JP2002535293A - Methods for enhancing needle-free transdermal powder drug delivery - Google Patents

Abstract

(57) The therapeutic agent is administered to a predetermined area of the skin or mucosa of a vertebrate subject by the following steps: (a) within this area of the skin or mucosa. Promoting the particles across or within and across this area; and (b) topically applying a first transdermal drug delivery device or first closed dressing over the area of skin or mucosa Wherein the particles, or the first transdermal drug delivery device or the first occlusive dressing, or a combination thereof, comprise a therapeutic agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates generally to methods for administering a therapeutic agent to a subject. More particularly, the present invention relates to methods for enhancing the delivery of therapeutic agents into vertebrate tissue using needleless powder injection techniques.

BACKGROUND OF THE INVENTION The ability to deliver drugs into or through the skin surface (transdermal delivery) offers many advantages over other steady state parenteral (sparental) delivery technologies. . In particular, transdermal delivery provides a safe, convenient, and non-invasive alternative to conventional administration systems, and most of the problems associated with conventional needles and syringes (e.g., needle pain, Risk of introducing an infection to an individual, risk of nursing contamination or infection caused by accidental needle sticks, and disposal of used needles)
Is conveniently avoided. Further, such delivery provides a high degree of control over the blood concentration of the administered drug.

[0003] Recently, a novel painless transdermal drug delivery system has been described that provides for the delivery of solid drug-containing particles into and through intact skin at controlled doses, It involves the use of a needleless syringe. In particular, U.S. Pat. No. 5,630,796 to Belhouse et al. Describes a needleless injector that delivers pharmaceutical particles entrained in a supersonic air stream in a painless manner. This needleless syringe (
"PowderJect needle-free syringe devices" are used for transdermal delivery of powdered drug compounds and compositions, delivery of genetic material to living cells (eg, gene therapy), and skin of biopharmaceuticals. , Muscle, blood, or lymph, and for delivery into and / or across mucosal surfaces. Needle-free injectors also deliver drugs and biologicals to organ surfaces, solid tumors and / or
Alternatively, it can be used to deliver to a surgical cavity (eg, a tumor bed or lumen after tumor resection). Pharmaceutical agents that can be suitably prepared in substantially solid particulate form can be safely and easily delivered using such devices.

[0004] One particular needleless injector generally comprises an elongated tubular nozzle having a rupturable membrane, which first closes a passage through the nozzle and is substantially adjacent the upstream end of the nozzle. Placed. The particles of the therapeutic agent to be delivered are placed adjacent to the rupturable membrane and delivered upstream of the membrane using an energizing means that applies sufficient gas pressure to rupture the membrane. And produces a supersonic airflow (entraining the pharmaceutical particles) through the nozzle for delivery from the downstream end of the nozzle. Thus, particles can be delivered from a needle-free injector at a high delivery rate between Mach 1 and Mach 8, which can be easily obtained upon rupture of the rupturable membrane.

[0005] Alternative needleless injector configurations generally include the same elements as described above, except that instead of having the pharmaceutical particles entrained in the supersonic airflow, the downstream end of the nozzle comprises a diaphragm. . The diaphragm has a stationary "invert" position (where the diaphragm is concave on the downstream surface to contain the pharmaceutical particles) and a discharge "evert" position (where the "invert" position). The diaphragm is movable to and from the downstream surface as a result of a supersonic shock wave impinging on the upstream surface of the diaphragm. In this manner, the pharmaceutical particles contained within the concave surface of the diaphragm are rapidly released from the device for transdermal delivery of the particles to the target tissue surface (ie, the skin or mucosal surface).

[0006] Transdermal delivery using the needle-free injector configuration described above generally requires 0.1 μm and 25 μm.
This is done with particles having an approximate size in the range between 0 μm. About 25
Particles larger than 0 μm can also be delivered from this device, up to the size of the particles that cause undesired damage to skin cells. The actual distance that the delivered particles penetrate is the particle size (eg, nominal particle size assuming approximately spherical particle geometry), particle density, initial velocity at which the particles strike the skin surface, and the density of the skin And kinematic viscosity. Target particle densities for use in needleless injection generally range between about 0.1 g / cm ³ and 25 g / cm ³ , and the injection rate is
Generally in the range between 200 m / s and 3,000 m / s.

[0007] A particularly unique feature of needle-free injectors is the ability to optimize the depth of penetration of the delivered particles, thereby allowing targeted administration of a pharmaceutical agent to various sites. For example, particle properties and / or device operating parameters can be selected to provide different penetration depths, for example, for epidermal or dermal delivery. One approach is between about 2 kg / sec / m and 10 kg / sec / m, more preferably about 4 kg / sec / m
Requires selection of particle size, particle density and initial velocity to provide momentum density (eg, particle momentum divided by particle frontal area) between 5 g / sec / m and 7 kg / sec / m. I do. Such control of momentum density allows for optimized, tissue-selective delivery of pharmaceutical particles.

[0008] The above-described systems provide a unique means for delivering vaccine antigens into or across skin or tissue. However, there are dose limitations for the administration of powdered drug formulations using needle-free injection devices of conventional size. Thus, the dose of drug delivered can be limited, thereby resulting in a residual powder drug formulation that does not penetrate skin or mucosal surfaces.

[0009] Accordingly, there remains a need for an effective and safe method of delivering powdered therapeutic formulations to enhance the dose of drug delivered.

SUMMARY OF THE INVENTION The present invention provides a unique method for increasing the dose of a therapeutic delivered by transdermal administration.

Accordingly, the present invention provides a method comprising: (a) accelerating particles into, across, or within and across skin or mucosa; and (b) skin Or locally disposing a first transdermal drug delivery device, or first occlusive dressing, over an area of the mucosa, wherein the particles or the first
A transdermal drug delivery device or first occlusive dressing, or a combination thereof,
Providing a use of the therapeutic agent in the manufacture of a medicament for administering the therapeutic agent to a predetermined area of skin or mucosa of a vertebrate subject by the method comprising: .

The present invention also provides: (a) accelerating the particulate medicament into, across, or within and across the skin or mucosa; and (b) Pre-determining a therapeutic agent in a vertebrate subject by a method comprising: locally disposing a first transdermal drug delivery device or first closure dressing over an area of skin or mucosa. Use of a therapeutic agent in the manufacture of a particulate medicament for administration to a defined area of skin or mucous membrane; by a first transdermal drug delivery device or a first closed dressing, the skin or mucosa of a vertebrate subject The use of a therapeutic agent in the manufacture of a composition for administering the therapeutic agent to a predetermined range of the method comprising: (a) dispersing the particles within the skin or mucous membrane; Across Or accelerating within and across the area; and (b) locally disposing a first transdermal drug delivery device, or a first occlusive dressing, over the area of the skin or mucosa. And (i) accelerating the particulate medicament and (ii) the placebo particles into, across, or within and across the skin or mucous membranes. Using the therapeutic agent in the manufacture of a particulate medicament for administering the therapeutic agent to a predetermined range of skin or mucosa in a vertebrate subject for administration by a method comprising the steps of: .

Accordingly, in one embodiment, a method is provided for administering a therapeutic agent to a predetermined area of the skin or mucosa of a vertebrate subject. The method includes accelerating the particles within, across, or within and across the area of the skin or mucous membrane. Subsequently, a transdermal delivery device or occlusive dressing is topically placed over the area of skin or mucous membrane. The particles, transdermal delivery device and / or occlusive dressing include a therapeutic agent. In addition, the method further comprises the step of pre-determining the predetermined area of the skin or mucosa within the area of the skin or mucous membrane, prior to the step of accelerating the particles within or across the area or across the area. Topically deploying a transdermal delivery device or occlusive dressing over the skin or mucous membrane of the subject.

[0014] In another embodiment, a method is provided for enhancing transdermal delivery of a therapeutic agent by needleless injection. The method comprises the step of co-administering particles containing the therapeutic agent and placebo particles.

[0015] These and other embodiments of the present invention will readily occur to those skilled in the art in light of the disclosure herein.

DETAILED DESCRIPTION OF THE INVENTION Before describing the present invention in detail, the present invention is not limited to particular transdermal drug delivery device configurations, particular drug / vehicle formulations, etc., but It should be understood that it can vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

As used in this specification and the appended claims, the singular forms “a”
It should be noted that ",""an" and "the" include plural objects unless the content clearly dictates otherwise. Thus, for example, reference to "a penetration enhancer" includes a mixture of two or more penetration enhancers, reference to "an excipient" or "vehicle" includes a mixture of excipients or vehicles, Reference to "particle" includes reference to two or more such particles and the like.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, preferred materials and methods are described herein. You.

In describing and claiming the present invention, the following terminology will be used in accordance with the provisions listed below.

As used herein, the terms “pharmaceutical agent”, “pharmaceutically active agent”
, "Therapeutic agent" or "therapeutically active agent" are used interchangeably and
When administered to an organism (human or animal), any compound or composition that induces a desired pharmaceutical and / or physiological effect by local and / or systemic effects is contemplated. Thus, the term includes these compounds or chemicals traditionally considered as drugs and vaccines, as well as biopharmaceuticals, including molecules such as peptides, hormones, nucleic acids, genetic constructs, and the like.

The term “transdermal” delivery refers to both transdermal (ie, “through the skin”) and transmucosal administration (ie, the passage of a therapeutic agent into the skin or mucosal tissue, or the skin or mucosa). Delivery by passage through a tissue). For example, Transde
rmal Drug Delivery: Developmental Iss
ues and Research Initiatives, Hadgraf
t and Guy (eds), Marcel Dekker, Inc. , (1989)
Controlled Drug Delivery: Fundamenta
ls and Applications, Robinson and Lee (eds.), Marcel Dekker Inc. , (1987); and Trans.
dermal Delivery of Drugs, Volumes 1-3, Kydon
ieus and Berner (eds.), CRC Press, (1987). Unless otherwise specified, aspects of the invention described herein in the context of "transdermal" delivery are meant to apply to both transdermal and transmucosal delivery. That is, unless expressly stated otherwise, it should be assumed that the compositions, systems and methods of the present invention are equally applicable to transdermal and transmucosal modes of delivery.

The term “passive transdermal delivery” refers to the delivery of a pharmaceutically acceptable composition to a body surface (eg, skin), or the body surface, without the use of applied electromotive force. Refers to delivery through. Passive transdermal delivery includes direct application to the skin, transdermal patches, membrane relief systems that provide controlled delivery, adhesive diffusion control systems, matrix-dispersed systems,
And microreservoirs, but can be accomplished using a number of means, including but not limited to: Such systems are known in the art, and
ngton: The Science and Practice of Ph
armacy, Mack Publishing Company, Easto
n, Pennsylvania, 19th Edition, 1995.

The terms “electrotransport”, “iontophoresis” and “iontophoretic” refer to one or more pharmaceutically acceptable by means of electromotive force applied to a reservoir containing the composition. Used herein to refer to the delivery of a novel composition to or across a body surface (eg, the skin).
Such delivery devices are alternatively referred to herein as "active transdermal delivery devices." The agent can be delivered by electromigration, electroporation, electroosmosis, or any combination thereof. Electroosmosis is also known as electrohydrokinesis, electroconvection (el
Electro-convection) and electro-induced osmosis. In general, electroosmosis into the tissue of a species is caused by the movement of the solvent containing the species (ie, the solvent flow induced by electromigration of other ionic species) as a result of the application of an electromotive force to the reservoir of the therapeutic species. Caused by During this electrotransport process, certain modifications or alterations of the skin, also referred to as "electroporation", can occur, such as the formation of transiently existing pores in the skin. Any electro-assisted transport of the species, which is increased by a modification or alteration to the body surface (eg, the formation of pores in the skin), is also included in the term “electro-transport” as used herein. Thus, as used herein, the terms “electrotransport”, “iontophoresis” and “iontophoretic” refer to (1) delivery of charged agents by electromigration, (2) the process of electroosmosis. (3) delivery of charged or uncharged drugs by electroporation, (4) delivery of charged drugs by a combined process of electromigration and electroosmosis, and / or (5) ) Refers to the delivery of a mixture of charged and uncharged drugs by a combined process of electromigration and electroosmosis.

“Needle-free syringe” means a device that does not have a conventional needle to pierce the skin and that delivers a particulate composition transdermally. Needleless syringes for use in the present invention are discussed throughout this document.

“Occlusive dressing,” when applied to a predetermined area of the skin or mucous membrane, facilitates the transdermal delivery of a pharmaceutically acceptable composition to the environmental aspects of the skin or mucous membrane area. Is to change. The occlusive dressing may provide a physical barrier to prevent (ie, increase delivery) the leakage of material applied and existing material on or around the skin or mucosal area. In addition, the application of an occluded dressing can cause or prevent an increase in water content, pH, oxygen environment, etc. in the area of the skin or mucous membranes. As used herein, the term "closed dressing" is prepared from bandages, gas and / or moisture permeable or impermeable synthetic polymer-based dressings, or natural or synthetic materials or combinations thereof. And other solid form dressings, topical formulations (eg, creams, gels, ointments or other liquid or semi-liquid materials) and the like. Occlusive dressings can be prepared to include a locally or systemically active therapeutic agent.

An “effective” amount of a therapeutic agent means a nontoxic but sufficient amount of the agent to provide the desired therapeutic or prophylactic effect. As used herein, an "effective" amount of a penetration enhancer is defined as skin or mucosal permeability, and, correspondingly, the desired depth of penetration, rate of administration, and amount of therapeutic agent delivered. Means the amount that provides the desired increase in

“Antigen” means a molecule that contains one or more epitopes that stimulate the host's immune system to generate an antigen-specific immune response or humoral antibody response of the cell. Thus, antigens include proteins, polypeptides, antigenic protein fragments, oligosaccharides, polysaccharides, and the like. Further, the antigen may be derived from any known virus, bacterium, parasite, plant, protozoan, or fungus, and may be the entire organism or an immunogenic portion thereof (eg, a cell wall component). The term also includes tumor antigens. Similarly, oligonucleotides or polynucleotides that express an antigen, for example, in a DNA immunization application, are also included in the definition of antigen. Synthetic antigens (eg, haptens, polyepitope, flanking epitopes, and other recombinantly or synthetically derived antigens) are also included in the definition of antigen (Bergm).
(1993) Eur. J. Immunol. 23: 2777-2781
Bergmann et al. (1996) J .; Immunol. 157: 3242-3
249; Suhrbier, A (1997) Immunol. and Cell
Biol. 75: 402-408; Gardner et al. (1998) 12th.
World AIDS Conference, Geneva, Switzerland
Land, June 28-July 3, 1998).

The term “vaccine composition” contemplates any pharmaceutical composition comprising an antigen, which composition can be used to prevent or treat a disease or condition in a subject. Thus, this term refers to subunit vaccines (ie, vaccine compositions comprising antigens separated and dispersed from all of the organisms to which they naturally bind) as well as killed, attenuated or inactivated bacteria, viruses, parasites Includes both compositions containing whole organisms or other microorganisms.

The viral vaccine compositions used herein include, inter alia, Picornaviridae (eg, poliovirus); Calciviridae; Togaviridae (eg, rubella virus, dengue virus, etc.); Flaviviridae; Coronaviridae; Reoviridae; Birnaviridae; Raboviridae (Rh
abodoviridae (eg, rabies virus, etc.); filoviridae; paramyxoviridae (eg, mumps virus, measles virus,
Orthomyxoviridae (eg, influenza viruses of type A, B and C); Bunyaviridae; Arenaviridae; Retroviridae (eg, HTLV-I; HTLV-II; HIV-). 1; and H
IV-2); viral vaccine compositions comprising or derived from members of the simian immunodeficiency virus (SIV) family. In addition, viral antigens include papilloma virus (eg, HPV); herpes virus; hepatitis virus (eg, hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), delta hepatitis virus ( HDV)
, Hepatitis E virus (HEV) and hepatitis G virus (HGV)); and tick-borne encephalitis virus. For descriptions of these viruses and other viruses, see, for example, Virology, 3rd edition (ed. By WK Joklik, 1988); Fundamental Virology, 2nd edition (B.N.
Fields and D.A. M. Knipe, 1991). Bacterial vaccine compositions as used herein include, but are not limited to, bacterial vaccine compositions that include or are derived from organisms that cause: diphtheria, cholera, tuberculosis, tetanus, pertussis , Meningitis, and other pathological conditions (
Meningococcus A; B and C, Hemophilus inf
luenza type B (HIB), and Helicobacter pyror
i). Examples of antiparasitic vaccine compositions include vaccine compositions from organisms that cause malaria and Lyme disease.

As used herein, the term “treatment” includes any of the following: prevention of infection or re-infection; reduction or elimination of symptoms; and reduction or complete elimination of pathogens. Treatment can be accomplished prophylactically (pre-infection) or therapeutically (post-infection).

“Vertebrate subject” means a subphylum cordata, in particular, any member of a mammal, including but not limited to humans and other primates. The term does not imply a particular age. Thus, it is intended to include both adult and newborn individuals.

The phrase “predetermined area of skin” refers to an intact unbroken living skin set
A defined range of woven or mucosal tissue is intended. This range is usually about 0.3 cm ^Two ~ 30cm^TwoRange, more usually about 5cm^Two~ About 10cm^TwoRange. I
However, the extent of skin or mucosal tissue (through which the drug is administered)
The ability to vary significantly depending on device configuration, dose, etc.
Will be understood by those skilled in the art.

As used herein, “permeation enhancement” or “penetration enhancement” refers to an increase in the permeability of a skin to a therapeutic agent (ie, the rate at which an agent penetrates the skin and enters the blood stream). For increasing). The increased penetration resulting from the use of such enhancers is observed by measuring the rate of diffusion of the drug through animal or human skin using diffusion cell devices well known in the art. Can be done.
Permeation enhancers can be used to facilitate absorption into or through the skin. Such permeation enhancers include water, alcohols (methanol, ethanol,
2-propanol, etc.), ethyl glycerol, methyl nicotinate, alkyl methyl sulfoxide, pyrrolidone, laurocapram,
Acetone, dimethylacetamide, dimethylformamide, tetrahydrofurfuryl; surfactant; glycerol monoester (GMO) (eg, glycerol monooleate); fatty acid; fatty acid ester; terpene; Solvents such as diethyl-m-toluamide).

As used herein, “carrier” or “vehicle” refers to a carrier material suitable for transdermal drug administration, and any such material known in the art (eg, , Any liquid, gel, solvent, liquid diluent, solubilizer, etc.)
They are non-toxic and do not interact with other components of the composition in a deleterious manner. Examples of suitable carriers for use herein include water, silicone, liquid sugar,
Wax, petroleum jelly, and various other materials. As used herein, the term "carrier" or "vehicle" also refers to stabilizers, crystallization inhibitors, or other types of additives that are useful to facilitate transdermal drug delivery. Get good.

“Optional” or “as needed” means that the event or situation described subsequently may or may not occur, and that the description is an example of when this event or situation occurs. , And instances where this event or situation does not occur. For example, the phrase "optionally, a transdermal delivery device is subsequently applied," may or may not result in the application of such a device, and the description refers to the application of such a device. It is meant to include both cases where application occurs and cases where application of such a device does not occur.

The present invention is directed to a method, wherein a flow of a therapeutic agent that is painlessly administered to a subject's skin or mucosa using a needle-free injector is directed to a transdermal delivery device to the site of drug administration. Or augmented by subsequent application of a closed dressing, or both a transdermal delivery device and a closed dressing. In addition, this method may result in some side effects and / or reduced local skin reactions.

The method includes accelerating the particles into, across, or across the skin or mucous membrane, or both within and across the range. Then
A transdermal delivery device or occlusive dressing is placed locally over the skin or mucous membrane. The transdermal delivery device or occlusion dressing generally promotes particles into and / or across the skin or mucous membrane, after 24 hours.
Up to an hour (eg, up to 6 hours, or up to 3 hours). The transdermal delivery device or occlusive dressing may be applied immediately or within one or two hours to facilitate the particles into and / or across the skin or mucous membrane. Typically, the transdermal delivery device or closure bandage will
It is applied after the particle bombardment while maintaining the hydrate.

In one alternative embodiment, the method comprises providing placebo particles (ie, particles without a therapeutic agent; particles with an adjuvant; or particles with an agent (eg, a vasoactive agent or a penetration enhancer)). , A pretreatment step of accelerating into the skin or mucous membrane. This pretreatment is intended to prepare a predetermined area of the skin or mucosa for subsequent administration of a therapeutic agent by application of a transdermal delivery device or occlusive dressing containing such an agent. In another alternative embodiment, the method comprises applying a preselected area of skin or mucosa to a transdermal drug delivery device or occlusion dressing (optionally) to prepare the skin or mucosa for subsequent treatment. ,
(Including permeation enhancers, vasoactive agents, etc.).
This area of the skin or mucous membrane then promotes the particles into and / or across the area of the skin or mucous membrane, followed by applying a transdermal delivery device or occlusive dressing to the area of the skin. Will be treated.

In a further alternative embodiment, both the particles containing the therapeutic agent and the placebo particles are administered to the skin or mucosal area, sequentially or simultaneously. Preferably,
The particles are facilitated using a needle-free injector, described more fully herein below. Optionally, following co-administration of the active agent and placebo particles, a transdermal delivery device or occlusive dressing is applied to the area of skin or mucosa.

When present in the formulation to be delivered, the placebo particles are inert high density particles (
For example, metal particles coated with gold, tungsten, penetration enhancers or surfactants, etc.), which are up to 75 μm in diameter, preferably about 1 μm to 50 μm in diameter, and in the formulation Of the total mass of the particles of about 0.1.
It is included in the range of 1% to about 10%. Pretreatment of the skin or mucosal area with placebo particles increases the rate at which transdermal drug delivery from a transdermal delivery device or occlusion dressing is achieved.

After pretreatment of the skin or mucous membrane area with the particles, a transdermal delivery device and / or
Or an occlusive dressing is placed topically on the pre-treated area of skin or mucous membrane. The application of this device or bandage is for the minimal purpose of protecting the residual particulate powder remaining on the surface of the skin or mucous membranes from accidental or intentional exfoliation, and furthermore, the topical coverage of the skin or mucous membrane area Simultaneous or simultaneous with the administration of the particles, for environmental changes or for the purpose of increasing the amount of particle powder available for continuous transdermal flow and reducing local skin reactions to enhance recovery. Intended to happen either immediately after. However, in situations where exfoliation of the residual powder is not considered an immediate concern (e.g., where the particles are administered to another protected or inaccessible area of the skin or mucous membranes), the transdermal delivery device or Application of the occlusive dressing may be delayed.

The transdermal delivery device can be a passive transdermal drug delivery device, an active drug delivery device (eg, an electrotransport drug delivery device), and the like. The closure bandage
It may be a bandage, or similar substance, or a closed topical formulation. Optionally, the transdermal delivery device or occlusive dressing includes a therapeutic agent.

In one embodiment, a needle-free injector is used to administer the desired therapeutic agent to a predetermined area of the skin or mucous membrane, leaving a residue of particulate powder on the surface of the skin or mucous membrane Can occur. Following administration by needle-free injection, a transdermal delivery device or occlusive dressing is applied to the area of the skin or mucous membrane that is free of therapeutic agent and acts to prevent residual drug loss into the environment. In this case, the transdermal delivery device or occlusive dressing may include an active agent, an anti-irritant (eg, a topical corticoid,
It may not include glycerin / green tea, etc., penetration enhancers, vasoactive agents, etc., which act to increase the uptake of the active agent administered by a needleless syringe.

In a second embodiment, following administration of the therapeutic agent by a needleless injector to a predetermined area of the skin or mucous membrane, a transdermal delivery device or closure dressing containing the therapeutic agent is applied. . The therapeutic agent administered from the transdermal delivery device or the occlusion dressing may be the same or different than the therapeutic agent administered by a needleless injector.

The method of the present invention can be used to administer an immunizing composition that includes a selected antigen and an adjuvant in combination. In one embodiment, the method optionally comprises providing a predetermined area of skin or mucous membrane of the vertebrate subject with:
Applying a transdermal delivery device or closure dressing containing an adjuvant, and removing the device or dressing after a range of 1 minute to 24 hours or longer; and And administering a particle containing the selected antigen and, if necessary, the same or a different adjuvant. Subsequently, a transdermal drug delivery device or occlusive dressing may be located locally over the skin mucosa to increase uptake of the composition. Finally, the device or bandage optionally includes an adjuvant.

In yet another embodiment, a needle-free injector may be used to administer a therapeutic agent-free placebo composition to a predetermined area of the skin or mucous membrane, followed by treatment. A transdermal delivery device or occlusion dressing containing the agent is applied. Without wishing to be bound by theory, in this embodiment, we consider that pre-treatment of the skin or mucosa area with a needle-free injector will increase permeability, or Acts to reduce the permeation barrier of the drug, thereby increasing transdermal delivery of the therapeutic agent to the subject from a transdermal delivery device or occlusion dressing. Delivery of larger therapeutically active biomolecules (eg, polypeptides) can also be effected more efficiently following treatment of the area of skin or mucosa with a needleless injector. Treatment of the skin or mucous membranes with a placebo composition also allows for the administration of the active agent using a transdermal delivery device or closure dressing having a smaller surface area of skin or mucosal contact.

This method can also be used to modify or design the pharmacokinetic profile of therapeutic agent delivery. A "pharmacokinetic profile" contemplates a change in drug concentration over time, for example, in skin, muscle, lymph, blood, serum or plasma, as a result of absorption, distribution and elimination of the drug. For example, a graphical representation of plasma therapeutic agent concentration versus time indicates the effective concentration of a single dose of the drug, characterized by its potential, time of peak effect, magnitude of peak effect, and duration of effect. These properties can be affected by changes in the rate of absorption, the dose of therapeutic agent administered, and the rate of removal.

Thus, for example, administration of a therapeutic agent to a predetermined area of the skin or mucous membranes by a needle-free injector results in a rapidly developed peak in drug concentration in the blood, followed by a relatively rapid increase in drug concentration. Can provide a bolus of drug that produces a significant reduction. This pharmacokinetic profile can be used, for example, to extend the duration of an effective blood concentration drug,
If desired, it can be modified by subsequent application of a transdermal delivery device or occlusive dressing that includes the same therapeutic agent for that area of the skin or mucosa.

A typical pharmacokinetic profile for transdermal delivery of a therapeutic agent to a predetermined area of the skin or mucous membrane is the relatively long-lasting duration of effective drug concentration in the blood following a prolonged period of absorption. Time. The pharmacokinetic profile is to enhance the absorption phase of therapeutic agent administration by pre-treatment of a predetermined range of skin or mucous membranes, for example, using needle-free injection of placebo particles or placebo particles covered with a penetration enhancer. Can be modified by Such pre-treatment may reduce the lag time in achieving therapeutic levels of the subsequently delivered drug.

Based on the foregoing disclosure, those skilled in the art will appreciate the ability to combine transdermal delivery devices and / or occlusive dressings to design dosing regimens to achieve any desired pharmacokinetic profile. Needle syringe technology may be used.

A particularly preferred needle-free injector useful in the methods disclosed and claimed herein is described in commonly owned US Pat. No. 5,630,796 (“the '796 patent”). . This syringe is used for transdermal delivery of the powdered therapeutic compound and composition to the skin, mucous membranes, blood or lymph. The syringe may also be used in conjunction with surgery to deliver a therapeutic agent to an organ surface, a solid tumor, and / or to a surgical cavity (eg, a tumor bed or cavity after tumor resection). Further embodiments of the above syringe are disclosed in the '796 patent and WO 96/04947.

[0052] A second preferred embodiment of a needle-free injector having a body including a lumen (shared US Patent WO 96/20022, the disclosure of which is incorporated herein by reference).
Are disclosed). The upstream end of the lumen is connected or arranged to be connected to a source of gas pressure that can be rapidly released into the lumen. The downstream end of the lumen is moveable between an inverted position and an everted outwardly convex position providing a recessed surface for containing particles containing the therapeutic agent. Ends behind an abductable diaphragm. The abductable diaphragm moves the diaphragm from its adduction position to its abduction position when the energizing gas stream is released into the lumen, thereby transferring particles from the diaphragm to the target surface. It is arranged to emit.

One type of transdermal delivery device that finds utility in the methods disclosed and claimed herein is Campbell et al., US Pat. No. 4,379,
No. 454, the disclosure of which is incorporated herein by reference. This system uses backing
) Layers, drug-containing drug reservoir layers, contact adhesives and release liners (releases)
(E. liner). Optionally, a rate controlling membrane is disposed between the drug reservoir layer and the contact adhesive. In another embodiment, the contact adhesive layer may also serve as a drug reservoir layer.

The backing layer serves as the first structural element of the device and provides much of its flexibility, drape, and preferably occlusivity to the device. The materials used for the backing layer are inert and cannot absorb drugs, enhancers or other components of the pharmaceutical composition contained within the device. The backing is preferably made of one or more sheets or films of a flexible elastomeric material that serves as a protective coating to prevent loss of drug and / or vehicle through transmission through the top surface of the device, and is preferably Gives the device some degree of closure so that the area of skin or mucous membrane that is covered during application remains hydrated and / or hydrated. The materials used for the backing layer allow the device to conform to the contours of the skin and reduce the likelihood of the device detaching from the skin due to differences in the flexibility and elasticity of the skin and the device Or without any area of the skin (eg,
Should be worn comfortably on joints or other parts of curvature), which are usually subject to mechanical strain. Examples of useful materials for the backing layer are polyester, polyethylene, polypropylene, polyurethane and polyetheramide. This layer preferably ranges in thickness from about 15 microns to about 250 microns and, if desired, is matt suitable for coloring, metallization, or writing.
e) may be provided with a finish.

[0055] The drug reservoir layer provides a means for containing the drug. As mentioned above, the drug reservoir may also include a contact adhesive. This reservoir layer generally comprises about 1
It ranges in thickness from about 100 microns, preferably from about 25 to 75 microns.

The pharmaceutically acceptable contact adhesive layer functions to secure the device to the skin during use. In an alternative embodiment, a peripheral ring of contact adhesive is provided on the base surface of the device. In a further alternative embodiment, the adhesive layer may also serve as a drug reservoir layer. A suitable contact adhesive material is a pressure-sensitive adhesive suitable for long-term skin contact, which also provides a physical Are chemically and chemically compatible. Preferred materials for this layer include, for example, polysiloxanes, polyisobutylene, polyacrylates, polyurethanes, plasticized ethylene vinyl acetate copolymers, low molecular weight polyetheramide block polymers (eg, PEBAX), adhesive rubbers (eg, polyisobutene, Polystyrene-isoprene copolymer, polystyrene-butadiene copolymer, and mixtures thereof).

Furthermore, to protect the basal surface of the device during storage and shortly before use,
A release liner is provided over the adhesive layer. Release liners are disposable elements that only serve to protect the device prior to application. Typically, release liners are formed of a material that is impervious to drugs, vehicles and adhesives, and are easily stripped from the contact adhesive. Release liners are typically treated with silicone or fluorocarbon. Polyesters covered with silicone are currently preferred.

If present, it may also be desirable to include a rate controlling membrane between the drug reservoir and the contact adhesive layer. The material used to form such a membrane is selected from the drug reservoir to limit the flux of the non-drug components (ie, enhancer, vehicle, etc.) while not limiting the flux of the drug. Is also selected. Representative materials useful for forming rate controlling membranes include polyolefins (eg, polyethylene and polypropylene), polyamides, polyesters, ethylene ethacrylate copolymers, ethylene vinyl acetate copolymers, ethylene vinyl methyl acetate copolymers, ethylene Examples include vinyl ethyl acetate copolymer, ethylene vinyl propyl acetate copolymer, polyisoprene, polyacrylonitrile, and ethylene propylene copolymer. A particularly preferred material useful for forming the rate controlling film is an ethylene vinyl acetate copolymer.

It will be appreciated by those skilled in the art that the present invention may be used in combination with a wide variety of passive transdermal systems, since the present invention is not limited in this regard. For an example of a passive system, see Gale et al., 4,588,58.
0, Campbell et al., 4,832,953, Gale et al., 4,698,06.
2, Campbell et al., 4,867,982 and Hunt et al., 5,268,
209, but is not limited to, any of these disclosed systems can be used with the present invention.

A transdermal system as described above can be prepared as follows. An adhesive is placed on the release liner. The solvent is evaporated therefrom, and then the adhesive is laminated onto the drug reservoir and then transferred onto the backing film and laminated. Alternatively, the drug reservoir is first laminated to the backing layer and then
It can be laminated to the previously placed adhesive layer.

The present invention can also be used in combination with a wide variety of electrotransport drug delivery systems, as the skilled artisan will appreciate that the method is not limited in any respect in this regard. Understood. For examples of electrotransport drug delivery systems, see U.S. Patent Nos. 5,147,296 to Theewes et al., 5,080,646 to Theeuwes et al., 5,169,382 to Theeuwes et al. And Gyory. No. 5,169,383 and US Pat. No. 5,224.
No. 5,927, No. 5,224,928, No. 5,246,418, No. 5,
Nos. 320,597, 5,358,483 and 5,135,479, and British Patent Application No. 2 239 803, the disclosures of which are incorporated herein by reference. .

As described in these patent documents, typical electrotransport delivery devices that can be used in combination with the present method include an upper housing, a circuit board assembly and associated electronic circuitry, a lower housing, an anode electrode , A cathode electrode, an anode drug / chemical reservoir, a cathode drug / chemical reservoir, a skin compatible adhesive, and a battery (all of which are integrated into a self-contained unit). The anode and cathode electrodes are mechanical and electrical directly on the top surface of the reservoir. The lower surface of the reservoir contacts the patient's skin through the opening in the adhesive, and by this means the device adheres to the patient's body.

The anode electrode is a metal species (eg, silver) that can undergo oxidation during operation of the device.
And the cathode electrode is preferably composed of a species (eg, silver chloride) that can undergo reduction during operation of the device.

[0064] The reservoir generally comprises a gel matrix, and the drug solution is uniformly dispersed in at least one of the reservoirs. Drug concentrations in the range of about 1 × 10 ⁻⁴ M to 1.0 M or greater can be used, with drug concentrations in the lower portion of this range being preferred. Suitable polymers for the gel matrix may include essentially any non-ionic synthetic and / or naturally occurring polymer material. The polar nature is preferred when the active drug is polar and / or ionizable and enhances drug solubility. Optionally, the gel matrix is water-swellable. Examples of suitable synthetic polymers include poly (acrylamide), poly (2-hydroxyethyl acrylate), poly (2-hydroxypropyl acrylate), poly (N-vinyl-2-pyrrolidone), poly (n-methylolacrylamide) ),
Poly (diacetone acrylamide), poly (2-hydroxyethyl methacrylate), poly (vinyl alcohol) and (allyl alcohol)
It is not limited to these. Hydroxy-functional condensation polymers (ie, polyesters, polycarbonates, polyurethanes) are also examples of suitable polar synthetic polymers. Polar naturally occurring polymers (or derivatives thereof) suitable for use as gel matrices include cellulose ethers, methylcellulose ethers, cellulose and hydroxylated cellulose, methylcellulose and hydroxylated methylcellulose, gums such as guar, locust (Hariendico ) (Locust), karaya, xanthan, gelatin and derivatives thereof). Ionic polymers can also be used when the available counterions are either drug ions or other ions that are oppositely charged to the active agent.
Can be used for matrices.

When an electrical current flows through the device, oxidation of the metal species or reduction of the chemical species occurs along at least one surface of the anode or cathode electrode. Although various electrochemical reactions may be utilized, the preferred reactions are a class of charge transfer reactions whereby at least a portion of at least one of the anode or cathode electrode participates in the charge transfer chemistry, i.e., Material is consumed or produced at at least one of the anode electrode or the cathode electrode. This is achieved through oxidation and / or reduction reactions occurring at the electrodes. Examples of preferred oxidation / reduction reactions include:

[0066]

Embedded image Wherein the reaction is an oxidation reaction that occurs at the anode electrode and the reverse reaction is a reduction reaction that occurs at the cathode electrode. Other standard electrochemical reactions and their respective reduction potentials are well known in the art. CRC Han
dbook of Chemistry and Physics, 8-21
See pages 8-31, Vol. 75 (1994-1995).

Any number of therapeutic agents and / or particles of therapeutic agents are administered to an organism via a needle-free injector, and the desired pharmacological, immunogenic effects due to local and / or systemic effects And / or may induce a physiological effect. Such therapeutic agents include compounds or chemicals traditionally considered as drugs, vaccines, and biopharmaceuticals, including molecules such as proteins, peptides, hormones, nucleic acids, genetic constructs, and the like. In addition, the compounds or compositions may have all major therapeutic areas (anti-infectives (eg, antibiotics and antivirals); analgesics and combinations of analgesics; local and general anesthetics; appetite suppressants; Anti-arthritic drugs;
Antiasthmatic; Antidepressant; Antihistamine; Anti-inflammatory; Antiemetic; Antimigraine; Antineoplastic; Antipruritic; Antipsychotic; Antipyretic; Anticonvulsant; Cardiovascular Preparations (including calcium channel blockers, beta blockers, beta agonists and antiarrhythmics); antihypertensives; diuretics; vasodilators; central nervous system stimulants; cough and cold preparations; Drugs; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressants; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides and fragments thereof (naturally occurring or chemically Synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, ribonucleotides). (RNA) or deoxyribonucleotide (DNA)
(Double- and single-stranded molecules and supercoiled molecules or condensed (conde
nsed) molecules, gene constructs, expression vectors, plasmids, antisense molecules, etc.).

The particles of a therapeutic agent (either alone or in combination with another drug or agent) typically comprise one or more additional materials (eg, carriers, vehicles, and / or excipients). )) Is prepared as a pharmaceutical composition. "Carrier", "vehicle" and "excipient" generally refer to substantially inert materials that are non-toxic and do not interact with the other components of the composition in a deleterious manner. These materials can be used to increase the amount of solid in the pharmaceutical composition in particulate form. Examples of suitable carriers include materials such as silicone, gelatin, wax, and the like. Examples of commonly used "excipients" include pharmaceutical grade glucose, sucrose, lactose, trehalose, mannitol, sorbitol, inositol, dextran, starch, cellulose, sodium or calcium phosphate, calcium sulfate, citric acid , Tartaric acid, glycine, high molecular weight polyethylene glycol (PEG), corrosive polymers (eg, polylactic acid, polyglycolic acid and copolymers thereof), and combinations thereof. Additionally, it may be desirable to include charged lipids and / or surfactants in the pharmaceutical composition.
Such materials may be used as stabilizers, antioxidants, or to reduce the likelihood of local irritation at the site of administration. Suitable charged lipids include, but are not limited to, phosphatidylcholine (lectin) and the like. The surfactant is typically a non-ionic, anionic, cationic or amphoteric surfactant. Examples of suitable surfactants include, for example, Tergitol®
Surfactants and Triton® surfactants (Union Carb
ide Chemicals and Plastics, Danbury, C
T), polyoxyethylene sorbitan (for example, TWEEN® surfactant (Atlas Chemical Industries, Wilming)
ton, DE)), polyoxyethylene ethers (eg, Brij), pharmaceutically acceptable fatty acid esters (eg, lauryl sulfate and its salts (SDS))
And the like.

Needleless syringes are useful for the transdermal delivery of therapeutic agents and compositions in powder form, both in vivo and ex vivo, for delivering genetic material to living cells (eg, gene therapy or nucleic acid vaccination) ) And for the delivery of biopharmaceuticals to the skin, muscle, blood or lymph. The syringe can also be used in conjunction with surgery to transfer therapeutic agents, drugs, immunogenic agents, and / or biologics to organ surfaces, solid tumors, and / or surgical cavities (eg, tumor bed after tumor resection) Or the tumor cavity). In theory, virtually any drug that can be prepared in substantially solid particulate form can be safely and easily delivered using the devices of the present invention.

The delivery of a therapeutic agent from a needle-free injector system is typically around 0.1-250 μ
This is generally done with particles having a size in the range of m. For drug delivery, the optimal particle size is usually at least about 10-15 μm (typical cell size). For gene delivery, the optimal particle size is generally substantially
less than m. Particles larger than about 250 μm can also be delivered from the device,
The upper limit is that the size of the particles causes inappropriate damage to skin cells. The actual distance that the delivered particles penetrate the target surface is the particle size (e.g., the nominal particle diameter assuming a roughly spherical particle shape), the particle density, the initial velocity at which the particles strike the surface, and the target Depends on the density and kinematic viscosity of the skin or mucosal tissue. In this regard, optimal particle densities for use during needle-free injection are generally between about 0.1 and 25
g / cm ³ , preferably between about 0.9 and 1.5 g / cm ³ , and injection speeds can range from about 200 to about 3,000 m / sec. , Preferably in the range of 200 to 2500 m / sec.

If a nucleic acid preparation (eg, a DNA molecule) can be delivered using the device of the invention, the preparation is optionally encapsulated, absorbed into carrier particles, or associated Is done. Suitable carrier particles can be composed of any dense biologically inert material. High-density materials are targeted at short-range targets,
It is preferred to provide particles that can be easily accelerated, where the particles are still sufficiently small in size compared to the cells to which they can be delivered.

In particular, tungsten, gold, platinum and iridium carrier particles can be used. Tungsten particles and gold particles are preferred. Tungsten particles have a diameter of 0
. It is readily available in an average size of 5-2.0 μm and is therefore suitable for intracellular delivery. Gold is a preferred material. Because gold has a high density, is relatively inert to biological materials, resists oxidation, and is readily available in a spherical form with an average diameter of about 0.2-3 μm. Because there is.

If desired, any of a number of therapeutic agents (ie, any compound suitable for transdermal or transmucosal administration to induce a desired systemic or local effect) can be administered via a transdermal delivery system. Or it can be incorporated into a closed bandage. Such materials include a broad class of compounds that are normally delivered through body surfaces and membranes, including the skin. Generally, the compounds include anti-infectives (eg, antibiotics and antivirals); analgesics and combinations of analgesics; appetite suppressants; anthelmintics; anti-arthritic drugs; Antidiabetic agent; Antidiarrheal drug; Antihistamine drug; Antiinflammatory drug; Antimigraine preparation; Antiemetic; Antineoplastic drug; Antiparkinsonian drug; Antipruritic drug; Antipsychotic drug; Antipyretic drug; Anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and β-blockers (eg, pindolol and antiarrhythmic drugs); antihypertensive drugs; diuretics; Vasodilators, including the cerebrum; central nervous system stimulants; cough and cold preparations (including decongestants); hormones (eg, estradiol and other steroids) Corticosteroids including steroids); hypnotics; immunosuppressant agents; muscle relaxants; parasympatholytics; psychostimulants; sedatives; as well as tranquilizers.

Preferred therapeutic agents that are administered in combination with the transdermal systems of the present invention are those that typically exhibit a low skin flux (eg, steroid drugs, calcium channel blockers and potassium channel blockers). Other preferred therapeutic agents are those that require a high flux to achieve the desired therapeutic effect, and thus may require the presence of enhancers during drug formulation.

Therapeutic agent formulations also include standard carriers or vehicles useful to facilitate drug delivery (eg, stabilizers, antioxidants, anti-irritants and crystallization inhibitors).
May be included.

[0076] Skin penetration enhancers may also be present in transdermal delivery devices or closed bandage drug formulations
I can do it. When the enhancer is incorporated into a device, it may be present in an amount of about 1% to 2% by weight of the drug formulation.
It is generally present on the order of 5% by weight. Suitable enhancers include dimethyl sulf
Foxide (DMSO), dimethylformamide (DMF), N, N-dimethylamine
Cetamide (DMA), N-methylpyrrolidone, decylmethylsulfoxide (C _Ten MSO), polyethylene glycol monolaurate (PEGML), propylene
Glycol (PG), propylene glycol monolaurate (PGML),
Lycerol monolaurate (GML), methyl laurate (ML) lauryl lac
Tate (LL), isopropyl myristate (IPM), terpene (eg,
Ton), C_Two~ C₆Diols, especially 1,2-butanediol, lecithin, 1-position
Azacycloheptan-2-one, especially 1-n-dodecylcycloazacycloheph
Tan-2-one (1-n-dodecylcyclazacyclohepta)
n-2-one) (Whitby Research Incorporate)
d, Richmond, V .; A. Based on the trademark Azone® from
Available), alcohols and the like, but are not limited thereto. Planting
Physical Oil Penetration Enhancer (described in US Patent No. 5,229,130 to Sharma)
Can also be used. Such oils include, for example, safflower oil, cottonseed
Oil and corn oil. For delivery of pharmaceutically active agents to the skin
Film-forming polymer compositions and their use are described in Samour et al., US Pat.
No. 5,807,957.

[0077] Preferred therapeutic formulations (ie, drug-containing compositions loaded into the drug reservoir) are typically on the order of about 0.1% to 20% by weight, preferably about 1% to 10% by weight. It contains the drug in the order of weight percent and the rest of the formulation represents other ingredients such as enhancers, vehicles and the like.

The following examples illustrate the invention.

Example 1 Enhanced Flux of Insulin Administered Using a Needleless Syringe To evaluate the ability of a closed dressing to enhance the flux of insulin administered via a particle injection device, The following in vitro studies were performed. For all studies, modified Franz cells (6.9 ml) were used to determine transdermal flux. The receiving medium in Franz cells was pH adjusted using NaOH.
Phosphate buffered saline (PBS) adjusted to 9.0, and the receiving medium is to minimize adsorption of insulin to glass and maintain infinite sink conditions Therefore, 2.5% of TWEEN
(Registered trademark) 80 was added. In addition, the temperature of the receiving medium was maintained at 32 ° C. during the study. The top of the Franz cells is lined with a very thick (approximately 300 m
m) Covered with sample.

[0080] Porcine insulin (100%) was obtained from a commercial source and lyophilized, compressed, and then crushed to produce insulin particles suitable for use in a particle injection device. This particle formation procedure is described in International Publication No. WO 97/48485 (published December 24, 1997), which is commonly owned by the present inventors (this publication is incorporated herein by reference). Different sieve fractions were obtained using a standard sieve.

All particle injections were performed using a PowderJect® needle-free injector (eg, the device described in commonly owned US Pat. No. 5,630,796 (the '796 patent)). . As described in the '796 patent, which is incorporated herein by reference, a three-layered structure having a membrane that breaks the particle payload (1, 2, or 3 mg in these studies) into upper and lower layers. Loaded in drug cassette. The device was operated as described in the '796 patent using a 60 bar gas source to deliver insulin particles across the skin and into the Franz cell receiving medium.

In the experimental group receiving a closed dressing, the dressing was applied to the Fra
The nz cells were placed on the overlying skin and left in place for the duration of the study.

After delivery, samples were removed from Franz cells and assayed for insulin content using HPLC. Information on specific study conditions, payload amount and particle size is reported by each individual study.

In the first study, the closing effect on insulin flux was evaluated. The insulin payload was 3 mg, the particle size fraction used in all groups was 38-53 μm, and the dressing was adjusted from a 3-5 mm elongated Parafilm®. 24
The accumulated amount of insulin (flux) delivered for each experimental group over time is reported in Table 1 below.

[0085]

[Table 1] As can be seen, the occlusive dressing had a significant enhancing effect on insulin flux.

In a second study, the closing effect of different dressing compositions on insulin flux was evaluated. The insulin payload is 3 mg, the particle size fraction used in all groups is 38-53 μm, and the closed dressing is 3-5
mm of elongated, Parafilm® or 72 hour dryable polyisobutylene (PIB) films. The accumulated insulin (flux) delivered for each experimental group over a 24 hour period is reported in Table 2 below.

[0087]

[Table 2] As can be seen, each closure bandage increased insulin flux by about 10-fold, and the PIB closure bandage performed substantially similar to the Parafilm bandage.

In a third experiment, the closing effect of different bandage compositions on insulin influx was evaluated again. The insulin payload is 3 mg, the particle size fraction used in all groups is 38-53 μm, and the closed bandage is 3
細 5 mm elongate, comprising (a) Parafilm®, (b) a film of polyisobutylene (PIB) that can be dried in 72 hours, or (c) 1 mg of neat porcine insulin that can be dried in 72 hours It was prepared from a thin film of polyisobutylene (PIB). The amount of accumulated insulin (flux) delivered for each experimental group over a 24-hour period was reported in Table 3 below.

[0089]

[Table 3] As shown, Parafilm and PIB closure dressings significantly improved insulin flux, and the addition of insulin to the closure dressing also
The flux was significantly improved compared to both the non-closed and normal closed treatment groups.

In a fourth study, the effect of combining a closed dressing with a modified insulin formulation was evaluated. The insulin payload is 3 mg, the particle size fraction used in all groups is 38-53 μm, and the closed dressing is 3-5 mm
Was prepared from a thin, 72-hour dry film of polyisobutyl (PIB). In some groups, 30% polyethylene glycol (PEG) was added to the insulin formulation before particle formation, while 50% trehalose was added to the insulin formulation before particle formation. The accumulated insulin (flux) delivered for each experimental group over a 24 hour period is reported in Table 4 below.

[0091]

[Table 4] As can be seen, the 30% PEG formulation combined with the PIB closure dressing showed significantly higher flux than the closure only and PEG only treatment conditions. The addition of 50% trehalose provided no benefit over the neat insulin formulation in both closed and non-closed treatment conditions.

In a fifth study, the effect of combining a closed dressing with a modified insulin formulation was evaluated for a range of delivered payloads. In addition, to assess whether longer closure duration has any beneficial effect, the flux is
Assessed 24 and 48 hours after continuous closure. The insulin payload is 1 mg, 3 mg, 5 mg or 7 mg, the particle size fraction used in all groups is 38-53 μm, and the closure dressing is 3-5 mm elongated,
Prepared from a thin film of polyisobutylene (PIB) that can be dried for 72 hours. In all groups, 30% polyethylene glycol (PEG) was added to the insulin formulation before particle formation. The accumulated insulin (flux) delivered for each experimental group over 24 and 48 hours is reported in Table 5 below.

[0093]

[Table 5] As can be shown, closure with the PIB bandage allowed a delivery (flux) almost equivalent to less than one third of the dose of insulin. In addition, an additional 24 hour closure period (48 hours total) did not provide a benefit for this particulate insulin formulation.

Example 2 Enhanced Flux of Insulin Administered Using a Needleless Syringe To evaluate the ability of a closed dressing to enhance the flux of insulin administered via a particle injection device, The following in vitro studies were performed. A 10% insulin (NaPO ₄ ) composition was obtained from a commercial source and lyophilized, compressed, and then ground to produce insulin particles suitable for use in a particle injection device. This particle forming procedure is the same as the procedure described above in Example 1. Then a sieve fraction of 38-53 μm was obtained using a standard sieve.

All particle injections were performed using a Pow equipped with a porous silencer.
derJect (registered trademark) model ND1 needleless syringe (PowderJe
ct Technologies, Inc, Fremont, CA). This device is disclosed in commonly owned U.S. Pat. No. 5,630,796.
And No. 6,004,286. Particle payload (1mg)
Was loaded into a 7-piece study drug cassette with a 20 μm polycarbonate rupture membrane. The device was operated as described in the '796 patent using a 60 bar gas source to deliver the insulin particles.

The closure patch was cut from the Parafilm® disc and Hi
Produced by immobilization in the same place by an 11-Top chamber. In an experimental group receiving an occlusive dressing, the patch was placed on the skin covering the particle administration site,
And left in place for the duration of this study.

[0097] Male Sprague Dawley rats (270-330 g) were anesthetized and a cannula was surgically placed in the right carotid artery. The lower right flank area (approximately 3 x 3 cm) was clipped and shaved. The granular insulin dose,
The shaved area was administered and the closure patch was quickly placed on the dosing site and left there for the rest of the study. Arterial blood samples were removed from the carotid artery prior to dosing and at 10, 30, 60, 120, 180, and 240 minutes after dosing. The sample was quickly centrifuged and the plasma was transferred to a new tube and stored at 2-8 ° C within one week prior to analysis. Insulin concentrations were determined from plasma samples by radiolabeled immunoassay according to standard methods. The coefficient of variation for this assay was 0.3 ng / m
At 1, 4 ng / ml and 40 ng / ml, 12%, 4%,
And 8%. The results of this study are shown in FIG. 1, where "DP
"J" indicates particle injection of the granular insulin composition into the dermis, "OCC" indicates closure, and "SC" indicates subcutaneous (control) administration.

The actual bioavailability (BA) and relative bioavailability were then determined using standardized plasma concentration data after subcutaneous (SC) and intravenous (IV) insulin administration in separate studies. It was calculated according to the mathematical equation. The bioavailability values are reported in Table 6 below.

[0099]

[Table 6] As can be shown, post-administration dosing site closure was achieved with PowerJect®.
Accelerate the systemic uptake of insulin delivered to rats anesthetized by a model ND1 needleless syringe.

Example 3 Enhanced Immunogenicity of a Granular Vaccine Composition Using Closure The closure method of the present invention provides a method for immunizing a particulate hepatitis B surface antigen (HbsAg) vaccine composition after epidermal delivery. The following studies were performed to evaluate whether response was improved.

Commercially available hepatitis B vaccine (augmented with alum) and hepatitis B surface antigen HbsAg (without alum) were purchased from Rhein Biotech-Ar.
Gentine obtained from a joint venture group. Granular HbsAg was prepared by combining the antigen with a mannitol / PVP excipient and then lyophilizing to obtain the appropriate particles. Then a 38-53 μm sieve fraction was obtained using a standard sieve.

[0102] All particle injections were made using open-vented spacers.
) Was performed using a PowderJect® model ND1 needle-free injector equipped with (PowderJect Technologies, Inc., Fre.
mont, CA). This device is disclosed in commonly-owned U.S. Pat.
, 796 and 6,004,286. Particle payload (2m
g) was loaded into a three-layer drug cassette with membranes that rupture in the upper and lower layers.
The device was operated as described in the '796 patent using a 60 bar gas source to deliver the HbsAg particles.

The closure patch was a 1-1.5 cm diameter Parafilm® disc secured in place by sports tape to avoid previous problems of patches getting out of place during the course of this study. Was produced by cleavage.
In the experimental group receiving an occluded dressing, the patch was placed on the overlying skin at each particle delivery site after each delivery and left in place overnight (or until the patch shifted due to normal animal behavior). ).

Mixed sex white pigs (approximately 20 lb) were collected in an experimental group of 5 animals per group. This study was performed on B with one human dose of alum adjuvant.
Starting by vaccinating all animals at week 0 using a single intramuscular (IM) injection of the hepatitis hepatitis vaccine. IM injection was applied outside the upper thigh muscle. The pigs were then boosted at 4 and 8 weeks with the powdered vaccine composition (100 μg of HbsAg at each boost) using a PowderJect needleless syringe as described above. Parafil in the group receiving the closure procedure
m.RTM. disks were placed in place after each particle dose and left overnight. Control animals were vaccinated with a single IM injection, but no closure was used.

Blood samples were collected at 10 weeks and the antibody response to HbsAg was
USAB Assay Kit (Abbott Laboratories, Abo
tt Park, IL).

The results of this study are shown in FIG. As can be seen, this control group (pigs immunized with a single IM injection) had a low level of antibody response at 10 weeks. In the second experimental group (pigs immunized with two boosts with the powdered vaccine composition after one IM priming) showed a 9-fold increase in antibody titers compared to the control group . However, a 52-fold increase was observed in the second experimental group (pig immunized with two boosts with the powdered vaccine composition after one IM priming and enhanced with a closed bandage, compared to the control group). ). When closure was used, animals sensitized with the antigen in antibody titers (ed animal) were observed. Therefore, animals that received the closure treatment showed a 6-fold higher antibody titer compared to animals that received the powder boost alone. The closure is
It is concluded that the immune response to powdered vaccine compositions delivered using the particle injection method can be improved.

Example 4 Clinical Evaluation of Post-Dose Patch Closure To evaluate the bioavailability of peptide drug (calcitonin) administered via particle injection, with and without post-dose patch closure (subcutaneous injection) The following clinical study was conducted.

For subcutaneous injection, the Micalcic® calcitonin product was obtained from a commercial source, and was approximately 25 μg / ml (100 IU).
Salmon calcitonin (sCT). For particle injection, the calcitonin composition was formed from 8% w / w sCT, 2% w / w PVP excipient in mannitol. The calcitonin composition was then lyophilized, compressed and then comminuted to produce particles suitable for use in a particle injection device. The procedure for forming the particles is the same as in Example 1 described above. A 38-53 μm sieve fraction was obtained with a standard sieve.

All particle injections were performed with a Pow equipped with a porous silencer.
derJect® Model ND1 Needleless Syringe (PowerJect
Technologies, Inc. , Fremont, CA). This device is described in commonly owned U.S. Patent Nos. 5,630,796 and 6,004,286. The particle payload was loaded into a three-layer drug cassette with upper and lower tear membranes. SCT
To deliver the particles, a 60 bar gas source was used and operated as described in the '796 patent.

An occlusive patch was produced by cutting a Parafilm® disc secured in place by an adhesive bandage. In the experimental group receiving an occluded dressing, the patch was placed on the skin over the site of particle administration after sCT delivery and left in place for the duration of the study (4 hours).

The overall approach involves measuring pharmacokinetic and pharmacological response parameters after sCT dosing in 24 healthy female subjects. The trial was designed as a single center, open, parallel group trial. This test matrix is reported as Table 7 below.

[0112]

[Table 7]n = 8 blood samples for each group, before administration of calcitonin dose and administration of calcitonin dose
After 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes,
At 180 and 240 minutes, collection was via an indwelling catheter. sCT plasma concentration
It was determined by ELISA (PPD Development, VA). plasma
Ionized calcium (Ca²⁺) Concentration is determined by Covance Laboratori
es (UK). sCT was measured in plasma in all subjects after dosing.
Detected. Maximum plasma levels achieved 5 minutes after particle injection and 20 minutes after SC delivery
did. Assuming nominal volume, compared to SC infusion for particle delivery and closure
Average bioavailability (BA) was 8.5%, while no closure
Was 5.1%. The notable difference in the area under the curve (AUC)
, Was not observed among the three groups (P> 0.05, one-way ANOVA)
Performance was reduced (<0.8). All treatments result in a temporary hypochloremia response
Was. When plotted against the time profile between the three treatment groups, the blood Ca ²⁺ There was no significant difference in the mean area above the concentration. sCT
The closure after particle delivery of C_maxOr T_maxDid not affect, but 30-240 minutes
Samples appeared to affect the removal rate over the time range. sCT plasma clear
Lance (clearance) is not affected by the application of closed bandages
Therefore, no obvious reduction in rate is possible if closed bandages are used
Due to prolonged uptake of sCT from the administration site into the bloodstream (does not affect absorption)
I can do it.

[0113] Systemic delivery of sCT is achieved by the particle delivery method of the invention, and post-administration dosing site closure is not the rate of physical uptake of sCT, but most likely by increasing persistence by 5%. It was decided to increase the relative bioavailability from 0.1% to 8.5%.

Thus, a novel method for administering a therapeutic agent is disclosed. Although the preferred embodiments of the main invention have been described in some detail, obvious modifications may be made without departing from the spirit and scope of the invention, as defined by the appended claims. It is understood that.

[Brief description of the drawings]

FIG. 1 shows the insulin concentration in plasma obtained in Example 2.

FIG. 2 shows an antibody response to hepatitis B surface antigen (HBsAg) obtained in Example 3.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) 39/106 39/12 39/12 39/125 39/125 39/145 39/145 39/15 39/15 39/155 39/155 39/20 39/20 39/205 39/205 39/21 39 / 21 39/215 39/215 47/08 47/08 47/10 47/10 47/14 47/14 47/16 47/16 47/20 47/20 47/22 47/22 A61M 5/30 A61M 5 / 30 37/00 37/00 A61P 1/08 A61P 1/08 3/04 3/04 9/00 9/00 9/10 9/10 9/12 9/12 11/06 11/06 13/00 13 / 00 17/04 17/04 19/02 19/02 21/02 21/02 25/08 25/08 25/18 25/18 25/20 25/20 25/24 25/24 25/28 25/28 29 / 00 29/00 31/04 31/04 31/12 31/12 35/00 35/00 37/06 37/06 43/00 113 43/00 113 A61K 37/02 (81) Designated State EP (AT, BE, CH, CY, DE, DK, ES, FI, FR GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE , GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK , SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW. AA10 BB01 CC07 DD02 4C076 AA73 BB31 CC01 CC03 CC04 CC06 CC07 CC11 CC15 CC16 CC17 CC21 CC27 CC29 CC30 CC31 CC35 DD37N DD38N DD40N DD45N DD46N DD52N DD54N DD55N DD59N DD60N FF34 FF67 FF68 4C08A ZA02A03 ZA082 ZA422 ZA592 ZA712 ZA832 ZA892 ZA942 ZA962 ZB082 ZB112 ZB262 ZB332 ZB352 ZC032 ZC132 4C085 AA03 BA09 BA12 BA17 BA20 BA52 BA55 BA56 BA57 BA61 BA63 BA64 BA65 BA71 BA87 BA88 BA89 FF24 GG10 ZA12A01 ZA02A01 ZA02A01 ZA36 ZA39 ZA42 ZA59 ZA71 ZA83 ZA89 ZA94 ZA96 ZB08 ZB11 ZB26 ZB33 ZB35 ZC03 ZC13 4C167 AA71 AA72 BB42 CC01 GG12 GG16 GG47

Claims (50)

[Claims] 1. (a) accelerating the particles into, across, or within and across the skin or mucous membrane; and (b) accelerating the skin or mucous membrane. Locally disposing a first transdermal drug delivery device or a first occlusive dressing over an area, wherein the particles or the first transdermal drug delivery device or the first A medicament for administering a therapeutic agent to a predetermined area of skin or mucosa of a vertebrate subject by a method comprising: wherein the one of the dressings, or a combination thereof, comprises the therapeutic agent. Use of a therapeutic agent in the manufacture of a. 2. The method of claim 1, wherein a second transdermal delivery device or a second dressing is topically placed over the skin or mucous membrane prior to step (a). Use of the description. 3. The use according to claim 2, wherein the second transdermal delivery device or the second occlusive dressing comprises a penetration enhancer. 4. The method of claim 1, wherein said particles comprise said therapeutic agent.
Use as described in section. 5. Use according to claim 4, wherein said particles comprise a biologically active protein, peptide, oligosaccharide, polysaccharide or vaccine composition. 6. The use according to claim 4, wherein said particles comprise an antigen. 7. The use according to claim 6, wherein said method further comprises, prior to said step (a), a pretreatment step of administering an adjuvant to said skin or mucous membrane area. 8. The pre-treatment step includes the step of topically placing a second transdermal delivery device or a second closure dressing containing an adjuvant over the area of the skin or mucous membrane. Use according to claim 7. 9. The method according to claim 1, wherein said particles comprise an adjuvant.
Use as described in section. 10. Use according to any one of the preceding claims, wherein the particles comprise a penetration enhancer. 11. The method according to claim 1, wherein said particles comprise a placebo.
Use as described in section. 12. The method of claim 1, wherein said particles comprise a therapeutic agent and a placebo.
Use according to any one of the preceding claims. 13. The use according to claim 11 or 12, wherein the placebo comprises particles selected from metal particles and metal particles coated with a penetration enhancer. 14. The method of claim 1, wherein the particles are accelerated toward the target skin or mucosal surface using a needleless syringe device.
Use as described in section. 15. The use according to any one of claims 1 to 14, wherein the particles are accelerated at a speed of about 200 to 3,000 m / s towards the skin or mucosal tissue. 16. Use according to any one of the preceding claims, wherein the particles have a diameter predominantly in the range of about 0.1 to 250 μm. 17. The method according to claim 1, wherein the step (b) includes a step of locally disposing the first transdermal drug delivery device over the area of the skin or mucous membrane. Or use according to item 1. 18. The use according to claim 17, wherein said first transdermal drug delivery device comprises said therapeutic agent. 19. The use according to claim 18, wherein said particles and said first transdermal delivery device comprise the same said therapeutic agent. 20. The use according to claim 17, wherein said first transdermal drug delivery device comprises an adjuvant. 21. The use according to any one of claims 17 to 20, wherein the first transdermal delivery device is a passive transdermal delivery device. 22. The use according to any one of claims 17 to 20, wherein the first transdermal delivery device is an active transdermal delivery device. 23. The method according to claim 1, wherein step (b) comprises the step of locally placing the first dressing over the area of the skin or mucous membrane. Use as described in. 24. The use according to claim 23, wherein the first occlusive dressing comprises the therapeutic agent. 25. The use according to claim 24, wherein the particles and the first occlusive dressing comprise the same therapeutic agent. 26. The first closure dressing comprises an adjuvant.
Use of the description. 27. (a) accelerating the particulate drug within, across, or within and across the skin or mucous membrane; and (b) skin or mucous membrane. Locally disposing a first transdermal drug delivery device, or first occlusive dressing, over a predetermined area of a vertebrate subject. Use of a therapeutic agent in the manufacture of a particulate medicament for administration to the skin or mucous membranes of a human. 28. The use according to claim 27, wherein said particles comprise an antigen. 29. The method according to claim 27 or 28, wherein step (b) comprises locally disposing the first transdermal drug delivery device over the area of the skin or mucous membrane. Use of the description. 30. The use according to claim 29, wherein said first transdermal drug delivery device comprises said therapeutic agent. 31. The method of claim 27, wherein step (b) comprises locally placing the first dressing over an area of the skin or mucous membrane.
Use according to 8. 32. The use according to claim 31, wherein the first occlusive dressing comprises the therapeutic agent. 33. A method for producing a composition for administering a therapeutic agent to a predetermined area of the skin or mucous membrane of a vertebrate subject by a first transdermal drug delivery device or a first closed dressing. The use of the therapeutic agent, wherein the method comprises: (a) accelerating particles into, across, or within and across the skin or mucosa. And (b) the first transdermal drug delivery device over an area of the skin or mucous membrane;
Or locally disposing said first closure dressing. 34. The use according to claim 33, wherein said therapeutic agent is an antigen. 35. The use according to claim 34, wherein said particles comprise an adjuvant. 36. Use according to claim 33 or claim 34, wherein said particles comprise an antigen. 37. Use according to claim 33 or claim 34, wherein the particles comprise a placebo. 38. The use according to any one of claims 33 to 37, wherein the particles comprise a penetration enhancer. 39. Accelerating (i) the particulate drug and (ii) the placebo particles into, across, or within and across the skin or mucosa. Using the therapeutic agent in the manufacture of a particulate medicament for administering the therapeutic agent to a predetermined area of the skin or mucosa of a vertebrate subject by the method. 40. The use of claim 39, wherein the particles comprising the therapeutic agent and the particles comprising the placebo are administered simultaneously. 41. The therapeutic agent-containing particles and the placebo particles are accelerated toward the area of the skin or mucosa using a needleless syringe device.
41. Use according to claim 39 or 40. 42. The use according to any one of claims 39 to 41, wherein the particles are accelerated at a speed of about 200-3000 m / s towards the skin or mucous membrane area. 43. The use according to any one of claims 39 to 42, wherein the particles comprising the therapeutic agent have a diameter predominantly in the range of about 0.1 to 250 μm. 44. The use of claims 39-43, wherein said placebo particles have a diameter predominantly in the range of about 10 μm to 50 μm. 45. The use of any one of claims 39-44, wherein said placebo particles comprise from about 1% to about 10% of the particles administered to said skin or mucosal area. 46. The use according to any one of claims 39 to 45, wherein the placebo particles comprise particles selected from metal particles and metal particles coated with a penetration enhancer. 47. (a) accelerating the particles into, across, or within and across the skin or mucosa; and (b) first transdermally Topically placing a drug delivery device or a first occlusive dressing over the area of the skin or mucous membrane, wherein the particles or the first transdermal drug delivery device or the first Wherein the closed dressing, or a combination thereof, comprises a therapeutic agent for administration to a predetermined area of skin or mucosa of a vertebrate subject by a method comprising: 48. Accelerating (i) the particulate pharmaceutical and (ii) the placebo particles into, across, or within and across the skin or mucosa. A therapeutic agent for administration to a predetermined range of skin or mucous membranes of a vertebrate subject by the method. 49. A method for administering a therapeutic agent to a predetermined area of skin or mucous membrane of a vertebrate subject, the method comprising: (a) administering the particles to the skin or mucosa. Accelerating within, across, or within and across the range; and (b) applying the first transdermal drug delivery device or the first closure dressing to the skin or mucous membrane Topically, wherein the particles or the first transdermal drug delivery device or the first occlusive dressing, or a combination thereof, comprises the therapeutic agent. A method comprising: 50. A method for administering a therapeutic agent to a predetermined area of skin or mucosa of a vertebrate subject, the method comprising: (i) particles containing the therapeutic agent; and (ii) a placebo. Administering particles to the area of the skin or mucosa, wherein the particles are accelerated into, across, or within and across the area of the skin or mucosa. The method comprising the steps of: