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  Pharmaceutical Patents  

 

Title:  Antidiabetic preparation for oral administration
United States Patent: 
7,488,498
Issued: 
February 10, 2009

Inventors: 
Makino; Chisato (Kawasaki, JP), Ninomiya; Nobutaka (Kawasaki, JP), Orita; Haruo (Kawasaki, JP), Sakai; Hidetoshi (Kawasaki, JP), Yabuki; Akira (Kawasaki, JP), Kato; Nobuo (Tokyo, JP), Shioya; Shigeru (Tokyo, JP)
Assignee: 
Ajinomoto Co., Inc. (Tokyo, JP)
Appl. No.:  11/246,453
Filed: 
October 11, 2005

 

George Washington University's Healthcare MBA


Abstract

There is provided a single preparation which directly decreases both of the post prandial blood glucose level and the fasting blood glucose level close to normal levels, by release-sustaining a drug capable of decreasing the post prandial blood glucose level of diabetic patients close to the normal level, or mixing a controlled release drug capable of decreasing the post prandial blood glucose level close to the normal level with an immediate release drug. It is particularly preferable that the drug capable of decreasing the post prandial blood glucose level close to the normal level is nateglinide.

Description of the Invention

The invention is to provide a preparation for directly decreasing both a post prandial blood glucose level and a fasting blood glucose level by one preparation to make them close to normal levels.

The present inventors have assiduously conducted investigations to solve the foregoing problems, and have consequently found that both a post prandial blood glucose level and a fasting blood glucose level can be decreased by one preparation to make them close to normal levels. This finding has led to the completion of the invention.

That is, the invention provides an antidiabetic preparation for oral administration characterized by containing active ingredient(s) for decreasing blood glucose level of diabetic patients and having a form to make both a post prandial blood glucose level and a fasting blood glucose level of diabetic patients close to normal levels.

The invention further provides an antidiabetic preparation for oral administration characterized by containing nateglinide in which in a dissolution test for 1 hour, a dissolution rate of the active ingredient is at least 1% and less than 70% at pH of 1.2, 4.0 and 6.8.

The invention still further provides an antidiabetic preparation for oral administration containing nateglinide in which a dissolution rate of nateglinide is dependent on pH and in a dissolution test for 1 hour, a dissolution rate of nateglinide at pH of 1.2 is at least 20% lower than a dissolution rate thereof at pH of 6.8.

The invention furthermore provides an antidiabetic preparation for oral administration containing nateglinide in which in a dissolution test for 1 hour, a dissolution rate of the active ingredient at pH of 4.0 is less than 20% and a dissolution rate of the active ingredient at pH of 6.0 is at least 20%.

The invention moreover provides an antidiabetic preparation for oral administration containing nateglinide and at least one material selected from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polylactic acid derivatives, polyoxyethylene derivatives, polyvinyl pyrrolidone derivatives, polyvinyl alcohol derivatives, oils and surfactants, nateglinide being dispersed in the material or being emulsified or microencapsulated with the material.

The invention moreover provides an antidiabetic preparation for oral administration containing nateglinide and at least one material selected from the group consisting of polysaccharide derivatives (except for hydroxypropylmethyl cellulose), polyacrylic acid derivatives, polylactic acid derivatives, polyvinyl pyrrolidone derivatives, polyvinyl alcohol derivatives, oils and surfactants, nateglinide being coated with the material.

BEST MODE FOR CARRYING OUT THE INVENTION

In the invention, "to make both a post prandial blood glucose level and a fasting glucose level of diabetic patients close to normal levels" means that a post prandial blood glucose level and a fasting glucose level of diabetic patients are decreased to make them close to a post prandial blood glucose level and a fasting glucose level of healthy persons respectively.

Active ingredient(s) for decreasing a blood glucose level of diabetic patients may include first active ingredient(s) for decreasing a post prandial blood glucose level and second active ingredient (s) for decreasing a fasting glucose level.

In this case, the first active ingredient(s) for decreasing a post prandial blood glucose level is/are drug(s) for making a post prandial blood glucose level of diabetic patients to a blood glucose level of healthy persons. It includes drug(s), for example, a fastacting post prandial blood glucose regulator such as nateglinide or the like, and an .alpha.-glycosidase inhibitor such as acarbose or the like. Especially, nateglinide is preferable.

Further, the second active ingredent(s) for decreasing a fasting blood glucose level is/are drug(s) for making a fasting glucose level of diabetic patients to a fasting glucose level of healthy persons. It includes drug(s) or example, a sulfonylurea drug (SU drug) such as tolbutamide or the like, a biguanide drug such as metformin hydrochloride or the like, and an insulin sensitizer such as troglitazone or the like.

The invention includes a case where the preparation has both an immediate release form and a controlled release form of the active ingredent(s) or a single form of sustained release belonged to controlled release.

In this case, the active ingredient(s) for decreasing a blood glucose level may be the first active ingredient(s) used singly or the first active ingredient(s) and the second active ingredient(s) used in combination. In these cases, each of the first active ingredient(s) and the second active ingredient(s) may be single or plural.

In the invention, the single use of the first active ingredient(s) is preferable, the combined use of nateglinide and another active ingredient(s) or the single use of nateglinide are more preferable. The single use of nateglinide is especially preferable.

The "immediate release form of the active ingredient(s)" here referred to is an immediate release tablet described in Japanese Patent Laid-Open No. 194,969/1993 or various dosage forms showing its similar release behavior. Those which quickly elute a drug in the stomach after administration are included therein. Meanwhile, the "controlled release form of the active ingredient(s)" includes (i) a single form that continuously releases a drug, namely, a single form of sustained release, and (ii) a single form that releases a drug after the lapse of a fixed period of time.

Examples thereof include a pH dependent type, a time dependent type, a time limit release type, a gastrointestinal site specific release type and the like. Of these, a pH dependent type, a time dependent type and a time limit release type are preferable.

In the invention, it is especially preferable to contain a single active ingredient for decreasing a blood glucose level and have a form to continuously release the actPn ingredient from post prandial through fasting in oral administration.

As the single active ingredient for decreasing the blood glucose level here, nateglinide is preferably used.

Here, the form to continuously release the active ingredient in the invention includes a combination of an mediate release form and a controlled release form which continuously releases the active ingredient and a single form of sustained release in controlled release of the active ingredient.

The imediate release form and the controlled release form or the sustained release form of the actve ingredent(s) for decreasing the blood glucose level can easily be obtained by dispersing the active ingredient(s) for decreasing the blood glucose level in a matrix materia coating the same with a coating material, emulsifying the same with an emulsion material or microencapsulating the same with a microcapsule material. Such a method is known as a matrix method a tablet coating method, a granule coating method, an emulsion method.mcroencapsulation method or the like. Further, other methods are also available.

It is advisable that the matrix material, the coating material, the emulsion material and the microcapsule material are independently selected from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polylactic acid derivatives, polyoxyethylene derivatives, polyvinyl pyrrolidone derivatives, polyvinyl alcohol derivatives, oils and surfactants.

The matrix method here is a method in which a drug is dispersed in the matrix material to control a release behavior. Examples of the matrix material include the foregoing polysaccharide derivatives, oils and polyacrylic acid derivatives, and the like. Any pharmaceutically acceptable compounds that form such a porous structure as to be able to diffuse a drug, water or the like in water will do.

Preferable examples thereof include cellulose derivatives, an ethyl acrylate.cndot.methyl methacrylate.cndot.chlorotrimethylammoniumethyl methacrylate copolymer, a methacrylic acid.cndot.methyl methacrylate copolymer, a methacrylic acid.cndot.ethyl acrylate copolymer, polylactic acid, a polylactic acid copolymer, polyoxyethylene, polyvinyl pyrrolidone, a 1-vinyl-2-pyrrolidone.vinyl acetate copolymer, polyvinyl alcohol, glyceride, a polyoxyethylene nonionic surfactant and a phospholipid, and these are used either singly or in admixture of two or more.

Preferable examples of cellulose derivatives here include ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose acetate succinate, sodium carmelose, carboxymethylethyl cellulose, cellulose acetate phthalate and hydroxyethyl cellulose, and these are used either singly or in admixture of two or more.

Further, methyl cellulose and mixtures with the foregoing compounds are also preferable.

Examples of a method of making a matrix include a high-speed agitation granulation method, a fluidized bed granulation method, a melt granulation method, a solvent removal method, a slug tableting method and the like. A method in which a drug and a matrix material can be mixed can be employed as a method of producing a matrix in the invention.

As types of a matrix, a non-erosion (non-collapsible) matrix in which a matrix structure does not collapse during release of a drug, and an erosion (collapsible) matrix in which a matrix structure collapses with release of a drug. In case of using a water-insoluble material, a non-erosion matrix is obtained. In case of using a water-soluble material, an erosion matrix is obtained.

At this time, various release behaviors can be obtained upon changing the type of the matrix material, the ratio of the matrix material and the drug or the production method. The drug release behavior is preferably a pH dependent type, a time dependent type or a time limit release type. However, the invention can be completed with other release behaviors so long as a drug can be released to make a post prandial blood glucose level and a fasting blood glucose level close to normal levels by decreasing these blood glucose levels. The specific weight ratio of the matrix material and the drug is 1:99 to 99:1, preferably 10:90 to 90:10.

The coating method includes a granule coating method and a tablet coating method. The granule coating method is a method in which core granules containing a drug are subjected to coating to control the release behavior.

As the coating material used in the coating method in the invention, for example, the foregoing polyacrylic acid derivatives, polysaccharide derivatives and oils are mentioned. Pharmaceutically acceptable compounds that form such a porous structure as to be able to diffuse a drug, water or the like in water or pharmaceutically acceptable compounds of which the solubility is dependent on pH are available. Preferable examples thereof include cellulose derivatives, an ethyl acrylate.methyl methacrylate.chlorotrimethylammonium-ethyl methacrylate copolymer, a methacrylic acid.methyl methacrylate copolymer, a methacrylic acid.ethyl acrylate copolymer, polylactic acid, a polylactic acid copolymer, polyoxyethylene, polyvinyl pyrrolidone, a 1-vinyl-2-pyrrolidone.vinyl acetate copolymer, polyvinyl alcohol, glyceride, a polyoxyethylene nonionic surfactant and a phospholipid, and these are used either singly or in admixture of two or more. As cellulose derivatives here, the same examples as listed on the matrix material are preferable.

Examples of the granule coating method include a fluidized bed coating method, a tumbling bed coating method and the like. Any method in which a coating film can be formed on core granules can be employed as the coating method in the invention.

The core granules here refer to original granules which are subjected to the coating. The core granules can be produced by a method of obtaining granules containing a drug and having a form appropriate for the coating, for example, an extrusion granulation method, a high-speed agitation granulation method, a spray drying method or the like.

The tablet coating method is a method in which core tablets containing a drug are coated. As the tablet coating method, a wet coating method or the like is mentioned. A method in which a coating film can be formed on core tablets can be employed as the coating method in the invention. The core tablets here refer to original tablets which are subjected to the coating. The core tablets can be produced by a method of obtaining tablets containing a drug and having a form appropriate for the coating, for example, a wet agglomerated granules compression method, a direct tableting method or the like.

Various release behaviors such as pH dependent release, time dependent release and the like can be obtained by changing a coating material, a coating film composition, a coating film thickness, a composition of core granules or tablets, a method of producing core granules or tablets, a coating method and the like.

The drug release behavior is preferably a pH dependent type, a time dependent type or a time limit release type. However, the invention can be completed with other release behaviors so long as a drug can be released to make a post prandial blood glucose level and a fasting blood glucose level close to normal levels by decreasing these blood glucose levels. Incidentally, examples of the pH dependent release include enteric coated granules and the like.

The emulsion method or the microencapsulation method is a method in which a drug is incorporated into an emulsion or a microcapsule to control the release behavior.

Examples of the material of the emulsion or the microcapsule include polysaccharide derivatives, polyacrylic acid derivatives, oils, surfactants and the like. Any pharmaceutically acceptable compounds that form such a structure as to control permeation of a drug from inside the emulsion or the microcapsule to the outside thereof in water will do.

Preferably, one or a admixture of two or more selected from the group consisting of cellulose derivatives, an ethyl acrylate.methyl methacrylate.chlorotrimethylammoniumethyl methacrylate copolymer, a methacrylic acid.methyl methacrylate copolymer, a methacrylic acid.ethyl acrylate copolymer, polylactic acid, a polylactic acid copolymer, polyoxyethylene, polyvinyl pyrrolidone, a 1-vinyl-2-pyrrolidone.vinyl acetate copolymer, polyvinyl alcohol, glyceride, a polyoxyethylene nonionic surfactant and a phospholipid can be used as inactive ingredient(s) material of the emulsion or the microcapsule in the invention. Preferable examples of cellulose derivatives here include ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose acetate succinate, sodium carmelose, carboxymethylethyl cellulose, cellulose acetate phthalate and hydroxyethyl cellulose, and these are used either singly or in admixture of two or more. Further, methyl cellulose and mixtures with the foregoing compounds are also preferable.

Examples of the emulsion method or the microencapsulation method include a submerged drying method, a phase separation method using an aqueous solution, an organic solvent or the like, a hot melt dispersion method, a spray drying method, an aerial suspension coating method, a fluidized bed coating method, a tumbling bed coating method, an interfacial polymerization method, a submerged cure-coating method and the like.

With respect to the drug release behavior, various release patterns such as pH dependent release, time dependent release and the like can be obtained by changing an inactive ingredient, a composition, a particle diameter, a production method or the like.

A pH dependent type, a time dependent type, a time limit release type are preferable. However, other release behaviors are also available so long as a drug can be released to make both a post prandial blood glucose level and a fasting blood glucose level close to normal levels by decreasing these blood glucose levels.

The second embodiment of the invention is an antidiabetic preparation for oral administration characterized in that in a dissolution test for 1 hour with one preparation containing nateglinide, the dissolution rate of the active ingredient is at least 1% and less than 70% at pH of 1.2, 4.0 and 6.8 (this embodiment corresponds to a time dependent release type of a matrix or the like, and to Examples 2, 3, 20 and 22). With respect to the dissolution test method here, in a dissolution test method by a puddle method (test solution 900 ml: 50 rpm) of Japanese Pharmacopeia 13 (hereinafter referred to as "JP"), JP disintegration test method 1st solution (JP 1 solution) containing 0.6w/v % polysorbate 80, a McIIvaine buffer solution of pH=4.0 diluted to 1/4 and containing 0.5 w/v % polysorbate 80 and a JP disintegration test method 2nd solution (JP 2 solution) are used as a test solution. It is advisable that the second embodiment is conducted with a matrix, a coating, an emulsion or a microcapsule.

The third embodiment of the invention is an antidiabetic for oral administration characterized in that in one preparation containing nateglinide, a dissolution rate of nateglinide is dependent on pH and in a dissolution test for 1 hour, a dissolution rate of nateglinide at pH of 1.2 is at least 20% lower than a dissolution rate thereof at pH of 6.8. (This embodiment corresponds to a pH dependent release type, a time dependent release type and the like, and to Example 9). With respect to the dissolution test method here, in a dissolution test method by a JP puddle method (test solution 900 ml: 50 rpm), a JP disintegration test method 1st solution (pH 1.2) containing 0.6 w/v % polysorbate 80 and a JP disintegration test method 2nd solution (pH 6.8) are likewise used as a test solution. It is advisable that the third embodiment is conducted with a matrix, a coating, an emulsion or a microcapsule.

The fourth embodiment of the invention is an antidiabetic for oral administration characterized in that in a dissolution test for 1 hour with one preparation containing nateglinide, a dissolution rate of the active ingredient at pH of 4.0 is less than 20% and a dissolution rate of the active ingredient at pH of 6.0 is at least 20% (this embodiment corresponds to a pH dependent release type, and to enteric coated granules C in Example 8).

With respect to the dissolution test method here, in a dissolution test method by a JP puddle method (test solution 900 ml: 50 rpm), a McIIvaine buffer solution of pH=4.0 diluted to 1/4 and containing 0.5 w/v % polysorbate 80 and a Clark-Lubs buffer solution (potassium dihydrogenphosphate-sodium hydroxide type: pH 6.0 or 6.5) are used as a test solution.

In the invention, it is further advisable that the dissolution rate of the active ingredient at pH of 6.5 is at least 60%.

The preparation having the foregoing dissolution characteristics can be obtained, as stated above, by dispersing the active ingredient for decreasing the blood glucose level in the matrix material, coating the same with the coating material, emulsifying the same with the emulsion material or microencapsulating the same with the microcapsule material.

The fifth embodiment of the invention is an antidiabetic preparation for oral administration containing nateglinide and at least one material selected from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polylactic acid derivatives, polyoxyethylene derivatives, polyvinyl pyrrolidone derivatives, polyvinyl alcohol derivatives, oils and surfactants, nateglinide being dispersed in the material or being emulsified or microencapsulated with the material.

Further, the sixth embodiment of the invention is an antidiabetic preparation for oral administration containing nateglinide and at least one material selected from the group consisting of polysaccharide derivatives (except for hydroxypropylmethyl cellulose), polyacrylic acid derivatives, polylactic acid derivatives, polyvinyl pyrrolidone derivatives polyvinyl alcohol derivatives, oils and surfactants, nateglinide being coated with the material.

In the fifth embodiment, the material is preferably selected from ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, sodium carmelose, carboxymethylethyl cellulose, cellulose acetate phthalate, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, an ethyl acrylate.methyl methacrylate.chlorotrimethyl-ammoniumethyl methacrylate copolymer, a methacrylic acid.cndot.methyl methacrylate copolymer, a methacrylic acid.cndot.ethyl acrylate copolymer, polylactic acid, a polylactic acid copolymer, polyoxyethylene, polyvinyl pyrrolidone, a 1-vinyl-2-pyrrolidone.vinyl acetate copolymer, polyvinyl alcohol, glyceride, a polyoxyethylene nonionic surfactant and a phospholipid, these being used either singly or in admixture of two or more.

Moreover, methyl cellulose and mixtures with the foregoing compounds are also preferable.

Further, in the sixth embodiment, it is preferably selected from the group consisting of ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, sodium carmelose, carboxymethylethyl cellulose, cellulose acetate phthalate, hydroxyethyl cellulose, hydroxypropyl cellulose, an ethyl acrylate.cndot.methyl methacrylate.cndot.chlorotrimethylammoniumethyl methacrylate copolymer, a methacrylic acid.cndot.methyl methacrylate copolymer, a methacrylic acid1.cndot.ethyl acrylate copolymer, polylactic acid, a polylactic acid copolymer, polyvinyl pyrrolidone, a 1-vinyl-2-pyrrolidone.cndot.vinyl acetate copolymer, polyvinyl alcohol, glyceride, a polyoxyethylene nonionic surfactant and a phospholipid, these being used either singly or in admixture of two or more. Moreover, methyl cellulose and mixtures with the foregoing compounds are also preferable.

As the material in the fifth and sixth embodiments, hydroxypropylmethyl cellulose phthalate or a methacrylic acid.ethyl acrylate copolymer is further preferable. The methacrylic acid.ethyl acrylate copolymer here is preferably a methacrylic acid copolymer LD or a dry methacrylic acid copolymer LD. With these, nateglinide can be formed into a controlled release preparation.

The preparation for oral administration in the invention includes various forms such as granules, tablets, powders, capsules and the like.

A form of sustained release of an active ingredient for decreasing a blood glucose level alone can make both a post prandial blood glucose level and a fasting blood glucose level close to normal levels. For example, it is possible in a form satisfying the fourth embodiment.

Specifically, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate and a methacrylic acid copolymer L can be used as the material of such a preparation. The use of hydroxypropylmethyl cellulose phthalate is especially preferable.

The combined use of an immediate release form and a controlled release form can decrease both a post prandial blood glucose level and a fasting blood glucose level with good accuracy to make them close to normal levels. A mixing ratio of a controlled release form of a drug for decreasing a post prandial blood glucose level to a normal level and an immediate release form of a drug for decreasing a post prandial blood glucose level to a normal level is 1:99 to 99:1, preferably 10:90 to 90:10 in terms of a weight ratio of a drug for decreasing a post prandial blood glucose level to make the same close to a normal level. A mixing method and a mixed form are not limited in the invention. A sustained release form can be used singly. The mixed form includes granules capsules, tablets, solutions and the like.

For example, when immediate release granules are mixed with controlled release granules, the form is granules. When these granules are encapsulated, the form is capsules. Tablets are obtained by tableting these mixed granules, tableting the respective granules in divided layers (multilayer tablet) or using a controlled release tablet formed of controlled release granules as an inner shell and immediate release granules as an outer shell and tableting them (dry coated tablet).

Further, in case of using the preparation of the invention, it can be administered at a dose of 1 mg to 10 g per day as an active ingredient, though depending on the ratio of the form for decreasing a post prandial blood glucose level to make it close to a normal level and the form for decreasing a fasting blood glucose level to make it close to a normal level and the extent of the pharmaceutical effect of the active ingredient(s).
 

Claim 1 of 57 Claims

1. A controlled release anti-diabetic preparation comprising nateglinide in an immediate release form and a controlled release form, wherein the controlled release form comprises nateglinide coated with a coating material, wherein the preparation is in the form of a tablet, wherein said tablet comprises a controlled release inner shell comprising nateglinide dispersed in a matrix comprising a material selected from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polyoxyethylene derivatives and polyvinyl pyrrolidone derivatives and an immediate release outer shell comprising nateglinide.

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