Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-11-09
2003-03-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S484000, C424S486000, C424S488000, C424S489000, C424S502000, C514S772000, C514S772100, C514S772200, C514S772300, C514S772600
Reexamination Certificate
active
06537584
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to various polymer blends that, when exposed to aqueous conditions, become hydrogels. These hydrogels are used for carrying and delivering bioactive agents or drugs in a biological environment. More specifically, the invention relates to polymer blends that, when exposed to aqueous conditions, form hydrogels that swell when exposed to an acidic environment (such as that found in the stomach) and deswell when exposed to a more neutral to alkaline environment (such as that found in the small and large intestines). When the hydrogel swells and deswells, the release of biologically active material contained in the hydrogel is modulated.
BACKGROUND OF THE INVENTION
There have been many approaches to meet the problems of regulating the delivery of bioactive agents or drugs to biological systems in the proper place, at the proper time and at the proper dose to achieve a desired effect. These systems depend on the utilization of physical or chemical stimuli in-the surrounding environment. Further, these environmental stimuli are usually of an external nature to the drug delivery system. Mechanisms that respond to such stimuli or signals include protein binding, hydrogel expanding or swelling, polymer erosion, membrane reorganization, solubility change, energy conversion, supply of activation energy for permeation, physical property changes of the materials that comprise the system, or phase transition phenomena, and the like. Examples are presented by Heller, Chemically self-regulated drug delivery systems, J. Control. Rel., 8, 111-125 (1988).
Particularly, gels have been used to deliver biologically active material to biological environments. For example, U.S. Pat. No. 4,034,756 is drawn to a device having two compartments, one filled with an osmotic agent or gel that swells in the presence of water and the other filled with a bioactive drug or other material. The expanding of the osmotic agent compartment or swelling of the gel forces the material contained in the second compartment through an orifice. A flexible partition between the two compartments acts to force the material in the second compartment through the orifices.
Other exemplary art includes U.S. Pat. Nos. 4,627,850; 4,717,566; 4,783,337; 4,743,247; 4,814,180; 4,837,111; 4,865,598; 4,871,544; 4,883,667; and 4,966,767, none of which have a flexible partition between the two compartments. The systems disclosed in these patents rely on the expanding of the osmotic agent compartment or gel swelling to force the drug out through orifices or a permeable membrane.
U.S. Pat. No. 4,320,759 includes additional partitioning membranes. U.S. Pat. Nos. 4,871,544 and 4,966,767 include osmotic agents to enhance the expanding or swelling of the gels. Osmotic agents are also mixed with beneficial agent formulations in the second compartment in the systems taught in U.S. Pat. Nos. 4,783,337 and 4,837,111. Some patents reveal the inclusion of a density member to keep the devices in an aqueous environment. The density member is dispersed in the expandable hydrogel compartment (U.S. Pat. Nos. 4,783,337 and 4,837,111) or in separate compartments (U.S. Pat. Nos. 4,717,566 and 4,865,598) that are placed in different locations in relation to other compartments.
U.S. Pat. No. 4,503,030 shows pH responsive release, that is, controlled release at low pH, but dumping of all remaining agents at high pH by disintegration of the devices. This action cannot be repeated with subsequent pH changes. U.S. Pat. No. 4,948,592 demonstrates a two mode release pattern, that is a one time burst releasing the beneficial agents at the beginning followed by a controlled release. This is based on the dissolution of a coating layer covering the osmotic devices, containing beneficial agents for quick release, followed by the timed sustained release of agents from the inner compartment of the device by osmotic squeezing. U.S. Pat. Nos. 4,814,180 and 4,871,544 contain temperature responsive materials in the devices disclosed. This material delivers the agent at body temperature with no release at storage temperature. At room or storage temperature, the material remains in the solid state, preventing squeezing of agents from the devices in the presence or absence of environmental water. However, at body temperature the material becomes a liquid allowing the formulation containing the beneficial agents to flow that can then be pushed out via a passageway(s) by osmotic force. A contracting or deswelling hydrogel for drug delivery purposes has been reported by Hoffman et al. J. Control. Rel., 4, 213-222 (1986). A temperature sensitive hydrogel was synthesized that deswelled at elevated temperatures and swelled at low temperatures. Vitamin B12 was entrained at a low temperature and released at a higher temperature by a deswelling or squeezing action. However, the overall release rate was quick and vitamin B12 was released in two steps; a fast squeezing and subsequent slow release due to a rigid surface formation on the hydrogel. It is expected that the release of the entrained drug from the unprotected hydrogel at low temperatures will be unacceptably high. Therefore, this system may not be suitable for repeated pulsatile drug release by temperature modulation.
The opposite release pattern from a monolithic device was reported by Bae et al., Makromol. Chem Rapid Commun., 8, 481-485 (1987) in which a pulsatile release was demonstrated using N-isopropylacrylamide based thermo-sensitive hydrogels (see also Hoffman et al, J. Control. Rel., 4, 213-222 (1986)). These polymers showed immediate rigid surface formation with contracting or deswelling process when the temperature was raised. This phenomenon blocks solute release from the gel matrices at an elevated temperature while allowing solute release at a low temperature. J. Kost (Ed.), Pulsed and Self Regulated Drug Delivery, CRC Press Inc., Boca Raton, Fla., (1990), Chapter 2, Temperature Responsive Control Drug Delivery, (authored by the present inventors) discloses the formation of a gel that expands or swells and contracts or deswells according to the temperature changes. This article indicates that the gel was used to entrain drug solutions but does not disclose or suggest that the gel can be contained within or used in a structured drug delivery device.
However, one patent, namely U.S. Pat. No. 5,226,902 which is incorporated herein by reference, does teach a beneficial agent in a hydrogel confined to a structured dispensing device that, when exposed to stimuli, forces the agent by contracting or deswelling into the space within the device previously occupied by the swollen hydrogel allowing the beneficial agent to be released from the device into the surrounding environment.
All of the pH sensitive synthetic hydrogels presently known in the art are covalently crosslinked. Though the use of covalently crosslinked pH sensitive hydrogels that deswell at physiological pH and swell at stomach pH were disclosed previously in U.S. Pat. No. 5,226,902, no specific polymer blend has been disclosed that exhibits these properties, i.e., rapidly swells in acidic conditions, slowly/extensively deswells in more basic conditions, contains no covalent crosslinking, is insoluble in acid and is safe for oral delivery among other properties.
In U.S. Pat. No. 5,904,927, a drug-delivery device is disclosed which is comprised of a cationic polymer such as chitosan and a second high molecular weight neutral polymer such as polyethylene oxide which is covalently crosslinked, freeze-dried and loaded with a drug composition. This drug delivery polymer composition is prepared using a low concentration of acetic acid (0.1 N) and is covalently crosslinked changing the properties of each individual polymer in the composition.
Additionally, in U.S. Pat. No. 5,620,706, insoluble hydrogels are disclosed which are comprised generally of xanthan and chitosan. Xanthan is a polysaccharide anion which is soluble in cold or hot water, but is not soluble in organic solvents. Xanthan (anionic) and chitosan (cati
Bark Jong-Seok
Liu Feng
Zentner Gaylen M.
Di Nola-Baron Liliana
MacroMed, Inc.
Page Thurman K.
Thorpe North & Western LLP
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