-section through another embodiment of the invention;

Figure 3 is a cross-section through a further embodiment of the invention.

Fig. 4 is a graph showing the flow through the skin in vitro versus time for a particular embodiment of the invention;

Fig. 5 is a graph showing the flow through the skin in vitro versus time for another specific embodiment of the invention;

Fig. 6 is a graph showing the flow through the skin in vitro versus time for another embodiment of the invention;

Fig. 7 is a graph showing the flow through the skin in vitro versus time for another embodiment of the invention and

Figure 8 is also a graph showing the flow through the skin in vitro versus time for one embodiment of the invention.

According to the invention, it has been found that fentanyl or its Derivatives administered to the human body transdermally can be used to achieve analgesia when they by an area of 5 to 100 cm², preferably 10 to 50 cm² of intact skin over a longer period at a speed in the range of 0.5 to 10 μg / cm 2 · h and preferably at a rate in the Range of 1 to 5 μg / cm 2 .h. On this way it is by appropriate selection of the surface or the size of the dispenser possible, total take-up speeds to achieve the drug that a reasonably accurate attitude to the needs of the individual Allow patients to have a safe and effective Dosage form is present. Uniform administration rates,  which are achieved according to the invention, are in the range of 10 to 300 ug / h and preferably 25 to 150 μg / h. The administration will be at least 12 hours and up to 7 days, where 1 to 3 days are preferred.

It has been shown that a relatively wider range as opposed to permeabilities of normal human skin Fentanyl exists and this permeability varies not just from person to person and body to body site, but also depends to a great extent on the chemical form of the active ingredient. It has now been found that fentanyl citrate, the form in which fentanyl is administered, in that way a small amount passes through the skin, that it does not is suitable for transdermal administration, even with help of penetration enhancers. It's against it now shown that the active ingredient to the above delivery rates to achieve in the transdermal therapeutic System must be in the form of the base. The Data obtained show that the permeability of normal human skin for fentanyl base about 4 ± 1.8 (SD) μg / cm² · h with limits of 1.2 and 5.7 μg / cm 2 .h observed were.

With respect to the other fentanyl dericates, it is believed that the following relationships exist between the relative permeability and the effectiveness:

active substance relative effectiveness (fentanyl = 1) 1) fentanyl 1 2) Sufentanyl 15 3) carfentanyl 34 4) Lofentanyl 15 5) Alfentanyl 0.25

relative skin penetration
(1) <(2) (3) <(4) <(5)

These relationships enable the therapeutic transdermal Administration of these fentanyl derivatives in the context of above given parameters.

While the invention in its simplest form, the release of fentanyl in therapeutic Quantities over extended periods of transdermal delivery systems of the matrix type, which is primarily on the permeability of the skin to control the rate of absorption of the active ingredient is used in preferred embodiments the active ingredient out of a the speed determining transdermal system delivered at which the system itself determines the maximum speed, with which the active ingredient is released through the skin.

The flow, J _net , of the drug delivered through the skin from a rate-controlling transdermal therapeutic delivery system is given by the following equation

Thus, to obtain a transdermals therapeutic system, in which at least 50% (and preferably more) of the speed determination by J _system, the flow from the system to an unlimited drop takes place, it is necessary J _skin, the flux through the skin, by Use of a penetration enhancer significantly increase. Suitable penetration enhancers are, for. For example, ethanol and other higher alcohols, n-decylmethylsulfoxide (nDMS), polyethylene glycol monolaurate, dilaurate and related esters, glycerol mono-olaet and related mono-, di- and trifunctional glycerides, diethyl-toluolamide, N, N Dimethyl laurylamide, N, N-dimethyl lauryl amine oxide, and the penetration enhancers described in U.S. Patent 4,415,563.

Since conservative analysis of the present data suggests that the permeability of normal skin to fentanyl base is in the range of 1 to 10 μg / cm 2 · hr, with the majority being in the range of 2 to 5 μg / cm 2 · h, it should preferably be sufficient Penetration enhancers for the controlled rate systems should be provided to increase the _skin for the least permeable skin parts to a value no less than J _system . The application of formula 1 clearly shows that with increasing J _skin , with J _system remaining constant, J _{net reaches} the value of J _system . This leads to a system in which at least 50% of J _net is controlled by the system. It would be particularly beneficial if the system were to control the flow rate at least 70%, and that could be achieved if the permeability of the skin were increased to at least 2.4 times that of steady state J _system .

When transdermal systems of the invention applied to the skin be the drug from the system in the Skin is transported and absorbed by the bloodstream  to develop its systemic analgesic effect. It has it has been shown that the skin has fentanyl binding sites, that need to be saturated before any appreciable Absorption into the bloodstream takes place. The variation of Person to person and body to body point is in Range of 25 to 75 μg / cm 2 fentanyl in base form or its derivatives and the initial saturation of these Digits should be fast, fast insertion to achieve analgesia. Because most transdermal therapeutic systems to an initial (temporary) lead to increased release of active ingredient with significantly higher speed than in stationary Condition that will be reached later is the incorporation of additional Amounts of active ingredient in contact with the skin coming area of the delivery system is not necessarily required. The systems described here are capable of Release drug at initial rates that the Onset of analgesic action within 2 to 4 Initiate hours after application, but the active ingredient may be the adhesive layer or another with the skin In contact with the layer to be added to the binding sites to saturate faster, if desired is.

The binding sites of the skin are also significant because they are the upper limit to the size of the transdermal therapeutic Systems and vice versa the lower limit for the determine appropriate delivery rate. The total amount to drug that is present at the binding sites is directly proportional to the surface area of the delivery system and is independent of the speed with which the Drug is delivered. If a system of maximum size of 100 cm² is applied according to the invention, the Total amount of active ingredient at the binding sites at least 2.5 to 7.5 mg. When such a system is removed If the total amount of bound active substance of  Body are absorbed before the effect of the agent stops. Due to the high efficacy of fentanyl and its Derivatives it is preferred that the amount of active ingredient, the dissolved in the skin, kept at or below 3.75 mg will be used to allow a rapid cessation of therapy.

If a continuous analgesic effect is desired is, the empty system must be removed and a new system be applied to another place. Because the saturation the binding sites in the skin in a conventional manner substantially at the same speed as the absorption of the bound drug remains the blood levels essentially constant.

The invention will be closer to the attached figures explained.

In Fig. 1 a preferred embodiment of a transdermal therapeutic system 1 according to the invention is provided, comprising a bag of an impermeable backing layer 2 , a speed-controlling membrane 3 controlling the rate of drug delivery and an amine-resistant contact agent adhesive layer 4 covered by a peelable protective layer 5 . The impermeable backing layer 2 is formed so as to form in the middle a volume or a cavity which contains the active substance reservoir 6 in the form of a gel in which the active substance is dissolved or dispersed. Although in preferred embodiments an amine-resistant adhesive layer is present, as indicated in Figure 1, other means may be employed to hold the system on the skin. Such means comprise a circumferential ring of adhesive outside the passageway of the active agent from the system to the skin. In this case, the adhesive need not be amine-resistant. The use of adhesives or patches, cover layers or other fasteners such as buckles, belts and elastic bracelets is also possible.

In the above-mentioned references is a variety of Materials specified for the preparation of different Layers of Fentanyl Transdermal Delivery Systems can be applied according to the invention.

Velocity-determining membranes are z. B. those of low density polyethylene (LDPE), Ethylene-vinyl acetate copolymers (EVA) (0-40 and preferably  5-18% VA), heat-sealable polyester and elastomeric Polyester block copolymers, as described in US Pat. No. 4,127,127, which is essentially the speed determine with which fentanyl is released. The driving one Force that causes the drug to slow down Membrane passes is the Thermodynamic activity of the drug dissolved in the drug reservoir and less the absolute concentration.

The rate-limiting membrane can be 0.0127 to 0.1270 mm thick, and is preferably 0.25 to 0.076 mm thick. To ensure a reasonable life of the system to achieve the gel content is 10 to 50 mg / cm², which is to a solids content of 0.01 to 5 mg / cm².

Fig. 2 shows a multilayer transdermal therapeutic delivery system according to the invention. Such a transdermal therapeutic system 11 comprises a plurality of layers joined together into a unitary structure. The uppermost layer 12 comprises the backsheet, the layer 16 comprises a polymeric drug reservoir, the layer 13 a rate limiting membrane, and the layer 14 an amine resistant pressure sensitive adhesive. The layer 15 is a peelable pad that can be removed before use. The elements or layers 12, 13, 14 and 15 can be made of similar materials as are used for the corresponding parts of Fig. 1, while the layer 16 is a polymeric material which can be softened and contain penetration enhancers, and in which the active ingredient is dissolved or dispersed. A typical composition for a laminated transdermal system is given in Table 3, wherein the rate-limiting membrane is preferably selected from the above-mentioned materials as well as from microporous materials.

Laminated system material Wt .-% reservoir Polyisobutylene softened with mineral oil (PIB / MO) or silicone polymer 50-95% Active substance in base form 5-50% Contact adhesive @ PIB / MO or amine-resistant silicone 0.025-0.076 mm

Another embodiment of a delivery system according to the invention is shown in Fig. 3, in which the transdermal therapeutic system 1 has a uniform (monolithic) structure. The system 21 comprises a backsheet 22 which is impermeable to the fentanyl, a peelable protective layer 25 which is similarly impermeable and readily peelable from the drug reservoir / contact adhesive layer 23 which consists of a pressure-sensitive adhesive in which the Active ingredient dissolved and, if desired, dispersed. Such a system has the advantage that it can be easily prepared but releases the active ingredient at a rate primarily determined by the permeability of the skin at the person's site of use. However, while this system can be used to achieve delivery rates for the drug within the stated limits, the actual delivery rate may not be controlled as accurately as is possible with the systems generally described in FIGS. 1 and 2. Suitable materials for the preparation of the contact adhesive / reservoir layer include EVA polymers with about 0 to 18% vinyl acetate and polyisobutylene / mineral oil containing 15 to 25% high molecular weight polyisobutylene (average molecular weight 1,200,000), 20 to 30% low molecular weight polyisobutylene (average Molecular weight 35,000) and the remainder light mineral oil having a viscosity at 38 ° C of about 10 mPa · s. In addition to the active ingredient, the reservoir / contact adhesive layer may also contain additives, penetration enhancers, and other materials as are well known.

Specific examples of various transdermal therapeutic Systems according to the invention which are suitable  for administration of fentanyl at the desired rates over longer periods will be discussed later in the examples described. To the remainder of active ingredient in the consumed To keep systems as low as possible, it has demonstrated that the initial concentration of fentanyl in the Matrix material should be chosen so that they are less is 0.5 mg / cm². In the following Examples are below percent - unless otherwise indicated - wt .-% to understand.

example 1

A transdermal multi-layered therapeutic system of the type described in Figure 2 was prepared by introducing low molecular weight polyisobutylene, PIB (average molecular weight 35,000), and high molecular weight PIB (average molecular weight 1,200,000) into a stirred tank in the ratio of 1.25 : 1. Light mineral oil (MO) was added to the same kettle in the ratio of about 1.125 to 1 part PIB. Then heptane was added and the mixture was stirred until the polymers had dissolved. Subsequently, sufficient fentanyl base was added to the solution to obtain a mixture containing 20% fentanyl in the PIB / MO. The polymer / drug mixture was poured as a solution onto a tight-fitting pad and the solvent was allowed to evaporate to form an approximately 0.05 mm thick drug reservoir. A microporous polypropylene film saturated with mineral oil was laminated by pressure on the reservoir layer. A PIB / MO blend as described above but containing sufficient additional fentanyl to give a 2% fentanyl content as undissolved solid was coated in a layer of about 0.05 mm thick onto a silicone-treated polyester resin. Protective layer and the resulting composite laminates were laminated to form a delivery system as shown in FIG . Individual systems were punched and packaged from this laminate in circular pieces of sizes 2.5, 5, 10 and 20 cm respectively. The fentanyl flux from the systems prepared by this example in vitro through cadaver skin at 32 ° C in an infinite environment is shown in FIG .

Samples were also prepared which differed from those described above in that they had a solid content of 3.2%. As can be seen in Figure 6, a 2% solids content is adequate to achieve a fast onset of action without unnecessarily high drug release at the onset, and after the initial transition time, both systems gave a uniform delivery rate of about 1, 8 μg / cm² · h over up to 70 h.

Example 2

A one-piece system according to Fig. 3 was prepared by forming a mixture of PIB / MO and fentanyl base as set forth in Example 1 which had been poured in a solvent onto a tight-fitting pad and, after evaporation of the solvent on the silicone-treated peelable protective layer was laminated. The PIB matrices were made containing 10, 20 and 30% fentanyl and the drug delivery rates from such a system through human cadaver skin at 32 ° C into an infinite environment were measured. The results are shown in FIG . However, the systems show the typical time-dependent release rate for the drug from a one-piece (monolithic) device but continuous delivery of relatively constant skin velocity over up to 80 hours within the ranges required by the invention.

Example 3

A one-piece system similar to that described in Example 2 was prepared using an amine-resistant, commercial silicone adhesive and a medical grade liquid silicone having a viscosity of 20 mm² / s dispersed in the 10 and 20% fentanyl bases, respectively. The migration rates from such a system through cadaver skin to an infinite environment are shown in FIG .

Claims (7)

A transdermal delivery system for administration of fentanyl and / or its analgesically active derivatives, comprising a drug reservoir, a skin support layer and a drug impermeable backing layer, characterized by a polymeric matrix reservoir containing the free base active agent in from 5 to 50% by weight, with transdermal drug delivery occurring at a rate of 10 to 300 μg / h for a period of at least 12 hours. 2. Delivery system according to claim 1, characterized in that the active ingredient delivery 25 to 150 μg / h. 3. Dispensing system according to claim 1 or 2, characterized in that the Reservoir contains a penetration enhancer for the active ingredient. 4. Dispensing system according to one of claims 1 to 3, characterized that the passage of the drug through a drug delivery controlling Membrane is limited so that the drug passage is slower than through the skin. 5. delivery system according to claim 4, characterized in that the drug delivery controlling membrane is much better permeable to the penetration enhancer as for the active ingredient. 6. Dispensing system according to one of claims 1 to 5, characterized that the initial drug concentration in the reservoir, after adjustment of equilibrium, not more than 0.5 mg / cm².   7. delivery system according to claim 1, characterized in that the polymeric Matrix is selected from polyisobutylene and silicone polymers.