Sri International

Pharmaceutical Delivery Systems, Inc.

Sandoz Pharmaceuticals Corp.

Sandoz Pharm. Corp.

Donald W Penhale

Jorge Heller

Steve Y Ng

Steven Y Ng

Robert F Helwing

Biodegradable ortho ester polymers based on mono- and poly-thiols are provided that are useful for making biodegradable sustained release agent dispensers and which contain at least one of the mer units (I), (II), (III) or (IV) ##STR1## wherein X is a quadrivalent organic grouping, A and B are independently selected from the group consisting of hydrogen and lower alkyl, and R is hydrocarbyl or oxyhydrocarbyl of 1 to 14 carbon atoms, if oxyhydrocarbyl, containing 1 to 4 oxy groups, and may be either aliphatic or aryl, unsubstituted or substituted with one or more lower alkyl, amino, nitro or halogen moieties.

Ortho and thio-ortho ester polymer

Biodegradable polymers that are useful for making biodegradable sustained release agent dispensers and which contain acetal, carboxy-acetal, ortho ester and/or carboxy-ortho ester linkages.

Polymers containing acetal, carboxy-acetal, ortho ester and carboxyortho

Polymers are provided that are useful for making biodegradable sustained release agent dispensers and which contain at least one of the following mer units (I) and (II) ##STR1## wherein X is a quadrivalent organic grouping, A and B are hydrogen or lower alkyl, and R is hydrocarbyl or oxyhydrocarbyl of 1 to 14 carbon atoms and, if oxyhydrocarbyl, containing 1 to 4 oxy groups, and may be either aliphatic or aryl, unsubstituted or substituted with one or more lower alkyl, amino, nitro or halogen moieties. Methods of synthesizing the novel polymers are also provided, as biodegradable beneficial agent dispensers prepared using the novel polymers.

Polymers containing carboxy-ortho ester and ortho ester linkages

Water-soluble polyacetal or polyketal having the formula ##STR1## wherein R.sub.1, and R.sub.2 are aliphatic, cycloaliphatic or aromatic groups, for ketals; R.sub.1 is hydrogen and R.sub.2 is aliphatic, cycloaliphatic, or aromatic groups for acetals; R.sub.3 and R.sub.4 are also aliphatic, alkoxy, cycloaliphatic or aromatic groups X represents groups as (CH.sub.2).sub.n, O(CH.sub.2).sub.N O or ##STR2## that connect the pendant unsaturation to the aliphatic, cycloaliphatic or aromatic R.sup.4 groups, the ratio of a to b is 0.5 to 10, and n is 10-100.

Polyacetal and polyketal hydrogels formed from acetals or ketals and

Biodegradible polymers are provided which may contain a biologically active substance, e.g. a drug such as insulin, which is released over a period of time as the polymer erodes when in contact with a body fluid. The polymer contains an amine functionality whereby it erodes faster at low acid pH's than at higher acid pH's. As an example, the polymer may contain insulin and may contain or may have an encapsulating hydrogel containing glucose oxidase. As the blood sugar level of a diabetic person rises, e.g., after a meal, glucose diffuses into the polymer or hydrogel and is converted to gluconic acid which lowers the pH, and accelerates erosion and the release of insulin.

Method of preparing bioerodible polymers having pH sensitivity in the

A therapeutic composition comprising a therapeutic macromolecular agent incorporated in cross-linked polyacetal.

Polyacetal hydrogels formed from divinyl ethers and polyols

Biodegradible polymers are provided which may contain a biologically active substance, e.g. a drug such as insulin, which is released over a period of time as the polymer erodes when in contact with a body fluid. The polymer contains an amine functionality whereby it erodes faster at low acid pH's than at higher acid pH's. As an example, the polymer may contain insulin and may contain or may have an encapsulating hydrogel containing glucose oxidase. As the blood sugar level of a diabetic person rises, e.g., afte a meal, glucose diffuses into the polymer or hydrogel and is converted to gluconic acid which lowers the pH, and accelerates erosion and the release of insulin.

Water soluble polyacetals having molecular weights from about 5,000-30,000 are formed by condensing three monomers, e.g. a divinyl ether, a water soluble glycol and a diol. The invention is used for the bioerodible controlled release of therapeutic agents from the polyacetal hydrogel.

Rearrangement of allyl acetals to ketene acetals is disclosed. The rearrangement is accomplished by mixing the allyl acetal with a solution of an alkali metal lower alkyl in a water-soluble primary amine. After several hours contact with the allyl acetal with the solution ketene acetal formed during the contact is separated from the reaction mixture.

Preparation of ketene acetals

This invention concerns ortho ester polymers having repeating mer units represented by the general formulas: ##STR1## The polymers are formed by a condensation reaction between ketene acetals having a functionality of two or more and hydroxyl containing compounds having a functionality of two or more. Unlike most conventional condensation reactions, the reaction between a ketene acetal and an alcohol proceeds without the evolution of small molecule by-products which must be removed by distillation in order to achieve high molecular weight. Hence, this new process produces high molecular weight poly (ortho esters) in short reaction times, at essentially room temperature and at atmospheric pressure. Furthermore, linear thermoplastic materials are produced when both the ketene acetal and alcohol have functionalities of two; and because no volatile materials are produced, void free, thermoset materials are produced when either or both the alcohol and ketene acetal have functionalities greater than two and crosslinking occurs. The polymers are bioerodible and are useful in the fabrication of devices and coatings for delivering beneficial agents.

Growing community of inventors

Menlo Park, CA, United States of America

Donald W Penhale