Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1998-09-04
2004-04-27
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S451000, C424S452000, C424S453000, C424S455000, C424S456000
Reexamination Certificate
active
06726924
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of Invention
The invention generally relates to the field of liposome based drug delivery systems.
2. Description of Background Art
The therapeutic effect of an administered substance is usually directly related to the quantity and rate ate which the substance reaches the bloodstream. There are many factors that affect the ability of the substance to reach the systemic circulation including; the site of entry into the body, the physical form of the substance, the design of the formulation of the product, various physicochemical properties of the compound and the excipients, and control and maintenance of the location of the substance at the proper absorption site.
Oral delivery of a therapeutic substance is the most common form of delivery today because of convenience and ease of administration, however, it is not the most reliable route of administration and can often be inefficient and erratic. Factors that influence the absorption, and thus the ability of the substance to reach the bloodstream, of an orally administered substance are related to the physicochemical properties or the substance, the physiologic factors in the gastrointestinal tract and the variables in the dosage form. Conventional oral dosage forms consist of solutions, suspensions, powders, two-piece gelatin capsules, soft gelatin capsules, compressed tablets, and coated tablets. It is generally the case that gastrointestinal absorption is most rapid with solutions and progressively slower as you move toward coated tablets in the above continuum. Liquid dosage forms are generally much faster absorbed than solid forms because dissolution is not a rate determining step in the absorption process.
It has long been the idealized object of drug delivery technology to design a dosage form that optimizes effectiveness, maximizes drug reliability and maximizes safety of the delivered compound. Oral dosage forms began to become optimized in the late 1940's and early 1950's when sustained-release technology appeared on the pharmaceutical scene. The principle benefit of this new type of delivery system was to improve drug performance by increasing the duration of drug action and reducing the dosing interval required to achieve a therapeutic effect. Controlled-drug delivery technology, a new concept for improving drug efficacy was developed in the late 1960's. The principle benefit of this technology is to control the rate of dissolution from the solid dosage form to enhance bioavailability, improve safety, and decrease the dosing interval. Within the last twenty years a newer concept in oral drug delivery technology has been developed and is referred to as a therapeutic system. The essential component of the therapeutic system is the incorporation of advanced engineering controls that release drug from the dosage form at appropriate times in response to stimuli, e.g., preprogrammed wax matrix.
Capsules are a convenient and popular solid dosage form used for drugs, vitamins and nutritional supplements worldwide. The drug substance is enclosed within gelatin walls of the capsule, which can be either a two piece hard shell or a soft shell (also known as the soft elastic capsule). The soft elastic capsule (SEC) is a soft, globular, gelatin shell somewhat thicker than that of hard gelatin capsules. The gelatin is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The greatest advantage of soft gel capsule over two piece gelatin capsules is that soft gels can encapsulate liquids, semiliquids, and pastes due to the manufacturing process which hermetically seals the two halves together. There are several manufacturing processes by which soft gel capsules are made, those include the plate process, the rotary die process, the Norton capsule machine and Accogel, or Stern machine. A newer technology allows a two-piece gelatin capsule to tolerate liquids, semiliquids and pastes by sealing the upper and lower pieces together to prevent leakage of encapsulated material.
Liposomes are microscopic, three-dimensional lipid vesicles, made up of a phospholipid bilayer membrane that surrounds and separate an aqueous compartment. The discovery of liposomes has been credited to Alec Bangham, a British biologist and physician, who first described swollen lipid particles in the early 1960's. (Bangham A., et al, J. Mol Biol., 13, 238, 1965). However there is evidence of the observation of multilamellar liposomes dating back to 1911. (Lasic, D.,
Liposomes,
1993). Two decades after Bangham and his colleagues described their discovery the field of liposome science began to take hold, and the pharmaceutical and pharmacological rational that justifies the use of liposomes as drug carriers was being put into practice. Today, the medical applications of liposomes range widely from systemic anticancer therapy to enhancing topical anesthesia and gene delivery.
The use of liposomes orally first begin in the mid 1970's. The attributes of phospholipid based liposomes, e.g., well organized structures able to encapsulate a variety of compounds, with an excellent safety profile, were well known at the time. Medical researchers believed that this would be an ideal application to potentially enhance gastrointestinal absorption, protect the encapsulated ingredient from metabolic degradation and perhaps release the encapsulate slowly, thus providing a form of sustained release. Early studies showed that liposome encapsulated drugs were better absorbed than non-liposome encapsulated or “free” drug. In addition to drug molecules, proteins, peptides and enzymes were delivered orally with liposomes. In an attempt to develop an oral treatment for hemophilia with blood clotting factor VIII, a novel technique was developed which made possible high-yield entrapment of Factor VIII in a liposome. (Gregoridias, G. et al., J. Microencap., 1(1):33-45,1984). Liposomal encapsulated Factor VIII was administered to patients orally and was absorbed from the intestines. (Sakuragawa N., Thrombosis Research 38(6):681-5, 1985). Early enthusiasm with liposome encapsulated insulin showed that small but significant amount of insulin could reach the circulation (Woodly, J F, Critical Rev Ther. Drug Carrier Sys. 2(1):1-18, 1985). Significant antibody response was elicited after oral administration of liposome-entrapped snake venom (enzymes and peptides) compared to no response from free venom. (New, R R, Toxicon. 23(2):215-9, 1985).
More recently, feasibility of oral liposomes for a variety of therapeutic uses has been demonstrated. Increased bioavailability of liposomally encapsulated superoxide dismutase (Regnault C., et al, Biopharm & Drug Disp 17,165-174, 1996) a potent antioxidant used in the treatment of radiation-induced fibrosis, which is poorly absorbed orally, from 14% (free) to 57% with liposomes with ceramides. Hypocalcemia was observed 1 h after the administration of liposomes loaded with 1 mg of calcitonin. (Arien a., et al, Pharm Research 12(9):1289-1292, 1995). This result was surprising because liposomes were presumed to be unstable against the action of bile salts, however they were able to partially protect the peptide from enzymatic degradation. In another study, recombinant human erythropoietin (Epo), used to treat renal anemia, was encapsulated in liposomes. Bioavailability of oral Epo is poor because it is a protein and broken down in the GI tract by proteolytic enzymes. Absorption and a long pharmacological effect and lag were observed, suggesting that liposomes were trapped in a site before entering the bloodstream, and eliciting a sustained release effect. (Maitani Y., J Pharm Sc 85(4):440-445, 1996).
The pharmaceutical related problems associated with administering liposomes orally are: 1) pH of the stomach, 2) bile salts and 3) digestive enzymes, primarily lipases. The unbuffered pH of the stomach can range from 1.5 to 2.5 and causes chemical instability of the liposome membrane surface.
Bile salts act as detergents and cause instability of the liposome bilayer by emulsification. Up
Biozone Laboratories, Inc.
Kishore Gollamudi S.
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