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Transdermal drug delivery device containing a desiccant

Abstrict

A transdermal drug delivery device involving a carrier containing a dissolved drug. The device also involves a desiccant package that is inert to the carrier, permeable to water vapor, and defines a desiccant compartment containing a desiccant. The device also involves water vapor impermeable product package that contains the carrier and the desiccant package.

Claims

The claimed invention is:

1. A method of inhibiting precipitation of a drug in the carrier of a transdermal drug delivery device, comprising the steps of: (i) providing a non-aqueous carrier comprising a dissolved drug that forms a solid hydrate when exposed to water vapor;

(ii) providing a desiccant package permeable to water vapor and defining a desiccant compartment containing a desiccant; and

(iii) placing said desiccant package and said carrier within a substantially sealed water vapor impermeable product package.

2. A method according to claim 1 wherein the desiccant is a synthetic or natural zeolite molecular sieve.

3. A method according to claim 2 wherein the zeolite molecular sieve is selected from the group consisting of 3A, 4A, and 5A molecular sieve.

4. A method according to claim 2 wherein the drug is estradiol.

5. A method according to claim 4 wherein the carrier comprises a pressure sensitive adhesive.

6. A method according to claim 1 wherein the desiccant package is immobilized within the product package.

7. A method according to claim 1 wherein the desiccant package comprises a first base sheet and a first coextensive cover sheet sealed together around their periphery and the product package comprises a second base sheet and a second coextensive cover sheet sealed together around their periphery.

Description

BACKGROUND OF THE INVENTION

1. Technical Field

This invention relates to transdermal drug delivery devices. In another aspect this invention relates to devices for delivering drugs to and/or across the skin. In yet another aspect, this invention relates to methods of inhibiting precipitation of drugs in a transdermal drug delivery device.

2. Description of the Related Art

Transdermal drug delivery can provide significant advantages as compared to other routes of drug delivery. For example in contrast to injection it is non-invasive. In contrast to oral administration it avoids first pass metabolism and gastrointestinal absorption difficulties caused by gastrointestinal pH or enzymatic activity. Transdermal administration is becoming increasingly useful with continued development of systems suitable for carrying and releasing drugs to the skin and systems for optimizing the rate of percutaneous absorption. Because of the above noted advantages of transdermal administration many drugs are being considered for transdermal delivery. Commercially available transdermal systems include ones that deliver steroid hormones (e.g., estradiol for treatment of symptoms of menopause), nicotine (for smoking cessation), nitroglycerine (for angina), scopolamine (for motion sickness), and fentanyl (a narcotic analgesic for treatment of pain).

Devices that have found use include adhesive matrix type devices wherein the drug is dissolved or dispersed in an adhesive matrix that is applied to the skin in order to deliver the drug. Reservoir type devices have also found use. The drug is dissolved or dispersed in a reservoir (e.g., a polymeric or liquid matrix sometimes involving a membrane that controls the rate of drug release from the device) and the reservoir is held in place on the skin by a pressure sensitive skin adhesive.

In devices wherein the drug is intended to be dissolved in an adhesive matrix or some other carrier, unexpected precipitation of the drug can cause the rate of drug delivery to decrease as the drug crystallizes. Such instability can render the product unsuitable for commercial use, which often involves storage of the product for periods of up to several years. It is therefore very desirable in certain transdermal drug delivery devices that the drug remain dissolved.

SUMMARY OF THE INVENTION

The several components of a transdermal drug delivery device generally contain at least small amounts of water, which might not be intentionally incorporated but could be incidentally present, e.g., as a result of method of manufacture or exposure to ambient moisture during manufacture or storage. Certain drugs tend to interact with this water and form relatively insoluble forms (e.g., solid hydrates). Consequently certain transdermal delivery devices involving dissolved drugs have shown a tendency to exhibit precipitation of the drug during storage. This problem is at least in part attributable to formation hydrate forms of the drug. Accordingly this invention provides a method of inhibiting precipitation of a drug in the carrier of a transdermal drug delivery device, comprising the steps of:

(i) providing a non-aqueous carrier comprising a dissolved drug that forms a solid hydrate when exposed to water vapor;

(ii) providing a desiccant package permeable to water vapor and defining a desiccant compartment containing a desiccant; and

(iii) placing said desiccant package and said carrier within a substantially sealed water vapor impermeable product package.

This invention also provides a transdermal drug delivery device comprising: a non-aqueous carrier comprising a dissolved drug that forms a solid hydrate when exposed to water vapor; a desiccant package permeable to water vapor and defining a desiccant compartment containing a desiccant; and a water vapor impermeable product package, wherein the carrier and the desiccant package are contained within the product package.

Through the use of a desiccant this invention lessens or avoids precipitation (e.g., crystallization) in transdermal drug delivery devices containing drugs that form hydrate forms upon exposure to water. The desiccant system can be made small, thin, and flexible, allowing incorporation into a flexible unit-dose transdermal drug delivery system product package without adversely affecting the appearance or shape of the product package.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is cross sectional view of a transdermal drug delivery device of the invention.

DETAILED DESCRIPTION OF THE INVENTION

A transdermal drug delivery device of the invention comprises a carrier, preferably a non-aqueous carrier, suitable for use in a transdermal drug delivery device. As used herein the term "non-aqueous carrier" refers to a substantially water free carrier that contains only small amounts of water, for example less than about one to five percent by weight of water as may be incidentally present in materials of construction that have not been dried prior to use. Examples of suitable carriers include pressure sensitive skin adhesives (e.g., those disclosed in U.S. Pat. Nos. RE 24906 (Ulrich), 4732808 (Krampe), and 5232702 (Pfister)), non-adhesive polymeric matrices (e.g., those disclosed in U.S. Pat. No. 4814173 (Song)), and other reservoir systems (e.g., those disclosed in U.S. Pat. Nos. 4834979 (Gale), 4820525 (Leonard), and 5310559 (Shah)). A particularly preferred carrier is an acrylate pressure sensitive adhesive such as that disclosed, e.g., in U.S. Pat. No. 5223261 (Nelson et al.) and commonly assigned copending application Ser. No. 08/305833. Depending on the particular carrier, suitable adjuvants and excipients can be included, e.g., in order to dissolve the drug or other excipients, or to enhance the rate of skin penetration. Suitable adjuvants and excipients that may be used include C.sub.8 -C.sub.22 fatty acids such as isostearic acid, octanoic acid, and oleic acid, C.sub.8 -C.sub.22 fatty alcohols such as oleyl alcohol and lauryl alcohol, lower alkyl esters of C.sub.8 -C.sub.22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate, di(lower) alkyl esters of C.sub.6 -C.sub.8 diacids such as diisopropyl adipate, monoglycerides of C.sub.8 -C.sub.22 fatty acids such as glyceryl monolaurate, tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monomethyl ether, N,N-dimethyldodecylamine-N-oxide, and combinations of the foregoing. Alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethyl ethers, and polyethylene oxide dimethyl ethers are also suitable, as are solubilizers such as dimethyl sulfoxide, glycerol, ethanol, ethyl acetate, acetoacetic ester, N-methyl pyrrolidone, and isopropyl alcohol.

In the preferred acrylate pressure sensitive adhesive carrier, preferred adjuvants include glyceryl monolaurate, diethylene glycol monomethyl ether, tetrahydrofurfuryl alcohol polyethylene glycol ether, diisopropyl adipate, propylene glycol, isopropyl myristate, ethyl oleate, methyl laurate, 2-(2-ethoxyethoxy)ethanol, and oleyl alcohol.

Generally the carrier will have a surface that is intended to be applied to the skin. The area of this surface is variable but is generally about 1 cm.sup.2 to about 25 cm.sup.2.

The carrier contains a dissolved drug that forms a solid hydrate when exposed to water vapor ("solid hydrate" as used herein refers to a material that is solid, for example crystalline, at 0.degree. C.). The carrier is preferably substantially free of undissolved drug.

Generally solid hydrates are less soluble than the anhydrous form in non-aqueous media. In the practice of the invention the drug is preferably one that, when exposed to water vapor, forms a hydrate crystal form that is less soluble than the anhydrous form of the drug in a non-aqueous transdermal carrier. Certain steroid hormones, including estradiol, are known to form such hydrates upon exposure to water. Other drugs that have been said to form hydrates include scopolamine, nicotine, secoverine, and benztropine.

A device of the invention also comprises a desiccant package. Suitable desiccant packages include those that are inert to the carrier (i.e., those that neither react chemically with, nor swell with, nor otherwise absorb components of the carrier). Preferably the desiccant package is free of components (e.g., plasticizers such as phthalates) that can be leached from the desiccant package by the components of the carrier. The desiccant package is permeable to water vapor in order that the desiccant inside may take up any water vapor that might be present in or become introduced into the product package. Suitable materials of construction of a desiccant package for use in connection with a particular carrier can be selected by those skilled in the art. Representative water vapor permeable materials include polyethylene, polypropylene, ethylene/vinyl acetate, polyethylene terephthalate, paper, coated paper, and perforated sheet materials including perforated laminates such as a perforated metallized polyethylene terephthalate/paper laminate. Other suitable materials that can be used along with a water vapor permeable material include impermeable materials such as styrene/butadiene copolymer films, e.g., OPTICITE SQZ label film.

The desiccant package can be configured in any manner that defines a desiccant compartment. It is preferred that the desiccant package define a closed desiccant compartment and be thin, flat, and flexible in order that it can be inconspicuous when incorporated into a transdermal drug delivery device. In a preferred embodiment the desiccant package comprises a base sheet and a coextensive cover sheet sealed together around the periphery (e.g., by an adhesive, by heat sealing, or by any other suitable sealing method). The desiccant compartment is formed by the two sheets and the peripheral seals therebetween. The base sheet, the cover sheet, or both are permeable to water vapor. In a preferred embodiment the base sheet is a water vapor impermeable styrene/butadiene copolymer film (OPTICITE SQZ label film, Dow Corning), the cover sheet is a metallized polyethylene terephthalate/paper laminate (Schwartz Paper Company), and the sheets are sealed around their periphery by an adhesive bond. In yet a further preferred embodiment the desiccant package is immobilized within the transdermal drug delivery device of the invention.

The desiccant compartment contains a desiccant in order to absorb, adsorb, react with, or otherwise remove water, such as any water that may be incidentally present in the various components of the device. Materials known for use as desiccants include barium oxide, calcium chloride, calcium oxide, calcium sulfate, lithium chloride, perchlorates such as lithium, barium, or magnesium perchlorate, phosphorous pentoxide, alumina, silica gel, and zeolite molecular sieve. The desiccant can be used in any amount that is effective to absorb water vapor from the product package over the shelf life of the product. The amount of desiccant that constitutes an effective desiccating amount depends on several factors readily assessed by those skilled in the art, including the amount of water present in the components of the device, the capacity of the selected desiccant to take up water, and the presentation of the desiccant relative to the components of the device containing water.

The desiccant preferably does not absorb, react with, or otherwise adversely affect the drug, other excipients or adjuvants, or packaging materials that are used in the transdermal device. Suitability and compatibility of particular desiccants for use in a particular transdermal device can be readily determined by those skilled in the art considering the particular components that are to be used. For example, while the most common desiccant system currently used by the U.S. pharmaceutical industry involves silica gel, silica gel has been found to adsorb materials such as fatty acid esters that are commonly used as excipients in transdermal drug delivery. Change in excipient level over time can cause unstable product performance. Thus silica gel is not preferred for use in devices where fatty acid ester content is critical to product performance.

Desiccants that selectively remove water vapor are preferred. Natural and synthetic zeolite molecular sieves, including zeolite A, e.g., 3 A, 4 A, and 5 A molecular sieve, are most preferred. A zeolite molecular sieve desiccant is preferably powdered, e.g., to a mesh size of about 30-40.

A device of the invention further comprises a product package, which contains the carrier and the desiccant package and isolates them from the ambient environment. The product package is substantially impermeable to water vapor. It can be configured in any manner that defines a sealed product-receiving space. In a preferred embodiment the product package comprises a base sheet and a coextensive cover sheet sealed together around the periphery (e.g., by an adhesive, by heat sealing, or by any other suitable sealing method), whereby the product receiving space is defined by the two sheets and the peripheral seals therebetween. Suitable materials for use as the product package include cold-sealable laminates such as paper/foil/polyethylene, paper/foil/vinyl primer, or paper/foil/polyvinyldichloride, flood coated or pattern coated with natural or synthetic adhesive, and heat sealable film laminates involving paper or foil and high, medium, low, or linear low density polyethylene, polypropylenes, or polyesters.

In a preferred embodiment the desiccant package is immobilized within the product package, e.g., by sealing into the peripheral seal about the base sheet and cover sheet or by means of an adhesive, such as a pressure sensitive adhesive layer, between the desiccant package and the inner surface of the product package.

Generally in a device of the invention the carrier is part of a laminate structure wherein the carrier is borne upon a backing. Suitable backings include flexible backing materials used for pressure sensitive adhesive tapes, such as polyethylene, particularly low density polyethylene, linear low density polyethylene, high density polyethylene, polyester such as polyethylene terephthalate, randomly oriented nylon fibers, polypropylene, ethylene:vinyl acetate copolymers, polyurethane, rayon, and the like. Backings that are layered, such as polyethylene-polyester-aluminum-polyethylene composites, are also suitable.

The surface of the carrier not covered by the backing is generally covered by a release liner, which can be removed from the laminate to allow application and adhesion to the skin. Suitable release liners include conventional release liners comprising a sheet material such as a polyester web, a polyethylene web, or a polystyrene web, or a polyethylene-coated paper, coated with a suitable fluoropolymer or silicone based coating. Suitable differential release liners include conventional differential release liners comprising a sheet material such as a polyester web, a polyethylene web, or a polystyrene web, or a polyethylene-coated paper, coated on both surfaces with suitable fluoropolymer or silicone based coatings. Referring now to the Drawing, device 10 shown in FIG. 1 comprises product package 12 comprising substantially coextensive water vapor impermeable sheets 14 and 16 sealed around their periphery to define product receiving space 18. Like the product package, desiccant package 20 comprises substantially coextensive sheets 22 and 24 at least one of which is permeable to water vapor, sealed around their periphery. Desiccant receiving space 26 contains desiccant 28. Sheet 22 bears layer 30 of pressure sensitive adhesive. The pressure sensitive adhesive layer adheres also to sheet 14 immobilizing the desiccant package within the product package.

Product receiving space 18 also contains a laminate comprising backing 32 carrier 34 and release liner 36. Backing 32 bears carrier 34 which in the illustrated embodiment is a pressure sensitive adhesive matrix comprising a drug. Release liner 36 covers carrier 34 and can be readily removed by bending the laminate such that the release liner splits at point 38 where the release liner is cut.

The components of a device of the invention (e.g., the various packaging materials, adhesives, drugs, desiccants, and other components of transdermal carriers including adjuvants and excipients) are readily available from commercial sources and/or readily prepared by those skilled in the art using well known methodology. For example a pressure sensitive adhesive coated desiccant package containing 4 A molecular sieve is available from Multiform Desiccants (Buffalo, N.Y.). A device of the invention can be prepared by assembling the several components into a transdermal drug delivery device using coating, laminating, and sealing methods well known to those skilled in the art and disclosed, e.g., in U.S. Pat. Nos. 5223261 (Nelson et al.), 5008110 (Benecke), 5370924 (Kochinke), and 5077104 (Hunt), WO 92/12004 (Cullen at al.), and EP 556 158 (Rudella), all incorporated herein by reference.

A device of the invention can be used in any application where transdermal drug delivery is useful, e.g., in treatment of symptoms of menopause by administration of estradiol, and is particularly useful in connection with transdermal delivery of drugs that when exposed to water form a hydrate that precipitates from the carrier. In use the carrier is removed from the product package and applied to a patient. The carrier is allowed to remain in place for a time sufficient to achieve and/or maintain a therapeutically effective blood level of the drug. The mount of drag and duration of treatment can be selected by those skilled in the art considering the particular drug to be administered and the particular intended therapeutic effect.


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