SI9010493A - Process for producing a transdermal therapeutic system with a phased release of active substance - Google Patents

Abstract

The invention refers to the preparation of transdermal system with a phased release of the active substance and to its use for the local and systemic dermal application of the active substance in human or veterinary medicine or in the cosmetics industry. It consists of the upper layer that is not in contact with the skin and is impermeable to the active substance(s), of the reservoir which contains the membrane and of the layer that sticks to the skin with the removable protective foil. This enables higher initial doses of the active substance and lower maintenance doses, which depends on the characteristics of the membrane.

Description

A process for the manufacture of a transdermal therapeutic system with stepwise delivery of the active substance

FIELD OF THE INVENTION

The invention relates to the field of liquid needs, and secondarily to the field of processing, and more specifically to the field of manufacture of a form of therapeutic agent for therapeutic use on the skin. The symbols of the International Patent Classification are: A 61 L15 / 03, A 61 L 15/06, A 61 F 13/02, A 61 M 37/00, B 32 B7 / 02, B 32 B 7/06, B 01 J 4 / 00, A 61 J 3/00, A 45 D 34/00 and A 24 F 47/00.

A technical problem

The technical problem is how to obtain a transdermal therapeutic system by gradually dispensing the active substance for topical and systemic administration of the active substance to the skin, which is achieved by applying the system to the skin using a sticky layer, and the system itself consists of a reservoir of active substance in the which is provided with a membrane that allows the active substance to be emitted through the skin in a controlled manner.

The state of the art

Transdermal therapeutic systems (TTS) have, in all of this, taken their place in the treatment of a wide variety of diseases. Their main advantage is that they bypass the primary

- a 2-way transition, which is obligatory for the orally administered active substance, and systemically the active substance has a direct effect through penetration through the skin and that a very constant plasma mirror can be achieved with the proper design of the system. This is especially important for active substances that have short delivery times and therefore require constant re-delivery of the active substance.

Because the system is applied externally, it can take up to a week for some systems to sell for a very long time - thus fulfilling their assigned function. This is impossible with oral agents because they leave the body after a maximum of one day due to digestive activity.

Such transdermal systems typically consist of an active substance impermeable back layer, an active substance reservoir, an attachment device for anchoring the system to the skin, and a removable protective film for the skin side of the system. An advantage of the mounting device is that the skin side of the system is at least partially self-adhesive.

In such systems, the reservoir is in the form of a bag containing a liquid or dissolved active substance, or the product is more like a film containing an active substance in a polymer formulation. The systems mentioned above are also called matrix systems and all of the following implementations refer to such systems.

if the reservoir of such a matrix system consists of a single homogeneous layer and there are no feed materials to the control layers between the side of the reservoir facing the application against the skin and the skin only, then feed the system to deliver the active substances if the matrix is supersaturated with the active substance by equation 1 oz. if this is not the case according to Equation 2.

θ “(^ dr * (Cdr C _SD r) * C _SDR * 1) en. 1

Q = 2 * C _DR * (D _dr * t / 3.14) en. 2

Q: Amount of active substance released at time t

-3t: time

D _dr : diffusion coefficient of the active substance in the matrix

C _DR : concentration of the active substance in the tank

C _SDR solubility of the active substance in the tank

Since Q is directly proportional to the square root of time, we also call this equation the root-t law. The release of the active substance in these systems is not constant and falls rapidly over time.

if a more constant delivery of the active substance is desired, this can be achieved by using the so-called control membrane.

Such a system is assembled from the back layer, from the reservoir of the active substance, from the control membrane, the adhesive-adhesive layer to attach the system to the skin, and from the removable protective film.

Q = C ₀ * e

-D / 1 * t en. 3

C _o = initial concentration of the active substance D = diffusion coefficient of the active substance in the membrane I = thickness of the membrane

However, in some active substance groups, constant delivery rates and constant plasma levels may be undesirable. These include e.g. agents that affect blood pressure and blood vessels, sedatives and sedatives, psychopharmaceuticals, painkillers, anti-angina pectoris, anti-asthmatics and addictive substances such as. nicotine.

For these substances, it is useful to be able to achieve the customized plasma mirrors.

In addition, some active substances are not given continuously, but only when needed

-4Options as long as possible. Such a substance, which is already on the market as a transdermal system, is e.g. scopolamine against travel problems.

Other active substances for which such occasional use is possible are e.g. painkillers, psychopharmaceuticals, tranquilizers, sedatives or appetite suppressants.

In the transdermal administration of such substances, the transdermal system should cause the active substance to flow through the skin, which is acceptable during the application time, taking care of the initial dose for rapid onset of effect and the maintenance dose for a sufficiently long constant or pre-programmed fall of the plasma mirror.

The transdermal therapeutic system for solving this problem is already described in EP-A 0 227 252. There, the active substance in the reservoir is contacted only with the penetration accelerator so that the accelerated penetration is maintained only during the defined initial application phase. The disadvantage is that a penetration enhancer must be found for each active substance.

Another solution to the problem is proposed by DE-OS 36 42 931. There are provided for at least two patches with different concentrations of active substance, adjacent to each other, with different concentrations of the active substance, so that in the first phase of the application, the active substance is released from both chambers with a high starting dose, when, after emptying the chambers with a lower concentration of the active substance, they only contribute to the chambers with a higher concentration of the active substance, resulting in a lower maintenance dose. This system is expensive because of the construction of the chambers and requires special measures regarding the different settings of the concentrations in the chambers.

A description of the solution to a technical problem with implementation examples and a description and brief description of the design drawings

The invention relates to a method of manufacturing a transdermal system with a graduated delivery

-5 active substances and their use for topical or systemic skin administration of the active substance in human or veterinary medicine or cosmetics.

Therefore, it is an object of the invention to provide a patch as a therapeutic system for the administration of the active substance to the skin by the gradual release of the active substance, which does not require the obligatory presence of a penetration enhancer, but offers, through the prior art, additional controls to control the delivery of the active substance the easy way.

The task of the invention is surprisingly so solved that the active substance contains a reservoir parallel to the delivery surface of at least one diaphragm which, by its surface dimension, is smaller than the delivery surface.

The subject of the invention is therefore a process for the manufacture of a transdermal system for the controlled, stepwise administration of active ingredients to the skin with a larger initial dose and a lower maintenance dose consisting of a skin-turned, for the active substance impermeable back layer, from a reservoir of active substance containing in parallel emits at least one membrane onto the surface, from a adhesive-adhesive attachment device to the skin system and possibly from a removable protective layer that overlaps the surfaces of the system against the skin, with the membrane either integrated into the reservoir or integrated into the reservoir surface of the active substance. is attached to the reservoir on the skin side and the membrane surface is smaller than the delivery surface of the active substance reservoir.

The term membrane is understood in this connection as a planarly shaped flexible formation whose permeability to the constituents of the active substance reservoir may also be zero. Therefore, the term membrane also falls, for example. thin metal foil. The usual thickness of such a membrane shrinks 50 pm, but thicker membranes in special cases are not excluded. Typical membrane thicknesses are 20 to 100 pm.

The membrane can be either integrated or. embedded in the tank or plugs into the skin side of the tank. According to one embodiment, the membrane for delivery of a particular active substance or particular active substances is impermeable. According to the second embodiment

-6 The formulation is of limited permeability to the active substance membrane. According to the invention, two membranes with different permeability can also be combined to deliver the intended substances, at least one of which has a smaller system delivery area. In this case, it is advantageous that the membrane, which is less than the surface area of the system's delivery surface, be impermeable and integrated into the reservoir for the substances to be emitted.

The active substance (s) may be present in the reservoir at a concentration that either does not exceed the saturation concentration or exceeds the saturation concentration.

The reservoir itself may again consist of different layers of different composition.

For all components of such a system, essentially the same materials described for conventional systems may be used. These materials are known to the person skilled in the art.

The backbone can be made of flexible or inflexible material and constructed one or more layers. Substances that can be used to make them are polymeric substances, such as e.g. polyethylene, polypropylene, polyethylene terephthalate, polyurethane or polyamide. Metallic foils such as e.g. aluminum foils, whether or not coated with a polymer coating. Textile planar formations may also be used if the components of the reservoir cannot escape due to their physical data through the gas phase.

In principle, the same materials can be used for removable protective film, but they must be additionally equipped with adhesive. Adhesive equipment can be achieved by special siliconisation. The tank or. the reservoir layers are composed of a polymeric matrix and of active substances, the polymeric matrix having such self-adhesiveness that consistency is assured in a multilayer structure. The polymeric matrix material may be e.g. consisting of polymers such as rubber, rubber-like synthetic homo-, co- or block-polymers, polyacrylic acid esters and their copolymerizates, polyurethane, a copolymer of ethylene and polysiloxane. In principle, all polymers used in the manufacture of adhesive adhesives that are physiologically acceptable are considered suitable. Accessories may also be used whose nature depends on the used

- polymer and active substances. According to their function, they can be divided into softeners, stickers, resorption mediators, stabilizers or fillers. Substances that are suitable for this purpose and are physiologically safe are known to the person skilled in the art.

All physiologically sound materials in the form of foils having a suitable permeability to the active substances or to the active substance may be used for membranes. subsidiary substances. Particularly suitable are polyethylene, polyamide, ethylene-vinyl acetate-copolymer and polysiloxane based membranes.

The invention will now be explained on the basis of the figures. In doing so, they show:

FIG. 1 is a cross-sectional view through the control membrane system of the prior art; FIG. 2 is an embodiment of the system of the invention; 3 shows a second view of the matrix of FIG. 2 with a membrane integrated into the array; 4 shows various embodiments of the membrane, FIG. 5a is a cross-sectional view of an embodiment of the invention that indicates a combination of an impermeable membrane with a membrane of greater permeability; FIG. 5b is an outline view of the embodiment of Figure 5a; 6 is a graph showing the release behavior of an embodiment with a membrane that is integrated into the reservoir and is impermeable to the active substance, of the form shown in Figure 4, wherein the cumulated released amount of the active substance is shown as a function of time. releases of the same system as in Figs. 6, but the graph shows the rate of emission of the active substance to the system and the clock as a function of time, FIG. 8 is a graphically depicting release behavior of a system according to the invention with a membrane which is limited permeability for the active substance, showing the cumulative release of the active substance over time, FIG. 9 in the graph shows the broadcast rate of the same system as in Fig. 8 per system and clock as a function of time.

1, the system described consists of the back layer 11 of the reservoir 12 of the active substance, the control membrane 13, the adhesive-adhesive layer 14 for attaching the system to the skin, and

-8 Removable Protective Sheets 15.

In many cases, the adhesive-adhesive layer 14 has the same formulation as the reservoir 12, so that, in principle, the membrane is integrated into the reservoir, and it can therefore be imagined that the reservoir consists of two parts.

The membrane achieves, if the active substance is in supersaturated concentration, release by zero order kinetics, ie. constant release over a period of application, and if the active substance is below this concentration, release by first order kinetics according to equation 3.

In FIG. 2 is a conceptual composition of the system of the invention. It consists of a backing layer 21, a reservoir 22, a membrane 23, a self-adhesive skin spread 24 and a removable protective film 25.

The diaphragm 23 is smaller than the surface of the tank because it has a circular shaped cutout in the middle.

In FIG. 3, the membrane 31 is integrated into the reservoir 32, which is thus divided into two halves 33,34. if the reservoir formulation is self-adhesive, the self-adhesive skin coating 24 in Figure 2 may be discarded. Provided that the surface of the diaphragm is always smaller than the entire surface of the reservoir, the reservoir and skin, respectively, have on the surface not covered by the diaphragm. tank and adhesive-adhesive layer or. both parts of the tank direct contact with each other.

FIG. 4 shows some examples for geometric shaping of such a membrane according to the invention, wherein the membranes are either screwed surfaces or non-screwed surfaces.

The embodiments of the invention of Figures 3 and 4 are particularly suitable for systems with only one active membrane impermeable membrane, e.g. as performed in FIG. 4.1 and integrated according to FIG. 3 into the tank.

-9First, such a system behaves as the specified matrix system, ie. throughout the delivery plot, the active substance is emitted according to the so-called root-t law. However, when the part of the reservoir under the membrane is emptied so much that the membrane has reached the depletion point, its behavior changes dramatically compared to the conventional matrix system. In the membrane-responsive plane, the release of the active substance decreases very rapidly, while in the partial plane not covered by the membrane, the release by root-t law continues unabated until the backbone depletion zone is reached. An additional starting dose originates from the surface below the membrane. Changes in the absolute size of the reservoir surface and the relationship between the membrane surface and the entire reservoir surface can affect the size and maintenance doses within very wide limits.

Such release behavior can, of course, also be achieved by giving the tank a stepped geometry. This has the disadvantage, however, that such a system is more difficult to manufacture and, because of the plastic design of the conventional reservoir formulation, such a system does not retain its step shape.

Particularly preferred is version 4.5 because there are no positioning problems due to the plurality of holes placed in the membrane.

By varying the ratio of the membrane surface area to the entire surface area and by selecting membranes with different permeability for the active substance, the release behavior of the system within wide limits can be affected, as shown below. In particular, very large starting doses can be given.

FIG. 5a and 5b show, in cross section and in plan, an embodiment according to the invention, indicating a combination of two different membranes.

It is particularly useful, for example. combination of permeability membrane 0 with greater permeability membrane. Such a system is shown in Figure 5a. It consists of an impermeable back layer 51, a reservoir 52, a membrane with permeability 0 for active substance 53,

-10Membranes with a permeability greater than 0 for active substance 54 and a removable protective layer 55.

Both membranes are again shown in Fig. 5b. The membrane with a permeability of 0 must, of course, be smaller in area than the total delivery area of the system, thus limiting the maximum emission of the active substance to the partial plane, corresponding to its size of the entire emission plane, since it cannot cross the active substance over its portion.

A membrane with a permeability greater than 0 leads on it to the corresponding partial plane of the entire delivery plane to the release of the active substance by zero or first order kinetics.

Both membranes need not necessarily lie in the same plane within the system. Their exact position adheres to the specific requirements and is an additional means of achieving the desired release behavior.

if a membrane with a permeability of 0 is closer to the emitting plane, the second membrane, without changing the release behavior, may be planarly as large as the entire emitting plane because it does not cause any action on the upper impermeable membrane.

In FIG. 6 and 7 show the release behavior of such systems with an active substance impermeable membrane, for example, a scopolamine patch. The samples shown below are considered to have a content of active substance of 450 pg / cm ² and a surface mass of a self-adhesive tank of 12.5 mg / cm ² .

Figure 6 shows the cumulative release of scopolamine as a function of time.

Curve I corresponds to a normal 2 cm ² large membrane-free system and serves as a comparison.

Curve II corresponds entirely to the 3 cm ² large system in which the tank is integrated

-11 impermeable membrane. The membrane has a surface of 1 cm ² and divides the reservoir into a layer with a surface mass of 10.4 mg / cm ² and into a layer with a surface mass of 2.1 mg / cm ² .

Curve III corresponds to a system with a total area of 4 cm ² and a membrane surface of 2 cm ² .

Fully higher emission of the active substance of the membrane system is clearly recognizable. Although this limited release of the active substance is limited to the initial release phase, it is better seen in FIG. 7, in which the rate of transmission to the system and time is plotted as a function of time, ie. flow.

This system is therefore particularly well suited to combine relatively high starting doses with an unconditionally constant maintenance dose.

FIG. 8 and 9 show the embodiment according to the invention with a membrane, for the active substance restricted to a transient, for example, a scopolamine patch and under the same conditions as shown in Figures 6 and 7.

The cumulative release is shown in Fig. 8 and the flow in Fig. 9. Curve I respectively. flow I corresponds to 2 cm ^{2 for a} large system containing a membrane of equal size, (comparison) curve II or. flow II corresponds to a 2.5 cm ² large system with a 2 cm ² large membrane and curve III or. lil flow corresponds to a 3 cm ² large system with a 2 cm ² large membrane.

Also, the system corresponding to curve I and flow I can emit a certain starting dose. This initial dose corresponds to the release by root-t law according to Equations 1 and 2, which is formed until the depletion zone of the active substance reaches the membrane.

Both other systems with a membrane that is smaller in surface area than the release surface of the system and which exemplify the invention, otherwise demonstrate how easily the initial dose can be increased. In this case, the initial dose is followed by a constant maintenance dose, the height of which depends on the permeability of the membrane and the membrane surface.

-12Manufacture of figures 6 to 9 of the system used according to the invention (sample)

230 g of polyacrylic resin adhesive (50% in ethyl acetate) g of scopolamine base g of cetiol S g of methanol are combined and the mixture is homogenized. This mixture is applied to a 100 µm thick siliconized polyethylene film of 100 µm (film I) and 100 µm (film II) of a thick layer and the films are dried at 50 ° C for 15 min. Film I had a surface mass of 103 g / m ² after drying and Film II of 21 g / m ² ·

Film II was lined with a circular membrane of appropriate size, and again film I. Siliconized polyester film of film I was torn off and replaced with a 15 pm thick non-siliconized film.

The individual samples were then cut so that the corresponding whole plate was created and the cut was in the middle.

Release in-vitro release

The release was carried out at 32 ° C using the Paddle-over-disk method using 50 ml of brine. For the collection of the sample, the entire release medium was replaced and the contents measured by the HPLC method.

Claims (7)

PATENT APPLICATIONS A process for the manufacture of a transdermal system for the controlled, stepwise administration of active ingredients to the skin with a larger initial dose and a lower maintenance dose consisting of skin withdrawn, for the active substance impermeable, the last layer, from a reservoir of active substance parallel to the surface The emitter contains at least one membrane, from a adhesive-adhesive attachment device to the skin system and optionally from a removable protective layer covering the surfaces of the system against the skin, characterized in that a membrane (13) is arranged parallel to the delivery surface of the active substance reservoir (13). ), (23), (31), (53) is either integrated into the reservoir (12), (22), (32), (52) or is connected to the reservoir on the side against the skin, and is the surface of the membrane (13), (23), (53) smaller than the delivery surface of the active substance tank (12), (22), (31), (52). Method according to claim 1, characterized in that a membrane (13), (23), (31), (53) is used which is impermeable to releasing a particular active substance / s. Method according to claims 1 and 2, characterized in that the membrane (13), (23), (31), (53) used is limited permeability to the active substance / active substances. A method according to claim 1, characterized in that at least two membranes (53), (54) are used which have different permeabilities for the emission of certain substances and at least one of which has a smaller surface than the system delivery surface. Method according to claim 4, characterized in that the membrane (53), which has a smaller surface area than the system delivery surface, is impermeable to the discharge of certain substances and is integrated into the reservoir (52). Method according to one of Claims 1 to 4, characterized in that the tank (12), (22), (32), (52) used contains the active substance / active substances at a concentration not exceeding the saturation concentration. -27. The method according to one of the preceding claims, characterized in that the reservoir (12), (32), (52) used contains the active substance / active substances at a concentration in excess of the saturation concentration. Method according to one of the preceding claims, characterized in that the parts containing the active substance of the tank (12), (22), (32), (52) used consist of several layers of different composition.