EP2485719A1

EP2485719A1 - Transdermal therapeutic system

Info

Publication number: EP2485719A1
Application number: EP09850203.2A
Authority: EP
Inventors: Venkata Surya Jagannath Yedida
Original assignee: Individual
Current assignee: Individual
Priority date: 2009-10-07
Filing date: 2009-11-20
Publication date: 2012-08-15
Also published as: RU2012119297A; AU2009353789A1; EP2485719A4; WO2011042913A1

Abstract

Transdermal Therapeutic System comprising of pouch (1) made of metallic foil, polymeric film, paper, laminates of these or a combination thereof which is sealed over the ages thermally, ultrasonically by application of pressure, gluing or a combination thereof, scraper layer (2) made of polymeric or metallic or non metallic powder or particles coated thereon, backing layer (3) which is provided on the top of the pouch, adhesive embedded with a drug mesh or net (4) at the bottom which is in contact with the pouch.

Description

TRANSDERMAL THERAPEUTIC SYSTEM

BACKGROUND OF THE INVENTION

The present invention relates to transdermal therapeutic system

Drugs are normally administered and / or delivered in the body of patient by injections, tablets and syrups and like manner. Specific problems arise in the pharmaceutical industry for delivery of drugs in the body (which may be human or animal) by above forms of delivery. In view of above, various attempts have been made to deliver the drugs, medicinal and pharmaceutical ingredients in the body by other forms such as transdermally through the skin for which purpose various devices and / or methods have been devised.

Thus the use of transdermal therapeutic system for the delivery various drugs, medicines, pharmaceutical ingredients transdermally through the skin was an important field of drug delivery for the pharmaceutical industry, due to specific problems that arise with other forms of drug delivery like injections, tablets and syrups.

However, designing a practical transdermal therapeutic system patches for various drugs that can be delivered through the skin with pharmaceutically significant amounts has met with various problems like low adhesiveness, low tack, viscosity, drug reactivity with the skin, uneven drug delivery etc.

A few of the said problems are discussed herein below:-

1) Long term wearablity of transdermal patches over a time period from one day to more than seven days met with practical problems like decrease in adhesion, cold flow, erratic drug delivery, skin irritation, microbial growth at the application site etc.

2) Transdermal patches designed as matrix type, reservoir type, drug-inadhesive type, monolithic type, multi-layer type are available all over the world for various drugs and pharmaceutical ingredients and medicines, but they are not found economical, easy to manufacture , handle the same and are not eco- friendly.

These known transdermal patches are formulated from various adhesives like silicon, acrylic, rubber etc with various polymers and co-polymers, along with excipients, stabilizers, plasticizers, catalysts, anti-microbials and other substances like enhancers, co-enhancers, cross-linkers etc. For example, Patent EP0561983 describes a transdermal patch for nitroglycerin with acrylic adhesive and sorbitan monooleate, propylene glycol as excipients along with others.

Known transdermal patches generally have some of the following physical entities: release liner, rate control membrane, reservoir layers, adhesive layers, backing layer. As an example, .Chandrasekaran et al., U.S. Pat. No. 4,201,211, describes a five layer transdermal system. Similarly, Enscore et al, U.S. Pat. No. 4,559,222, a six-layer skin patch is disclosed with Clonidine as the drug ingredient with a backing layer, drug reservoir, control membrane, skin contact adhesive layer, a prime coat layer, and a release liner.

Finally transdermal patches are sealed in various size pouches that incorporate characteristics to suit various requirements to keep the transdermal patch away from atmospheric gases and dust as well as from moisture and provide necessary stability to the ingredients. The pouches or packages of the transdermal patches are generally made up of paper, metallic foils, polymer films or a combination thereof with incorporating various heat sealable components or pressure sealable components.

It is of common knowledge that the skin is impervious to many drugs and presents a significant barrier.

Furthermore Skin is generally covered with dust and dead cells that may act as additional barriers to drug transfer thus resulting in decrease in adhesion of the patch on the skin.

As skin is a major barrier for most of the drugs, transferring pharmacologically significant amounts of drugs in the body requires the use of various excipients, catalysts, enhances which increases the cost of the product and treatment.

To solve the above problem various attempts have been made and one of the such attempt had been to increase the surface area of the patch that is in contact with the skin increases the transfer of drug across the skin into the body but increasing in size in turn will increase the chance of dislodging of the patch from the skin as well as presenting a significant cosmetic problem for application over the body as well as a practical problem of finding the application site on the body that can carry the patch without bending or flexing it which is not desirable and liked by good number of patients.

One of the most important problems is that adherence of a transdermal patch over skin causes occlusion: trapping of moisture between the patch and the skin. Managing the degree of occlusion is an important aspect of designing a transdermal system. It effects the flux of drug across the skin significantly high degree of occlusion can decrease the adhesion of the patch, thus the patch can dislodge from the skin. On the other hand, little or in-significant occlusion can make the patch adhere aggressively with the skin and can result in skin irritation and as well as skin injury when the patch is removed. Occlusion by and large depends on the moisture vapor transfer rate (MVTR) characteristic of the backing layer. Thus composition of the backing layer is used to control the occlusion property of the patch.

Occlusion has bearing on the cold flow property of the adhesive component of the patch. As the occlusion decreases, the adherability of the adhesive over the skin increases and thus increasing the possibility of cold flow thus leaving adhesive deposits over the skin once the patch is removed after its use.

Transdermal patches are worn for extended time periods depending on the drug as well as its usage and generally span from one day to seven days. Once the time period is elapsed the patch needs to be removed and a new patch is to be worn. Compliance for this application procedure depends on the patient's recall of the time when he or she worn the patch. This results in significant patient compliance issues.

The drug ingredient has to diffuse though the skin barrier to be available to the body. The transfer of drug through the skin generally modeled along the Fick's laws of diffusion. The concentration of drug at the site of application profoundly effects the flux of drug across the skin barrier. Hence a high concentration of drug at the application site results in an increase of flux of drug through the skin into the body. One option to achieve a high concentration is to supersaturate the adhesive with drug. Another option was to create high concentrated deposits of drug formulation at various parts of the patch.

Thus the search for improved transdermal drug delivery system continues for application in pharmaceutical field for various drugs relating to therapies ranging various time periods.

SUMMARY OF THE INVENTION

It has been therefore long felt need to develop transdermal system particularly in patch form which obviates the disadvantages mentioned above and is more economical and practical and patient friendly to use and does not unnecessary create cosmetics problems which now a days is a major problem in the industry and in the pharmaceutical field.

These and above objects have been achieved by the transdermal system patch made according to teachings of the present invention which not only overcomes above disadvantages but also is easier to manufacture and use economical and patient friendly and does not create major cosmetic problems. -

A major aspect of the present embodiment is to provide a design for a increasing the drug concentration at the vicinity of the skin by incorporation of a drug formulation mesh or a net in close contact with the skin with an adhesive layer above it.

An aspect of the present invention is to provide a inclusive common physical layer that performs as a release liner as well as one side of the pouch that carries the transdermal patch.

Another aspect of the present embodiment is to provide for a in-built skin scraper or a cleaner as a part of the transdermal system that assists in removal of dust, debris, dead cells etc invariably present on the application site over the skin thus assisting in better adherability and improved drug transfer flux characteristics.

Yet another aspect of the present invention is to provide for a physical system that can control the degree of occlusion selectively over the area of the patch.

Another aspect of the present invention is to provide a unique design for application of large surface patches to various sites on the body.

A further aspect of the invention is to provide for a physical shaping of the transdermal patch for it to stay in place on the skin thorough out the time period of its intended use.

One important aspect of the present invention is to provide for a in-built color coded indicative system that can visually cue the patient for the removal of the patch and to put on a new one in needed.

The present invention provides for various design aspects of transdermal system patch that alleviate various problems described above as well as means to control them thus providing an improved design for a transdermal therapeutic system patch. According to present invention there is provided transdermal therapeutic system comprising of pouch(l) made of metallic foil, polymeric film, paper, laminates of these or a combination thereof which is sealed over the ages thermally, ultrasonically by application of pressure, gluing or a combination thereof, scraper layer (2) made of polymeric or metallic or non metallic powder or particles coated thereon , backing layer (3)which is provided on the top of the pouch, adhesive embedded with a drug mesh or net (4) at the bottom which is in contact with the pouch.

Said adhesive layer and drug mesh/ net combination is in close contact with the skin(5).

Said drug mesh is made of supersaturated drug in the form of solution powder, gel, particles on in a combination thereof, embedded, loaded, sprayed on to a various polymer fibers, strands such as polyethylene, polyester, polyurethane foam, polypropylene, PTFE, PBT, fabrics, non-woven, laminates and a combination thereof.

Permeation enhancers, stabilizers, catalysts, excipients or a combination thereof are included in the mesh as and when desired.

Final laminate is made with drug mesh, adhesive and backing layer.

In the said transdermal system, bands are used to keep the transdermal patch in place.

Said bands which may be extended are two or more in number and are attached to the side of transdermal patch which is made of metal foils, polymer films, woven fabrics, non-woven fabrics, laminates or a combination thereof.

Fine coat of bio-compatible adhesive is applied to the arms on the inner side which touch the skin.

If desired, two lines of fine mesh or net preferable transparent are used for cosmetic reasons.

Color coding cue is applied to transdermal patch which assists in improved compliances of the patient to remove the patch after desired time DETAILED DESCRIPTION OF THE INVENTION

We shall now describe the present invention with reference to accompanying drawings which are given by way of illustration but does not restrict the scope of the present invention.

Fig.l shows an embodiment of the present invention comprising of pouch, scraper layer, backing layer, adhesive embedded with a drug mesh or net at the bottom.

Fig.2A shows another embodiment of the present invention comprising of the backing layer incorporated with micro perforations or pin holes spanning various areas.

Fig.2B shows further embodiment of the present invention comprising of the backing layer incorporated with micro perforations or pin holes spanning various areas.

Fig.2C shows an embodiment of the present invention comprising of the backing layer incorporated with micro perforations or pin holes spanning various areas.

Fig.3 shows the view of backing layer, adhesive and drug mesh laminate applied at a site on the skin.

Fig.4 shows a schematic of the present invention comprising of physical entity shaping of transdermal patch.

Fig.5 shows an embodiment of the present invention with color coded cue developed over a defined time period.

Fig.6 shows yet another schematic of the present invention comprising of an alternative physical entity shaping of transdermal patch.

The pouch that carries the transdermal patch till the time of use is generally made of metallic foil, polymeric film, paper, laminates of these or a combination thereof. It is sealed over the edges thermally, ultrasonically, by application of pressure, gluing₍ or a combination thereof. A four side seal is preferred for the present embodiment. We shall now describe the various components of the transdermal system in detail:

1- Scraper component:

The scraper layer is made up of polymeric or metallic or non-metallic powder or particles that are coated preferably by a spray on to inner side of the upper layer of the pouch. The powder or particles can also be embedded into the pouch layer itself while it is manufactured from metallic foil, polymeric film, paper, laminates of these or a combination thereof. The particles preferably be coated or embedded firmly on the pouch layer so that they would not the dislodged while being used during the application.

Once the pouch is teared on all the four sides at the edges of the package, the top side portion of the pouch that has the scraper made underneath is used to rub over the skin to remove any dust, debris or dead cells from over the site of application. Removal of this debris generally results in improved adhesion as well as better permeation of the drug moiety across the skin barrier.

2- Pouch component:

The lower side of the pouch has the transdermal patch with backing layer on the top and the adhesive and the drug mesh/net at the bottom in contact with the pouch. (Fig.l)

The patch now can easily be removed from the lower side of the pouch by peeling of the un-eclipsed portion of pouch that is available beside the patch. This aspect of the present embodiment assists in quick removal of patch from the pouch and its subsequent application on the skin and additionally cuts down the amount of materials needed to manufacture the patch by removing the requirement of a release liner for the patch.

3- Backing Layer component:

The backing layer is made up of polymer film, paper, woven fabric, non-woven fabric, laminates of these or a combination thereof.

As occlusion depends on the moisture vapor transfer rate (MVTR) characteristic of the backing layer, various combinations of polymers and co-polymers ranging from polyethylene, polyester, polyurethane foam, polypropylene, PTFE, PBT, laminates and combination thereof are used. The present embodiment provides for an design element for precise control of occlusion. Fig. 2 illustrates the use of micro perforations, micro pin holes in various arrangements (A, B & C) on the backing layer.

Since a perforation provides a zero barrier for moisture transfer across the backing layer at that precise location, a fine control is made available by using location of the perforations as well as the number of perforation per square centimeter.

In Fig.2, arrangement A consists of perforation all over the backing layer. This embodiment provides almost zero occlusion aspect on to the transdermal patch which may result in aggressive holding of patch over the skin.

If a slight occlusion is preferable, number of perforations per square centimeter of the patch can be reduced thus effectively decreasing the moisture escape from the skin through the patch thus increase in occlusion.

Alternatively, in Fig.2, arrangement B shows perforations made along the perimeter of the backing layer. This arrangement provides for less occlusion but good adhesion along the edges of the patch while still providing for good amount of occlusion in the middle that helps the penetration of certain type of drug moieties across the skin.

Alternatively, in Fig.2, arrangement C shows perforations made around the center of the patch. This arrangement provides for less occlusion in the center but more at the edges of the patch. The patch in this design has less chance to develop cold flow as the occlusion is more at the edges of the patch.

4-Drug Mesh component:

The present embodiment provides for a adhesive layer and drug mesh/net combination in close contact with the skin as illustrated in Fig.3.

The adhesive layer is made of silicon, rubber, acrylic type of adhesives or a combination thereof. If desired the drug moiety can be dissolved into the adhesive to make a drug-in-adhesive formulation. Alternatively, a choice of permeation enhancers, stabilizers, catalysts, excipients or a combination thereof can be included in the adhesive Jayer as desired. As illustrated in Fig.3, the drug mesh is sandwiched between the adhesive layer and skin. This arrangement provides for a very close contact of the drug moiety with the skin. Since the drug concentration is very high (supersaturated) in the drug mesh, according to the diffusion model, an increase in flux of drug moiety across the skin is seen.

The drug mesh is made up of supersaturated drug in the form of solution, powder, gel, particles on in a combination thereof, embedded, loaded, sprayed on to various polymer fibers, strands like polyethylene, polyester, polyurethane foam, polypropylene, PTFE, PBT, fabrics, non-woven, laminates and a combination thereof. A choice of permeation enhancers, stabilizers, catalysts, excipients or a combination thereof can be included in the mesh as desired.

The final laminate is made with' drug mesh, adhesive and backing layer.

Since the adhesive layer adheres to the skin tightly, the sandwiched drug mesh is kept in close contact with the skin, without dislodging, thus assisting the drug to penetrate the skin in increasing amounts.

As the majority of the drug moiety is embedded into the mesh embodiment, and very little is embedded into the adhesive layer, better adhesion of the transdermal patch to the skin results.

5-Bands component:

Since the transdermal patch needs to stay in place on the skin for extended periods of time, formulations, tend to increase the adhesive strength thus increasing the chances of cold flow as well as skin irritation and inflammation.

Fig.4 illustrates a physical entity shaping with the use of bands to keep the transdermal patch in place without the increase of adhesive strength of the adhesive.

The two extended bands, as illustrated, attach to the side of the transdermal patch and are made of metal foils, polymer films, woven fabrics, non-woven fabrics, laminates or a combination thereof. A fine coat of bio-compatible adhesive is applied to these arms on the inner sides that touch the skin.

Transdermal patches are applied preferably to the arms. As-- illustrated in the embodiment in Fig.4, the extended bands wrap around the arm or the leg or a thigh and overlap on each other' at the other end. The patch is adhered to the site of application stays put without dislodging due to the extra strength that is provided by the bands.

An alternative is to use two lines of fine mesh or a net, preferably transparent for cosmetic reasons.

6-Color Code component:

Time based color coding cue (Fig.5) is an important aspect of the present invention. The development of a colored entity over the transdermal patch assists in improved compliance of the patient to remove the patch after the desired time period and put another one. As the time period can range from twelve hours to more than seven days in some instances, compliance is assured with this aspect of the present invention.

The color coding cue is bought in by the exposure of the transdermal patch to the atmosphere as it is removed from the protective pouch and applied on the skin.

Various organic dyes, organic molecules, chemical moieties, inorganic complexes or a combination thereof are used to formulate the color coder to bring about the color desired which is in contrast to the color of the backing layer so as to be starkly visible to the patient.

Constant and extended exposure of the color coding formulation to gases, carbon dioxide, nitrogen, moisture, preferably oxygen or a combination thereof is used to bring about the chemical, physical changes that appear as color development at the desired time period over the backing layer as illustrated in Fig.5.

Designing various formulations brings about color change at and about the desired time period that can span from twelve hours to more than seven days.

A color coding cue in the shape of a circle in the center of the transdermal patch on the backing layer is illustrated in Fig.5. Alternatively, any abstract shape or shapes desired can be incorporated. Additionally, if desired, words of required text can be printed using the color code formulation over the backing layer that appear and give instructions to the patient at the desired time period.

7-Shape component: Drug moieties differ widely in molecular size, chemical structure etc thus effecting the permeation of the drugs through the skin. Drugs^'like diclofenac, a pain reliever, permeate feebly through the skin.

Another important aspect is the therapeutic levels that are needed for a drug in the body to perform its functions.

In case of drugs like diclofenac, a combination of low permeability and the required high therapeutic levels dictate the size of the transdermal system.

The larger the surface area of the transdermal patch higher is the permeation of the drug moiety into the skin and quicker achievement of therapeutic levels in the body.

Large area patches have higher probability of folding, bunching when applied over the skin.

Occlusion control becomes another issue due the very nature of the size of the patch.

Another issue to be confounded with is the poor adherability of a large patch on the skin due to movement of skin tissues under the skin. Thus the patch is prone to dislodgement from the site of application.

Currently commercially available patches are mostly of rounded squares or rectangles. Ovals and circles are also commonly available.

As illustrated in Fig.6, as an embodiment of the present invention, the transdermal patch is shaped as a single band that is wrapped ^"around the site of application preferably around the arm or a leg or a thigh.

Once applied, the length of the patch is enough to go around the arm or the leg and to overlap the one end on the other.

The main aspect of the embodiment is the thinness of the patch thus providing better adherence and occlusion properties.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the claims under present invention.

Claims

WHAT CLAIMED IS:

1. Transdermal Therapeutic System comprising of pouch(l) made of metallic foil, polymeric film, paper, laminates of these or a combination thereof which is sealed over the ages thermally, "ultrasonically by application of pressure, gluing or a combination thereof, scraper layer (2) made of polymeric or metallic or non metallic powder or particles coated thereon , backing layer (3)which is provided on the top of the pouch, adhesive embedded with a drug mesh or net (4) at the bottom which is in contact with the pouch.

2. Transdermal Therapeutic System as claimed in claim 1 wherein said adhesive layer and drug mesh/ net combination is in close contact wit the skin(5).

3. Transdermal Therapeutic System as claimed in claim 1 or claim 2 wherein said drug mesh (4) is made of supersaturated drug in the form of solution powder, gel, particles on in a combination thereof, embedded, loaded, sprayed on to a various polymer fibers, strands such as polyethylene, polyester, polyurethane foam, polypropylene, PTFE, PBT, fabrics, non-woven, laminates and a combination thereof.

4. Transdermal Therapeutic System as claimed in any one of the claims 1 to

3 wherein permeation enhancers, stabilizers, catalysts, excipients or a combination thereof are included in the mesh as an when desired.

5. Transdermal Therapeutic System as claimed in any one of the claims 1 to

4 wherein final laminate is made with drug mesh, adhesive and backing layer.

6. Transdermal Therapeutic System as claimed in any one of the claims 1 to

5 wherein bands are used to keep the transdermal patch in place.

7. Transdermal Therapeutic System as claimed in any one of the claims 1 to

6 wherein extended bands which may be two or more in number or attached to the side of transdermal patch and are made of metal foils, polymer films, woven fabrics, non-woven fabrics, laminates or a combination thereof.

8. Transdermal Therapeutic System as claimed in claim 7 wherein a fine coat of bio-compatible adhesive is applied to the arms on the inner side which touch the skin.

9. Transdermal Therapeutic System as claimed in any one of the claims 1 to 8 wherein two lines of fine mesh or net preferable transparent are used for cosmetic reasons. lO.Transdermal Therapeutic System as claimed in any one of the claims 1 to 9 wherein color coding cue is applied to transdermal patch which assists in improved compliances of the patient to remove the patch after desired time