Emulsified drug delivery systems

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules

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424463, 514250, 514552, 514784, 514785, 514786, A61K 966, A61K 948

Patent

active

059520043

DESCRIPTION:

BRIEF SUMMARY
The ability of drugs to be administered via the oral route depends on several factors. The drug must be soluble in the gastrointestinal fluids in order for the drug to be transported across biological membranes, or be suitable for an active transport mechanism. Very small particulates (less than 300 nanometers) can be absorbed through the lymphatic system via the Peyer's Patch system in the intestinal tract. However, this mechanism is not capable of absorbing large doses of drugs into the systemic circulation.
A problem arises for hard to dissolve drugs. In the case of conventional drugs, some drugs are relatively insoluble in gastrointestinal fluids. If the extent of solubility is low, this may cause incomplete and/or erratic absorption. If the rate of solubility, is low, then absorption will most probably be erratic on an intra-patient and inter-patient basis. Peptide drugs can be water soluble, and these are not as problematic as insoluble peptides. Like conventional drugs, insoluble peptides typically exhibit incomplete or low extent of absorption and erratic absorption or bioavailability.
The primary difficulty involved in delivering peptides orally is their degradation by hydrolysis and proteolytic enzymes. There are two basic approaches to eliminating this difficulty. The first is an "enteric" coating that releases the drug only in neutral to basic pH (usually pH 6-8), like that found in the intestine, so that the peptide is not exposed to gastric juices. However, this approach alone is not sufficient to protect the peptide since proteolytic enzymes exist in the upper intestinal tract, and degradation of the drug can still occur. The other, approach is to incorporate the peptide in a hydrophobic material so that aqueous fluids cannot penetrate the system. It is important to select a hydrophobic material that can erode or slowly dissolve in the intestinal tract so that the drug is released. In this way, the peptide is protected from proteolytic enzymes. In addition, it is possible to combine the two approaches. See, for example, with relation to the enteric coating approach.
However, there are inherent difficulties with the approaches outlined above. First, many drugs are released too slowly from hydrophobic systems. Also, some peptides will partition into the hydrophobic phase so that they will not be fully released from these systems. Thus, both the rate and extent of drug release are crucial components of any drug delivery system, and are even more important for many peptide drugs.
In accordance with the present invention there is provided a pharmaceutical composition comprising a pharmaceutical agent incorporated into a pharmaceutical carrier emulsion comprised of a hydrophobic material selected from the group consisting of a long chain carboxylic acid, long chain carboxylic acid ester, long chain carboxylic acid alcohol and mixtures thereof emulsified with a hydrophilic material.
The composition is used for convenient delivery of drugs. A wide range of active agents can be administered in the composition, including antibiotics, antimicrobials, antineoplastics, antivirals, cardiovascular and renal agents, immunosuppressive and immunostimulatory agents, and CNS active agents, but it is of particular value for peptides. Microemulsion, compared with normal (macro-) emulsions, form easily, even spontaneously, without high energy input, and scale-up easily. They are stable, with long shelf life, and, being translucent, are easy to monitor spectroscopically. They have low viscosity for easy transport and mixing. Drug solubilization, protection against enzyme hydrolysis and, therefore, oral bioavailability, particularly for peptides, are enhanced.
In one embodiment, the hydrophobic material forms the discontinuous phase and the hydrophilic material forms the continuous phase in which the hydrophobic material is emulsified (oil-in-water). The hydrophobic discontinuous phase and the hydrophilic continuous phase can each independently be solid, semisolid or liquid. The pharmaceutical agent may be dispersed

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