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CUTANEOUS ADMINISTRATION SYSTEM
CROSS REFERENCE TO RELATED
This is a continuation of application Ser. No. 09/697,603 filed on Sep. 28, 2001 now U.S Pat. No. 6,723,077 which is hereby incorporated by reference herein.
This invention relates generally to the administration of compositions (such as pharmaceutical compositions) for 10 cutaneous administration, including transdermal absorption through the skin. In particular, this invention combines the previously unrelated technologies of pharmaceutical administration and inkjet technology.
Pharmaceutical compositions provide effective treatments 15 for a variety of illnesses. Unfortunately, there are many obstacles to the administration of therapeutically effective doses of many medications. For example, some drugs (particularly peptide based drugs such as insulin) are partially or totally inactivated following oral ingestion, by the highly 20 acidic environment of the stomach. Another problem is the "first pass" effect, which refers to the partial inactivation of orally ingested drugs in the liver, after they have been absorbed from the gastrointestinal system, but before they have exerted their full therapeutic effect. Even when these 25 problems are overcome, patients often fail to take their medications at the proper prescribed intervals, or for the necessary period of time, to achieve an optimal therapeutic response.
Inhalational and intranasal administration have been used as alternative routes of drug delivery. Inhaled drugs can be 30 absorbed directly through the mucous membranes and epithelium of the respiratory tract, thereby minimizing initial inactivation of bioactive substances by the liver. Inhalational delivery can also provide drugs directly to therapeutic sites of action (such as the lungs or the sinuses). This mode of admin- 35 istration has been particularly effective for the delivery of pulmonary drugs (such as asthma medications) and peptide based drugs (usually via intranasal administration), using metered dose inhalers (MDIs). However, MDIs often require coordinating inspiration with actuation of the MDI, and some 40 patients are not able to master this technique. Moreover, patients still often forget to take the medication at prescribed times, or for the necessary period of time to achieve clinical goals. Other patients inadvertently or inappropriately use medications, leading to hospitalizations, morbidity, and even 45 death.
In an effort to overcome such problems, some drugs are administered by passive cutaneous routes, such as transdermal delivery of drugs from a patch applied to the skin. Examples of drugs that are routinely administered by this 50 route are nitroglycerin, steroid hormones, and some analgesics (such as fentanyl). Transdermal administration avoids initial inactivation of drugs in the gastrointestinal tract, and provides continuous dosages usually over a relatively short period of time (such as a day), without requiring active par- 55 ticipationby the patient. Continuous sustained administration provides better bioavailability of the drug, without peaks and troughs, and eliminates the problem of the patient forgetting to take multiple doses of the drug throughout the day. However the patch must be changed regularly, usually each day, to 60 provide a necessary drug concentration in the patch to establish the correct concentration gradient for delivery of the appropriate dose of the drug across the skin.
In addition to transdermal systemic delivery of drugs, topical delivery of drugs to the surface of the skin is also used for 65 treating many skin conditions. For example, antibiotics are topically administered to the skin to treat infection, anesthet
ics to treat pain, retinoids to treat acne, and minoxidil to treat hair loss. These drugs must be repeatedly applied to the skin to achieve their effect, and much of the dosage may be lost by drainage of liquid from the application site, or being inadvertently wiped away. Moreover, excess drug is usually applied to the skin, which can lead to undesired toxic effects particularly if the drug is absorbed through the skin.
Devices and methods are disclosed herein for improving the cutaneous delivery of drugs, by using inkjet-like applicators for transdermal and other cutaneous delivery of drugs. Kits and systems for administrating drugs in this fashion are also described.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective, fragmented, and partially schematic, view of one form of a transdermal application system illustrated herein, having a dispenser and a transdermal patch applied to a human arm.
FIG. 2 is an enlarged, side elevational view of the transdermal application system of FIG. 1, shown in place over a transdermal patch for dispensing.
FIG. 3 is an enlarged, front elevational view of the dispenser of FIG. 1, showing a container module removed from the applicator and a protective cap for placement on the droplet head during periods of inactivity. This figure also schematically illustrates how the applicator may be connected to a remote control device, such as a computer.
FIG. 4 is a top plan view of another form of a transdermal patch, which may be used in conjunction with the transdermal application system of FIG. 1.
FIG. 5 is a perspective, fragmented, and partially schematic, view of a more compact alternative form of a transdermal application system illustrated herein, having a compact dispenser which may be used with or without a patch, here shown retained against a human arm.
FIG. 6 is a cross-sectional, side elevational view of a removable module of the dispenser of FIG. 5.
FIG. 7 is a bottom plan view of the module of FIG. 7.
FIG. 8 is a schematic view, partially in cross-section, of an alternative embodiment, in which a bioactive agent is administered from a thermal jet dispenserto a cutaneous target, such as a pad, acting as a substitute for conventional intravenous ("IV") administration of the bioactive agent.
FIG. 9 is a side elevational view, partially in cross-section, of the transdermal application system of FIG. 5, taken along lines 9-9 thereof, showing application of a bioactive-composition-attracting agent, such as a cream, a paste, or a salve to the skin, here on a skin blemish, such as a wart.
DETAILED DESCRIPTION OF PARTICULAR
Unless otherwise noted, technical terms are used according to conventional usage. Definitions of common terms in pharmacology may be found in Remington: The Science and Practice of Pharmacy, 19th Edition, published by Mack Publishing Company, 1995 (ISBN 0-912734-04-3). Transdermal delivery is discussed in particular at page 743 and pages 1577-1584.
The singular forms "a," "an," and "the" refer to one or more than one, unless the context clearly dictates otherwise. The term "comprising" means "including."
An "array" refers to a predetermined pattern, which can be either regular or irregular. Examples of arrays are linear distributions or two-dimensional matrices.
A "bioactive" composition, substance or agent is a composition which affects a biological function of a subject to which it is administered. An example of a bioactive composition is a pharmaceutical substance, such as a drug, which is given to a subjectto alter physiological condition ofthe subject, suchas 5 a disease. Bioactive substances, compositions and agents also include other biomolecules, such as proteins and nucleic acids, or liposomes and other carrier vehicles that contain bioactive substances.
"Cutaneous" refers to the skin, and "cutaneous delivery" 10 means application to the skin. This form of delivery can include either delivery to the surface of the skin to provide a local or topical effect, or transdermal delivery, in which a drug diffuses through the skin surface and into the underlying microvasculature, often for systemic administration of the 15 drug.
The present disclosure concerns an applicator for cutaneous delivery of a bioactive composition using a jet dispenser, such as a piezoelectric orthermal jet dispenser, for instance of a construction used in the inkjet printing arts. The dispenser 20 includes a container for holding the bioactive agent and delivering it to a dispenser orifice, or an array of dispenser orifices. The thermal or piezoelectric jet propels precise amounts of droplets from the dispenser toward a cutaneous target. In one embodiment, a spacer is also provided between the dispenser 25 orifice and a cutaneous target, to space the dispenser a desired distance away from the cutaneous target during delivery of the bioactive agent. This spacer may be attached to either the skin or the dispenser, or merely be interposed between them, to provide an interface across which the bioactive substance 30 may be distributed from the orifice, or from an array of orifices, to a cutaneous target. The target may include skin or a skin patch, such as a transdermal drug delivery patch, which acts as a reservoir for subsequent prolonged transdermal delivery of the agent. 35
In certain embodiments, the dispenser includes the bioactive agent in the container. Examples of agents that can be included in the container include pharmaceutical compositions that are capable of transdermal delivery. Such agents include drugs having sufficient lipophilicity or hydrophilicity 40 to move through the skin surface and stratum corneum. Certain of these agents are designed to reach the microvasculature of the skin, for subsequent systemic absorption and distribution. Examples of agents that are suitable for transdermal delivery include scopolamine, nitrates such as nitroglycerine, 45 an antihypertensive or anti-adrenergic drug such as clonidine, steroid hormones such as 17-beta-estradiol and testosterone, analgesics, such as the opioid analgesic fentanyl, and treatments for nicotine withdrawal, such as nicotine. Many analogues of these drugs retain their biological activity, and are 50 also suitable for transdermal delivery. Although the disclosed dispenser is particularly suited for transdermal delivery of drugs, it can also be used for topical surface application of drugs, suchas antibiotics, corticosteroids, minoxidil or retinoids (such as Retin A). 55
The dispenser may also include a controller for manually or automatically dispensing the bioactive substance from the dispenser at selected times. The controller may take the form of an actuator that is manually depressed to activate the dispenser and dispense the agent. Alternatively, the controller 60 may be a microprocessor which is programmed to dispense the bioactive substance at predetermined intervals, for example several times a day, directly on to the skin or on to a patch. Alternatively, the controller can be used to adjust dosages of drug administered, for example for a particular time of 65 day, an event (such as an activity that will require a dosage modification), or detection of a physiological condition (such
a an adverse drug reaction that requires reduction or cessation of drug administration). When the dispenser is used with a patch, the dispenser may be used to recharge the patch and avoid the necessity of changing the patch as often. Either with or without a patch, complex administration protocols may be followed, for example applying different drugs at different times throughout the day or longer period, for example as long as a week, a month, or even longer.
In certain examples, the container may carry multiple container modules, such as removable and replaceable modules that contain the bioactive agent(s). Several modules may contain the same or different agents, for example different agents that combine before or at the time of delivery to modify one or both of the agents, or to produce a desired bioactive effect. An example of a modifying substance that may be combined at the point of ejection is a penetration enhancer that improves cutaneous penetration of the other bioactive substance. Penetration enhancers that may be mixed with a bioactive agent at the time of delivery include solvents such as water; alcohols (such as methanol, ethanol and 2-propanol); alkyl methyl sulfoxides (such as dimethyl sulfoxide, decylmethyl sulfoxide and tetradecylmethyl sulfoxide); pyrrolidones (such as 2-pyrrolidone, N-methyl-2-pyrroloidone and N-(2-hydroxy ethyl)pyrrolidone); laurocapram; and miscellaneous solvents such as acetone, dimethyl acetamide, dimethyl formamide, and tetrahyrdofurfuryl alcohol. Other penetration enhancers include amphiphiles such as L-amino acids, anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, fatty acids and alcohols. Additional penetration enhancers are disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition (1995) on page 1583. Of course agents such as penetration enhancers can also be premixed with the bioactive agent prior to the point of ejection, for example the bioactive agent and modifying substance can be present together in the container.
The bioactive agent may be any flowable fluid (for example a liquid, gel or powder), although liquids are particularly of use in the dispenser. In some embodiments, at least one of the container modules may contain a bioactive agent in powder or other dry form. The powder or other agent is dispensed from the container, and may be combined with a liquid (such as a penetration enhancer) en route to the cutaneous delivery site. The interface provided by a spacer between the orifice plate and the target allows chemical reactions to occur, as well as phase changes to stabilize (such as a change from a solid to a liquid state). This interface may also provide flexibility in the distribution of the drug across a larger target area, as compared to application of the agent from an orifice that abuts the target. Using existing inkjet technology, distribution of the drug to the target may be carefully controlled, and exact dosing of the drug may be achieved. Controllers may be used to dispense simple or complex drug regimens, which is of particular advantage in patients who require numerous daily medications. Computerized control of medication dosing, which may be programmed by medical personnel for subsequent automated delivery, can help avoid toxic drug interactions, overdosages, and deaths.
The applicator is suitable for use in a variety of ways. For example, the applicator may be intermittently applied to the skin to administer a dosage of a drug directly to the skin. Alternatively, the applicator may be applied to a transdermal patch to recharge it with medication, instead of replacing the patch. In another embodiment, the applicator may be selectively retained in prolonged contact with the cutaneous target, for example by securing the applicator to the skin with an attachment member, such as a strap or adhesive. In this manner, the active agent may be administered from the dispenser