Hyperbranched polymeric micelles for encapsulation and delivery of hydrophobic molecules

Abstract

Polymeric micelles for encapsulation of hydrophobic molecules are provided. Methods and formulations for delivering hydrophobic molecules to a host via these micelles are also provided. Methods of stabilizing liposomes or lipid based formulations by addition of polymeric micelles are also provided.

Description

INTRODUCTION [0001] This application is a continuation-in-part of U.S. application Ser. No. 09 / 298,729, filed Apr. 23, 1999.FIELD OF THE INVENTION [0002] The present invention relates to new hyperbranched colloidal polymers with micellar properties. The polymers comprise a mucic acid, alkyl chains and poly(ethylene glycol). Hydrophobic molecules encapsulated within these polymeric micelles are thermodynamically stable in aqueous solutions, suspensions, dispersions, emollients, lotions, creams, salves, balms and ointments at ambient, refrigerated and elevated temperatures. Further, these polymers have been found to stabilize liposomes and other lipid based structures used routinely in these types of formulations for extended periods of time such that precipitation is prevented and optical transparency is maintained. While the polymers of the present invention can be used to encapsulate and deliver any hydrophobic molecule, these colloids are particularly useful in delivery of hydroph...

AI Technical Summary

Benefits of technology

[0057] The present invention contemplates the use of polymer-encapsulated hydrophobic molecules at concentrations as high as 1 M and greater, up to 106 M. At the same time, another advantage of the present invention is the thermodynamic stability of the polymers, which permit the formation of low concentration stable aqueous solutions of the polymer encapsulates, far below the CMCs of conventional surfactants. Stable aqueous solutions as low as 10−10 M have been obtained, although, at present, concentrations of 10−8 and greater are expected to have the greatest commercial utility. The polymers of the present invention are believed to form stable aqueous encapsulate solutions below the presently available limits of detection, i.e., below 10−10 M.

[0058] In a preferred embodiment of the present invention, the polymers are used to solubilize hydrophobic molecules with biological or pharmaceutical activity for drug delivery.

[0059] Pharmaceutical dosage forms of polymer-encapsulated hydrophobic molecules having biological or pharmaceutical activity may be formulated using physiologically acceptable carriers, excipients, stabilizers and the like, and may be provided in sustained release or timed release formulation. Acceptable carriers, excipients and diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Science (A. R. Gennaro Edit., Mack Publishing Co., 1985). Such materials are non-toxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin and immunoglobulins, hydrophilic polymers such as poly(vinyl pyrrolidinone), amino acids such as glycine, glutamic acid, aspartic acid and arginine, monosaccharides, disaccharides, and other carbohydrates, including cellulose and its derivatives, glucose, mannose and dextrines, chelating agents such as EDTA, sugar alcohols such as mannitol and sorbitol, and conventional cationic and nonionic surfactants such as TWEEN, PULRONICS, and PEG. Dosage formulations to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes, or by other conventional methods such as irradiation or treatment with gases or heat. The pH of the dosage formulations of this invention typically will be between 3 and 11, and more preferably from 5 to 9. Hosts in need of treatment (typically mammalian) using the dosage formulations of this invention can be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of host being treated, and in the case of animals, its sex, weight, diet, concurrent medication, overall clinical condition, the particular hydrophobic compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the arts will recognize.

[0060] Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular dosage form of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the host. For the various suitable routes of administration, the absorption efficiency must be individually determined for each hydrophobic compound by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art.

[0061] Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.

[0062] A typical dosage might range from about 0.001 mg to about 1,000 mg of hydrophobic material, per kg of patient weight. Preferred dosages range from about 0.01 mg / kg to about 100 mg / kg, and more preferably from about 0.10 mg / kg to about 20 mg / kg. Advantageously, the dosage forms of this invention may administered several times daily, and other dosage regimens may also be useful.

Problems solved by technology

However, the formation of micelles is both temperature- and concentration-dependent.

Because of the change in micellar structure and size, control over the release of drugs within the micellar microcontainer cannot be maintained for long periods.

Typically drug is released over a period of hours and this release is often inconsistent over this period.

Thus, the thermodynamic equilibrium between surfactant and micelles may ultimately cause serious toxicity problems due to potentially large fluctuations in drug concentrations accompanied by the breakdown in micellar structure into surfactant molecules.

This dilution is particularly large after oral and intravenous administration and can cause unwanted precipitation of hydrophobic drugs.

Thus, while micelles are frequently evaluated for use as drug delivery systems, there are only a few products on the market that are considered practical.

This is due to the eventual aggregation and / or precipitation of drugs resulting from equilibration of micelles back to the monomer and the solubilization capacity being too low to be of practical use.

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