HK1068589B - Packaging system for transdermal drug delivery systems - Google Patents

Description

Packaging system for transdermal drug delivery systems

This application claims the benefit of provisional application No.60/285,976 filed on 23/4/2001.

Background

1. Field of the invention

The present invention relates to stabilizing a medicament in a packaged product. More particularly, the present invention relates to packaging systems for preventing degradation of drug products, particularly controlled release drug delivery devices such as transdermal systems.

2. Correlation technique

The use of transdermal drug delivery systems or "patches" as a means of topical administration is well known. Such systems dissolve or disperse the drug into a carrier composition, such as a polymer and/or pressure sensitive adhesive composition, from which the drug is released. These transdermal drug delivery systems are typically adhered to the skin or mucosa of the user and the drug diffuses from the adduct reservoir or layer into the skin or mucosa and is absorbed into the blood at a controlled rate. Such transdermal systems are described, for example, in U.S. Pat. Nos. 4,814,168, 4,994,267,5,474,783, 5,656,286, 5,958,446 and 6,024,976, which are incorporated herein by reference in their entirety.

Typical packaging systems for transdermal systems include enclosing them in a packaging material that is sealed to form a container, such as a sealed pouch, in which the system can be stored for extended periods of time before being removed and used. Several factors must be considered to ensure the storage stability of the packaged transdermal system.

Conventional transdermal systems incorporating solid or crystalline drugs require that the drug be dissolved in a polymeric and/or pressure sensitive adhesive composition to deliver a therapeutically effective amount. The ability of transdermal systems to deliver a therapeutically effective amount over their intended period of use requires that the active agent remain in an amorphous or dissolved form within the carrier composition prior to use.

The ability of transdermal systems to deliver therapeutically effective amounts over their intended period of use also requires that the drug remain stable (i.e., not degrade, transform, decompose, etc.) in its active form. The therapeutic activity of many drugs is related to their molecular conformation. Many drugs exist in different structural forms (being "chiral") with the ability to rotate the plane of plane polarized light. In describing such drugs, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center. The prefixes d and 1 or (+) and (-) are used to denote the sign of the rotation of a compound to plane polarized light, and (-) or 1 means that the compound is left-handed. The compound with the prefix (+) or d is dextrorotatory. There is no correlation between the nomenclature of absolute stereochemistry and the nomenclature of the rotation of enantiomers. Thus, D-lactic acid is equivalent to (-) lactic acid, and L-lactic acid is (+). For a given chemical structure, these chiral compounds exist as a pair of enantiomers (called stereoisomers) that are identical except that they are non-overlapping mirror images of each other. Particular stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomers or racemic mixtures.

Preventing drug degradation can be important because of the chirality of 50 of the first 100 drugs worldwide. See, e.g., s.c. stinson, Chemical & Engineering News, American Chemical Society, Washington, DC, vol.76(sept.21, 1998) pg.83; and Chiral Drugs ", S.C. Stinson, Chemical & Engineering News, American Chemical Society, Wasbington, DC, (Oct.9, 1995). One example is the L-form of the beta adrenergic blocker, propranolol, which is known to be 100-fold more potent than the D-enantiomer. In addition, some isomers may actually be deleterious rather than simply deactivated or inert. For example, the D-enantiomer of thalidomide is proposed to be a safe and effective sedative when administered for the control of morning sickness during pregnancy, while the corresponding L-enantiomer was identified as an effective teratogenic agent.

Therefore, any packaging material used to encapsulate a transdermal system must not absorb, react with, or otherwise adversely affect the drug or other excipient or component used in the transdermal system. For example, U.S. patent No.5,008,110 discloses that certain polyolefin materials used in transdermal devices are susceptible to absorption of lipophilic solvents and/or enhancers, which can significantly reduce the solubility of the drug in the carrier composition and cause physical failure of the packaging material. U.S. patent No. 4,943,435 discloses that nicotine can adversely affect many conventional transdermal system component materials such as adhesives, films, backing layers, and release liners. It has further been found that methylphenidate, a chiral drug which exists in 4 enantiomers and only one of which is currently considered to have significant pharmacokinetic activity, is unstable in the presence of certain types of packaging materials for transdermal systems.

It is also known that general environmental factors such as the presence of water (liquid or gaseous), air and light can adversely affect the stability of some drugs. See, for example, U.S. Pat. No.5,077,104. Such environmental factors can further affect the solubility of the drug in the carrier composition, thereby also significantly affecting the shelf life of the transdermal system. For example, the presence of moisture tends to promote the growth or crystallization of many drugs during storage in transdermal systems. Since only dissolved drugs can be released from transdermal systems, any packaging material enclosing transdermal systems must be provided with control against such environmental factors.

In the manufacture of packaged transdermal systems, the interior of the sealed package may, and often does, contain trapped moisture. The source of such moisture can include an amount of moisture that is entrained in the transdermal system components or upon exposure to the environment when the transdermal system is first packaged. To prevent or control the amount of moisture within such sealed packages, a variety of methods have been employed. These methods include drying of the starting material, further drying of the transdermal system or storage in a dry atmosphere prior to packaging, vacuum packaging or packaging in a dry room.

However, the ability to prevent or eliminate moisture within a sealed package, especially over long periods of storage, also depends on the moisture permeability of the packaging material. Therefore, packaging materials made of multiple layers, many of which incorporate metal foil, are often required to provide an environmental barrier. Such packaging requirements often make the material and production more costly and require controlled production to achieve a uniform and desirable level of water impermeability. Such packages may be difficult to open without the aid of mechanical tools such as scissors and, even the best packages, may still be permeable to moisture to some extent.

While careful control of manufacturing conditions and packaging materials can reduce the presence of moisture in sealed pouches containing transdermal systems, the use of desiccants is often still required.

The use of desiccants in packaged products is well known in the packaging industry. For example, U.S. patent No.5,322,161 discloses a package for packaging moisture sensitive materials. In this patent, the desiccant is stored in a desiccant bag. The desiccant can be molecular sieve and silica gel. The package of this patent also includes a heat seal layer for sealing the package.

Desiccant materials have also been used with pharmaceutical products. For example, U.S. Pat. No.5,698,217 discloses a method of inhibiting the precipitation of a drug in the presence of moisture to form a solid hydrate in a transdermal system. This patent achieves this by sealing the desiccant material within the same product package containing the transdermal system. The desiccant material is further sealed in its own package. Therefore, each individual transdermal system requires a package containing a desiccant. In addition, such desiccant packages and desiccant materials must be carefully selected to ensure compatibility and compatibility with the drugs and other components of the transdermal system in proximity or contact therewith (i.e., contamination control issues).

Us patent No.5,114,003 discloses a container or package for protecting water sensitive materials, characterised by a sealed desiccant canister attached to the inside of the container or package. The sealed desiccant is then perforated and the container sealed with a lid prior to insertion into the hygroscopic substance in the container.

U.S. patent No.6,050,400 discloses a packaging system for moisture sensitive drug substances comprising a moisture permeable inner container and a moisture impermeable and desiccant containing outer container sealing the inner container. This patent does not teach the use of a pouch for a transdermal system that is permeable to moisture vapor while meeting the packaging requirements for child-resistant packaging.

There is no teaching in the art of a cost effective packaging system for transdermal delivery systems that employs a desiccant and moisture permeable pouch within a container to preserve the transdermal system inert to the drug and other transdermal components to prevent degradation reactions of the drug caused by contamination of certain packaging materials and moisture while also providing a child-resistant package for the transdermal system. Furthermore, none of the prior art teaches the importance of controlling the packaging materials and moisture to prevent degradation reactions of the chiral drug and its pharmaceutically active enantiomer within the transdermal system.

The present invention relates to drugs, particularly chiral drugs and their pharmaceutically active enantiomers, that are stabilized in a carrier composition of a transdermal system prior to use of the system by providing a product packaging system to prevent or control degradation reactions that may be caused by certain packaging materials or moisture while providing a child-resistant package for the transdermal system.

Summary of The Invention

It is an object of the present invention to provide a cost effective packaging system for transdermal drug delivery systems that improves the contamination of the drug, such as crystallization and degradation, and protection from other environmental factors during storage of the system prior to use.

It is another object of the present invention to provide a packaging system for a transdermal system that does not significantly absorb, react with, or otherwise adversely affect the drug or other excipients or components of the transdermal system during storage prior to use of the system.

It is an object of the present invention to provide a packaging system that provides physical characteristics that meet the requirements of child-resistant packaging.

It is another object of the present invention to provide a packaging system for transdermal systems which improves the stability of the chiral drug and its pharmaceutically active enantiomer contained within the transdermal system during storage prior to use.

It is a further object of the present invention to provide a method of making a packaging system from materials that allow visual detection of its content.

The above and other objects of the present invention are achieved by providing a pouch for a transdermal system that is inert to the composition of the transdermal system, permeable to moisture to allow removal of moisture from the pouch, and is child-resistant. The pouched transdermal system is further sealed in a substantially moisture impermeable product package containing a desiccant material. The drug incorporated in the transdermal system remains substantially dissolved and stabilized in the carrier composition of the transdermal system free from desiccant or moisture contamination when the system is stored in the product packaging prior to use.

Brief Description of Drawings

Fig. 1 is a sectional view of a bag in an embodiment of a double-layered structure.

Fig. 2 is a cross-sectional view of a product package including a transdermal system-containing pouch and a desiccant, the pouch being in a two-layer configuration embodiment.

Detailed Description

The term "topical" or "locally" as used herein is its conventional meaning and refers to direct contact with an anatomical site or surface area on a mammal, including the skin, teeth, nails, and mucous membranes.

The term "mucosal membrane" as used herein refers to any mammalian moist anatomical membrane or surface such as the oral, buccal, vaginal, rectal, nasal or ocular surface.

The term "transdermal", as used herein, refers to the delivery of an active agent, either topically or systemically, into and/or through the skin or mucosa.

As used herein, "therapeutically effective" means an amount of a drug sufficient to obtain a desired local or systemic effect or result when topically applied during the intended use, e.g., for the prevention, cure, diagnosis, alleviation, or treatment of a disease or disorder. The necessary amount may be known from the literature or may be determined by methods known in the art, but is generally from about 0.1mg to about 20,000mg, and preferably from about 0.1mg to about 1,000mg, and most preferably from about 0.1 to about 500mg per 24 hours for an adult human or mammal of about 75kg body weight.

The term "system" as used herein is intended to broadly refer to transdermal drug delivery devices for topical application to a mammal for the purpose of providing some beneficial or therapeutic effect, and includes all patch-type devices, generally referred to in the art as reservoirs, matrices, adhesive matrices, liners, membranes and multilayer devices, iontophoretic devices, and medicated bandages and pads. Further details and embodiments of transdermal systems are described in U.S. patent nos. 4,994,267,5,006,108, 5,446,070, 5,474,787, 5,656,286, 5,719,197 and serial nos. 60/115,987 and 09/163,351, all assigned to Noven Pharmaceuticals, inc.

The term "carrier composition" as used herein refers to any non-aqueous material known in the art to be suitable for transdermal administration of drugs and includes any polymer in which a drug may be dissolved, alone or in combination or admixture with other additives and excipients, including solvents, penetration enhancers, diluents, stabilizers, fillers, clays, buffers, biocides, humectants, anti-irritants, antioxidants, preservatives, plasticizers, cross-linking agents, flavoring agents, colorants, pigments and the like. Regardless of the type of transdermal system used in the practice of the present invention, the carrier composition is preferably substantially free of water (i.e., the composition contains less than about 10% by weight water, preferably less than about 5% by weight, and most preferably less than about 3% by weight water, based on the total weight of the composition prior to topical application).

The term "solubilized" refers to the uniform dispersion or dissolution of the active agent at the crystalline, molecular, or ionic level in the carrier composition.

The term "degradation" as used herein refers to any change in the drug that may occur during storage in the transdermal system that results in (a) an adverse by-product, such as through hydrolysis or oxidation of the drug, or an adverse form, such as crystals, or (b) loss of the drug, such as through absorption into the transdermal system or other material within the pouch, or evaporation.

As used herein, "product package" broadly refers to a sealed package that is substantially impermeable to moisture vapor, which defines a space that contains and encloses a transdermal system sealed in a pouch and a desiccant within the product package. The term "substantially moisture vapor impermeable" means a moisture vapor transmission rate of no more than about 0.0002 g/day/2.5 cm at 40 ℃/75% Relative Humidity (RH)². Therefore, for a typical shelf life of two years, the product package should allow no more than about 1g of moisture to permeate through at 25 ℃/60% RH.

The term "bag" as used herein broadly refers to any packaging material containing or covering a transdermal system and sealed on at least one side. A bag may comprise two sheets or laminates of the packaging material of the present invention joined along all edges. It may also comprise a single layer or a laminate which has been folded and sealed at all edges, or sealed along all non-folded edges thereof. It may also comprise a bag or pouch sealed along one or more edges. The perimeter of the bag may be of any design, shape or form, irregular or regular. Regular shapes such as square, rectangular, circular and oval are preferred to facilitate the sealing and manufacturing process. Sealing may be performed by heat, ultrasound, laser, adhesive, and the like. The preferred packaging material is self-sealing (i.e., capable of forming a stable bond between two outer surfaces of the same material without the use of an adhesive).

In order to obtain effectively the so-called "child-resistant" mechanical strength characteristics (i.e. substantially reducing the ability of the child to open the container by hand, according toFederal RegisterRequirements cited in Vol.60, No.140, pp.37710-3744, 1995 for the Special Packaging of Household sustances with changes), preferably the pouch is a two-layer structure. While a single layer film or sheet may be used, a corresponding thickness is required which may affect other desirable properties such as moisture vapor transmission and self-sealing performance as well as increasing packaging costs.

The preferred packaging material for the base layer 11 of the pouch is a thermoplastic polymer that does not absorb, react with, or adversely affect the drug or other excipients or ingredients used in transdermal systems. A particularly preferred thermoplastic material is a nitrile rubber modified acrylonitrile-methyl acrylate copolymer. Such materials are disclosed, for example, in U.S. patent 3,426,102, and are sold under the trademark Barex by BP Chemicals, Inc., Cleveland, Ohio^*And (5) selling. Barex can be obtained^*Various material combinations of resins, e.g. Barex^*210, 2218 (which has a rubber modification content greater than 210) and 214. Barex is particularly preferred^*210。

In the practice of the preferred embodiment of the invention, the thickness of the base layer 11 is from about 0.5 mil/0.0127 mm to about 2.5 mil/0.0635 mm, more preferably from about 0.75 mil/0.01905 mm to about 1.5 mil/0.0381 mm, and even more preferably from about 1.0 mil/0.0254 mm to about 1.5 mil/0.0381 mm. Although thinner and thicker widths may be used, the inner layer 11 should not be so thin as to affect its permeability and stability, nor so thick as to adversely affect its self-sealing and packaging properties.

The second layer 12 may be a sheet or laminate comprising metal foil, polyethylenes, polyesters, vinyl acetate resins, ethylene/vinyl acetate copolymers, polyurethanes, polyvinyl chloride, woven and non-woven fabrics, cloth and paper. In a preferred embodiment of the invention, the thickness of the second layer 12 is from about 0.2 mil/0.00508 mm to about 3.0 mil/0.0762 mm, more preferably from about 0.2 mil/0.00508 mm to about 1.5 mil/0.0381 mm, and more preferably from about 0.5 mil/0.0127 mm to about 1.0 mil/0.0254 mm. While thinner and thicker widths may be used, the second layer 12 should not be so thin as to compromise the permeability and tear resistance of the bag, nor so thick as to adversely affect the main layer 11 and the packaging of the bag.

It is particularly preferred that the material used for the second layer 12 have a higher melting temperature than the base layer to provide a heat seal structure, and also be translucent (i.e., impart visible transparency) so as not to lose the ability to view and detect the contents of the bag. The preferred material for the second layer 12 is a polyester. Particularly preferred polyesters are those available and sold under the trademark Mylars by E.I. du Pont de Nemours and Company, Wilmington, Delaware^*And Melinex^*Sold under the trade and comprising Mylar^*S，Melinex^*S and Melinex^*800 polyester film.

The second layer 12 may be attached to the base layer 11 by any technique known in the art. Preferably by means of heat fusion or by means of an adhesive, in particular a pressure-sensitive adhesive. The use of adhesives is preferred for the purpose of achieving higher tear resistance, which is desirable in providing a child resistant package.

In the meaning of the term used herein, an adhesive is a pressure-sensitive adhesive if it has the properties of a pressure-sensitive adhesive by itself or if it has the properties of a pressure-sensitive adhesive by mixing with a tackifier, a plasticizer, a crosslinking agent, or other additives.

Pressure sensitive adhesives include all non-toxic natural and synthetic polymers known or suitable for use in transdermal systems, including solvent-based, hot melt and graft adhesives, and may be used alone or in combination, mixture or blend. Examples of suitable adhesives include polyacrylates, polysiloxanes, silicones, rubbers, gums, polyisobutylenes, polyvinyl ethers, polyurethanes, styrene block copolymers, styrene/butadiene polymers, polyether block amide copolymers, ethylene/vinyl acetate copolymers, and vinyl acetate based adhesives. Suitable polysiloxanes include those available and sold under the trademark BIO-PSA by Dow Corning Corporation, Midland, Michigan^*And (4) selling.

Pressure sensitive adhesives particularly suitable for practicing the present invention include polyacrylates of one or more monomers of acrylic acid or other copolymerizable monomers. Polyacrylate binders also include polymers of alkyl acrylates and/or alkyl methacrylates and/or copolymerizable secondary monomers, or monomers having functional groups. The term "polyacrylate" is used interchangeably with the terms acrylic acid, acrylate and polyacrylic acid as used herein and is well known in the art. Suitable pressure sensitive acrylic adhesives are available and are sold under the trademark DURO-TAK by National Starch and Chemical Company, Bridgewater, New Jersey^*And by Solutia, Inc., St.Louis, Missouri in GELAS^*Sold under Multipolymer Solution.

In the practice of the preferred embodiment of the package, the adhesive is applied to the second layer 12 and dried to a thickness that should preferably not exceed about 1 mil/0.0254 mm, and preferably range from about 0.3 mil/0.00762 mm to about 0.75 mil/0.01905 mm, after which the adhesive-coated second layer 12 is pressure sealed to the base layer 11.

Whatever material or structure is used to construct the pouch that does not significantly absorb, react with, or otherwise adversely affect the drug or other excipient or component used in the transdermal system, and at the same time meets the requirements of a child-resistant package, it must also be capable of permeating water vapor for removal by an external desiccant. Preferably, the pouch is preferentially permeable to moisture vapor rather than the non-aqueous components or drugs of the transdermal system. The term "preferentially water vapor permeable" means that the package has a water vapor transmission rate of no more than about 2.5 grams per hour per square meter at 40 deg.C/95% RH as determined by the method described in ASTM E-96-95 according to the water vapor transmission of American Society of Testing and Materials (ASTM).

In order to provide protection to the drug from light, which may be further degraded by light, it may be desirable to use a modified form of the material of the second layer 12. For example, the material may be dyed to provide an incomplete barrier which is only affected by certain wavelengths of light, or which is substantially opaque as in metallized polyester films.

Referring to fig. 1, there is shown a cross-sectional view of a preferred embodiment of a pouch 9 containing a transdermal system 10 of the present invention. A base layer 11 comprising a nitrile rubber modified acrylonitrile methyl acrylate copolymer is attached to a second layer 12 comprising a polyester by an adhesive 13. The laminate in the form of the package 9 may be sealed at the edges, for example by heating.

The present invention relates generally to an improved packaging system for transdermal systems containing methylphenidate. Methylphenidate exists in four enantiomers, which are the (2R: 2 'R) - (+) -threo-enantiomer, (2S: 2' S) - (-) -threo-enantiomer, (2R: 2 'S) - (+) -erythro-enantiomer, and (2S: 2' R) - (-) -erythro-enantiomer, but only d-threo-methylphenidate is currently generally considered to have significant activity. An "active" enantiomer refers to a chiral pharmaceutical isomer having higher pharmacokinetic activity than its counterpart enantiomer. The major degradants include ritalinic acid and erythro enantiomers (d: l and l: d). The term "degradant" as used herein refers to any impurity, metabolite, non-metabolite, enantiomer, etc. that has no or very low pharmacokinetic activity or desirable beneficial effect when compared to its drug molecule or another enantiomer when used for a particular therapeutic purpose.

In the presence of moisture, the formation of ritalinic acid by hydrolysis of methylphenidate is observed. It was further found that contact with moisture resulted in the formation of the erythro enantiomer. While not wishing to be bound by a particular scientific theory, it is believed that this degradation reaction involves the formation of enolate as a reaction intermediate, which subsequently undergoes autoxidation and racemization. In non-aqueous carrier compositions that provide a low or non-polar environment, water promotes enolate formation by lowering the overall degradation reaction activation energy. Thus, other drugs that contain ketone, aldehyde, ester or benzyl functionalities and also form enolates, such as norethindrone (norethindone), norethindrone acetate, and estradiol, benefit by preventing moisture contamination in transdermal systems.

While particularly preferred embodiments of the present invention relate generally to transdermal systems containing methylphenidate, particularly in the form of its free base, packaging materials suitable for use in the present invention are systems suitable for containing any drug that is incompatible (unstable) with conventional packaging materials, as described in the examples herein (e.g., polyethylene or polypropylene). Such drugs include chiral drugs, e.g., ceftriaxone, thalidomide, propranolol, ibuprofen, ketoprofen, naproxen, peroxetine, finasteride, sertraline, paclitaxel, terfenadine, verapamil, enalapril, lisinopril, ifosfamide, methyldopa, indacrinone, bupivacaine, loxigumide, amlodipine, pyridinium, levalslmedan, ondansetron, salmeterol, ketorolac, doxazosin, cisapride, salbutamol, oxybutynin, selective 5-hydroxytryptamine reuptake inhibitors such as fluoxetine, loratadine, fexonandine, cetirizine, formoterol, tamarides such as sumatriptan, doxazosin, zolpidem, sibutramine, atovavan, nalalol, naltrexofenadine, citalopram, citalopidine, glitazobactam, glitazone, oxsultam, olazone, lorazepam, loxopropioglitazone, oxsultam, loxacin, omeprazole, levofloxacin, captopril and diltiazem.

It should be understood that while the description of the exemplary embodiments is primarily directed to transdermal systems containing methylphenidate, particularly in its free base form, the present invention also encompasses any drug that forms crystals or degradants in the presence of moisture.

The term "drug" as used herein is intended to have the broadest possible meaning and may be used interchangeably with active agents, drugs, medicaments and any substance intended to provide a beneficial effect (including therapeutic, prophylactic, pharmacological or physiological substances), cosmetic and personal care formulations, and mixtures thereof. More specifically, any substance capable of producing a local or systemic pharmacological response, whether therapeutic, diagnostic, cosmetic or prophylactic, is contemplated by the present invention. It should be noted that the drugs may be used alone or in combination and mixture. Although there is no limitation on the type of active agent that may be used in the present invention, drugs that are solid at room temperature are preferred.

The active agent contained in the carrier composition may be in different forms depending on solubility and desired release properties, for example as a neutral molecule, a component of a molecular complex, and a pharmaceutically acceptable salt, free acid or base, or a quaternary ammonium salt thereof. Simple derivatives of the drug, such as pharmaceutically acceptable ethers, esters, amides, etc., as well as enzymes, pro-active forms, prodrugs, etc., which have the desired retention and release characteristics, but are readily metabolized at body pH, may be used.

The product packaging of the present invention should separate and protect its contents from ambient environmental factors such as moisture, air and light that may adversely affect them. Suitable packaging materials for use as product packaging are well known in the art and include polyethylene, polyester, polypropylene, polyurethanes, polyolefins, polyvinyl alcohol, polyvinyl chloride, polyvinylidene, polyamide, vinyl acetate resin, BAREX^*Ethylene/vinyl acetate copolymer, ethylene/ethyl acrylate copolymer, metal vapor deposited film or sheet thereof, rubber sheet or film, expanded synthetic resin sheet or film, nonwoven fabric, foil and paper. Such materials may be used alone, in combination, as laminates (cold seal, heat seal or full or patterned coating with natural or synthetic adhesives) or as coextrudates, provided they provide the desired permeation and barrier properties to the external environment.

The product package may be shaped in any manner and may be flexible or rigid. It may comprise two sheets joined along all of their edges. It may also comprise a single sheet or laminate folded and sealed along all of its edges, or sealed along all of its non-folded edges. May further comprise a bag or pouch sealed along one or more edges. Alternatively, the product package may be moulded or formed into the shape of an open container, for example a tube or box, and a lid or cover made from the second sheet of packaging material sealed around its periphery. The lid or cover may be made of the same or different packaging material and is resealable. When a piece of packaging material is used as the lid, it is preferred to have a laminate of foil, paper or nylon to create a suitable surface for the printed product information and to provide sufficient water impermeability. Sealing may be accomplished by any suitable method, such as by a conventional sealed pressure device, or by laser, heat, ultrasound, adhesive, and the like.

In a preferred embodiment, the product package is substantially rigid and comprises a 46 mil/1.1684 mm polypropylene-based backsheet 18 formed into an open tubular shape. Polypropylene is a relatively inexpensive material that can be used alone as a single piece, easily molded or formed into a predetermined shape, and is reusable. A 5 mil/0.127 mm polyethylene/foil/nylon coextensive laminate lidding sheet 16 was then heat sealed to the tube opening. A reusable patch of suitable packaging material such as polyester or polypropylene may further be used to continue to maintain the pouched transdermal system in a dry environment after the cover sheet 16 is removed until the supply of the system is exhausted.

The size of the container should be sufficient to accommodate at least one month of supply of the pouched transdermal system (i.e., about 30) and up to three months of supply. Having a width of about 35 square inches/88.9 cm²The surface area product package preferably contains the contents as well as a desiccant material.

The type of desiccant material that can be used will depend on the nature of the composition of the transdermal device and can be determined by one skilled in the art through routine experimentation. Materials suitable for use as desiccants include oxides of aluminum, calcium, titanium, zirconium, silicon, thorium, magnesium and barium, alumina hydrates, natural and synthetic molecular sieves, silica gels, precipitated silicas, clays, perchlorates, zeolites, natural gums, magnesium or calcium sulfate, calcium chloride, lithium or cobalt chloride, and calcium carbonate. While moisture-selective desiccant materials, such as molecular sieves, may be used, it is preferred to use packaging bags that substantially prevent or control the permeation of the drug or any non-aqueous high vapor pressure component or other excipient (e.g., glycols) or drug. Indicator dyes may also be added to the desiccant material to monitor the amount of moisture absorbed during storage of the product package. The desiccant material is compatible with the particular transdermal system.

The amount of desiccant that can be used will depend on several factors, including the water permeability of the various types of materials used in preparing the package and product packaging, the moisture absorption capacity of the particular desiccant material, and the predetermined shelf life of the transdermal system. The minimum amount used is an amount effective to absorb water vapor in the product packaging over a predetermined shelf life of the transdermal system, typically two years, and to achieve an acceptable level of drug loss due to crystallization or degradation in order to deliver a therapeutically effective amount of the drug. The desiccant should be capable of absorbing at least about 1.5g to about 5g of moisture over a predetermined shelf life and use of the product package. The amount of desiccant material needed to prevent moisture contamination can be determined by one of ordinary skill in the art by providing routine experimentation.

Barex contained in a package sealed to a polypropylene product^*In a preferred embodiment of the packaging system comprising methylphenidate transdermal system in a/adhesive/polyester laminated heat-sealed pouch, the preferred desiccant material is about 4-5 grams of silicone gel.

Suitable desiccant materials may be incorporated in the product packaging in any manner, including compressed pellets, or sealed within a receptacle such as a capsule, sachet, or container. Any material that is permeable to moisture vapor and that does not react with or adversely affect (e.g., by leaching or absorption) the components of the transdermal system or other materials used in the package or product packaging is suitable for forming the desiccant reservoir. Such materials include polyethylene, polyethylene terephthalate, polypropylene, coated and uncoated paper, and perforated sheets and laminates. A preferred material for the desiccant reservoir is a non-woven polyolefin.

The packaging system may be prepared by loading the contents of the product package (i.e., the package and desiccant) by any suitable or conventional manufacturing operation and sealing method. Referring to fig. 2, a cross-sectional view of a product package of a preferred embodiment of the present invention is shown containing the plurality of pockets 9, desiccant 15, substrate sheet 18, cover sheet 16 and reusable lid 17 of fig. 1.

Examples

The following method illustrates how transdermal systems are prepared in general and specifically described for use in bags of the different packaging materials described in the experimental examples.

Transdermal systems containing methylphenidate in free base form and containing about 50% d-threo-methylphenidate and 1-threo-methylphenidate, respectively, in a pressure sensitive adhesive carrier composition were prepared by combining 6.0 parts methylphenidate base with 4.5 parts ethyl cellulose (Ethocels)^*20, dow chemical corp., Midland, Michigan) and mixed in 22.75 parts of ethyl acetate followed by the addition of 8.6 parts of a polyacrylate adhesive (GMS 3067; solutia inc, st. louis, Missouri) and 24.5 parts of a silicone adhesive (BIO-PSA)^*7-4302; dow corning corp., Midland, Michigan) and mixed well. The carrier composition was then wet cast at 20 mils using a wet open bar over a fluorocarbon release liner (Scotch Pak)^*1022, 3M, Minneapolis, Minnesota) and passed through an oven to evaporate off the volatile solvent. Laminating the dried composition to a (polyester) backing film (Scotch Pak)^*1012, 3M, Minneapolis, Minnesota). The carrier compositions have the ingredient concentrations on a dry weight basis as shown below.

Components	Dry weight%
		Silicone adhesive (BIO-PSA)*7-4302) polyacrylate Binder (GMS3067) Ethyl cellulose (Ethocels)*20) Methylphenidate base	50151520100

10cm²The transdermal system samples were then die cut and placed at 2.5in²/6.3cm²The heat-sealed bag of (1), the bag comprising a plurality of material combinations as described in each of the following examples.

Example 1: will Barex^*210 was heat laminated to 0.35/0.00889mm mil aluminum foil. The aluminum foil was then bonded with 35# Kraft paper using an adhesive (a laminate made by Richmond Technology, Redlands, California).

Example 2: barex laminated with a urethane adhesive to a polyester film^*210, 1.25 mil/0.03175 mm film is commercially available as 94035 and is sold by Lawson Mardon (Shelbyville, Kentucky).

Example 3: barex is treated with an adhesive^*210 was laminated with aluminum foil, which was subsequently laminated with an adhesive to a polyester film, commercially available as 90580 and sold by lawson mardon.

Example 4: barex^*210 (available from Greenway plastics Industries Corporation, Wayne, N.J.).

Example 5: same as in example 1.

Example 6: scotch Pak^*1012 2.0 mil/0.0508 mm film (a polyester film laminated to an ethylene/vinyl acetate heat seal layer made by 3M).

Example 7: scotch Pax^*1009 2.0 mil/0.0508 mm film (a polyester film laminated to aluminum foil and ethylene/vinyl acetate heat seal layer made by 3M).

Example 8: a3 mil/0.0762 mm film of a proprietary laminated barrier film is commercially available as 5488-.

Example 9: barex laminated to 2 mil/0.0508 mm polyester film with acrylate adhesive^*210 (Duro-Tak available from National Starch and chemical corporation, Bridgewater, N.J.) at 1.25 mil/0.03175 mm^*87-2296)。

Example 10: same as example 9 except that 0.92 mil/0.02337 mm polyester film was used.

Example 11: the same as example 9 except that a 0.2 mil/0.00508 mm polyester film was used.

Example 12: a 3 mil/0.0762 mm film of a proprietary laminated barrier film, commercially available as 5488-99A and sold by Kappler Protective apparatus & Fabrics, inc.

Example 13: 2 mil/0.0508 mm polyester film.

Example 14: barex^*210 was heat sealed to a 1.25 mil/0.03175 mm film in a 2 mil polyester heat sealed bag.

Each sample containing 3 samples of the transdermal system was then placed in an oven at 80 ℃ for 4 days to accelerate aging (i.e., simulating shelf life storage of about 2 years). The transdermal system was then removed from the package and placed in an extraction solution of acidified methanol after removal of the release liner. The extraction solution containing the system was sonicated for 45 minutes at room temperature. Aliquots were thereafter extracted and the percentage of degradants and active drug loss were judged and measured by high pressure liquid chromatography assays.

The same extraction procedure was used for the pouch material to determine and measure the amount of active drug absorbed by the material (i.e., d-threo-methylphenidate) in mg on a dry weight basis. The results are shown in Table I.

TABLE I

Examples	Total degradation%	Loss of drug (%)	MedicinePhysical absorption (mg)
				1*	0.1	0	0.108
2	9.7	10.1	0.440
				3	25.3	23.7	0.254
4	8.6	6.2	0.265
				5	15.0	14.1	0.209
6	8.3	16.9	2.979
				7	8.6	19.2	3.182
8	8.5	12.1	1.692
				9	8.7	7.9	0.176
10	8.7	6.6	0.107
				11	8.6	6.9	0.117
12	8.7	21.4	2.217
				13	8.6	4.8	0.204
14	8.7	6.2	0.147

^*Example 1 was used as a control, which was stored at room temperature for 4 days.

Significant drug loss was also observed in the presence of vinyl acetate. Use of Barex^*And polyester film laminates have been demonstrated to have good stability over time.

After being placed at 2.5in²/6.35cm²25cm inside a heat-sealed bag containing the material described in example 10²The effect of using a desiccant to control degradation caused by moisture contamination was tested in the transdermal system sample (prepared as above).

About 40 bags were placed in two desiccators that were not permeable to moisture vapor. In one dryer, the bottom is lined with particles of the dry salt calcium sulfate. The desiccator was then placed in an oven at 40 ℃ and 75% relative humidity for 1 month to accelerate aging. After removal of the bags from the dryer, three bags were randomly selected and the transdermal systems contained therein were placed in an extraction solution of acidified methanol after removal of the release liner. The extraction solution containing the system was sonicated for 45 minutes at room temperature. Aliquots were thereafter extracted and the percentage content of the main degradants, Ritalinic Acid (RA) and erythro-isomers (EI), was determined and measured by high pressure liquid chromatography testing.

The same extraction method was used to determine and measure the amount of major degradants in three samples in a control bag set, which were kept frozen at 8 ℃ and 2% relative humidity to reduce susceptibility to degradation at room temperature. The results are shown in Table II.

TABLE II

Examples	％RA	％EI	Total% degradants
				Non-drying 1	2.60	2.27	4.87
Non-drying 2	2.57	2.26	4.81
				Non-drying 3	2.57	2.27	4.81
Drying 1	0.33	0.69	1.02
				Drying 2	0.34	0.67	1.01
Drying 3	0.34	0.69	1.03
				Control 1	0.34	0.32	0.66
Control 2	0.32	0.32	0.64
				Control 3	0.33	0.30	0.63

Claims (18)

1. A product packaging system for preventing drug degradation in a carrier composition of a transdermal drug delivery system, comprising: (a) a substantially moisture impermeable and sealable product package, and (b) a desiccant, characterized in that the product package contains one or more moisture permeable bags comprising:

(i) a base layer that does not absorb a drug or a reactive thermoplastic material;

(ii) a second layer of sheet or laminate selected from the group consisting of metal foil, polyethylene, polyester, vinyl acetate resin, ethylene/vinyl acetate copolymer, polyurethane, polyvinyl chloride, woven fabric, nonwoven fabric, cloth and paper, secured to the base layer by means of heat or adhesive; and

(iii) transdermal drug delivery systems containing a therapeutically effective amount of a drug in a non-aqueous carrier composition, each sealed in one or more pouches,

wherein the one or more pouches and desiccant are sealed in the product package.

2. The product packaging system of claim 1, wherein the product packaging comprises a barrier material selected from the group consisting of thermoplastics, foils, and papers.

3. The product packaging system of claim 1, wherein the one or more bags are self-sealing.

4. The product packaging system of claim 1 wherein the base layer is a nitrile rubber modified acrylonitrile-methyl acrylate copolymer and the second layer is a polyester.

5. The product packaging system of claim 1, wherein the transdermal drug delivery system comprises a therapeutically effective amount of a chiral drug.

6. The product packaging system of claim 5, wherein the chiral drug is methylphenidate.

7. The product packaging system of claim 1, wherein the desiccant is capable of absorbing at least 1.5 grams of moisture over a 1 year shelf life.

8. The product packaging system of claim 1 wherein the product package is formed into a container shape having an opening and a substantially moisture impermeable cover coextensive with said opening and secured by heat or adhesive means.

9. The product packaging system of claim 8, wherein the product packaging comprises polypropylene.

10. The product packaging system of claim 8, wherein the product package further has a reusable lid on top of the flap.

11. The product packaging system of claim 8, wherein the one or more bags are self-sealing.

12. The product packaging system of claim 8, wherein the one or more pouches are child-resistant.

13. The product packaging system of claim 8 wherein the base layer is a nitrile rubber modified acrylonitrile-methyl acrylate copolymer and the second layer is a polyester.

14. The product packaging system of claim 8, wherein the transdermal drug delivery system comprises a therapeutically effective amount of a chiral drug.

15. The product packaging system of claim 14, wherein the chiral drug is methylphenidate.

16. The product packaging system of claim 8, wherein the desiccant is capable of absorbing at least 1.5 grams of moisture over a 1 year shelf life.

17. A product packaging system for protecting a drug from degradation in a carrier composition of a transdermal delivery system having (a) a substantially moisture impermeable and thermoplastic product package formed into a container shape having an opening and a substantially moisture impermeable cover sheet coextensive with the opening and secured by heat or adhesive means, and (b) a desiccant, characterized in that the product package contains one or more child-resistant moisture permeable pouches comprising:

(i) a base layer of a nitrile rubber modified acrylonitrile-methyl acrylate copolymer;

(ii) a second layer of polyester, which is fixed to the base layer by means of heat or adhesive; and

(iii) a transdermal drug delivery system comprising a therapeutically effective amount of methylphenidate in a non-aqueous carrier composition, said transdermal drug delivery system each sealed in one or more pouches,

wherein the desiccant is capable of absorbing at least 1.5g of moisture over a 1 year shelf life, and the one or more pouches and desiccant are sealed in the product packaging.

18. A product packaging system for protecting a drug from degradation in a carrier composition of a transdermal delivery system having (a) a substantially moisture impermeable and flexible product package shaped into a pouch and (b) a desiccant, characterized in that the product package contains one or more child-resistant moisture permeable pouches comprising:

(i) a base layer of a nitrile rubber modified acrylonitrile-methyl acrylate copolymer;

(ii) a second layer of polyester, which is fixed to the base layer by means of heat or adhesive; and

(iii) a transdermal drug delivery system comprising a therapeutically effective amount of methylphenidate in a non-aqueous carrier composition, said transdermal drug delivery system each sealed in one or more pouches,

wherein the desiccant is capable of absorbing at least 1.5g of moisture over a 1 year shelf life, and the one or more pouches and desiccant are sealed in the product packaging.