JP2688266B2 - Pharmaceutical composition having aldose reductase inhibitory action and good absorbability - Google Patents

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition having an aldose reductase inhibitory action and a good absorbability, and preventing various diabetic complications which are considered to be intractable diseases. Or used for treatment.

(Prior Art) With regard to diabetes, special chronic complications such as diabetic cataract, retinopathy, neuropathy and renal disorder may occur.

As part of research and development of preventive or therapeutic drugs for these diabetic complications, there is a search for aldose reductase inhibitors. This is because aldose reductase is an enzyme that reduces aldoses such as glucose and galactose in humans and other animals and converts them into the corresponding polyols sorbitol and galactitol, and the generated soribitol and galactitol are diabetic patients and diabetic patients. This is because it was known that the above-mentioned complications are expressed when accumulated in the lens, peripheral nerves, kidneys, etc. of patients with galactitolemia ("Jap. J. Opthamol." Vol. 20, p. 399 ( 1976
), “Int.Congr.Ser.Excerpta Med.” Volume 403, 594
Pp. (1977) and "Methabolism" 28, 456 (1
979).

The applicant company has also been conducting research and development on aldose reductase inhibitors, and as a result, the optically active hydantoin derivative represented by the following general formula exhibits an excellent aldose reductase inhibitory action, and therefore We obtained the knowledge that it is effective for the prevention and treatment of intractable diabetic complications, and have already filed a patent application to that effect (JP-A-61-2).
00991 and 63-57588).

{Wherein W is a halogenomethyl group, 1H-tetrazole-5-
Group, -COOR group [R represents hydrogen, an alkyl group,-(CH ₂ CH ₂
O) nCH ₃ group (n means an integer of 1-113) or a substituted phenyl group], a group [R ¹ and R ² are the same or different and each represents hydrogen, an alkyl group, a-(CH ₂ CH ₂ O) nCH ₃ group (n represents an integer of 1-113) or a substituted phenyl group, or R ¹ and R ²
May together form a 5-6 membered multiple ring together with an adjacent nitrogen atom or with another nitrogen atom or an oxygen atom], a —CH ₂ OR ₃ group (R ₃ is hydrogen or Means an alkyl group), or a group (R ⁴ and R ⁵ are the same or different and each represents hydrogen or an alkyl group), X represents an oxygen or sulfur atom, Y and Z are the same or different, and each represents a hydrogen atom, a halogen atom or an alkyl group. , Which means an alkoxy group or an alkylmercapto group} (Problems to be solved by the invention and object of the invention) Dissolution of an oral preparation obtained by attempting formulation of a drug containing the hydantoin derivative as an active ingredient by a conventional method As a result of examining the sex and administering it to humans and examining the absorption rate, it was found that the solubility was insufficient and the absorption rate was about 40%, and there was a problem in the bioavailability.

In general, improving the bioavailability and bioavailability of a drug in formulation is extremely important from the viewpoint of achieving constant expression of pharmacological action and reduction of side effects due to individual differences, and therefore vigorous research That is what is being done. However, since the bioavailability and bioavailability of a drug differ depending on the type of drug used, there are various methods for improving the bioavailability.

It is known that an ionic or nonionic surfactant is blended as a general measure for improving the solubility and the dissolution rate as the above-mentioned problems with the hydantoin derivative. However, diabetic complications are intractable diseases and continuous long-term administration is performed for healing. In such a case, when a surfactant is added to the preparation, damage to living mucous membranes is caused. Is concerned.

Therefore, a main object of the present invention is an aldose reductase inhibitory drug composition for preventing or treating diabetic complications, which comprises the hydantoin derivative as an active ingredient, and has good solubility in vivo upon administration thereof. Accordingly, the object is to provide a pharmaceutical composition having remarkably improved absorbability and bioavailability.

An additional object of the present invention is to provide the above-mentioned pharmaceutical composition capable of controlling the release of the drug hydantoin derivative.

(Means and Actions for Solving Problem and Achieving Object) According to the present invention, the general formula {Wherein W is a halogenomethyl group, 1H-tetrazole-5
-Yl group, -COOR group [R is hydrogen, an alkyl group,-(CH ₂ C
H ₂ O) nCH ₃ group (n means an integer of 1-113) or a substituted phenyl group], a group [R ¹ and R ² are the same or different and each represents hydrogen, an alkyl group, a-(CH ₂ CH ₂ O) nCH ₃ group (n represents an integer of 1-113) or a substituted phenyl group, or R ¹ and R ² together may form a 5-6 membered multiple ring together with an adjacent nitrogen atom or with another nitrogen atom or an oxygen atom], —CH ₂ OR ³ group (R ³ means hydrogen or an alkyl group), or a group (R ⁴ and R ⁵ are the same or different and each represent hydrogen or an alkyl group), X represents an oxygen or sulfur atom, Y ′ and Z ′ are the same or different, and each represents a hydrogen or halogen atom. Means a purified sucrose, sucrose, lactose, glucose, sucrose fatty acid ester, xylit, glycerin monostearate, glucosamine, dodecylamine, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose. , A polyvinylpyrrolidone and albumin are uniformly dispersed in at least one kind of polymer carrier for pharmaceutical preparations in an equimolar ratio to form a preliminary composition, and the preliminary composition is mixed with a conventional pharmaceutical carrier. And then processed by a conventional method. The main purpose of the above is achieved by that the pharmaceutical composition.

The ancillary purpose above is that the pre-composition comprises hydroxypropyl cellulose, prior to mixing with conventional pharmaceutical carriers.
Hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose,
It is achieved by mixing with a water-soluble polymer substance selected from pullulan, polyvinyl alcohol, glucomannan and gum arabic.

The above water-soluble polymer substance swells while gradually absorbing gastrointestinal juice, especially gastric juice, with administration of water, for example, when the drug substance as an active ingredient is formulated as an oral agent, and then gradually dissolves. Therefore, in order to control the release of the drug substance in the living body, at least one kind, preferably two kinds or more, in consideration of the specific gravity, swelling property, adhesive property, etc. of the water-soluble polymer substance. The above water-soluble polymer substances are selected according to the purpose and used in combination.

Among the optically active hydantoin derivatives represented by the above general formula (hereinafter sometimes referred to as “the drug substance”), a typical example of a specific compound is d-6-fluoro-2,3-dihydro- 2 ', 5'-Dioxo-spiro [4H-1-benzopyran-4,4'-imidazolidine] -2-carboxamide, d-2-chloromethyl-6-fluoro-2,3-dihydro-spiro [4H- 1-benzopyran-4,4'-imidazolidine] -2 ', 5'-dione and d-2-bromomethyl-6-fluoro-2,3-dihydro-spiro [4H-1-
Benzopyran-4,4'-imidazolidine] -2 ', 5'-
Dione can be exemplified.

The dosage form of the pharmaceutical composition according to the present invention is generally oral, and the dosage form includes, for example, tablets, granules,
Powders, capsules, etc., which are pharmaceutically acceptable excipients, lubricants, binders, flavoring agents, disintegration aids, coating agents, preservatives, coloring agents, and other preparations when formulated. Additives can be used if desired.

The dose varies depending on the type of drug substance selected, the type of target disease, the age, weight and symptoms of the patient, the estimated duration of treatment, etc. When administered for the purpose of preventive treatment, the dose is approximately 10-2000 mg / day in terms of the active drug, hydantoin derivative, and 1-3
It is preferable to administer in divided doses once / day.

(Examples) Next, the present invention will be described in more detail and specifically with reference to formulation examples and test examples.

In addition, in the following formulation examples and test examples, d-6-fluoro-2,3-
Dihydro-2 ', 5'-dioxo-spiro [4H-1-benzopyran-4,4'-imidazolidine] -2-carboxamide (hereinafter referred to as "general substance A") was exclusively adopted.
d-2-chloromethyl-6-fluoro-2,3-dihydro-spiro [4H-1-benzopyran-4,4'-imidazolidine] -2 ', 5'-dione, d-2-bromomethyl-6
Similar results are obtained with the adoption of -fluoro-2,3-dihydro-spiro [4H-1-benzopyran-4,4'-imidazolidine] -2 ', 5'-dione.

Test Example 1 Purified sucrose and albumin were adopted as the polymer carrier for the formulation, and each was mixed with the drug substance A at various ratios to give a test drug composition.

SD male rats weighing about 50 g were used as experimental animals, and the test drug composition was forcibly orally administered once daily at a dose of 0.4-5 mg / kg under the feeding of a powdered diet containing 30% galactose. Administration, the sciatic nerve of the experimental animal was excised on day 9 (1 day after the last administration of the test drug composition and the control substance containing no drug substance A) to measure the galactitol accumulated amount, The 50% inhibitory capacity of galactitol accumulation in the test drug composition-administered group (ED ₅₀ −conversion to standard A) was calculated.

The results are shown in Tables 1 and 2 below. When purified sucrose or albumin is used as the polymer molecule carrier for the formulation, the mixing ratio of these carriers to the drug substance is about 1: 1. It has been found to be suitable (homogeneous dispersions of such a ratio of drug substance and carrier are referred to as "modified drug substance").

Test Example 2 (Ratio of dissolution rate constant of drug substance A) a) Sample As a test sample, drug substance A and various polymer carriers for pharmaceuticals were mixed or dissolved in a ratio of 1: 9 or 1: 1. (Depending on the physical properties of the selected polymer carrier for formulation) were used.

b) Test method According to the 11th revision of the Japanese Pharmacopoeia, “Dissolution test method” in the general test methods.

 Test method: Paddle method, 50 rpm.

 Sample volume, liquid volume: 50 mg as drug substance A, 5 ml.

Dissolution test solution, volume: 1st solution according to the disintegration test method, pH 1.
2,900 ml.

 Sampling time: 2,4,6,8,10,20,30,60 and 120 minutes.

c) Quantitative method After the start of the test, the eluate was weighed out to 5 ml over time, the absorbance of the solution was measured at a wavelength of 282 nm, and the measured absorbance value was collated with a calibration curve prepared in advance to determine the concentration of the drug substance A. The amount of release was determined, the dissolution rate constant was determined from this by a conventional method, and the ratio of the dissolution rate constants to the drug substance A as a control was calculated.

d) Results and Discussion The results are as shown in Tables 3 and 4 below,
It has been found that the dissolution rate of drug substance A can be increased by appropriately setting the type and amount of the polymer carrier for formulation to be prescribed.

Formulation Example 1 Formulation: Raw material A 30.0 (g) Purified white sugar 30.0 Crystalline cellulose 15.6 Carboxymethyl cellulose calcium 8.4 Polyvinylpyrrolidone 4.2 Lactose 30.6 Magnesium stearate 1.2 120.0 (g) Modified raw material by uniformly dispersing raw material A in purified white sugar After that, crystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone and lactose are added and kneaded, and then magnesium stearate is added and mixed after drying, and then tableting is performed to obtain a plain tablet (each. The plain tablet contains 30 mg of drug substance A).

Film coating was applied to these plain tablets by a conventional method.

Formulation Example 2 Formulation: Drug A 30.0 (g) Crystalline cellulose 40.0 Carboxymethyl cellulose calcium 8.4 Lactose 40.4 Magnesium stearate 1.2 120.0 (g) Drug A is added to 30.0 g of crystalline cellulose and uniformly dispersed to form a modified drug substance. After that, the remaining crystalline cellulose, carboxymethylcellulose calcium and lactose were added and kneaded, and then dried and then magnesium stearate was added and mixed, and then tableting treatment was performed to obtain plain tablets (each plain tablet). The tablet contains 30 mg of drug substance A).

Film coating was applied to these plain tablets by a conventional method.

Formulation Example 3 Formulation: Drug A 30.0 (g) Glucose 30.0 Crystalline cellulose 15.6 Carboxymethyl cellulose calcium 8.4 Corn starch 12.0 Lactose 22.2 Sodium lauryl sulfate 0.6 Magnesium stearate 1.2 120.0 (g) Drug A is added to glucose and uniformly dispersed. After it becomes a modified drug substance, crystalline cellulose, carboxymethyl cellulose calcium, corn starch and lactose are added and kneaded, and then dried and then magnesium stearate is added and mixed, followed by tableting to form an uncoated tablet. Obtained (each plain tablet contained 30 mg of drug substance A).

Film coating was applied to these plain tablets by a conventional method.

Formulation Example 4 Formulation: Raw material A 30.0 (g) Purified white sugar 30.0 Crystalline cellulose 15.6 Carboxymethyl cellulose calcium 8.4 Corn starch 12.0 Lactose 23.4 Magnesium stearate 1.2 120.0 (g) Raw material A is added to purified white sugar and modified homogeneously to modify Crystalline cellulose, carboxymethylcellulose calcium, corn starch and lactose were added after kneading and kneading, and then magnesium stearate was added and mixed after drying, and then tableting was performed to obtain a plain tablet. (Each plain tablet contains 30 mg of drug substance A).

Film coating was applied to these plain tablets by a conventional method.

Comparative Formulation Example 1 Formulation: drug substance A 30.0 (g) crystalline cellulose 15.6 carboxymethyl cellulose calcium 8.4 corn starch 12.0 polyvinylpyrrolidone 4.2 lactose 48.6 magnesium stearate 1.2 120.0 (g) drug substance A crystalline cellulose, carboxymethyl cellulose calcium, corn starch, Polyvinylpyrrolidone and lactose were added and kneaded, followed by drying, then magnesium stearate was added and mixed, and then tableting was performed to obtain plain tablets (each plain tablet contains 30 mg of drug substance A). .

Film coating was applied to these plain tablets by a conventional method.

Test Example 3 (Dissolution Rate Constant Ratio of Tablets) As the test sample, the tablets obtained in Formulation Example 1-4 were used and the same as in Test Example 2 except that dissolution of the tablet A according to Comparative Formulation Example 1 into the drug substance A was performed. The rate constant ratio was calculated.

The results are shown in Table 5 below, and it was found that the dissolution rate can be adjusted by appropriately setting the type and amount of the polymer carrier for formulation.

Test Example 4 (concentration of drug substance A in blood) a) Sample As a test sample, tablets (film-coated tablets) according to Formulation Example 4 and Comparative Formulation Example 1 were used.

b) Test method Six healthy volunteers were divided into two groups, one group was orally administered with the tablet according to Formulation Example 4 and the other group was orally administered with the tablet according to Comparative Formulation Example 1, and blood was collected over time. The blood was centrifuged to obtain plasma, which was acidified with hydrochloric acid and fractionated by thin-layer chromatography, and then subjected to high performance liquid chromatography, and then the absorbance was measured at a wavelength of 284 nm. The blood concentration value of the drug substance A was obtained by collating the measured absorbance values with, and then the average value of the three persons was calculated.

c) Results and discussion The results are shown in Fig. 1, and the area under the curve (AU
Each Formulation Example C _0-12 h) is 4: 1020ng · hr / ml Comparative Formulation Example 1: 612ng · hr / ml at a in the pharmaceutical compositions according to the present invention (Formulation Example 4 bulk and pharmaceutical polymeric carrier and Once the drug substance is made into a modified drug substance,
A pharmaceutical composition prepared according to a conventional method except that this modified drug substance is used is a pharmaceutical composition according to a conventional method (Comparative Formulation Example 1-The drug substance is not modified into a modified drug substance, and various components are added and blended one after another. It was found that a high blood concentration was maintained and its bioavailability reached about twice as high as that of the compound prepared in the above).

Formulation Example 5 (capsule) Formulation: Drug substance 30.0 (g) Glucose 30.0 Crystalline cellulose 15.6 Carboxymethyl cellulose calcium 8.4 Corn starch 12.0 Lactose 23.4 Magnesium stearate 0.6 120.0 (g) Drug substance A is moistened, dissolved, and evenly dispersed in glucose. Lactose, crystalline cellulose, carboxymethyl cellulose calcium, and corn starch powder are added and kneaded after being made into a modified drug substance, then dried and then magnesium stearate is added and mixed, and this mixed powder is mixed. The gelatin capsules were filled to obtain capsules (each capsule contains 30 mg of the drug substance A).

In addition, the dissolution rate constant ratio of this capsule is as shown in Comparative Preparation Example 1
Was 3.54 for the film-coated tablets according to.

Formulation Example 6 (tablets) Formulation: drug substance A 30.0 (g) glucose 30.0 crystalline cellulose 15.6 carboxymethyl cellulose calcium 8.4 corn starch 12.0 lactose 23.4 magnesium stearate 0.6 120.0 (g) drug substance A is added to glucose and dispersed evenly After it becomes a modified drug substance, crystalline cellulose, carboxymethyl cellulose calcium, corn starch and lactose are added and kneaded, and then dried and then magnesium stearate is added and mixed, followed by tableting to form an uncoated tablet. Obtained (each plain tablet contained 30 mg of drug substance A).

Film coating was applied to these plain tablets by a conventional method.

Formulation Example 7 (tablets) Formulation: drug substance A 30.0 (g) xylit 30.0 carboxymethyl cellulose calcium 8.4 crystalline cellulose 15.6 corn starch 12.0 lactose 23.4 magnesium stearate 0.6 120.0 (g) drug substance A is moistened, dissolved and uniformly dispersed in xylit. Crystalline cellulose, carboxymethyl cellulose calcium, corn starch and lactose are added after kneading to form a modified drug substance, and then kneaded, followed by drying and then addition and mixing of magnesium stearate, followed by tableting treatment to obtain uncoated tablets. Was obtained (each plain tablet contains 30 mg of drug substance A).

Film coating was applied to these plain tablets by a conventional method.

Formulation Example 8 (tablets) Formulation: drug substance A 30.0 (g) stearyl alcohol 30.0 crystalline cellulose 15.6 carboxymethyl cellulose calcium 8.4 corn starch 12.0 lactose 23.4 magnesium stearate 0.6 120.0 (g) drug substance A in stearyl alcohol wet, dissolved, uniform After being dispersed into a modified drug substance, crystalline cellulose, carboxymethyl cellulose calcium, corn starch and lactose are added and kneaded, and then dried and then magnesium stearate is added and mixed, followed by tableting treatment. Uncoated tablets were obtained (each uncoated tablet contained 30 mg of drug substance A).

Film coating was applied to these plain tablets by a conventional method.

Formulation Example 9 (capsule) Formulation: drug substance A 30.0 (g) glycerin monostearate 30.0 hydroxypropylmethyl cellulose 30.0 lactose 29.4 magnesium stearate 0.6 120.0 (g) drug substance A is added to glycerin monostearate and dispersed evenly. Hydroxypropyl methylcellulose and lactose are added after the modified raw material has been prepared, and the mixture is kneaded to further uniformly disperse, then dried, and magnesium stearate is added thereto and mixed, and the mixed powder is put into a gelatin capsule. Filled to obtain capsules (each capsule contains
Contains 30 mg).

Formulation Example 10 (capsule) Formulation: Drug substance A 30.0 (g) Hydroxypropyl methylcellulose 30.0 Lactose 59.4 Magnesium stearate 0.6 120.0 (g) Drug substance A is added to hydroxypropyl methylcellulose and uniformly dispersed to form a modified drug substance. After that, lactose was added, and the mixture was kneaded to further uniformly disperse, then dried, and magnesium stearate was added thereto and mixed, and the mixed powder was filled in a gelatin capsule to obtain a capsule (each). The capsule contains 30 mg of drug substance A).

Formulation Example 11 (capsule) Prescription: Drug substance A 30.0 (g) Xylit 30.0 Carboxymethyl cellulose 30.0 Lactose 29.4 Magnesium stearate 0.6 120.0 (g) Drug substance A is moistened, dissolved and uniformly dispersed in xylit to form a modified drug substance. After that, add carboxymethylcellulose and lactose, knead and further uniformly disperse, then dry, add magnesium stearate to this and mix, and fill this mixed powder into a gelatin capsule to obtain a capsule. (Each capsule contains 30 mg of drug substance A).

Formulation Example 12 (capsule) Formulation: Drug substance A 30.0 (g) Glucose 30.0 Hydroxypropylmethylcellulose 30.0 Lactose 29.4 Magnesium stearate 0.6 120.0 (g) Drug substance A is added to glucose and uniformly dispersed to form a modified drug substance. After that, add hydroxypropylmethylcellulose and lactose, knead and further uniformly disperse, then dry, add magnesium stearate to this and mix, and fill this mixed powder into a gelatin capsule to form a capsule. Obtained (each capsule contains 30 mg of drug substance A).

Formulation Example 13 (capsule) Formulation: drug substance A 30.0 (g) glucosamine 30.0 pullulan 30.0 lactose 29.4 magnesium stearate 0.6 120.0 (g) Drug substance A was added to glucosamine and uniformly dispersed to obtain a modified drug substance. After that, pullulan and lactose were added, and the mixture was kneaded to further uniformly disperse, then dried, magnesium stearate was added thereto and mixed, and the mixed powder was filled in a gelatin capsule to obtain a capsule (each). The capsule contains 30 mg of drug substance A).

Formulation Example 14 (capsule) Formulation: drug substance A 30.0 (g) dodecylamine 30.0 pullulan 30.0 crystalline cellulose 15.0 lactose 14.4 magnesium stearate 0.6 120.0 (g) drug substance A is moistened, dissolved and uniformly dispersed in dodecylamine. After it becomes a chromogen, pullulan, crystalline cellulose and lactose are added, kneaded to further uniformly disperse, then dried, magnesium stearate is added to this and mixed, and this mixed powder is filled into a gelatin capsule. To obtain capsules (each capsule contains 30 mg of drug substance A).

Comparative formulation example 2 (tablets) Formulation: drug substance A 30.0 (g) hydroxypropyl cellulose 3.0 carboxymethyl cellulose calcium 10.0 crystalline cellulose 6.4 lactose 70.0 magnesium stearate 0.6 120.0 (g) drug substance A to crystalline drug A, carboxymethyl cellulose calcium, hydroxypropyl Cellulose and lactose were added and kneaded, followed by drying, then magnesium stearate was added and mixed, and then tableting was performed to obtain plain tablets (each plain tablet contains 30 mg of drug substance A).

Film coating was applied to these plain tablets by a conventional method.

Test Example 5 (Dissolution test of drug substance A) a) Sample As test samples, tablets and capsules according to Formulation Examples 6, 9 and 10 and tablets according to Comparative Formulation Example 2 were used.

b) Test method According to the 11th revision of the Japanese Pharmacopoeia, “Dissolution test method” in the general test methods.

Test method: Paddle method, 50 rpm.

Sample volume, liquid volume: 50 mg as drug substance A, 5 ml.

Dissolution test solution, volume: 1st solution according to the disintegration test method, pH 1.2, 9
00ml.

Sampling time: 2,4,6,8,10,20,30,60,70,80 and 90
Minutes.

c) Quantitative method After the start of the test, the eluate was weighed out to 5 ml over time, the absorbance of the solution was measured at a wavelength of 282 nm, and the measured absorbance value was collated with a calibration curve prepared in advance to determine the concentration of the drug substance A. The amount released was determined and the dissolution rate of drug substance A from each formulation was calculated.

d) Results and Discussion The results are shown in FIG. 2, in which the pharmaceutical composition according to the present invention (according to Formulation Examples 9 and 10) is compared with the pharmaceutical composition according to the conventional method (according to Comparative Formulation Example 2). Moreover, since the drug substance A is slowly eluted, it tends to be gradually absorbed in the digestive tract as compared with the pharmaceutical composition according to Comparative Example 2. on the other hand,
Among the pharmaceutical compositions according to the present invention, those according to Formulation Example 6 are
When compared with the pharmaceutical composition according to Comparative Example 2, the dissolution of the drug substance A is rapid, and rapid effect is expected.

Therefore, by combining these, it becomes possible to bring about fast-acting and sustained drug efficacy.

Test Example 6 (Absorption Test by Oral Administration) a) Sample As test samples, tablets and capsules according to Formulation Examples 6, 9 and 10 and tablets according to Comparative Formulation Example 2 were used.

b) Test method Beagle dogs fasted overnight (3 dogs in each group, weight approximately)
The blood concentration of drug substance A was determined in the same manner as in Test Example 4 except that 10 kg) was used as an experimental animal.

c) Results and Discussion The results are as shown in Table 6 and FIG. 3 below,
It has been found that the pharmaceutical composition according to the present invention can maintain a high blood concentration when compared with the conventional pharmaceutical composition, and the bioavailability is approximately doubled.

(Effects of the Invention) In the pharmaceutical composition according to the present invention, the optically active hydantoin derivative (original substance), which is the active ingredient, is uniformly dispersed in the polymer carrier for pharmaceutical preparation, and as a result, the above-mentioned pharmaceutical composition is not When administered to, the drug substance is efficiently absorbed and the bioavailability is improved. In the pharmaceutical composition according to the present invention, when a water-soluble polymer substance is further added as a drug release controlling carrier, the drug substance, which is a drug substance, can be provided with a rapid-acting property and a sustained pharmacological effect.

The pharmaceutical composition according to the present invention is used for the treatment or prevention of diabetic complications, which are considered to be intractable diseases. Therefore, continuous administration for a relatively long period of time is envisaged. The high bioavailability (about twice as much as that of the conventional formulation) means that stable pharmacological action can be expected and, along with this, suppression of side effects due to overdose can be expected. .

[Brief description of the drawings]

FIG. 1 is a graph showing the results of investigating the change in blood concentration of the drug by orally administering the drug composition of the present invention according to Formulation Example 4 and the drug composition according to Comparative Formulation Example 1 to a healthy person, and FIG. FIG. 3 is a graph showing changes over time in the dissolution rate of the drug from the pharmaceutical composition according to the present invention according to Formulation Examples 6, 9 and 10 and the pharmaceutical composition according to Comparative Formulation Example 2, FIG.
2 is a graph showing the results of examining changes in blood concentration of a drug by orally administering the drug composition according to the present invention of 10 and the drug composition of Comparative Formulation Example 2 to beagle dogs.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area A61K 47/38 A61K 47/38 E 47/40 47/40 E 47/42 47/42 E (72 ) Inventor Yoshiya Kondo 35, Higashi-Tobori-cho, Higashi-ku, Nagoya, Aichi Prefecture, Sanwa Chemical Research Institute (72) Inventor, Tsuneaki Inoue, 35, Higashi-Tobori-cho, Higashi-ku, Nagoya, Aichi Prefecture, Sanwa Chemical Research Institute (72) ) Inventor Akiharu Inoue, Sanwa Chemical Research Institute, 35 Higashi Sotobori-cho, Higashi-ku, Nagoya, Aichi Prefecture (72) Inventor Kiichi Sawai, 35 East Higashi-Obori-cho, Higashi-ku, Nagoya, Aichi Prefecture Sanwa Chemical Research Institute (56) ) Reference JP 61-200991 (JP, A) JP 63-57588 (JP, A)

Claims (3)

(57) [Claims] (1) General formula {Wherein W is a halogenomethyl group, 1H-tetrazole-5-
Group, -COOR group [R represents hydrogen, an alkyl group,-(CH ₂ CH ₂
O) nCH ₃ group (n means an integer of 1-113) or a substituted phenyl group], a group [R ¹ and R ² are the same or different and each represents hydrogen, an alkyl group, a-(CH ₂ CH ₂ O) nCH ₃ group (n represents an integer of 1-113) or a substituted phenyl group, or R ¹ and R ²
May together form a 5-6 membered multiple ring together with an adjacent nitrogen atom or with another nitrogen atom or an oxygen atom], a —CH ₂ OR ³ group (R ³ is hydrogen or Means an alkyl group), or a group (R ⁴ and R ⁵ are the same or different and each represents hydrogen or an alkyl group), X represents an oxygen or sulfur atom, Y ′ and Z ′ are the same or different, and each represents a hydrogen atom or a halogen atom. Means a purified sucrose, sucrose, lactose, glucose, cyclodextrin, sucrose fatty acid ester, xylit, glycerin monostearate, stearyl alcohol, glucosamine, dodecylamine, crystalline cellulose, hydroxy. A preparative composition is prepared by evenly dispersing the same in an equimolar ratio in at least one kind of polymer carrier for formulation selected from propylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and albumin. Mixed with a carrier for the formulation of Ide, characterized in that those treated by a conventional method, and the absorption of good pharmaceutical composition having aldose reductase inhibiting activity. 2. Prior to mixing with a conventional pharmaceutical carrier, the preliminary composition comprises hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, pullulan,
The aldose reductase according to claim 1, which is mixed with a water-soluble polymer selected from polyvinyl alcohol, glucomannan and gum arabic to control the release of the hydantoin derivative in vivo. A pharmaceutical composition having an inhibitory action and good absorbability. 3. A hydantoin derivative is a) d-6-fluoro-2,3-dihydro-2 ', 5'-.
Dioxo-spiro [4H-1-benzopyran-4,4'-imidazolidine] -2-carboxamide, b) d-2-chloromethyl-6-fluoro-2,3-dihydro-spiro [4H-1-benzopyran- 4,4'-Imidazolidine] -2 ', 5'-dione, and c) d-2-bromomethyl-6-fluoro-2,3-dihydro-spiro [4H-1-benzopyran-4,4'-imidazo A drug selected from the group consisting of lysine] -2 ', 5'-dione and having an aldose reductase inhibitory action and good absorbability according to claim (1) or (2). Composition.