Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-08-13
2001-08-28
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S478000, C424S466000, C424S474000, C424S489000, C424S490000, C514S770000, C514S937000, C514S938000
Reexamination Certificate
active
06280770
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of oral pharmaceutical compositions which have a convenient, patient acceptable formulation and good bioavailability. In particular, the oral pharmaceutical compositions of the present invention include solid, oral dosage forms that incorporate drug-containing microemulsions.
BACKGROUND OF THE INVENTION
The difficulty of bringing pharmaceutical substances with problematic bioavailability into a satisfactory pharmaceutically administerable form is generally known. With several drugs, absorption may be as little as 30%, or less, of the orally administered dose when administered in a conventional dosage form, i.e., when no special mechanism is used to enhance absorption of the drug. In addition, poorly adsorbed drugs often display large inter- and intra-subject variability in bioavailability. See Aungst, B. J., J. Pharm. Sci., 82:979-987, 1993. Specific examples (with the average bioavailability given in parentheses) include methyldopa (25%) with a range of 8% to 62%; and nalbuphine (approximately 17%) with a range of 6% to 40%.
The absorption of most drugs depends on two processes: (1) the dissolution of the drug in physiological fluids and (2) the absorption process itself, i.e., the process by which a drug in solution enters the cells at the absorption site and, finally enters general circulation. Many drugs are adsorbed by passive diffusion, i.e., a spontaneous migration of drug molecules from a region of high concentration to a region of low concentration. Other drugs are adsorbed by facilitated or active transport which involve the expenditure of energy by the body. In either event, the dissolution of the drug is the first step in the absorption process unless the drug is administered as a solution. On the other hand, some drugs are adsorbed by the process of pynocytosis or endocytosis which involve the engulfing of solid particles and the incorporation of such particles into the cellular contents.
To compensate for the poor adsorption displayed by many drugs, a pharmaceutical formulation may utilize one or more mechanisms to increase the extent to which the administered drug is adsorbed. While there are a vast number of such techniques, these techniques may be grouped into the following broad categories: (1) enhancement of the rate or extent of dissolution; (2) facilitation of an absorption process that would have occurred naturally; and (3) inducement of an absorption mechanism that would not naturally have occurred or which would have occurred to an insignificant extent. Thus, incorporation of a chemical substance that opens tight junctions in order to increase the rate of absorption of a drug that would normally have been adsorbed slowly through the paracellular route is an example of the second technique. On the other hand, incorporation of a drug within oil droplets for the purpose of involving the lymphatic system in the absorption of the drug (where this would not, otherwise, have occurred) is an example of the third technique.
More recently, powdered solution technology has been proposed as a technique for the delivery of water-insoluble drugs. See Spireas et al., “Powdered Solution Technology: Principles and Mechanisms, Pharm. Research, Vol. 9, No. 10 (1992) and Sheth, A. and Jarowski, C. I., “Use Of Powdered Solutions To Improve The Dissolution Rate Of Polythiazide Tablets,” Drug Development and Industrial Pharmacy, 16(5), 769-777 (1990). The concept of powdered solutions involves converting drug solutions or liquid drugs into a dry, nonadherent, free-flowing compressible powder by admixing the liquid drugs or drug solutions with a selected carrier. Although the drug is in a solid form, it is held in a solubilized liquid state, which increases the wetting properties of the drug, and therefore enhances the dissolution. Unfortunately, the application of powder solution technology has been limited because the resulting admixture powder generally has poor and erratic flowability and compressibility properties.
SUMMARY OF THE INVENTION
Novel pharmaceutical compositions which improve the rate and/or extent of absorption of drugs are disclosed. The novel pharmaceutical compositions of the present invention comprise drug-containing microemulsions adsorbed onto solid particles which may be further formulated into solid dosage forms. The compositions and dosage forms in the preferred forms of the present invention improve the bioavailability of a wide range of drugs, including those that are known, or suspected of having poor bioavailability, by the utilization of several different mechanisms.
In one aspect of the invention, the administration of the microemulsions on solid particle adsorbents that preferably have diameters in the nanometer range facilitates the absorption of the drug. Although the present invention is not limited by any means of operation, it is believed that upon disintegration of a tablet or multiparticulate which contains the microemulsion, the adsorbent particles aid in the distribution of the microemulsion droplets through a large volume of the gastrointestinal fluids which prevents the formation of large agglomerates of individual droplets.
In another aspect of the invention, the compositions and dosage forms of the present invention are used to enhance the bioavailability of poorly adsorbed drugs that are oil soluble by administering these drugs as oil-in-water (o/w) microemulsions. The oil soluble drug is distributed as droplets of an oily solution throughout the dose. Oil droplets may be adsorbed together with the incorporated drugs, or the oil droplets may be positioned adjacent to the adsorbing surface. From such oil droplets the drug diffuses into the cell membrane. In addition, due to the fact that there are many such droplets, the surface area of the adsorbing tissues with which the droplets make contact is large, thus facilitating absorption.
In a further aspect of the present invention, the microemulsion compositions of the present invention may be used to promote absorption though the M-cells of Peyer's patches which are involved in the absorption of very small solid particles of the order of 10 micrometers. The individual solid support particles only partially release the microemulsions droplets. Thus, following administration there is free microemulsion droplets as well as a number of microemulsion droplets that remain attached to the solid particles. The small size of microemulsion droplet particles means that they may be adsorbed via this route as well.
In addition, drugs that are subject to metabolic breakdown or degradation in the gastrointestinal tract, such as, for example, peptides, proteins, oilgonucleotides and other substances of biological origin, may be protected within the oil droplets of the microemulsions. The microemulsion component of the present invention makes it difficult for enzymes and other chemical substances to react with such drug molecules when they are encased in oil.
Microemulsions have previously been delivered only in the form of soft or hard gelatin capsules, or as a liquid dispensed directly into the patient's mouth. The microemulsions of the present invention are administered in the form of solid particles which may be further formulated into solid dosage forms. The drug-containing microemulsions are adsorbed onto a solid particulate (i.e., powder). Although the drug is in a solid form, it is maintained as a microemulsion, or in the case of self-microemulsifying drug delivery system (“SMEDDS”), in a state readily converted to a microemulsion in vivo, which thereby enhances the dissolution.
In addition to enhancing the saturation concentration (saturation solubility) of the pharmaceutical substance, the pharmaceutical compositions and solid dosage forms of the present invention also increases the substance surface area of the drug-containing microemulsion. The adsorbent particles increase the area available for interaction with gastro-intestinal fluids and/or with the site of absorption to thereby promote absorption of the drug.
Eichman Jonathan D.
Gupte Sangeeta V.
Hontz John
Khankari Rajendra K.
Kumbale Ramya
Cima Labs Inc.
Lerner David Littenberg Krumholz & Mentlik LLP
Spear James M.
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