The purpose of this chapter is to review drug release from bioerodible polymers with major emphasis on those systems where drug release proceeds by kinetics that are close to zero order, or on research currently underway directed towards that objective. Unable to display preview. Download preview PDF. Skip to main content. This service is more advanced with JavaScript available.

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The present invention is in the fields of polymer chemistry and drug delivery, and it concerns certain ortho ester polymers and methods for their preparation. These materials are bioerodible polymers, i. These bioerodible polymers are useful for the controlled release of therapeutic agents. Thus, -the invention relates to drug dosage forms prepared with the novel polymers, including solid implantable drug dosage forms as well as soft forms, such as ointments, gels, creams and the like.

The invention additionally relates to the use of these bioerodible drug dosage forms and the treatment of disease conditions such as deep wounds, periodontal disease, and the like. Bioerodible polymers used to control the release of therapeutic agents physically dispersed in the polymer matrix have been described in a variety of contexts. One matrix which has been successful is a family of pol ortho esters. These materials contain the pH-sensitive ortho ester linkage in their polymer backbone.

Such polymers are described, for example, in U. Patent No. The method of preparing polymers according to the aforementioned patent comprises the addition of polyols to diketene acetals as- shown in Scheme 1. SCHEME 1 Using this scheme, almost any diketene acetal and any diol can be used, and the synthetic method is thus extremely versatile. Polymers synthesized by this method are, however, not optimal for preparing soft or amorphous drug dosage forms such as bioerodible ointments, creams or gels due to the relatively rigid pentaerythritol segment in the polymer backbone.

There is a need in the art for a bioerodible composition which has a molecular structure of sufficient flexibility to enable its use as a bioerodible matrix in soft dosage forms such as ointments, gels, creams, or the like.

An ideal material would enable the topical delivery of an effective dose level of pharmaceutical agent from an ointment or the like at a desired rate for a period of time dictated only by clinical considerations and not by limitations of the ointment cream or gel formulation. The ability to achieve this is particularly important in cases where excessive and uncontrolled application of a drug can produce serious side effects.

The present invention is addressed to these considerations, and provides bioerodible compositions which may be prepared in either solid implantable forms or in soft dosage forms such as ointments or the like, as noted above. In these bioerodible drug dosage forms, the release rate of the drug to be delivered—as well as the desired time period for drug delivery—can be carefully controlled. It provides materials which bioerode to small, water-soluble molecules that leave no residues in the tissue of the patient undergoing treatment.

This opens the door for improved treatment of burns, wounds, especially deep wounds, and like applications by the controlled delivery of drugs over prolonged periods of time. Disclosure of the Invention. It is accordingly a primary object of the present invention to address the aforementioned needs in the art, and to provide bioerodible compositions useful in either solid implantable or soft dosage forms for the controlled release of therapeutic agents.

It is another object of the invention to provide these bioerodible compositions in the form of bioerodible solid implants. It is still another object of the invention to provide these bioerodible compositions in the form of bioerodible ointments, gels, creams or the like. Is it yet another object of the invention to provide a novel method of synthesizing certain bioerodible ortho ester polymers useful for such compositions, as well as certain novel bioerodible ortho ester polymers themselves.

It is a further object of the invention to provide a bioerodible ointment and method for the treat- ment of deep wounds, periodontal disease, and the like. In accord with this invention, a method is provided for synthesizing a bioerodible ortho ester polymer. This method involves: reacting a monomeric ortho ester having the general formula. This reaction forms an ortho ester polymer containing a mer unit having the following general formula I.

This ortho ester polymer is another aspect of this invention. In another aspect of the present invention, bioerodible pharmaceutical compositions are provided based on these ortho ester polymers. These compositions are either in solid implantable form or in a soft dosage form, and contain one or more of these bioerodible ortho ester polymers and an effective amount of a selected therapeutic agent. This aspect of the invention also relates to a method for the prolonged treatment of disease states in man and animals such as treating burns, deep wounds, and the like.

This method comprises either administering topically to such a patient a pharmaceutical ointment, gel, cream, or the like, or implanting a solid formulation of this invention and thus achieving controlled bioerosion of the ortho ester polymer and the gradual exposure and controlled delivery of the therapeutic agent.

Figure 1 is a graph illustrating the effect of an acidic excipient on the rate of bioerosion of the ortho-ester-based compositions of this invention. Detailed Description of the Invention. The term "mer" is used to mean the structurally recurring units or monomer units of the ortho ester polymers provided by the present invention.

The mer units of any given polymer may be the same or different; when different, they may be arranged in block or random fashion. When all the mer units of a polymer are the same, the polymer is called a homopolymer.

When there are 2 or more mer units in a polymer, the polymer is called a copolymer. The present invention involves both homopolymers and copolymers. The term "bioerodible" as used herein to describe the polymers of the present invention is synonymous with the term of art "biodegradable.

The term "effective amount" as used herein intends that quantity of a therapeutic agent that, when administered to a patient, is required to provide the desired or intended beneficial effect without intolerable side effects, such as toxicity. The term "soft dosage form" as used herein is intended to mean a bioerodible ointment, gel, cream or the like, typically intended for topical administration of a drug.

The term "lower alkyl" is intended to mean linear, branched or cyclic alkyl moieties having 1 to 6, and more typically carbon atoms, inclusive. The terms "alkylene" and ""cycloalkylene" have their usual meaning defining aliphatic linking groups, preferably aliphatic hydrocarbon groups which serve as a bridge between 2 or more other groups. The term "oxyalkylene" defines an aliphatic linking group containing 1 or more ether oxygens and providing 2 or more carbons as bridge points to other groups.

Oxyalkylene groups can be linear, branched or cyclic. In the synthesis aspects of the present inven- tion, a method is provided for synthesizing certain bioerodible ortho ester polymers. The synthesis is a simple, straightforward reaction which may be accomplished in one step in a single reaction vessel. The synthesis involves the reaction of a monomeric ortho ester having the general formula.

OR' wherein R is a hydrogen or an alkyl of 1 to 10 carbon atoms and each of the Rs is independently selected from lower alkyls, with a triol having the general formula. In this triol, A is an alkylene or a cycloalkylene moiety of 5 carbon atoms or more, or is an oxyalkylene.

If cycloalkylene or a cyclic oxyalkylene, A will preferably contain 1 to 3, more preferably l. In preferred embodiments, the R moiety of the monomeric ortho ester reactant is lower alkyl, and the R' moieties are the same alkyl, either methyl or ethyl.

In preferred embodiments, the triol reactant, the A moiety, is either alkylene or cycloalkylene or oxyalkylene of 5 carbon atoms or more, preferably 5 to 20 carbon atoms, and more preferably 5 to 10 carbon atoms. It is preferred that 2 of the hydroxyl groups of the triol be separated by either 2 or 3 carbon atoms i. This spacing of the third hydroxyl unit will prevent interference with the ring-forming reaction.

Thus, in one group of preferred triols, A is a linear alkylene moiety, i. CR" 2 y -OH. OH OH in which the various R" groups are independently selected from the group consisting of hydrogen and lower alkyls, x is 0 or 1, and y is greater than or equal to 2. If A is cycloalkylene, the ring structure preferably is such as to give this preferred hydroxyl spacing and facilitate ring closure. If oxyalkylene, A may be a cyclic sugar residue in which 2 of the triol hydroxyl moieties are , -cis so as to facilitate ring formation, while the other, third hydroxyl moiety is trans to the first 2 hydroxyl groups and separated therefrom by 3 or more carbon atoms, typically located in the 5'-position of a pentafuranose ring as in the structure:.

Compounds containing analogous substituted pentafuranose rings are within the purview of the present invention as well. Examples of other cyclooxyalkylene moieties include:.

The synthesis reaction of the ortho ester monomer and triol is carried out either neat or in an aprotic solvent such as tetrahydrofuran THF , cyclohexane, ethylene glycol dimethyl ether glyme , diglyme, cymene, cumene, chlorinated hydrocarbons, or the like.

More typically, solvent is present. In either case, care must be taken to maintain anhydrous conditions. The Novel Bioerodible Polymers. The novel ortho ester polymers useful in the drug dosage forms provided herein preferably contain mer units represented by Formula I wherein.

Typically, although not necessarily, the polymers of the invention have molecular weights ranging from several thousand to 10,,, but can have molecular weights as low as or as high as 50, or more.

These polymers have the desirable properties of being able to undergo bioerosion and of being less rigid and more flexible and conforming than prior ortho ester polymers. The bioerodible ointments, gels and creams of the invention will include: an ointment, gel or cream base comprising one or more of the bioerodible ortho ester polymers described herein and a selected therapeutic agent.

The therapeutic against, whether present as a liquid, a finely divided solid, or any other physical form, is dispersed in the ointment, gel or cream base. Typically, but optionally, the compositions include one or more other components, e. For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.

The amount of active agent will be dependent upon the particular drug employed and condition being treated. Typically the amount of drug represents about 0. The quantity and type of ortho ester polymer incorporated into the implant, ointment, gel, cream, etc. For a more viscous composition, a higher molecular weight polymer is used. If a less viscous composition is desired, a lower molecular weight polymer can be employed, i.

The product may be based on only one polymer or it may comprise a mixture of polymers. While not essential for topical or transdermal administration of many drugs, it may in some cases, with some drugs, be preferred that a skin permeation enhancer be coadministered therewith.

Any number of the many skin permeation enhancers known in the art may be used. It is additionally preferred to incorporate an acidic excipient into the bioerodible dosage form in order to control the rate of polymer bioerosion. The ortho ester linkages of the bioerodible polymers are relatively stable at basic or neutral pH and are hydrolized at progressively increasing rates as the pH of the medium surrounding the polymer decreases.

Thus, hydrolytic lability and the rate of erosion and drug release can be increased by incorporation of one or more acidic components. Solid but water soluble aliphatic acids are generally favored. Examples of acidic excipients useful in conjunction with the present invention include adipic, citric, suberic, maleic and itaconic acids. Basic excipients may also be used to slow the rate of release.

The variety of different therapeutic agents which can be used in conjunction with the bioerodible compositions of the invention is vast. Other preferred drugs for use with the presently disclosed polymers include proteinaceous drugs such as epidermal growth factors or growth hormones. The present invention also encompasses veterinary applications of the presently disclosed polymers, pharmaceutical compositions, and methods of treatment. Administration and Use Depending on dosage form, the pharmaceutical compositions of the preceding section may be administered in different ways, i.

Preferred dosage forms are solid implants or soft dosage forms which can be applied directly to the af- flicted tissue for the delivery of drug. This can result in prolonged delivery over, say, 1 to 10, hours, preferably 2 to hours of effective amounts say, 0. Topical application can be enhanced by occlusion, i. Topical administration or implantation is preferred for wound healing and in the treatment of periodontal disease.

The bioerodible ointment, gel or cream may be injected as is or in combination with one or more auxiliary components as described above.


Bioerodible polymers for controlled release systems

We'd like to understand how you use our websites in order to improve them. Register your interest. This study evaluates a new class of bioerodible polymers as periodontal inserts for the controlled release of metronidazole. The system is based on association polymers formed from compatible blends of cellulose acetate phthalate CAP and a hydrophobic block copolymer of polyoxyethylene and polyoxypropylene, Pluronic L In addition to characterizing these polymers by thermal analysis, their erosion and metronidazole release characteristics were determined both in vitro, and in vivo using a rat model.

IEC 60332-3A PDF

Bioerodible Polymers for Ocular Drug Delivery

Development of ophthalmic drug-delivery systems has always been challenging. The commonly used route for drug delivery to the anterior segment of the eye has been the conjunctival cul-de-sac. Because of drawbacks associated with this route, new approaches have been investigated for delivery of drugs to the eye by means of polymeric delivery systems. Development of controlled drug-release devices has been a major step forward in this respect.


A New Bioerodible Polymer Insert for the Controlled Release of Metronidazole

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. Read article at publisher's site DOI : Kumar MN , Kumar N.


Controlled release from bioerodible polymers: effect of drug type and polymer composition.

The present invention is in the fields of polymer chemistry and drug delivery, and it concerns certain ortho ester polymers and methods for their preparation. These materials are bioerodible polymers, i. These bioerodible polymers are useful for the controlled release of therapeutic agents. Thus, -the invention relates to drug dosage forms prepared with the novel polymers, including solid implantable drug dosage forms as well as soft forms, such as ointments, gels, creams and the like.

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