WO1994008572A1 - Dispositif d'administration transdermique a action retardee - Google Patents

Dispositif d'administration transdermique a action retardee Download PDF

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Publication number
WO1994008572A1
WO1994008572A1 PCT/US1993/009637 US9309637W WO9408572A1 WO 1994008572 A1 WO1994008572 A1 WO 1994008572A1 US 9309637 W US9309637 W US 9309637W WO 9408572 A1 WO9408572 A1 WO 9408572A1
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WO
WIPO (PCT)
Prior art keywords
skin
mucosa
therapeutic agent
rate
nicotine
Prior art date
Application number
PCT/US1993/009637
Other languages
English (en)
Inventor
Eun Soo Lee
Su Il Yum
Felix Theeuwes
Original Assignee
Alza Corporation
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
Application filed by Alza Corporation filed Critical Alza Corporation
Priority to MX9306237A priority Critical patent/MX9306237A/es
Priority to AU53549/94A priority patent/AU5354994A/en
Publication of WO1994008572A1 publication Critical patent/WO1994008572A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin

Definitions

  • the present invention relates to diffusional drug delivery devices, and more particularly to novel methods and compositions for delaying the onset of therapeutic agent delivery for transdermal systems.
  • transdermal route of parenteral delivery of drugs provides many advantages, and transdermal systems for delivering a wide variety of drugs or other beneficial or therapeutic agents are described in, for example, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,742,951, 3,948,262, 4,031,894, 4,144,317, 4,201,211, 4,286,592, 4,314,557, 4,379,454, and 4,568,343, all of which are incorporated herein by reference.
  • a drug or other active agent is released by diffusion from a reservoir through the agent releasing surface of the device to the skin or mucosa at which the device is applied.
  • Such devices perform well in the administration of many agents but are not suitable for the administration of an agent whose dosage regime requires that the onset of therapeutic effect be delayed for a significant period of time after application of the device at the site of delivery.
  • the surface through which the agent is released, at the time of application contains the agent in an amount that is typically at or above saturation and is capable of delivering at a rate that can give rise to therapeutic blood levels.
  • the initial rate of release is unacceptably high, and a method for reducing the initial "burst" of agent delivery is described in U.S. Pat. No. 3,923,939.
  • the agent-releasing surface of the diffusional embodiment contains agent and delivery commences immediately in the manner described above.
  • a continuous release dosage form such as a transdermal drug delivery device over oral dosing of medications is the improvement in patient compliance that is obtained from the concurrent removal of one device and application of a new device at the same time. This advantage is lost when removal and application occur at different times or where onset of a therapeutic effect is desired at an inconvenient time such as shortly prior to awakening from sleep.
  • the devices of this invention are particularly useful over standard transdermal devices in providing a predetermined delayed onset of therapeutic effect for any desired time period after application to the skin. Thus, a device could be removed and a new one applied simultaneously, wherein the desired drug-free interval is still obtained for a period after application. Additionally, a common problem encountered with transdermal delivery devices is how to deal with unstable active agents.
  • agents in their active or otherwise preferred, usually neutral acid or base, form are unstable in transdermal delivery devices. They may be very soluble in most polymer matrices and rate-controlling membranes of transdermal devices, and there are those that tend to degrade the adhesive or other system components. They also usually have a high vapor pressure which requires special concern in packaging. Additionally, storage of the devices "on the shelf” for extended periods prior to use also creates a significant problem for maintaining stability of the active agent itself over an extended period of time. While it is known that many therapeutic agents are stable in the salt form, these agents may be readily absorbable through the skin only in either the free base form, the free acid form or the ester form, for example.
  • transdermal delivery devices storing the agent in the form suitable for absorption through the skin could have an undesirably short storage life. Similarly, those storing the agent in a form suitable for storage could have an undesirable low agent delivery rate through skin.
  • Transdermal delivery devices having agent together with an ion exchange resin for providing storage stability are known. However, these do not provide an initial delay period from the time of placement on the skin to start of delivery of agent from the devices.
  • U.S. Pat. No. 4,692,462 discloses a transdermal drug delivery system having a drug reservoir composed in part of an ion exchange resin. However, the drug reservoir also contains water as well as a hydrophilic polymer gel. The presence of water in the drug reservoir causes some of the drug to become unbound from the ion- exchange resin and, therefore, immediately available for delivery upon placement of the device on the skin.
  • transdermal therapeutic system that provides a delayed onset of delivery and at the same time provides stability of the drug or therapeutic agent and all components of the device.
  • the present invention is directed to a transdermal delivery device for the controlled release of a drug or other therapeutic agent to skin or mucosa and adapted to delay the onset of therapeutic agent delivery at a therapeutically effective rate for a predetermined time after placement of the device onto the skin or mucosa.
  • the device comprises a nonaqueous reservoir which contains a therapeutic agent in complexation with an ion-exchange resin and also contains an activating agent, the reservoir having a surface through which the therapeutic agent is released to the skin or mucosa; and a rate-controlling membrane disposed between the skin or mucosa and the releasing surface of the reservoir for controlling the rate at which water is absorbed into the reservoir and, to a much lesser extent, the rate at which the therapeutic agent is released from the device, the rate-controlling membrane being substantially free of therapeutic agent prior to placement of the device onto the skin or mucosa.
  • the rate-controlling membrane being substantially free of therapeutic agent prior to placement of the device onto the skin or mucosa.
  • the system becomes hydrated as a result of the absorbed water and thereby activates the activating agent, which aqueous solution of activating agent then promotes dissociation of the therapeutic agent from the ion-exchange resin.
  • the delay of delivery is caused primarily by the time required for water from the skin to permeate through the rate-controlling membrane and into the reservoir to activate therapeutic agent displacement.
  • the rate-controlling membrane controls the rate at which water is transported from the skin into the reservoir; the membrane thereby controls the delay time and indirectly controls the therapeutic agent release rate.
  • the present invention has the additional advantage of providing the therapeutic agent in a stable form prior to placement on the skin or mucosa as well as in a form suitable for absorption after such placement.
  • FIG. 1 illustrates in cross section a delivery device of the present invention.
  • FIG. 2 illustrates in cross section another delivery device of the present invention.
  • FIG. 3 illustrates in cross section yet another delivery device of the present invention.
  • FIG. 4 illustrates in cross section another delivery device of the present invention.
  • FIG. 5 is a graph showing the release rate vs. time for nicotine devices of Examples 1 through 6.
  • FIG. 6 is a graph showing the release rate vs. time for nicotine from a device of Example 8, both newly prepared and after 13 months' storage, in comparison with a prior art nicotine transdermal delivery device.
  • FIG. 7 is a graph showing the release rate vs. time for nicotine from devices of Example 10, both newly prepared and after 8 weeks' storage at different temperatures.
  • FIG. 8 is a graph showing the release rate vs. time for nicotine from devices of Example 12.
  • Therapeutic agents suitable for transdermal administration exist in various forms, some of which are more suitable for stable storage and some of which are more suitable for administration through skin or mucosa.
  • a therapeutic agent delivery device in which the therapeutic agent is present in the administration-suitable, but often unstable form in such manner that it is also stable in the device. This is accomplished by complexing the therapeutic agent with an ion-exchange resin.
  • the therapeutic agent/ion-exchange complex forms a matrix that is stable at high temperature and over an extended period of time. There is no evaporation, migration or solubilization. It is, in fact, so stable that agent cannot be released at a therapeutic rate from the delivery device into the skin unless and until it is freed by another cation or anion, depending on the nature of the agent, or by neutralization of the ionic form of the drug under moist conditions.
  • Neutralization and release of the therapeutic agent is provided in the present invention by the presence of an acid or base activating agent together with the therapeutic agent/ion-exchange resin complex. In the absence of water, this activating agent will not react with the complex. However, in the presence of water which has been absorbed from the skin or mucosa, the activating agent forms a solution and promotes the dissociation of the therapeutic agent and the resin, making the therapeutic agent available for delivery from the device.
  • Any nontoxic pharmaceutical grade ion-exchange resin used to bind cationic or anionic agent molecules at the ion exchange sites may be employed in this invention.
  • any wide range of cationic (for basic pharmacological agents) or anionic (for acidic agents) ion exchange resins can be employed.
  • Examples of cationic resins would be weak acid cation exchange resins with the functional moiety being a carboxylic acid (-C00H) group. This could be derived from polymers or copolymers such as methacrylic acid or polymethacrylate.
  • a strongly acidic cation exchange resin having the functional group -S0 3 Na derived from the polymer styrene could also be employed.
  • anionic resins are those having the functional group NH.NH 2 which are weakly basic and could be derived from phenolic polya ines, or the strongly basic type having as the functional group -N(R 3 ), also derived from polystyrenes.
  • Ion exchange resins are well known in the art, and the present invention encompasses all ion exchange resins.
  • the ion exchange resins discussed above are known in the art as the amber!ite class, such as, for example, Amberlite ® IR-120, A ber!ite ® IRP-69, Amberlite ® IRP-64, Amberlite ® IRP-58, or Amberlite ® IRC-50. It is believed that this invention has utility in connection with the delivery of any ionizable drug within the broad class normally delivered through body surfaces and membranes, including skin and mucosa.
  • drug As used herein, the expressions "drug”, “active agent” and “therapeutic agent” are used interchangeably and are intended to have their broadest interpretation as any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial, effect. In general, this includes therapeutic agents in all of the major therapeutic areas including, but not limited to, those disclosed in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,286,592, 4,314,557, 4,379,454 and 4,568,343, all of which are incorporated herein by reference.
  • This invention has particular utility in connection with the delivery of drugs that are very unstable in their neutral acid or base form (also referred to herein as their "active form") . It is also useful for those drugs that are too soluble in their active form in delivery devices to maintain the system's integrity during shelf life; that is, they tend to degrade one or more of the components of the system, including the adhesive, upon prolonged exposure such as is the case under storage conditions. This invention also eliminates the initial burst of drug from the device. This is particularly beneficial in delivering drugs that have a tendency in large doses to irritate the skin.
  • the present invention is particularly useful in delivering those drugs which should not be delivered in a continuous manner over a prolonged period of time, such as drugs that, through continuous administration, become addictive or develop a tolerance in the host.
  • Other agents which may be beneficially delivered according to this invention include drugs where a therapeutic effect is desired at an inconvenient time or where no therapeutic effect is desired for a particular initial time period.
  • Agents may be selected from hypnotics, opioids, analgesics, anti-inflammatories, nonsteroidal anti-inflam atories, anticholinergics, hormones, hydrogen antagonists, antiparkinsonian agents, vitamins, nutrients, antiangina agents, stimulants, depressants, antihypertensives, and the like.
  • Particular drugs which may be employed with the present invention include, but are not limited to, peptides and proteins, cimetidine, pseudoephedrine, ephedrine, chlorpheniramine, oxybutynin, dextromethorphan, phenylpropanolamine, phenylephrine, propylhexedrine, nicotine, nitroglycerin, amyl nitrate, propranolol, timolol, atenolol, terbutaline, salbutamol, ergonovine, ergotamine, melatonin, caffeine, aspirin, indomethacin, acetaminophen, para-aminosalicy!ic acid, fentanyl , sufentanyl , scopolamine, secoverine, benztropine, naprosin, isosulfide mononitrate, isosulfide dinitrate, nicorandil, and the 1ike.
  • One drug which is particularly suitable for delayed delivery according to the present invention is nicotine.
  • Transdermal delivery devices for the immediate delivery of nicotine have been recently introduced for the treatment of smoking cessation. These devices are available for delivery over 24 hours, where the patient replaces the device once every 24 hours, and for delivery over 12 hours, where the patient may either replace the device once every 12 hours or wear a device for a 12-hour period, followed by no device for 12 hours.
  • Each of these regimens can provide drawbacks.
  • With delivery of nicotine continuously over 24 hours (with either the 24-hour patch or two 12-hour patches), certain side effects have been reported that are associated with delivery of nicotine during sleeping hours. These include abnormal dreams and insomnia.
  • a new nicotine patch would not be applied until after awakening in the morning.
  • the plasma nicotine concentrations will be low and smokers encounter early morning withdrawal symptoms such as "morning craving" and the urge to smoke. Placement of a nicotine patch after awakening will not immediately relieve these cravings, and this could greatly decrease the efficacy of the transdermal devices for stopping the smoking habit.
  • a delayed delivery device of the present invention can be designed to be placed on the skin at dinner time or at bedtime, for example, and would not begin delivery of nicotine to the skin until shortly prior to awakening, such as one to three hours prior to awakening, usually five to eight hours after initial placement, after which time therapeutic levels of nicotine would be delivered for about the next sixteen to nineteen hours.
  • This initial delay of nicotine delivery could reduce or eliminate the side effects of abnormal dreams and insomnia because significant drug delivery will only occur during waking hours.
  • efficacy will be maintained because plasma nicotine concentrations will be achieved in sufficient time prior to awakening to overcome any morning craving and the urge to smoke.
  • Adsorption of drugs onto ion exchange resins is well known to the art, as is disclosed in, for example, U.S. Pat. Nos. 2,990,332 and 4,221,778, the disclosures of which are incorporated herein by reference.
  • the activating agent which is present in the drug reservoir together with the drug/resin complex is anhydrous and can be either an acid or a base, depending on the nature of the particular therapeutic agent.
  • Suitable acids include, but are not limited to, citric acid, succinic acid, oxalic acid, succinic anhydride, phthalic acid, phthalic anhydride, sodium bisulfate and salicylic acid.
  • Suitable bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, monobasic sodium phosphate, dibasic sodium phosphate, sodium oxalate, sodium succinate, sodium citrate, sodium salicylate, and all other salts of organic acids.
  • Any organic or inorganic salt containing the appropriate counter ion for the ion exchange resin can be employed according to this invention.
  • a therapeutic agent is transdermally administered to the skin or mucosa from a diffusional delivery device, the agent being stored in the delivery device in complexation with an ion-exchange resin.
  • the therapeutic agent is dissociated from the ion-exchange resin during delivery from the device by reaction with an activating agent which has formed a solution with water supplied by the body. While the dissociated therapeutic agent is able to permeate the layers of the delivery device and ultimately the skin itself, the complexed therapeutic agent cannot. The inability of the therapeutic agent in its complexed form to permeate the system and the skin ensures that the therapeutic agent will remain within the reservoir until the onset of delivery is desired.
  • the agent/resin complex and the activating agent are maintained in an anhydrous environment prior to use.
  • the specific structure of the delivery device is not critical to this invention.
  • the therapeutic agent/ion-exchange resin complex and the activating agent may be dispersed within an anhydrous or hydrophobic matrix, either as a solid, non-aqueous liquid or gel, or mixed with suitable anhydrous or hydrophobic carriers, permeation enhancers and the like as is known in the art.
  • the matrix or carrier and other excipients must be chosen from those which do not solubilize the activating agent.
  • Materials which may be suitable as matrices and carriers include, but are not limited to, ethylene vinyl acetate copolymers (preferably having from 9 wt% to 60 wt% vinyl content), silicone oil, mineral oil, sesame oil, olive oil, and polybutene. Other materials are known to the art or may be determined without undue experimentation.
  • the devices are preferably in the form of an adhesive patch or the like but can also be in the form suitable for application to the skin or mucosa such as an anhydrous ointment, gel or matrix, for example. If desired, means for controlling the release rate of the therapeutic agent can also be used, as is known in the art.
  • the activating agent is activated by water which is readily available from the site of administration, such as the cutaneous surface, particularly in occluded skin regions.
  • the delivery devices of the present invention include a rate-controlling membrane between the drug-releasing surface of the reservoir and the skin or mucosa for controlling the rate at which water from the skin or mucosa is taken up into the reservoir, which in turn controls the rate of dissolution of the activating agent.
  • the delay of delivery of active agent or drug from the device is caused primarily by the time required for water to permeate through the rate-controlling membrane and into the reservoir to activate drug displacement.
  • the rate-controlling membrane thereby controls the delay time to onset of delivery of the drug from the device.
  • the rate-controlling membrane may be fabricated from permeable, semipermeable or microporous materials which are known to the art to control the rates of agents or fluids into and out of delivery devices.
  • Materials suitable for use as the water-uptake rate- controlling membrane include, but are not limited to, polyolefins such as polyethylene, polypropylene, polyester, polycarbonate, and the like; and copolymers such as polystyrene-butadiene copolymer, ethylene vinyl acetate copolymer, ethylene acrylic acid copolymer, ethylene ethylacrylate copolymer, ethylene methylacrylate copolymer, copolyester elastomers of tetramethylene terephthalate and poly(tetra ethylene ether)glycol terephthalate (Hytrel ® ), and the like.
  • FIG. 1 shows transdermal delivery device 10 which includes a drug-impermeable backing layer 102, an anhydrous reservoir 104 containing a drug in complexation with an ion-exchange resin and also an activating agent admixed with the complex, and a rate-controlling membrane 106.
  • Backing layer 102 and rate-controlling membrane 106 are sealed together at their edges, preferably by means of a heat seal, to form a sealed pouch for containing reservoir 104.
  • Reservoir 104 is an anhydrous environment for containing the drug/resin complex and the activating agent prior to placement on the skin. Reservoir 104 may also contain stabilizing agents, thickeners, permeation enhancers or other additives as are known to the transdermal delivery art.
  • Rate-controlling membrane 106 is preferably substantially free of dissolved active agent or drug. As used herein, the term “substantially free of active agent” means either free of agent or containing an amount of active agent or drug insufficient to establish and maintain therapeutically effective active agent delivery rates at the time of application to the delivery site. As used herein, the term “therapeutically effective" rate or amount refers to a rate or amount of active agent that provides a therapeutic or beneficial result or effect.
  • Device 10A shown in FIG. 2, in addition to backing layer 102, reservoir 104 and rate-controlling membrane 106, has adhesive layer 108 on the skin-contacting surface of the device for maintaining the device on the skin.
  • Silicone compounds are commonly used as adhesives for the contact adhesive layer 108; however, numerous materials are known to the art which possess the requisite strength and skin compatibility, examples of which are given in the patents previously incorporated herein by reference.
  • a removable release liner 110 on the skin-contacting surface of adhesive layer 108 which liner is removed prior to placement of the device on the skin or mucosa.
  • Such release liners are known to the art and are typically of siliconized paper or siliconized polymer or the like.
  • FIG. 3 illustrates a laminated device 100 according to this invention.
  • Device 100 has a drug- impermeable backing layer 102, a reservoir lamina layer 104a containing the drug/ion-exchange resin complex and the activating agent, a rate-controlling membrane 106a and an in-line contact adhesive layer 108.
  • Device 100 may also include a removable release liner (not shown) adjacent to adhesive layer 108.
  • Reservoir lamina 104a may, in addition to permeation enhancers and stabilizing agents for example, contain anhydrous or hydrophobic rheological modifiers, viscosity boosters or thixotropic/gelling agents to prevent flow of the drug matrix beyond the device confines.
  • Rate- controlling membrane 106a does not flow, as this membrane, generally, has a rigidity when dry and, when moistened, it will continue to retain its integrity.
  • Device 200 illustrated in FIG. 4, is similar to device 100 of FIG. 3, except that device 200 has an anhydrous reservoir 104b comprising two lamina layers, a first layer 112 which contains the activating agent and a second layer 114 which contains the drug/ion- exchange resin complex.
  • Activating agent layer 112 may be positioned either between drug/resin complex layer 114 and rate-controlling membrane 106a, as illustrated in FIG. 4, or between complex layer 114 and backing layer 102 (not shown).
  • the activating agent becomes activated and the resulting aqueous solution of activating agent migrates from layer 112 into layer 114 to promote dissociation of the drug from the ion-exchange resin, making the drug available for delivery from the device.
  • EXAMPLE 1 Transdermal delayed delivery devices for the delayed onset of delivery of nicotine according to the present invention and generally as illustrated in FIG. 3 were prepared as follows.
  • a cation exchange resin having a -S0 3 H functional group (Amberlite ® IRP-69, the sodium form; Aldrich Chemicals) was immersed in 5 volumes of 2 N HC1 solution and stored overnight. The swollen resin was washed on a sintered glass filter with 10 volumes of 0.5 N HC1 and then 10 volumes of distilled water. The acidic resin was dried under vacuum at 50 ⁇ C overnight.
  • the nicotine/resin complex 37.5% of the nicotine/resin complex, 12.5% of micronized sodium carbonate (the activating agent), and 50.0% ethylene vinyl acetate copolymer having a 40% vinyl content (EVA40) were melt-blended together on a hot plate or in a mill or mixing machine, and the formulation was then melt-pressed to a 15 mil (0.38 mm) film to form the nicotine reservoir layer.
  • the reservoir layer was then laminated to a backing layer of pigmented Medpar ® (a trilaminate of pigmented medium density polyethylene/aluminum- polyethyleneterephthalate/low density polyethylene; 3M) .
  • pigmented Medpar ® a trilaminate of pigmented medium density polyethylene/aluminum- polyethyleneterephthalate/low density polyethylene; 3M
  • Hytrel® 4056 (33% tetramethylene terephthalate/67% poly(tetramethylene ether)glycol-terephthalate; the rate-controlling membrane) was then laminated onto the opposite surface of the reservoir layer.
  • Silicone adhesive 355 containing 13% silicone medical fluid lOOcs was cast onto FCD/polyester 1022 release liner to give the adhesive layer, and the exposed side of the adhesive layer was then laminated onto the bottom side on the rate- controlling membrane and the device cut to a desired size/shape to give the final nicotine delayed onset delivery device ("System Type I").
  • EXAMPLE 2 Transdermal delayed delivery devices for the delayed onset of delivery of nicotine according to the present invention and generally as illustrated in FIG. 2 were prepared as follows.
  • the delivery device 37.5% of the nicotine/resin complex (from Example 1) was mixed together under anhydrous conditions with 12.5% micronized sodium carbonate (the activating agent) and 50.0% polyethylene glycol with a molecular weight of 400 (PEG 400) to form a reservoir matrix.
  • An amount of 400 mg of the reservoir formulation was heat-sealed between Hytrel ® 4056 (1.5 mil, 0.038 mm; the rate-controlling membrane) and a backing membrane (made by casting Hytrel ® 4056 onto 1 mil, 0.025 mm, polyester) to give a 10 cm 2 device.
  • Silicone adhesive 355 containing 13% silicone medical fluid lOOcs was cast onto FCD/polyester 1022 release liner to give the adhesive layer, and the exposed side of the adhesive layer was then laminated onto the bottom side of the device on the rate- controlling membrane and the device cut to the desired size/shape to give the final nicotine delayed onset delivery device ("System Type II").
  • Nicotine-containing devices were prepared which were identical to those in Example 2, except that the drug reservoir was composed of 60% nicotine/resin complex, 20% micronized sodium carbonate and 20% micronized sorbitol as a dry powder. Loading of the powder was 250 mg for a 10 cm 2 device ("System Type III").
  • Nicotine-containing devices were prepared which were identical to those in Example 3, except that the drug reservoir was composed of 75% nicotine/resin complex and 25% micronized sodium carbonate as a dry powder. Loading of the powder was 200 mg for a 10 cm 2 device ("System Type IV").
  • Nicotine-containing devices were prepared which were identical to those in Example 2, except that the drug reservoir was composed of 50% nicotine/resin complex and 50% PEG 400. The reservoir did not contain sodium carbonate. A 10 cm 2 device contained 400 mg of the reservoir formulation ("System Type V").
  • Nicotine-containing devices were prepared which were identical to those in Example 4, except that the drug reservoir was composed of 100% nicotine/resin complex as a dry powder. The reservoir did not contain sodium carbonate. Loading of the powder was 200 mg for a 10 cm 2 device ("System Type VI").
  • EXAMPLE 7 The devices of Examples 1 through 6 were tested in vitro for nicotine release. Release rates of nicotine over time through a 1.5 mil (0.038 mm) Hytrel® membrane into an aqueous bath at 35 ⁇ C were determined, the Hytrel membrane being used because it simulates the water transport properties of human skin. For the test, the release liner was removed from each device, or system, and each device was covered at its drug release surface with the Hytrel membrane to control water availability to the test system in all release rate tests. Each test was run over 24 hours at 35°C. The release medium was distilled water. Drug concentration was determined by UV absorption at 259 nm.
  • FIG. 5 shows the release rate profile of each type of system.
  • System types I, III and IV all exhibited an initial delay prior to release of nicotine.
  • System II had a higher initial release rate due to the partial solubilization of sodium carbonate in PEG 400.
  • System types V and VI did not contain the sodium carbonate activating agent and, as can be seen, they did not release any detectable nicotine.
  • Nicotine-containing delivery devices similar to those of Example 2 were prepared, except that the reservoir contained 20% nicotine/resin complex (where the ion exchange resin is cation exchange resin Amberlite ® IRP-64, with sulfonic acid functionality, sodium form acidified to -S0 3 H prior to binding with nicotine), 6% sodium carbonate and 74% silicone fluid, and the backing was composed of a 1.5 mil (0.038 mm) polyester/1.8 mil (0.046 mm) Hytrel ® 4056 laminate. Additionally, the thickness of the Hytrel rate-controlling membrane was 1.8 mil (0.046 mm).
  • the stability of the above devices after prolonged storage was determined as follows. The devices were stored in a sealed pouch for 13 months at 30°C. They were then tested for their release rate through a Hytrel membrane, following the procedures of Example 7, in comparison with newly prepared devices and also in comparison with a prior art device (the Nicoderm® transdermal patch, identified as
  • a benztropine delivery device is prepared as follows. Ten grams of dried acidified cation exchange resin (Amberlite® IRP-69) is mixed with 15 g of benztropine base in 100 mL of water. The mixture is stirred well, and the pH of the resin slurry is adjusted to 5. The slurry is then filtered on a sintered glass filter and washed well with water. The wet resin is dried under vacuum at 50°C overnight. An analysis of benztropine complexed with the resin shows that 0.54 mg of benztropine is bound to every milligram of the drug/resin complex.
  • benztropine/resin complex 20 wt% of the benztropine/resin complex is mixed together under anhydrous conditions with 5 wt% of micronized sodium carbonate (the activating agent) and 75 wt% of polybutene (a mixture of 68 parts of PB L-100 and 55 parts of PB H- 350) to form a reservoir matrix.
  • An amount of 400 mg of the reservoir formulation is heat-sealed between a rate-controlling membrane layer of EVA 33 (2 mils, 0.05 mm; EVA having 33% vinyl acetate content) and a backing layer of pigmented Medpar ® .
  • Acrylic adhesive (MSP041991P, 3M) is then laminated onto the rate-controlling membrane to give the final ion exchange resin/benztropine complex delivery device.
  • EXAMPLE 10 A nicotine-containing delivery device was prepared as follows, generally according to the procedures of Example 1.
  • a mixture of 52% of nicotine/resin complex prepared as in Example 1 and having 37.8% nicotine content
  • 18% of micronized anhydrous sodium carbonate the activating agent
  • 30% ethylene vinyl acetate copolymer having a 28% vinyl acetate content (EVA28; ELVAX ® 210, from DuPont) was blended together using a dispersion mixer.
  • the formulation was then extruded to a 4 mil (0.10mm) film to form the nicotine reservoir.
  • the reservoir layer was then laminated to a backing layer of pigmented Medpar ® .
  • a 1 mil (0.025mm) layer of EVA40 was then laminated to the opposite surface of the drug reservoir layer to provide a rate controlling membrane.
  • Acrylic adhesive (MSP041991P, from 3M) was laminated onto the bottom side of the device on the rate controlling membrane to give the final nicotine delay onset delivery device.
  • Example 7 The release rate of nicotine from devices prepared according to this example, both those devices freshly made and those which had been stored at either 4 ⁇ C, room temperature or 30° C for eight weeks, was tested following the procedures of Example 7, except that the Hytrel ® 4056 test membrane was 5 mil (0.13mm) thick.
  • Nicotine-containing transdermal delayed-deli very devices were prepared following the procedures of Example 2.
  • the devices consisted of a Hytrel 4056 rate-controlling membrane (1.5 mil; 0.038 mm), contact adhesive layer of silicone adhesive 355 containing 13% silicone medical fluid 100 cs, and a drug reservoir having nicotine/resin complex (with 37.6% nicotine payload), 21.4 mg/10 cm 2 and micronized sodium carbonate (as the activating agent).
  • the mole ratio of sodium carbonate to nicotine was either 0.347, 0.495, 0.693, 0.851, 1.040 or 1.386.
  • Example 12 The release rate of nicotine from the devices at 35°C was tested following the procedures of Example 7. The results showed that the release rate and 24 hour cumulative drug released increased linearly with the increasing mole ratio of sodium carbonate to nicotine. The rate, however, leveled off at the ratio of 0.851.
  • EXAMPLE 12 The effect of the particle size of sodium carbonate on the release rate of a drug from devices having a solid drug reservoir matrix was evaluated as follows. A nicotine-containing delivery device was prepared as follows, generally according to the procedures of Example 1.
  • a mixture of 48% of nicotine/resin complex (prepared as in Example 1 and having 31.2% nicotine content), 12% of anhydrous sodium carbonate (the activating agent) and 40% ethylene vinyl acetate copolymer having a 40% vinyl acetate content (EVA40) was blended together using a dispersion mixer.
  • the particle size of the sodium carbonate was varied in different formulations.
  • the formulation was then extruded to a 5 mil (0.125mm) film to form the nicotine reservoir.
  • the reservoir layer was then laminated to a backing layer of pigmented Medpar®.
  • a 2 mil (0.050mm) layer of EVA40 was then laminated to the opposite surface of the drug reservoir layer to provide a rate controlling membrane.
  • Acrylic adhesive (MSP041991P, from 3M) was laminated (1 mil, 0.025mm) onto the bottom side of the device on the rate controlling membrane and the device cut to a desired size/shape to give the final nicotine delay onset delivery device.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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Abstract

Un dispositif (10) d'administration transdermique contrôlée d'un médicament ou d'un autre agent thérapeutique par la peau ou les muqueuses permet de retarder le début de la libération de l'agent thérapeutique à un taux thérapeutiquement efficace pendant une durée déterminée jusqu'à un moment qui suit le placement du dispositif sur la peau ou les muqueuses. Le dispositif comprend un réservoir (104) non aqueux qui contient un agent thérapeutique complexé avec une résine échangeuse d'ions, ainsi qu'un agent d'activation. Le réservoir présente une surface à travers laquelle l'agent thérapeutique est administré à la peau ou aux muqueuses. Une membrane (106) d'ajustement de la rapidité d'administration est située entre la peau ou les muqueuses et la surface d'administration du réservoir (104) afin de régler la vitesse d'absorption d'eau dans le réservoir. La membrane (106) d'ajustement de la rapidité d'administration est sensiblement dépourvue d'agent thérapeutique avant que le dispositif ne soit placé sur la peau ou les muqueuses. L'invention a l'avantage supplémentaire de mettre à disposition l'agent thérapeutique sous une forme stable avant son placement sur la peau ou les muqueuses, ainsi que sous une forme convenable d'absorption après son placement sur la peau ou les muqueuses.
PCT/US1993/009637 1992-10-15 1993-10-07 Dispositif d'administration transdermique a action retardee WO1994008572A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
MX9306237A MX9306237A (es) 1992-10-15 1993-10-07 Dispositivo de suministro transdermico, de inicio retardado.
AU53549/94A AU5354994A (en) 1992-10-15 1993-10-07 Delayed onset transdermal delivery device

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US96124592A 1992-10-15 1992-10-15
US961,245 1992-10-15

Publications (1)

Publication Number Publication Date
WO1994008572A1 true WO1994008572A1 (fr) 1994-04-28

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Country Link
AU (1) AU5354994A (fr)
WO (1) WO1994008572A1 (fr)
ZA (1) ZA937452B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027844A1 (fr) * 1996-01-30 1997-08-07 Novagent Oy Composition pour un apport transdermique de medicaments
WO2005053691A2 (fr) * 2003-12-02 2005-06-16 Fertin Pharma A/S Produit d'administration de nicotine et son procede de production
EP1549633A1 (fr) * 2002-05-28 2005-07-06 Cambrex Charles City, Inc. Composition contenant de la nicotine a liberation lente et procede
WO2006081518A2 (fr) * 2005-01-28 2006-08-03 Collegium Pharmaceutical, Inc. Excipients non aqueux non ioniques pour administration topique et par voie orale d'agents actifs lies a un support

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1349207A (en) * 1972-01-10 1974-04-03 Galat A Pharmaceutical compositions
US3901248A (en) * 1970-07-22 1975-08-26 Leo Ab Chewable smoking substitute composition
GB1462356A (en) * 1973-07-10 1977-01-26 Beecham Group Ltd Pharmaceutical compositions
EP0195643A2 (fr) * 1985-03-18 1986-09-24 MENLEY & JAMES LABORATORIES, LIMITED Compositions et appareil pour le controle de la pénétration d'agents topiques et systématiques
US4650484A (en) * 1983-02-03 1987-03-17 Alza Corporation Method for treating ischemic conditions
EP0316065A2 (fr) * 1987-11-09 1989-05-17 Alza Corporation Appareil pour l'administration de médicaments à travers la peau
WO1989012470A1 (fr) * 1988-06-14 1989-12-28 Alza Corporation Dispositif de distribution transcutanee sous-saturee
EP0384267A2 (fr) * 1989-02-18 1990-08-29 LTS Lohmann Therapie-Systeme GmbH & Co. KG Système thérapeutique pour l'administration transdermique ou transmucosale retardée et controlée d'agents actifs

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3901248A (en) * 1970-07-22 1975-08-26 Leo Ab Chewable smoking substitute composition
GB1349207A (en) * 1972-01-10 1974-04-03 Galat A Pharmaceutical compositions
GB1462356A (en) * 1973-07-10 1977-01-26 Beecham Group Ltd Pharmaceutical compositions
US4650484A (en) * 1983-02-03 1987-03-17 Alza Corporation Method for treating ischemic conditions
EP0195643A2 (fr) * 1985-03-18 1986-09-24 MENLEY & JAMES LABORATORIES, LIMITED Compositions et appareil pour le controle de la pénétration d'agents topiques et systématiques
EP0316065A2 (fr) * 1987-11-09 1989-05-17 Alza Corporation Appareil pour l'administration de médicaments à travers la peau
WO1989012470A1 (fr) * 1988-06-14 1989-12-28 Alza Corporation Dispositif de distribution transcutanee sous-saturee
EP0384267A2 (fr) * 1989-02-18 1990-08-29 LTS Lohmann Therapie-Systeme GmbH & Co. KG Système thérapeutique pour l'administration transdermique ou transmucosale retardée et controlée d'agents actifs

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027844A1 (fr) * 1996-01-30 1997-08-07 Novagent Oy Composition pour un apport transdermique de medicaments
US6254883B1 (en) 1996-01-30 2001-07-03 Novagent Oy Composition for transdermal delivery of drugs
EP1549633A1 (fr) * 2002-05-28 2005-07-06 Cambrex Charles City, Inc. Composition contenant de la nicotine a liberation lente et procede
EP1549633A4 (fr) * 2002-05-28 2007-04-04 Cambrex Charles City Inc Composition contenant de la nicotine a liberation lente et procede
WO2005053691A2 (fr) * 2003-12-02 2005-06-16 Fertin Pharma A/S Produit d'administration de nicotine et son procede de production
WO2005053691A3 (fr) * 2003-12-02 2005-07-14 Fertin Pharma As Produit d'administration de nicotine et son procede de production
US8741935B2 (en) 2003-12-02 2014-06-03 Fertin Pharma A/S Nicotine delivery product and method for producing it
US9801408B2 (en) 2003-12-02 2017-10-31 Fertin Pharma A/S Nicotine delivery product and method for producing it
WO2006081518A2 (fr) * 2005-01-28 2006-08-03 Collegium Pharmaceutical, Inc. Excipients non aqueux non ioniques pour administration topique et par voie orale d'agents actifs lies a un support
WO2006081518A3 (fr) * 2005-01-28 2006-11-23 Collegium Pharmaceutical Inc Excipients non aqueux non ioniques pour administration topique et par voie orale d'agents actifs lies a un support

Also Published As

Publication number Publication date
ZA937452B (en) 1994-06-07
AU5354994A (en) 1994-05-09

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