Transdermal/transmucosal patch packaging

ES 2 286 331 T3

DESCRIPTION

Transdermal / transmucosal patch container.

Background of the invention

Transdermal and transmucosal patches containing drugs such as estradiol, levonorgestrel, testosterone, scopolamine, nitroglycerin, heparin, melatonin, diagnostic compounds, and other ingredients are usually required to be packaged in individual thin-foil and / or plastic bags. hermetically sealed. Such packaging is necessary in order to maintain hygienic conditions and avoid degradation, contamination, and / or loss of ingredients sensitive to exposure to the environment. In many cases, the material used for such packaging has to be sufficiently impermeable to volatile active ingredients, eg nitroglycerin and environmental factors, eg humidity, to allow the device to remain stable under conditions. long-term storage, up to several years.

A major disadvantage of conventional packaging is that the user has to tear open a separate bag each time he needs one of the transdermal and transmucosal patches. Furthermore, it is desirable for many pharmaceutical products that the container material is difficult for children to open, that is to say that it is a so-called "child-resistant" container. These usual bags may not be child-proof, but they can be difficult to open, particularly for the elderly and for those with handicapped strength and / or dexterity conditions, and especially if the packaging is made of sturdy materials. tearing or difficult to grip. Even for those who do not have special difficulties, opening such bags when they have to do so frequently over a long period of time can pose a substantial inconvenience. Furthermore, individual packages can be expensive and wasteful, due to the large amount of material required for the package and the manufacturing costs for individual packaging. WO 98/24393 relates to a dispenser containing multiple transdermal / transmucosal patches, which can be conveniently removed through an opening in the dispenser. For long-term storage the dispenser can be permanently packaged in a waterproof bag made of a thin sheet of flexible metal and polymer material.

It would be desirable to package transdermal and transmucosal drug-containing patches in such a way that they are easy to open by adult patients, difficult to open by children, inexpensive, waterproof enough to avoid loss of volatile components, and easy to manufacture.

Summary of the invention

The present invention provides a dispenser for conveniently dispensing multiple transdermal / transmucosal drug-containing patches from a single container, according to claim 1. The dispenser has a separate inner shell having walls made of an impermeable material, wherein the inner cartridge it is hermetically sealed during storage. A plurality of individual patches are contained within the inner cartridge, and the patches can be removed from the dispenser through at least one opening. The dispenser further comprises a housing comprising a base and an outer cover, wherein the housing is adapted to completely enclose the inner cartridge and is capable of forming a waterproof seal defining an outer chamber.

In a preferred embodiment, the inner cartridge opening is sealed with a thin foil seal, such that the inner cartridge is hermetically sealed during storage. The seal is then opened, broken, or otherwise removed, in order to allow the enclosed transdermal patches to be removed from the inner cartridge during use. The inner cartridge is enclosed in a housing that has a base and an outer cover.

Preferably, the opening has a secondary seal, such as a plastic film with a slit in the center, or overlapping plastic films, which allow patches to be removed, but otherwise minimize transfer. of air to the inner cartridge and act as a barrier for foreign matter.

In use, the inner cartridge is contained within the housing that contains other functional parts of the dispenser, such as a cover, buttons, or other opening mechanisms, while defining the cosmetic appearance of the dispenser.

An advantage of this embodiment is the ability to improve stability, as the inner cartridge is the main stability chamber of the container during the shelf life. The housing only has to maintain the stability of the transdermal patch from the moment the seal is removed from the inner cartridge until the transdermal patches are exhausted from the dispenser. The separation of the functions of the inner cartridge and the housing allows for greater design flexibility for the housing, since cosmetic changes to the housing can be made with little or no impact on pharmaceutical stability. Separating the functionality of the inner cartridge and the housing also provides the ability to make manufacturing processes more efficient and low cost, while providing a more convenient means of allowing the dispenser to be refillable.

ES 2 286 331 T3

In yet another aspect, a child resistant mechanism is incorporated into the dispenser. The dispenser has an inner cartridge defined by walls made of an impermeable material, in which the inner cartridge is hermetically sealed during storage. A plurality of individual patches are contained within the inner cartridge, and the patches can be removed from the dispenser through at least one opening. The dispenser further comprises an outer cover adapted to enclose the opening when the outer cover is in a closed position.

The child-resistant mechanism may consist of a locking mechanism, an "exclusion" mechanism, an opening mechanism that is not readily apparent to children or is not easily activated by children, or any combination of the above. The locking mechanism may include, for example, key or combination locks, encrypted locks, or locks activated by biometric identification, such as through the use of fingerprints. An "exclusion" mechanism may need, for example, to be activated, by a magnetic or radio frequency identification signal, before allowing the mechanism to open. Preferably, one or more firing mechanisms, such as buttons, latches, levers, and the like, would have to be activated before the dispenser could be opened to dispense medicine. A “gravity switch” (ie, a switch, latch, latch, or similar mechanism, having gravity-dependent operability, related to physical orientation) could be used, in which the actuation of the trigger mechanism allows the trigger to open. dispenser only if the dispenser is held in a particular fixed orientation, such as parallel to the ground. Placing the dispenser in the proper alignment relative to the ground, such that the gravity switch allows the dispenser to open, can be described as "actuation" of the gravity switch.

In a particularly preferred embodiment, the dispenser is opened by activating a button, while the dispenser is aligned such that a gravity switch is activated.

In another particularly preferred embodiment, the dispenser is opened by simultaneously activating two (or more) buttons while the dispenser is aligned such that the gravity switch is activated.

An advantage of this invention is to reduce the likelihood that a person other than the user will be accidentally exposed to the active pharmaceutical ingredients contained in a transdermal / transmucosal patch. In addition, embodiments with locking mechanisms can be used to curb abuse of transdermal patches and "lockout" mechanisms can be used to prevent patients from dosing with too many patches at one time. In a preferred embodiment, the dispenser has an exclusion mechanism and contains a controlled substance (eg, a substance regulated in the US by the Agency for Drug Enforcement, such as morphine. , fentanyl, buprenorphine, or testosterone.

The transdermal / transmucosal patches are preferably arranged such that removal of one patch allows the next patch to be grasped and removed in doing so, and more preferably the patches are interconnected so as to be separable, such that the The action of removing one of the transdermal / transmucosal patches moves another patch, bringing it into position for later removal.

In a particularly preferred embodiment, the walls of the dispenser defining the inner cartridge are made of rigid plastic and the opening is in the form of a single slot, through which each of the transdermal / transmucosal patches is pulled. Each patch is preferably interconnected so that it is detachable to an adjacent patch, so that pulling a patch out of the slot pulls a portion of the next patch through the slot to leave it in position to later be caught and withdrawn. The interconnection so that they are separable from the patches is preferably effected in one of three essential ways:

(1) through a continuous release liner on which individual transdermal / transmucosal patches are commonly adhered, in which case the liner is preferably perforated between each patch, to facilitate separation, (2) without a continuous release liner , but where either a part with adhesive is added between the release liner and the backing of the successive patches, either a part of the adhesive that is under a patch is adhered directly to a part of the upper surface of the next patch to be dispensed, or (3) without a continuous release liner, but in which a part of each patch is sandwiched below a portion of the next patch to be dispensed.

The patches, which are generally not individually packaged, can be folded, stacked, and / or sandwiched one on top of the other within the cartridge, so that a large number of patches can be efficiently stored in a small space.

Alternatively, the individual transdermal / transmucosal patches may not be folded, stacked, or interleaved one on top of the other, but may be arranged successively in a roll, or in a flat strip or continuous loop arrangement. In this case, depending on the design, the dispenser can either have a single opening, or have multiple openings (one for each patch). In addition, the opening may include an elastic sealing member to help prevent the escape of volatile components and / or environmental contamination from the cartridge containing the transdermal / transmucosal patches.

In addition, the dispenser may contain additional features such as a desiccant, a moisture exposure indicator strip, a ratchet actuation mechanism, or a ratchet mechanism.

ES 2 286 331 T3 counter, as described in pending US Patent Application Serial No. 08/982813 (Richard G Sitz et al., File Number 52883US002), the disclosure of which is incorporated herein by reference.

The preferred drug-containing transdermal / transmucosal patches to be dispensed from a dispenser in accordance with the present invention are those that are administered on a one-per-week, two-per-week, or one-per-day basis, such as patches. hormone replacement therapy and fertility control patches, containing, for example, estradiol, progestogens, and / or testosterone. Other examples of preferred patches include frequently applied patches, such as nitroglycerin, nicotine, and fentanyl.

Finally, the present invention also provides a method for packaging transdermal / transmucosal drug-containing patches for convenient dispensing, comprising the steps of: (i) providing a dispenser unit having walls defining an inner cartridge, an opening, and a housing adapted to completely enclose the inner cartridge, and (ii) packaging a plurality of drug-containing transdermal / transmucosal patches within the cartridge interior and, preferably, arranging the patches so as to allow (and preferably require) the removal of one patch at a time, following a predetermined successive order, through the opening.

Brief description of the drawings

Preferred embodiments will be described in greater detail below, with reference to the accompanying drawings, in which:

Fig. 1 is a perspective view of the inner cartridge.

Fig. 2 is a perspective view of the inner cartridge after the seal has been removed from the opening.

Fig. 3 is a perspective view of the housing in the closed position.

Fig. 4 is a perspective view in the open position of one embodiment of the housing, with a base face plate.

Fig. 5 is a perspective view of the inner cartridge with an inner cover in the open position.

Fig. 6 is a perspective view of another embodiment of a housing in the open position.

Fig. 7 is a perspective view in the closed position of a housing with a side button.

Fig. 8 is a perspective view of the underside of a housing with a button on the underside.

Fig. 9 is a perspective view showing a cut away portion of the outer cover, exposing some of the mechanisms used to latch the cover open and closed.

Fig. 10 is a perspective view of the interior of a housing, showing the mechanisms related to the opening and latching of the outer cover.

Fig. 11 is an exploded view of part A of a gravity switch.

Fig. 12 is an exploded view of part B of a gravity switch.

Detailed description of the invention

In Fig. 1 the inner cartridge 100 of a dispenser is shown, according to a preferred embodiment of the invention. The inner cartridge 100 includes an inner cartridge upper portion 102, an inner cartridge lower portion 104, and optional attachment flaps 108. In this figure, the inner cartridge is sealed with a thin sheet seal 106 that covers the opening. interior 112 (shown in Fig. 2). A gasket 110 is included to allow a waterproof seal to be created between the housing 200 (shown in Fig. 3) and the top 100 of the inner cartridge.

The thin foil seal 106 is preferably made such that it is waterproof enough to prevent substantial losses of volatile components from the transdermal / transmucosal patches and / or degradation or contamination by environmental factors, such as humidity, microbes, and the like.

As illustrated in FIG. 2, a portion of the drug-containing transdermal / transmucosal patch 116 extends through the inner opening 112. The transdermal / transmucosal patch 116 is depicted, for convenience, as a single film layer. . It will be understood that the transdermal / transmucosal patch will typically be composed of two or more layers, including a backing layer and at least one adhesive layer. The transdermal / transmucosal patch may also comprise a release liner that is removed prior to use. The drug contained in the transdermal / transmucosal patches can be in a reservoir, or mixed in at least one of

ES 2 286 331 T3 the adhesive layers or the backing layers. Excipients, such as penetration stimulators and crystallization inhibitors, may also be included. Furthermore, it is to be noted that there is no requirement that the transdermal / transmucosal patches be uniform, layered transdermal / transmucosal patches such as those depicted. For example, patches can vary in size or shape, and can include various structures, such as drug reservoirs.

When a user picks up and pulls the drug-containing transdermal / transmucosal patch 116, they can remove it from the dispenser and simultaneously the next transdermal / transmucosal patch will be put into position, with a portion of it extending outwardly through the inner opening 112.

Suitable materials for use as the inner cartridge 100 include, for example, polyetherimide; polyethylene, such as high-density polyethylene and low-density polyethylene; polypropylene; copolymers of polypropylene with other olefins; polycarbonate, polymethyl methacrylate; polyamides; styrene-acrylonitrile (SAN) polymers; acrylonitrile-styrene-butadiene (ABS) polymers; and polyesters such as polyethylene terephthalate and polyethylene terephthalate. It is to be understood that the cartridge is waterproof enough to prevent substantial losses of volatile components from transdermal / transmucosal patches and / or to prevent degradation or contamination by environmental factors such as humidity, microbes, and the like. Those skilled in the art will appreciate that the types of materials that are sufficiently impermeable may vary depending on the nature and chemical constituents of the transdermal / transmucosal patches contained within the cartridge.

The inner cartridge 100 depicted in Figs. 1 and 2 is located within a housing 200 shown in Fig. 3, in which the outer cover 202 is in a closed position against the base 204. The attachment fins 108 (shown in Figs. 1 and 2) they can facilitate the attachment of the inner cartridge 100 to the housing 200. The outer cover can be secured in the closed position with a latch hook 252 which engages a latch slot 254 (shown in Fig. 4). In Fig. 4 the housing 200 is shown in the open position, in which the outer cover 202 has been rotated to the open position along the hinge 210, exposing the base face plate 206 , which constitutes the upper surface of the base. The opening 220 in the base face plate is positioned relative to the inner opening 112 so that the transdermal / transmucosal drug-containing patch 116 extending from the inner opening 112 will also extend through the opening 220 of the base face plate. In this embodiment, the thin sheet seal 106 will also have a fin extending through the opening 220 of the base face plate, which allows the thin sheet seal to be removed prior to initial use. The outer cover 202 forms a seal with the base face plate 206, to allow sealing of the dispenser after the thin sheet seal 106 has been removed. In a preferred embodiment, a gasket 222 may be used to improve the seal between the outer cover 202 and the base face plate 206.

Suitable materials for use for gasket 222 include, for example, fluorocarbon polymers, ethylene propylene rubber (EP), ethylene propylene diene rubber (EPDN), styrenic block copolymers, nitrile rubber, and butyl rubber.

Suitable materials for use for housing 200 include, for example, polyethylene, such as high-density polyethylene and low-density polyethylene; copolymers of ethylene with other olefins, such as linear low-density polyethylene or ultra-low-density polyethylene; polypropylene; copolymers of polypropylene with other olefins; polycarbonate; polymethyl methacrylate; polyamides; styrene acrylonitrile (SAN) polymers; acrylonitrile-styrene-butadiene (ABS) polymers; and polyesters, such as poly (butylene terephthalate) and poly (ethylene terephthalate). It is also to be understood that the housing may consist of any suitable polymers or copolymers for use in injection molding, blow molding, or extrusion processing.

In another embodiment, shown in Fig. 5, there may be an inner cover 150 attached to the bottom 104 of the inner cartridge through a hinge 152. In this embodiment, the base 204 of the housing 200 contains an open cavity 208 (shown in Fig. Fig. 6), where the inner cartridge is located. The inner cover 150 is joined to the outer cover 202, such that the inner cover 150 is part of the housing and will open in conjunction with the opening of the outer cover 202. This connection is preferably by welding or fusing the outer surface from the inner cover 150 to the inner surface of the outer cover 202. Opening the inner cover 150 exposes the top 102 of the inner cartridge. The inner cover 150 forms a seal with the top 102 of the inner cartridge. In a preferred embodiment, a gasket 110 may be used to improve the seal between the inner cover 150 and the top 102 of the inner cartridge. In this embodiment, stability after removal of the thin sheet seal 106 is provided entirely by the inner cartridge 100, the gasket 110, and the inner cover 150. The external portions of the housing 200 do not have to provide stability, and can be designed entirely to meet cosmetic or other wear requirements.

Fig. 7 shows a side button 260 that can be depressed, pulled out, or otherwise activated to open the outer cover 202. Fig. 8 shows a button 250 on the underside that can be pressed, pulled out, or otherwise activated, to open the outer cover 202. These buttons constitute an opening mechanism that is not readily apparent to children, nor / or is it easy to activate by children. The relationship of the side button 260 to the opening mechanism of the outer cover 202 is shown in Fig. 9. Activation of the side button 260 causes the latch 262 of the side button to disengage from, or move relative to the, release member of

2 286 331 T3 the cover 264. The latch 266 of the cover release member is preferably integrally connected to the cover release member 264, such that movement of the cover release member 264 causes the The latch 266 of the cover release member disengages from the hook 268 of the outer cover, thereby allowing the outer cover 202 to be opened.

In a preferred embodiment, these buttons will only activate the opening of the outer cover when a "gravity switch" is activated, thereby positioning the dispenser in a particular fixed orientation, such as parallel to the ground. Placing the dispenser in the proper alignment relative to the ground, such that the dispenser opens, can be described as "actuation" of the gravity switch. Preferably, the gravity switch is activated when the underside of the dispenser is positioned parallel to the ground.

A preferred embodiment of a gravity switch mechanism is depicted in Fig. 10, wherein the longitudinal rocker 300 of the gravity switch and the transverse rocker 310 of the gravity switch are positioned relative to the release member 264 of the cover. , such that they do not interfere with the movement of the cover release member 264, which allows the opening of the outer cover 202.

As illustrated in Fig. 11, the longitudinal rocker 300 of the gravity switch is positioned, relative to the longitudinal slot 302 of the gravity switch, such that when the dispenser is held parallel to the ground, the rocker 300 of the gravity switch hangs in a neutral position. of the longitudinal rocker pivot 306, and does not impede the movement of the cover release member 264, thereby allowing the dispenser to open when all other latch release buttons incorporated in the dispenser are activated. The inclination of the dispenser of Figs. 9 and 10 along the longitudinal axis will cause the rocker arm 304 to move in the direction of the arrows shown in Fig. 11. Tilting the dispenser beyond a preset minimum tilt angle will cause the rocker arm 304 to engage in the longitudinal slot 302 of the gravity switch sufficiently to prevent movement of the cover release member 264, and prevent movement of the cover release member 264. thereby opening the outer cover 202. The preset angle can be adjusted based on the shape and size of both the rocker arm 304 and the longitudinal slot 302 of the gravity switch. The previously established minimum angle of inclination may be between 2 ° and 60 °, more preferably between 10 ° and 30 °, and most preferably it is approximately 20 °.

As illustrated in Fig. 12, the transverse beam 310 of the gravity switch is positioned relative to the transverse slot 312 of the gravity switch so that when the dispenser is held parallel to the ground, the transverse beam 310 of the gravity switch hangs in a neutral position from the pivot. 316 of the transverse rocker and does not impede the movement of the cover release member 264, thereby allowing the dispenser to open when all other release buttons incorporated in the dispenser have been activated. The inclination of the dispenser of Figs. 9 and 10 along the transverse axis will cause the transverse rocker 310 of the gravity switch to move in the direction of the arrows shown in Fig. 12. Tilting the dispenser beyond a preset minimum tilt angle will cause the transverse rocker 310 of the gravity switch to engage in the transverse slot 312 of the gravity switch sufficiently to prevent movement of the cover release member 264 and thereby preventing the opening of the outer cover 202. The preset angle can be adjusted based on the shape and size of both the transverse rocker 310 of the gravity switch and the transverse groove 312 of the gravity switch. The minimum preset angle of inclination may be between 2 ° and 60 °, more preferably between 10 ° and 30 °, and most preferably about 20 °.

The combination of the transverse and longitudinal gravity switches ensures that the outer cover 202 cannot be opened unless the dispenser is positioned substantially parallel to the ground, as defined by the previously established minimum tilt angles, for both directions, the longitudinal and transversal. It is to be understood that the gravity switches need not be aligned such that they are in the longitudinal and transverse directions relative to the dispenser as a whole.

The bottom face button 250 of FIG. 8 is a preferred opening mechanism, as it is not visible to the patient when the dispenser is in the proper orientation to activate the gravity switch. This bottom face button and gravity switch combination requires a user to position the dispenser in an orientation in which the button is not directly visible when activated. This concealed button activation can be particularly unintuitive for a child, and can be quite effective in preventing unauthorized or accidental opening of the dispenser by a child.

Examples

Example 1

As an example of the present invention, dispensers of the design generally depicted in Figs. 7 and 8, incorporating a gravity switch of the design generally depicted in Figs. 9 to 12.

The dispensers were generally tested in accordance with the Federal Regulations of the US Code Title 16 Chapter 2, Section 1700.20, “Test Procedure for Specialty Containers”. Are

ES 2 286 331 T3 tests are both those relating to the ability of children to gain access to the contents of the packages, and for adults and the elderly to be able to obtain it. The child test consists of two successive five-minute test periods, during which each child (ages 42-51 months) tries to open the dispensers. The children are given a closed dispenser, and they are not given instructions on how to open the dispensers, although before the second testing period they are told that they can use their teeth, if they wish. This test was carried out with a group of subjects made up of 12 children. The results have been reported as the total number of openings in each of the five-minute periods, and a cumulative success rate, which is defined as the percentage of children who were unable to open the container during both test periods. .

The adult and senior trial consists of a five-minute trial period followed by a one-minute trial period, during which time each adult (ages 50-70) tries to open the dispensers. Adults are given instructions for opening the dispensers, and are allowed to refer to the instructions during each trial period. Adults who are unable to open the dispenser during the first five minute trial period are given two non-child resistant containers to open during the subsequent one minute trial period. Those adults who are unable to open non-child resistant containers are not counted as part of the test panel results. This test was carried out with a group of subjects made up of 25 adults. The results have been reflected in Table 1, as the total number of open containers in the first test period, total open containers in the second test period, and a cumulative success rate, which is defined as the percentage of adults who were able to open the container during both test periods.

<td colspan="4">Table 1</td>

<td>Population for the proof</td><td>First Period of Test (total of openings)</td><td>Second period Test (total of openings)</td><td>Cup of Successes</td>

<td>Children (n = 12)</td><td>OR</td><td> 0</td><td> 100%</td>

<td>Greater (n = 25)</td><td> 20</td><td> 20</td><td> 80%</td>

Example 2

As an example of the present invention, they were cast in polyetherimide (Ultem^TM supplied by GE Plastics) inner cartridges with inner covers of the design generally depicted in Fig. 5.

The patches were prepared by combining 50% copolymer adhesive (67:13:20 isooctylacrylate; acrylamide; vinyl acetate), 9% propylene glycol, 7% testosterone, and 34% terpineol, in a solvent mixture of ethyl acetate and methanol, where all percentages are by weight of solids. This composition was mixed in a rotating drum until a homogeneous coating formulation was obtained. The formulation was coated with a wet thickness of 508 µm on a fluoropolymer release liner. The coated release liner was dried in a three-zone oven, at temperatures ranging from 49 ° C to 60 ° C. The coated liner was then laminated to a thickness of 51 µm on a polyester backing (Scotchpak ™ 9732). The laminate was die cut into 45 cm transdermal patches², with a slit loose lining. Patch stacks were prepared by mounting 30 patches in a single stack. The adhesive side of each patch in the stack was partially covered with a semi-release liner (ie, a release liner that covers half of the adhesive surface of the patch). The exposed adhesive portion of each patch was adhered to the patch below it, with the exception of the bottom patch of the stack, which was adhered to a base liner that was attached to the bottom of the inner cartridge. The patches were oriented so that the release half-beads alternated from one side of the pile to the other. Each stack of patches was loaded into the bottom of an inner cartridge. The upper part of the inner cartridge was then ultrasonically welded to the bottom. The inner cartridge was sealed by heat welding a thin foil seal over the opening. A rubber gasket was placed around the sealed inner cartridge, and closed with an inner cover against the inner cartridge and gasket.

Analysis of the initial drug and excipient content in the patches was performed by removing the thin sheet seal from a cartridge and removing 10 patches for chromatographic analysis (patches numbers 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30, in order of withdrawal). Data on drug and excipient contents were obtained using the following procedure. The liner was removed from the patches and the patches were placed in a jar where the backing and coating were removed with a solution consisting of a 75:25 volume ratio of ethyl acetate (EtOH) methanol (MeOH) with an internal standard. decanol. The samples were shaken for 2 hours or until the adhesive was completely dissolved. Aliquots of the extraction solutions were then placed in autosample vials for analysis. The analysis of the samples was carried out by gas chromatography with detection

ES 2 286 331 T3 by flame ionization (GC-FID) using a J&amp;W DB-1 capillary column (30 mx 0.53 mm id 1.5 pm film) with helium carrier gas.

The initial content was 7.1% testosterone, 6.1% propylene glycol, and 29.3% terpineol, on a weight basis of the coated formulation.

Samples of the sealed inner cartridges were placed at room temperature (25 ° C / 60% relative humidity) and under accelerated temperature conditions (40 ° C / 75% relative humidity) during the long-term stability test.

The present invention has been described with reference to various embodiments thereof. The detailed description and examples set forth above have been provided for better understanding only, and are not to be inferred from unnecessary limitations. It will be apparent to those skilled in the art that many changes can be made to the described embodiments, without exceeding the scope of the invention as described in the accompanying claims. Accordingly, the scope of the invention should not be limited to the exact details of the compositions and structures described herein, but rather by the content expressed in the claims that follow.