HU0201454A2 - A method of improving adaptability, mass transfer through the semipermeable védőgátakon - Google Patents

A method of improving adaptability, mass transfer through the semipermeable védőgátakon Download PDF

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Publication number
HU0201454A2
HU0201454A2 HU0201454A HU0201454A HU0201454A2 HU 0201454 A2 HU0201454 A2 HU 0201454A2 HU 0201454 A HU0201454 A HU 0201454A HU 0201454 A HU0201454 A HU 0201454A HU 0201454 A2 HU0201454 A2 HU 0201454A2
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preferably
weight
acid
cm
penetrating
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HU0201454A
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Hungarian (hu)
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HU0201454A3 (en
Inventor
Gregor Cevc
Holger Richardsen
Andrea Weiland-Weibel
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Idea Ag.
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Priority to PCT/EP1999/004659 priority Critical patent/WO2001001962A1/en
Application filed by Idea Ag. filed Critical Idea Ag.
Priority to PCT/EP2000/006367 priority patent/WO2001001963A1/en
Publication of HU0201454A2 publication Critical patent/HU0201454A2/en
Publication of HU0201454A3 publication Critical patent/HU0201454A3/en
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=8167360&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=HU0201454(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1271Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids

Abstract

The present invention relates to a method for controlling the flow of materials that penetrate through a semi-permeable, porous protective barrier, wherein the process is to produce the penetrating agents suspended or dispersed in the form of liquid droplets surrounded by a multilayer membrane-like coating, wherein the coating comprises at least two types or forms of amphiphilic materials. which tend to aggregate and at least one of the at least one factor 10 differs in solubility in said polar liquid; and wherein the penetrating agent is capable of delivering the active substance through the pores of the barrier or allowing the active agent to penetrate through the barrier pores after penetrating the pores into the pores, select the dose amount of the excipients to be applied in the predetermined area of the barrier to control the flow of penetration through the barrier and a porous protective barrier is applied to the selected dosage amount of the composition containing the penetrating agents. HE

Description

COPIES

The present invention relates to a method for controlling the flow of substances that penetrate through a semi-permeable, porous protective barrier, wherein the method is to prepare the penetrating agents in a polar liquid, suspended or dispersed in the form of liquid droplets surrounded by a multilayer membrane-like coating, wherein the coating has at least two types or in the form of an amphiphilic material in a form that is susceptible to aggregation, and at least two of the at least 10 substances differ in solubility in said polar fluid; and wherein the penetrating agents are capable of delivering the active substance through the pores of the barrier or allowing the active substance to penetrate through the pores of the barrier, after penetration of the penetrating materials into the pores, to select the dose amount of penetrating agents to be used in the predetermined area of the barrier to control the penetrating materials the flow rate through the protective barrier and the appropriate area of the porous protective barrier is applied to the selected dosage amount of the composition containing the penetrating agents.

2002 SEPT 20.

Ρ02Ο ί 4 5 4

3978

DISCLOSURE EXAMPLE

A method for improving material transfer through adaptive, semi-permeable protective barriers

The present invention relates to the field of drug delivery, in particular to the delivery of drug through the barrier. More particularly, the invention relates to a method for controlling the flow of intruders through an adaptive, semi-permeable, porous protective barrier. The invention further relates to a kit and a patch that allow the active ingredient to be administered in a controlled manner.

The term porous protective barrier, as used herein, is any barrier that contains pores that are too narrow to allow penetration of penetrating materials in a diffuse manner. This necessarily means that the intruders are larger than the average diameter of such a pore.

Some protective gels, such as artificial, porous membranes, such as polycarbonate membranes containing ion beam passages, may have permanent properties while others exhibit possible changes in their properties. Most importantly, pore size, and rarely, pore density, may vary as a function of the environment of the penetrating material and / or the flow of penetrating material through pores in the barrier. The latter is also found in living tissues, such as cells and cellular organs, which are separated by boundaries having such properties.

In the following, the skin is used to illustrate the operating principle of such a barrier.

The most important skin barrier properties are determined by the outermost skin region, ie the stratum corneum. This layer of corn is due to its special chemical and anatomical characteristics, which most effectively exclude the penetration of any material in the skin.

In the skin layer of the skin, 20-30 coherent layers of skin cells (especially corneocytes) are organized into columns. The columns are vertical to the surface of the skin, allowing the cells of adjacent columns to overlap each other and to force the cells of one layer to overlap and compress. In addition, the links between cells in the stratum corneum are tightly sealed by specific lipids, especially ceramides, which are abundant in the skin. The skin lipids are also predominantly well compressed: they typically form multiple layers of multilamellar lipids which covalently bind to adjacent cell membranes. Some multilamellar beams that run parallel to the cell surface are associated with less well-ordered lipid portions. In such parts, non-ceramide-like lipids (fatty acids, cholesterol sulfate, etc.) are the rulers.

The tendency of the skin lipids to settle themselves into densely compacted multilayer structures can be enhanced or controlled in the skin by hydration or certain ionic concentrations (e.g., Ca 2+ ). This may explain why similar lipid organization is not observed elsewhere in the body, except in the oral cavity, with much less variation.

The skin permeation enhancing chemicals, such as dimethyl sulfoxide, promote the diffusion of drugs through the skin by dissolving or dissolving certain intercellular (intercellular) lipids from the barrier. Transcutaneous material transfer is therefore most effective in less tightly compressed lipid regions where hydrophobic pores are most readily formed in the barrier. Through such pores, the relatively small and lipophilic agents are able to diffuse along the transcutaneous gradient (s) of concentration. The resulting skin permeability does not depend on the concentration of the active ingredient, unless the drug acts as a permeability enhancer, but permeability depends on the concentration and choice of the skin permeability enhancing agent (s).

However, the hydrophobic pores in the skin are not large enough to allow any material of any type to be perceived to be perceptible. Owing to the self-locking willingness of intercellular lipid domains, the pores are also quite short-lived. The lipophilic nature of the characteristic pores in the skin also precludes the transfer of hydrophilic, i.e., highly polar, molecules through the body. Thus, conventional skin permeation enhancement methods can only be used for the delivery of fatty substances that do not irritate the skin too much, and that in many cases the permeation-mediated substance transfer and irritation are poorly tolerated by consumers.

Therefore, to date, drug delivery based on transdermal permeation is only successful for small drugs with a molecular weight below 400 Da. Such agents are capable of dispersing in the intracellular lipid matrix in the skin and then being able to diffuse through the tiny hydrophobic pores in the stratum corneum to the real skin first and then into the deeper, deeper body tissues. The resulting solid material transfer is introduced by a short delay time while the active substance passes through the barrier. However, the transfer through the skin is not disturbed by the first pass effect.

Such conventional devices typically exhibit a bioavailability of less than 50% of the transdermal delivery agents and often less than 25% (Hadgraft, 1996; Cevc, 1997).

Large hydrophobic molecules normally pass through the skin only in negligible amounts. As already mentioned above, this is due to the lack of appropriate flights in the skin. The transcutaneous transfer of macromolecules therefore depends mainly on the molecular diffusion through the connections, for example through the hair units. For this reason, the transfer of bulky and highly polar materials through the skin requires procedures other than those traditionally employed. For example, various skin pore-forming techniques have been introduced to form hydrophilic pores for this purpose in the skin (such hydrophilic pores will be referred to as channels to avoid confusion).

The easiest and most primitive solution for creating a wide channel through the skin is to mechanically remove the skin shield. For example, a large hydrophilic antidiuretic peptide, 1-deamino-8-D-arginine vasopressin, is used to remove a small portion of the epidermis by vacuum aspiration to deliver the transdermal patch through the skin (Svedman et al., 1996).

Furthermore, the most common method of opening a wide channel through the skin is the use of an injection needle or mechanical action (s) (injection; powder injection). It is also possible to focus the skin in one place. This is by using local heat (thermoporation); using high voltage pulses (> 150 V; electroporation); or acoustic energy, such as ultrasound (some W / cm 2 ; sonophoration). The size of the resulting channel depends on the nature and intensity of the skin treatment, but does not depend on the nature and amount of molecules used.

In the above-described methods, the skin openings or craters recover quite slowly under normal conditions of use; the wider the gateway, the slower. The skin can thus act as an adaptive but slow healing barrier.

Even the most commonly used methods for the formation of pores in the skin are based on the experience of special tools and characteristic operation; even disinfect the skin to protect the patient. However, their harmfulness and inconvenience are tolerated until they achieve a therapeutic advantage.

The most up-to-date device for forming hydrophilic air in the barrier, such as the skin, is provided by microscopic barrier penetrating materials that directly and reversibly open said hydrophilic channels. Such intruders are independent of the external energy source and do not rely on any special tools. Such materials are also well tolerated by the skin.

The so-called intrusive materials known so far belong to the class of easily deformable complex droplets (Transfersomes®). Such drops adapt to the pores of the sheath, which are then effectively passed through, provided that the components of the drops and the composition are carefully selected and / or optimized. An appropriately adaptable and hydrophilic drop can thus spontaneously pass through the barrier, such as the skin. Such hydrophilic channels are temporarily opened by the moving intruder after the shape of the latter material forms the appropriate shape to achieve the purpose. This allows the droplets formed into the desired shape to act as carriers for the transport of various hydrophilic or hydrophobic agents through a protective barrier.

The most suitable droplets comprise an aqueous core surrounded by a highly flexible mixed lipid bilayer which makes the aggregate ultra-deformable and highly hydrophilic in surface. Both are needed for effective transdermal delivery (Cevc, 1997). Said droplets have been shown to be transported relatively efficiently through the skin under optimum application conditions (Cevc, 1997).

Other types of aggregates (liposomes, niosomes, nanoparticles, microemulsions, etc.) are also claimed to be effective in penetrating the skin, but it has not been proven anywhere that the associated active ingredients are actually delivered to the skin in practically meaningful amounts. It is believed that, unlike the easily deformable droplets (Transfersomes®), the aggregates used are either not sufficiently deformable and / or too unstable to achieve the goal. Instead, conventional aggregates act as simple drug repositories on the skin: aggregates that cannot pass through the barrier remain on the skin, while the active ingredient is gradually released from the carrier (vehicle), and then diffuses itself appropriately on the skin barrier. The main effect of conventional drug-containing suspensions is therefore to increase the hydration of the skin barrier and / or to bring the molecules with skin permeability enhancing ability into the tissue.

In contrast, the complex, highly deformable lipid droplets (Transfersomes®) are deformed and then penetrate the skin rather than to merge locally. The movement of such aggregates through the skin appears to occur along the natural moisture gradient (s) between the skin cells that lead the aggregates into the hydrophilic (virtual) channels of the organ.

The primary shapes of the channels that allow easily adaptable droplets through the skin are initially so narrow that they allow only the (rather small) water molecules to evaporate through the skin. However, it appears that these originally tiny pores (diameter <0.5 nm) are reversibly opened when the pressure caused by the partial dehydration of one drop, which forces the droplet in the channel mouth under non-occlusive conditions, increases too much. The highly hydrophilic nature and mass of the drop are factors that maximize the tendency of the droplets to pass through the skin; however, the adaptability of the drop is an indispensable condition for the success of said movement.

It appears that the movement of the droplets through the skin takes place on the route used by the water molecules when passing through the skin in the opposite direction. The droplets thus enter the intercellular regions exactly where the above-described skin-closing lipids are the weakest and less tight. The appropriate skin region covered with the channels is estimated to be about 4% or less of the total skin area.

It is possible to combine small and large hydrophobic and hydrophilic molecules with extremely deformable and readily adaptable droplet aggregates. By using such complex aggregate droplets, all types of molecules can thus be transferred through the protective barrier, such as the skin layer of the skin.

Typically, high systemic availability of the delivered drug can be achieved. In most cases, the relative efficacy of transdermal delivery exceeds 50% (Cevc et al., 1996). Steady state is reached within a few hours (Cevc et al., 1998).

·· ···· ··

It has already been shown that the skin barrier completely regains its original condition after the drops are removed from the skin surface. In contrast, channels created by other means, such as ultrasound, remain open for at least 20 hours. In reality, they do not close completely before 2 days, even when using relatively weak therapeutic ultrasound. Stronger perturbation causes more permanent skin damage (Mitragorti et al., 1995). (In extreme cases, when the barrier is removed by vacuum suction, the skin will regain its original shape only after 8 weeks.)

The exact size distribution of the ducts in the skin through which the easily deformable droplets migrate on the skin's horn layer is not known yet, but is probably asymmetric. The average width, i.e. the distribution maximum, is estimated at 20-30 nm under commonly used conditions of use. The asymmetric distribution can be the result of the presence of two quantitatively different qualitatively similar transdermal transdermal pathways (Schátzlein & Cevc, 1998), which together form a family of transdermal routes.

The first inter-cluster pathway leads to groups of corneocytes. This represents the upper limit of the channel size distribution and typically starts from the bottom of the interstitial cleft. From there, it follows such crevice-filled sinter material and provides the lowest penetration resistance at the junctions where multiple sets meet.

The second, cross-link pathway leads to some corneocytes in the corneocyte sets. This path typically follows the surface of the lipid layers. In a part extending beyond the outer layer of the horn layer of the skin, the intercostal pathway resembles a transversal three-dimensional network that includes all cells in the organ (Schátzlein & Cevc, 1998).

The above-mentioned differences are inherently quantitative differences. There is no doubt that the ducts through the skin, apart from the hairy units, are resistant to the penetration of non-deformable, large aggregates.

The channel properties are also sufficiently stable to exhibit small space, individual, variety, or carrier variability. In the prior art, the relative bioavailability of the various active ingredients in the blood is quite constant after the administration of easily adaptable droplets (Transfersomes®) (Cevc, 1997). The pore distribution is slightly dependent on the nature of the penetrating agent and the active ingredient. The same is true for dose dependence, which is determined to influence the depth of the penetrating agent and the distribution of the active ingredient quite simply. A low dose per unit area has been found to favor local (surface) retention, while a high dose per unit area has been shown to provide relatively high systemic availability.

Surprisingly, and contrary to the above-mentioned conclusions, it has been found that changing the applied dose above a certain threshold and in a sufficiently wide range not only influences the drug / penetration distribution but also determines the rate of material transfer through the barrier.

Our new and unexpected recognition provides a means for controlling the rate of transcutaneous drug delivery each time we use easily deformable carriers on the barrier; this recognition also provides the basis for designing better, ie more reasonable means of transport. This can be particularly rewarding for the development of skin patches that can be used together with easily adaptable carriers (Transfersomes®). The consequence should be products with improved therapeutic and higher commercial value.

It goes without saying that the observed new effect also expresses the widening of the channels in the barrier, but the applicant does not insist on this assumption. Newly recognized dose-dependent pore widening is likely to be different for different transdermal channels: originally narrower pores are likely to change more than relatively broad (e.g., interstitial) channels. The effect of the relative channel size, i.e. the ratio of the channel to the penetrating material, suggests that it takes much longer to transfer a certain amount of intruder through the narrower channels than through the wide channels.

• · · · · · · ··· ·· ·· ···· ··

If the channels function as units that differentiate the delivered quantities and adjust their width according to the flow, the tight channels will remain much longer in their original high penetration resistance than the wide channels. However, once they respond to the penetration of multiple intruders by increasing their width, such channels begin to behave like originally wide channels. There are several options available, but only up to a certain limit.

Another potentially important factor that works in the same direction is hydration of the skin surface, which tends to increase with the topical administration. In each case, the average width and size distribution of the ducts in the skin will move toward higher values at increasing doses applied. This effect will then result in higher final transcutaneous currents.

In order to avoid any doubt, all relevant information, definition and listing from our prior patent applications will be incorporated herein by reference.

Kits and, in particular, devices for administering the active compounds through a protective barrier, such as the skin or mucosa, have already been described. These devices are typically divided into matrix systems and liquid storage systems.

Container-type containers are often formed as pockets between the backsheet and the rate-controlling membrane through which the drug passes through the skin. The pressure-sensitive adhesive layer is normally located beneath the membrane and the active substance passes through it through its path to the skin.

As mentioned above, it is common for transdermal drug delivery patches to be prepared with a backsheet and a rate-controlling membrane (Ogiso,,., Y. Ito et al., (1989) Membrane-controlled transdermal. clonazepam and anticonvulsant activity after its applicator Chem Pharm Bull (Tokyo), 37, 446-9; Ito, Y., T. Ogiso et al., (1993) "Percutaneous absorption of acemetacin from a membrane controlled transdermal. system and prediction of the drug in rats ”Bioi. Pharm. Bull, 16, 583-8).

Many storage-type systems have been described.

Chang et al. U.S. Pat. No. 829,224 discloses, for example, a device having a storage portion defined by a backing membrane and an active agent permeable membrane layer. There is a ring-shaped layer made of an adhesive material on the surface of the storage part. A peelable lining layer is located under the membrane. A second release liner, the release liner, is located beneath the entire structure. A first heat barrier layer connects the backing to the membrane and surrounds the container. A second heat-sealing layer which is concentric with the first heat-sealing layer connects the backing to the release liner. The second heat-sealing layer breaks down when the release liner is removed. The structure may include an inner liner located beneath the portions of the membrane and the backsheet. This inner lining is removed after removal of the release liner, so that the membrane is exposed.

Chang et al. U.S. Patent No. 4,983,395 relates to another device having a backsheet and a membrane layer defining a container portion. A retractable inner liner is located underneath the container and the backside of the container surface and some portions of the membrane layers. An adhesive layer is located underneath the inner lining and the remainder of the membrane layers. There is a release liner under the adhesive layer. A first heat seal layer connects the backing and membrane layers on the surface of the container. A second heat seal layer is located under the first heat seal layer and connects the membrane to the inner liner. When applied, the release liner and inner liner are pulled out to expose the lower surface of the membrane and the adhesive layers before the device is applied to the skin or mucosa.

In WO 96/19205, Theratech, Inc. discloses a device for administering an active ingredient to a patient's skin or mucosa, which is from an adhesive coating, from a backsheet located below the central portion of the adhesive coating, from a permeable membrane. , wherein the backsheet and membrane define a container portion comprising the active ingredient composition, a laminated composition of a release liner located under the permeable membrane, and a heat-sealing layer around the surface of the release liner, wherein the drug-permeable membrane and backsheet are provided. and the removable release liner is located under the opening cover and the release liner. The adhesive layer is positioned above and around the pathway of the active ingredient into the skin or mucosa, and several thermal seals protect against degradation by the components of the container. The release liner protects against the release of the reservoir containing the active ingredient, and the release liner protects the adhesive from being exposed to the environment before use.

In US 5,202,125, Theratech, Inc. discloses a transdermal delivery system for transporting nitroglycerin, which carries the active ingredient with increased transdermal currents. In addition to nitroglycerin, the systems comprise a permeation enhancer which is either a sorbitan ester, an aliphatic alcohol having from 8 to 22 carbon atoms, or a mixture thereof. Methods for administering nitroglycerin with such permeation enhancers are also disclosed.

Theratech, Inc., in WO 90/11065, discloses a transdermal drug delivery device comprising a reservoir containing a backsheet and a drug-permeable membrane layer, a removable inner liner that extends from the container and the container surrounding the container. located underneath the backsheet / diaphragm portion, an adhesive layer located beneath the extended lining of the inner lining and the membrane / backsheet and comprising a release liner which is a first constant between the backsheet and the membrane around the periphery of the container; lies under an adhesive layer with a heat-sealing layer, and another peelable (transient) sealing layer is placed between the membrane and the inner liner under the first constant heat-sealing layer, wherein the heat-sealing layers and the peel-off barrier layer form shields that select the pharmaceutical composition from the adhesive.

Depending on the characteristics to be attained, the backsheet has a sealing or permeable property and is generally made of synthetic polymers such as polyester, "· ·" · · · · · · · · · · · · · ····· ·· · · Polyethylene, polyvinylidene chloride (PVDC), polyurethane or natural polymers such as cotton, wool, etc. come. It is possible to use porous, microporous, for example polypropylene or polyethylene, or even macroporous, nonwoven or nonwoven materials as a backsheet for transdermal patches. The backs are generally chosen from these materials depending on the active ingredient to be delivered.

The occlusion backs in the classical TTS (transdermal delivery systems) tend to promote greater displacement and a higher rate of penetration of the active substances or inactive substances into the skin relative to the non-occluding backs. Closure backs, for example, are desirable to enhance the delivery of steroids to the lower layers of the epidermis when treating inflammations and skin disorders. Examples include Actiderm® (dermatological patch) or Cordran® (tape and patch).

Semi-occlusive films, such as polyurethanes and polyolefin copolymers, and non-occlusive, woven and nonwoven fiber-based materials, such as cotton and polyester, allow water vapor to be transferred from the skin surface and the patch. These semi-occlusive or non-sealing materials are rarely used as backing in TTS. Thicker non-closure backs are only preferred for corn and bone removal products, as the active ingredient is only to be delivered to the top of the skin stratum corneum. Non-sealing, nonwoven and non-woven materials used in many of these products are mainly used as protective cushions.

Commercially available speed control membranes commonly used in TTS are thin (26-78 µm) non-porous ethylene vinyl acetate films such as Transderm-Nitro® (Ciba-Geigy and ZAFFARONI), Duragesic®, Estraderm® and EstraGest ®. In addition, thin (26-78 µm) microporous polyethylene films, such as Transderm-Scop®, Catapres® films, are used as a speed control membrane for multilayer solid state storage patches or liquid storage TTS. Other examples of such microporous PE membranes are β-Estro® and Androderm®. These membranes are usually intended to limit the rate of diffusion of the active ingredient into and through the skin.

·

As described above, transfersomes (Transfersomes®) are capable of mediating the drug or drug delivery through the skin through a hydration gradient across the biological barrier. In contrast to conventional transdermal delivery systems, where drug delivery is generally dependent on the classical Fick of diffusion, therapeutic systems suitable for the transfersomes and useful in the method of the invention must meet different criteria.

It is also problematic that transdermal delivery of transdermal-mediated drug delivery from a patch is obstructed by the use of a occlusive backsheet material. The use of the occluding membrane as a backsheet causes increased transfusion of the hydration, for example, the vapors cannot escape from the patch. Accordingly, the hydration gradient and hence the transfusion domain transfer force drops dramatically.

Another problem is that many non-occluding, woven and nonwoven backing sheets, which normally serve as a protective paw, hold back the transfersomes due to the adherence of lipids and proteins and retention by the fibrous structure.

In addition, conventional microporous and non-porous velocity control membranes having a pore size of less than about 20 nm may, due to dimensional exclusion, prevent the transfusion of the transgenes from passing through the pores.

It will be appreciated by those skilled in the art that known transdermal patches with conventional backing and speed control membranes are not suitable for mediating transfersomes of the invention. Similar to matrix-type patches.

Matrix-type transdermal patches are those in which the drug is contained in a polymer matrix and is released therefrom. Typically, the matrix is made of a pressure sensitive adhesive and determines the lower surface of the patch (i.e. the surface that adheres to the skin).

Several matrix-type systems have been described.

U.S. Patent No. 5,460,820 to Theratech, Inc. discloses a method of providing testosterone replacement therapy for a woman in need of such a therapy, wherein the method comprises applying a testosterone delivery patch to said woman's skin, which is a patch. transmits 50500 pg / day of testosterone to the skin through the skin. The skin patch is a laminate composition consisting of a backsheet and a matrix layer containing a testosterone solution in a polymeric support, wherein said matrix layer provides a sufficient daily dose of testosterone for said therapy.

U.S. Patent No. 5,783,208 to Theratech, Inc. discloses a matrix-type transdermal patch for the combined administration of estradiol and another steroid, wherein the matrix is an N-vinyl-2-pyrrolidone-containing acrylic copolymer of pressure-sensitive adhesive, estradiol, it consists of another steroid and optionally a permeation enhancer, and the steroid streams of estradiol and the other from the matrix are independent of the other steroid and estradiol concentrations in the matrix.

All relevant information, definitions, and listings from U.S. Patents and Patent Applications of Theratech, Inc., are incorporated herein by reference.

As mentioned above, as usual, storage type patches for transdermal drug delivery are prepared with a membrane backing and a rate control membrane. These membranes typically form a chamber containing the appropriate composition. This may be a mostly alcoholic or aqueous solution, an aqueous suspension or a gel containing gelling polymers. The parameters of the active ingredient (s) and binders, such as chemical and physical stability, viscosity, concentrations are not critical for commercially available single-chamber storage types, as most drugs (drugs) are currently stable, low molecular weight (nicotine, fentanyl, estradiol, scopolamine, and others) which generally do not interact with, for example, additional ingredients such as antioxidants, stabilizers, auxiliary solvents, and penetration enhancers.

As already mentioned, the delivery of transfersome-mediated drug delivery through the barrier is clearly different from the delivery of the drug through conventional skin. While it is not possible to administer high molecular weight agents with transdermal patches known in the art, transfersomes are, in principle, suitable carriers for high molecular weight agents such as peptides (such as insulin) and proteins (serum albumin). One skilled in the art will recognize that problems may arise if, for example, labile proteins are mixed with interacting or destabilizing ingredients for a longer storage period in conventional single-chamber patches.

In many cases, adequate stability of all components is not achieved within a chamber. For example, transfersome-forming phospholipids are most stable at pH 6.5, while optimal stability of proteins occurs at other pH levels (e.g., interferon-α-2b at pH 7.4 or pH 3). Therefore, it may be necessary to keep said materials in a different medium if stored for a long time. For example, T-type transfersomes are stable and formulated in phosphate buffer while hepatocyte growth factor (HGF) is stable in citrate buffer. In addition, organic solvents (auxiliary solvents) are generally used to introduce antioxidants, such as BHT, into lipid aggregates. Said solvents (auxiliary solvents) can contribute to reduced solubility of proteins by reducing the total dielectric constant, thereby reducing electrostatic repulsion. This can lead to unregulated, at least unwanted aggregation and denaturation of proteins.

An important object of the present invention is to regulate the flow of readily deformable penetrating materials (transfersomes) through an adaptive, semi-permeable, porous protective cover, such as the skin or the skin of a human or animal body. Another object of the invention is to regulate the flow of adaptive, semi-permeable, porous protective barrier through an easily deformable penetrating material using a kit or transdermal delivery system that allows the composition to be administered in the selected dose / area unit amount. It is a further object of the present invention to provide a transdermal patch suitable for the delivery of transdermally mediated drug or drug via intact skin. Another object of the invention is a long-nerve-stable, multi-chamber storage-type transdermal patch comprising segregated chambers and suitable for delivery of transfusion-mediated drug or drug via intact skin.

According to the present invention, this is achieved by a method for controlling the flow of the penetrating material through a semi-permeable, porous protective barrier, the method comprising the following steps:

preparing a composition such that said penetrating agents are suspended or dispersed in a polar liquid in the form of liquid droplets surrounded by one or more layers of membrane-like coating, wherein the coating comprises at least two types or forms of amphphilic material susceptible to aggregation, provided that said at least the solubility of the two materials in said polar solvent is at least one factor 10, and / or said materials having a homoaggregate (in the case of a more soluble substance) or a hetero aggregate (in any combination of both said materials) having an average diameter less than that of only the diameter of the less soluble homo aggregates and / or the more soluble substance tends to make the droplet soluble, and the amount of such material is up to 99 mole percent of the dissolution concentration or the saturation concentration down up to 99 mol% of the undissolved droplet, whichever is higher;

and / or the presence of the more soluble material reduces the average elastic energy of the membrane-like coating to at least one fifth, preferably one-tenth and most preferably more than one-tenth, than the elastic energy of the red blood cells or phospholipid bilayers having liquid aliphatic chains, said penetrating agents are capable of delivering said active ingredients to said protective barrier pores. by passing through the pores of said protective barrier, after penetration of the penetrating materials into the pores, the dose amount of penetrating agents to be used in the predetermined area of said protective sheath to control the flow of said penetrating material through said barrier;

applying the selected dose amount of the penetrating composition to the porous barrier area.

Preferably, the flow of penetrating material through the barrier is increased by increasing the dose amount of the penetrating agent used.

It is then preferred that the pH of the composition is between 3 and 10, more preferably between 4 and 9, most preferably between 5 and 8.

According to another preferred feature of the invention, the composition comprising the penetrating agents comprises:

at least one thickening agent in an amount which increases the viscosity of the composition to a maximum of 5 kN s / m 2 , preferably 1 kN s / m 2 , most preferably 0.2 kN s / m 2 , thus allowing the composition to spread and retention of the active ingredient in the field of application and / or at least one antioxidant in an amount that reduces the increase of the oxidation index by less than 100% in 6 months, more preferably less than 100% in 12 months, most preferably less than 100% 50% reduction in 12 months and / or at least one antimicrobial agent in an amount that reduces the amount of 1 million germ bacteria added to the aerobic bacteria to less than 100 in 4 days for the total weight of the preparation, for enterobacteria less than 10 and less than Pseudomonas aeruginosa or Staphylococcus aureus

Reduces to 1.

In addition, it is preferred that said at least one antimicrobial is added to the composition in an amount of less than 1 million germs per g of bacteria added over a period of 3 days, more preferably within 1 day, to less than 100 for aerobic bacteria and less for enterobacteria. less than 10 and less than 1 for Pseudomonas aeruginosa or Staphylococcus aureus.

It is further preferred that the thickener is selected from pharmaceutically acceptable hydrophilic polymers such as partially etherified cellulose derivatives such as carboxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropylmethyl or methylcellulose; fully synthetic hydrophilic polymers such as polyacrylates, polymethacrylates, poly (hydroxyethyl), poly (hydroxypropyl), poly (hydroxypropylmethyl) methacrylates, polyacrylonitriles, metallyl sulfonates, polyethylenes, polyoxyethylenes, polyethylene glycols; polyethylene glycol lactides; polyethylene glycol diacrylates; natural gums such as alginates, carrageenans, guar gums, gelatins, tragacanth, amidites, pectins, xanthanes, chitosan collagen, agarose; mixtures thereof and further derivatives or copolymers thereof and / or other pharmaceutically or at least biologically acceptable polymers.

Preferably, the concentration of said polymer is selected such that it ranges from 0.01% to 10% by weight, more preferably from 0.1% to 5% by weight, more preferably from 0.25% to 3.5% by weight. and in the range of 0.5% to 2% by weight.

Furthermore, it is preferred that said antioxidant is selected from the group consisting of synthetic phenolic antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and di-tert-butylphenol (LY178002, LY256548, HWA131, BF- 389, CI-986, PD-127443, E-5119, BI-L-239XX, etc.), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), 1-O-hexyl-2,3,5-trimethyl -hydroquinone (HTHQ); aromatic amines (such as diphenylamine, p-alkylthio-o-anisidine, ethylenediamine derivatives, carbazole, tetrahydroindenoindole); phenols and phenolic acids (such as guaiacol, hydroquinone, vanillin, gallic acids and their esters, protocol acid, cinnamic acid, siring acid, ellagic acid, salicylic acid, nordihydrogen butter (NDGA), eugenol); tocopherols (including alpha, beta, gamma, delta tocopherols) and derivatives thereof, such as tocopheryl acylate (e.g., acetate, laurate, myristate, palmitate, ololeol, linoleic, etc., or any other suitable tocopheryl) lipoate), tocopheryl POE succinate; trolox and the corresponding amide and thiocarboxamide analogs; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6) -o-alkyl ascorbic acid, ascorbyl esters (e.g. 6-o-lauroyl, myristoyl, palmitoyl, oleoyl or linoleoyl-L-ascorbic acid, etc.) ; non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, diclofenac, mefenamic acid, flufenamic acid, phenylbutazone, oxyphen-butazone acetylsalicylic acid, naproxen, diflunisal, ibuprofen, ketoprofen, piroxicam, penicillamine, penicillamine disulfide, primacin, quinine, chloroquine , hydroxychloroquine, azathioprine, phenobarbital, acetaminophen; amino-salicylic acids and their derivatives; methotrexate, probucol, antiarrhythmic agents (e.g., amiodarone, aprindin, aza-azole), ambroxol, tamoxifen, b-hydroxy tamoxifen; calcium antagonists (such as nifedipine, nizoldipine, nimodipine, nicardipine, nilvadipine), beta-blockers (e.g., atenolol, propranolol, nebivolol); sodium bisulfite, sodium metabisulphite, thiourea; chelating agents such as EDTA, GDTA, desferrals; endogenous protection systems such as transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion, hemopexin, albumin, glucose, ubiquinol-10; enzymatic antioxidants such as superoxide dismutase and metal complexes of similar activity, including catalase, glutathione peroxidase, and less complex molecules such as beta-carotene, bilirubin, uric acid; flavonoids (e.g., favones, flavonols, flavonons, flavanones, chakons, anthocyanins), N-acetylcysteine, mezna, glutathione, thiohistidine derivatives, triazoles; tannins, cinnamic acid, hydroxycinnamate acids and their esters (e.g., coumic acid and its esters, coffee acid and its esters, ferulic acid, (iso-) chlorogenic acid, synapse); spice extracts (for example, cloves, cinnamon, sage, rosemary, nutmeg, oregano, allspice, nutmeg); carnosic acid, carnosol, carzolic acid; rosemary acid, rosemary diphenol, gentic acid, ferulic acid; oatmeal extracts such as avenanthramide 1 and 2; thioethers, dithioethers, sulfoxides, tetralkylthiuram disulfides; phytic acid, steroid derivatives (e.g. U74006F); tryptophan metabolites (e.g., 3-hydroxyquinurenine, 3-hydroxy-anthranilic acid), and organic chalcogenides, or an oxidation-inhibiting enzyme.

In addition, the concentration of BHA or BHT is often between 0.001 and 2%, more preferably between 0.0025 and 0.2%, most preferably between 0.005 and 0.02%, TBHQ and PG are between 0.001 and 2%, more preferably 0.005. and between 0.2% and 0.02%, most preferably between 0.01 and 0.02%, the concentration of tocopherols between 0.005 and 5%, more preferably between 0.01 and 0.5%, most preferably between 0.05 and 0.075%. , the concentration of ascorbic acid esters ranging from 0.001 to 5% by weight, more preferably from 0.005 to 0.5% by weight, most preferably from 0.01 to 0.15% by weight, ascorbic acid concentration between 0.001 and 5% by weight, more preferably from 0.005 to 0% , Between 5% by weight, most preferably from 0.01 to 0.1% by weight, of sodium bisulphite or sodium metabisulphite, from 0.001 to 5% by weight, more preferably from 0.005 to 0.5% by weight, most preferably between 0.01 and 0.15% by weight, the concentration of thiourea between 0.0001 and 2% by weight, more preferably between 0.0005 and 0.2% by weight, most preferably between 0.001 and 0.01% by weight, most typically 0.005% cysteine concentrations between 0.01 and 5% by weight, more preferably between 0.05 and 2% by weight, most preferably between 0.1 and 1.0% by weight, most typically between 0.5% by weight and monothioglycerol concentrations 0 , Between 01 and 5 wt%, more preferably between 0.05 and 2 wt%, most preferably between 0.1 and 1.0 wt%, the concentration being most typically 0.5 wt%, the concentration of NDGA between 0.0005 and 2 wt% , more preferably between 0.001 and 0.2% by weight, most preferably 0.005 to 0.02% by weight, most typically 0.01% by weight, glutathione to 0.005% to 5%, more preferably 0.01 to 0.2% by weight most preferably between 0.05 and 0.2 most preferably 0.1% to 5%, more preferably 0.005 to 0.5%, most preferably 0.01 to 0.2%, most typically 0.05% to 0.5%, most preferably 0.05 to 0.5%, most preferably 0.01 to 0.2%, 0.975% by weight, the concentration of citric acid being between 0.001 and 5% by weight, more preferably between 0.005 and 3% by weight, most preferably between 0.01 and 0.2% by weight, most typically between 0.3 and 2% by weight.

In addition, it is preferred that said microbial agent is selected from the group consisting of lower alcohols, such as ethyl and isopropyl alcohol, chlorobutanol, benzyl alcohol, chlorobenzyl alcohol, dichlorobenzyl alcohol; hexachlorophene; phenolic compounds such as cresol, 4-chloro-m-cresol, p-chloro-m-xylenol, dichlorophen, hexachlorophen, povidone iodine; parabens, in particular alkyl paraben, such as methyl, ethyl, propyl or butyl paraben, benzyl paraben; acids such as sorbic acid, benzoic acid and its salts; quaternary ammonium compounds such as salts of ammonium such as benzalkonium salts, especially chlorides or bromides, cetrimonium salts such as bromide; phenoalecinium salts such as phenododecinium bromide, cetylpyridinium chloride, or the like; mercury (II) compounds such as phenyl mercury (II) acetate, borate, or nitrate, thiomers; chlorhexidine or gluconate; antibiotically active compounds of biological origin or mixtures thereof.

• · • ·

Preferably, the total concentration of the lower alcohols for ethyl, propyl, butyl or benzyl alcohol is up to 10% by weight, more preferably up to 5% by weight, most preferably 0.5 to 3% by weight, and 0.3 to 0 for chlorobutanol. In a 6 wt% range; in the range of from 0.05 to 0.2% by weight of parabens, in particular methyl paraben, and from 0.002 to 0.2% by weight for propyl paraben; the total concentration of sorbic acid in the range of 0.05 to 0.2% by weight and in the range of 0.1 to 0.5% by weight for benzoic acid; the total concentration of phenols, triclosan is in the range of 0.1-0.3% by weight, and the total concentration of chlorhexidine is in the range of 0.01-0.05% by weight.

It is preferred that the less soluble material among the aggregating agents is a lipid or lipid-like substance, in particular a polar lipid, while a more soluble substance in the suspending fluid that reduces the average elastic energy of the droplet has a surfactant or surfactant-like properties and / or a form of said lipid or lipid-like material which is similarly soluble as said surfactant or surfactant-like substance.

Preferably, the lipid or lipid-like substance is a lipid or lipoid from a biological source, or a suitable synthetic lipid, or any modification thereof, said lipid being preferably a pure phospholipid of the formula 12 -O--<

I r 2 -o- 2 ch oi 3 CH 2 -OPOR 3

I

Belongs to the class of OH where:

R1 and R2 are an aliphatic chain, typically a C10-C20 acyl or alkyl group, or a partially unsaturated fatty acid residue, in particular an oleoyl, palmitoyl, elaidoyl, linoleyl, linolenyl, linolenoyl, arachidoyl, vaccine, lauroyl, myristoyl, palmitoyl or stearoyl; and wherein R 3 is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C 1-4 alkyl, C 1 -C 5 alkyl, C 1-5, C 2-5 C-C-Cített-Cil alkyl, Cox-C,, carboxyl- and hydroxy-substituted alkyl, or C vagy-C carboxyl and amino substituted alkyl, inositol, sphingosine, or salts of said materials, said lipid further comprising glycerides, isoprenoid lipids, steroids, sterols or sterols, lipids containing sulfur or carbohydrates, or any other lipid forming double layers, particularly semi-protonated liquid fatty acids, said lipids selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylinosites, phosphatidic acids, phosphatidylserines, sphingomyelin or other sphingophospholipids, glycosphingolipids (including cerebrosides, ceramides, polyhexosides, sulfatides, sphingoplasmalogens), gangliosides and other glycolipids or synthetic lipids, in particular the corresponding sphingosine derivatives, or any other glycolipids, where two similar or different chains may be attached to the backbone via ester groups (such as diacyl) and dialkenoyl) or ether linkages to the backbone as in dialkyl lipids.

Preferably, the surfactant or surfactant-like substance is a non-ionic, zwitterionic, anionic or cationic surfactant, in particular a fatty acid or alcohol, an alkyl triis / methylammonium salt, an alkyl sulphate salt, a coke, deoxycholate, glycocholate, glycodoxyoxolate, taurodezoxycolate, taurocholate, etc., a monovalent salt, an acyl or alkanoyl dimethylaminoxide, in particular a dodecyldimethylaminoxide, an alkyl or alkanoyl N-methyl glucamide, N-alkyl-N, N-dimethylglycine, 3- (acyldimethylammonio) alkanesulfonate, N-acylsulphobetane, a polyethylene glycol octylphenyl ether, in particular nonaethylene glycol octylphenyl ether, a polyethylene acyl ether, especially nonaethylene dodecyl- ether, a polyethylene glycol isoacyl ether, especially octaethylene glycol isotridecyl ether, polyethylene acyl ether, especially octaethylene dodecyl ether, polyethylene glycol sorbitan acyl ester such as polyethylene glycol-20 monolaurate (Tween 20 ) or polyethylene glycol-20 zorbitan monooleate (Tween 80), polyhydroxyethylene acyl ether, especially polyhydroxyethylene lauryl, myristoyl, cetyl stearyl or oloyl ether such as polyhydroxyethylene 4 or 6 or 8 or 10 or 12- etc.,-lauryl ether (as in the Brij series), or in the appropriate ester such as polyhydroxyethylene 8stearate (Myrj 45), laurate or oleate, or polyethoxylated castor oil

40, a sorbitan monoalkylate (e.g., in Arlacel or Span), in particular sorbitan monolaurate, an acyl or alkanoyl N-methylglucamide, especially in decanoyl or dodecanoyl-N-methylglucamide, an alkyl sulfate ( salt), such as lauryl or oleoyl sulfate, sodium deoxycholate, sodium glycodoxoxolate, sodium oleate, sodium taurate, a fatty acid salt such as sodium elaidate, sodium linoleic acid, sodium laurate, a lysophospholipid such as n- octadecylene (= oleoyl) glycerylphosphatidic acid, phosphorylglycerol or phosphorylserine, η-acyl, e.g. - elaidoyl, vaccenyl lysophospholipid or a suitable short chain phospholipid, or a surfactant polypeptide.

According to a preferred embodiment of the invention, the average diameter of the penetrating material is between 30 nm and 500 nm, more preferably between 40 nm and 250 nm, more preferably between 50 nm and 200 nm and particularly preferably between 60 nm and 150 nm.

In another preferred embodiment of the invention, the total dry weight of the droplets in the composition is from 0.01 to 40% by weight, more preferably from 0.1 to 30% by weight and most preferably from 0.5 to 20% by weight of the composition.

According to the invention, it is advantageous to mix at least one edge-active or surfactant and / or at least one amphiphilic material and / or at least one hydrophilic liquid and the active ingredient, if necessary separately, to form a solution, then combining the (partial) blends or solutions obtained in order to produce, by mechanical energy, such as shaking, mixing, vibration, homogenization, ultrasonic, shear, freezing and thawing, or filtration at an appropriate propulsion pressure, to form the penetrating agents which bind to the active ingredient; / or include the active ingredient.

Preferably, the amphiphilic materials are in volatile solvents such as alcohols, especially ethanol, or other pharmaceutically acceptable organic solvents such as ethanol, 1 and 2-propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight 200-400 Da) or glycerol, in other pharmaceutically acceptable organic solvents, for example, in a refrigerated gas, particularly in supercritical CO2, which are then removed prior to final preparation, in particular by evaporation or dilution.

According to the invention, the formation of said penetrating material is preferably effected by the addition of the required materials to the fluid phase, by evaporation from the reverse phase, by injection or by dialysis, if necessary by mechanical constraints, such as shaking, mixing, especially high-speed mixing, vibration, homogenization, ultrasound, shear, freezing and releasing, or suitable, under particularly low (1 MPa) or medium (maximum 10 MPa) filtration pressure.

When the formation of said intruders is preferably effected by filtration, the filter material has a pore size of between 0.01 and 0.8, more preferably between 0.02 and 0.3, most preferably between 0.05 and 0.15. of which several filters can be used sequentially or in parallel.

According to the invention, said active ingredients and penetrating agents are preferably at least partially after formation of penetrating agents, for example, with a pharmaceutically acceptable liquid such as ethanol, 1 and 2-propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight 200-400 Da). ) or after injecting the active ingredient solution with glycerol into the suspending medium, simultaneously with the formation of the penetrating agent, if necessary, by the use of an auxiliary solution of the drug and at least some penetrating agents.

It is preferred that said penetrating agents with which the active ingredient is incorporated, if appropriate, are prepared immediately prior to use of the composition from a suitable concentrate or lyophilisate.

The composition according to the invention is preferably applied to the application area by spraying, lubrication, ball dispenser or sponge, in particular a dispenser, lubricant, ball device, sponge or non-sealed patch as appropriate.

It is preferred that the protective barrier is part of a mammal's body and / or a plant, preferably a skin and / or at least partially keratinized endothelium and / or nasal mucosa or any other mucosa.

The surface dose of said penetrating agent is preferably 0.1 mg / cm 2 to 40 mg / cm 2 , more preferably 0.25 mg / cm 2 to 30 mg / cm 2 , more preferably 0.5 mg / cm 2 and 15 mg / cm 2 when the penetrating agent is applied to the skin and / or at least partially keratinized in the interior.

The surface dose of said penetrating agent is preferably between 0.0001 mg / cm 2 and 0.1 mg / cm 2 , more preferably between 0.0005 mg / cm 2 and 0.05 mg / cm 2 , more preferably 0.001 mg / cm 2 and It is between 0.01 mg / cm 2 when the penetrating material is applied to plants, plant leaves or plant needles.

The surface dose of said penetrating agent is preferably between 0.05 mg / cm 2 and 20 mg / cm 2 , more preferably between 0.1 mg / cm 2 and 15 mg / cm 2 , more preferably 0.5 mg / cm 2 and 10 mg / cm 2 in the case where the penetrating agent is applied to the nasal mucosa and / or other mucosa.

In another preferred aspect of the invention, there is provided a kit comprising said composition in an amount that allows the composition to be used at the dose / area values selected as mentioned above.

In addition, it is preferred that the composition is contained in a bottle or any other packaging container.

The kit preferably comprises a device for administering the composition.

According to another aspect of the invention, there is provided a patch comprising an amount of the composition resulting in the aforementioned dose / area value. The patch or transdermal patch of the present invention is intended for use on a protective barrier, including the skin, mucosa or plants. The term "transdermal" should include these already mentioned barriers.

The patch preferably comprises: a non-occlusive backing;

··· ·· · · · · · · "· · · · · · · · · · · · · an inner liner where the backsheet and inner liner define a storage part;

and / or a matrix layer.

It is preferred that said non-occluding backsheet shows an average vapor transmission rate (MVTR) higher than 1000 g / m 2 , preferably greater than 5000 g / m 2 , more preferably 10,000 g / m 2 . Preferably, the non-occluding backsheet has pores smaller than 100 nm, preferably pores less than 70 nm, more preferably pores less than 30 nm, most preferably with large pores such as the distance between the inner molecules of the backsheet material. In a further preferred embodiment, the non-occluding backsheet is a polyurethane membrane, preferably a banded porous polyester membrane, more preferably a banded porous polycarbonate membrane, most preferably a microporous polyethylene membrane.

The inner liner and / or matrix layer of the present invention forms the skin connection. Preferably, the inner liner prevents unwanted release of the composition from the patch during storage, and allows rapid wetting of the skin when in contact with the skin. According to the invention, it is also preferred that the inner liner comprises a homogeneous membrane, preferably a banded porous polyester membrane or a banded porous polycarbonate membrane. In addition, such inner lining membranes preferably have a maximum pore density of 5%, preferably a maximum of 15%, more preferably a maximum of 25%, more preferably greater than 25%, and / or between 20 nm and 200 nm, preferably between 50 nm and 140 nm, most preferably 80 nm and They have a pore size of 120 nm.

Further preferred liner materials include a hydrophobic mesh membrane and / or non-woven wool with openings made with hydrophobic fibers. In another preferred embodiment, the inner liner is a microporous polyethylene membrane having an average pore diameter of between 50 nm and 3000 nm, preferably between 500 nm and 2000 nm, most preferably about 1500 nm.

According to a further preferred embodiment of the invention, the patch comprises a pressure sensitive adhesive layer, preferably an adhesive layer consisting of a polyacrylate, a polyisobutylene, a silicone, an ethylene vinyl acetate copolymer, a polyvinylpyrrolidone or a polyethylene oxide hydrogel.

According to another preferred embodiment of the invention, the composition comprises penetrating agents having an average diameter of less than 150 nm, preferably less than 100 nm. It is further preferred that the total dry weight of the drops in the composition is at least 5%, preferably 7.5% to 30%, more preferably 10% to 20%.

The patch according to the invention preferably comprises a composition wherein the viscosity of the composition is at most 200 mPas, more preferably 40 mPas, most preferably 8 mPas.

The drug release membrane has a surface of between 0.5 cm 2 and 250 cm 2 , more preferably between 1 cm 2 and 100 cm 2 , more preferably between 2 cm 2 and 50 cm 2 , most preferably between 4 cm 2 and 25 cm 2 .

In a particularly preferred embodiment, it is preferred that the patch comprises one or more additional layers of layers comprising a desiccant, matrix layers, foam layers, and / or protective layers.

It has been found that the use of a backsheet is preferred, which is capable of promoting the evaporation of the suspending medium of the transfersomes. According to the invention, they are preferably higher than 1000 g / m 2 or even better than the average vapor transmission rate (MVTR) of more than 10000 g / m 2 . The disappearance of the solvent at a sufficiently high rate through such barrier barriers contributes to the formation and maintenance of an activity gradient that passes through the flow of the transferant aggregates through the protective mat.

Suitable backs according to the invention are polyurethane membranes, such as CoTran 9701 (3M Medica, Borken, Germany), Tegaderm (3M Medica, Borken, Germany), Arcare 8311 (Adhesive Research, Limerick, Ireland), IV3000 (Smith and Nephew). Even more suitable are banded porous polyester membranes (10 nm pore size) (Osmonics, Minnetonka, USA) and banded porous polycarbonate membranes (10 nm pore size) (Osmonics, Minnetonka, USA). The most suitable are microporous polyethylene membranes such as Cotran 9711 (3M Medica, Borken, Germany), 14P01A, • · · · · ···· · · · · · · · · · · · «

10Ρ05Α, 8Ρ07Α, Ε011 D (DSM Solutech, Heerlen, The Netherlands). In the classical TTS known in the art, the latter materials are often used for rate-controlling membranes.

The said backsheet should be fluid-tight to prevent loss of, for example, the transdermal drug. In order to ascertain whether or not the membrane is fluid-tight, we measure the transmittance through the membranes using low hydrostatic pressures. Cotran 9711 (3M Medica, Borken, Germany) and the 14P01A polyethylene membrane are liquid sealant up to a pressure of 1 MPa. Furthermore, all the polyurethane membranes applied are fluid-tight.

Another important feature of the patch according to the invention is the use of the inner liner membrane instead of the conventional rate controlling membranes, which allow rapid skin wetting with the transdermal composition, while preventing the (undesirable) release of the composition during storage or application of the device to the skin. Because the invention is directed specifically at transfusion-containing patches, the term "rate-controlling membrane is misleading because the rate of transfusion mediated material transfer is ideally controlled by water activity in the biological barrier and barrier. Thus, the term "inner lining" is used herein instead of "speed control membrane".

An inner liner membrane according to the present invention is a homogeneous membrane having a high pore density. Passage through pores depends on the ratio of the lipid / surface tension / surface tension of the lipid slurry, P m in = 2 σ cos Θ / r, where P min denotes the minimum pressure required to overcome the Laplace pressure, the suspension-air interface surface tension (~ 30mN / m), θ the inclination angle of the preparation on the membrane material and the pore radius (-100 nm). Accordingly, cos θ <0 is required to maintain the composition in pores, which means that the membrane must be hydrophobic. According to this, it is assumed that a 0.6 MPa Laplace pressure is required to move the air suspension interface through the pore, allowing the suspension to pass through the barrier.

Suitable inner liner membrane materials according to the present invention are banded porous polyester membranes (100 nm pore size) (Infiltec, Speyer, Germany) and banded porous polycarbonate membranes (100 nm pore size) (Infiltec, Speyer, Germany).

Additionally, hydrophobic mesh membranes such as Fluortex 09/70/22, Fluortex 09/85/27 (INFILTEC, Speyer) and non-woven wools, such as Parafil R20, Parafil RK 20, Parafil R30 Natural, Parafil RK 30, Paratherm PR 220/18, Paratherm PR 220/20 (LTS, Andernach, Germany) is recommended. These sieve materials correspond well to the patches according to the invention as an inner liner.

The said liners form mesh openings formed from hydrophobic fibers. These prevent transfersomes from passing through when the lining does not come into contact with the skin. The air / water or air / transfusion suspension interface provides a high y contact angle for the hydrophobic surface of the fiber. The mesh openings allow the transferers to pass through the lining when in contact with the skin. This is caused by the energy obtained by wetting the hydrophilic or less hydrophobic surface (e.g., the skin), which exceeds the surface energy required for the complete wetting of the fibers.

Specifically, said "power-on effect" can be explained as follows. Let be the distance between the centers of two threads. Let it be a ray of thread:

π rz Ywt = zdy ws

The surface tension of the water on the skin is y ws = 40 mN / m "Transdermal and Drug Delivery Systems", Buffalo Frove, Interpharm Press, Ghosh, Pfister et al. 1997 publication. The surface tension of the water on the hydrophobic fiber is Ywt = 70 mN / m. (The surface tension of the suspension on the skin is also y ws = 40 mN / m, the surface tension of the suspension on the hydrophobic strand γ = 35 mN / m, due to the presence of a monomolecular detergent layer). By reordering the previous formula, we get the following equation: · · · 9 · · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · suspension for the suspension (y ^ ~ y ws ). This suggests that the ratio of fiber radius to pore diameter should preferably be in the range of about 0.3.

According to the invention, the use of microporous polyethylene membranes as an inner liner is particularly preferred. The term "microporous" as used herein means a pore size of at least 20 nm, preferably 50 nm to 3000 nm. Examples of these are Solupor - E011 D (average pore size 1500 nm), Solupor 8P07A (mean pore size 700 nm) and Solupor - 10P05A (mean pore size 500 nm) (DSM Solutech, Heerlen, The Netherlands), showing high permeability at low pressures, thus exposing to allow transfersomes to moisturize the skin upon contact.

For all of the above-mentioned inner liner membranes, the surface tension, σ, and the contact angle, y, will change when in contact with the skin. There are various factors that can cause changes in surface tension, σ, and contact angle, y. One factor may be the increase in moisture and the capillary condensation of transepidermally released water. Hydrophilic bridge formation resulting from the interaction between corneocytes / hair follicles and the inner membrane can also contribute to rapid skin moisturizing. Finally, the hydrophilization of the pore nucleus impurities, such as microscopic skin fragments, can modify the surface tension, σ, and the contact angle, y. As a consequence, the minimum P m in pressure required to overcome the Laplace pressure is reduced, and the composition can pass through the inner liner and dampen the skin surface.

The patches of the invention can be prepared by a number of known methods. Laying (laminating) of the backsheet and the inner lining can generally be carried out by thermal coating or by adhesive coating or by any other known layering process.

In the thermal lamination processes, the liners are glued by melting at least one material at elevated temperatures and under increased pressure for a short period of time. The melt (s) merge and coalesce during cooling and solidification. The temperature and pressure are applied either in pulses, such as microwave radiation or continuously heated metal scraper. Polyethylene and polyurethane membranes are generally thermally layered at 120-20CTC, preferably 140-160 ° C and 100-600 kPa, preferably 300-400 kPa. Good layer properties are achieved by using a pressure of 400 kPa for transfersome-containing patches for about 0.1-5 seconds, preferably about 1-2 seconds.

The adhesive coating of the liners is achieved by a pressure-sensitive adhesive layer, such as polyacrylate, polyisobutylene, silicone, ethylene-vinyl acetate copolymer, or polyvinylpyrrolidone and polyethylene oxide hydrogel adhesive (PVP / PEO). The adhesive liner is pre-cut to a suitable shape, such as a 1 cm concentric ring. The backsheet and the inner liner are layered on the ring and the patch is cut out of the net. Suitable films include, for example, pressure sensitive, transportable films (Arcare 7396), elastic plastic film coated on both sides by a medically pure pressure-sensitive adhesive (Arcare 8570 pure polyester) or on both sides by a pressure-sensitive acrylate adhesive (Polyolefin 3M 1777; 3M 1779; 3M 9751, polyvinyl chloride 3M 9772L). The latter example encapsulates a volume of a given volume due to the defined thickness of the foam strip, while the previous two examples determine the volume of the trans-tension by the elasticity and / or the hidden area of the liners.

The filling of the patch according to the invention with a single compartment part can be carried out by a number of known methods.

One possible upload process is based on a two-step layering process. In the first step, the main body is layered while maintaining a small opening. Through this opening, a tap or a tube is formed and injected into the preformed storage portion of the transfection today. After retracting the tap or tube, complete the layering of the hole. Thermal layering as well as adhesive layering can also be used in said process. In the case of thermal layering, the hotplate layeres a C-shaped ring. After filling the inner part of the AC, the hotplate is rotated by 45 °, and the thermal layering is repeated a second time, now closing the open portion of C. In the case of adhesive layering, the release liner of the conveyor belt is not completely removed, thus enabling the filling opening to be made. After filling, the remainder of the release liner is removed and the opening is sealed. Folding the back cover and / or the inner liner • • • · leads to a similar result: a collar-like opening is formed which is closed by refolding the membranes after the filling process.

Techniques related to design, topping and sealing are well known and can be used to produce patches according to the invention. In the first step, the backsheet film is placed over a desired dimension of the recess. The sheet absorbs this shape in a vacuum and lugs the recess. A tap is then loaded into the recess of the transdermal composition. After retracting the pin, the inner liner membrane is applied to the web. A concentric sealing ring laminates both films either by heat or by adhesive lamination as described above.

In a further process for preparing TTS, the transdermal composition is injected through a pre-positioned tube following the lamination process. The tube is inserted from the side into the foam in a similar manner to the venous catheter set for continuous injection. The tube is connected to a syringe filled with a transdermal preparation through a luer-lock connector. The desired amount of preparation is injected into the container and the tube is removed and / or sealed if necessary.

In another important aspect of the invention, there is provided a patch which is also characterized in that the patch comprises at least two compartments separated from each other during storage. According to another aspect of the invention, there is provided a patch comprising the composition in an amount such that the aforesaid unit dose is obtained, wherein the patch comprises a plurality of, preferably less than 5, more preferably less than 3, most preferably two separate internal compartments. which are combined before or during the application of the preparation. Preferably, at least one compartment is located inside and / or outside the patch.

It is preferred that the composition and / or the individual components and / or active ingredient and / or the suspension / dispersion of the active ingredient and / or the penetrating agent are kept in the storage compartment in a plurality of, preferably less than 5, more preferably 3, most preferably 2, separate compartments. in this case, the patch is applied before or during application or after application.

In another preferred embodiment, the outer compartments comprise injection systems, preferably syringes, which are associated with the patch portion of the patch. Preferably, the compartments are vertically and / or side by side and / or one compartment comprises a second compartment, preferably without being secured to the second compartment.

Preferably, the compartments are located within the container portion defined by the backsheet and the inner liner. It is further preferred that the compartments are separated by an adjustable opening barrier, preferably a membrane and / or a seal and / or a compartment forming layer.

According to the invention, combining and mixing the components of the compartments is achieved by direct mechanical action, such as pressure, abrasion, kneading, twisting, tearing and / or indirectly by altering the temperature, osmotic pressure or electrical potential to remove or destroy the separating barrier ( s) are.

In a further preferred embodiment of the invention, the patch comprises:

a non-occluding backsheet according to the invention, a reservoir defining membrane divided into at least two compartments, wherein the composition is in direct contact with the skin when the composition is released from the container or compartments.

The multi-compartment storage type patch of the present invention comprises at least two separate compartments and a mixing compartment, wherein the mixing compartment may be a storage compartment containing an ingredient or composition of the composition, or a compartment that is not filled during storage.

According to the invention, the storage compartments containing the critical components can be separated from the mixer compartment. The storage compartments contain some, if not all, components during storage after preparation and prior to use. The mixer compartment serves to mix the separated components • after storage. After mixing, the composition is released from the mixing chamber to the skin. The mixing chamber may have an adjustable skin contact surface to allow surface dose control. This can be done by combining smaller subunits of the mixer compartments.

The mixer should be in contact with the skin. This is achieved as follows:

1. direct contact with the skin (no inner lining membrane) or

2. an inner liner of the invention by means of a membrane. Reference is made to the one-compartment patch described above. The same inner liner membranes can be used for multi-compartmental TTS.

The number of storage compartments can be at least two, and their number depends on how incompatible the components are for a long time.

Storage compartments may be part of the patch and may be made of the same material (s). The storage compartment, in the simplest case, may be two syringes comprising the liquid components which are injected successively or simultaneously into the mixing chamber via one or more tubes. The twin syringe, to which two pistons are attached, facilitates simultaneous injection and the consistency of the proportion of ingredients. An additional tube with ideal microbes, as used in HPLC sample preparation, can cause turbulence in the mixed fluid. Similarly, a T-shaped switch with an ideal turbulence chamber works. Thus, optimal mixing of the components is achieved even at high viscosities and high lipid concentrations.

The mixing compartment according to the invention may be a separate compartment, which is empty during storage, but at the same time fills up when the patch is applied to the skin, or may be one of the existing storage compartments in which other ingredients are added from other storage compartments or may be formed by combining two or more storage compartments.

Combining or mixing the ingredients can be achieved by perforating or destroying the diaphragm separating membranes. This can be accomplished, for example, by pressing or kneading the patch, this mechanical constraint causes the diaphragm separating membranes to burst, or by actuating an inner or outer activation of a sharp object, such as a needle, to puncture the aperture separating membrane.

Another way of combining or mixing the components is based on opening a pipe system between compartments. For example, said opening can be achieved by pressing or kneading the patch so that the seal or plug sealing the tubes between the separated compartments during storage is released from the tubes due to the pressure applied.

According to the invention, it is also possible that the layering, which forms the separate storage compartments, is united by opening and mixing the components. This can be done, for example, by applying a small but uniform pressure on the filled storage chambers, but can also be carried out by thermal stratification or by adhesive coating. The stratification of the diaphragm-forming membranes opens and the liquids are pressed into the mixing compartment through the self-formed channels.

The storage and mixing compartments can be stacked vertically or placed side by side. For example, three membranes may be layered by attaching half of the middle membrane to the lower membrane (e.g., inner liner) and the other half to the upper membrane (backsheet). The upper and lower membranes are welded at the edge of the right, left, bent and backwardly bent portions to form a two-compartment pouch. The middle membrane can be impermeable to liquids, but it is easy to crack. Suitable materials for the middle membranes include thin polyurethanes. In one embodiment, in the case of a transfersome composition, the reservoir may be the left-closure fluid compartment, while the transfersome release is effected from the right ventricle through the inner liner membrane of the invention when in contact with the skin. For example, the right ventricle may serve as a storage compartment (lyophilized) for the active ingredient (s). It will be appreciated by those skilled in the art that combinations of the above-mentioned embodiments, such as the combination of vertical stacking and adjacent arrangement, are also suitable for the purposes of the invention.

After the mixing process in the mixer compartment, the empty storage compartments are unnecessary. The compartments can be pulled out (for internal compartments such as • syringes) or removed. For example, the tubes can be detached and the openings can be sealed with tape or seals or plugs. Open seals can be layered again by applying pressure.

In another important aspect of the present invention, there is provided a method for administering the active ingredient to a mammalian body or plant, wherein said active ingredient is delivered to a protective barrier, wherein the protective barrier is an intact skin, mucosa and / or upper epithelial layer of said body or plant and said active ingredient is a drug. is bound to an penetrating material which is capable of transporting the active substance through the pores or through the passages of the mucosal or upper epithelium, or is capable of permeating the active ingredient through the pores after the said penetrating material has been opened and / or entered into said pores includes the following steps:

preparing a composition such that said penetrating agents are suspended or dispersed in a polar liquid in the form of liquid droplets surrounded by a multilayer membrane-like coating, wherein said coating comprises at least two types or forms of amphiphilic materials that are susceptible to aggregation, provided that said coating is present. at least two substances differ by at least one factor 10 in solubility in said polar liquid and / or in the preferred average diameter of said materials when they are in the form of homo aggregates (for the more soluble material) or hetero aggregates (for any combination of both) , less than the diameter of only the less soluble substance homo aggregates, and / or the more soluble material tends to make the droplet soluble and the amount of such material is up to 99 mol% of the dissolution concentrate or up to 99 mol% of saturation concentration in the non-solubilized droplet, whichever is higher;

and / or the presence of the more soluble material reduces the average elastic energy of the membrane-like coating to at least one-fifth, preferably one-tenth, most preferably more than one-tenth, than the elastic energy of red blood cells or phospholipid bilayers having liquid aliphatic chains,

said penetrating agents are capable of transporting the active ingredients through the pores of said protective barrier or facilitating the penetration of the drug through the pores of the skin after penetration of the penetrating pores into the pores of a predetermined area of said barrier to control the flow of intruders through the barrier of penetration. and applying the selected dosage amount of the composition containing the intruders to the porous barrier area.

It is preferable to increase the flow of intruders through the barrier by increasing the applied dose amount of the penetrating material.

The pH of the composition is preferably selected between 3 and 10, more preferably between 4 and 9, and most preferably between 5 and 8.

In this approach of the invention, it is preferred that the composition comprises:

at least one thickening agent in an amount that raises the viscosity of the composition to a maximum of 5 kN s / m 2 , preferably 1 kN s / m 2 , and most preferably 0.2 kN s / m 2 , to spread the composition, and allowing retention of the drug in the application area and / or at least one antioxidant in an amount that reduces the increase of the oxidation index by less than 100% in 6 months, more preferably less than 100% in 12 months and most preferably less than 50% in 12 months and / or at least one antimicrobial agent in an amount that reduces the amount of 1 million germ bacteria added to less than 100 aerobic bacteria in 4 days, based on 1 g of the total weight of the preparation reduces to less than 10 in Enterobacteriaceae and reduces Pseudomonas aeruginosa or Staphylococcus aure to less than 1 us.

In addition, it is preferred that said at least one microbial agent be added to the composition in an amount of less than 1 million germs per gram of added total weight of the composition, less than 100 days, less than 100 days, less than 1 day. less than 10 for enterobacteria and less than 1 for Pseudomonas aeruginosa or Staphylococcus aureus.

The thickener is preferably selected from the group consisting of pharmaceutically acceptable hydrophilic polymers, such as partially etherified cellulose derivatives such as carboxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropylmethyl or methylcellulose; fully synthetic hydrophilic polymers such as polyacrylates, polymethacrylates, poly (hydroxyethyl), poly (hydroxypropyl), poly (hydroxypropylmethyl) methacrylates, polyacrylonitriles, metallylsulfonates, polyethylenes, polyoxyethylenes , polyethylene glycols, polyethylene glycol lactides, polyethylene glycol diacrylates, polyvinylpyrrolidones, polyvinyl alcohols, poly (propyl methacrylamides), poly (propylene fumarate-co-ethylene glycols), polyoxyamines, polyaspartamides, hydrazine cross-linked hyaluronic acids silicones; natural gums such as alginates, carrageenans, guar gums, gelatins, tragacanth, amidites, pectins, xanthanes, chitosan collagen, agarose; mixtures thereof and further derivatives or copolymers thereof and / or other pharmaceutically or at least biologically acceptable polymers.

The concentration of the polymer is preferably in the range of 0.01% to 10% by weight, more preferably in the range of 0.1% to 5%, more preferably in the range of 0.25% to 3.5% by weight, and most preferably Selected from 0.5% to 2% by weight.

According to the invention, it is preferred that said antioxidant is a synthetic phenolic antioxidant such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and di-tert-butylphenol (LY178002, LY256548, HWA-131, BF- 389, CI-986, PD127443, E-5119, BI-L-239XX, etc.), tert-butyl hydroquinone (TBHQ), propyl gallate (PG), 1-O-hexyl-2,3,5-trimethyl -hydroquinone (HTHQ); aromatic amines (e.g., diphenylamine, p-alkylthio-o-anisidine, ethylenediamine derivatives, carbazole, tetrahydroindenoindole); phenols and phenolic acids (e.g., guaiacol, hydroquinone, vanillin, gallic acids and their esters, protocol acid, quinic acid, siring acid, ellagic acid, salicylic acid, nordihydrogen acid (NDGA), eugenol); tocopherols (including tocopherols (alpha, beta, gamma, delta) and derivatives thereof, such as tocopheryl acylate (e.g., acetate, laurate, myristate, palmitate, ololeol, linoleic, etc., or any other suitable tocopheryl lipoate), tocopheryl POE succinate; trolox and the corresponding amide and thiocarboxamide analogs; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6) -o-alkyl-ascorbic acid, ascorbyl esters ( for example, 6-o-lauroyl, myristoyl, palmitoyl, oleoyl or linoleoyl-L-ascorbic acid, etc.); non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, diclofenac, mefenamic acid, flufenamic acid, phenylbutazone, oxyphenebutazone acetylsalicylic acid, naproxen, diflunisal, ibuprofen, ketoprofen, piroxicam, penicillamine, penicillamine disulfide, primacvin, quinine, chloroquine, hydroxychloroquine, azathioprine, phenobarbital, acetaminophen; aminosalicylic acids and their derivatives; for example am iodarone, aprindin, azajnol), ambroxol, tamoxifen, b-hydroxytamoxifene; calcium antagonists (e.g., nifedipine, nizoldipine, nimodipine, nicardipine, nilvadipine), beta-receptor blockers (e.g., atenolol, propranolol, nebivolol); sodium bisulfite, sodium metabisulphite, thiourea; chelating agents such as EDTA, GDTA, desferrals; endogenous protection systems such as transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion, hemopexin, albumin, glucose, ubiquinol-10; enzymatic antioxidants such as superoxide dismutase and metal complexes of similar activity, including catalase, glutathione peroxidase and less complex molecules such as beta-carotene, bilirubin, uric acid; flavonoids (e.g., favones, flavonols, flavonons, flavanones, chakons, anthocyanins), N-acetylcysteine, mezna, glutathione, thiohistidine derivatives, triazoles; tannins, cinnamic acid, hydroxycinnamate acids and their esters (e.g., co-acids and esters, coffee acid and esters, ferulic acid, (iso) chlorogenic acid, synapse); spice extracts (for example, cloves, cinnamon, sage, rosemary, nutmeg, oregano, allspice, nutmeg); carnosic acid, carnosol, carzolic acid; rosemary acid, rosemary diphenol, gentic acid, ferulic acid; oatmeal extracts such as avenanthramide 1 and 2; thioethers, dithioethers, sulfoxides, tetralkylthiuram disulfides; phytic acid, steroid derivatives (e.g. U74006F); tryptophan metabolites (e.g., 3-hydroxyquinurenine, 3-hydroxy-anthranilic acid) and organic chalcogenides or an oxidation suppressing enzyme.

In addition, it is preferred that the concentration of BHA or BHT is between 0.001 and 2% by weight, more preferably between 0.0025 and 0.2% by weight, and most preferably between 0.005 and 0.02% by weight, the concentration of TBHQ and PG is between 0.001 and 2% by weight. , more preferably between 0.005 and 0.2% by weight, and most preferably between 0.01 and 0.02

·

the concentration of tocopherols between 0.005 and 5% by weight, more preferably between 0.01 and 0.5% by weight, and most preferably between 0.05 and 0.075% by weight, the concentration of ascorbic acid esters ranging from 0.001 to 5% by weight, more preferably Between 0.005 and 0.5% by weight, and most preferably between 0.01 and 0.15% by weight, the ascorbic acid concentration between 0.001 and 5% by weight, more preferably between 0.005 and 0.5% by weight, and most preferably between 0.01 and 0%, The concentration of sodium bisulphite or sodium metabisulphite between 0.001 and 5% by weight, more preferably between 0.005 and 0.5% by weight, and most preferably between 0.01 and 0.15% by weight, the concentration of thiourea is 0.0001 and between 2% by weight, more preferably between 0.0005 and 0.2% by weight, and most preferably between 0.001 and 0.01% by weight, most typically 0.005% by weight, with a cysteine concentration between 0.01 and 5%, more preferably 0.05% and between 2% by weight and most preferably from 0.1% by weight to 1.0% by weight, most typically from 0.5% by weight, to the concentration of monothioglycerol in the range of 0.01 to 5% by weight, more preferably in the range of 0.05 to 2% by weight, and most preferably between 0.1 and 1.0% by weight, most typically 0.5%, NDGA concentration between 0.0005 and 2%, more preferably between 0.001 and 0.2%, and most preferably 0.005 and 0.02% , most preferably 0.01% by weight, glutathione concentration from 0.005 to 5% by weight, more preferably from 0.01 to 0.2% by weight and most preferably from 0.05 to 0.2% by weight, most typically 0.1% by weight %, EDTA concentrations between 0.001 and 5% by weight, more preferably between 0.005 and 0.5% by weight, and most preferably between 0.01 and 0.2% by weight, most typically between 0.05 and 0.975% by weight, citric acid concentration is 0.001 and 5% by weight, more preferably 0.005% to 3% by weight; and most preferably between 0.01 and 0.2% by weight, most typically between 0.3 and 2% by weight.

Preferably, the microbial agent is selected from the group consisting of lower alcohols such as ethyl and isopropyl alcohol, chlorobutanol, benzyl alcohol, chlorobenzyl alcohol, dichlorobenzyl alcohol; hexachlorophene; phenolic compounds such as cresol, 4-chloro-m-cresol, p-chloro-m-xylenol, dichlorophen, hexachlorophen, povidone iodine; parabens, in particular alkyl parabens, such as methyl, ethyl, propyl or butyl paraben, benzylparaben; acids such as sorbic acid, benzoic acid and its salts; quaternary ammonium41 compounds, such as, for example, ammonium salts such as benzalkonium salts, especially chlorides or bromides, cetrimonium salts such as bromide; phenalkecinium salts such as phenododecinium bromide, cetylpyridinium chloride or the like; mercury (II) compounds, such as phenyl mercury (II) acetate, borate or nitrate, thiomersal; chlorhexidine or gluconate; antibiotically active compounds of biological origin or mixtures thereof.

In addition, it is preferred that the total concentration of the lower alcohols for ethyl, propyl, butyl or benzyl alcohol is up to 10% by weight, more preferably not more than 5% by weight, most preferably between 0.5 and 3% by weight, and 0.3 for chlorobutanol. and in the range of 0.6% by weight; in the range of from 0.05 to 0.2% by weight of parabens, especially methyl paraben, and from 0.002 to 0.2% by weight of propyl paraben; the total concentration of sorbic acid in the range of 0.05 to 0.2% by weight and in the range of 0.1 to 0.5% by weight for benzoic acid; the total concentration of phenols, triclosan ranges from 0.1 to 0.3% by weight, and the total concentration of chlorhexidine ranges from 0.01 to 0.05% by weight.

It is further preferred that the less soluble material among the aggregating materials is a lipid or lipid-like substance, in particular a polar lipid, while a more soluble substance in the suspending fluid that reduces the average elastic energy of the droplet has a surfactant or surfactant properties and / or or a form of said lipid or lipid-like material which is similarly soluble as said surfactant or surfactant.

Preferably, the lipid or lipid-like substance is a lipid or lipoid from a biological source or a suitable synthetic lipid or any of its modifications, said lipid being preferably a class of pure phospholipids having the general formula:

'CH.-OR,

I

R 2 -O- 2 CH O * II 3 CH 2 -OPOR 3

I

OH wherein R and R 2 is an aliphatic chain, typically a C10-20 acyl, or -alkyl or partly unsaturated fatty acid residue, in particular, an oleoyl, palmitoelil-, elaidoil-, linoleyl, linolenyl, linolenoyl arachidoil- , vaccinyl, lauroyl, myristoyl, palmitoyl or stearoyl; and R 3 is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C 1-4 -alkyl, C 1-5 -carboxyl-substituted alkyl, C 2-5 -hydroxy-substituted alkyl , C2-C5 carboxyl and hydroxy substituted alkyl or C2-5 carboxyl and amino substituted alkyl, inositol, sphingosine, or salts of said materials, said lipid also includes glycerides, isoprenoid lipids, steroids, sterols or sterols, sulfur and carbohydrate-containing lipids, or any other double-layered lipid, particularly semi-protonated liquid fatty acids, said lipid selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylinosites, phosphatidic acids, phosphatidylserines, sphingomyelin or other sphingophospholipids, glycosphingolipids (including cerebellar) ceramides and other glycolipids or synthetic lipids, in particular the corresponding sphingosine derivatives, or any other glycolipids, from which two identical or different chains may be attached via ester groups to the skeleton (as well as diacyl and diacyl). dialkenoyl) or ether linkages to the skeleton as in dialkyl lipids.

Preferably, the surfactant or surfactant is a nonionic, twin ionic, anionic or cationic surfactant, in particular a fatty acid or fatty alcohol, an alkyl triis / methylammonium salt, an alkyl sulfate salt, and a monobasic salt. salt, deoxycholate, glycocholate, glycodezoxycolate, taurodezoxolate, taurocholate, etc., an acyl or alkanoyl dimethylaminoxide, especially a dodecyldimethylaminoxide, alkyl or alkanoyl N-methyl glucamide, N-alkyl-N, N- dimethylglycine, 3 (acyldimethylammonio) alkanesulfonate, N-acylsulfobetane, polyethylene glycol octylphenyl ether, in particular nonaethylene glycol octylphenyl ether, polyethylene acyl ether, especially nonaethylene dodecyl ether, polyethylene glycol isoacyl ether, especially octaethyleneglycol isotridecyl ether, polyethylene acyl ether, especially octaethylene dodecyl ether, polyethylene glycol sorbitan acyl ester such as polyethylene glycol -20-monolaurate (Tween 20) or polyethylene-g lycol 20-sorbitan monooleate (Tween 80), polyhydroxyethylene acyl ether, especially polyhydroxyethylene lauryl, myristoyl, cetyl stearyl or oloyl ether, such as polyhydroxyethylene 4 or 6; 8 or 10 or 12, etc., lauryl ether (as in the Brij series) or in the appropriate ester such as polyhydroxyethylene-8-stearate (Myrj 45), laurate or oleate, or polyethoxylated castor oil 40- , a sorbitan monoalkylate (e.g., in Arlacel or Span), in particular sorbitan monolaurate, an acyl or alkanoyl N-methylglucamide, in particular decanoyl or dodecanoyl-N-methylglucamide, an alkyl sulfate (salt) ), for example, in lauryl or oleyl sulfate, sodium deoxycholate, sodium glycodoxoxolate, sodium oleate, sodium taurate, fatty acid salt such as sodium elaidate, sodium linoleide, sodium laurate, a lysophospholipid such as n-octadecylene ( = oleoyl) glycerophosphatidic acid, - phosphoryl glycerol or phosphoryl serine ; or a surfactant polypeptide.

The average diameter of the penetrating material is preferably between 30 nm and 500 nm, more preferably between 40 nm and 250 nm, more preferably between 50 nm and 200 nm, and particularly preferably between 60 nm and 150 nm.

The total dry weight of the droplets in the composition is preferably selected from 0.01 to 40%, more preferably from 0.1 to 30%, most preferably from 0.520% by weight of the total composition.

Preferably at least one flange-active substance or surfactant and / or at least one amphiphilic material and / or at least one hydrophilic fluid and the active ingredient are mixed together, if necessary, to form a solution, the resulting (partial) mixtures or solutions are then interleaved. combining the formation of penetrating materials, preferably by mechanical energy, such as shaking, mixing, vibrating, homogenizing, ultrasonic, shearing, freezing and melting, or filtering, to form the penetrating material which binds to the active ingredient and / or encapsulates the active ingredient. .

It is further preferred that said amphiphilic materials are then in volatile solvents such as alcohols, especially ethanol, or other pharmaceutically acceptable organic solvents such as ethanol, 1 and 2 propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight 200-400 Da) or in glycerol, other pharmaceutically acceptable organic solvents such as supercooled gas, especially supercritical Cet, which are then removed prior to final preparation, in particular by evaporation or dilution.

The formation of said penetrating materials is then preferably effected by the addition of the required materials to the fluid phase, by evaporation from the inverted phase, by injection or by dialysis, if necessary by mechanical constraints, such as shaking, mixing, especially high-speed mixing, vibration, homogenization, ultrasound, shear, freezing and melting, or suitable, especially under low (1 MPa) or medium (maximum 10 MPa) filtration.

In addition, it is preferred that the formation of said penetrating agents be effected by filtration, wherein the filter material is between 0.01 and 0.8, more preferably between 0.02 and 0.3, and most preferably between 0.05 and 0.15. has a pore size, of which several filters can be used in sequence or in parallel.

Said active ingredients and penetrating agents are prepared, at least in part, after the formation of penetrating agents, for example, with a pharmaceutically acceptable liquid such as ethanol, 1-propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight: 200-400 Da) or glycerol. after injecting the active ingredient solution into the suspending medium, simultaneously with the formation of the penetrating agent, if necessary with the aid of the active ingredient and at least some penetrating constituents.

In addition, it is preferred that said penetrating agents with which the active compound is incorporated are prepared immediately prior to use, if appropriate, from a suitable concentrate or lyophilisate.

According to this, the composition is applied by spraying, lubrication, ball bearing or sponge application in the field of application, in particular a dispenser, lubricant, ball, sponge or non-sealed patch, as appropriate.

It is further preferred that the protective barrier is the skin and / or the at least partially keratinized endothelium and / or the nose or any other mucosa.

The surface dose of said penetrating agent is preferably 0.1 mg / cm 2 to 40 mg / cm 2 , more preferably 0.25 mg / cm 2 to 30 mg / cm 2 , and more preferably 0.5 mg / cm 2 to 15 mg / cm 2 when the penetrating agent is applied to the skin and / or to said at least partially keratinized interior.

The surface dose of said penetrating agent is preferably between 0.05 mg / cm 2 and 20 mg / cm 2 , more preferably between 0.1 mg / cm 2 and 15 mg / cm 2 , and more preferably between 0.5 mg / cm 2 and 10 mg. / cm 2 in the case where the penetrating agent is applied to the nose or other mucosa.

The surface dose of said penetrating agent is preferably between 0.0001 mg / cm 2 and 0.1 mg / cm 2 , more preferably between 0.0005 mg / cm 2 and 0.05 mg / cm 2 , and more preferably 0.001 mg / cm 2 and It is between 0.01 mg / cm 2 when the penetrating material is applied to the plant, plant leaves or plant leaves.

It is preferred that the method be used to vaccinate an immune response by administering said mammal to a human or other mammal.

It is preferred that the method be used to produce a therapeutic effect in a human or other mammal.

According to the invention, the above-mentioned method is preferably used for the treatment of the following diseases: inflammatory diseases, skin disorders, kidney and liver failure, bronze age, aspiration symptom group, Behcet syndrome, milling and stinging, blood-related disorders such as cold-haemagglutinin disease, eradication of red blood cells due to anemia, excessive proliferation of eosinophils in the blood, hypoplastic anemia, proliferation of macroglobulins in the blood serum, thrombocytopenic purpura, bone disorders, cerebral palsy, Cogan's syndrome, hereditary adrenal hyperplasia, connective tissue disorders such as ringworm, lupus erythematosus, polymyalgia rheumatica, polymyositis and dermatomyositis, epilepsy, eye abnormalities such as cataracts, Graves' sore throat, hemangioma, herpes infections, nerve weaknesses, retinal veins adrenocortical inflammation, some gastrointestinal disorders such as inflammatory bowel disease, nausea and esophageal injury, higher than normal blood calcium levels, infections such as eye infection (such as mononucleosis infection), Kawasaki disease, myasthenia gravis, various pain symptom groups such as post-herpetic neuralgia, polyneuropathies, pancreatitis, respiratory disorders such as asthma, rheumatic disease and osteoarthritis, rhinitis, sarcoidosis, skin diseases such as hair loss, eczema, reddening of the skin, ringworm, blistering of the skin and blistering of the bladder, psoriasis, hives, purulent skin inflammation , hives, thyroid and vascular disorders.

The invention is illustrated by the following examples.

General experimental design and sample preparation

Test preparation

The easily adaptable aggregate droplets (oligo) used in our work are in the form of a double-layered vesicle. Typically, the test composition contained biocompatible (phospho) lipids, such as phosphatidylcholine and (bio) surfactants such as sodium cholate or polysorbate (Tween 80). Different phospholipid / detergent ratios have been chosen to maintain or select the greatest possible aggregate formability.

The production was carried out as described in our previous applications. Briefly, a solution of phosphatidylcholine (SPC; Natterman Phospholipids, Cologne, Germany) in chloroform was labeled with triturated SPC (Amersham, XXX) and mixed with sodium cholate (Merck, Darmstadt, Germany) to give 3.75 / mole (mole / m mol) phospholipid / detergent ratio. The mixture was dispersed in phosphate buffer (pH 7.2) to obtain a 10% total lipid solution.

The vesicles in the suspension were frozen three times and thawed. Subsequently, the composition was subjected to pressure over several microporous filters (first 200 nm; then 100 nm followed by 50 nm or 80 nm; Poretics, Canada). To check the reproducibility of vesicle production, the average size of the vesicles in the range of 80 nm to 150 nm was measured by a dynamic light scattering method.

Test animals

NMRI mice were 8-12 weeks old at the time of the experiment. They freely accessed the standard food and water and kept them in cages for groups of 4 to 6 people. Prior to administration of the test preparation, the application area on the back of all animals was carefully shaved. The test preparation was added under general anesthesia (0.3 ml / mouse amount of 0.0017% Rompunt (Bayer, Leverkusen, Germany) and 14.3 mg / ml Ketavet (Parke-Davis, Rochester, NY)). in. Apply to the skin with a high precision pipette, leaving the skin free. Finally, each animal was placed in a separate cage where they were kept for one day. Another cage was used for at least 24 hours for each animal. 4 animals were used per test group.

Test measurements

Blood samples were collected from the tail end at least after the end of the experiment. In one series of experiments we carried out early blood sampling every 2 hours. The organ samples include the liver, spleen, kidney and skin. The surface of the latter was also examined for 10 strips (using Tesa-Film).

The processing of the organ samples was performed according to standard procedures: for the 3H measurements, a small piece of each organ and 100 µl of carotid lysate were used to obtain the desired and quoted experimental data. These were tested according to standard procedures.

To determine the complete recovery of the label, the carcasses of the test animals were dissolved and washed with 50 ml of perchloric acid.

Recovery (% of activity used) was determined and the recovered doses (% of organ activity) and total intake [pg lipid / g organ] were calculated.

• · · ·

1-5. example

Short-term administration

Easy-to-adapt complex drops (ultra-deforming vesicles; transfersomes)

87.4 mg of phosphatidylcholine (SPC) from soybean

12.6 mg NaCl (NaChol) with trace amount of 3 H-DPPC 750 pCi / 500 µl specific activity 0.9 ml phosphate buffer, pH 7.3 Duration of the experiment: 8 hours.

Application area: 1 cm 2 at the top of the back. The various doses applied to the test area are given in the following table.

Group 1 Group 2 Group 3 Group 4 Group 5
Applied Volume [pl] 1.0 5.0 7.0 15.0 30.0
Lipid content [mg] 0.10 0.50 0.75 1.50 3.00
Applied activity [counts] 108 998 544 991 817 486 1634972 3269943

The results of the measurements are shown in Figures 1-6. Figure 1B.

6-8. example

Long-term administration

Easy-to-adapt complex drops (ultra-deforming vesicles; transfersomes)

87.4 mg of phosphatidylcholine (SPC) from soybean

12.6 mg NaCl (NaChol) trace amount with specific activity of 3 H-DPPC at 250 pCi / ml 0.9 ml phosphate buffer, pH 7.3 Duration of the experiment: 24 h.

Application area: 1 cm 2 . The dose per unit area is given in the following table.

• «

Group 6 Group 7 Group 8
Applied Volume [pl] 10.0 50.0 100.0
Lipid content [mg] 1.00 5.00 10.00
Applied activity [counts] 145 599 727 997 1E + 06

In order to study the long-term effect of the dose change applied to the area unit, even larger suspension volumes were used on the upper back of the test mice.

The data obtained were examined and presented with the results obtained from the previous experimental series. FIGS.

Figure 1 shows the recovery of relative activity (amount of penetrating substance) in different skin layers as a function of the dose (dose) used.

Figure 2 shows the amount of radioactivity from the vehicle ( 3 H-DPPC) in the blood as a function of time and the amount of intraperitoneally administered agent as a percentage of the applied dose. As can be seen in the figure, the relative amount of non-invasively administered lipid reaches a detectable level in the blood after about 4 hours of pure delay, but is nearly independent of the dose used.

Figure 3 shows the relative accumulation of radioactivity from the carrier in the various organs at two different times after the increased weight of the ultra-forming carriers is applied to the skin. It will be appreciated that while the relative amount of radioactivity from the carrier decreases with the applied dose at both time points, the amount of phospholipid in the blood, in the dermis and in the liver increases simultaneously at t = 8 hours, but remains almost unchanged until t = 24 hours.

Figure 4 shows the absolute penetrating material distribution profile (in arbitrarily selected units) in the different layers of the skin as a function of the dose (dose) used. Low dose dependence can be seen in the cornea at doses ranging from 0.5 mg / cm 2 to 1.5 mg / cm 2 , but higher intracellular quantities are more efficiently deposited in the protective sheath. This is true for 8 hours after the suspension and for 24 hours. The dose-dependent * * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · over the live skin dose will accumulate the material from the intruder in the entire observed range.

Figure 5 shows the total amount of penetrating material recovered at different times in different tissues (skin, blood, liver), increasing the dose applied to each area following the administration of an increasing amount of ultra-deformable penetrating agents to the skin. However, while at t = 8 h a clear saturation tendency is observed for doses greater than 1.5 mg / cm 2 , at a time of t = 24 h the dose dependence is linear.

Figure 6 shows the time dependency of the radioactivity of the penetrating substance in the blood as a function of the volume of suspension (lipid amount) administered by the epicutane. As can be seen from the figure, the intrinsic characteristic of the intruder is essentially independent of the dose used: after a delay of 4-6 hours, a near steady state is observed.

Figure 7 shows the radioactivity of the penetrating substance in the blood as a function of the dose administered epicutaneously, which is measured 8 hours or 24 hours after application. Linear extrapolation suggests that the protective barrier begins to adapt itself to the penetrating material at about 0.75 mg / cm 2 .

Non-occluding single-compartment and multi-compartment patches

Figure 8 shows the results obtained by measuring the average vapor permeation rate (MVTR) of five microporous polyethylene membranes, four polyurethane membranes and a banded polycarbonate membrane.

We use the following abbreviations:

First acronyms:

DSM DSM Solutech, Heerlen, The Netherlands
3M 3M Medica, Borken, Germany
ARCA Adhesives Research, Limerick, Ireland
SM Smith and Nephew
Infiltec Infiltec, Speyer, Germany

Second acronyms:

PE microporous polyethylene

PU polyurethane

PCTE banded polycarbonate

The third acronyms refer to article numbers.

Figure 9 is a diagram illustrating the principle of "switching effect" observed, for example, with the hydrophobic mesh membranes of the present invention. The cross-section of the two filaments of the filament is given. In Figure 1, the fibers are coated with a transfersome composition or a lipid suspension without contact with the skin, for example, during storage. Skin contact results in fluid bridges on the skin surface (Figure 2), which ultimately leads to complete wetting of the skin and release of the transfersomes through a "sieve" (Figure 3).

Figure 10 shows the permeability of three different microporous polyethylene membranes for transfersomes, namely Type-C membranes; Solupor - E011 D, Solupor 8P07A and Solupor - 10P05A (DSM Solutech, Heerlen, The Netherlands). They exhibit high permeability at low pressures, allowing transfersomes to wet the skin upon contact. In addition, it can be seen from the figure that no permeation through the membrane is observed for the transfersomes when the pressure is 0.

Fig. 11 is a schematic view of a multi-particle patch having twin syringe-shaped outer compartments according to the invention serving as storage compartments and a taper or T-piece coupling part attached to the patch.

Fig. 12 is a schematic diagram of a multi-particle patch according to the invention having vertically superimposed compartments.

Fig. 13 is a schematic illustration of a multi-particle patch according to the invention in which the compartments are arranged side by side with a vertically inserted partition wall.

Fig. 14 is a schematic illustration of a multi-particle patch according to the invention where the compartments are arranged side by side with a separate layering.

The following is an example of a patch for applying a transdermal composition (V = 0.6 ml) according to the invention. Said transdermal patch may be used as a single-compartment patch according to the invention and may also be secured to external compartments to form a multi-compartment patch according to the invention.

Type Material Size
Backing COTRAN 9701 / 3M 2ml Polyurethane 70-0000-3993-6 SLP P261450106 Inner diameter 3.6 cm outer rectangular square 4.5 cm * 4.5 cm
Compartment 3M Foam tape 1779 Polyolefin Ribbon Double Layer # 70-0000-6467-8
Interior lining PCTE 100 nm Poretics; Kaa. 19410 HORSE AE84AG11C024
Edge protection Leukoplast
Injection tube Sealing Ring Venflon 1.2 mm / 18G L45 mm Article No. 4253-1 HORSE 931208 Pre-mounted tube; removable after injection of TFS; the aperture is closed by Leukoplast
Area of use 10 cm 2
Application District 3.6 cm
Circular seal width > 0.8 cm
Total area 20.25 cm 2

• ··· · ·

Another example of a patch for application of the transdermal composition according to the invention is given below. Said patch has no inner liner membrane and is intended for direct application on the skin. For example, the mixing chamber (formed by the backsheet and the skin) can be filled with external syringes connected to the mixing compartments.

Type Material Size
Backing Microporous Polyethylene 9711; 3M Medica # KG-90054 6 cm * 8.6 cm rectangular rectangle
Compartment 3M Foam tape 1779 Polyolefin Ribbon Double Layer # 70-0000-6467-8 outer rectangular rectangle 6 cm * 8.6 cm inner circumference 4.4 cm * 7 cm
Release Coating 1 Habszalagból
Edge protection Leukoplast
Injection tube Sealing Ring Venflon 1.2 mm / 18G L45 mm Article No. 4253-1 HORSE 931208 Pre-mounted tube; removable after injection of TFS; the aperture is closed by Leukoplast
Area of use 25 cm 2
Application District 4.4 cm * 7 cm
Circular seal width > 0.8 cm
Total area 51.6 cm 2

• ·

Claims (14)

Claims
1 - _ · 'TO · · · · · · · · ···· ··
P020J454
Figure 1
P02 01 4 5 4
DISCLOSURE EXAMPLE
The amount of H-DPPC in the blood
1/14 DISCLOSURE EXAMPLE
Dose [% of activity used]
ZZ zz zz ZZ zz ZZ zz zz e '(Phi '(Phi '(Phi TFI '(Phi '(Phi '(R '(Phi (phi '(Phi 50 He He υ Q He υ ü He He ü -HE X-Z esi co HORSE CD ob σ> He 50 He He He HE He HE He He He
Dissolve in 1- and 2-propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight 200-400 Da) or glycerol in other pharmaceutically acceptable organic solvents such as supercooled gas, particularly supercritical CCl, which are then prepared by preparing the final formulation. before removal, especially by evaporation or dilution.
77. The method of claim 73 or 76, wherein the penetrating materials are formed by the addition of the required materials to the liquid phase, by evaporation from the reverse phase, by injection or by dialysis, if required by mechanical constraints such as shaking, stirring, in particular high-speed mixing, vibration, homogenization, ultrasound, shear, freezing and thawing, or suitable, especially low (1 MPa) or medium (maximum 10 MPa) filtration.
78. The method of claim 77, wherein the formation of penetrating materials is effected by filtration, wherein the filter material is between 0.01 and 0.8, more preferably between 0.02 and 0.3, and most preferably 0, A pore size between 05 pm and 0.15 pm, several filters may be used sequentially or in parallel.
79. Process according to one of Claims 1 to 3, characterized in that the active substances and penetrating agents are at least partially after the formation of the penetrating agents, for example with a pharmaceutically acceptable liquid such as ethanol, 1 and 2-propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight: 200-400 Da) or after the injection of the active ingredient solution with glycerol into the suspending medium, simultaneously with the formation of the penetrating agent, if necessary with the active ingredient co-solvent and at least some penetrating constituents.
80. Process according to any one of claims 1 to 3, characterized in that the penetrating agents with which the active ingredient is incorporated are prepared immediately prior to use of the composition, if possible from a suitable concentrate or lyophilisate.
81. The 60-80. Method according to one of Claims 1 to 3, characterized in that the composition is applied by spraying, lubrication, ball application or sponge to the application area, in particular a dispenser, lubricant, ball device, sponge or non-sealed patch according to the application.
82. A method according to any one of claims 1 to 4, characterized in that the barrier skin is at least partially keratinized and / or nasal or any other mucosa.
83. The method according to claim 82, wherein the surface dose of the penetrating agent is preferably between 0.1 mg / cm 2 and 40 mg / cm 2 , more preferably between 0.25 mg / cm 2 and 30 mg / cm 2 , and more preferably between 0.5 mg / cm 2 and 15 mg / cm 2 when the penetrating agent is applied on the skin and / or at least partially keratinized on the inside.
84. The method of claim 82, wherein the surface dose of the penetrating agent is between 0.05 mg / cm 2 and 20 mg / cm 2 , more preferably between 0.1 mg / cm 2 and 15 mg / cm 2 and more more preferably between 0.5 mg / cm 2 and 10 mg / cm 2 when the penetrating agent is applied to the nasal and / or other mucosa.
85. The method of claim 82, wherein the surface dose of the penetrating agent is between 0.0001 mg / cm 2 and 0.1 mg / cm 2 , more preferably 0.0005 mg / cm 2 and 0.05 mg / cm Between 2 and more preferably between 0.001 mg / cm 2 and 0.01 mg / cm 2 when the penetrating material is applied to the plant strain, plant leaves or plant pine needles.
86. The method of claim 59, wherein the method is used to vaccinate a mammal in a human or other mammal to provide an immune response.
87. The method of claim 59, wherein the method is used to produce a therapeutic effect in a human or other mammal.
88. The method of claim 59, wherein the method is for the treatment of the following diseases; inflammatory disease, dermatitis, kidney and liver failure, bronze age, aspiration symptom group, Behcet syndrome, milling and stinging, blood disorders such as cold haemagglutinin disease, hemolytic anemia, excessive proliferation of eosinophil cells in the blood, hypoplastic anemia, macroglobulinemia, thrombocytopenic purpura, and bone disorders, cerebral palsy, Cogan's syndrome, hereditary adrenal hyperplasia, connective tissue disorders such as ringworm, lupus erythematosus, polymyalgia rheumatica, polymyositis and dermatomyositis, epilepsy, eye abnormalities such as gray cataracts, gaves of ophthalmia, haemangioma, herpes infections, nerve weakness, retina vasculitis, inflammation of the lining, some gastrointestinal disorders such as inflammatory bowel disease, nausea and esophagus injury, hypercalcaemia, infections such as eye infection (such as mononucleosis infection) diseases), Kawasaki disease, myasthenia gravis, various pain syndromes, such as post-herpetic nerve pain, nerve diseases, pancreatitis, respiratory disorders such as asthma, rheumatic disease and osteoarthritis, rhinitis, sarcoidosis skin disorders such as hair loss, eczema, multiple forms of redness, eczema for treatment of ringworm, skin blistering and bladder conditions, psoriasis, hives, purulent dermatitis, hives, thyroid and vascular disorders.
2002 SZEPI2 0.
Patent and Trademark Office 1024 Budapest, East! Károly u. 13 / b Frankné dr. Machytka Daisy Patent Attorney «· •» · · · · · ··· ·· ·· · · · · · ·
P02 0 I45 4
Dissolve in 1- and 2-propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight 200-400 Da) or glycerol in other pharmaceutically acceptable organic solvents such as chilled gas, particularly supercritical CO 2 , which are then prepared prior to final preparation. removed, in particular by evaporation or dilution.
19. A method according to claim 17 or 18, wherein the penetrating material is formed by the addition of the required materials to the fluid phase, by evaporation from the reverse phase, by injection or by dialysis, if necessary by mechanical compression, e.g. especially high-speed mixing, vibration, homogenization, ultrasonic, shear, freezing and thawing, or suitable, especially low (1 MPa) or medium (maximum 10 MPa) filtration.
20. The method of claim 19, wherein the formation of penetrating materials is effected by filtration, wherein the filter material is between 0.01 and 0.8, more preferably between 0.02 and 0.3, and most preferably 0, It has a pore size of between 05 and 0.15 pm, which can be used in series or in parallel.
21. The 17-20. Process according to any one of claims 1 to 3, characterized in that the active substances and penetrating agents are at least partially after the formation of the penetrating agents, for example the active ingredient with a pharmaceutically acceptable liquid such as ethanol, 1 and 2-propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight) : 200-400 Da) or a solution of glycerol in the suspending medium, coupled with the formation of the penetrating agent, if necessary with the aid of the active ingredient and at least some penetrating constituents.
22. Method according to any one of claims 1 to 3, characterized in that the penetrating agents with which the active ingredient is incorporated are prepared immediately prior to use of the composition, if possible from a suitable concentrate or lyophilisate.
23. The method of 1-22. Method according to one of Claims 1 to 3, characterized in that the composition is applied by spraying, lubrication, ball bearing or sponge to the application area, in particular by a metering nebulizer, a lubricant, a ball device, a sponge or a non-sealed patch according to the application.
24. References 1-23. A method according to any one of claims 1 to 4, characterized in that the protective barrier is part of a mammal's body and / or a plant, preferably a skin and / or at least partially keratinized endothelium and / or nasal or any other mucosa.
25. The method of claim 24, wherein the surface dose of the penetrating agent is preferably between 0.1 mg / cm 2 and 40 mg / cm 2 , more preferably between 0.25 mg / cm 2 and 30 mg / cm 2 , and more preferably between 0.5 mg / cm 2 and 15 mg / cm 2 when the penetrating agent is applied on the skin and / or at least partially keratinized on the inside.
26. The method of claim 24, wherein the penetrating agent has a surface dose of between 0.05 mg / cm 2 and 20 mg / cm 2 , more preferably between 0.1 mg / cm 2 and 15 mg / cm 2 and more more preferably between 0.5 mg / cm 2 and 10 mg / cm 2 when the penetrating agent is applied to the nasal and / or other mucosa.
27. The method of claim 26, wherein the penetrating agent has a surface dose of between 0.0001 mg / cm 2 and 0.1 mg / cm 2 , more preferably 0.0005 · · · · · · · · · · • · · · · · · · · · · ·· ·· • «· · in mg / cm 2 to 0.05 mg / cm 2 and more preferably from 0.001 mg / cm 2 and 0.01 mg / cm 2, preferably in the case where the penetrating material is applied to the plant strain, plant leaves or plant pine needles.
28. A patch comprising the compound of claims 1-27. The composition according to any one of claims 1 to 5, in an amount corresponding to the desired dose per unit area.
The patch of claim 28, comprising a non-occlusive backing and an inner liner, wherein the backsheet and inner liner define a container portion.
A patch according to claim 28, comprising a non-occlusive backing sheet and a matrix layer.
31. The patch of claim 29 or 30, wherein the non-sealing backsheet has an average vapor permeability (MVTR) of greater than 1000 g / m 2 , preferably greater than 5000 g / m 2 , more preferably 10,000 g / m Higher than 2 days.
A patch according to claim 30 or 31, characterized in that the flow of penetrating material through the barrier is controlled by the removal of the solvent through the non-occluding backsheet.
33. The 28-32. A patch according to any one of the preceding claims, wherein the non-occluding backsheet has pores less than 100 nm, preferably less than 70 nm, most preferably less than 30 nm.
34. A patch according to any one of claims 1 to 3, characterized in that the non-occluding backsheet comprises a membrane which is preferably selected from the group consisting of a polyurethane membrane, a banded porous polyester membrane, a banded porous polycarbonate membrane and a microporous polyethylene membrane.
35. The 28-34. A patch according to any one of claims 1 to 4, characterized in that the inner liner prevents unwanted release of the composition from the patch during storage and allows rapid wetting of the skin when in contact with the skin.
36. A patch according to any one of claims 1 to 4, characterized in that the inner liner comprises a homogeneous membrane, preferably a banded porous polyester membrane or a banded porous polycarbonate membrane.
37. The patch of claim 36, wherein the membrane has a pore density of up to 5%, preferably up to 15%, more preferably up to 25% and most preferably greater than 25%, and / or pore size between 20 nm and 200 nm, preferably 50 nm. and 140 nm, most preferably between 80 nm and 120 nm.
38. The 28-37. A patch according to any one of claims 1 to 3, characterized in that the inner liner comprises a non-woven wool with a hydrophobic mesh membrane and / or mesh openings formed by hydrophobic fibers.
39. The 28-38. A patch according to any one of the preceding claims, wherein the inner liner comprises a microporous polyethylene membrane having an average pore diameter of between 50 nm and 3000 nm, preferably between 500 nm and 2000 nm, most preferably about 1500 nm.
40. Articles 28-39. Patch according to any one of the preceding claims, characterized in that the patch is a pressure-sensitive adhesive layer, preferably an adhesive layer • • ···· ·· · t t • · · φ comprises a poliacilátból, polyisobutylene, silicone, ethylene vinyl acetate copolymer, polyvinylpyrrolidone or polyethylene oxide hydrogel.
41. Articles 28-40. A patch according to any one of claims 1 to 3, characterized in that the patch comprises one or more additional layers comprising layers of drying agent, matrix layers, foam strips and / or protective layers.
42. The 28-41. A patch according to any one of claims 1 to 3, characterized in that the drug release membrane has a surface area of 0.5 cm 2 to 250 cm 2 , more preferably 1 cm 2 to 100 cm 2 , more preferably 2 cm 2 to 50 cm 2 and most preferably 4 cm 2 and 25 cm 2 .
43. The 28-42. A patch according to any one of claims 1 to 4, characterized in that the patch comprises at least two compartments which are separated from each other during storage.
44. Articles 28-43. A patch according to any one of claims 1 to 3, characterized in that at least one of the compartments is inside and / or outside the patch.
45. Articles 28-44. A patch according to any one of claims 1 to 3, characterized in that the composition and / or the individual formulation components and / or the active ingredient and / or the suspending agent / dispersion of the penetrating agent during the storage are more than 5, more preferably less than 3, more preferably 3 , most preferably, in 2 separate compartments, which are combined prior to, or during, application of the patch.
46. The 28-45. A patch according to any one of claims 1 to 4, characterized in that the outer compartment (s) comprises an injection system which is connected to the container part (s).
··· · «• ·
47. Articles 28-45. A patch according to any one of the preceding claims, characterized in that the compartments are within the container portion defined by the backsheet and the inner liner.
48. A patch according to any one of the preceding claims, characterized in that the compartments are vertically superimposed and / or arranged side by side and / or one compartment is housed within a second compartment, preferably without securing to the second compartment.
A patch according to claim 47 or 48, characterized in that the compartments are separated from each other by a controllably opening protective barrier, preferably a membrane and / or a seal and / or a compartmenting layer.
50. The 43-49. Patch according to one of Claims 1 to 5, characterized in that the separated compartments can be combined and the components of the compartments can be mixed by direct mechanical action, such as pressure, abrasion, kneading, twisting, tearing and / or indirectly by changing the temperature, osmotic pressure or electrical potential.
51. A patch according to claim 28, wherein said patch is as shown in FIG. The non-occlusive backsheet according to any one of claims 1 to 5, comprises a reservoir defining a storage portion divided into at least two compartments, characterized in that the composition is in direct contact with the skin when the composition is released from the container.
52. The procedure of 43-51. Use of a patch according to any one of the preceding claims, characterized in that the components of the compartments are combined and mixed by direct mechanical action such as pressure, abrasion, kneading, twisting, tearing and / or indirectly by changing the temperature, osmotic pressure or electrical potential.
···· ·· • ·
53. A composition according to any one of claims 1 to 3 in an amount that allows the composition to be administered in a dose amount of the selected area unit according to any one of the preceding claims.
54. The kit of claim 53 wherein said composition is contained in a bottle or any other container.
55. The kit of claim 53 or 54 further comprising means for administering the composition.
56. The kit of claim 55, wherein the device for administering the composition is an insert 28-51. A patch according to any one of claims 1 to 4.
57. The kit of claim 55, wherein the device for administering the composition comprises an injection system, preferably a syringe, attached to the container portion of the patch.
58. The kit of claim 55, wherein the device for administering the composition is a metering nebulizer, a lubricating brush, a ball device, or a sponge.
59. A method of administering an active substance to a mammalian body or a plant by transferring the active substance through a barrier, wherein the protective barrier is a cuticle of intact skin, mucosa and / or mammalian body or plant, and the active ingredient is bound to an infiltrating agent capable of delivering the drug. through the pores of the skin or through the passages of the mucosa or cuticle, or to allow the drug to pass through the pores of the skin after the penetrating material has opened the pores and / or penetrated into the pores, characterized in that the composition is produced by the intruder. materials in a polar liquid suspended or dispersed in the form of liquid droplets surrounded by one or more layered membrane-like coatings, wherein the coating comprises at least two amphiphilic materials of a variety or shape that are susceptible to aggregation and the solubility of the at least two materials at least one factor 10 in the polar fluid differs from each other, and where the penetrating agents are capable of delivering the active agent through the pores of the barrier or allowing the active agent to penetrate through the pores of the barrier, after penetration of the penetrating materials into the pores, the protective barrier is forwarded the amount of penetrating agent to be applied in the defined area for controlling the flow of penetrating material through the barrier and applying the selected dosage amount of the penetrating composition to the area of the porous barrier.
60. The method of claim 59, further comprising increasing the flow of penetrating material through the barrier by increasing the dose of penetrating agent per unit area.
61. The method of claim 59 or 60, wherein the pH of the composition is between 3 and 10, more preferably between 4 and 9, most preferably between 5 and 8.
62. Articles 59-61. A method according to any one of claims 1 to 3, wherein the composition comprises:
at least one thickening agent in an amount which increases the viscosity of the composition to 5 kN s / m 2 , preferably up to 1 kN s / m 2 , most preferably up to 0.2 kN s / m 2 , to allow dispersal of the formulation and retention of the active ingredient in the field of application and / or at least one antioxidant in an amount that reduces the increase of the oxidation index by less than 100% in 6 months, more preferably by less than 100% in 12 months and most preferably less than 50% in 12 months and / or at least one antimicrobial agent in an amount that reduces the amount of 1 million germ bacteria added to less than 100 days of aerobic bacteria to less than 100 in 1 day for less than 10 enterobacteriaceae and reduces Pseudomonas aeruginosa to less than 1; For Staphylococcus aureus.
63. The method of claim 62, wherein the at least one microbial agent is added to the composition in an amount of less than 1 million germs per day, less than 1 g per 100 g of the composition, more preferably less than 1 day. for aerobic bacteria, reduces it to less than 10 for enterobacteria, and reduces it to less than 1 for Pseudomonas aeruginosa or Staphylococcus aureus.
64. The method of claim 62 wherein said thickening agent is selected from the group consisting of pharmaceutically acceptable hydrophilic polymers, such as partially etherified cellulose derivatives, such as carboxymethyl, hydroxyethyl, hydroxypropyl, hydroxy, and the like. propylmethyl or methylcellulose; fully synthetic hydrophilic polymers such as polyacrylates, polymethacrylates, poly (hydroxyethyl), poly (hydroxypropyl), poly (hydroxypropylmethyl) methacrylates, polyacrylonitriles, metallyl sulfonates, polyethylenes, polyoxyethylenes, polyethylene glycols, polyethylene glycol lactides, polyethylene glycol diacrylates, polyvinylpyrrolidones, polyvinyl alcohols, poly (propyl methacrylamides), poly (propylene fumarate-co-ethylene glycols), polyoxyamines, polyaspartamides, (hydrazine cross-linked) hyaluronic acids, silicones ; natural gums such as alginates, carrageenans, guar tires, gelatins, tragacanth, (amidated) pectins, xanthanes, chitosan collagen, agarose; mixtures thereof and further derivatives or copolymers thereof and / or other pharmaceutically or at least biologically acceptable polymers.
65. The method of claim 64, wherein the polymer has a concentration in the range of 0.01% to 10%, more preferably in the range of 0.1% to 5%, more preferably 0.25%. in the range from% to 3.5% by weight and most preferably from 0.5% to 2% by weight.
66. The method of claim 62, wherein the antioxidant is synthetic phenol antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and di-tert-butylphenol (LY178002, LY256548, HWA131, BF-389, CI-986, PD-127443, E-5119, BI-L-239XX, etc.), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), 1-O-hexyl-2,3 5-trimethylhydroquinone (HTHQ); aromatic amines (e.g., diphenylamine, p-alkylthio-o-anisidine, ethylenediamine derivatives, carbazole, tetrahydroindenoindole); phenols and phenolic acids (e.g., guaiacol, hydroquinone, vanillin, gallic acids and their esters, protocol acid, quinic acid, siring acid, ellagic acid, salicylic acid, nordihydrogen acid (NDGA), eugenol); tocopherols (including tocopherols (alpha, beta, gamma, delta) and derivatives thereof, such as tocopheryl acylate (e.g., acetate, laurate, myristate, palmitate, ololeol, linoleide, etc., or any other suitable tocopherol) -lipoate), tocopheryl POE succinate; trolox and corresponding amide and thiocarboxamide analogs; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6) -o-alkyl ascorbic acids, ascorbyl esters (e.g. o-lauroyl, myristoyl, palmitoyl, oleoyl, or linoleoyl-L-ascorbic acid, etc.); non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, diclofenac, mefenamic acid, flufenamic acid, phenylbutazone, oxyphenbutazone acetylsalicylic acid, naproxen, diflunisal, ibuprofen, ketoprofen, piroxicam, penicillamine, penicillamine disulfide, primacvin, quinazine, chloroquine, hydroxycloroquine, azathioprine, phenobarbital, acetaminophen; forming materials such as EDTA, GDTA, desferrals, glucose, ubiquinol-10; enzymatic antioxidants such as superoxide dismutase and metal complexes of similar activity, including catalase, glutathione peroxidase, and less complex molecules such as beta-carotene, bilirubin, uric acid; flavonoids (e.g., favones, flavonols, flavonons, flavanones, chakons, anthocyanins), N-acetylcysteine, mezna, · · · glutathione, thiohistidine derivatives, triazoles; tannins, cinnamic acid, hydroxycinnamate acids and their esters (e.g., co-acids and esters, coffee acid and esters, ferulic acid, (iso-) chlorogenic acid, synapse); spice extracts (for example, cloves, cinnamon, sage, rosemary, nutmeg, oregano, allspice, nutmeg); carnosic acid, carnosol, carzolic acid; rosemary acid, rosemary diphenol, gentic acid, ferulic acid; oatmeal extracts such as avenanthramide 1 and 2; thioethers, dithioethers, sulfoxides, tetralkylthiuram disulfides; phytic acid, steroid derivatives (e.g. U74006F); tryptophan metabolites (e.g. 2-hydroxyquinurenine, 3-hydroxy-anthranilic acid), and organic chalcogenides, or an oxidation suppressing enzyme.
67. The method of claim 66, wherein the concentration of BHA or BHT is between 0.001 and 2% by weight, more preferably between 0.0025 and 0.2% by weight, and most preferably between 0.005 and 0.02% by weight of TBHQ. and the concentration of PG between 0.001 and 2%, more preferably between 0.005 and 0.2%, and most preferably between 0.01 and 0.02%, the concentration of tocopherols ranging from 0.005% to 5%, more preferably 0.01 and 0%, Between 5% by weight and most preferably between 0.05 and 0.075% by weight, the ascorbic acid ester concentration is between 0.001 and 5% by weight, more preferably between 0.005 and 0.5% by weight, and most preferably between 0.01 and 0.15% by weight, the concentration of ascorbic acid ranges from 0.001 to 5% by weight, more preferably from 0.005 to 0.5% by weight, and most preferably from 0.01 to 0.1% by weight, sodium bisulfite or sodium metabisulphite in a concentration of 0.001 to 5% by weight, more preferably Between 0.005 and 0.5% by weight, and most preferably between 0.01 and 0.15% by weight, the concentration of thiourea is between 0.0001 and 2%, more preferably between 0.0005 and 0.2%, and most preferably 0.001 and 0.2% by weight. From 0.01% by weight, most typically from 0.005% by weight, to cysteine concentrations from 0.01 to 5% by weight, more preferably from 0.05 to 2% by weight, and most preferably from 0.1 to 1.0% by weight, most typically 0, 5% by weight, the concentration of monothioglycerol ranging from 0.01 to 5% by weight, more preferably from 0.05 to 2% by weight, and most preferably from 0.1 to 1.0% by weight, most typically from 0.5% by weight to NDGA 0 , Between 0005 and 2% by weight, more preferably between 0.001 and 0.2% by weight, and most preferably between 0.005 and 0.02% by weight, most typically 0.01% by weight, with glutathione concentration between 0.005% and 5%, more preferably 0.01% and between 0.2% by weight and most preferably between 0.05 and 0.2% by weight t, most typically 0.1 wt%, EDTA concentration between 0.001 and 5 wt%, more preferably between 0.005 wt% and 0.5 wt%, and most preferably between 0.01 and 0.2 wt%, most typically 0.05 and 0.975 wt% the concentration of citric acid is between 0.001 and 5% by weight, more preferably between 0.005 and 3% by weight, and most preferably between 0.01 and 0.2% by weight, most typically between 0.3 and 2% by weight.
68. The method of claim 62 wherein said microbial agent is selected from the group consisting of lower alcohols such as ethyl and isopropyl alcohol, chlorobutanol, benzyl alcohol, chlorobenzyl alcohol, dichlorobenzyl alcohol; hexachlorophene; phenolic compounds such as cresol, 4-chloro-m-cresol, p-chloro-xylene, dichlorophen, hexachlorophen, povidone iodine; parabens, in particular alkyl parabens, such as methyl, ethyl, propyl or butyl paraben, benzyl paraben; acids such as sorbic acid, benzoic acid and its salts; quaternary ammonium compounds, for example, alkonium salts such as benzalkonium salts, especially chlorides or bromides, cetrimonium salts such as bromide; phenalkecinium salt such as phenododecinium bromide, cetylpyridinium chloride, or the like; mercury (II) compounds such as phenyl mercury (II) acetate, borate or nitrate, thiomers; chlorhexidine or gluconate; antibiotically active compounds of biological origin or mixtures thereof.
69. The method of claim 68, wherein the total concentration of the lower alcohols for ethyl, propyl, butyl or benzyl alcohol is up to 10% by weight, more preferably up to 5% by weight, and most preferably 0.5-3% by weight and in the range of 0.3 to 0.6% by weight for chlorobutanol; in the range of from 0.05 to 0.2% by weight of parabens, in particular methyl paraben, and from 0.002 to 0.2% by weight for propyl paraben; the total concentration of sorbic acid in the range of 0.05 to 0.2% by weight and in the range of 0.1 to 0.5% by weight for benzoic acid; the total concentration of phenols, triclosan in the range of 0.1 to 0.3% by weight, and the total concentration of chlorhexidine in the range of 0.01 to 0.05% by weight.
70. Articles 59-69. Method according to any one of claims 1 to 3, characterized in that the less soluble material between the aggregating materials is a lipid or lipid-like substance, in particular a polar lipid, while a more soluble substance in the suspending fluid which reduces the average elastic energy of the droplet is a surfactant or a surfactant-like agent. has properties and / or a lipid or lipid-like form that is similarly soluble as a surfactant or surfactant-like substance.
71. The method of claim 70, wherein the lipid or lipid-like material is a lipid or lipoid from a biological source, or a suitable synthetic lipid, or any of its modifications, the lipid preferably being a class of phospholipids having the general formula:
'Ch ^ o-r
I r 2 -o 2 ch oi ii 3 CH 2 -OPor 3 I
OH, wherein R1 and R2 are an aliphatic chain, typically a C10-C20 acyl or alkyl group, or a partially unsaturated fatty acid residue, in particular an oleoyl, palmitoleoyl, elaidoyl, linoleyl, linolenyl, linolenyl, arachidoyl, vaccine, lauroyl, myristoyl, palmitoyl or stearoyl; and wherein R 3 is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C 1-4 alkyl, C 1-5 carboxyl-substituted alkyl, C 2-5 hydroxy substituted alkyl, C 2-5 alkyl substituted with carboxyl and hydroxy, or C 2-5 carboxyl and amino substituted alkyl, inositol, sphingosine, or salts of said materials, said lipid also includes glycerides, isoprenoid lipids , steroids, sterols or sterols, lipid-containing lipids and carbohydrate-containing lipids, or any other double-layered lipid, in particular semi-protonated liquid fatty acids, said lipid selected from the group consisting of phosphatidylcholines, phosphatidyl ethanol; amines, phosphatidylglycerols, phosphatidylinositins, phosphatidic acids, phosphatidylserines, sphingomyelin or other sphingophospholipids, glycosphingolipids (including cerebrosides, ceramidopolyheosides, sulfatides, sphingoplasmalogens), gangliosides and other glycolipids or synthetic lipids, in particular the corresponding sphingosine derivatives, or any other glycolipids, where two similar or different chains may be attached to the backbone via ester groups (such as the diacyl and dialkenoyl compounds), or may be linked to the backbone by ether bonds as in dialkyl lipids.
72. The method of claim 70, wherein the surfactant or surfactant-like substance is a nonionic, twin ionic, anionic or cationic surfactant, in particular a fatty acid or alcohol, an alkyl tri / di-methylammonium. salt, an alkyl sulphate salt, a monobasic salt of cholate, deoxycholate, glycocholate, glycodioxoxolate, taurodezoxycolate, taurocholate, etc., an acyl or alkanoyl dimethylaminoxide, in particular a dodecyldimethylaminoxide, alkyl or alkanoyl-N -methylglucamide, N-alkyl-N, N-dimethylglycine, 3- (acyldimethylammonio) alkanesulfonate, Nacyl sulfobetane, polyethylene glycol octylphenyl ether, especially nonaethylene glycol octylphenyl ether, polyethylene acyl ether, in particular nonaethylene dodecyl ether, polyethylene glycol isoacyl ether, especially octaethylene glycol isotridecyl ether, polyethylene acyl ether, especially octaethylene dodecyl ether, polyethylene glycol sorbitan, an acyl ester such as polyethylene glycol-20 monolaurate (Tween 20) or polyethylene glycol-20-sorbitan monooleate (Tween 80), polyhydroxyethylene acyl ether, especially polyhydroxyethylene lauryl, myristoyl, cetyl stearyl or ololeoyl ether such as polyhydroxy -ethylene-4 or 6 or 8 or 10 or 12, etc., lauryl ether (as in the Brij series), or in the corresponding ester, e.g., polyhydroxyethylene-8-stearate (Myrj 45), laurate or oleate type, or polyethoxylated castor oil 40, a sorbitan monoalkylate (e.g., Arlacel or Span), in particular sorbitan monolaurate, an acyl or alkanoyl N-methylglucamide, especially decanoyl or dodecanoyl-N-methylglucamide , an alkyl sulphate (salt) such as lauryl or oleoyl sulfate, sodium deoxycholate, sodium glycodoxoxolate, sodium oleate, sodium taurate, a fatty acid salt such as sodium elaidate, · Sodium linoleide, sodium laurate, a lysophospholipid such as n-octadecyl n (= oleoyl) -glycerophosphatidic acid, phosphorylglycerol or phosphoryl serine, η-acyl such as lauryl or oleoyl glycero-phosphatidic acid, phosphoryl glycerol or phosphoryl serine, n-tetradecylglycerophosphatidic acid, phosphorylglycerol, or phosphoryl serine, a suitable palmitoleoyl, elaidoyl, vaccenillisophospholipid, or a suitable lower phospholipid, or a surfactant polypeptide.
73. Articles 59-72. A method according to any one of claims 1 to 3, characterized in that the average diameter of the penetrating material is between 30 nm and 500 nm, more preferably between 40 nm and 250 nm, more preferably between 50 nm and 200 nm and particularly preferably between 60 nm and 150 nm.
74. Articles 59-73. Process according to any one of claims 1 to 4, characterized in that the total dry weight of the droplets in the composition is from 0.01 to 40% by weight of the composition, more preferably from 0.1 to 30% by weight, and most preferably from 0.5 to 20% by weight.
75. Articles 59-74. A method according to any one of claims 1 to 3, characterized in that the at least one amphiphilic material and / or at least one flange-active substance or surfactant and / or at least one hydrophilic liquid and the active ingredient are mixed together, if necessary, to form a solution, (partial) mixtures or solutions are then sequentially combined to advantageously produce, through mechanical propulsion, such as shaking, mixing, vibration, homogenization, ultrasonic, shear, freezing and thawing, or filtering, the formation of penetrating agents by means of an appropriate propulsion pressure or force. bind and / or encapsulate the active ingredient.
76. The method of claim 75, wherein the amphiphilic materials are in volatile solvents, such as alcohols, especially ethanol, or other pharmaceutically acceptable organic solvents such as ethanol, · ··· «·· ·· ·· • · · · · «« · · · · · ··· ·· · · · «« ·
A method for controlling the flow of materials that penetrate through a semi-permeable, porous protective barrier, the method comprising the steps of:
the composition is prepared by dispersing or dispersing the penetrating agents in the form of liquid droplets surrounded by a multilayer membrane-like coating in a polar liquid, wherein the coating comprises at least two types or forms of amphiphilic materials that are susceptible to aggregation and at least two of the at least 10 factors differ from each other solubility in said polar liquid; and wherein the penetrating agents are capable of delivering the active agent through the pores of the barrier or allowing the active agent to penetrate through the pores of the barrier, after penetration of the penetrating materials into the pores, the dose amount of penetrating agents to be used in the predetermined area of the protective barrier through the barrier of the penetrating material. and administering the selected dose amount of the penetrating composition to the appropriate area of the porous barrier.
Figure 2
P02 0 1 i54
DISCLOSURE EXAMPLE
2/14
Time after administration [hours]
Method according to claim 1, characterized in that the current through the barrier is increased by increasing the dose of penetrating material per unit area.
Figure 3
P0207454
3/14
H-DPPC dose / organ [% of applied dose]
Process according to claim 1 or 2, characterized in that the pH of the composition is between 3 and 10, more preferably between 4 and 9, most preferably between 5 and 8.
Figure 4
Publication P02 0/45 4
Recovered dose [mg lipid / g organ]
4/14 DISCLOSURE EXAMPLE
Dose (activity / sample / relative unit)
4. Referring to 1-3. A method according to any one of claims 1 to 3, wherein the composition comprises:
at least one thickening agent in an amount that will have a viscosity of up to 5 kN s / m 2 , preferably 1 kN s / m 2 , most preferably
Raises to 0.2 kN s / m 2 so that the composition spreads and allows the retention of active ingredient in the application area and / or at least one antioxidant in an amount that reduces the increase of the oxidation index by less than 100% In less than 6 months, more preferably less than 100%, decreases in 12 months and most preferably less than 50% in 12 months, and / or at least one microbial agent in an amount that is added to 1 g of the total weight of the composition 1 million germs reduce bacteria to less than 100 in 4 days, reduce it to less than 10 for enterobacteria, and reduce it to less than 1 for Pseudomonas aeruginosa or Staphylococcus aureus.
Figure 5
5. The method of claim 4, wherein the at least one microbial agent is added to the composition in an amount of 1 million germ of bacteria per day, less than 1 day, more preferably 1 day less than 1 g of the composition. for aerobic bacteria, reduces it to less than 10 for enterobacteria and reduces it to less than 1 for Pseudomonas aeruginosa or Staphylococcus aureus.
6. Figure 02 pi p 0H5i
6/14
EXAMPLE OF DISCLOSURE p. 020J454
Dose of H-DPPC in the blood ^ g / mL)
Estimated amount of drug in the blood ^ g / mL)
6. The method of claim 4, wherein said thickening agent is selected from the group consisting of pharmaceutically acceptable hydrophilic polymers, such as partially etherified cellulose derivatives, such as carboxymethyl, hydroxyethyl, hydroxypropyl, hydroxy, and the like. propylmethyl or methylcellulose; fully synthetic hydrophilic polymers such as polyacrylates, polymethacrylates, poly (hydroxyethyl), poly (hydroxypropyl), poly (hydroxypropylmethyl) methacrylates, polyacrylonitriles, metallyl sulfonates, polyethylenes, polyoxyethylenes, polyethylene glycols; polyethylene glycol lactides; polyethylene glycol diacrylates; natural gums such as alginates, carrageenans, guar gums, gelatins, tragacanth, amidites, pectins, xanthanes, chitosan collagen, agarose; mixtures thereof and further derivatives or copolymers thereof and / or other pharmaceutically or at least biologically acceptable polymers.
Figure 7
Average vapor permeation rate [g / day m 2 ]
7/14
H-DPPC (mg / g blood)
Dose administered [mg Iipid / cm 2 ]
7. A process according to claim 6, wherein the polymer has a concentration in the range of 0.01% to 10% by weight, more preferably in the range of 0.1% to 5% by weight, more preferably 0.25% by weight. in the range from% to 3.5% by weight, most preferably from 0.5% to 2% by weight.
Figure 8 • · · · · ·
P020Í454
8/14
DISCLOSURE EXAMPLE
Membrane Type (Manufacturer - Material - Item No.)
Average vapor permeability losses for two experimental settings
8. The method of claim 4, wherein the antioxidant is synthetic phenol antioxidants, such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and di-tert-butylphenol (LY178002, LY256548, HWA-131, BF389, CI-986, PD-127443, E-5119, BI-L-239XX, etc.), tert-butylhydroquinone (TBHQ), propyl gallate (PG), 1-O-hexyl-2 , 3,5-trimethylhydroquinone (HTHQ); aromatic amines (e.g. diphenylamine, p-alkylthio-o-anisidine, ethylenediamine derivatives, carbazole, tetrahydroindenoindole); phenols and phenolic acids (e.g., guaiacol, hydroquinone, vanillin, gallic acids and their esters, protocol acid, cinnamic acid, sirenic acid, ellagic acid, salicylic acid, nordihydrogen acid (NDGA), eugenol); tocopherols (including tocopherols (alpha, beta, gamma, delta) and derivatives thereof, such as tocopheryl acylate (e.g., acetate, laurate, myristate, palmitate, olole, linoleic, etc., or any other suitable tocopherol) lithate), tocopheryl POE succinate; trolox and the corresponding amide and thiocarboxamide analogues; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6) -o-alkyl-ascorbic acid, ascorbyl esters (e.g. , myristoyl, palmitoyl, oleoyl or linoleoyl-L-ascorbic acid, etc.); non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, diclofenac, mefenamic acid, flufenamic acid, phenylbutazone, oxyphen-butazone acetyl salicylic acid, naproxen, diflunisal, ibuprofen, ketoprofen, piroxicam, penicillamine, penicillamindisulfide, primacvin, quinazine, chloroquine, hydroxychloroquine, azathioprine, phenobarbital, acetaminophen; substances such as EDTA, GDTA, desferral, glucose, ubiquinol-10; enzymatic antioxidants such as superoxide dismutase and metal complexes of similar activity, including catalase, glutathione peroxidase, and less complex molecules such as beta-carotene, bilirubin, uric acid; flavonoids (e.g., favones, flavonols, flavonons, flavanones, chakons, anthocyanins), N-acetylcysteine, mezna, glutathione, thiohistidine derivatives, triazoles; tannins, cinnamic acid, hydroxycinnamate acid and their esters (e.g., co-acids and esters, coffee acid and esters, ferulic acid, (iso) chlorogenic acid, synapse); spice extracts (for example, cloves, cinnamon, sage, rosemary, nutmeg, oregano, allspice, nutmeg); carnosic acid, carnosol, carzolic acid; rosemary acid, rosemary diphenol, gentic acid, ferulic acid; oatmeal extracts such as avenanthramide 1 and 2; thioethers, dithioethers, sulfoxides, tetralkylthiuram disulfides; phytic acid, steroid derivatives (e.g. U74006F); tryptophan metabolites (e.g. 2hydroxyquinurenine, 3-hydroxy-anthranilic acid) and organic chalcogenides, or an oxidation suppressing enzyme.
Figure 9 • ·
9/14
The method of claim 8, wherein the concentration of BHA or BHT is between 0.001 and 2% by weight, more preferably between 0.0025 and 0.2% by weight, and most preferably between 0.005 and 0.02% by weight of TBHQ. and the concentration of PG between 0.001 and 2%, more preferably between 0.005 and 0.2%, and most preferably between 0.01 and 0.02%, the concentration of tocopherols ranging from 0.005% to 5%, more preferably 0.01 and 0%, Between 5% by weight and most preferably between 0.05 and 0.075% by weight, the concentration of ascorbic acid esters ranging from 0.001 to 5% by weight, more preferably from 0.005 to 0.5% by weight, and most preferably from 0.01 to 0.15% by weight; concentration of ascorbic acid between 0.001 and 5% by weight, more preferably between 0.005 and 0.5% by weight, and most preferably between 0.01 and 0.1% by weight, sodium bisulfite or sodium metabisulphite having a concentration of between 0.001 and 5%, more preferably 0.0 Between 05 and 0.5% by weight, and most preferably between 0.01 and 0.15% by weight, the concentration of thiourea is between 0.0001 and 2% by weight, more preferably between 0.0005 and 0.2% by weight, and most preferably 0.001 and 0.2% by weight. From 0.01% by weight, most typically from 0.005% by weight, to cysteine concentrations from 0.01 to 5% by weight, more preferably from 0.05 to 2% by weight, and most preferably from 0.1 to 1.0% by weight, most typically 0, 5% by weight, the concentration of monothioglycerol ranging from 0.01 to 5% by weight, more preferably from 0.05 to 2% by weight, and most preferably from 0.1 to 1.0% by weight, most typically from 0.5% by weight to NDGA 0 , Between 0005 and 2% by weight, more preferably between 0.001 and 0.2% by weight, and most preferably between 0.005 and 0.02% by weight, most typically 0.01% by weight, with glutathione concentration between 0.005% and 5%, more preferably 0.01% and 0.2% by weight, and most preferably between 0.05 and 0.2% by weight, most typically 0.1% by weight, EDTA concentration between 0.001 and 5% by weight, more preferably between 0.005 and 0.5% by weight, and most preferably between 0.01 and 0.2% by weight, most typically between 0.05 and 0.975% by weight, the concentration of citric acid is between 0.001 and 5% by weight, more preferably between 0.005 and 3% by weight, and most preferably between 0.01 and 0.2% by weight, most typically between 0.3 and 2% by weight.
Figure 10
P02 01454
10/14
DISCLOSURE EXAMPLE
P02 01454
Pressure [MPa]
Penetration capability of transfecting poppy Ch.B .: 261099-100 with different polyethylene membranes
10 0
Dose used [mg lipid / cm 2 ]
10. The method of claim 4, wherein the microbial agent is selected from the group consisting of lower alcohols such as ethyl and isopropyl alcohol, chlorobutanol, benzyl alcohol, chlorobenzyl alcohol, dichlorobenzyl alcohol; hexachlorophene; phenolic compounds such as cresol, 4-chloro-m-cresol, p-chloro-xylene, dichlorophen, hexachlorophen, povidone iodine; parabens, in particular alkyl parabens, such as methyl, ethyl, propyl or butyl paraben, benzyl paraben; acids such as sorbic acid, benzoic acid and its salts; quaternary ammonium compounds, for example, alkonium salts such as benzalkonium salts, especially chlorides or bromides, cetrimonium salts such as bromide; phenoalecinium salts such as phenododecinium bromide, cetylpyridinium chloride or the like; mercury (II) compounds such as phenyl mercury (II) acetate, borate, or nitrate, thiomers; chlorhexidine or gluconate; antibiotically active compounds of biological origin, or mixtures thereof.
11/14
PUBLISHING EXAMPLE Mixing Box { O ω
o ro
11. The method of claim 10, wherein the total concentration of the lower alcohols in the ethyl, propyl, butyl alcohol or benzyl alcohol is up to 10% by weight, more preferably no more than 5% by weight, and most preferably 0.5-3% by weight of chlorine. -butanol is in the range of 0.3 to 0.6% by weight; the total concentration of the parabens, in particular methyl paraben, is in the range of 0.05 to 0.2% by weight, in the case of propyl paraben, in the range of 0.002 to 0.2% by weight; the total concentration of sorbic acid in the range of 0.05 to 0.2% by weight and in the range of 0.1 to 0.5% by weight for benzoic acid; the total concentration of phenols, triclosan is in the range of 0.1-0.3% by weight, and the total concentration of chlorhexidine is in the range of 0.01-0.05% by weight.
Figure 12 • · • · · p 02 0 H5i ····
12/14 «ΰζζ,
COPIES
12. Process according to any one of claims 1 to 3, characterized in that the less soluble material between the aggregating materials is a lipid or lipid-like substance, in particular a polar lipid, while the suspended liquid is a more soluble substance that reduces the average elastic energy of the droplet, a surfactant or a surfactant. and / or a lipid or lipid-like material that is similarly soluble as a surfactant or surfactant.
Figure 13 • · ···· ·· • ·
Ρ02 0 Η54
14/14
DISCLOSURE EXAMPLE
13/14
13. The method of claim 12, wherein the lipid or lipid-like substance is a lipid or lipoid from a biological source, or a suitable synthetic lipid or any of its modifications, preferably a class of phospholipids having the general formula:
'C ^ -O-R
I r 2 -o- 2 ch o
Ii 3 CH 2 - O - P - O - R 3
I
OH wherein R and R 2 is an aliphatic chain, typically a C10-20 acyl, or -alkyl or partly unsaturated fatty acid residue, in particular, an oleoyl, palmitoleoyl, elaidoil-, linoleyl, linolenyl, linolenoyl arachidoil- , vaccinyl, lauroyl, myristoyl, palmitoyl or stearoyl; and wherein R 3 is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C 1-4 alkyl, C 1-5 carboxyl-substituted alkyl, C 2-5 hydroxy substituted alkyl, C 2-5 alkyl substituted with carboxyl and hydroxy or substituted with C 5 -C 5 carboxylic and amino groups, inositol, sphingosine or salts of said materials, said lipid further comprising: glycerides, isoprenoid lipids, steroids, sterols or sterols, sulfur and carbohydrate-containing lipids, or any other double-layered lipids, especially semi-protonated, liquid fatty acids, said lipids selected from the group consisting of phosphatidylcholine, phosphatide -ethanolamines, phosphatidylglycerols, phosphatidylinositins, phosphatidic acids, phosphatidylserines, sphingomyelin or other sphingophospholipids, glycosphingolipid (including cerebrosides, ceramidopolyhexosides, sulfatides, sphingoplasmalogens), gangliosides and other glycolipids or synthetic lipids, in particular the corresponding sphingosine derivatives, or any other glycolipids, where two similar or different chains may be attached via ester groups to the backbone (as in the diacyl and dialkenoyl compounds) ) or with ether bonds to the skeleton as in dialkillipids.
14. The method of claim 12, wherein the surfactant or surfactant is a nonionic, twin ionic, anionic or cationic surfactant, in particular a fatty acid or alcohol, an alkyl diisomethyl ammonium salt. , an alkyl sulphate salt, a monobasic salt of cholate, deoxycholate, glycolate, glycodioxoxolate, taurodezoxycolate, taurocholate, etc., an acyl or alkanoyl dimethylaminoxide, in particular a dodecyldimethylaminoxide, alkyl or alkanoyl N-methyl -glucamide, N-alkyl-N, N-dimethylglycine, 3- (acyldimethylammonio) alkanesulfonate, N-acylsulphobetane, polyethylene glycol octylphenyl ether, especially nonaethylene glycol octyl -phenyl ether, polyethylene acyl ether, especially nonaethylene dodecyl ether, polyethylene glycol isoacyl ether, especially octaethyleneglycol isotridecyl ether, polyethylene acyl ether, especially octaethylene dodecyl ether, polyethylene glycol ether sorbitan acyl ester such as polyethylene glycol-20-mono laurate (Tween 20) or polyethylene glycol-20-sorbitan monooleate (Tween 80), polyhydroxyethylene acyl ether, especially polyhydroxyethylene lauryl, myristoyl, cetyl stearyl or ololeoyl ether as polyhydroxy ethylene 4 or 6 or 8 or 10 or 12, etc.,-lauryl ether (as in the Brij series), or in the appropriate ester such as polyhydroxyethylene-8-stearate (Myrj 45), laurate or oleate or polyethoxylated castor oil 40, a sorbitan monoalkylate (e.g., Arlacel or Span), in particular sorbitan monolaurate, an acyl or alkanoyl N-methylglucamide, especially decanoyl or dodecanoyl-N-methyl- in glucamide, an alkyl sulphate (salt) such as lauryl or oleoyl sulfate, sodium deoxycholate, sodium glycodoxycolate, sodium oleate, sodium taurate, fatty acid salt such as sodium elaidate, sodium linoleide, sodium laurate, a lysophospholipid such as n-octadecylene (= oleoyl) glycerophosphatidic acid, forylglycerol or phosphoryl serine, η-acyl such as lauryl or oleoyl glycero-phosphatidic acid, phosphoryl glycerol, or phosphoryl serine, ntetradecylglycerophosphatidic acid, phosphoryl glycerol, or phosphoryl serine, a suitable palmitoleoyl, elaidoyl, vaccenyl lysophospholipid, or a suitable short chain phospholipid, or a surfactant polypeptide.
15. Referring to Figures 1-14. A method according to any one of claims 1 to 3, characterized in that the average diameter of the penetrating material is between 30 nm and 500 nm, more preferably between 40 nm and 250 nm, more preferably between 50 nm and 200 nm and particularly preferably between 60 nm and 150 nm.
16. Examples 1-15. Process according to any one of claims 1 to 4, characterized in that the total dry weight of the droplets in the composition is from 0.01 to 40% by weight of the composition, more preferably from 0.1 to 30% by weight, most preferably from 0.5 to 20% by weight.
17. References 1-16. A method according to any one of claims 1 to 3, characterized in that the at least one amphiphilic material and / or at least one edge active agent or surfactant and / or at least one hydrophilic liquid and the active ingredient are mixed together, if necessary, to form a solution, the resulting (partial ) mixtures or solutions are then sequentially combined, preferably by mechanical energy, such as shaking, stirring, vibration, homogenization, ultrasonic, shear, freezing and melting, or by filtration, to produce the penetrating material associated with the active ingredient. and / or include the active ingredient.
18. The method of claim 17, wherein the amphiphilic materials are in volatile solvents such as alcohols, especially ethanol, or other pharmaceutically acceptable organic solvents such as ethanol.
Figure 14
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EP1031346B1 (en) 1999-01-27 2002-05-02 Idea Ag Noninvasive vaccination through the skin
AU5409699A (en) * 1999-07-05 2001-01-22 Idea Ag A method for the improvement of transport across adaptable semi-permeable barriers
US7763663B2 (en) * 2001-12-19 2010-07-27 University Of Massachusetts Polysaccharide-containing block copolymer particles and uses thereof
CA2476859C (en) * 2002-03-13 2011-09-20 Collagenex Pharmaceuticals, Inc. Water-based delivery systems
US8435942B2 (en) 2002-05-31 2013-05-07 Transdermal Biotechnology, Inc. Methods for formulating stabilized insulin compositions
US20040018237A1 (en) 2002-05-31 2004-01-29 Perricone Nicholas V. Topical drug delivery using phosphatidylcholine
US20040057983A1 (en) 2002-09-25 2004-03-25 David Schmidt Biomolecular wearable apparatus
US20040105881A1 (en) * 2002-10-11 2004-06-03 Gregor Cevc Aggregates with increased deformability, comprising at least three amphipats, for improved transport through semi-permeable barriers and for the non-invasive drug application in vivo, especially through the skin
GB2398495B (en) * 2003-01-23 2007-08-22 Kent G Lau A drug delivery preparation comprising at least one anti-tumour drug and a topical carrier for the drug
TWI322008B (en) * 2003-01-31 2010-03-21 Kaneka Corp Fatigue improving agent including reduced coenzyme q10
US7354980B1 (en) 2004-03-12 2008-04-08 Key Medical Technologies, Inc. High refractive index polymers for ophthalmic applications
JP2008514606A (en) * 2004-09-24 2008-05-08 リポ ケミカルズ インコーポレイテッド Delivery systems for topically applied compound
US20080095722A1 (en) * 2004-11-12 2008-04-24 Idea Ag Extended Surface Aggregates in the Treatment of Skin Conditions
US7446157B2 (en) 2004-12-07 2008-11-04 Key Medical Technologies, Inc. Nanohybrid polymers for ophthalmic applications
CA2594546A1 (en) * 2005-01-14 2006-07-27 Lipo Chemicals, Inc. Composition and method for treating hyperpigmented skin
WO2008010788A2 (en) 2005-07-18 2008-01-24 University Of Massachusetts Lowell Compositions and methods for making and using nanoemulsions
DE102005051550A1 (en) * 2005-10-27 2007-05-03 Fibertex A/S Superhydrophobic coating a polymeric web, in particular a polypropylene non-woven fabric
US9486408B2 (en) 2005-12-01 2016-11-08 University Of Massachusetts Lowell Botulinum nanoemulsions
PT1959994T (en) 2005-12-01 2017-11-30 Univ Of Massachusetts Lowell Botulinum nanoemulsions
US9393218B2 (en) 2005-12-23 2016-07-19 Epinamics Gmbh Use of film-forming hair care polymers from the group of polyurethanes and pharmaceutical preparations and patches that contain these polymers
US20070154403A1 (en) * 2006-01-05 2007-07-05 Thomas Skold Oral, Pulmonary and Transmucosal Delivery Composition
JP5292304B2 (en) 2006-12-01 2013-09-18 アンテリオス, インコーポレイテッド Peptide nanoparticles and their use
JP2010528981A (en) 2006-12-01 2010-08-26 アンテリオス, インコーポレイテッド Amphiphilic entity nanoparticles
US7713196B2 (en) * 2007-03-09 2010-05-11 Nellcor Puritan Bennett Llc Method for evaluating skin hydration and fluid compartmentalization
KR20150028856A (en) 2007-05-31 2015-03-16 안테리오스, 인코퍼레이티드 Nucleic acid nanoparticles and uses therefor
EP2230911A4 (en) * 2007-12-21 2013-07-03 Zars Pharma Inc Patches, formulations, and associated methods for transdermal delivery of alprazolam and other drugs
US20090184047A1 (en) * 2008-01-14 2009-07-23 Sankaran Thayumanavan Functionalized nanopore membranes and related methods of use
US20090286907A1 (en) * 2008-01-23 2009-11-19 Beltz Mark W Fumaric Acid/Diol Polyesters and Their Manufacture and Use
US8602961B2 (en) * 2008-05-15 2013-12-10 Lifewave Products Llc Apparatus and method of stimulating elevation of glutathione levels in a subject
MX2010013562A (en) * 2008-06-26 2011-02-15 Anterios Inc Dermal delivery.
US20100009424A1 (en) * 2008-07-14 2010-01-14 Natasha Forde Sonoporation systems and methods
US20110033515A1 (en) * 2009-08-04 2011-02-10 Rst Implanted Cell Technology Tissue contacting material
WO2011022707A1 (en) * 2009-08-21 2011-02-24 Henk-Andre Kroon Vesicular formulations
WO2011073998A1 (en) * 2009-12-16 2011-06-23 Shasun Pharmaceuticals Limited Composition of dexibuprofen transdermal hydrogel
US20110316919A1 (en) * 2010-06-29 2011-12-29 Baldy Jr William J First drop dissimilarity in drop-on-demand inkjet devices and methods for its correction
AU2011353698B2 (en) * 2011-01-05 2017-05-11 Livon Laboratories Methods of making liposomes, liposome compositions made by the methods, and methods of using the same
CN103327965B (en) 2011-01-25 2017-07-18 宝洁公司 Liposomes and personal care compositions containing liposomes
US8668937B2 (en) 2011-03-17 2014-03-11 Transdermal Biotechnology, Inc. Topical nitric oxide systems and methods of use thereof
US20140017302A1 (en) * 2011-03-21 2014-01-16 Gregor Cevc Optimised preparations of highly adaptable aggregates
US8685106B2 (en) 2011-11-15 2014-04-01 Abraham Lin Method of a pharmaceutical delivery system for use within a joint replacement
EP2785201A1 (en) * 2011-11-29 2014-10-08 Unilever Plc. A meal intended for human consumption
US9656051B2 (en) 2011-12-01 2017-05-23 Avery Dennison Retail Information Services, Llc Devices with selectively permeable barriers
GB201205642D0 (en) 2012-03-29 2012-05-16 Sequessome Technology Holdings Ltd Vesicular formulations
US8871260B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Methods and compositions for muscular and neuromuscular diseases
US8871261B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Cancer treatments and compositions for use thereof
US8871259B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Techniques and systems for treatment of neuropathic pain and other indications
US8871254B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Systems and methods for treatment of acne vulgaris and other conditions with a topical nitric oxide delivery system
US8871257B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Prevention and treatment of cardiovascular diseases using systems and methods for transdermal nitric oxide delivery
US8871262B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Compositions and methods for treatment of osteoporosis and other indications
US8871256B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Methods and systems for treatment of inflammatory diseases with nitric oxide
US8871258B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Treatment and prevention of learning and memory disorders
US8871255B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Treatment of skin and soft tissue infection with nitric oxide
CA2925546A1 (en) * 2012-10-29 2014-05-08 The University Of North Carolina At Chapel Hill Methods and compositions for treating mucosal tissue disorders
US9339457B2 (en) 2013-03-13 2016-05-17 Transdermal Biotechnology, Inc. Cardiovascular disease treatment and prevention
US9849160B2 (en) 2013-03-13 2017-12-26 Transdermal Biotechnology, Inc. Methods and systems for treating or preventing cancer
US9314423B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Hair treatment systems and methods using peptides and other compositions
US9314433B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Methods and systems for treating or preventing cancer
US20140271938A1 (en) 2013-03-13 2014-09-18 Transdermal Biotechnology, Inc. Systems and methods for delivery of peptides
US9387159B2 (en) 2013-03-13 2016-07-12 Transdermal Biotechnology, Inc. Treatment of skin, including aging skin, to improve appearance
US9393265B2 (en) 2013-03-13 2016-07-19 Transdermal Biotechnology, Inc. Wound healing using topical systems and methods
US20140271731A1 (en) 2013-03-13 2014-09-18 Transdermal Biotechnology, Inc. Cardiovascular disease treatment and prevention
US9320706B2 (en) 2013-03-13 2016-04-26 Transdermal Biotechnology, Inc. Immune modulation using peptides and other compositions
US9295647B2 (en) 2013-03-13 2016-03-29 Transdermal Biotechnology, Inc. Systems and methods for delivery of peptides
US9393264B2 (en) 2013-03-13 2016-07-19 Transdermal Biotechnology, Inc. Immune modulation using peptides and other compositions
US9314422B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Peptide systems and methods for metabolic conditions
US9241899B2 (en) 2013-03-13 2016-01-26 Transdermal Biotechnology, Inc. Topical systems and methods for treating sexual dysfunction
US9724419B2 (en) 2013-03-13 2017-08-08 Transdermal Biotechnology, Inc. Peptide systems and methods for metabolic conditions
US9750787B2 (en) 2013-03-13 2017-09-05 Transdermal Biotechnology, Inc. Memory or learning improvement using peptide and other compositions
US9687520B2 (en) 2013-03-13 2017-06-27 Transdermal Biotechnology, Inc. Memory or learning improvement using peptide and other compositions
US9320758B2 (en) 2013-03-13 2016-04-26 Transdermal Biotechnology, Inc. Brain and neural treatments comprising peptides and other compositions
US9295637B2 (en) 2013-03-13 2016-03-29 Transdermal Biotechnology, Inc. Compositions and methods for affecting mood states
US9295636B2 (en) 2013-03-13 2016-03-29 Transdermal Biotechnology, Inc. Wound healing using topical systems and methods
US9314417B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Treatment of skin, including aging skin, to improve appearance
US20140271937A1 (en) 2013-03-13 2014-09-18 Transdermal Biotechnology, Inc. Brain and neural treatments comprising peptides and other compositions
US9511144B2 (en) 2013-03-14 2016-12-06 The Proctor & Gamble Company Cosmetic compositions and methods providing enhanced penetration of skin care actives
CN103285742B (en) * 2013-06-26 2014-09-03 浙江大学 Preparation method of quaternary ammonium salt type cationic polymer modified chitosan nanofiltration membrane
EP3019130A4 (en) * 2013-07-10 2016-12-14 Jie Zhang A kit for sustained transdermal drug delivery using liquid or semisolid formulations and method of using the same
EP3102185A1 (en) 2014-02-03 2016-12-14 Apurano Pharmaceuticals GmbH Nanosuspension of natural materials and preparation method thereof
RU2571072C1 (en) * 2014-11-24 2015-12-20 Гурам Георгиевич Сабаев Agent for treating and preventing itching dermatosis
AU2016247674A1 (en) * 2015-04-14 2017-10-19 Atossa Genetics Inc. Compositions and methods of treatment of breast disorders and estrogen-related disorders
WO2017079758A1 (en) * 2015-11-06 2017-05-11 Bkr Ip Holdco Llc Modified transdermal delivery device or patch and method of delivering insulin from said modified transdermal delivery device
CN105727773B (en) * 2016-03-02 2018-11-13 同济大学 The method of preparing a polymer separation membrane and stain Antibacterial
CN106176607A (en) * 2016-07-10 2016-12-07 中国农业科学院烟草研究所 Method for embedding tobacco chlorogenic acid nano-liposome
CN106669439B (en) * 2016-12-28 2019-04-16 前沿新材料研究院(深圳)有限公司 Reverse osmosis membrane of stable against biological contamination and preparation method thereof

Family Cites Families (110)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12680A (en) * 1855-04-10 Railroad-cab
US106345A (en) * 1870-08-16 Improvement in recording pressure-gages
US37877A (en) * 1863-03-10 Improvement in lining lead pipes with tin
US12849A (en) * 1855-05-15 Adams
US147238A (en) * 1874-02-10 Improve went in loom-harness
US48596A (en) * 1865-07-04 Improved washing-machine
US119188A (en) * 1871-09-19 Improvement in processes and apparatus for extracting fatty substances
US3179A (en) * 1843-07-20 Machine for sawing clapboards
US33273A (en) * 1861-09-10 Improvement in railroad-car wheels
US4369182A (en) * 1978-09-27 1983-01-18 A. Nattermann & Cie Gmbh Inflammation-preventing pharmaceutical composition of oral administration
JPH0240644B2 (en) 1979-05-02 1990-09-12 Kureha Chemical Ind Co Ltd
IL64397D0 (en) * 1981-01-07 1982-02-28 Weder Hans G Process for the preparation of liposomal medicaments
DE3374837D1 (en) * 1982-02-17 1988-01-21 Ciba Geigy Ag Lipids in the aqueous phase
EP0102324A3 (en) 1982-07-29 1984-11-07 Ciba-Geigy Ag Lipids and surfactants in an aqueous medium
USRE33273E (en) * 1982-08-18 1990-07-24 Georgia Tech Research Corporation Materials having improved nonfouling characteristics and method of making same
FR2542998B1 (en) * 1983-03-24 1986-01-31 Rhone Poulenc Sante New transdermal form isosorbide dinitrate
GB8321913D0 (en) * 1983-08-15 1983-09-14 Acacia Chem Ltd Spray method
EP0152379A3 (en) 1984-02-15 1986-10-29 Ciba-Geigy Ag Process for preparing pharmaceutical compositions containing unilamellar liposomes
US4897269A (en) * 1984-09-24 1990-01-30 Mezei Associates Limited Administration of drugs with multiphase liposomal delivery system
US4921706A (en) * 1984-11-20 1990-05-01 Massachusetts Institute Of Technology Unilamellar lipid vesicles and method for their formation
IN166447B (en) * 1985-11-27 1990-05-12 Ethicon Inc Method for the preparation of a sterile composition in the form of micro capsules
DE3542773A1 (en) * 1985-12-04 1987-06-11 Roehm Pharma Gmbh Skin Effective drugs with liposomes as wirkstofftraeger
US4937182A (en) * 1985-12-19 1990-06-26 Peralta Cancer Research Institute Method for predicting chemosensitivity of anti-cancer drugs
US5244678A (en) * 1986-01-14 1993-09-14 Ire-Celltarg S.A. Pharmaceutical composition containing a local anesthetic and/or centrally acting analgesic encapsulated in liposomes
FR2597367B1 (en) 1986-04-22 1988-07-15 Oreal A method for facilitating the formation of lipid spherules in dispersion in an aqueous phase and to improve their stability and their degree of encapsulation, and corresponding dispersions.
US5154930A (en) * 1987-03-05 1992-10-13 The Liposome Company, Inc. Pharmacological agent-lipid solution preparation
US4911928A (en) * 1987-03-13 1990-03-27 Micro-Pak, Inc. Paucilamellar lipid vesicles
US4855090A (en) 1987-03-13 1989-08-08 Micro-Pak, Inc. Method of producing high aqueous volume multilamellar vesicles
US4783450A (en) * 1987-04-13 1988-11-08 Warner-Lambert Company Use of commercial lecithin as skin penetration enhancer
US5238613A (en) * 1987-05-20 1993-08-24 Anderson David M Microporous materials
US4983395A (en) * 1987-11-12 1991-01-08 Theratech Inc. Device for administering an active agent to the skin or mucosa
US4849224A (en) * 1987-11-12 1989-07-18 Theratech Inc. Device for administering an active agent to the skin or mucosa
US4937078A (en) * 1988-08-26 1990-06-26 Mezei Associates Limited Liposomal local anesthetic and analgesic products
US5043165A (en) * 1988-12-14 1991-08-27 Liposome Technology, Inc. Novel liposome composition for sustained release of steroidal drugs
US4944948A (en) * 1989-02-24 1990-07-31 Liposome Technology, Inc. EGF/Liposome gel composition and method
WO1991001716A1 (en) * 1989-08-03 1991-02-21 Hisamitsu Pharmaceutical Co., Inc. Skin cream preparation for external use
US5104661A (en) * 1989-08-14 1992-04-14 Technology Unlimited, Inc. Reverse loading of liposomes
US5209720A (en) * 1989-12-22 1993-05-11 Unger Evan C Methods for providing localized therapeutic heat to biological tissues and fluids using gas filled liposomes
US6165500A (en) * 1990-08-24 2000-12-26 Idea Ag Preparation for the application of agents in mini-droplets
CA2067754C (en) 1990-08-24 2002-06-04 Gregor Cevc Preparation for the application of agents in mini-droplets
US5202125A (en) * 1990-12-10 1993-04-13 Theratech, Inc. Method and systems for administering nitroglycerin transdermally at enhanced transdermal fluxes
US5552160A (en) * 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
DE4107153A1 (en) 1991-03-06 1992-09-10 Gregor Cevc Compsns. for application of active agents
DE4107152C2 (en) 1991-03-06 1994-03-24 Gregor Cevc Preparations for non-invasive administration of antidiabetics
JP2922017B2 (en) 1991-03-25 1999-07-19 第一製薬株式会社 Oral lipid membrane structure
US5498420A (en) * 1991-04-12 1996-03-12 Merz & Co. Gmbh & Co. Stable small particle liposome preparations, their production and use in topical cosmetic, and pharmaceutical compositions
HU223343B1 (en) * 1991-05-20 2004-06-28 Novartis Ag. Pharmaceutical compositions and their preparation containing allylamine derivative
WO1992022292A1 (en) * 1991-06-10 1992-12-23 Schwarz Pharma Ag Nitroglycerine plaster and process for making it
GB9116610D0 (en) * 1991-08-01 1991-09-18 Danbiosyst Uk Preparation of microparticles
WO1993007902A1 (en) * 1991-10-16 1993-04-29 Richardson-Vicks, Inc. Enhanced skin penetration system for improved topical delivery of drugs
EG20380A (en) * 1991-10-16 1999-02-28 Richardson Vicks Inc Enhanced skin penetration system for improved topical delivery of drugs
US5985860A (en) * 1992-06-03 1999-11-16 Toppo; Frank System for transdermal delivery of pain relieving substances
AU4673993A (en) * 1992-07-28 1994-02-14 Procter & Gamble Company, The Pharmaceutical composition for topical use containing a crosslinked cationic polymer and an alkoxylated ether
DK0616799T3 (en) * 1993-03-24 2000-09-18 Collaborative Lab Inc Cosmetic application system for salicylic acid, and process for its preparation
WO1994026257A1 (en) 1993-05-06 1994-11-24 Lts Lohmann Therapie-Systeme Gmbh Transdermal therapeutic system containing estradiol
US5460820B1 (en) * 1993-08-03 1999-08-03 Theratech Inc Method for providing testosterone and optionally estrogen replacement therapy to women
FR2714601B1 (en) * 1993-12-30 1996-02-09 Oreal Depigmenting composition for the simultaneous treatment of the surface and deep layers, its use.
US5536263A (en) * 1994-03-30 1996-07-16 Lectec Corporation Non-occulusive adhesive patch for applying medication to the skin
US5540934A (en) * 1994-06-22 1996-07-30 Touitou; Elka Compositions for applying active substances to or through the skin
AT223202T (en) * 1994-09-30 2002-09-15 Mika Pharma Ges Fuer Die Entwi pharmaceutical composition
IT1270678B (en) * 1994-10-20 1997-05-07 Bayer Ag Liposomes to chetoprofen
US20020048596A1 (en) 1994-12-30 2002-04-25 Gregor Cevc Preparation for the transport of an active substance across barriers
DE4447287C1 (en) 1994-12-30 1996-11-07 Cevc Gregor Droplet-in-fluid composition to transport agent e.g. through skin
US5763422A (en) * 1995-01-27 1998-06-09 Board Of Regents, The University Of Texas System Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein
US5510118A (en) 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
IT1275955B1 (en) * 1995-03-22 1997-10-24 Dompe Spa Pharmaceutical formulations in form of thixotropic gel
US5654337A (en) * 1995-03-24 1997-08-05 II William Scott Snyder Topical formulation for local delivery of a pharmaceutically active agent
DE19512181C2 (en) * 1995-03-31 2003-11-06 Hexal Pharma Gmbh Transdermal system with ramipril and / or trandolapril as ACE inhibitors
DE19518221A1 (en) * 1995-05-10 1996-11-14 Schering Ag Use of nonsteroidal anti-inflammatory drugs to improve the physiological compatibility particulate pharmaceutical preparations
US6214386B1 (en) * 1995-11-22 2001-04-10 Recordati, S.A. Prompt-release oral pharmaceutical compositions for extemporaneous suspensions
US5716621A (en) * 1996-07-03 1998-02-10 Pharmadyn, Inc. Nonocclusive drug delivery device and process for its manufacture
US5783208A (en) * 1996-07-19 1998-07-21 Theratech, Inc. Transdermal drug delivery matrix for coadministering estradiol and another steroid
US5837289A (en) * 1996-07-23 1998-11-17 Grasela; John C. Transdermal delivery of medications using a combination of penetration enhancers
IL119417A (en) * 1996-10-13 2003-02-12 Moshe Kushnir Pharmaceutical composition for transdermal administration of levodopa for parkinson's disease
US6797276B1 (en) * 1996-11-14 2004-09-28 The United States Of America As Represented By The Secretary Of The Army Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response
US5891472A (en) * 1996-11-19 1999-04-06 Meri Charmyne Russell Treatment of equine laminitis
AU5777498A (en) * 1997-01-13 1998-08-03 Cilag A.G. Liposome-based topical tretinoin formulation
US6090800A (en) * 1997-05-06 2000-07-18 Imarx Pharmaceutical Corp. Lipid soluble steroid prodrugs
ES2284202T3 (en) * 1997-05-14 2007-11-01 Senju Pharmaceutical Co., Ltd. aqueous suspension preparations with excellent redispersibility.
US6083996A (en) * 1997-11-05 2000-07-04 Nexmed Holdings, Inc. Topical compositions for NSAI drug delivery
IT1298214B1 (en) * 1998-01-28 1999-12-20 Dompe Spa Salts of (r) 2- (3-benzoylphenyl) propionic acid and pharmaceutical compositions thereof.
US6193996B1 (en) * 1998-04-02 2001-02-27 3M Innovative Properties Company Device for the transdermal delivery of diclofenac
US6200598B1 (en) * 1998-06-18 2001-03-13 Duke University Temperature-sensitive liposomal formulation
SE9802864D0 (en) * 1998-08-27 1998-08-27 Pharmacia & Upjohn Ab Transdermally Administered Tolterodine as antimuscarinic agent for the treatment of overactive bladder
CN1391470A (en) 1998-09-03 2003-01-15 洛马林达大学医学中心 Pharmaceutical composition and method for treatment of inflammation
CA2356080C (en) * 1998-12-23 2009-05-12 Idea Ag Improved formulation for transportation of corticosteroid through pores of a barrier
US6294192B1 (en) * 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US6362227B1 (en) 1999-03-02 2002-03-26 Sepracor, Inc. Methods for the treatment of tinnitus and other disorders using R(−)ketoptofen
US7063859B1 (en) * 1999-04-28 2006-06-20 Noven Pharmaceuticals, Inc. Barrier film lined backing layer composition and method for topical administration of active agents
CA2377559A1 (en) * 1999-06-18 2000-12-28 Powerlung,Inc Pulmonary exercise device
AU5409699A (en) * 1999-07-05 2001-01-22 Idea Ag A method for the improvement of transport across adaptable semi-permeable barriers
JP2001036949A (en) * 1999-07-19 2001-02-09 Hitachi Ltd Method and system for radio communication
US6685928B2 (en) 1999-12-07 2004-02-03 Rutgers, The State University Of New Jersey Therapeutic compositions and methods
US6248353B1 (en) * 1999-12-10 2001-06-19 Dade Behring Inc. Reconstitution of purified membrane proteins into preformed liposomes
US6835394B1 (en) * 1999-12-14 2004-12-28 The Trustees Of The University Of Pennsylvania Polymersomes and related encapsulating membranes
US6562370B2 (en) * 1999-12-16 2003-05-13 Dermatrends, Inc. Transdermal administration of steroid drugs using hydroxide-releasing agents as permeation enhancers
US6582724B2 (en) * 1999-12-16 2003-06-24 Dermatrends, Inc. Dual enhancer composition for topical and transdermal drug delivery
US6645520B2 (en) * 1999-12-16 2003-11-11 Dermatrends, Inc. Transdermal administration of nonsteroidal anti-inflammatory drugs using hydroxide-releasing agents as permeation enhancers
US6586000B2 (en) * 1999-12-16 2003-07-01 Dermatrends, Inc. Hydroxide-releasing agents as skin permeation enhancers
EP1116485A3 (en) * 2000-01-10 2002-01-16 Gerhard Dr. Gergely Instant granulate and process for its preparation
US20020119188A1 (en) 2000-02-08 2002-08-29 Susan Niemiec Method of manufacturing liposomes
US6604698B2 (en) 2000-05-10 2003-08-12 Skyepharma Canada, Inc. Media milling
AU7789101A (en) 2000-07-26 2002-02-05 Alcon Universal Ltd Pharmaceutical suspension compositions lacking a polymeric suspending agent
US6387383B1 (en) * 2000-08-03 2002-05-14 Dow Pharmaceutical Sciences Topical low-viscosity gel composition
JP2002063747A (en) * 2000-08-18 2002-02-28 Sony Corp Recording medium, recording medium master plate, and method for manufacturing recording medium
US6868686B2 (en) * 2002-04-04 2005-03-22 Matsushita Electric Industrial Co., Ltd. Refrigeration cycle apparatus
US20040105881A1 (en) * 2002-10-11 2004-06-03 Gregor Cevc Aggregates with increased deformability, comprising at least three amphipats, for improved transport through semi-permeable barriers and for the non-invasive drug application in vivo, especially through the skin
US7387788B1 (en) * 2003-10-10 2008-06-17 Antares Pharma Ipl Ag Pharmaceutical compositions of nicotine and methods of use thereof
GB0417494D0 (en) * 2004-08-05 2004-09-08 Glaxosmithkline Biolog Sa Vaccine

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