Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-12-22
2002-03-05
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S464000, C424S469000, C424S488000, C514S178000
Reexamination Certificate
active
06352722
ABSTRACT:
STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH
Not applicable.
TECHNICAL FIELD
This invention relates to derivatized carbohydrates, compositions comprised thereof and methods for their use. The derivatized carbohydrates can be used to form solid delivery systems useful for the dissolution, encapsulation, storage and delivery of a variety of therapeutic and diagnostic molecules.
BACKGROUND ART
Solid delivery systems are useful in a wide variety of applications such as controlled release of labile molecules, particularly bioactive materials such as organic pharmaceutical compounds, enzymes., vaccines and biological control agents such as pesticides and pheromones.
Drugs and other biologically active agents are frequently administered orally by means of solid dosage forms, such as tablets and capsules. Other oral solid dosage forms include lozenges and other hard candies. Solid dosage forms can also be implanted, such as subcutaneously for drug delivery. Additionally, solid dosage forms can be delivered intravenously, or by inhalation to the pulmonary system.
Solid dose delivery of bioactive materials to biological tissues such as mucosal, dermal, ocular, subcutaneous, intramuscular, intradermal and pulmonary offers several advantages over methods such as hypodermic injection and transdermal administration via so-called “patches”. Using injection, there is a risk of infection using conventional needles and syringes. Dosing using multidose vials is sometimes variable, and physical discomfort often attends hypodermic injection. Devices used for administering drugs transdermally usually comprise a reservoir layer of drug and a laminated composite which adheres to the skin, i.e., transdermal patches, such as described in U.S. Pat. No. 4,906,463. Many drugs can not be effectively delivered transdermally, nor have transdermal drug release rates for those capable of such delivery been perfected. Additionally, transdermal patches often cause topical reactions, in many instances precluding their long-term use.
Subdermal implantable therapeutic systems have been formulated for slow release of certain pharmaceutical agents for extended periods of time such as months or years. A well-known example is the Norplant® implant for delivery of steroid hormones. In membrane permeation-type controlled drug delivery, the drug is encapsulated within a compartment enclosed by a rate-limiting polymeric membrane. The drug reservoir can contain either drug particles or a dispersion (or solution) of solid drug in a liquid or a solid type dispersing medium. The polymeric membrane can be fabricated from a homogeneous or a heterogeneous nonporous polymeric material or a microporous or semipermeable membrane. The encapsulation of the drug reservoir inside the polymeric membrane can be accomplished by molding, encapsulation, microencapsulation, or other techniques.
The implants release drugs by dissolution of the drug in the inner core and slow release across the outer matrix. The drug release from this type of implantable therapeutic system is dependent on drug dissolution rate in the polymeric membrane, often causing a biphasic release rate. The inner core substantially dissolves; however, generally, the outer matrix does not dissolve.
Implants are placed subcutaneously by making an incision in the skin and forcing the implants between the skin and the muscle. At the end of their use, if not dissolved, these implants must be surgically removed. U.S. Pat. No. 4,244,949 describes an implant which has an outer matrix of an inert plastic such as polytetrafluoroethylene resin.
Other implantable therapeutic systems involve matrix diffusion-type controlled drug delivery. The drug reservoir is formed by the homogeneous dispersion of drug particles throughout a lipophilic or hydrophilic polymer matrix. The dispersion of drug particles in the polymer matrix is accomplished by blending the drug with a viscous liquid polymer or a semisolid polymer at room temperature, followed by cross-linking of the polymer, or by mixing the drug particles with a melted polymer at an elevated temperature. The drug reservoir can also be fabricated by dissolving the drug particles and/or the polymer in an organic solvent followed by mixing and evaporation of the solvent in a mold at an elevated temperature or under vacuum. The rate of drug release from this type of delivery device is generally not constant. An example of this type of implantable therapeutic system is the Compudose implant.
A variety of formulations have been provided for administration in aerosolized form to mucosal surfaces, particularly “by-inhalation” (naso-pharyngeal and pulmonary). Compositions for by-inhalation pharmaceutical administration generally comprise a liquid formulation of the pharmaceutical agent and a device for delivering the liquid in aerosolized form. U.S. Pat. No. 5,011,678 describes suitable compositions containing a pharmaceutically active substance, a biocompatible amphiphilic steroid and a biocompatible (hydro/fluoro) carbon propellant. U.S. Pat. No. 5,006,343 describes suitable compositions containing liposomes, pharmaceutically active substances and an amount of alveolar surfactant protein effective to enhance transport of the liposomes across a pulmonary surface. U.S. Pat. No. 5,608,647 describes methods for administering controlled amounts of aerosol medication from a valved canister.
One drawback to the use of aerosolized formulations is that maintenance of pharmaceutical agents in aqueous suspensions or solutions can lead to aggregation and loss of activity and bioavailability. The loss of activity can be partially prevented by refrigeration; however, this limits the utility of these formulations. The use of powdered formulations overcomes many of these drawbacks. The requisite particle size of such powders is 0.5-5 microns in order to attain deep alveolar deposition in pulmonary delivery. Unfortunately, powders of such particle size tend to absorb water and clump, thus diminishing deposition of the powder in the deep alveolar spaces. PCT GB95/01861 described powders suitable for use in by-inhalation delivery. The powders are of uniform particle size and can be produced with varying degrees of hydrophobicity to reduce clumping and increase drug release in the surfactant environment of the lung.
Solid dose delivery vehicles for ballistic, transdermal administration have also been developed. For example, in U.S. Pat. No. 3,948,263, a ballistic animal implant comprised of an exterior polymeric shell encasing a bioactive material is described for veterinary uses. Similarly, in U.S. Pat. No. 4,326,524, a solid dose ballistic projectile comprising bioactive material and inert binder without an exterior casing is disclosed. Delivery is by compressed gas or explosion. Ballistic delivery at the cellular level has also been successful. Klein (1987)
Nature
, 327:70-73. There are few existing formulations suitable for ballistic delivery. Powder formulations of pharmaceuticals generally used are unsuitable for ballistic administration, because they vary in size, shape and density. The particles described in PCT GB95/01861 are useful for ballistic delivery due to their discrete size.
For drug delivery, it is advantageous to provide solid drug delivery systems of defined size, shape, density and dissolution rate. It is also advantageous to provide solid drug delivery systems that are capable of sustained, controlled release of the drug. It is further advantageous to provide solid dose delivery systems that can be formulated using simple and economical methods.
PCT/GB 90/00497 describes slow release glassy systems for formation of implantable devices. The described implants are bioabsorbable and need not be surgically removed. However, these devices are severely limited in the type of bioactive material that can be incorporated as these must be stable to heat and/or solvent to enable incorporation into the delivery device. PCT WO 93/10758 describes a carbohydrate glass matrix for the sustained release of a therapeutic agent, wh
Hartley Michael G.
Morrison & Foerster / LLP
Quadrant Holdings Cambridge Limited
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