JP2000247883A - Liquid agent for internal use containing dihydropyridine- based compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a liquid agent for internal use containing a dihydropyridine- based compound, easy for taking even by a patient who has difficulty in swallowing tablets, etc., and excellent in preservation stability. SOLUTION: This liquid agent containing a dihydropyridine-based compound, a polyethylene glycol and/or an alcohol has excellent effect in the improvements of solubility of the medicine, stability and taste of the agent, and by adding tocopherol thereto, the stability of the dihydropyridine-based compound in the aqueous polyethylene glycol solution is increased.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a liquid medicine for internal use,
More specifically, the present invention relates to a liquid medicine for internal use containing a dihydropyridine compound, which is used in the medical field.

More specifically, the present invention relates to providing a liquid medicine for internal use which contains a dihydropyridine compound (eg, a dihydropyridine calcium antagonist) and is easy to take even for patients who have difficulty swallowing tablets and the like. It is.

[0003]

2. Description of the Related Art Among dihydropyridine-based compounds such as dihydropyridine-based calcium antagonists, there are some compounds that are hardly soluble in water, such as nilvadipine, and when a liquid preparation for internal use containing them is prepared, the drug may be dissolved. Due to problems in the properties and stability in solution, they are usually marketed as tablets.

[0004]

[Problems to be solved by the invention] For example, in elderly people,
Easy to take even for patients who have difficulty swallowing tablets,
Also, there has been a demand for a liquid preparation for internal use containing a dihydropyridine compound having excellent storage stability.

[0005]

Means for Solving the Problems The inventors of the present invention provide:
Among dihydropyridine compounds, especially dihydropyridine calcium antagonists, there are compounds that are poorly soluble in water such as nilvadipine. 1) The addition of polyethylene glycol and / or alcohol exhibits an excellent effect of improving the solubility and stability of the drug. 2) The further addition of propylene glycol and / or glycerin further improves the solubility of the drug. And that it also has an excellent effect in improving the taste of the liquid preparation for internal use. 3) By adding tocopherol, the stability of the dydropyridine compound in a solution containing polyethylene glycol can be dramatically improved. And found this invention Form was. There are three main issues in designing a liquid preparation for internal use of a dihydropyridine compound, namely, improvement of solubility, improvement of stability, and improvement of taste. It is considered that the smaller the amount of liquid, the easier to take. In addition, among the dihydropyridine-based compounds, it is considered difficult to prepare an aqueous solution because some compounds have extremely low solubility in water.However, in order to develop a liquid medicine for internal use that is easy to take, use an aqueous solution. It is desirable. Hereinafter, of the dihydropyridine-based compounds, nilvadipine, which is a dihydropyridine-based calcium antagonist, will be described as an example of a compound that is hardly soluble in water, but the present invention will be described. Nilvadipine is hardly soluble in water, but relatively well soluble in non-aqueous solvents such as ethanol (hereinafter referred to as EtOH), polyethylene glycol (hereinafter referred to as PEG), and propylene glycol (hereinafter referred to as PG). I do. In addition, in the case of nilvadipine, when using 2 mg of the drug, the liquid volume is 3 m in consideration of ease of taking.
The study was carried out with the goal of using 1 (0.667 mg / ml) of liquid for internal use. (1) Examination in PEG / water mixed solvent system From the solubility of nilvadipine, 60% PEG (PEG400
The use of nilvadipine in an aqueous solution was studied. (A) The stability of the solution varies depending on the lot of PEG400, but even in the case of poor stability, the stability was further improved by replacing the head space of the storage container with nitrogen (Table 1). Therefore, it was considered that oxygen was involved in the stability of the drug when a PEG solution was used.

[0006]

[Table 1] Table 1 The presence or absence of nitrogen substitution and 70 ° C of nilvadipine
9 days stability

Drug concentration: 0.667 mg / ml (60
% PEG aqueous solution)-Fill ampoule with liquid-n. d. : Not detected The structures of nilvadipine and related substances are shown below.

[0008]

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[0009]

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(B) The azoxybenzene has a structure in which two molecules of nilvadipine are reductively condensed, and PEG4
It was presumed that the reaction mechanism was such that 00 was oxidized to generate a decomposed product having a reducing property, and this decomposed product reduced and condensed nilvadipine. (2) Examination of PEG / alcohol / water mixed solvent system EtOH / PEG obtained by adding EtOH as an alcohol to a solvent
As a result of studying a three-component formulation of 400 water, the following was found. (A) When PEG400 was reduced and EtOH was increased, the stability of nilvadipine tended to be improved (Table 2).

[0011]

Table 2 Solvent composition and stability of nilvadipine at 70 ° C for 9 days

-Drug concentration: 1 mg / ml-Fill the ampule with the liquid-No nitrogen replacement (b) Two lots of PEG400 (Lot A and B) showing a difference in the stability of nilvadipine in a 60% PEG400 aqueous solution The stabilizing effects of nitrogen substitution and addition of tocopherol were investigated. When tocopherol was not added, the formation of an azoxybenzene compound could not be sufficiently suppressed even with nitrogen substitution, whereas when 0.1% of tocopherol (using α-tocopherol) was added, it was bad. The production of azoxybenzenes was suppressed even when nitrogen was not replaced by using lot B that showed a stabilizing effect (Table 3).

[0013]

Table 3 PEG400 / EtOH / water-based formulation 7
Effect of Nitrogen Substitution and Addition of α-Tocopherol on the Stability of Nilvadipine at 0 ° C. for 9 Days

[0014]

Drug concentration: 0.667 mg / ml (Et
(OH / PEG400 / water = 20/35/45)-Fill the ampule with the liquid agent. (3) Examination with EtOH / PEG400 / PG / glycerin / surfactant / water mixed solvent system Taste with irritation when administered orally And so on, E
An oral solution that does not use tOH was considered optimal,
Considering the production of liquid preparations, it was considered necessary to use a small amount of EtOH in the dissolution step of nilvadipine, so EtOH was reduced to 5%
Alternatively, the formulation was studied in the direction of reducing the amount to a very small amount of about 10%. If the amount of EtOH as a solvent is reduced and the reduced amount is supplemented with water, the solubility of nilvadipine decreases. In order to prevent this, a formulation containing PG, a non-aqueous solvent, glycerin, and HCO-60, a surfactant, was studied. First, the solubility of nilvadipine in an EtOH / PEG400 / PG / glycerin / HCO-60 aqueous system was measured. The solvent composition was such that HCO-60 was fixed at 5%, glycerin was fixed at 30%, PEG400 and PG were the same amount, and 1%.
5, 20, and 25% each. The solubility was measured by setting the level of EtOH to 0 (control), 5 and 10% (v / v) (Tables 4 and 5). The solubility decreased as the ratio of EtOH decreased to 10% and 5%, but the solubility increased as the ratio of PEG400 to PG increased. The compositions were selected from the compositions having the required solubility (0.667 mg / ml), and 0.1% α-tocopherol was added to these compositions (Tables 6 and 7). The stability at 70 ° C. for 9 days was evaluated. In any of the formulations, the residual ratio exceeded 95%, and no azoxybenzene was formed, and the stability was good (Tables 8 and 9).
Furthermore, by adding PG and glycerin, EtOH and PE
The irritation and astringency derived from G400 were alleviated, and the liquid preparation for internal use was easy to take.

[0016]

Table 4 Solvent composition (%) and solubility of nilvadipine (mg / ml, 25 ° C)

[0017]

[Table 5] Table 5

[0018]

Table 6 Stability at 70 ° C for 9 days (EtOH 5%)

[0019]

[Table 7] Table 7

-Drug concentration: 0.667mg / ml-Fill the ampule with liquid-No nitrogen replacement

[0021]

[Table 8] Table 8 Results of stability evaluation at 70 ° C for 9 days

[0022]

[Table 9] Table 9

Hereinafter, preferred examples and amounts of each component used in the liquid preparation for internal use according to the present invention will be described.
For glycerin, polyoxyethylene hydrogenated castor oil and tocopherol, the values are in W / V%, and for alcohols, the values are in V / V%. Examples of the dihydropyridine-based compound used in the present invention include dihydropyridine-based calcium antagonists such as nilvadipine, amlodipine, nifedipine, benidipine, nicardipine, manidipine, nitrendipine, nisoldipine, among which nilvadipine is the most preferable, and usually a total solution. Is used at a ratio of 0.001% to 1%, more preferably 0.01% to 0.1%. The polyethylene glycol used in the present invention includes PEG1
00, PEG200, PEG300, PEG400, P
EG600, PEG1000, PEG4000, PEG
6000 and the like, preferably PEG100,
PEG200, PEG300, PEG400, PEG6
00, among which PEG 400 is more preferred, and usually 5% to 70%, more preferably 10% to 30%, based on the total amount of the solution.
Used in proportions. Examples of the alcohol used in the present invention include ethanol, propanol, isopropanol and the like. Ethanol is most preferred, and usually 1% to 50%, more preferably 3% to 2%, based on the total amount of the solution.
Used at 0%. Propylene glycol used in the present invention is usually 1% to 50% of the total liquid,
More preferably, it is used at a ratio of 5% to 30%. Glycerin used in the present invention is usually 1 to all liquids.
% To 50%, more preferably 5% to 30%. Surfactants used in the present invention include polyoxyethylene hydrogenated castor oil (HCO-60, etc.), cremophor EL, polysorbate (polysorbate 8)
0) and the like, preferably polyoxyethylene hydrogenated castor oil, more preferably HCO-60, and usually 0.5% to 20%, more preferably 3% to 10%, based on the total amount of the solution. Used in percentages. As the tocopherol used in the present invention, α-, β-, γ-,
Although δ-tocopherol and the like can be mentioned, α-tocopherol is more preferable, and usually 0.01% to
It is used at a rate of 1%, more preferably 0.03% to 0.3%. When polyethylene glycol and alcohol are contained, usually 5% to
70% and 1% to 50%, more preferably 10% to 3
It is used at 0% and at a rate of 3% to 20%. When polyethylene glycol, alcohol, propylene glycol and glycerin are contained, they are usually 5% to 70%, 1% to 50%, 1% to 50%, respectively, based on the total amount of the solution.
And 1% to 50%, more preferably 10% to 30%,
It is used in proportions of 3% to 20%, 5% to 30% and 5% to 30%. Polyethylene glycol, alcohol,
When propylene glycol, glycerin and a surfactant are contained, usually 5% to
70%, 1% to 50%, 1% to 50%, 1% to 50% and 0.5% to 20%, more preferably 10% to 30%
%, 3% to 20%, 5% to 30%, 5% to 30% and 3% to 10%. When polyethylene glycol, alcohol, propylene glycol, glycerin, a surfactant and tocopherol are contained, they are usually 5% to 70%, 1% to
50%, 1% to 50%, 1% to 50%, 0.5% to 20
% And 0.01% to 1%, more preferably 10% to 3%
0%, 3% to 20%, 5% to 30%, 5% to 30%, 3
% To 10% and 0.03% to 0.3%. The liquid medicine for internal use of the present invention may be unstable to light. In such a case, it is desirable to store the liquid medicine for internal use under light shielding. The liquid preparation for internal use according to the present invention includes sweeteners used in ordinary liquid preparations for internal use, such as sugars such as sucrose, glucose, fructose, maltose and lactose, sugar alcohols such as D-sorbitol, mannitol and xylitol, and glycyrrhizic acid. Or a salt thereof (eg, sodium salt, dipotassium salt, ammonium salt, etc.), saccharin or a salt thereof (eg, sodium salt, potassium salt, etc.)
And the like can be further added. The liquid preparation for internal use according to the present invention includes, in addition to the above, for example,
Organic agents such as tartaric acid, malic acid and lactic acid or alkali metal salts thereof, etc., flavors (natural or synthetic flavors such as strawberry flavor, orange flavor, vanilla flavor, l-menthol and coloring agents (synthesis of yellow No. 5, etc.) Pigments, natural pigments such as caramel, etc.), preservatives (eg, benzoic acid, sodium benzoate,
Additives commonly used in internal liquids such as parabens, thickeners (methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.), solubilizers, stabilizers and the like may be added as appropriate. In particular, by adding l-menthol, a liquid medicine for internal use having a refreshing feeling and easy to take can be obtained. The liquid medicine for internal use of the present invention can be produced by a conventional method, and an example thereof is as follows. An ethanol solution (concentrated nivazil solution) containing nilvadipine and α-tocopherol is prepared. A separately prepared solvent mixture (a mixture of PEG400, propylene glycol, glycerin, HCO-60, and purified water) and a concentrated nivazil solution are mixed, and the whole amount is adjusted with purified water to prepare a liquid preparation for oral use of nivazil.

[0024]

The following tests were conducted to show the usefulness of the liquid preparation for internal use of the present invention. (1) Oral Absorption Test Using Dog (a) Oral Absorption of Formulation A bioavailability (hereinafter referred to as BA) test was performed using a dog with the formulation. The test was performed with 5 animals per group. The day before administration was fasted (water was free). After administration of 3 ml of the formulation by a sonde, 30 ml of water was forcibly administered by the sonde. Blood was collected at 10, 20, 30 minutes, 1, 1.5, 2, 4, 6, and 8 hours after administration. Eight hours after administration, blood was collected and fed a normal diet. The BA parameters are shown in Table 10.

[0025]

Table 10 BA parameters (mean ± standard deviation) of BA test (formulation)

· Hr: time · Cmax: maximum plasma concentration · Tmax: time to reach maximum plasma concentration · AUC: area under the plasma concentration-time curve Also, although nilvadipine liquid preparation is unstable to light, Sufficient stability was obtained by shading. As a result of the above study, it was possible to design a formulation of nilvadipine oral solution having the same immediate effect and absorption as tablets, excellent solubility and stability, and improved taste.

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which, of course, are merely examples. Example 1 Method for Preparing Liquid Preparation for Oral Administration of Nivazil

[0027]

Table 11 Formulations of Examples

[0028]

Table 12 Formulation of concentrated nivazil solution

1. Preparation of concentrated nivazil solution (10 mL) Weigh 200 mg of α-tocopherol and add about 7 mL of ethanol
Dissolve in 133.3 mg of nilvadipine is weighed and dissolved. The total volume is made up to 10 mL with ethanol to make a concentrated nivazil solution. 2. Preparation of solvent mixture Mix 30 mL of purified water and 20.0 g of propylene glycol. HCO-60 pre-heated and melted (50 ° C or higher)
Dissolve 5.0 g of the mixture. Is mixed with 20.0 g of PEG400 and 15.0 g of glycerin. Mix 5 mL of concentrated Nivazil solution with this mixture. The total volume is adjusted to 100 mL with purified water, and the mixture is uniformly mixed to prepare a filling liquid for a liquid preparation for oral administration of Nivazil.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA12 BB01 CC11 CC23 DD37 DD38 EE23 EE53 4C086 AA01 BC16 MA03 MA05 MA17 MA52 NA02 NA03 NA10 ZA39 ZA42 ZC50

Claims (10)

[Claims] A liquid preparation for internal use containing a dihydropyridine compound, polyethylene glycol and / or alcohol. 2. The liquid preparation for internal use according to claim 1, further comprising propylene glycol and / or glycerin as an essential component. 3. The liquid preparation for internal use according to claim 2, further comprising a surfactant. 4. The dihydropyridine compound is nilvadipine, and the alcohol is ethanol.
The liquid preparation for internal use according to 1. 5. The liquid preparation according to claim 3, wherein the dihydropyridine compound is nilvadipine, the alcohol is ethanol, and the surfactant is polyoxyethylene hydrogenated castor oil. 6. A liquid preparation for internal use containing a dihydropyridine compound and tocopherol as essential components. 7. The liquid preparation for internal use according to claim 6, further comprising polyethylene glycol. 8. The liquid preparation for oral administration according to claim 6, wherein the dihydropyridine compound is nilvadipine, and the tocopherol is α-tocopherol. 9. A method for stabilizing a liquid medicine for internal use containing a dihydropyridine compound and polyethylene glycol, which is stored under anaerobic conditions or tocopherol is added. 10. A method for stabilizing a liquid preparation for internal use containing nilvadipine and polyethylene glycol, which comprises adding tocopherol.