Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-06-08
2004-07-13
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S043000, C424S433000, C424S436000, C424S441000, C424S445000, C424S455000, C424S456000, C424S458000, C424S463000, C424S464000, C424S465000, C424S489000, C424S490000, C424S725000, C514S772200, C514S772300, C514S777000, C514S779000, C514S781000, C514S783000, C514S784000, C514S785000, C514S786000, C514S937000, C514S944000
Reexamination Certificate
active
06761903
ABSTRACT:
TECHNICAL FIELD
The present invention relates to drug delivery, and in particular to pharmaceutical compositions and methods for the improved solubilization of both triglycerides and surfactants and improved delivery of therapeutic agents, particularly polysaccharide drugs, including low molecular weight heparin. The invention has utility in the fields of pharmaceutical formulation, pharmacology and medicine.
BACKGROUND
A wide variety of therapeutic agents are conventionally formulated in oil/water emulsion systems. These conventional emulsions take advantage of the increased solubility of many therapeutic agents in oils (triglycerides). Thus, one conventional approach is to solubilize a therapeutic agent in a bioacceptable triglyceride solvent, such as a digestible vegetable oil, and disperse this oil phase in an aqueous medium. The dispersion may be stabilized by emulsifying agents and provided in emulsion form. Alternatively, the therapeutic agent can be provided in a water-free formulation, with an aqueous dispersion being formed in vivo in the gastrointestinal environment. The properties of these oil-based formulations are determined by such factors as the size of the triglyceride/therapeutic agent colloidal particles and the presence or absence of surfactant additives.
In simplest form, a triglyceride-containing formulation suitable for delivering therapeutic agents through an aqueous environment is an oil-in-water emulsion. Such emulsions contain the therapeutic agent solubilized in an oil phase that is dispersed in an aqueous environment with the aid of a surfactant. The surfactant may be present in the oil-based formulation itself, or may be a compound provided in the gastrointestinal system, such as bile salts, which are known to be in vivo emulsifying agents. The colloidal oil particle sizes are relatively large, ranging from several hundred nanometers to several microns in diameter, in a broad particle size distribution. Since the particle sizes are on the order of or greater than the wavelength range of visible light, such emulsions, when prepared in an emulsion dosage form, are visibly “cloudy” or “milky” to the naked eye.
Although conventional triglyceride-based pharmaceutical compositions are useful in solubilizing and delivering some therapeutic agents, such compositions are subject to a number of significant limitations and disadvantages. Emulsions are thermodynamically unstable, and colloidal emulsion particles will spontaneously agglomerate, eventually leading to complete phase separation. The tendency to agglomerate and phase separate presents problems of storage and handling, and increases the likelihood that pharmaceutical emulsions initially properly prepared will be in a less optimal, less effective, and poorly-characterized state upon ultimate administration to a patient. Uncharacterized degradation is particularly disadvantageous, since increased particle size slows the rate of transport of the colloidal particle and digestion of the oil component, and hence the rate and extent of absorption of the therapeutic agent. These problems lead to poorly characterized and potentially harmful changes in the effective dosage received by the patient. Moreover, changes in colloidal emulsion particle size are also believed to render absorption more sensitive to and dependent upon conditions in the gastrointestinal tract, such as pH, enzyme activity, bile components, and stomach contents. Such uncertainty in the rate and extent of ultimate absorption of the therapeutic agent severely compromises the medical professional's ability to safely administer therapeutically effective dosages. In addition, when such compositions are administered parenterally, the presence of large particles can block blood capillaries, further compromising patient safety.
A further disadvantage of conventional triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis. Although colloidal emulsion particles can transport therapeutic agents through the aqueous environment of the gastrointestinal tract, ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa. The triglyceride carrier is emulsified by bile salts and hydrolyzed, primarily by pancreatic lipase. The rate and extent of lipolysis, however, are dependent upon several factors that are difficult to adequately control. For example, the amount and rate of bile salt secretion affect the lipolysis of the triglycerides, and the bile salt secretion can vary with stomach contents, with metabolic abnormalities, and with functional changes of the liver, bile ducts, gall bladder and intestine. Lipase availability in patients with decreased pancreatic secretory function, such as cystic fibrosis or chronic pancreatitis, may be undesirably low, resulting in a slow and incomplete triglyceride lipolysis. The activity of lipase is pH dependent, with deactivation occurring at about pH 3, so that the lipolysis rate will vary with stomach contents, and may be insufficient in patients with gastric acid hyper-secretion. Moreover, certain surfactants commonly used in the preparation of pharmaceutical emulsions, such as polyethoxylated castor oils, may themselves act as inhibitors of lipolysis. Although recent work suggests that certain surfactant combinations, when used in combination with digestible oils in emulsion preparations, can substantially decrease the lipolysis-inhibiting effect of some common pharmaceutical surfactants (see, U.S. Pat. No. 5,645,856), such formulations are still subject to the other disadvantages of pharmaceutical emulsions and triglyceride-based formulations.
Yet another approach is based on formation of “microemulsions.” Like an emulsion, a microemulsion is a liquid dispersion of oil in water, stabilized by surfactants. Conventional microemulsions, however, present several safety and efficiency problems. The amount of triglyceride that can be solubilized in a conventional microemulsion is generally quite small, resulting in a poor loading capacity. In order to solubilize significant amounts of triglycerides, large amounts of hydrophilic surfactant and/or solvents must be used. These high concentrations of hydrophilic surfactant and solvents raise questions of safety, since the levels of hydrophilic surfactant and solvent needed can approach or exceed bioacceptable levels.
Thus, conventional triglyceride-containing formulations suffer from limitations and safety concerns including, for example, instability of the formulation, dependence on lipolysis and poor loading capacity of the therapeutic agent. Triglyceride-containing formulations incorporating a therapeutic agent, in particular a polysaccharide drug, that do not suffer from these and other limitations and safety concerns are desired.
Administration of one particular class of therapeutic agents, the polysaccharide drugs, is severely hampered by the permeation barrier imposed by the intestinal epithelial cell membrane as well as the junctional structure between the epithelial cells. In addition, chemical degradation in the acidic environment of the stomach, enzymatic inactivation, and binding or interference by mucous and other contents of the gastrointestinal (GI) tract can also contribute to the reduced availability of polysaccharide drugs in the GI tract for absorption. As a result, the administration of polysaccharide drugs frequently calls for invasive approaches such as subcutaneous or intravenous injection, resulting in severe restrictions in clinical use and problems with patient compliance.
Heparin is a polysaccharide drug of particular interest and importance because it is a potent anticoagulant drug widely used in the prevention and treatment of thrombosis. It decreases the rate of coagulation by increasing the rate at which antithrombin (also termed “heparin cofactor” or “antithrombin III”) inhibits activated coagulation factors, particularly thrombin, a key enzyme in the coagulation cascade. Heparin is a gly
Chen Feng-Jing
Fikstad David T.
Patel Mahesh V.
Lipocine Inc.
Spear James M.
Thorpe North & Western LLP
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