Patent Application
20060079841
Various approaches have been used for drug delivery within animal bodies, including human bodies. Of these, perhaps oral delivery and direct injection are the most common. In addition, it has been proposed to administer drugs by injection into channels drilled into the body. Factors influencing the choice of drug delivery method include timing, such as the need for rapid diffusion of the drug into body tissue, and site specificity, such as when delivery of the drug to a specific organ or diseased area is required. This invention is directed towards an improved method of drug delivery. In addition, the method also provides for site specific cooling of body tissue.
Therefore, it is an object of the invention to provide a method to enhance molecular and or thermal diffusion in tissue targets. The method is intended to be very rapid, very easy and flexible. According to an aspect of the invention, the method comprises subcutaneous injection of gas into a body to cause insufflation of a cavity followed by infusion of a fluid into the cavity. The fluid preferably carries an active agent, for example a dissolved gas or solute. The method may include iontophoresis of the cavity to enhance diffusion of the active agent into target tissue. Insufflation creates a closed conduit pneumatic flow path between an insufflation gas source and the cavity that allows solution to be injected into the cavity.
This method provides for enhanced thermal or molecular diffusion, and in a trauma situation may only take a few seconds for both injection steps. Injection of gases such as CO2 and NO cause vasodilation and increased permeability of microvasculature between cavity and skin or cavity and other tissue. Apparatus is also provided for insufflation followed by liquid injection, including a needle tip locator for avoiding organ damage from the needle tip of a catheter used to inject the gas and liquid.
These and other aspects of the invention are described in the detailed description of the invention and claimed in the claims that follow.
There will now be described preferred embodiments of the invention, with reference to the drawings, by way of illustration only and not with the intention of limiting the scope of the invention, in which like numerals denote like elements and in which:
In this patent document, “comprising” means “including”. In addition, a reference to an element by the indefinite article “a” does not exclude the possibility that more than one of the element is present.
A harmless gas as used in this patent document is a gas that does not harm animal body tissue, as for example nitrous oxide, nitric oxide, carbon dioxide, oxygen and any of the noble gases. An interstitial space of an animal is a space between tissue of an animal, as for example a subcutaneous space or an intramuscular space, the insufflation of which does not significantly damage the tissue. The tissue may be muscle tissue or skin, and may be diseased tissue such as a tumour. A solution is a liquid carrying a solute. The solute may be an active agent. An active agent may be any compound having a beneficial effect on the animal, and includes any medical pharmaceutical and genetic material such as DNA and RNA. Examples of active agents include nutrients, blood products, preventive agents, for example vaccines, diagnostic agents, for example tracers of various types and imaging enhancers, therapeutic agents, for example drugs, peptides, and radiation, vaccine and virus vectors, and combinations of these classes. The active agent may include gas antidotes, biophysical modulators, for example paramagnetics, emitters, for example electromagnetic wave emitters, and imaging enhancers. The active agent may be carried as the solute in the electrolyte.
An animal, such as a human being, is treated by insufflation according to an embodiment of the invention by injecting a harmless gas, from a source of gas, into an interstitial space of the animal to create an artificial compartment within the animal and by infusing a solution into the artificial compartment. Basic method steps are illustrated in
An apparatus for insufflation of tissue is shown in
Various designs of the catheter 24 may be used. For example, to enhance cooling, the catheter 24 could have multiple perforations 40 and a tapering structure to cause a venturi effect and thus potentially enhanced vaporization.
The solution 16 may be used to increase blood volume and maintain blood pressure. A preferred site for insufflation to increase blood volume is any interstitial space. Insufflation may be applied to an organ, such as for the delivery of pharmaceuticals or genetic material to the organ, where the organ has available delaminateable interstitial space for insufflation, and is not so vascular that there is a danger of the gas entering the blood stream. Insufflation of muscle may promote release of skeletal muscle stem cells into the circulation, and thus allow for regeneration of tissues requiring these stem cells after injury.
In particular, insufflation may be used as part of a process of cooling of tissue. In this embodiment, cooling may use the heat of dissolution, in which the gas coming out of solution absorbs heat from the surroundings, or the cooling effect of evaporation. In the example of infusion of carbonated solution 16, a needle is inserted into the cavity 14 to liberate the gas from the cavity 14 by creation of an exit wound 42. The release of the dissolved gas in the compartment 26 causes rapid local cooling of tissue surrounding the compartment. One example of cooling is cooling of the brain. Scalp tissues are insufflated by injection of gas under the scalp. Rapid release of gas by puncturing of the compartment causes local brain cooling, which may be advantageous for treating for example a stroke.
Iontophoresis may be applied to the electrolytic solution in the compartment. Iontophoresis is a system for promoting or accelerating transmittance of a drug molecule through a tissue barrier due to moving force of an electric field between an anode and cathode. [see Journal of Controlled Release, 18, 213-220 (1992); Advanced Drug Delivery Review, 9, 119 1992); and Pharmaceutical Research, 3, 318-326 (1986)]. Various means may be used to establish the electric field, such as by a first electrode extending into the compartment, and a second electrode applied to tissue adjacent the compartment.
The volume of the compartment 26 is dependent on the pressure used for insufflation. Large volumes of solute can be infused in a matter of minutes with for example a target pressure such as 1-5 psi. Preferred gases used for insufflation and dissolution include CO2, which causes local vasodilation, and NO, which causes intense vasodilation and increases permeability of the local vascular bed lining the artificial compartment 14. Other potential gases for use with an embodiment of the invention include noble gases, such as xenon and argon and pain relieving gases.
Injection of antibiotic into a compartment formed between fascial planes may be particularly suitable for diseases that follow fascial lines. As for example, insufflation interstitially between fascial planes at the site of flesh eating disease may be followed by injection of antibiotic into the resulting compartment and hence rapid delivery of the antibiotic to the site of the infection.
Example
Tissue in the anterior (front) leg of a dog was insufflated with a 2 second gas injection. The insufflation compartment was on the anterior aspect of the forelimb 2 cm before it joins the thorax. Then 100 cc of carbonated solution was injected into the insufflation compartment. An injectable thermometer was inserted in the center of a muscle 6 cm away. Baseline temperature of the compartment was 34.6 C. After CO2 insufflation, the temperature was 34.5 C. Cooled carbonated fluid was then injected into the cavity, causing the temperature to reduce to 34.4 C after three minutes. Gas was then allowed to flow from the exit wound for 1.5 minutes, and the temperature reduced to 32.4 C. After a further 5 minutes, the temperature was 32.6 C. Thus, insertion of the gas and cold carbonated solution had no significant effect on the temperature, but after releasing the CO2 gas to allow evaporation, the temperature dropped by 1.9 C in 3 minutes, and maintained this drop for as long as the CO2 was being injected into the cavity. Next, a dose of epinephrine (adrenalin) was injected into the cavity and intracavity inotophoresis was initiated. The heart rate of the dog increased from 80 to 87 beats per minute. This showed that insufflation can generate artificial compartments or cavities that can be brought into temperature equilibrium with surrounding tissues, and entry of drugs into the systemic circulation is feasible. Moreover, the cooling effect is apparent at a remote site 6 cm away from the insufflation with dense material, in this case the scapula of the subject dog, between the temperature sensor and the insufflation compartment. Thus, the cooling of an insufflation compartment has a cooling effect on tissues that are not in direct contact with the insufflation compartment.
Care should be taken to avoid placement of the needle in an organ or blood vessel. The length of the needle is chosen depending on the depth of the location of the compartment, and various known techniques may be used to prevent the needle from penetrating more than is desired, such as is taught for example in U.S. Pat. No. 6,656,160 issued Dec. 2, 2003, the content of which is hereby incorporated by reference. For insufflation of a tumour, the needle tip is placed into the tumour and a gas that is not absorbable by the tumour, such as nitrogen gas, is injected to insufflate the compartment. Care should be taken to avoid nitrogen entering the blood stream. If this cannot be avoided, due for example to the tumour being vascular, then nitrogen should be avoided.
Various needle tip locators, now known or later developed, for detecting needle tip proximity to blood vessels or organs may be employed. These may involve the measurement of ultrasonic frequencies, dielectric properties, resistivity of different tissues, or the reflection and absorption of infra-red.
As shown in
As shown in
As shown in
Alternatively, tissue resistivity may be used to detect needle tip proximity to blood flow. Different tissues have different resistivities. Therefore, tip electrical resistance may be measured to indicate the type of tissue adjacent to the needle tip.
As shown in
Immaterial modifications may be made to the embodiments described here without departing from the invention.
