WO2002078604A2 - Transdermal delivery of bioactive material - Google Patents

Transdermal delivery of bioactive material Download PDF

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Publication number
WO2002078604A2
WO2002078604A2 PCT/US2002/010086 US0210086W WO02078604A2 WO 2002078604 A2 WO2002078604 A2 WO 2002078604A2 US 0210086 W US0210086 W US 0210086W WO 02078604 A2 WO02078604 A2 WO 02078604A2
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WO
WIPO (PCT)
Prior art keywords
delivery device
liquid
composition
wt
bioactive material
Prior art date
Application number
PCT/US2002/010086
Other languages
French (fr)
Other versions
WO2002078604A3 (en
Inventor
Jesus Miranda
Christopher Adams
Original Assignee
Elan Transdermal Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US28053201P priority Critical
Priority to US60/280,532 priority
Application filed by Elan Transdermal Technologies, Inc. filed Critical Elan Transdermal Technologies, Inc.
Publication of WO2002078604A2 publication Critical patent/WO2002078604A2/en
Publication of WO2002078604A3 publication Critical patent/WO2002078604A3/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007Drug-containing films, membranes or sheets

Abstract

A transdermal delivery device comprising a multi-phase matrix which includes a solid liquid-retaining member and associated therewith a bioactive material in liquid form, for example, a transdermal delivery device comprisinga barrier layer affixed to one face of the matrix and having an exposed face, the exposed face having affixed thereto a mounting layer, and the other face of the matrix having affixed therto a removable layer, an example of the liquid-retaining member being an absorbent material, for example, a natural or synthetic fiber gauze, a non-woven medical absorbent, a natural sponge, and a synthetic sponge.

Description

Transdermal Delivery of Bioactive Material

Reference to Related Application

This application claims the benefit of the filing date of U.S. Provisional Application No. 60/280,532, filed March 30, 2001.

Field of the Invention

This invention relates to the administration of a bioactive material to a patient. More particularly, this invention relates to the transdermal delivery of a bioactive material.

The present invention is described initially in connection with the bioactive material pergolide. However, it should be understood that the invention has wider applicability as discussed herein below.

Pergolide, like other bioactive materials, is a drug that is used to treat various health conditions that afflict individuals. For example, pergolide has been used in the treatment of the symptoms of Parkinson's disease and in the reduction of plasma concentrations of prolactin in conjunction with the treatment of hyperprolactinemia. In the treatment of Parkinson's disease, the typical course of medication is a gradual increase in the oral dose over 14 days, with a concomitant gradual increase in blood serum levels. Blood serum levels ranging between a maximum of about 500 picograms/ml (maximum serum level 2-3 hours following a 2.5 mg oral dose) to about 60 picograms/ml (serum level 8 hours following a 0.5 mg oral dose) have been considered within a therapeutic range from oral dosing studies of pergolide mesylate in the treatment of Parkinson's disease. Typically, oral dosing is 3 mg/24 hours, divided into three doses, with serum concentrations peaking at approximately 200pg/ml.

The oral administration of pergolide and various other drugs offers the advantage of being simple to administer. However, with oral administration of various drugs, including, for example, pergolide, blood serum levels fluctuate between dosages and the drug must pass through the liver before systemic distribution in the blood stream, requiring a dosage level high enough to account for metabolic losses in the hepatic system. Accordingly, there are disadvantages associated with the oral administration of various drugs.

It is known also to administer various drugs, including, for example, pergolide by transdermal delivery, such means of delivery having advantages relative to oral delivery. The present invention relates to the transdermal delivery to an individual of a bioactive material.

Reported Developments

European published patent application EP 0913128A1 discloses a transdermal device for delivering a variety of medicaments, for example, pergolide. The device utilizes a layer of polymeric adhesive in which the medicament is dispersed homogeneously. The medicament-containing adhesive layer is prepared by dissolving the constituents in a solvent(s). The resulting solution solidifies to form the medicament-containing layer upon evaporation of the solvent. The device includes also a backing layer on one side of the adhesive layer to protect the adhesive layer during use and storage and a strippable release layer on the other side of the adhesive layer to protect the otherwise exposed side of the adhesive layer during storage. The strippable layer is removed before application of the adhesive layer of the device to the body membrane.

Transdermal delivery of pergolide is disclosed in U.S. Patent No. 6,001,390 to Yum. The '390 patent discloses the delivery of pergolide mesylate in vitro across samples of human skin. In one embodiment of the delivery devices disclosed in the Yum patent, a liquid pergolide-containing composition is held within the device in a space from which the pergolide is delivered to the body membrane by diffusion through a micro-porous membrane in contact therewith. The device includes a strippable layer which covers the face of the micro-porous membrane that is placed in contact with the body membrane and which is removed at the time of use. In another embodiment disclosed in the Yum patent, the pergolide is contained in a solid polymeric film which is prepared by forming a solution of the pergolide and polymeric carrier and evaporating the solvent to form the polymeric film.

One of the shortcomings of the present means for delivering bioactive materials transdermally is that relatively large amounts of the material must be used in the delivery device in order to achieve desired therapeutic results. A delivery device having a relatively large surface area for delivery of the bioactive material must be used because of the low delivery flux of the material. This is a serious shortcoming. The present invention relates to improved means for the transdermal delivery of a bioactive material to a patient. Summary of the Invention

In accordance with the present invention, there is provided a transdermal delivery device comprising a multi-phase matrix which includes a solid liquid-retaining member and associated therewith a bioactive material in liquid form. In a preferred embodiment, the liquid-retaining member is, for example, a non-woven medical absorbent and the bioactive material is dissolved in a suitable solvent.

Another aspect of the present invention is the provision of a method for the transdermal delivery of a bioactive material comprising delivering to a body membrane bioactive material in liquid form and from a liquid bioactive material-carrying member which is in direct contact with the body membrane. In this embodiment of the invention, the bioactive material is delivered from a supply source directly to the body membrane unimpeded by a material interposed between the source and the surface of the body membrane.

The present invention provides the means to efficiently deliver relatively high amounts of a bioactive material transdermally and to achieve desired blood serum levels of the bioactive material. And this can be accomplished without irritating the membrane of the patient.

Brief Description of the Drawings

Figures 1 to 4 are graphical representation of in vitro pergolide delivery flux from a transdermal delivery device of the present invention.

Figure 5 is a graphical representation of in vivo pergolide blood serum levels attained by a transdermal delivery device of the present invention. Figure 6 is a graphical representation of in vitro pergolide delivery flux involving the use of a comparative composition comprising a solid solution of pergolide.

Figures 7 to 9 are graphical representations of in vitro pergolide delivery flux from direct application to the skin of a liquid pergolide composition.

Figures 10 and 11 are graphical representation of in vitro ondansetron delivery flux from direct application to the skin of a liquid ondansetron-containing composition.

Figures 12 to 14 are graphical representations of in vitro naltrexone delivery flux from direct application to the skin of a liquid naltrexone-containing composition.

Detailed Description of the Invention

The present invention relates to the transdermal delivery of a liquid bioactive material from a transdermal delivery device held in contact with a membrane of an animal to which the bioactive material is to be delivered. The delivery device of the present invention comprises a multi-phase matrix which includes a solid material for holding the liquid bioactive material. The device may include other elements which relate to the use or functioning of the device. Examples of such elements are a layer to secure the device in place during use, a barrier layer on that surface of the matrix which is not in contact with the body membrane to prevent the liquid bioactive material from exiting that surface, and a release layer which shields the other surface of the matrix from the ambient when the device is not in use. The multi-phase matrix of the delivery device has at least two elements, the bioactive material in liquid form and a solid material which has an affinity for the liquid and so functions as a liquid-retaining member. The affinity between the composition comprising the liquid bioactive material and the solid liquid-retaining member may be due, for example, to adsorption such as physi- or chemi-sorption or to absorption within void spaces in the material.

Typically, the liquid bioactive material is contained in a composition which can include other constituents, as described below. The composition is held by the liquid- retaining member with sufficiently strong force to withstand pressure that the device may be subjected to in the ordinary course of use and handling without expelling the composition therefrom.

The liquid-retaining member of the delivery device of the present invention can be made of any suitable material. Speaking generally, the material should exhibit an affinity for some or all of the components of the composition which comprises the liquid bioactive material. The material comprising the liquid-containing member should not irreversibly react or interact with any of the components of the composition. For example, it should resist being degraded by the composition. Conversely, the material should not affect adversely any components of the composition. In this respect, materials which are inert toward the components of the composition and do not dissolve therein are suitable materials for use in fabricating the liquid-retaining member.

Examples of suitable materials are reticulated materials represented by the natural and synthetic fibers in the form of woven gauze, relatively long staple absorbent masses, non-woven fiber web, and a non-woven web which is surface-treated with a porous polymer. A preferred material is a non-woven material comprising rayon web covered with porous polyethylene, for example, 1603 non-woven medical absorbent available from 3M. Such materials are capable of retaining the composition comprising the liquid bioactive material in cavities, pores or channels that comprise the materials of the liquid-retaining member. The liquid-retaining member can also comprise a material which adsorbs the liquid bioactive material. For example, a surface of a component of the liquid composition can be adsorbed to a surface of the material comprising the liquid-retaining member and, by cohesive interaction with un-adsorbed components of the liquid composition, the bulk of the composition is retained by the member.

The solid liquid-retaining member of the delivery device of the present invention has associated therewith a bioactive material in liquid form. The term "bioactive material" is used herein to refer to any substance which has a desired beneficial effect on a living organism, including, for example, a therapeutic, prophylactic, or diagnostic effect. Pergolide is an example of a bioactive material for use in the practice of the present invention. The term "pergolide" is used herein to mean any pharmaceutically acceptable species of ergoline having pharmaceutical properties like those of the free base 8 β-[(methylthio)methyl]-6-propyl ergoline. It is recognized that there are many species of pergolide which are suitable for the treatment of abnormal bodily conditions, for example, treating the symptoms of Parkinson's disease and hyperprolactinemia. In addition to the aforementioned free base, acid salts of the free base and compounds which have structural variations of the ergoline ring are known to be pharmaceutically active. Examples of pharmaceutically acceptable salts of pergolide and compounds with structural variations of the ergoline ring that exhibit pharmacological properties and that may be used in the practice of the present invention are disclosed in U.S. Patent No. 4,166,182 to Kornfeld et. al.. A mixture of two or more species of pergolide may be used in the practice of the present invention. Preferred forms of pergolide for use in the practice of the present invention are pergolide mesylate and pergolide free-base both of which are a solid at room temperature and which are sufficiently soluble in water or nonaqueous solvents to provide a solution which contains pharmaceutically effective amounts of the dissolved pergolide species.

A few examples of other bioactive materials that can be delivered transdermally accoring to the present invention include antiemetics and seretonin receptor antagonists, for example, ondansetron, other dopamine receptor agonists, vaccines, and opioid receptor antagonists, for example, nalthraxone. Many of the bioactive materials that are suitable for use in the present invention are solids at ambient temperatures.

Accordingly, the matrix of the delivery device will typically contain a composition which comprises a solvent for dissolving the bioactive material. It is likely that a solvent will be used also with those bioactive materials that are liquids under ambient conditions to function as a diluent or carrier of the liquid bioactive material.

Any suitable liquid solvent (inorganic or organic) which is capable of dissolving the bioactive material in an amount which is considered sufficient for including in the matrix of the delivery device can be used. Water, alcohols, for example, ethanol, dimethyl sulfoxide (DMSO), and glycols, for example, polyethylene glycol and polypropylene glycol are examples of solvents that can be used.

It is known that sltin and mucous membranes are irritated by direct application thereto of a relatively high amount of various types of bioactive materials. The solvent for the bioactive material serves also as a diluent and functions to reduce undesirable irritation. The solvent can act also to improve the permeability of the skin or mucous membrane to the bioactive material. In addition, the solvent can function as a diffusion media which helps to conduct the bioactive material to the body membrane through which it enters the body.

The composition which includes the bioactive material can comprise a single phase composition, for example, a liquid solution of the bioactive material, or it can comprise a multi-phase composition, for example, an emulsion, a gel, or a dispersion which includes the bioactive material in liquid form. An emulsion can comprise liquid droplets of a solution of the bioactive material dispersed in a continuous liquid phase. A gel can comprise a phase of a continuous solution thickened by an appropriate gelling agent which comprises a dispersed phase. A dispersion can comprise a liquid solution of dissolved bioactive material having dispersed therein solid particles of bioactive material, for example, nanoparticles thereof.

In preferred form, the composition comprises a solution of the bioactive material having a viscosity at room temperature such that the solution flows readily, for example, from a pipette which is used to deliver the solution to the liquid-returning member of the matrix. An aqueous-based solution which includes a hydrocarbon-based solvent is particularly preferred for those bioactive materials which are sufficiently water soluble.

The composition containing the bioactive material can include one or more additives which function to impart desired properties to the composition. For example, the composition can include a cosolvent to improve the solubility of the bioactive material in the principal solvent. The use of an alcohol as a cosolvent to improve the solubility of pergolide in water is exemplary. The composition can include an enhancer which functions to enhance the ability of the bioactive material to be delivered transdermally. Examples of enhancers are alcohols, gly cols, fatty acids, and fatty acid esters. Another example of an additive is a thickening agent, for example, hydroxymethyl cellulose, which functions to impart to the composition a desired viscosity.

Other examplary additives are, for example, stabilizers, preservactives, and antioxidants. A stabilizer is an art-recognized compound defined in the "Handbook of Pharmaceutical Additives," Ash, Micahel and Irene, Gower 1995, to be a pharmaceutical additive that thickens, prevents separation, retards oxidation by increasing viscosity, and gives a smoother product. An antioxidant is also an art- recognized compound and is defined by the Handbook of Pharmaceutical Additives to be a substance that retards oxidation, deterioration, rancidity, and gum formation in organic substances. A preservative is also an art-recognized compound defined by the Handbook of Pharmaceutical Additives to be a substance, either natural or synthetic, that protects a pharmaceutical composition against spoilage, discoloration, or decay and is used to retard or prevent microbial or chemical spoilage. The "Handbook of Pharmaceutical Excipients," Kibbe H. Arthur, 3rd ed. American Pharmaceutical Association 2000 lists many compounds which are recognized: as stabilizers, for example, L-Methionine; as antioxidants, for example, citric acid, ascorbic acid, butylated hydroxy anisole (BAH), and butylated hydroxy toluene (BHT); and as preservatives, for example, benzyl alcohol, ethyl alcohol, and citric acid. Compositions of the present development can include also one more of such compounds.

Some additives may improve more than one property of the