Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
1999-08-04
2001-11-13
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S078020, C424S078030, C424S078180
Reexamination Certificate
active
06316011
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to polymers and compositions useful in a variety of pharmaceutical and personal care products and applications, and in particular, compositions useful topical and/or mucosal applications, such as esophageal, otic, vaginal, rectal, ophthalmic and treatments of disorders and imperfections of the skin.
One of the major concerns in the delivery of drugs is the bioavailability of the drug. Depending upon the nature of the drug and the route of delivery, the bioavailability may be very low due to, for example, the degradation of oral-delivered drugs by hepato-gastrointestinal first-pass elimination or rapid clearance of the drug from the site of application. The net result is that frequent dosing may be required with higher than needed amounts of drug, which can lead to undesired side effects. Thus, it is desired by the pharmaceutical industry to have ways of administering drugs such that their availability can be controlled in an even dosing manner, the amounts of drugs can be kept as low as possible to minimize side effects, and dosing regime can be kept to a minimum to provide greater convenience to the subject, thus promoting greater compliance with appropriate dosing.
The mucosal tissue is an ideal site for drugs to be delivered locally and systemically because these tissues are exposed to an abundant blood supply. In addition, drug transport is aided by the fact that diffusion equilibria are not approached. Also, mucosal tissues have a very thin epithelium with minimal keratinized tissue that does not hinder the drug transport as compared to normal epidermal skin containing thick layers of keratinized tissues. Therefore, mucosal tissues offer an attractive surface to promote drug absorption.
Despite the advantages of mucosal tissue as a site for drug delivery, direct topical application of pharmacological agents onto mucosal tissues has very limited value, due to the facile clearance of those agents via washing or rubbing. The difficulty in the administration of such systems is the necessity for the drugs to remain in contact with the target tissue for a sufficient period of time to provide sufficient amount of drug to achieve the desired therapeutic effect. In addition to protection from pH, enzymatic attack and physiological removal by swallowing, the system needs to provide a long-term delivery to enhance the therapeutic profile (Guo, J-H; “Bioadhesive Polymer Buccal Patches for Buprenorphine Controlled Delivery: Formulation, In-vitro Adhesion and Release Properties”,
Drug Dev. Ind. Pharm.,
20(18), 2809, 1994; McQuinn, R. L.; et al; “Sustained Oral Mucosal Delivery in Human Volunteers of Buprenorphine from a Thin Non-eroding Mucoadhesive Polymeric Disc”,
J. Control Rel.
34, 243, 1995). Hence, specific formulations having improved bioadhesion designed to prolong the availability of the therapeutic product on the surface and to enable sustained release of the active ingredient are desired.
Bioadhesion or mucoadhesion is generally understood as the ability of a biological or synthetic material to “stick” to mucous membrane, resulting in adherence of the material to the tissue for protracted period of time. This concept has received significant attention because of enhanced drug bioavailability due to the increased amount of time in which the bioadhesive dosage form is in contact with the targeted tissue, as compared to a standard dosage form. In order for the material to be bioadhesive, it must interact with mucous which is a highly hydrated, viscous anionic hydrogel layer protecting the mucosa.
Many instances are known in the pharmaceutic industry where it is desired to have certain properties of viscosity in order to facilitate the objectives noted above. Hydrogels, such as cellulosics, have been included as thickeners in pharmaceutic compositions. A hydrogel is a polymer composition, in which the polymer forms a network swollen in water that is sufficiently stabilized either by covalent bonding or by physical bonding (hydrogen, ionic, hydrophobic, or van der Waals interactions). The hydrophilic areas of the polymer chain absorb water and form a gel region. The extent of gelation depends upon the volume of the solution which the gel region occupies.
Reversibly gelling solutions are known in which the solution viscosity increases and decreases with an increase and decrease in temperature, respectively. Such reversibly gelling systems are useful wherever it is desirable to handle a material in a fluid state, but performance is preferably in a gelled or more viscous state.
A known material with these properties is a thermal setting gel using poly(ethyleneoxide)/poly(propyleneoxide) block copolymers available commercially as Pluronic® poloxamers (BASF, Ludwigshafen, Germany) and generically known as poloxamers. See. U.S. Pat. Nos. 4,188,373, 4,478,822 and 4,474,751. Adjusting the temperature of the polymer gives the desired liquid-gel transition. However, concentrations of the poloxamer polymer of at least 18-20% by weight are needed to produce a composition which exhibits such a transition at commercially or physiologically useful temperatures. Also, solutions containing 18-20% by weight of responsive polymer are typically very viscous even in the “liquid” phase, so that these solutions can not function under conditions where low viscosity, free-flowing is required prior to transition. In addition, these polymer concentrations are so high that the material itself may cause unfavorable physiological interactions during use.
Another known system which is liquid at room temperature, but forms a semi-solid when warmed to about body temperature is formed from tetrafunctional block polymers of polyoxyethylene and polyoxypropylene condensed with ethylenediamine, commercially available as Tetronic® poloxamers. These compositions are formed from approximately 10% to 50% by weight of the poloxamer in an aqueous medium. See, U.S. Pat. No. 5,252,318. Although Pluronic®- and Tetronic®-based block copolymers exhibit reversible viscosification, they did not offer any bioadhesion properties.
Various attempts have been made with limited success to combine the properties of a thermally gelling polymer and a bioadhesive polymer.
Himmelstein in U.S. Pat. No. 5,599,534 described the combination of a carboxylic acid-containing polymer such as poly(acrylic acid) with alkyl cellulose derivatives such as hydroxypropylmethylcellulose. Yet, the system required a pH shift in order to observe gelation.
Joshi et al. in U.S. Pat. No. 5,252,318 reports reversible gelling compositions which are made up of a physical blend of a pH-sensitive gelling polymer (such as a cross-linked poly(acrylic acid) and a temperature-sensitive gelling polymer (such as methyl cellulose or block copolymers of poly(ethyleneoxide) and poly(propyleneoxide)). In compositions including methylcellulose, 5- to 8-fold increases in viscosity are observed upon a simultaneous change in temperature and pH for very low methylcellulose levels (1-4% by weight). See,
FIGS. 1 and 2
of Joshi et al. In compositions including Pluronic® and Tetronic® poloxamers, significant increases in viscosity (5- to 8-fold) upon a simultaneous change in temperature and pH are observed only at much higher polymer levels. See,
FIGS. 3-6
of Joshi et al.
Hoffman et al. in WO 95/24430 and D. Hourdet, F. L'alloret, A. Durand, F. Lafuma, R. Audebert, and J-P. Cotton, Small-Angle Neutron Scattering Study of Microphase Separation in Thermoassociative Copolymers,
Macromolecules,
31(16): 5323-5335, 1998, incorporated herein by reference, disclose block and graft copolymers comprising a poly(acrylic acid) component and a temperature-sensitive polymer component. The block and graft copolymers are well-ordered and contain temperature- or salt-sensitive polymer grafts bonded to the poly(acrylic acid) backbone. The copolymers are described as having a lower critical solution temperature (LCST), at which both sol-gel transition and visible or microphase separation occur. Thus, the gelation is accompanied by
Bromberg Lev
Ron Eyal S.
Temchenko Marina
Jones Dameron L.
Madash LLC
LandOfFree
End modified thermal responsive hydrogels does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with End modified thermal responsive hydrogels, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and End modified thermal responsive hydrogels will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2616728