Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Polymers from only ethylenic monomers or processes of...
Reexamination Certificate
1999-05-19
2001-10-02
Wu, David W. (Department: 1713)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Polymers from only ethylenic monomers or processes of...
C526S932000, C526S324000, C526S329700, C526S329500, C526S332000, C526S923000, C526S930000
Reexamination Certificate
active
06297337
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to improved crosslinked ionic polymers useful as bioadhesives, thickeners, emulsifiers, emulsion stabilizers, suspending aids, and pharmaceutical controlled release excipients.
BACKGROUND OF THE INVENTION
Bioadhesion refers to the ability of certain synthetic and biological macromolecules and hydrocolloids to adhere to biological tissues. Bioadhesion is a complex phenomenon, depending in part upon the properties of polymers, biological tissue, and the surrounding environment. Several factors have been found to contribute to a polymer's bioadhesive capacity: the presence of functional groups able to form hydrogen bridges (—OH, COOH), the presence and strength of anionic charges, sufficient elasticity for the polymeric chains to interpenetrate the mucous layer, and high molecular weight.
Bioadhesion systems have been used in dentistry, orthopedics, ophthalmology, and in surgical applications. However, there has recently emerged significant interest in the use of bioadhesive materials in other areas such as soft tissue-based artificial replacements, and controlled release systems for local release of bioactive agents. Such applications include systems for release of drugs in the buccal or nasal cavity, and for intestinal or rectal administration.
Bioadhesive properties of certain natural cellulosics and crosslinked polyacrylic acids are described by Blanco-Fuente et al,
Intl. J. Phann
., 138, 103-112 (1996). The bioadhesive properties of PNVP (poly-N-vinylpyrrolidone), and PHEMA (polyhydroxyethyl-methacrylate) are described by Robert et al, Acta.
Pharm. Technol
., 34(2):95-98 (1988). The bioadhesive capacity of certain anionic polymers (crosslinked polyacrylic acids and their salts) and natural non-ionic materials (i.e., carraggeenan, xanthan gum, etc.) has also been reported. Tobyn et al.,
European Journal of Pharmaceutics and Bio-pharmaceutics
, 41(4), 235-241 (1995) and Tobyn et al.,
European Joumal of Pharmaceutics and Biopharmaceutics
42(1), 56-61 (1996). The bioadhesive capacity of cationic material (such as chitosan) was reported by Henriksen et al,
International Joumal of Pharmaceutics
, 145, 231-240 (1996).
Tobyn et al. conducted a bioadhesion study in which the pellet was brought into contact with the section of stomach at 0.5N for ten minutes. The standard deviation for Tobyn's results, however, ranged from approximately 20% to over 100%. In addition, the pig's stomach had to be freshly obtained and prepared. This presents many feasibility problems including availability, sensitivity to storage conditions, reproducibility between stomachs, and aesthetic considerations. Other references pertinent to measuring bioadhesion are: Ahuj et al.,
Drug Development and Industrial Pharmacy
, 23(5), 489-515 (1997); Tamburic et al.,
European Journal of Pharmaceutics and Biopharmaceutics
44, 159-167 (1997); Tobyn et al.,
European Joumal of Pharmaceutics and Biopharmaceutics
41(4), 235-241 (1995), Tobyn et al.,
European Joumal of Pharmaceutics and Biopharmaceutics
42(1), 56-61 (1996).
U.S. Pat. No. 4,778,786 describes compositions for transdermal drug delivery containing polysaccharides, polyethylene glycol, salicylic acid, and AMPS (2-acrylamido 2-methylpropane-sulfonic acid). McCormick et al.,
Macromolecules
, 19, 542-547 (1986) describes the phase behavior of certain acrylamide water-soluble copolymers compared to certain carboxylated and sulfonated polymers.
During or after its processing, certain undesirable residual materials can be removed from a polymeric composition. These residual materials are termed “extractables,” referring to low molecular weight materials, such as residual monomers, residual solvents, and residuals from initiators (where organic initiators are used). Crosslinked ionic hydrogel polymers may be divided into two groups of materials: those which may be used for thickening, suspending and bioadhesive applications and those which may be used as superabsorbant material. The superabsorbant material is generally characterized in that it has a particle size of about 0.5-15 mm and the Elasticity Modulus is such that the particles have resistance to deformation and flow.
Gel strength relates to the tendency of the hydrogel formed from these polymers to deform or “flow” under usage stresses. Gel strength for superabsorbants needs to be such that the hydrogel formed does not deform and fill to an unacceptable degree the capillary void spaces in the absorbent structure or article, thereby inhibiting the absorbent capacity of the structure/article, as well as the fluid distribution through the structure/article. This type of behavior is undesirable in thickening, emulsifying and bioadhesive applications where the capacity to fill the void space is high in order to increase the viscosity of a solution without apparent graininess. Certain superabsorbant polymer particles are described in U.S. Pat. No. 4,654,039 to Brandt et al., reissued as Re. No. 32,649.
U.S. Pat. No. 4,794,166 describes a method of washing a superabsorbant polyacrylic acid polymer to remove oligomers by bringing the hydrogel into contact with a single-phase mixture of water and a solvent and then separating the mixture of water and solvent from the hydrogel. The process described in that patent was specifically chosen so that the hydrogel neither shrinks nor swells. The process introduces water swollen polymeric material to the washing step and thus the solvent mixture is chosen so that the polymer neither swells more or shrinks. After the mixture of water and solvent has been removed from the hydrogel, the hydrogel is usually dried or steamed, or steamed and then dried. Steaming is not an acceptable process, however, for a number of polymers.
In characterizing materials used as thickeners, emulsifiers and suspending aids, the response of these fluids to stress and simple flow fields may be used to determine their material functions such as viscosity and response to stress. Mathematical models have been developed to describe these properties. The measurement of material functions in these flows defines the practice of rheometry. Rheological measurements on gels, or thickened and suspended materials define the structure and properties of the material and can be used to identify changes and characteristics of an improved material over that being currently used. To those skilled in the art, interpretation of the response of a polymeric dispersion or gel to stress and strain is highly indicative of the material.
There is currently a need for polymeric compositions having improved bioadhesive properties, as well as a need for improved methods of making these polymer compositions. There is also a need for improved polymeric compositions for use as thickeners, emulsifiers, suspending aids, and pharmaceutical controlled release excipients.
SUMMARY OF THE INVENTION
The invention relates to crosslinked ionic polymers or salts thereof having a soluble polymer fraction of less than about 15 wt %, and at least one of the following characteristics: (I) a yield value of between about 10 and about 150 pascal; (ii) a Brookfield viscosity of between about 2,000 and about 150,000 mPa·S; or (iii) a microviscosity value of between about 0.01 and about 25.0 Pa·S when measured at a polymer concentration of 0.5 wt % in deionized water.
The crosslinked polymers can be homopolymer, copolymer, terpolymer, or interpolymer hydrogels. These hydrogels are preferably ionic, and may be polycarboxylic acids, polysulfonic acids, or salts thereof, and other vinyl polymerizable monomers. Preferred polysulfonic acids include: AMPS, sulfoethylmethacrylate (SEM), sulfopropyl methacrylate (SPM), sulfopropyl acrylate (SPA), N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl)ammonium betaine, methacrylic acid amidopropyl-dimethyl ammonium sulfobetaine, and SPI {itaconic acid-bis(1-propyl sufonizacid-3) ester di-potassium salt}. Preferred carboxylic acids include acrylic acids, methacrylic acids, and maleic acids.
It will be appreciated that for carboxylic acids
Amjad Zahid
Marchant Nancy S.
Yu Simon Hsaio-Pao
Dunlap Thoburn T.
Harlan R.
Kolkowski Brian M.
PMD Holdings Corp.
Wu David W.
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