New compositions formed from the combination of an active substance with a hydrogel carrier moiety are provided. The compositions are suitable for use in high-velocity transdermal particle injection techniques. Methods of providing the new compositions are also provided. In addition, methods for administering pharmacologically active agent to a subject are provided. These methods are useful for delivering drugs, biopharmaceuticals, vaccines and diagnostics agents.

TECHNICAL FIELD

The present invention relates generally to particulate pharmaceutical compositions. More particularly, the invention pertains to particulate pharmaceutical compositions that are suitable for transdermal particle delivery from a needleless syringe system, and to methods for producing such compositions.

BACKGROUND OF THE INVENTION

The ability to deliver pharmaceuticals agents into and through skin surfaces (transdermal delivery) provides many advantages over oral or parenteral delivery techniques. In particular, transdermal delivery provides a safe, convenient and noninvasive alternative to traditional administration systems, conveniently avoiding the major problems associated with oral delivery (e.g. variable rates of absorption and metabolism, gastrointestinal irritation and/or bitter or unpleasant drug tastes) or parenteral delivery (e.g. needle pain, the risk of introducing infection to treated individuals, the risk of contamination or infection of health care workers caused by accidental needle-sticks and the disposal of used needles).

However, despite its clear advantages, transdermal delivery presents a number of its own inherent logistical problems. Passive delivery through intact skin necessarily entails the transport of molecules through a number of structurally different tissues, including the stratum corneum, the viable epidermis, the papillary dermis and the capillary walls in order for the drug to gain entry into the blood or lymph system. Transdermal delivery systems must therefore be able to overcome the various resistances presented by each type of tissue.

In light of the above, a number of alternatives to passive transdermal delivery have been developed. These alternatives include the use of skin penetration enhancing agents, or "permeation enhancers," to increase skin permeability, as well as non-chemical modes such as the use of iontophoresis, electroporation or ultrasound. However, these alternative techniques often give rise to their own unique side effects such as skin irritation or sensitization. Thus, the spectrum of agents that can be safely and effectively administered using traditional transdermal delivery methods has remained limited.

More recently, a novel transdermal drug delivery system that entails the use of a needleless syringe to fire powders (i.e., solid drug-containing particles) in controlled doses into and through intact skin has been described. In particular, commonly owned U.S. Pat. No. 5,630,796 to Bellhouse et al describes a needleless syringe that delivers pharmaceutical particles entrained in a supersonic gas flow. The needleless syringe is used for transdermal delivery of powdered drug compounds and compositions, for delivery of genetic material into living cells (e.g., gene therapy) and for the delivery of biopharmaceuticals to skin, muscle, blood or lymph. The needleless syringe can also be used in conjunction with surgery to deliver drugs and biologics to organ surfaces, solid tumors and/or to surgical cavities (e.g., tumor beds or cavities after tumor resection). In theory, practically any pharmaceutical agent that can be prepared in a substantially solid, particulate form can be safely and easily delivered using such devices.

Hydrogel compositions are well-known in the biomedical arts, and are commonly used as substrates for cell and tissue culture, impression materials for prosthetics, wound-packing materials, or as solid phase materials in size exclusion or affinity chromatography applications. For example, nonporous, deformed and/or derivatized agarose hydrogel compositions have been used in high-performance liquid chromatography and affinity chromatography methods (Li et al (1990) Preparative Biochem. 20:107-121), and superporous agarose hydrogel beads have been used as a support in hydrophobic interaction chromatography (Gustavsson et al (1999) J. Chromatography 830:275-284). In the pharmaceutical fields, hydrogel monomers (natural or synthetic) are commonly added to pharmaceutical compositions (with an initiator and, sometimes, cross-inking agents) and then allowed to polymerize, thereby encapsulating a guest pharmaceutical within a hydrogel matrix. These techniques are used to provide microsphere carrier systems for drug targeting or controlled release systems. For example, cross-linked hydrogel microspheres have been used to encapsulate islet cells for the treatment of diabetes (Lim et al (1980) Science 210:908-910) or cancer cells that produce cancer-suppressing materials (U.S. Pat. No. 5,888,497), and biodegradable hydrogel microspheres are widely used to encapsulate a wide variety of drug compositions, most commonly peptides and proteins (Wang et al (1997) Pharm. Dev. and Technology 2:135-142). In these applications, the particular hydrogel system employed in the formulation is selected to provide long-term entrapment of the guest cell or pharmaceutical substance (e.g., to provide for targeted delivery or sustained- or delayed-release pharmacokinetics).

SUMMARY OF THE INVENTION

This invention is based on the discovery that pharmacologically-active agents can be associated with hydrogel particles for transdermal particle injection into a subject, particularly a human. The composition is in the form of a powder that comprises materials including a suitable pharmacologically-active agent associated with a hydrogel particles, wherein the particles that make up the powder have an average cross-sectional dimension of about 0.1 to 250 microns, preferably about 10 microns to 100 microns, i.e., 10 to 100 μm mass mean aerodynamic diameter in size.

The composition finds use with a device that effects the direct injection of the composition into or through skin, muscle or tissue, e.g. across the stratum corneum or into transmucosal membranes, thus defeating their barrier functions. Generally this is achieved by accelerating the particles in a transient supersonic helium gas jet to velocities of 100-3000 meters/second. The pharmacological agents included with the hydrogel include drugs (i.e., small organic molecules), biopharmaceuticals (i.e., peptides, larger proteins, and oligonucleotides), traditional and DNA vaccines, and gene therapies that provide a biochemical and physiological effect on the subject to which it is being administered. The effect may be such that it prevents or ameliorates a disease in the man or animal treated. The advantages of the invention include easy processing, high loading of the active agent, and a narrow-size distribution of the particles within the composition.

Accordingly, the present invention provides use of a pharmacologically active agent in the manufacture of a particulate medicament also comprising a hydrogel, for use in the therapeutic treatment of a subject by particle injection.

The invention also provides a method for making a powdered pharmaceutical composition suitable for administration by particle injection, said method comprising:

• (a) contacting hydrogel particles with an aqueous composition containing a pharmacologically active agent, thereby to load the particles with the agent;
• (b) optionally, separating the thus loaded hydrogel particles from the aqueous composition in an at least partial drying step and contacting the separated particles with an aqueous composition containing said pharmacologically active agent, thereby to load further the particles with the agent;
• (c) if step (b) has been carried out, optionally repeating said step one or more times such as from one to twenty times;
• (d) separating the thus loaded hydrogel particles from the aqueous composition in a drying step; and
• (e) obtaining the desired powdered pharmaceutical composition suitable for use in a transdermal powder injection device.

In one embodiment of the invention, a particulate medicament consisting essentially of a hydrogel loaded with an expressible gene construct encoding an antigen can be used as a nucleic acid for delivery to a subject by particle injection. In another embodiment, a particulate medicament consisting essentially of a hydrogel loaded with an antigen can be used as a vaccine for delivery to a subject by particle injection.

It is an advantage of the present invention that hydrogel particles can be used as carrier systems for pharmacologically active guest agents, thereby facilitating high-velocity particle injection delivery performance of such agents. Since release of the guest agent will typically be dependent upon factors such as: degree of swelling experienced by the hydrogel when delivered to an aqueous environment; dissolution of a crystallized guest agent; the cross-linking density of the hydrogel matrix; diffusion of the active from the hydrogel matrix; degradation of the hydrogel matrix; and the like, numerous delivery profiles can be readily tailored for each guest agent. In addition, the methods for loading preformed hydrogel beads with a guest substance allows for presizing of the hydrogel carriers prior to loading of expensive active ingredients, thus avoiding possible loss of such agent upon typical particle sizing operations.
 

Claim 1 of 15 Claims

1. A method for making a powdered pharmaceutical composition, said method comprising:

(a) providing a mixture of pre-formed hydrogel particles;

(b) contacting the hydrogel particles with an aqueous composition containing at least one pharmacologically active agent for a period sufficient to allow the agent to associate with the hydrogel particles and be incorporated therewith;

(c) separating the hydrogel particles from the aqueous composition in at least a partial drying step to obtain primary loaded hydrogel particles having the active agent incorporated therewith;

(d) contacting the primary loaded hydrogel particles with an aqueous composition containing said pharmacologically active agent for a period sufficient to allow further agent to associate with the hydrogel particles and be incorporated therewith;

(e) separating the hydrogel particles formed in step (d) from the aqueous composition in at least a partial drying step to obtain secondary loaded hydrogel particles having the active agent incorporated therewith; and

(f) drying the secondary loaded hydrogel particles to obtain a powdered pharmaceutical composition.
 

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