JPH05500511A - Transdermal delivery device with delayed onset of delivery - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] (c) the microporous membrane is in communication with the patient's skin for release of the active compound; means for adhering the device to the skin of the person so as to A device equipped with.

12. A par□us fabric is provided, and the microporous membrane and the The device of claim 11 further comprising a core layer disposed between the reservoir. Place.

13. The device of claim 12, wherein the core layer comprises a nonwoven fabric.

14. said means for adhering is such that the active compound is substantially present prior to rupture of said reservoir; 12. The device according to claim 11, wherein the adhesive layer is not permeable to active compounds.

Specification delayed the start of delivery transdermal delivery device Technical field The present invention provides methods for administering biologically active compounds through the skin, i.e. transdermally. The present invention relates to an apparatus and a method. Specifically, the present invention provides transdermal delivery with delayed onset of delivery. Relating to an apparatus and method for achieving this.

Shutomo E and L Yu There are many advantages to delivering compounds through the skin.

First, transdermal delivery is comfortable and easy to use (as well as a drug that does not affect healthy tissue). Provide a means of delivery. By avoiding administration through the gastrointestinal tract, is degraded, deactivated by metabolic processes, or absorption is reduced. Such compounds can be used. Additionally, complications such as gastrointestinal irritation are avoided. It will be done. Also, transdermal delivery using continuous-release type devices can, for example, If necessary, such as when an effect occurs or when the concentration of the drug in the plasma increases too much. If necessary, administration can be stopped immediately.

Drug delivery devices are generally either ``matrix'' or ``reservoir'' in structure. It can be classified into either. The matrix, or integrated device, is generally It has a drug-permeable solid polymer with the drug dispersed throughout. Matrix equipment The device can be formed from erodible or non-erodible polymers (transdermal devices typically is non-erosive). The reservoir device generally consists of an essentially contains a reservoir of pure drug (or drug with excipients), where it is passed through the membrane. The rate of dispersion of the drug as a molecule controls the rate of release. Equipped with matrix and rate controlling membrane Combinations with other reservoirs have also been proposed. This typical design standard providing a constant and continuous release rate and delivering a therapeutically effective amount of the compound. The goal is to provide a release rate that can be obtained. Additionally, the device must be non-irritating. stomach. Preferably, the size is designed to be easy to use.

Traditional transdermal devices deliver therapeutic compounds at a more or less constant rate (“zero-order” delivery). It is designed with the purpose of However, when several compounds are Administration can create drug tolerance. To prevent tolerance, Transdermal devices of this type require periodic peeling to interrupt continuous delivery.

This in turn affects patient compliance and the need for continued adhesion to the skin. This poses another problem: batch adhesive design (which should not be used) and may also interfere with patient circadian rhythms. Not adapted.

Nitroglycerin is currently used for coronary insufficiency, particularly angina and congestive heart failure. Vasodilators are being administered. Nitroglycerin cannot be administered orally Therefore, it is typically administered sublingually or in transdermal batches. Trans Commercially available batches such as derm N1trρ and N1tro-Dur@ , nitroglycerin whose concentration in the plasma is essentially constant over a period of 24 hours. provided and replaced daily. However, recent research shows that nitroglycene Continued administration creates tolerance and concomitant loss of efficacy for the patient.

European Patent Application No. 0290262 (published on November 9, 1988) A transdermal device is disclosed that delays the onset of administration of nitrate drugs to patients. this is , backing layer (backing 1 ayer), backing layer and nonwoven fabric layer A rupturable body sandwiched between a barrier membrane that is initially drug-impermeable, and an adhesive layer , and a release liner. The bod consists of two layers, and these layers are broken into the surrounding area. It has a tearable seal that plasticizes the drug and barrier membrane to gradually release the drug. forming a lumen containing an activating liquid that can increase permeability to the activator.

This device relies on plasticization of the barrier membrane to delay the administration of nitrate drugs. is possible, but this has several important and practical drawbacks. This point In , the delay is carried out through the use of an activating liquid. When using activators, the treatment However, the economics and regulatory approvals for the equipment are complicated. Furthermore, the drug release rate of the device However, it depends on the permeability of the barrier membrane, which changes depending on the degree of membrane plasticization (please note that it is complicated). becomes.

An object of one embodiment of the present invention is to (1) not contain an activating liquid; and (2) Transdermal drugs with delayed onset of delivery with release characteristics that are less dependent on variables The present invention provides a delivery device. It is an object of another embodiment of the invention to does not include a drug reservoir, but instead allows the components of the device to be assembled immediately prior to use. It is an object of the present invention to provide a transdermal drug delivery device with delayed onset of delivery that is more effective. .

Engrave Dansarajo The device of the invention provides continuous and constant transdermal release of active substance. The opening of this release The onset is delayed from 1 to 24 hours depending on the length of time the drug is delivered. This is it A “wash-out” period is provided during which the patient's tissue is removed from the previously worn device. It is possible to reduce the concentration of compounds left behind in the plasma to near the baseline level. become. Therefore, patients can remove the patch by replacing it with a new patch before going to sleep. Can be worn for 24 hours. The washout period thus takes place while the patient is asleep; During the waking hours at °C, the active compounds reach an effective concentration in the plasma.

One aspect of the invention provides for administering the active compound transdermally to the skin of a patient with delayed onset. This is a kit to prepare a device for. The kit: a first layer comprising a polymer matrix impregnated with said active compound; The compound and the matrix have a molecular weight of about 10-5 to about 10-110 in the matrix. a first layer selected to obtain a first compound dispersion coefficient of 11127 seconds; and an adhesive that does not contact the first layer and is capable of adhering to the first layer and the patient's skin; a second layer of about 10-5 to about 10-” am2 in the matrix; a second layer having a second dispersion coefficient of /sec and substantially completely free of said active compound. ;

Another aspect of the invention provides for administering the active compound to a patient by wearing a controlled release device. In this method, the start of administration is delayed from when the device is attached. Ru. The method includes: laminating a first layer and a second layer to form an adhesive laminate. wherein the first layer comprises a polymer matrix impregnated with the active compound; The compound and matrix have a molecular weight of about 10-5 to about 1 (1-1) in the matrix. was selected to obtain a first compound dispersion coefficient of 1 cm 27 s, and the second layer was , an adhesive capable of adhering to the first layer and the patient's skin; a second dispersion coefficient of about 10"' to about 10-" am2/sec at the forming an adhesive laminate in which the two layers are initially substantially free of the active compound; and before the active compound reaches equilibrium in the adhesive laminate; applying an adhesive laminate to the patient's skin.

Yet another aspect of the invention provides for delayed onset of the active compound after application to the patient's skin. It is also a device for transdermal administration. The device: (a) a rupturable reservoir containing an active compound in liquid form; (b) said rupturable reservoir; an active compound-permeable microporous membrane located below the membrane, the pores of the upper membrane being located beneath the reservoir; before the rupture of the membrane, and the upper membrane has an inherent constant immersion for the liquid active compound. (c) the microporous membrane has a permeability, and (c) the microporous membrane is capable of releasing the active compound. The hand that adheres the device to the patient's skin so that it is in communication with the patient's skin for release. A stage is provided.

Figure iλ Emperor - simple skimming FIG. 1 shows a schematic cross-sectional view of a presently preferred embodiment of the invention, in which active The sexual compound is sequestered in a rupturable capsule.

FIG. 2 is a schematic cross-sectional view of an embodiment of the kit of the invention as applied by the user. It is. The illustrated layer is a thin, homogeneous membrane, preferably flexible and/or elastic. It is attached by the user just before installation. The illustration shows the protective emission line. 2 shows a cross-sectional view of the device with inner and liner/carrier; FIG.

Figure 3 shows an embodiment of the kit just before lamination, after peeling off the top release liner. A perspective view of the figure is shown.

Figure 4 shows the implementation of the kit immediately after lamination and after peeling off the liner/carrier. Figure 3 shows a schematic cross-sectional view of an embodiment.

FIG. 5 is a schematic cross-sectional view of another presently preferred embodiment of one of the drug reservoirs of the device. It has a rupturable capsule formed as a section.

FIG. 6 shows a cross section of a dispensing device suitable as the dispensing device of the invention shown in FIG. 1 or FIG. It is a diagram.

FIG. 7 shows the results of the experiment described in Example 1 as a graph.

FIG. 8 shows the results of the experiment described in Example 2 as a graph.

FIG. 9 shows the results of the experiment described in Example 3 as a graph.

As used herein, the term "active compound" refers to a compound that is administered to an animal in order to obtain a beneficial effect. means a substance that can be administered. Active compounds include, for example, nitroglycerin, Vascular, such as milnitrate, dinitrate or mononitrate of isosorbide Expanding drugs, 1. , -D OP A, analgesics, anti-inflammatory drugs, antihistamines, antibiotics Medications useful to prevent or improve certain deficiencies, such as , antihypertensive drugs, and hormones It can be an agent. Other active compounds include contraceptives, such as estradiol ( estradiol), levonorgestrel (levonorgestrei) , 3-ketodesogestrel (3-ketodesogestrel), Guess gestodene, etc.), vitamins, appetite suppressants, nicotine, cuffs and other stimulants and growth promoters (particularly when administered to livestock). be caught. Suitable active compounds within the scope of the invention include those that are capable of being dispersed or absorbed through the skin. It is possible.

The term "mammal" includes humans, domestic animals such as cows, sheep, goats, and horses, dogs, Small animals such as cats and rats, wild animals such as elephants, wild animals, tigers, and antilobes Includes objects and animals, such as animals in zoos. The term "animal" refers to mammals, and poultry such as chickens, geese, ducks, turkeys, and fighting cocks. Taste.

The term "liquid carrier" refers to the reservoir matrix and adhesive layer, as well as the skin. means a solvent that is compatible with the skin and in which the active compound is dissolved. The active compound is preferably Solubility in the carrier is moderate. Suitable carriers generally include those of the present invention. This increases the rate of release of the active compound from the device.

Examples of carriers include methanol, ethanol, propatool, isopropyl lower alcohols such as tools, glycols such as propylene glycol, and Coal ethers and esters, dimethyl sulfoxide, tetrahydrofuran , acetone, etc.

As used herein, the term "delayed onset" means that the device of the invention is applied to the skin. refers to the condition in which the active compound is not released from the device until a certain amount of time has passed after the device has been applied. Taste. For 24 hour batches, this delay period is typically 1-18 hours, preferably Or it lasts about 12 hours. Batch designed for long duration ( For example, a one week patch) may have a correspondingly long delay period.

B. Two cane goya no tate FIG. 1 depicts a presently preferred device of the invention, illustrating a rupturable device containing the active compound prior to administration. It has a capable capsule. This embodiment 20 allows the active compound to be dispersed but not in a reservoir. It has an optional core layer 23 which does not act as a core layer. This core layer is preferably do not absorb the active compound to any significant extent and therefore do not retain substantial amounts of the compound.

The core layer is preferably formed by a non-woven fabric and under the conditions of use (e.g. active compound and when saturated with excipients) must be able to adhere to adjacent layers. impermeable A backing layer 21 forms the outer surface of the device to allow active compound to be lost through the upper surface. prevent being exposed. The backing layer is preferably occluded, water resistant, chemical resistant ( (at least during the administration period of the device) and suitable for being bonded to adjacent layers. It is. The backing layer 21 is heat sealed or crimped to the adjacent layer to provide a peripheral A region 22 is formed, which is formed by the void between the backing layer 21 and the adjacent layer 23. The reservoir area 27 formed is sealed.

The backing layer 21 and the adjacent layer 23 are bonded together to form the reservoir volume 27. Ru. The reservoir volume contains the active compound 33 and optionally excipients, penetration enhancers. A rupturable membrane containing a stimulant, a solubilizing agent, etc. sealed within an impermeable membrane wall material 31. This is the space that contains the capsule 30. The capsule 30 is maintained in a contactless state. active compound 33 is not present in the reservoir volume and is removed from the core layer (or is not exposed to other layers). The capsule contains the active compound and its excipients. Desired to be osmotic and release the active compound (and carrier, if present) It may be formed of a material that can rupture and activate the device when it is released. completely non-penetrating If a transdermal capsule is available, it is usually used in transdermal devices due to its volatility. It becomes possible to use compounds that cannot be used. Volatile compounds are inside the internal capsule ethanol, acetone, methanol, and ethyl acetate. Excipients and accelerators such as tate may be used, or active compounds such as nicotine. can be used without loss from the device prior to administration. Traditional non-rupture devices During transportation and storage prior to administration, This results in the loss of volatile compounds. (Traditional equipment where volatile compounds are placed in sachets) Even if the compound is contained within the device, the compound is not properly dispensed within the device upon administration. )rupture Possible capsules can rupture at seams (or deliberately weakened parts of their walls) may have a strong seal or be made of fragile or brittle materials (e.g. glass, silica, crystalline or brittle polymers, etc.). crush this a cut section that can be ruptured by bending the batch to make a profit. Accordingly, in presently preferred embodiments, the capsule is rupturable. A heat seal film with heat seal 32 laminated with aluminum foil is used. is formed. This membrane is flexible and consists of a single layer of aluminum (approximately OJ to 1 mil) and EVA, polypropylene, or modified polyethylene (approximately 0.3 to 0.8 mil ). However, if the capsule becomes brittle or torn It may be formed by a flexible container or membrane. For example, thin glass capsules or Brittle (eg crystalline) polymers may be used instead. Capsules if desired It may be possible to make it easier to break by providing a cut portion or forming a neck. capsule the backing layer 21 or a layer adjacent to the backing layer (23, 24, or 25) ) may be attached. Or just surround it in the unfixed reservoir volume 27. good.

A microporous membrane layer 24 and a contact adhesive layer 25 are formed below the reservoir and core layer. . Layer 24 provides a means of slowing the penetration of the drug into the skin through the device. Together, they provide structural integrity to the device. The pores are preferably empty prior to rupture of the reservoir. be. This means that the microporous membrane contains active compound and excipients prior to rupture of the reservoir. Substantially no agents are present. Additionally, the microporous membrane layer 24 has an active compound composition. It is not made equilateral even by the components. Suitable membranes for layer 24 include, for example, Bopp. Lopylene (e.g. Celgard sold by Ce1anese), polyethylene tyrene (e.g. sold by 3M), or polytetrafluorocarbon (e.g. sold by 3M); Made of Tel'1on sold by e-tex, the thickness is approximately 0.5 to 3, and the diameter is O mil. These include, but are not limited to, black pore membranes.

The adhesive layer 25 in contact with the skin is a pressure sensitive adhesive suitable for attachment to human skin. It is. The adhesive selected is also compatible with the active compound and its excipients and It must be suitable for bonding with sublayers. Currently preferred contact Layer adhesives include acrylic resin, silicone, polyisobutylene, polyurethane, S IS, and SBS pressure sensitive adhesives.

This layer can range in thickness from about 0.5 to about 5.0 mils. This adhesive layer is preferable ( 7. Prior to administration, it is protected by a release liner 26. Release liners are generally , easily peeled off from the adhesive layer 1. It is a thin film or sheet that is processed to obtain

In this device, the active compound is isolated within a non-permeable capsule prior to activation. . Therefore, the release liner is only needed to protect the contact adhesive and The properties of the active compound need to be taken into account because the time limit is not applied to the active compound. do not have. This means that the release liner does not have to be impermeable to the active compound, so it is widely available. A range of materials are available. Therefore, the policy Silicone instead of expensive polymer membranes such as esters or polycarbonates paper that has been treated with carbon, or has been treated with fluorocarbons, or polystyrene. can be used. The thickness of the release liner is not critical and can be determined by aesthetic criteria. Ru. Generally, the release liner is 1. Easily peeled or removed from the contact adhesive layer of sufficient thickness and structural integrity to obtain, preferably of one or two pieces. It must be thrown with something suitable. Generally a thickness of about 3 mils is sufficient.

This embodiment completely sequesters the active compound prior to activation, so that the active compound is Packaging is much easier than non-isolated devices. That is, the active compound is The packaging material must be impermeable to the compound as it is completely encapsulated within the compound. There isn't. Therefore, a simple cardboard or plastic container, paper or plastic Tick sachets and the like may be used. 7. if desired. The release liner is suitable for It comes in the form of a long foot lip with a number of spaced apart cutouts, which The device of the present invention can be used as a “cut-off” roll or stacked in accordion pleats. may be provided. Therefore, to treat one patient for one month, a sufficient number of devices are required. It may be provided in a strip, a tube, or in a container. Zara ("5 each device Labeling the prescription with a number or date can help the patient follow the prescription.

For example, on the Δ day of the month, check whether the device marked “4” is peeled off. This allows the patient to know whether they have worn the device that day. Ru. 4: This is a problem for devices that are worn on a daily or weekly basis for long periods of time. Very advantageous.

Another embodiment of the invention is shown in FIG. In this variant, the rupturable capsule is It is provided as part of the backing layer 2J, rather than as a separate layer 31. this place In this case, the impervious layer 34 is laminated to the core layer 23, and the rupturable membrane 15 is attached to the core layer 23. Rezano ζ in contact with the volume part 7 provided for separation from the isolated part It will be done.

Finally, the device automatically ruptures the capsule and/or releases the cap upon removal. It may be packaged in a container in which the inner peeling is performed. Such a device is shown in Figure 6. Ru. The container may be a suitably shaped box 46: 1. After rupture of the capsule, the device 44 is Pressure means 4] and 42 are provided above and below a hole 48 having a size that accommodates the pressure. long carry The yarn strip 26 is equipped with a plurality of devices, including a large diameter spool 45 (curved The capsule is rolled into a roll around the pre-ruptured (not large enough) ing. To dispense the device, the carrier is passed through pressure means 4J and 42. , ruptures the capsule and passes through the hole 48. The pressure means are as shown ] A pair of pressure rollers, one roller facing a flat surface, or a device dispensed It is simply two flat surfaces whose distance becomes narrower in the direction of travel. could be. The pressure means are preferably cam-shaped rollers. 1 pressurizing means is required Depending on the situation, it may be pressurized by a spring or other device (not shown). outfit The installation further separates the carrier/liner 26 from the equipment, such as the row 43. A means to do so may be provided. In this embodiment, the carrier 26 has individual holes 4 9 and can be discharged through. The spool 45 may be attached to the inside of the enclosure 46 as required. A shaft 47 attached thereto may be provided. If desired, the shaft 47 may further include a knob or clamp. A rank (not shown) may be connected to the carrier roll to advance the book. An inventive device is distributed. Alternatively, simply place the device in the carrier roll until it is ejected. The device may be dispensed by pulling on the knob 26. In this embodiment The carrier chosen should be as close as possible to pulling the device through the pressurizing means. It must be strong. The pressurizing means is designed to ensure that the device completely passes through the pressurizing means. and the carrier portion so that the capsule ruptures before separation from the carrier. 13 cases where it is necessary to be sufficiently far away from separation means 43 (if deployed) For example, a batch roll is an accordion-shaped fold placed on a pleated carrier. can be replaced by a batch stack that has been created. The pressure means is a crank instead of a supply roll. (especially when the pressure means are rollers). A mosquito with a brittle cut. When using capsules, the device is designed to bend the capsule until it ruptures. It can be done. Other variations will be apparent to those skilled in the art.

1 and 5, the capsule 31 is ruptured by pressurization and activated. The compound is released from the capsule into the reservoir volume 27. This allows the device to be flat xeA by placing it on a surface and pressing the capsule with your finger or thumb, or by A suitable roller such as a wringer (similar to a wringer as found in old-fashioned washing machines) By external pressurization, such as through a mechanical pressure device.

or create a weak or cut by bending or folding the This can be done by rupturing the area.

The device comprising the contact layer 25 can be placed on the upper arm, thigh, chest, lower arm, etc. It is applied to an appropriate area of the skin where the drug has not yet been administered, such as the abdomen. or , the device can be applied to the skin before activation by rupture of the capsule. , the active compound and excipients are released from the capsule and dispersed through the adjacent layers.

The core layer allows the activated color to spread throughout the bottom layer and flow beyond the device area. put out. The compound is dispersed through the core layer, into the microporous membrane layer, and into the contact layer. Reach sufficient concentration so that the tactile layer can begin dispersion into the patient's skin at a sufficient rate. is accumulated until Due to the fact that the intermediate layer has not reached equilibrium with the compound 1, A substantial delay occurs before significant dispersion into the skin occurs.

Figure 2 shows another embodiment of invention 1 (2, active compound 13, and optionally , a liquid carrier 19 and a resin-containing polymer layer 12. do. This reservoir layer is permanently bonded to the impermeable barrier/king layer and IJ. Ru. The rose wintering layer prevents the loss of active compounds from the "non-contact" side of the device, It may also provide some structural support. Layers 11 and 12 are herein Although shown as separate layers, the pubking layers are thermally and chemically cross-linked. radiation The matrix reservoir can be formed from part of a single layer by suitable processing such as The surface is virtually impermeable to active compounds and keys (if present). considered to be sexual. Layer 11 is preferably supported by liner 7/carrier 17 L4゜L/Zaba single layer 12 is preferably on the other side (the backing IJ is on the opposite side). Protected by a removable protective liner 16. Contact with the reservoir layer 12 1-+ A non-contact adhesive layer 14 may be provided and act as a retardation layer. The adhesive layer 14 can be active compound 13 may contain liquid carriers, penetration enhancers, etc. Qualitatively, it does not contain it at all. If desired, another release liner 15 can be applied to the adhesive layer 14. Can be combined. The release liner 15 and adhesive layer 14 are attached to the liner/carrier. 1., preferably the same as those supporting the reservoir 12 and backing 11. Leek Supported by Ina/Ushi Yariya 17. Adhesive layer 14 is preferably Cover the top surface (opposite the optional release inner 15) with another removable protective layer. protected by an extension of the protective liner 1G. Ru. If desired, between the contact adhesive layer 14 and the protective liner 16 (not shown) may be bonded together.

To use the device shown in FIG. 2, first peel the protective liner 16 from the top surface of the device. Ru. Next, the exposed surface of the adhesive layer 14 is bonded to the exposed surface of the laser layer 12.

In devices where both layers 12 and 14 are supported by the same carrier 17, this The bonding is preferably carried out by fold lines or crease lines 18 as shown in FIG. Subsidized. For bonding, fold the single ε folding device along the fold line, and layer 14 with MJ12. This is done by pressing them together. Reservoir and backing subrami Sublaminate the adhesive layer and liner, liner, 7/carrier Folding along the creases ensures that these complete device shoes are fully assembled (make sure they overlap) 4 and 5 are preferably arranged on the inner/carrier. This result is shown in Figure 4. It has an eel structure. At this point, the liner/carrier 17 is inserted into the cancer 14 (or If so, it is peeled off from the release liner 15). Release liner 15 deployed If so, this is also peeled off and the exposed adhesive layer 14 is applied to the patient's skin. It will be done. The carrier 17 is then peeled from the backing layer 11, leaving layers 11.12 and 11. and 14 are left on the patient's skin. Then active compound 13 (and the necessary When necessary, the liquid carrier 19) begins to disperse into layer 4 and finally reaches the patient's epidermis. Spread. Due to the fact that layer 14 is not in equilibrium with reservoir 12 when installed. Therefore, a substantial period of time elapses before the active compound begins to disperse into the epidermis at a significant rate. Delays occur.

The device of the invention is particularly suitable for repeated administrations. Nitroglycerin (e.g., for the treatment of congestive heart failure) or nicotine (e.g., for the treatment of cigarette cravings) When used for administering (to reduce It is worn just before going to bed. Due to the delayed onset of release, most of the time the patient is asleep. Or no compound is released at all. Instead, the compound is released when the patient wakes up or just before waking up. The device will be available at 4pm. The active compound continues to be released over a period of time. The device is then stripped and a new device is installed. replaced by Therefore, plasma levels of active compounds are based on the patient's sleep period. can be reduced to normal levels without causing tolerance or undesirable side effects. stomach.

In the case of appetite suppressants, it is preferred to put on the device of the invention just before breakfast.

This allows the patient to have a healthy breakfast and appetite suppression only hours later when it is most needed. happen.

Backing layers 11 and 21 are preferably essentially impermeable to the active compound. preferably formed by a sheet or membrane of flexible, elastic material. this The layer preferably has a thickness of about 0.01 to 0.0. ! 1mII+, as needed (e.g. For example, it may be colored to resemble the patient's skin color. Ideally, this layer should be joints or other flexures that can mimic the contours of the skin and are normally exposed to mechanical tension It is made of a material that can be comfortably worn on areas of the skin such as the skin. This allows the skin to Possibility of device dislodgement or peeling due to differences in flexibility or elasticity between skin and device is reduced. Examples of elastic polymers used to prepare the backing layer 11 include , polyether block amide polymers (e.g., FEBAX: ff poly?- ), NUKRBl, Lbo I77-, etc. Rock copolymer (EMA), PELLATHANE or ESTANE poly Polyurethane such as mer, silicone elastomer, polyurethane such as HYTREL Ester block copolymers, rubber-based polyisobutylene, styrene, and and styrene-butadiene and styrene-isoprene copolymers. Soft Flexible polymers include polyethylene, polypropylene, and polyester Includes polyesters such as terephthalate (PET), which are made into membranes or laminates. can be provided as a nate. Also use any laminate or combination of materials mentioned above It is possible.

The polymer matrix reservoir 12 has a low or moderate solubility of the active compound. It is made of a polymeric material that is flexible and capable of dispersing the active compound at high speeds. Leather The bar layer must also be capable of adhering to adjacent layers to prevent delamination. do not have. Therefore, the selection of specific materials depends, in part, on the active compounds selected (and, e.g. excipients such as solubilizers, penetration enhancers) and the adhesive used. Break Devices of the invention using rupturable capsules preferably contain liquid or gel form. Contains active compounds. Following rupture of the capsule that isolates the excipient It must be able to flow out. Typically, excipients include silicone fluids, PGML, and It includes carriers such as PI/glycol and other lactose.

The contact adhesive layers 14 and 25 generally provide an irritant to the reservoir socks. Formed by active compound-permeable polymers that co-adhere to mammalian skin without imparting It will be done. Examples of materials forming layers 14 and 25 include polysiloxane, polyethylene Sobutylene, polyacrylate, polyurethane, plasticized ethylene-vinyl acetate Tate copolymer, low molecular weight polyether block amide copolymer (FEBA X copolymers), and mixtures thereof.

The specific materials used depend on the active compounds in the adhesive layer (and, if necessary, the liquid adhesive). carrier) and the dispersion coefficient in the reservoir layer. in general Both dispersion coefficients should be in the range of about 10-5 to about 10-” CM2/sec. It is possible.

Various carriers and release liners have the desired degree of flexibility and impermeability. It can be formed from any material. These liners are generally silicone or full A surface treatment with orocarbon is used to make it "peelable" from the contact adhesive layer.

The devices of the present invention are generally prepared by standard thin film lamination techniques.

Blood five on C3 The examples presented below are provided as further guidance to those skilled in the art and are Nor shall it be construed as limiting the invention in terms of taste.

X supervisor (In vitro delayed flow measurement) Water-based acrylic adhesive (Flexcryl 1625, solids content 69z ) to a silicone-treated polyester film with a thickness of 0.075 mm. It was coated to a thickness of n+m. Cure this adhesive coating for 30 minutes at 75°C. to remove all moisture. The thickness after hardening is 0.01 mm (10 m g/am2). Dice-cut the cured adhesive disc to attach the surface of a human cadaver. It was attached to the stratum corneum side of the skin disc. This skin/adhesive complex is dispersed in glass. Place the receptor compartment membrane on the skin side of the cell (effective flow area 0.713c+2). It was placed facing towards the front. Measured amount of receiver solution (NaC to 0.0% in deionized water) 1 and 0.01% NaN5) into the receptor compartment. donna - 2.5% by weight nitroglycerin, 48.8% by weight Dot 360 silico 350 cts of one fluid, 23.8% by weight propylene glycol monolau Gattefasse, and 24.7% lactose by weight It was a suspension of 1.5 g of nitroglycerin. Apply this nitroglycerin suspension to into the donor compartment in direct contact with the adhesive. Next, go to the toner compartment. The vent was occluded and the cell was maintained at 32°C. Regular sample of Lember solution The amount of nitroglycerin permeated over a certain period of time was collected and analyzed by HPLC. The amount was measured.

This experiment was carried out using a commercially available NitroGlycium phosphorus excipient in the adhesive layer and Nitroglyc. Replace with N1tro-DurO, a lyserine transdermal device, and repeat exactly. went.

Figure 7 shows the results of this test. The black circle is the amount of the above complex per am2 per hour. Indicates 〈microgram〉. The white circle is N1tr.

-Due results are shown. As shown in the figure, N1trO-Du@ substantially reached maximum flow rate by 2 to 4 hours after administration, but with the composition of the present invention, Adequate onset was delayed until 4.5-5 hours after administration.

Soso Wataru (In vitro delayed flow measurement) Water-based acrylic adhesive (Flexcryl 1625, solids content 69 %) to a silicone-treated polyester film with a thickness of 0.075 mm. It was coated to a thickness of 5 mm. Cure this adhesive coating for 30 minutes at 75°C. to remove all moisture. Thickness after hardening is 0.05 +11111 (5mg/an2). Dice-cut the cured adhesive disc to create a human It was attached to the stratum corneum side of the epidermal disk of a cadaver. This skin/adhesive complex is Place the skin side of this receptor in a lath dispersion cell (effective flow area 0.713 am”). It was placed facing the compartment. - Receiver solution (deionized water) on the foot side 0.9% NaCl and 0.01% NaN5) into the receptor compartment. I put it in the The donor was 2.3% by weight nitroglycerin, 75.0% by weight D ow 360 silicone fluid 350 ets.

1.5 g of nitroglycerin suspension consisting of 22.5% by weight lactose. Ta. This nitroglycerin suspension is placed in the donor compartment in direct contact with the adhesive. I put it in The donor concentration chamber was then occluded and the cells were kept at 32°C. Ta. Samples of the receiver solution were taken periodically and analyzed by FIPLC. , the amount of nitroglycerin permeated over a certain period of time was measured. This experiment was carried out using adhesive layer and and nitroglycerin excipient with N1tro-Duρ and repeat exactly. Return [7 went.

Figure 8 shows the results of this test. The black circles represent the cts2 per hour of the above complex. ! (microgram). White circles are Nitr.

The results obtained using -Duρ are shown. As shown in the figure, the old tro-Du@ Substantially the maximum flow rate was reached by 2 to 4 hours after administration, but with the compositions of the present invention, , adequate onset was delayed until 5-6 hours after administration.

K Shiwata 1 (In vitro delayed flow measurement) (A) Water-based acrylic adhesive (Flexcryl 1625, solids content 69%) was applied to a silicone-treated polyester film having a thickness of 0.075 am. It was coated to a thickness of 125 cm. Cure this adhesive coating for 30 minutes at 75°C. to remove all moisture. The thickness after hardening is 0.05 mm (5 m g/c++12). Human cadavers made by dicing cured adhesive discs was attached to the stratum corneum side of the epidermal disc. Next, a 2 m11 microporous polyp Ropyrene membrane disc (Cel anese/Celg sold by Hoecht) ard 2400) was laminated to the contact adhesive as a retardation film. This skin/adhesion The agent complex was coated in a glass dispersion cell (effective flow area 0.713 am2) a (1 111 was placed facing the receptor compartment. -Window-side metered receiver - solution (0.9% NaCl and 0,01% Na113 in deionized water) into the receptor compartment. Donor is 10 times propylene glycol 1.5 g of solution containing % nitroglycerin. This nitroglycerin solution was placed in the donor compartment in direct contact with the adhesive. Next Donako The compartment was closed and the cell was maintained at 32°C.

Samples of the receiver solution are taken periodically and analyzed by HPLC. The amount of nitroglycerin that penetrated between them was measured. This experiment was performed using adhesive layer and nitride layer. Exactly repeat the procedure by replacing the loglycerin excipient with N1tro-Duβ. It was.

(B) The procedure described in A above was repeated using a Celgard 2400 membrane with microporous pores. Lipropylene membrane/nonwoven polypropylene lamination 1111 (Celgard 4410) and repeated exactly.

(C) Figure 9 shows the results of these tests. The black circle is batch rAJ (Celga rd 2400) is shown. White circles indicate batch r BJ (C elgard 4410). Black angle of view is N1tro -Results using Duμ are shown. As shown in the figure, N1tro-Dur@ reached high flow rates by 2 to 4 hours after administration, whereas with the compositions of the present invention, the onset was There was a significant delay between 8 and 12 hours after administration.

FIG, I FIG. 2 FIG.3 FIG.4 ',' + (μg/cm2-hr) international search report

Claims (14)

[Claims] 1. for administering the active compound transdermally to the patient's skin with delayed onset of delivery. A kit for preparing a device comprising: a polymer matrix impregnated with said active compound. a first layer having a composition, the compound and the matrix having a The first compound is selected to have a dispersion coefficient of about 10-5 to about 10-10 cm2/sec. a first layer selected from the group; and not in contact with the first layer and on the first layer and the patient's skin. a second layer comprising a bondable adhesive, about 10 -5 to about 10-10 cm2/sec, wherein the active compound is substantially A kit comprising a second layer that does not exist at all. 2. further comprising a backing layer bonded to the first layer, the backing layer being bonded to the first layer; 2. The kit of claim 1, wherein the plug layer is substantially impermeable to the compound. 3. 3. The method according to claim 2, further comprising a backing layer bonded to the second layer. Kit as described. 4. a release liner laminated to the second layer on the side opposite the backing layer; The kit according to claim 2, further comprising: 5. further comprising a backing layer bonded to the first and second layers, The kit of claim 1, wherein the backing layer is substantially impermeable to the compound. to. 6. A release layer attached to the first and second layers on the side opposite to the backing layer. 6. The kit of claim 5, further comprising an exit liner. 7. said active compound is selected from the group consisting of nitroglycerin and nicotine; The kit according to claim 1, wherein the kit comprises: 8. Method of administering an active compound to a patient by wearing a controlled release device A method for delaying the start of administration from when the device is attached, a step of laminating a first layer and a second layer to form an adhesive laminate, the step of bonding a first layer and a second layer together, the step One layer comprises a polymer matrix impregnated with the active compound, wherein the compound and the matrix 10-5 to about 10-10 cm2/sec in the matrix. 1 and the second layer is selected to obtain a compound dispersion coefficient of 1 and the second layer is the second layer comprises an adhesive capable of adhering to the patient's skin; a second dispersion coefficient of from 0-5 to about 10-10 cm2/sec; forming an adhesive laminate initially substantially free of said active compound; ;and Before the active compound reaches equilibrium in the adhesive laminate, the adhesive laminate is applying to the patient's skin. 9. Claim wherein said active compound is selected from nitroglycerin and nicotine. The method according to item 8. 10. Peel off the adhesive laminate after 24 hours and install a new adhesive laminate. 9. The method of claim 8, further comprising the step of: 11. After application to the patient's skin, the active compound is administered transdermally with delayed onset of delivery. A device comprising: (a) a rupturable reservoir containing an active compound in liquid form; (b) a rupturable reservoir containing a liquid active compound; ) an active compound permeable microporous membrane located below the rupturable reservoir; so that the pores of the membrane are not filled before the reservoir ruptures, and the membrane has an inherent constant permeability to the active compound in liquid form; a microporous membrane that is not plasticized by a chemical compound; and (c) the microporous membrane is in communication with the patient's skin for release of the active compound; means for adhering the device to the patient's skin so as to A device equipped with. 12. a porous fabric, the microporous membrane and the The device of claim 11 further comprising a core layer disposed between the reservoir. Place. 13. 13. The device of claim 12, wherein the core layer comprises a nonwoven fabric. 14. The means for adhering is such that the active compound is substantially present prior to rupture of the reservoir. 12. The device according to claim 11, wherein the adhesive layer is not permeable to active compounds.