Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-01-21
2002-01-29
Nola-Baron, Liliana Di (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S486000, C424S487000
Reexamination Certificate
active
06342241
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a composition of a hydroxy acid-based oligomer (A) and a drug (B), wherein the oligomer (A) has a lactic acid unit useful as a base material for sustained releasing a drug, and holds a fluidity to enable itself to be injected, further, when the oligomer (A) is supplied into water, it is insoluble and does not show an acidity.
2. Description of the Related Art
Heretofore, there has been present an approach that a biological and absorbable polymer is applied to DDS (drug delivery system). The DDS is a system in which the biological and absorbable polymer is used as a base material and the polymer sustainedly releases a drug in according with a proper manner. As an example of the system, there is a method in which a micro sphere of drug is formed by using the biological and absorbable polymer.
Examples of this biological and absorbable polymer include poly-&agr;-hydroxy acids such as polylactic acid (PLA) and polyglycolic acid (PGA). Japanese Patent Application Laid-Open No. 64824/1987 discloses a method that glycolide (GLD) which is a cyclic dimer of glycolic acid and lactide (LTD) which is a cyclic dimer of lactic acid are subjected to ring-opening polymerization to thereby obtain a low-molecular weight polydispersive lactic acid-glycolic acid copolymer (PLGA) which is useful as the basic material for sustainedly releasing a drug. However, in the DDS utilizing the conventional biological and absorbable polymer, every polymer to be used is solid at ordinary temperature, and hence, there is required a contrivance that micro-spheres are dispersed in a dispersion medium such as pure water and then used for injection.
On the other hand, German-A1-3716302 discloses that the biological and absorbable polymer is not used as the micro-spheres but as an absorbable bone wax for a polyester oligomer comprising glycolic acid or lactic acid and glycerin. Furthermore, U.S. Pat. No.5725881 discloses a mixture of an amorphous and viscous oligomer based on lactic acid having a number-average molecular weight of less than 600 and a crystalline oligomer or polymer based on lactic acid having a number-average molecular weight of from 600 to 10000, i.e., an absorbable material which is plastically deformable and biologically adaptable.
In the technical field of the DDS, however, a base material has been desired that can be mixed with a drug and then injected directly orally (dentistry) or hypodermically by a syringe or the like and has a function of sustainedly releasing a drug component. If a polymer which is used as the base material is acidic (e.g., pH=less than 5) in an organism (under water-soluble conditions), there is a fear that the base material gives rise to irritation, inflammation or the like in the organism. In view of this point, for example, Japanese Patent Application Laid-Open No. 221871/1993 discloses a polypeptide medicament which comprises a polypeptide stable to an acid and a polymer or a copolymer of lactic acid and glycolic acid and which is pharmaceutically active and stable to the acid.
The problems of these conventional techniques can be summarized as follows.
(i) In the case of a hydroxy acid-based oligomer, if a carboxyl group at its molecular terminal is not esterified, the oligomer shows an acidity less than pH 5 when added to distilled water or physiologic saline. Therefore, when such a hydroxy acid-based oligomer is used as the base material and is mixed with a drug, and is administered into an organism, there is a fear that it shows an acidity in the organism and hence causes irritation, inflammation or the like occurs.
(ii) With regard to the hydroxy acid-based oligomer, if the carboxyl group at its molecular terminal is not esterified, its water-solubility is usually high. Therefore, even when such a hydroxy acid-based oligomer is used as the base material and is mixed with a drug, and is administered into an organism, clearance is too rapid, so that a sustained releasable effect of drug cannot be expected.
(iii) A certain kind of hydroxy acid-based oligomer which has no fluidity cannot pass through a needle of a syringe at room temperature (25° C.), so that it cannot be used as the sustained releasable base material for a physiologically active substance.
SUMMARY OF THE INVENTION
An object of the present invention is to solve the above problems of the conventional techniques, concretely to provide a medical composition having the following advantages.
(i) When the medical composition is administered into an organism (inclusive of an oral cavity), a base material does not show an acidity (e.g., less that pH 5), so that irritation, inflammation or the like scarcely occurs.
(ii) The base material is suitably insoluble, so that clearance can be prolonged and hence the sustained releasable effect of drug can be exerted.
(iii) Since the base material shows fluidity at room temperature (25° C.), the medical composition can be administered into the organism by a syringe or the like.
The present inventors have intensively investigated with the intention of achieving the above object, and as a result, it has been found that when a specified hydroxy acid-based oligomer (A) in which the carboxyl group at a molecular terminal is esterified is used, there can be obtained a medical composition which has fluidity at ordinary temperature, is suitably water-insoluble, does not show an acidity in an organism, and particularly has a good sustained releasability. In consequence, the present invention has been completed.
That is to say, the present invention is directed to a medical composition comprising a hydroxy acid-based oligomer (A) and a drug (B), wherein the hydroxy acid-based oligomer (A) is an oligomer in which the carboxylic acid-terminals are at least partially esterified, and the oligomer (A) has a function of becoming pH 5 to 8 when administered into an organism, and the oligomer (A) shows fluidity at 25° C.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A hydroxy acid-based oligomer (A) for use in the present invention has a function of becoming pH 5 to 8 when administered into an organism. Therefore, when a medical composition of the present invention is administered into the organism (inclusive of an oral cavity), it does not become come acidic (less than pH 5), so that a problem of irritation or inflammation which is caused by a low pH scarcely occurs. Thus, the medical composition including the hydroxy acid-based oligomer (A) is very useful as a sustained releasable medical composition.
In the present invention, judgement as to whether or not the hydroxy acid-based oligomer (A) becomes pH 5 to 8 when administered into the organism can pretendedly be made by adding 10 g of a sample to 100 g of distilled water, and then measuring a pH at 37° C. In addition to such a way using distilled water, the judgement can be made by a pretended technique such as (i) a way which comprises adding 10 g of a sample to 100 g of a 0.9% NaCl solution, and then measuring a pH at 37° C., (ii) a way which comprises adding 10 g of a sample to 100 g of a 0.1 N phosphoric acid (pH 7.3) buffer solution, and then measuring a pH at 37° C., or (iii) a way which comprises adding 10 g of a sample to 100 g of physiologic saline, and then measuring a pH at 37° C.
A preferable embodiment of the hydroxy acid-based oligomer (A) for use in the present invention, is a oligomer having
a repeating unit represented by the following chemically structural formula (1) and/or a repeating unit represented by the following chemically structural formula (2) as at least a part of repeating units,
—R in the following chemically structural formula (3) and/or —R in the following chemically structural formula (4) as one of at least a part of molecular terminals, and
—OH in the following chemically structural formula (5) and/or —OH in the following chemically structural formula (6) as another of at least a part of molecular terminals:
in the chemically structural formulae (3) and (4), each R is independently an alkyl group h
Asou Yukiko
Shinoda Hosei
Tamatani Hiroaki
Burns Doane Swecker & Mathis L.L.P.
Di Nola-Baron Liliana
Mitsui Chemicals Inc.
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