JP5897299B2 - Lotion preparation - Google Patents

Description

The present invention relates to an oil-in-water emulsion lotion containing 22-oxa-1α, 25-dihydroxyvitamin D ₃ (hereinafter referred to as maxacalcitol).

  Psoriasis is one of the intractable inflammatory keratosis characterized by abnormal growth of skin cells. Its etiology has not been fully elucidated, but it develops when an internal (diabetes, hyperlipidemia, etc.) or external (infection, mental stress, etc.) element is added to a constitutional element (genetic predisposition) It is considered to be. The skin of patients with psoriasis has papules and scales. Psoriasis is classified according to symptoms into psoriasis vulgaris, psoriasis vulgaris, pustular psoriasis, psoriatic arthritis, etc. Among them, psoriasis vulgaris is the most common and is said to account for about 90% of all cases. Although psoriasis was initially recognized as a disease common to Westerners, the number of patients has been increasing in Japan in recent years, and therefore, the development of a treatment method is desired.

The current general treatments for psoriasis and keratosis include topical treatments that apply steroids and vitamin D ₃ , phototherapy that irradiates medium wavelength ultraviolet rays and long wavelength ultraviolet rays, and oral treatments such as retinoids and cyclosporine. Used alone or in combination. Among them, in particular, external therapy plays a central role from the viewpoint of direct action on the affected area and burden on the patient.

Maxacalcitol is a vitamin D ₃ derivative having a cell growth inhibitory action on dermal fibroblasts (Patent Document 1), and is used as an external medicine in the treatment of psoriasis and keratosis. For example, 25 μg / g of Oxalol (registered trademark) ointment and 25 μg / g of Oxalol (registered trademark) lotion are commercially available psoriasis and keratosis treatments containing maxacalcitol represented by the following structural formula as an active ingredient. (Non-Patent Document 1).

  As a dosage form of maxacalcitol, a lotion is superior to an ointment because of its ease of application to haired parts such as the head. Since psoriasis is likely to develop not only in the trunk but also in hairy parts such as the head, when maxacalcitol is used as an oil-based ointment, the ointment adheres to the hair and is sufficient for the affected skin. It becomes difficult to apply the amount (Patent Document 2). In this respect, the lotion is easy to apply to the hair part.

  The above-mentioned oxalol (registered trademark) lotion 25 μg / g and maxacalcitol lotion described in Patent Document 2 use medium-chain fatty acid triglyceride as a solubilizer. It has been described that such a lotion is superior in transdermal absorbability of maxacalcitol and is still less irritating to the skin even if its liquidity is made basic in order to improve its chemical stability.

  However, since the skin of the patient to be treated suffers from a skin disease, it is weaker to the stimulus than a healthy person, and even a small stimulus may be forced to bear a small burden. Therefore, it is still necessary to make an effort to reduce the skin irritation as much as possible while maintaining the efficacy and stability of the active ingredient, which is consistent with the patient's desire.

Japanese Patent No. 2522996 Patent No. 4060347

Revised March 2011 (12th edition) Chugai Pharmaceutical Co., Ltd. “Oxalol® Ointment / Lotion 25 μg / g” package insert

  An object of the present invention is to provide a lotion containing maxacalcitol, having little skin irritation and excellent storage stability.

  In order to solve the above-mentioned problems, the present inventors have added a large number of solvents, solubilizers, stabilizers, surfactants and other pharmaceutical formulation additives that can be used in the pharmaceutical field, As a result of trial production of a lotion preparation containing a combination with Toll and detailed examination of its drug properties, surprisingly, a lotion preparation containing maxacalcitol and a propylene glycol fatty acid ester is the present invention. The present inventors have found that the above problem can be solved, and further earnestly studied to complete the present invention.

That is, the present invention
(1) Lotion agent containing 22-oxa-1α, 25-dihydroxyvitamin D ₃ , propylene glycol fatty acid ester, water and a surfactant,
(2) The lotion agent according to (1), comprising propylene glycol dicaprylate as a propylene glycol fatty acid ester,
(3) The lotion agent according to (1) or (2), further comprising a solubilizing agent,
(4) The lotion preparation according to (3), comprising anhydrous ethanol as a solubilizing agent,
(5) The lotion agent according to any one of (1) to (4), wherein the propylene glycol fatty acid ester contains about 5 to 7% (w / w) with respect to the whole lotion agent.

  According to the present invention, a lotion agent with less skin irritation and excellent storage stability is provided. Moreover, the lotion of the present invention does not hinder the efficacy of maxacalcitol, which is an active ingredient.

  Hereinafter, the present invention will be described in detail.

  The present invention relates to a pharmaceutical lotion. In the context of the present invention, “lotion” means what is defined in the Japanese Pharmacopoeia General Rules for Preparations. More specifically, the lotion of the present invention is an oil-in-water lotion in which the oil phase portion is dispersed in the water phase portion.

The active ingredient for treating keratosis such as psoriasis vulgaris of the lotion of the present invention is maxacalcitol. “Maxacalcitol” is a compound described in Patent Document 1, and can also be specified by the common name of 22-oxa-1α, 25-dihydroxyvitamin D ₃ . Maxacalcitol used in the present invention may be produced according to a known production method, for example, the method described in Patent Document 1. In the present invention, maxacalcitol is blended in the oil phase portion of the lotion.

  The lotion of the present invention contains a propylene fatty acid ester as a solubilizer for maxacalcitol. In the context of the present invention, “propylene glycol fatty acid ester” means a compound in which one (monoester type) or two (diester type) fatty acid is linked to propylene glycol. Propylene glycol fatty acid esters used in the present invention are commercially available as solubilizers, bases, suspending agents and the like in pharmaceutical formulations (Pharmaceutical Additives Dictionary 2007). The propylene glycol fatty acid ester currently used may be used, and what was manufactured in accordance with the well-known method may be used. The propylene glycol fatty acid ester is preferably a diester type and having 8 to 10 carbon atoms in the fatty acid, and examples include propylene glycol dicaprylate, propylene glycol dicaprylate / dicaprate, and propylene glycol dicaprate. More preferred is propylene glycol dicaprylate. By using propylene glycol fatty acid ester as a solubilizing agent for maxacalcitol, the present inventors have made irritation to the skin without interfering with the efficacy of maxacalcitol compared to the case of using other solubilizing agents. It was found that the degradation stability of maxacalcitol could be improved.

  The lotion of the present invention contains a surfactant for emulsification. In the context of the present invention, “surfactant” is used in a broad sense and includes any compound that contributes directly or indirectly to the stabilization of the interface between water and oil. Accordingly, the “surfactant” includes not only an amphiphilic compound having both a hydrophilic group and a hydrophobic group, but also a compound that assists the surface active action of such an amphiphilic compound. The surfactant used in the present invention is not particularly limited, but is preferably nonionic. For example, monostearic acid such as polyoxyethylene (5) glyceryl monostearate and polyoxyethylene (15) glyceryl monostearate Polyoxyethylene glycerin, self-emulsifying glyceryl monostearate, polyoxyethylene (10) glycol monostearate, polyoxyethylene (20) hydrogenated castor oil, hexaglyceryl monomyristate, sorbitan monolaurate, polyoxyethylene tristearate (20) Examples include sorbitan, polyoxyethylene tetraoleate (30) sorbit, and the like.

  The amount of maxacalcitol used in the whole lotion preparation of the present invention is usually about 0.001 to 0.01% (w / w), preferably about 0.001 to 0.005% (w / w). w), more preferably about 0.0025% (w / w).

  The amount of propylene glycol fatty acid ester used for the whole lotion of the present invention is usually about 0.5 to 20% (w / w), preferably about 3 to 15% (w / w), more Preferably, it is about 5 to 7% (w / w).

  The amount of the surfactant used relative to the whole lotion of the present invention is usually about 0.001 to 5% (w / w), preferably about 0.01 to 2.5% (w / w). More preferably, it is about 0.05 to 1.5% (w / w).

  The lotion of the present invention may further contain other components as desired. Such a component is any component that can be used in a skin external preparation, and can be used as one or a mixture of two or more. For example, it may contain a solubilizer, an oily base, a water-soluble base, a thickener, a pH adjuster, a preservative, a stabilizer and the like.

More specifically,
Examples of the solubilizer include anhydrous ethanol and isopropanol. A solubilizer is used when it is desired to promote dissolution of maxacalcitol in a solubilizer.
Examples of the oily base include liquid paraffin, petrolatum, squalane, paraffin, honey beeswax, carnauba wax, ceresin wax, stearic acid, batyl monostearate, behenic acid, cetanol, stearyl alcohol, and behenyl alcohol.
Examples of the water-soluble base include water, glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, polyglycerin, and polyethylene glycol 300-1500.
Examples of the thickener include polyvinyl alcohol, polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer, xanthan gum and the like.
Examples of the pH adjuster include organic amines such as monoethanolamine, diisopropanolamine and triethanolamine, and inorganic salts such as sodium hydroxide and sodium hydrogenphosphate.
Examples of the preservative include parabens and sorbic acids.
Examples of the stabilizer include tocopherol acetate, DL-α-tocopherol, sodium citrate, dibutylhydroxytoluene, L-arginine and the like.

  The lotion of the present invention is produced according to usual means. For example, prepare oil phase part containing maxacalcitol, propylene glycol fatty acid ester, oily base, surfactant etc. and water phase part containing aqueous base, pH adjuster, thickener etc. separately. It can manufacture by mixing. Any means may be used for mixing, but for example, a high-speed stirrer such as a homomixer is conveniently used. The pH is considered to be neutral to basic for the stabilization of maxacalcitol, and is usually adjusted to a pH of 8 to 11, preferably pH 8.5 to 11. The viscosity is appropriately adjusted according to the purpose of preventing dripping.

  In a preferred embodiment, the lotion of the present invention comprises about 0.001 to 0.005% maxacalcitol, about 3 to 15% propylene glycol fatty acid ester, and about 0.01 to 2.5% surfactant. About 0.001 to 1% of solubilizing agent, about 10 to 30% of 1,3-butylene glycol, about 0.1 to 0.5% of carboxyvinyl polymer, and pH is adjusted to 8.5 to 11 Are adjusted (both w / w). In a more preferred embodiment, maxacalcitol is about 0.0025%, propylene glycol fatty acid ester is about 5-7%, surfactant is about 0.05-1.5%, and solubilizing agent is about 0.01- 1%, 1,3-butylene glycol is contained about 15-25%, carboxyvinyl polymer is contained about 0.1-0.3%, pH is adjusted to 9 to 10.5 (both w / w) .

  The lotion of the present invention can be used as an external preparation. In that case, for example, an appropriate amount of the lotion of the present invention is applied to the affected area twice a day for patients with keratosis such as psoriasis vulgaris. In addition, it is preferable to reduce the number of times as appropriate depending on the symptom, and to apply up to 10 g per day.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

[Preparation of drug]
The drugs of Examples 1 to 5 were prepared according to the formulation shown in Table 1 below. Unless otherwise indicated,% which shows content in the following shows the mass%.

  Monostearic acid (5) Polyoxyethylene glycerin, batyl monostearate, dibutylhydroxytoluene, and propylene glycol dicaprylate were weighed in the proportions listed in Table 1, heated and melted, and then the maxacalcitol was added to the melt. An anhydrous ethanol solution was added to prepare an oil phase. On the other hand, 1,3-butylene glycol and diisopropanolamine in the proportions shown in Table 1 were dissolved in an appropriate amount of purified water to prepare an aqueous phase 1. Separately, carboxyvinyl polymer and L-arginine were dissolved in an appropriate amount of purified water to prepare an aqueous phase 2. The oil phase heated to about 80 ° C. and the water phase 2 heated to about 60 ° C. are sequentially added to the aqueous phase 1 heated to about 60 ° C., and further stirred, cooled to 30 ° C. or lower. I got the drug. The pH was adjusted to 10.

[Stability test]
A stability test was performed using the drugs of Examples 1 to 3 as samples. The maxacalcitol content was measured when the drug was stored for 1 month in a 10 g polyethylene container at 40 ° C./75% RH (relative humidity). Note that 25 μg / g of Oxalol (registered trademark) lotion of Comparative Example was stored in a 10 g polypropylene container. The maxacalcitol content was measured by adding an internal standard solution, a sodium chloride solution and a 2-propanol mixed solution (1: 2) to about 1 g of each sample, stirring and sonicating. This solution is cooled in ice water to 0.4
The sample solution was obtained by filtering with a 5 μm filter. This was subjected to reverse phase high performance liquid chromatography (column; AQUITY BEH C18 (manufactured by Waters), detection wavelength: 265 nm, mobile phase: ammonium dihydrogen phosphate buffer (pH 6.0) / acetonitrile mixture (55:45)). The amount of maxacalcitol contained in each sample was measured.

  The residual ratio of the maxacalcitol content after 1 month storage to the maxacalcitol content before storage was determined. The results are shown in Table 2 below.

  In the drugs of Examples 1 to 3 using propylene glycol dicaprylate as a solvent, the stability under the condition of 40 ° C./75% RH is equal to or higher than that of the comparative example Oxalol (registered trademark) lotion 25 μg / g. there were.

[Skin irritation test (rabbit skin primary irritation test)]
A skin irritation test (rabbit skin primary irritation test) was performed on the drugs of Examples 1 and 3 and Comparative Example.
Each formulation 0.5 g / 1 site was occluded for 24 hours on the rabbit back normal and damaged skin, and the skin reaction was observed before application, and at 1, 24, 48 and 72 hours after removal of the obstruction. Five animals were used, and four sites were attached per animal. For each normal skin and damaged skin, the examples were performed at 3 sites each (4 sites in the comparative example) and evaluated according to the Draize method (Draize, JH, Woodard, G and Calvery, HO: Methods for the study of irritation and toxicity of
substances applied topically to the skin and mucous membranes. J. Pharmacol. Exp. Ther. 82,377-390, 1944). The results are shown in Table 3 below. The numbers in the table are average values.

  The drugs of Examples 1 and 3 were evaluated as having no irritation in both normal skin and damaged skin, and it was found that the preparation was less irritating than the comparative example of mild irritation. The most significant difference appeared at 1 hour after the removal of the sticking, and erythema was confirmed in the comparative example, whereas none of the drugs of Examples 1 and 3 was confirmed.

[Intradermal pharmacokinetic study]
In order to confirm the skin absorbability of the lotion of the present invention, a pharmacokinetic test was conducted.
Application time: 4, 8 hours Subjects: 6 subjects 10 mg of the sample preparation was applied to the back of the subjects, and after each application time, the drug was wiped off with cotton and an adhesive tape was applied. The pressure-sensitive adhesive tape was peeled off after pressing the applied part. Pasting and peeling were repeated for a total of 22 adhesive tapes. The first two were discarded and the next 20 were sampled. Twenty adhesive tapes were immersed in 10 mL of a 0.1% polyoxyethylene (20) cetyl ether aqueous solution and subjected to ultrasonic treatment for 10 minutes. The mixture was further shaken for 10 minutes, centrifuged at 3000 rpm for 5 minutes, and filtered through a 0.45 μm filter to obtain a sample solution. The amount of maxacalcitol recovered was measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS) under the following conditions.

Measuring apparatus: HPLC (Shimadzu Corporation), MS / MS (Thermo Fisher Scientific Incorporated)
Column: Inertsil ODS-3 (2.1 mmφ × 50 mm, 3 μm, GL Science)
Column temperature: 50 ° C
Injection volume: 10 μL
Mobile phase: 2 mM ammonium formate aqueous solution / 2 mM ammonium formate methanol solution mixture (35:65)
Flow rate: About 0.3 mL / min
Ionization method: positive ESI

  The drug of the example showed a drug recovery amount of 7 ng in 4 hours and 8 ng in 8 hours.

[Separation stability test]
In order to confirm the separation stability of the lotion preparation of the present invention, the following tests were conducted.
The separation stability of the lotion was visually evaluated when the chemicals of the Examples were stored in a 10 mL glass test tube at 40 ° C. 75% RH (relative humidity) or 50 ° C. for 1 month.

[Skin irritation test (human)]
About the chemical | medical agent of an Example and a comparative example, the patch test by a monitor and the sensory test (questionnaire) were implemented.

  From this test, it was confirmed that the lotion preparation of the present invention containing propylene glycol dicaprylate as a solubilizer exhibits superior separation stability and low irritation compared to formulations containing other solubilizers.

Claims (5)

A lotion preparation containing 22-oxa-1α, 25-dihydroxyvitamin D ₃ , propylene glycol fatty acid ester, water and a surfactant.   The lotion preparation according to claim 1, comprising propylene glycol dicaprylate as the propylene glycol fatty acid ester.   The lotion preparation according to claim 1 or 2, further comprising a solubilizing agent.   The lotion preparation according to claim 3, comprising anhydrous ethanol as a solubilizing agent.   The lotion preparation according to any one of claims 1 to 4, wherein the propylene glycol fatty acid ester contains about 5 to 7% (w / w) of the whole lotion preparation.