Patent 6,673,361

A polymer having a satisfactory balance between in vivo degradability and satisfactory mechanical properties, which is an A¹ BA² type polymer comprising a segment A¹ and a segment A² each having a modified amino acid and a segment B consisting of polyethylene glycol with a number-average molecular weight of 8000 or higher bonded at one end to the segment A¹ and at the other end to the segment A², and has a number-average molecular weight of 10000 to 600000; an in vivo degradable material which comprises the polymer; and a film for preventing tissue adhesion, an artificial dura mater, a suture, an implant preparation, or a sustained-release drug base each comprising the degradable material.

PREFERRED EMBODIMENTS OF THE INVENTION

The A¹ BA² -type polymer of the present invention is a polymer of a particular number average molecular weight which is composed of a segment A¹ and a segment A², each having modified amino acids, and a segment B composed of polyethylene glycol of a particular number average molecular weight. The segment A¹ is bonded to one end of the segment B while the segment A² is bonded to the other end of segment B.

The polymer of the present invention has a number average molecular weight of 10000 to 600000. When the number average molecular weight of the polymer is less than 10000 or greater than 600000, it is difficult to achieve a desirable biodegradability that satisfies the mechanical properties and non-irritancy required for the materials to be placed in a living body.

In the A¹ BA² -type polymer of the present invention, the segment B has a number average molecular weight of 8000 or more, preferably 8000 to 50000, more preferably 10000 to 40000, and most preferably 12000 to 30000, in order to balance the desired rate of degradation and the mechanical properties of the polymer in vivo. When the number average molecular weight of the segment B is less than 8000, desired properties may not be obtained. When the number average molecular weight of the segment B exceeds 50000, viscosity of PEG material products becomes high, making it difficult to handle the products during production.

In the A¹ BA² -type polymer of the present invention, each of the segments A¹ and A² preferably has a number average molecular weight of 200 to 1 50000, more preferably 200 to 40000, and most preferably 500 to 1 0000, in order to balance the mechanical properties and the rate of degradation of the obtained polymer. The total number average molecular weight of the segments A¹ and A² is preferably in the range of 1000 to 300000, more preferably in the range of 2000 to 80000, and most preferably in the range of 4000 to 20000. When the total number average molecular weight of the segments A¹ and A2 is smaller than 1000, or larger than 300000, it is difficult to obtain a polymer with sufficient mechanical properties.

The number average molecular weight of each segment of the present invention can readily be adjusted by adjusting the molecular weights and the amounts of materials upon preparation of each segment.

The segment B, a constituent of the polymer of the present invention, is a hydrophilic segment composed of polyethylene glycol having the above-specified number average molecular weight.

The segment B may be a commercially available PEG that has a primary amino group at either terminus. Examples of the terminal amino groups include aminomethyl, aminoethyl, and aminopropyl groups.

The segment A¹ and the segment A², each of which is a constituent of the polymer of the present invention, are segments having modified amino acids that have hydrophobicity and may or may not be identical to one another. While each of the segments A¹ and A² is composed of at least one unit, it is preferred that each of the segments A¹ and A² be a poly(modified amino acid) composed only of a plurality of modified amino acid units to provide the resulting polymer with a desired biodegradability.

The term modified amino acid or poly(modified amino acid) may refer to an amino acid or a poly-amino acid with its functional groups such as a carboxyl group, an amino group, a hydroxyl group, and a thiol group protected by protecting groups for the synthesis of amino acid-N-carboxylic anhydrides (NCA) using the phosgene method.

The protecting group in the modified amino acid or poly(modified amino acid) may include, for example, benzyl, methyl, ethyl, n-propyl, isopropyl, and higher alkyl groups when the functional group to be protected in the amino acid molecule is a carboxyl group. The protecting group may include, for example, benzyloxycarbonyl, benzyl, and o-nitrophenylsulfenyl groups when the functional group to be protected is an amino group. The protecting group may include, for example, benzyl and acetyl groups when the functional group to be protected is a hydroxyl group. The protecting group may include, for example, a benzyl group when the functional group to be protected is a thiol group.

Preferred examples of the amino acids in the modified amino acid or poly(modified amino acid) may include alanine, leucine, lysine, or valine.

Preferred examples of the modified amino acids that compose the segment A¹ and segment A² may include .gamma.-benzylglutamate (which may be referred to simply as BLG, hereinafter) represented by the formula (1) and .beta.-benzylaspartate (which may be referred to simply as BLA, hereinafter) represented by the formula (2). ##STR1##

Preferably, the A¹ BA² -type polymer of the present invention may be a tri-block copolymer as represented by the formula (3) especially when the polymer is applied in the fields where low irritancy to a living body is desired. ##STR2##

In the formula, the letters a and d each represent the number of repeats of the segments A¹ and A², respectively, and are each preferably an integer from 5 to 80. The letter b represents the number of repeats of methylene units in the region where the segment B is bonded to the segment A¹ or the segment A² and is preferably an integer from 1 to 10. A letter c represents the number of repeats of oxyethylene groups and is preferably an integer from 200 to 1200. R is preferably a unit depicted either as --CH₂ --CO₂ --CH₂ -CH₆ H₅ or --CH₂ --CH₂ --CO₂ --CH₂ --C₆ H₅. Each R may or may not be identical to one another. The repeat numbers may be suitably adjusted to obtain the above-described number average molecular weights.

Preferably, the A¹ BA² -type polymer of the present invention is a mixture of one or more types of the tri-block copolymers represented by the formula (3).

The polymer of the present invention may be produced through a suitable combination of known synthesis techniques. For example, the polymer of the present invention may be obtained by a ring-opening polymerization of the modified amino acid-N-carboxylic anhydrides (NCA) with the above-mentioned commercially available PEG having primary amino groups at both termini as a starting material.

In the polymerization reaction, at least one solvent selected from the group consisting of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylacetoamide (DMAC), and 1,4-dioxane, or a mixed solvent of a solvent selected therefrom and dichloromethane or chloroform may be used.

Preferably, the ring-opening polymerization is carried out at a temperature of 20^oC. to 50^oC. for 6 to 36 hours.

This type of polymerization has long been known as the living anion polymerization, in which amino acids do not undergo racemization and polymers with relatively uniform molecular weights can be obtained.

A multiple-block copolymer can be synthesized by extending the chains of the tri-block copolymer that has the number average molecular weight of 10000 or less.

However, the multiple-block copolymerization requires chain-extending agents or catalysts. In such cases, tendency of the molecules to disperse becomes large, making it difficult to control the molecular weight and mechanical properties. Also, the presence of residual chain-extending agents or reaction catalysts often causes a problem. The polymer of the present invention can be produced without using such reaction catalysts or the chain-extending agents and, therefore, does not have problems associated with the use of these agents.

The biodegradable material of the present invention is the material containing the above-described polymer of the present invention and may be obtained by forming the polymers into desired shapes. For example, the polymer of the present invention may be dissolved in an organic solvent such as methylene chloride and/or chloroform and shaped into a sheet by casting or the like.

The biodegradable material thus obtained has a double-phase microstructure composed of modified amino acids or poly(modified amino acid) as the segments A¹ and A² and PEG as the segment B and exhibits a mechanical strength and rubber elasticity that are dependent upon the lengths of the block segments and the segment ratios.

The polymers in which the segments A¹ and A² are poly-.beta.-benzyl-L-aspartate and/or poly-.beta.-benzyl-L-glutamate exhibit particularly preferable biocompatibility and bioabsorbability since they are composed of PEG known as a low toxic and low stimulus polymer, and esters of an optically active amino acid and benzyl alcohol which is used as an additive of medications.

The rate of degradation in vivo of the biodegradable material of the present invention can be adjusted by suitably controlling the ratio of the

hydrophobic segments A¹ and A² to the hydrophilic segment B in the polymer of the present invention used, with respect to number average molecular weight or molecular weight. When the polymer is shaped into a sheet, the rate of biodegradation can readily be adjusted by suitably controlling the dimensions, such as thickness, of the sheets.

The biodegradable material of the present invention may contain other polymers than the polymer of the present invention. Examples of such other polymers may include hyaluronic acid, collagen, polycaprolactone, polylactate, and carboxymethylcellulose.

The membrane for preventing tissue adhesion and artificial dura mater of the present invention may be obtained by shaping the polymer of the present invention into sheets by known methods for forming membranes. The rate of biodegradation of the membrane for preventing tissue adhesion and artificial dura mater can be suitably adjusted by adjusting molecular weights of the polymer of the present invention used and the ratio of the molecular weights of the segments or the thickness of the sheet. The suture thread of the present invention may be obtained by shaping the polymer of the present invention into fibers. The rate of degradation of the suture thread of the present invention can be suitably adjusted by adjusting the molecular weight of the polymer of the present invention used or the ratio of the molecular weights of the segments.

The implant preparation or sustained-release drug base of the present invention may be obtained by forming a hydrophobic drug and the polymer of the present invention into the forms of sheets or microgels. The rate of drug release may be controlled by suitably varying the total number average molecular weight of the polymer of the present invention and the average number molecular weights of the segment A¹ and segment A².

In cases of implant preparations, the polymer of the present invention may be shaped into the forms of hollow threads or tubes. Such implant preparations may be used in applications where the implant preparations are placed in a living body and then degrade in a sustained manner.

Since the polymer of the present invention has unique characteristics such as the ability to retain water, the ability to form a hydrogel, and the ability to

hydrolyze in a living body, it can be widely applied to various products including toiletries and cosmetics, as well as the above-described applications.

Since the polymer of the present invention includes the hydrophobic segments A¹ and A² and the segment B of the hydrophilic PEG with a predetermined molecular weight and has a number average molecular weight of 10000 to 600000, the degradation rate can be adjusted by suitably selecting the molecular weights of the segments or the ratio of the molecular weights of the segments, while desired mechanical properties and non-irritancy are retained in a living body. Accordingly, the polymer of the present invention is suitable for use in biodegradable elements to be embedded in a living body such as membranes for preventing tissue adhesion, suture threads, implant preparations or sustained-release drug bases.

Also, when placed in water, the polymer of the present invention takes the form of hydrogel. The hydrogel has a sufficient flexibility. When the hydrogel is left in water as a swollen state at room temperature for a prolonged time, the hydrogel can retain the original shape that it assumes immediately after it has swollen in water. This preferred characteristic of the hydrogel makes the polymer of the present invention applicable in a wide variety of applications.

The biodegradable material of the present invention is particularly advantageous when it is used in the membrane to prevent tissue adhesion since it makes handling of the membrane easy while the membrane is being placed in tissue and provides the membrane with a high followability to follow soft tissue after it has become gel.

Claim 1 of 10 Claims

What is claimed is:

1. An A¹ BA² -type polymer having a number average molecular weight of 10000 to 600000, wherein the polymer is composed of a segment A¹ and a segment A² each including hydrophobic poly modified amino acids, and a segment B composed of polyethylene glycol with a number average molecular weight of 8000 or higher, the segment A¹ being bonded to one end of the segment B while the segment A² is bonded to the other end of the segment B, wherein the total number average molecular weight of the segment A¹ and the segment A² is from 4000 to 20000.

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