Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-07-13
2001-06-12
Martin, Jill D. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S455000, C435S320100, C435S173100, C424S009500, C424S009520, C536S024310
Reexamination Certificate
active
06245747
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a new and improved pharmaceutical composition and method for delivery of bioactive substances. The methods and composition of the invention can be used with several agents and can achieve site specific delivery of a biologically active substance. This can allow for lower doses and for improved efficacy with drugs particularly agents such as oligonucleotides which are plagued with problems in achieving therapeutic concentrations in targeted organs.
BACKGROUND OF THE INVENTION
Drug delivery techniques are employed in the formulation of all drug therapy to augment drug availability, to reduce drug dose, and consequently to reduce drug-induced side effects. These techniques serve to control, regulate, and target the release of drugs in the body. The goals have been to provide less frequent drug administration, to maintain constant and continuous therapeutic levels of a drug in the systemic circulation or at a specific target organ site, to achieve a reduction in undesirable side effects, and to promote a reduction in the amount and dose concentration required to realize the desired therapeutic benefits. Finally, a method to noninvasively target the delivery of a desired drug to a target organ is needed.
To date, drug delivery systems have included drug carriers based upon proteins, polysaccharides, synthetic polymers, erythrocytes, DNA and liposomes. New generation biologicals such as monoclonal antibodies, gene therapy vectors, anti-cancer drugs such as taxol, viral based drugs, and oligonucleotides (ODN) and poly nucleotides have presented several problems with regard to delivery. In fact drug delivery may be the primary hurdle to achieving mainstream therapeutic use of these agents whose initial potential seemed unlimited but whose therapeutic parameters have prevented realization of full benefit.
Synthetic oligodeoxyribonucleotides (ODN's) which are chemically modified to confer nuclease resistance represent a fundamentally different approach to drug therapy. The most common applications to date are antisense ODN's with sequences complementary to a specific targeted MRNA sequence. An antisense oligonucleotide approach to therapy involves a remarkably simple and specific drug design concept in which the ODN causes a mechanistic intervention in the processes of translation or an earlier processing event. The advantage of this approach is the potential for gene-specific actions which should be reflected in a relatively low dose and minimal non-targeted side effects.
Phosphorothioate analogs of polynucleotides have chiral internucleoside linkages in which one of the non-bridging ligands is sulfur. The phosphorothioate analog is currently the most commonly employed analogue in biological studies including both in vitro and in vivo. The most apparent disadvantages of phosphorothioate oligonucleotides include the high cost of preparation of sufficient amounts of high quality material and non-specific binding to proteins. Hence, the primary advantages of the antisense approach (low dose and minimal side effects) fall short of expectations.
Drug delivery efforts with regard to oligonucleotides and polynucleotides have focused on two key challenges; transfection of oligonucleotides into cells and alteration of distribution of oligonucleotides in vivo.
Transfection involves the enhancement of in vitro cellular uptake. Biological approaches to improve uptake have included viral vectors such as reconstituted viruses and pseudovirions, and chemicals such as liposomes. Methods to improve biodistribution have focused on such things as cationic lipids, which are postulated to increase cellular uptake of drugs due to the positively charged lipid attraction to the negatively charged surfaces of most cells.
Lipofection and DC-cholesterol liposomes have been reported to enhance gene transfer into vascular cells in vivo when administered by catheter. Cationic lipid DNA complexes have also been reported to result in effective gene transfer into mouse lungs after intratracheal administration.
Cationic liposomal delivery of oligonucleotides has also been accomplished, however, altered distribution to the lung and liver was experienced. Asialoglycoprotein poly(L)-lysine complexes have met with limited success as well as complexation with Sendai virus coat protein containing liposomes. Toxicity and biodistribution, however, have remained significant issues.
From the foregoing it can be seen that a targeted drug delivery system for delivery of biologics, particularly poly and oligo nucleotides is needed for these drugs to achieve their fullest potential.
One object of this invention is to provide a novel composition of matter to deliver a pharmaceutical agent to a targeted site in vivo.
Another object of the invention is to provide a method for delivering a pharmaceutical agent to a specific site with the use of low frequency ultrasound.
Another object of the invention is to provide a method of enhancing the effectiveness of currently available drugs including plasma-bound drugs with the use of albumin or orosomucoid-albumin perfluorocarbon containing microbubbles when combined with diagnostic ultrasound.
Another object of the invention is to provide a method of enhancing the stability and decreasing the size of perfluorocarbon containing microbubbles by sonicating them in a nitrogen-free environment.
Other objects of the inventions will become apparent from the description of the invention which follows.
SUMMARY OF THE INVENTION
According to the invention a new biologically active agent delivery method and composition are disclosed. The compositions and methods can be used to deliver agents such as therapeutics or diagnostics which have been plagued with delivery problems such as oligonucleotides as well as traditional agents and can drastically reduce the effective dosages of each, increasing the therapeutic index and improving bioavailability. This in turn can reduce drug cytotoxicity and side effects. Furthermore, this invention can enhance the effectiveness of other plasma-bound drugs such as heparin, diltiazem, lidocaine, propanolol, cyclosporine, and chemotherapeutic agents which require blood pool activation. For example, applicants have shown that the anticoagulant properties of heparin can be dramatically enhanced by first combining the medicament with orosomucoid-labeled perfluorocarbon exposed sonicated dextrose albumin, and then given the combination intravenously.
The invention employs equilibrium binding of the biologic agent with a filmogenic protein which is formed as a protein shell microbubble encapsulating an insoluble gas. The conjugates are designed for parenteral administration as an aqueous suspension. After administration and timed with travel of the injected bolus to the site of interest, energy administered in the form of sound waves causes the microbubbles to cavitate; the agent is then released and concomitantly delivered to the organ or other site or interest.
Improved gas-filled microbubbles are achieved by forming the microbubbles in the presence of a nitrogen-free environment. The nitrogen-free environment makes microbubbles which are smaller but more stable in venous and arterial blood. These smaller microbubbles produce greater diagnostic ultrasound contrast in the myocardium and therefore can carry drugs to these regions with greater efficacy in therapeutic embodiments.
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Iversen Patrick L.
Meyer Gary D.
Porter Thomas R.
Gorthey LeeAnn
Martin Jill D.
Nebel Heidi S.
The Board of Regents of the University of Nebraska
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