JPH11246417A - Pharmaceutical composition for treating diabetic nephropathy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition useful in treating diabetic nephropathy by including efonidipine hydrochloride as active ingredient. SOLUTION: This pharmaceutical composition is obtained by including pref. about 0.1-99.5 wt.% of efonidipine hydrochloride of the formula 1,4-dihydro-2,6- dimethyl-5-(5,5-dimetyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitro phenyl)-3- pyridinecarboxylic acid 2-[benzyl(phenyl)amino]ethyl ester hydrochloride-ethanol solvate (1:1)} as active ingredient. The daily clinical dose of this composition is, normally, pref. 5-80 mg/adult calculated as efonidipine hydrochloride. This composition is administered pref. to such patients as to be contraindicative or hesitate against the administration of angiotensinase inhibitory agents among others or patients suffered from hyperpotassemia.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for treating diabetic nephropathy.

[0002]

2. Description of the Related Art Diabetic nephropathy is to classify, based on the clinical course, the stages that serve as guidelines for selecting a method for treating nephropathy into first to fifth stages. Has been published by the Ministry of Health and Welfare Diabetes Investigation and Research Group (see the Ministry of Health and Welfare Diabetes Investigation and Research Group Report, p. 320, 1991). Similar classifications have been made in Europe and the US [Diabete (Diabete
s), Volume 32, Supplement No. 2, pp. 64-78, 1983
Year).

In the first stage, pre-nephropathy, and in the second stage, early nephropathy, which is diagnosed by detection of microalbuminuria,
Glycemic control therapy and antihypertensive therapy have been proposed. In the third stage, overt nephropathy, persistent proteinuria has been detected, and glycemic control therapy, antihypertensive therapy, and protein-restricted diet have been proposed. In the fourth stage of renal failure, antihypertensive therapy, low protein diet therapy and dialysis therapy have been proposed. In the fifth phase of dialysis therapy, dialysis therapy and kidney transplantation have been proposed.

The angiotensin converting enzyme inhibitor used in antihypertensive therapy has a clear urinary protein reduction effect and a suppressive effect on the progression of diabetic nephropathy from meta-analysis of diabetic nephropathy. However, a dihydropyridine calcium antagonist having a hypotensive effect has not been found to have a therapeutic effect on nephropathy. [Archives of Internal Medicin
e), volume 155, pages 1073-1080, 1996)

However, in the following cases of diabetic nephropathy, administration of an angiotensin converting enzyme inhibitor is contraindicated or hesitant. 1) When showing side effects such as dry cough. 2) When renal dysfunction is severe, filtration function is reduced, and serum creatinine level is 3 mg / dl or more [Archives of Internal Medicine (Arch
ives of Internal Medicine), 151, 2367-2372,
1991]. 3) Patients with hyperkalemia [Cardiology, Vol. 42, pp. 234-241, 1997].

[0006] Therefore, the first to fourth stages of diabetic nephropathy.
The current situation is that there is no drug that can be used consistently in each phase, and this is a problem to be solved.

[0007]

Means for Solving the Problems As a result of diligent studies on the above problems, the present inventors have been known to have a vasodilator effect and a blood pressure lowering effect by calcium antagonism (Japanese Patent Publication No. 6-99458). No., U.S. Pat.
284, EP 230944) 1,4-dihydro-2,6-dimethyl-5- (5,5-dimethyl-2-oxo-1,3,2-dioxaphospholinan-2-yl)
4- (3-nitrophenyl) -3-pyridinecarboxylic acid 2- [benzyl (phenyl) amino] ethyl ester hydrochloride-ethanol solvate (1: 1) (hereinafter referred to as efonidipine hydrochloride) increased due to diabetes It has been found that it has an effect of reducing the excreted urinary albumin excretion amount and creatinine clearance value and suppressing the progress of glomerular lesions. From this, the invention of pharmaceutical use of efonidipine hydrochloride as a therapeutic drug for diabetic nephropathy was completed.

[0008] The present invention provides a pharmaceutical composition for treating diabetic nephropathy containing efonidipine hydrochloride as an active ingredient, and in particular, is strongly contraindicated or hesitant to administer an angiotensin converting enzyme inhibitor, and has strong side effects such as empty cough and renal dysfunction. It is a pharmaceutical composition for treating diabetic nephropathy of a patient who is concerned about reduced filtration function or a patient with hyperkalemia.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The efonidipine hydrochloride of the present invention has a structural formula of the formula (I)

[0010]

Embedded image

## EQU1 ##

The compound (I) is, for example,
No. 99458, U.S. Pat. No. 4,885,284, European Patent 2
It can be easily produced by the method described in No. 30944.

Efonidipine hydrochloride has extremely low toxicity and can be applied to diabetic nephropathy in mammals such as humans, dogs, cows, horses, rabbits, mice and rats.

[0014] The pharmaceutical composition according to the present invention comprises parenteral injection (subcutaneous, intravenous, intramuscular, intraperitoneal injection), ointment, suppository, aerosol, etc., or tablet for oral administration, It can be formulated into capsules, granules, pills, syrups, solutions, emulsions, suspensions and the like.

Tablets, capsules, granules or pills for oral administration include excipients such as sucrose, lactose, glucose, starch, mannitol; binders such as hydroxypropylcellulose, syrup, acacia, gelatin, Sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone; disintegrants such as starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose,
Polyethylene glycol; prepared using a lubricant such as talc, magnesium or calcium stearate, silica; a lubricant such as sodium laurate, glycerol and the like.

[0016] In order to enhance the absorption of efonidipine hydrochloride in an oral administration preparation, a particularly preferable method for improving the wettability and dispersibility of the drug substance particles and improving the solubility of the drug substance is to amorphize the drug substance. This is a method for producing a solid dispersion by a method. The solid dispersion is a dispersion in which a drug is dispersed in a carrier in a monomolecular state, and is a dispersion in which the drug is kept in a completely amorphous state. In general, the amorphous form is in a higher energy state and is expected to have higher absorption than the crystalline form.

As a method for producing a solid dispersion of efonidipine hydrochloride, efonidipine hydrochloride and hydroxypropyl methylcellulose acetate succinate (hereinafter referred to as HPMC-A
S) is dissolved in an organic solvent, and the resulting solution is dried under reduced pressure, spray-dried, freeze-dried, or the like to remove the solvent to obtain a powdery or granular substance, or a granular excipient as a core, This is sprayed with the base material solution and coated by fluidized bed coating method, centrifugal fluidized coating method, pan coating method, etc., or the base material solution is added to the excipient,
It is known that the mixture is kneaded and then dried to obtain a granular material (Japanese Patent Application Laid-Open No. 2-49728, US Pat. No. 4,983,593, European Patent No. 344603).
issue).

Injections, solutions, emulsions, suspensions, syrups and aerosols are mainly used as solvents such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; For example, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ether of hydrogenated castor oil, lecithin; suspending agents, for example, cellulose derivatives such as carboxymethyl sodium salt, methylcellulose, tragacanth, and Arabic It is prepared using natural rubbers such as rubber; preservatives, for example, esters of paraoxybenzoic acid, benzalkonium chloride, sorbate and the like.

Ointments which are transdermal preparations are prepared using, for example, white petrolatum, liquid paraffin, higher alcohol, macrogol ointment, hydrophilic ointment, aqueous gel base and the like. Suppositories are prepared using, for example, cocoa butter, polyethylene glycol, lanolin, fatty acid triglycerides, coconut oil, polysorbate and the like.

The above pharmaceutical composition contains about 0.1 to 99.5%, preferably 0.5 to 95%, of efonidipine hydrochloride.

[0021] The pharmaceutical composition of the present invention may contain other pharmaceutical compounds.

The clinical dose varies depending on age, body weight, patient sensitivity, degree of symptoms and the like. Usually, the daily dose for human adult is 5 to 80 mg of efonidipine hydrochloride.
It is about. However, if necessary, an amount outside the above range can be used.

[0023]

EXAMPLES Next, test examples and preparation examples of the present invention will be described, but the present invention is not limited to these examples.

Test Method Eighteen eight-week-old male spontaneously hypertensive rats (SHR) and eighteen normotensive Wistar Kyoto rats (WKY) (Charles River, Japan) weighing 250-280 g were fasted overnight. After that, each 10 animals were intravenously administered a 45 mg / kg dose of streptozotocin (Sigma Chemical, USA) to induce diabetes. The remaining eight non-diabetic rats were
SHR and WKY were used as controls.

Three days after the administration of streptozotocin, efonidipine hydrochloride was orally administered at a dose of 15 mg / kg / day to 12 SHRs and 5 WKYs each having a blood glucose level of 300 mg / dl or more for 12 weeks.

Body weight, systolic blood pressure and urinary albumin excretion were measured every four weeks. Systolic blood pressure was measured by indirect tail cuff plethysmography under pre-warmed non-anesthesia. Urinary albumin excretion was measured by an enzyme-linked immunosorbent assay. All rats were sacrificed after 12 weeks. Blood glucose and creatinine clearance are 12
Measured after a week. The blood sugar level was measured by a glucose kit (Eiken Chemical Co., Tokyo) by a conventional method. The creatinine clearance value was calculated by a conventional method by measuring the serum creatinine concentration by the method of Jaffe (Eiken Chemical Co., Tokyo).

A portion of the kidney was fixed in buffered formalin (pH 7.4) for pathological examination by light microscopy.
The kidney section (3 μm) was subjected to periodic acid-Schiff staining.
50 skin glomeruli of each sample were examined. The glomerular / Bowman's capsule area ratio indicates the glomerular and Bowman's capsule area as Zeis.
s Semi-automatic image analysis system (I
BAS, Carl, Zeiss, Oberkochen, Germany).

Test Example 1 The administration of efonidipine hydrochloride did not affect the effects of diabetes-induced increase in blood sugar and weight loss.

Test Example 2 Administration of efonidipine hydrochloride was performed as shown below for diabetes S
In HR, a statistically significant reduction effect was observed on the increased creatinine clearance value. Table 1
The creatinine clearance value of each group at the end of the test is shown as the mean ± standard error.

[0030]

[Table 1]

Test Example 3 Administration of efonidipine hydrochloride statistically significantly reduced the increased urinary albumin excretion in diabetic SHR at 8 and 12 weeks. Also, the increased urinary albumin excretion of diabetic WKY was significantly reduced at 12 weeks. FIG. 1 shows the change over time in the amount of urinary albumin excreted in each group.

Test Example 4 In a pathological examination using an optical microscope, administration of efonidipine hydrochloride improved glomerular enlargement of diabetic SHR. Table 2
The ratio of glomerular / Bowman's capsule area ratio of each group at the end of the test is shown by the average value ± standard error.

[0033]

[Table 2]

Formulation Example [Solid dispersion tablet] Efonidipine hydrochloride 60 g, HPMC
Dissolve 180 g of AS and 30 g of urea in 3 L of a mixed solution of ethanol and methylene chloride {1: 1 (V / V)}, and spray this solution on 120 g of granular anhydrous calcium hydrogen phosphate using a fluidized bed coating apparatus. After drying, a granular solid dispersion was obtained. After mixing the following components in the usual way,
Solid dispersion tablet 1, containing 20 mg of active ingredient in 1 tablet
000 tablets were manufactured. Solid dispersion 130 g Microcrystalline cellulose 23.6 g Crosslinked polyvinyl pyrrolidone 12 g Light anhydrous silicic acid 0.4 g Magnesium stearate 1 g Total amount 167 g

[Tablets] After mixing the following ingredients in a conventional manner, sugar-coated tablets containing 20 mg of the active ingredient in each tablet were prepared by mixing 10.0 or 1.0 tablets.
00 tablets were manufactured. Efonidipine hydrochloride 200 g Lactose 270 g Microcrystalline cellulose 400 g Corn starch 350 g Hydroxypropyl cellulose 100 g CMC-Ca 150 g Magnesium stearate 30 g Total amount 1,500 g

[Capsules] The following ingredients were mixed in a conventional manner, and then filled into gelatin capsules to produce 10,000 capsules containing 20 mg of the active ingredient in one capsule. Efonidipine hydrochloride 200g Lactose 350g Microcrystalline cellulose 900g Magnesium stearate 50g Total amount 1,500g

[Soft capsule] After mixing the following components,
No. 3 soft gelatin capsules were filled by a conventional method, and soft capsules containing 10 mg of the active ingredient in one capsule were prepared.
00 capsules were produced. Efonidipine hydrochloride 200g PEG400 479g Saturated fatty acid triglyceride 1,310g Mentha oil 1g Polysorbate 80 10g Total amount 2,000g

[Injection] The following components were dissolved when used. Efonidipine hydrochloride 10mg Polyoxyethylene hydrogenated castor oil 50mg Distilled water for injection 10ml

[0039]

As described above, efonidipine hydrochloride reduces urinary albumin excretion increased by diabetes,
It has an effect of improving the creatinine clearance value and suppressing the progress of glomerular lesions, and is therefore effective for treating renal damage in diabetic nephropathy.

[0040]

[Brief description of the drawings]

FIG. 1 shows the time course of urinary albumin excretion in each group.

[Explanation of symbols]

WKY rats: Wistar Kyoto rats SHR rats: spontaneously hypertensive rats WKY + DM rats: diabetic WKY rats SHR + DM rats: diabetic SHR rats WKY + DM + L rats: diabetic WKY + drug-treated rats SHR + DM + L rats: diabetic SHR + drug-treated rats diabetic SHR and diabetic SHR Statistical significance for excretion (one-way analysis of variance) *: p <0.01 (significance for diabetic SHR) #: p <0.05 (significance for diabetic WKY)

Claims (3)

[Claims] 1. 1,4-dihydro-2,6-dimethyl-
5- (5,5-dimethyl-2-oxo-1,3,2-dioxaphospholinan-2-yl) -4- (3-nitrophenyl) -3-pyridinecarboxylic acid 2- [benzyl (phenyl) A pharmaceutical composition for treating diabetic nephropathy, comprising as an active ingredient amino [ethyl ester • hydrochloride-ethanol solvate (1: 1)]. 2. The pharmaceutical composition according to claim 1, which is used for treating diabetic nephropathy in a patient in whom administration of an angiotensin converting enzyme inhibitor is not preferable or in a patient with hyperkalemia. 3. An oral administration preparation solid-dispersed,
The pharmaceutical composition according to claim 1.