JP6067399B2 - Pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition suitable for a solubilizer-type ointment.

In the treatment of fungal diseases such as athlete's foot, an ointment dosage form in which the active ingredient is not diffused by the exudate and is not irritating to the wound because the affected part is damaged and the body fluid exudes is useful. It is thought that there is. For ointment dosage forms, drugs dispersed directly in hydrophilic ointment bases such as polyethylene glycol and hydrophobic ointment bases such as petrolatum, and drugs that dissolve well into drugs that are familiar with the ointment base A solubilizer form, a droplet dispersion form in which droplets in which a drug is dissolved are dispersed, and the like are known. In particular, hydrophobic droplet dispersion forms in which a solution in which a drug is dissolved in a polyhydric alcohol or the like is dispersed as a droplet in a hydrophobic ointment base such as petrolatum, has a wide range of applications. (For example, Patent Document 1 and Patent Document 2)
See). In particular, the ointment dosage form is an indispensable item because it has an advantage that it can be administered to the heel part without irritation in the antifungal pharmaceutical composition.

On the other hand, in the pharmaceutical composition, it is also important to design the active ingredient to maintain an effective concentration for a long time in the stratum corneum that is a lesion (for example, see Patent Document 3). The maintenance of effective concentration has been a major issue. This means that it is necessary to increase the drug concentration in the stratum corneum immediately after administration in an ointment preparation that tends to decrease in the stratum corneum with a monotonically decreasing curve. It can be said that it was desired.

(However, in the formula, R ₁ and R ₂ each independently represents a hydrogen atom or a halogen atom.)

Special table 2007-505107 gazette JP 2005-528425 Gazette JP 2002-265388 A

  The present invention has been made under such circumstances, and an object of the present invention is to provide a pharmaceutical composition in the form of an ointment in which the drug concentration in the stratum corneum is improved.

In view of such circumstances, the present inventors have taken antifungal agents as examples, and in the ointment preparations, the concentration of the compound represented by the general formula (1) and / or a salt thereof, which is an antifungal agent, is increased. As a result of intensive research efforts to find a preparation having an action to maintain in the stratum corneum for a long time, a hydrophobic ointment base ointment containing a diester carbonate in a hydrophobic ointment base The inventors have found that such features can be seen, and have completed the invention. That is, the present invention is as follows.

<1> A pharmaceutical composition comprising 1) a hydrophobic ointment base, 2) a compound represented by the following general formula (1) and / or a salt thereof, and 3) a carbonic acid diester: .

(However, in the formula, R ₁ and R ₂ each independently represents a hydrogen atom or a halogen atom.)
<2> The pharmaceutical composition according to <1>, wherein the compound represented by the general formula (1) is luliconazole.
<3> The pharmaceutical composition according to <1> or <2>, wherein the carbonic acid diester is propylene carbonate.
<4> The pharmaceutical composition according to any one of <1> to <3>, wherein the pharmaceutical composition belongs to an oily ointment according to the 16th revised Japanese pharmacopoeia.

  ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition of the ointment form which improved the chemical | medical agent density | concentration in a stratum corneum can be provided.

<1> Hydrophobic ointment base which is an essential component of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is an ointment based on a hydrophobic ointment base. Here, the hydrophobic ointment base is a group of compositions that determine the properties of the ointment, and means those that are incompatible with water. Specifically, petrolatum, silicone elastomer, mole, carnauba wax , Beeswax, gay wax, candelilla wax, liquid paraffin, squalane, fatty acid ester of glycerin, fatty acid ester of higher alcohol, and the like are mixed to prepare a paste. A preferred base is petrolatum. As a particularly preferred base, liquid hydrocarbons such as liquid paraffin and squalane, solid fats such as mole, geiwa, carnauba wax, beeswax, and candelilla wax were appropriately added to 80% by mass or more of petrolatum to prepare a paste. Is. The petrolatum may be ordinary petrolatum or purified petrolatum such as sun white petrolatum. In mixing the hydrophobic ointment base, it is preferable that the components are heated, and after all the components become liquid, they are stirred and cooled to obtain a paste-like composition having a uniform component. The base is preferably 80 to 98% by mass, more preferably 85 to 95% by mass with respect to the total amount of the pharmaceutical composition.

<2> The compound represented by the general formula (1) and / or a salt thereof which is an essential component of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is an ointment form and has a general formula having an antifungal effect It contains the compound represented by (1) and / or a salt thereof. That is, the pharmaceutical composition of the present invention can be used as an antifungal pharmaceutical composition. Specific examples of the compound represented by the general formula (1) include lanaconazole in which R ₁ is a chlorine atom and R ₂ is a hydrogen atom, and luliconazole in which both R ₁ and R ₂ are chlorine atoms. In particular, it is preferable to use luliconazole. Such a compound can be produced, for example, by the method described in JP-A No. 09-1000027. The preferred content of these components is 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, based on the total amount of the pharmaceutical composition. This is because if the amount is too large, the effect of the pharmaceutical composition of the present invention may not be achieved, and if the amount is too small, the antifungal effect may not be achieved.

<3> Carbonic acid diester which is an essential component of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is an ointment form and contains a carbonic acid diester as an essential component. Preferred examples of the carbonic acid diester include cyclic carbonic acid diesters such as ethylene carbonate and propylene carbonate, and acyclic carbonic acid diesters such as diethyl carbonate and dicapryl carbonate. Of these, cyclic diesters are preferable, and ethylene carbonate, propylene carbonate and the like can be particularly preferably exemplified. The pharmaceutical composition of the present invention contains one or more selected from such carbonic acid diesters. Of these carbonic acid diesters, propylene carbonate is particularly preferred. This is because the ointment preparation of the present invention has two effects of improving the initial concentration in the stratum corneum and maintaining the concentration in the stratum corneum after a long period of time. In order to exert such action, the content of the carbonic acid diester is 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, based on the total amount of the pharmaceutical composition. Moreover, it is preferable that carbonic acid diester is 1: 10-10: 1 in mass ratio with the sum total of the mass of benzyl alcohol and N-alkyl- 2-pyrrolidone. By adopting such a mass ratio, it is possible to adjust the slope of the retained amount in the stratum corneum 30 minutes after administration and the retained amount in the stratum corneum 24 hours later.

<4> Pharmaceutical Composition of the Present Invention The pharmaceutical composition of the present invention is an ointment dosage form and preferably contains a polyhydric alcohol. The polyhydric alcohol is not particularly limited as long as it has two or more hydroxyl groups in one molecule, but is preferably a liquid at 1 atm. Specifically, propylene glycol, glycerin, 1,3-butanediol, dipropylene glycol, polyethylene glycol having a molecular weight of 200 to 800, diglycerin, triglycerin and the like can be suitably exemplified, and propylene glycol, glycerin, 1,3- One or more selected from butanediol, dipropylene glycol, polyethylene glycol and diglycerin are particularly preferred. Among these, it is particularly preferable to contain only propylene glycol. The total content of such polyhydric alcohols is preferably 1 to 10% by mass, and particularly preferably 3 to 8% by mass. Moreover, in a preferable form, it is preferable that this mass is 400-700% with respect to the total mass of the compound represented by the said General formula (1) and / or its salt. Such a component works together with a nonionic surfactant described later and has an action of increasing the concentration of the compound represented by the general formula (1) and / or a salt thereof in the stratum corneum.

  The pharmaceutical composition of the present invention preferably contains a nonionic surfactant in addition to the above essential components. As such a nonionic surfactant, those having a polyoxyethylene ester structure are preferable, and pastes having the same degree as the base are preferable. Moreover, it is preferable that it is a hydrophilic surfactant more than HLB10. Specifically, polyoxyethylene hydrogenated castor oil having an addition mole number of oxyethylene of 14 or more, sorbitan fatty acid ester having an addition mole number of oxyethylene of 20 or more, and the like can be preferably exemplified. Such a nonionic surfactant may contain only one species or may contain two or more species in combination. The preferred content of these nonionic surfactants is preferably 0.5 to 6% by mass, particularly 1.5 to 3.5% by mass, based on the total amount of the pharmaceutical composition. preferable. In this range, it works with the polyhydric alcohol to increase the drug concentration in the stratum corneum.

  The pharmaceutical composition of the present invention contains the essential components, and is usually pasty at 1 atm. 25 ° C., and exhibits a droplet dispersion state or a one-phase state. Here, the one-phase state means that when the preparation is taken and observed under a microscope, the droplet cannot be clearly observed. In addition to the essential components, the pharmaceutical composition of the present invention may contain optional components for stabilizing components such as solvents, antioxidants, chelating agents, pH adjusters, and ultraviolet absorbers. The pH adjuster is preferably an organic acid, and more preferably an α-hydroxy acid such as lactic acid, glycolic acid or gluconic acid. Of these, lactic acid is particularly preferred. It is preferable that this pH adjuster is 1-10 mass% with respect to content of an antifungal agent. Further, as the stabilizer, antioxidant components and chelating agents can be particularly preferably exemplified, and as the antioxidant, BHT, BHA, tocopherol, ascorbic acid and derivatives thereof can be suitably exemplified, and as the chelating agent, edetic acid, Preferred examples include phytic acid and pentetic acid. As solvents, N-alkyl-2-pyrrolidone such as N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-hexyl-2-pyrrolidone, diethyl adipate Dibasic acid diesters such as diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, monoalkyl esters of ethylene glycol such as triacetin and ethyl glycol, trialkyl esters of citric acid such as triethyl citrate, benzyl alcohol, phenethyl alcohol, Mention may be made of phenoxyethanol. Among these, N-alkyl-2-pyrrolidone is preferable and can be used. This is because N-alkyl-2-pyrrolidone suppresses the temporal change in the drug concentration in the stratum corneum and is excellent in the effect of maintaining a constant concentration for a long time. In order to exert such an effect, it is preferable to contain N-alkyl-2-pyrrolidone in a total amount of 0.1 to 5% by mass, and 0.5 to 3% by mass with respect to the total amount of the pharmaceutical composition. Particularly preferred.

  The pharmaceutical composition of this invention can be manufactured in accordance with a conventional method. As the essential component and optional component, commercially available products can be used, or those synthesized by a conventional method can be used. For example, a hydrophobic ointment base is dissolved by heating at 90 to 99 ° C. Ingredients other than the hydrophobic ointment base, the compound represented by the general formula (1) and / or a salt thereof are similarly dissolved by heating at 90 to 99 ° C., and the compound represented by the general formula (1) and / or Alternatively, the salt can be added and dissolved, and then gradually added to the dissolved hydrophobic ointment base with stirring, and stirred and cooled to room temperature to obtain a paste-like pharmaceutical composition. The pharmaceutical composition of the present invention thus prepared is preferably a preparation classified as “oil-based ointment” as referred to in the 16th revised Japanese Pharmacopoeia. Such a preparation means a semi-solid preparation in which an active ingredient is dissolved or dispersed in an oily base. Such a formulation does not form an emulsion with water, unlike a cream formulation. The absence of an emulsion with water makes the stratum corneum dynamics significantly different from cream formulations.

  The pharmaceutical composition of the present invention is preferably used for the treatment of diseases caused by fungi or prevention of deterioration by utilizing the properties of the compound represented by the general formula (1) such as luliconazole and / or a salt thereof. Examples of fungal diseases include foot ringworms such as athlete's foot, body ringworms such as Candida and Denpu, and ringworms of hard keratin such as onychomycosis, and the effect on the stratum corneum is remarkable. Therefore, it is particularly preferable to use it for the treatment of soft keratin parts such as foot ringworm, Candida and body ringworm such as Denpu, in other words, a clear part of the stratum corneum. The effect of the pharmaceutical composition of the present invention is particularly preferably expressed in the skin, but also extends to mycosis of the nail and the keratinous proliferative part, so that the pharmaceutical composition for mycosis of the nail and the keratoproliferative part satisfying the configuration of the present invention Products also belong to the technical scope of the present invention.

The mode of use can be appropriately selected in consideration of the patient's weight, age, sex, symptom, etc. In general, for adults, it is preferable to administer 0.01 to 1 g of luliconazole per day. Moreover, the usage-amounts, such as luliconazole normally used for the disease by fungi, can be referred.
For example, an appropriate amount can be applied to the site of the disease once or several times a day, and such treatment is preferably performed every day.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples.
<Example 1>
An ointment that is a pharmaceutical composition of the present invention was prepared according to the following formulation. That is, components (a) and (b) were dissolved with stirring at 95 ° C., respectively. After confirming solubilization by adding the component C to the component B, the mixture was gradually added to the solution under stirring and cooled by stirring to obtain an ointment which is the pharmaceutical composition of the present invention. At the same time, Comparative Example 1 in which propylene carbonate was replaced with petrolatum was also prepared in the same manner. For these, the concentration of luliconazole in the stratum corneum was measured over time using the stratum corneum of the pig ear. The results are shown in Table 2. From this, it can be seen that the concentration of luliconazole in the stratum corneum is maintained high by propylene carbonate at a long time of 6 hours and 24 hours after administration.

<Method for measuring the concentration of luliconazole in the stratum corneum>
The stratum corneum of the pig ear is attached to a Franz cell, the specimen is applied to the receiver filled with physiological saline, the drug is extracted from the stratum corneum over time, the drug concentration is obtained, and the drug is stored in the stratum corneum Check the drug concentration. To determine the concentration in the stratum corneum, weigh the stratum corneum mass and extract with methanol. The concentration of luliconazole in methanol is determined by LC-MS-MS method (device name: UPLC-MS / MS system ACQUITY TQD; (Company name: Nihon Waters Co., Ltd.). LC-MS
-The LC conditions for MS were 4.6 x 250 mm columns packed with Wakosil 5C18 (Wako Pure Chemical Industries, Ltd.), the column temperature was adjusted to 40 ° C, and 5 mM formic acid aqueous solution: methanol = 20: 80 was the mobile phase, and the flow rate was 1 ml / min.

<Example 2>
In the same manner as in Example 1, according to the following formulation, an ointment which is a pharmaceutical composition of the present invention was obtained.

<Example 3>
Regarding the pharmaceutical compositions of Examples 1 and 2, the concentration in the stratum corneum was examined over time by using the ears of pigs together with the ointments of Comparative Examples shown below. The concentration in the stratum corneum of commercially available “Lulicon cream” was also examined. The results are shown in Table 5. It can be seen that the pharmaceutical composition of the present invention is similar in behavior to the cream formulation and in the stratum corneum.

<Concentration change in stratum corneum>
Using pig ears, the concentration of antifungal agent in the stratum corneum was measured. That is, a circular part with a diameter of 2.5 cm was prepared, 25 μL of sample was administered, the stratum corneum was collected by tape stripping 6 hours and 24 hours after administration, extracted with methanol, and high performance liquid chromatography tandem mass spectrometry Total (device name: UPLC-MS / MS system ACQUITY TQD; distributor: Nihon Waters Co., Ltd.)
The amount of the antifungal agent was quantified, and the concentration in the stratum corneum per 1 cm ^{2 of} skin was measured.

  The present invention can be applied to pharmaceutical compositions.

Claims (4)

1 ) Hydrophobic ointment base of 80 to 98% by mass relative to the total amount of the pharmaceutical composition ,
2) 0.1 to 10% by mass of the compound represented by the following general formula (1) and / or a salt thereof with respect to the total amount of the pharmaceutical composition ,
3) 0.1 to 10% by mass of carbonic acid diester with respect to the total amount of the pharmaceutical composition , and 4) mass ratio of carbonic acid diester to the sum of the masses of benzyl alcohol and N-alkyl-2-pyrrolidone 1:10 10: 1 is benzyl alcohol and / or N- alkyl-2-pyrrolidone, characterized that you containing, ointment form pharmaceutical compositions.

(However, in the formula, R ₁ and R ₂ each independently represents a hydrogen atom or a halogen atom.) The pharmaceutical composition according to claim 1, wherein the compound represented by the general formula (1) is luliconazole . The pharmaceutical composition according to claim 1 or 2, wherein the carbonic acid diester is propylene carbonate . The said pharmaceutical composition belongs to the oleaginous ointment in the 16th revision Japanese Pharmacopoeia, The pharmaceutical composition of any one of Claims 1-3 characterized by the above-mentioned .