KR20160004703A - Transdermal delivery system having alleviated skin irritation - Google Patents

Abstract

In the present invention, provided is a transdermal drug formulation comprising a pharmaceutical active ingredient and allantoin as an abirritant for alleviating skin irritation. The transdermal drug formulation, according to the present invention, effectively reduces or prevents skin irritation while keeping skin permeability of the pharmaceutical active ingredient.

Description

[0001] The present invention relates to a transdermal delivery system having alleviated skin irritation,

The present invention relates to percutaneous absorption preparations with reduced skin irritation, and more particularly to percutaneous absorption preparations containing allantoin as a skin irritation relieving agent.

Dementia, hypertension, osteoporosis, obesity, diabetes, and asthma treatment drugs are being developed as medicines to improve the quality of life for a rapidly aging society. Among them, the development and formulation of medicines using the transdermal / Are being studied actively.

Among them, dementia is a normal neuropsychiatric disorder that causes mature brain to be damaged due to acquired trauma or illness, resulting in decline of cognitive function, behavior, and mental function such as general intelligence, learning, and language. Dementia is not only a physiological phenomenon occurring at an age, but also a pathological symptom manifested by various diseases, and patients with such symptoms are increasing every year. Various formulations for the prevention and / or treatment of dementia and products with active ingredients have been continuously developed. ( Welfare Administration , Vol. 18 No. 2, 115 ~ 142 (2008))

In the case of the percutaneous absorption preparation, it is possible to avoid side effects such as gastrointestinal tract disorders such as gastrointestinal tract disorders and the like, to avoid the first passage of the liver, to constantly release the drug to keep the drug concentration constant, It is possible to improve the patient's compliance with the medication. ( J. Kor . Pharm . Sci . , Vol. 33, No. 3, 163-169 (2003))

Skin irritation often occurs during the development of percutaneous absorption preparations. Accordingly, there is a need in the art for effective reduction or prevention of skin irritation such as erythema, edema, itching, and the like accompanied by the penetration of a pharmaceutically active ingredient through the skin (for example, KR 10-1998-0061493).

The present inventors have conducted various studies to develop a percutaneous absorption preparation that can effectively prevent skin irritation such as erythema, edema and itching. As a result, it has been found that allantoin extracted from natural products can act as an effective skin irritant emollient without changing the skin permeability of the pharmaceutically active ingredient in the percutaneous absorption preparation.

Accordingly, it is an object of the present invention to provide a percutaneous absorption preparation containing allantoin as a skin irritation modifying agent, the skin irritation being alleviated.

According to one aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically active ingredient; And a percutaneous absorption agent comprising allantoin as a skin irritation reducing agent.

The percutaneous absorption preparation of the present invention may have a formulation of a patch, a cataplasma, a gel, a cream, or an ointment. The allantoin in the percutaneous absorption preparation of the present invention may be present in the range of 1 to 20 parts by weight based on 100 parts by weight of the pharmaceutically active ingredient.

In one embodiment, the ribastigmine free base; Allantoin; And a drug-containing matrix layer containing a pressure-sensitive adhesive.

In another embodiment, the ribastigmine free base; Allantoin; gelatin; Carboxymethylcellulose sodium; And kaolin. ≪ / RTI >

In another embodiment, the ligastigin free base; Allantoin; Hydrophilic polymers; And a transdermal absorption agent having a gel formulation containing ethanol or an aqueous solution of ethanol.

In another embodiment, the ligastigin free base; Allantoin; Cetanol; Stearyl alcohol; And propylene glycol. ≪ Desc / Clms Page number 2 >

In another embodiment, the ligastigin free base; Allantoin; And an ointment formulation containing cetanol.

The percutaneous absorption preparation according to the present invention can effectively reduce or prevent skin irritation without changing the skin permeability of the pharmaceutically active ingredient by containing allantoin as a skin irritation reducing agent.

Figure 1 shows the results of skin permeability measurements of patch preparations prepared according to the present invention.

The present invention relates to a pharmaceutical composition comprising a pharmaceutically active ingredient; And allantoin as a skin irritant.

It has been found by the present invention that allantoin can effectively reduce or prevent skin irritation without altering the skin permeability of the pharmaceutically active ingredient. The allantoin is a compound having a structure represented by the following general formula (1) and is known to be extracted from wheat, tobacco seed, comfy tree, oak tree, sugar beet and the like.

≪ Formula 1 >

The allantoin may be used in percutaneous absorption preparations in an amount necessary to achieve a skin irritation alleviating effect, for example, in a range of 1 to 20 parts by weight, preferably 1 to 10 parts by weight, based on 100 parts by weight of the pharmaceutically active ingredient Can be used.

The pharmaceutically active ingredient used in the percutaneous absorption preparation of the present invention is not particularly limited, but preferably includes a drug used for the prevention and treatment of dementia. For example, the pharmacologically active ingredient may be selected from the group consisting of rivastigmine or a pharmaceutically acceptable salt thereof, pleiostigmine or a pharmaceutically acceptable salt thereof, pyridostigmine or a pharmaceutically acceptable salt thereof, But are not limited to, a pharmaceutically acceptable salt thereof, a procyclidine or a pharmaceutically acceptable salt thereof, and donepezil or a pharmaceutically acceptable salt thereof. The pharmaceutically active ingredient may preferably be ribastigmine or a pharmaceutically acceptable salt thereof, more preferably a ribastigmine free base.

The pharmaceutically active ingredient may be used as a therapeutically effective amount. For example, in the case of patch formulations, ribastigmine or a pharmaceutically acceptable salt thereof may contain in the range of 9 to 27 mg per unit patch, preferably about 18 mg. For example, in the case of a cataplasma formulation, ribastigmine or a pharmaceutically acceptable salt thereof may contain in the range of 9 to 27 mg, preferably about 12 mg, per unit cat plasma. For example, in the case of a gel formulation, ribastigmine or a pharmaceutically acceptable salt thereof may contain from 0.45 to 1.35 mg per unit gel, preferably about 0.9 mg. For example, in the case of a cream formulation, the levastigmine or a pharmaceutically acceptable salt thereof may contain from 0.45 to 1.35 mg, preferably about 0.9 mg, per unit creams. For example, in the case of an ointment formulation, the levastigmine or a pharmaceutically acceptable salt thereof may contain from 0.45 to 1.35 mg per unit ointment, preferably about 0.9 mg.

The percutaneous absorption preparation of the present invention may have a formulation of a patch, a cataplasma, a gel, a cream, or an ointment.

In one embodiment, the transdermal absorption formulation of the present invention comprises a ribastigmine free base; Allantoin; And a drug-containing matrix layer containing a pressure-sensitive adhesive. The patch formulation may consist of a support layer, a drug-containing matrix layer and a release layer.

In the percutaneous absorption preparation of the patch formulation according to the present invention, the allantoin may be present in the range of 1 to 20 parts by weight, preferably 1 to 10 parts by weight, based on 100 parts by weight of the free base of the ribastigmine. Further, the pressure-sensitive adhesive may be an acrylate (for example, DURO-TAK ^TM 87-9088, GELVA GMS 3253, DURO-TAK ^TM 87-2510, DURO-TAK ^TM 87-235A, etc., by Henkel Technologies), ethylhexyl acrylate (For example, DURO-TAK ^占 87-9301, DURO-TAK ^占 87-900A, DURO-TAK ^占 87-901A, etc., manufactured by Henkel Technologies, Inc.), and copolymers of acrylate and vinyl acetate (Such as DURO-TAK ^TM 87-4098, DURO-TAK ^TM 87-2516, DURO-TAK ^TM 87-2196, DURO-TAK ^TM 87-2287, etc., Henkel Technologies, Inc.), polyisobutylene (E.g. DURO-TAK ^占 87-608A, Henkel Technologies), polystyrene (e.g. DURO-TAK ^占 87-611A, Henkel Technologies), and silicon (e.g. Bio PSA 7-4101, Bio PSA 7-4102, Dow Corning). ≪ / RTI > Preferably, the pressure-sensitive adhesive may be an acrylate pressure-sensitive adhesive that does not contain a functional group. The amount of the pressure sensitive adhesive to be used may be in an amount sufficient to impart tackiness, and may range, for example, from 500 to 5,000 parts by weight based on 100 parts by weight of the drug (for example, a ribastigmine free base).

The percutaneous absorption preparation of the patch formulation according to the present invention may further comprise at least one acid selected from the group consisting of acetic acid, methanesulfonic acid, oxalic acid, phosphoric acid, and lactic acid as a drug release modifier. The acid may be present in the range of 0.01 to 2 equivalents, preferably 0.01 to 1 equivalent, based on 1 equivalent of the ribastigmine free base. As an example, the percutaneous absorption preparation of the patch formulation of the present invention comprises 18 mg of ribastigmine free base per unit patch; 0.2 to 20 mg of allantoin; 4.3 mg of acetic acid, and 171.2 mg of an acrylate pressure-sensitive adhesive.

In another embodiment, the transdermal absorption formulation of the present invention comprises a ribastigmine free base; Allantoin; gelatin; Carboxymethylcellulose sodium; And kaolin. ≪ / RTI > The percutaneous absorption preparation of the cataplasma formulation according to the present invention may contain, if necessary, a crosslinking agent such as dihydroxy aluminum aminoacetate; Stabilizers such as sodium edetate (including hydrates); PH adjusting agents such as tartaric acid; And emulsifiers such as polyethylene glycol and sorbitan oleate, and surfactants.

In another embodiment, the transdermal absorption formulation of the present invention comprises a ribastigmine free base; Allantoin; Hydrophilic polymers; And a gel formulation comprising an aqueous solution of ethanol or ethanol. As the hydrophilic polymer, a carboxyvinyl polymer (for example, Carbomer # 940, Carbomer # 941, Carbomer # 980, Carbomer # 981, etc.), xanthan gum (for example, Keltrol F etc.) But is not limited thereto. The aqueous ethanol solution may be about 94% ethanol aqueous solution. The gel-type percutaneous absorption preparation according to the present invention may further comprise a pH adjusting agent such as triethanolamine, arginine, sodium hydroxide, potassium hydroxide, etc., and a neutralizing agent, if necessary.

In another embodiment, the transdermal absorption formulation of the present invention comprises a ribastigmine free base; Allantoin; Cetanol; Stearyl alcohol; And propylene glycol. The percutaneous absorption preparation of the cream formulation according to the present invention may further contain a thickening agent such as a carbomer, if necessary.

In another embodiment, the transdermal absorption formulation of the present invention comprises a ribastigmine free base; Allantoin; And an ointment formulation comprising cetanol. The percutaneous absorption preparation of the ointment formulation according to the present invention may contain, if necessary, an emulsifier such as sorbitan monostearate, polysorbate # 60 and a surfactant; And a humectant such as concentrated glycerin.

The percutaneous absorption preparations of the patch, cataplasma, gel, cream, or ointment formulations according to the present invention may be prepared according to the conventional methods used in the pharmaceutical industry, using the ingredients described above.

For example, the percutaneous absorption preparation of the present invention having a patch formulation can be produced by forming the above-mentioned drug-containing matrix layer on the release layer, and then forming a support layer thereon. The release layer may be a release liner commonly used in the field of percutaneous absorption preparation or a laminate thereof. Examples of the release liner include polyethylene, polyester, polyvinyl chloride, polyvinylidene A film such as chloride, paper, or a laminate thereof may be used. In addition, a support layer (also referred to as a backing membrane) can also be used as a drug-absorptive and flexible substance commonly used in the field of percutaneous absorption preparations, such as polyester, polyurethane, polyethylene, A single layer film such as polypropylene, polyolefin, polyethylene terephthalate or aluminum-treated polyester, or a multi-layer laminated film in which the above-mentioned single layer film is laminated with nonwoven fabric, cotton cloth or fabric having water absorbing ability. For example, the percutaneous absorption preparations of the present invention having a patch formulation can be prepared by dissolving a drug (e.g., a free base of ribastigmine), acetic acid, and allantoin together with an acrylate coagulant, Coating a release liner, drying it, and then forming a polyethylene vinyl acetate laminate film as a support layer.

Hereinafter, the present invention will be described in more detail through examples and test examples. However, these examples and test examples are for illustrating the present invention, and the present invention is not limited to these examples and test examples.

Example  1 to 4 patches

Percutaneous absorption preparations were prepared according to the ingredients and contents in Table 1 below. The contents in Table 1 refer to the content of each component per unit patch. Ribastigmine free base, acetic acid, and allantoin were added to an acrylate pressure-sensitive adhesive (DURO-TAK ^占 87-9301, Henkel Technologies) and dissolved by stirring. After removing air bubbles in the obtained solution, it was applied to a release liner coated with silicone, dried at 90 ° C for 4 minutes, covered with a polyethylene vinyl acetate laminate film, pressed using a roll to produce a patch (10 cm 2) Respectively.

ingredient Example 1 Example 2 Example 3 Example 4 Active ingredient Ribastigmine free base 18.00 mg 18.00 mg 18.00 mg 18.00 mg Skin irritation emollient Allantoin 0.20 mg 0.50 mg 0.70 mg 2.00 mg mountain Acetic acid 4.30 mg 4.30 mg 4.30 mg 4.30 mg Adhesive Acrylate tackifier 171.20 mg 171.20 mg 171.20 mg 171.20 mg The drug-containing matrix layer thickness 85.0 탆 85.3 탆 85.5 탆 86.8 탆

Example  5. Gelse

1.30 g of carboxyvinyl polymer (Carbomer # 940) was dissolved in 48.0 g of ethanol, and the mixture was allowed to stand at room temperature to remove air bubbles. Thus, a solution of ribastigmine- Containing gel was prepared.

Example  6. Ointment system

3.0 g of ribastigmine free base, 0.2 g of allantoin, 9.5 g of hard liquid paraffin, 3.0 g of concentrated glycerin, 5.0 g of cetanol, 2.5 g of sorbitan monostearate, 0.07 g of methyl paraoxybenzoate, 1.7 g of polysorbate # 60 Were uniformly mixed to prepare an ointment agent.

Example  7. Cataplasma

To 50.0 g of purified water, 4.18 g of gelatin and 0.5 g of tartaric acid were added and dissolved at 50 캜. 35.1 g of concentrated glycerin, 0.14 g of dihydroxy aluminum aminoacetate, 0.15 g of titanium oxide, 0.84 g of sorbitan oleate (Span 80), 0.28 g of sodium edetate, 3.76 g of carboxymethylcellulose sodium, 3.4 g of kaolin, After uniformly mixing 0.11 g of methyl benzoate, 0.16 g of polyethylene glycol, 0.59 g of castor oil, 0.33 g of mint oil, 0.06 g of butylhydroxytoluene, 2.0 g of allantoin and 18.0 g of free base of ribastigmine, To prepare a coating liquid. The obtained coating liquid was applied to a nonwoven fabric to a thickness of 1 mm, laminated with a release film, and cut into a size of 10 cm ² . The obtained cataplasma was aged at room temperature for 7 days to prepare a ribastigmine-containing cataplasma agent.

Example  8. Cream

3.0 g of ribastigmine free base, 0.2 g of allantoin, 1.0 g of myristic acid isopropyl, 0.05 g of butylhydroxytoluene, 2.0 g of cetanol, 1.8 g of sorbitanonostearate, 6.8 g of stearyl alcohol and 20.0 g of propyleneglycol , And 1.6 g of polysorbate # 60 were uniformly mixed to prepare a cream preparation.

Test Example  1. skin irritation test

Skin irritation was evaluated for the percutaneous absorption preparations prepared in Examples 1, 2, 3, 4, and 7. The patch Exelon ^(TM Patch Exelon, Norvatis) available on the market as a comparison example was used. Each formulation was attached to the arms of five healthy adult males and skin irritation was assessed after 30 minutes. The degree of redness was analyzed by checking the skin color (erythema, a value) before and after the attachment using a colorimeter (CHROMA METER CR400, KONICA MINOLTA). The results are shown in Table 2 below. The values in Table 2 are the mean values of each test group.

Redness [a value] Comparative Example 5.24 Example 1 4.09 Example 2 4.07 Example 3 4.27 Example 4 3.98 Example 7 3.50

As can be seen from the results of Table 2, the skin irritation was significantly reduced (P-value < 0.05) in the patch preparation according to the present invention as compared with the conventional patch formulation (Comparative Example) Of the total.

In addition, the formulations of Examples 5, 6 and 8 showed the degree of stimulation relaxation and no significant skin irritation.

Test Example  2. Percutaneous permeation test

Comparative Example was evaluated using the patch Exelon ^(TM Patch Exelon, Norvatis)], Examples 1, 2, and the skin permeation rate human cadaver skin (3 × 3 ㎠ ) of the patch preparation prepared in three. The skin permeability test was carried out using a Franz type diffusion cell having a diffusion area of 1.77 cm 2. The volume of the storage chamber solution was 12.5 mL. Each patch was pressed against the skin with a patch formulation and the skin / patch laminate was clamped between the feed chamber and the containment chamber of the Franz cell against the skin surface against the chamber solution. The temperature of the diffusion apparatus was maintained at 32.0 ° C by adding phosphate buffer solution (pH 7.4) to the storage chamber of Franzcell. The buffer solution in the storage room was stirred at a constant speed of 600 rpm. A 0.2 mL sample was taken from the storage room at each time point and filled with the same volume of fresh phosphate buffer solution to maintain the sink condition. Ribastigmine stocks permeated through the skin were analyzed using high performance liquid chromatography under the analytical conditions of Table 3 below.

Analysis Column 4.6 mm x 250 mm, a column similar to C18, 5 m Mobile phase Acetonitrile: buffer = 16: 84 (v / v)
* Buffer solution: 1.15 g of ammonium phosphate is dissolved in water to make 1 L, add 1 mL of triethylamine, and add phosphoric acid to adjust to pH 5.6. Flow rate Make the retention time of the ribastigin 14 minutes. Analytical wavelength 217 nm Temperature 40 ℃

The results of the skin permeability test as described above are shown in Fig. As can be seen from the results in Fig. 1, no significant change in skin permeability was observed by the addition of allantoin.

Claims (16)

A pharmaceutically active ingredient; And allantoin as a skin stimulant. The percutaneous absorption preparation according to claim 1, which has a formulation of a patch, a cataplasma, a gel, a cream, or an ointment. 3. The method of claim 1, wherein the pharmaceutically active ingredient is selected from the group consisting of riastystimin or a pharmaceutically acceptable salt thereof, fisostigmine or a pharmaceutically acceptable salt thereof, pyridostigmine or a pharmaceutically acceptable salt thereof, Tin or a pharmaceutically acceptable salt thereof, procyclidine or a pharmaceutically acceptable salt thereof, and donepezil or a pharmaceutically acceptable salt thereof. 2. The percutaneous absorption preparation according to claim 1, wherein the allantoin is present in a range of 1 to 20 parts by weight based on 100 parts by weight of the pharmaceutically active ingredient. The method of claim 1, wherein the ligand is selected from the group consisting of ribastigmine free base; Allantoin; And a drug-containing matrix layer comprising a pressure-sensitive adhesive. 6. The percutaneous absorption preparation according to claim 5, wherein the patch preparation comprises a support layer, a drug-containing matrix layer and a release layer. 6. The percutaneous absorption preparation according to claim 5, wherein the allantoin is present in the range of 1 to 20 parts by weight based on 100 parts by weight of the free base of the ribastigmine. 6. The method of claim 5, wherein the pressure sensitive adhesive is selected from the group consisting of acrylate, a copolymer of ethylhexyl acrylate and methyl acrylate, a copolymer of acrylate and vinyl acetate, polyisobutylene, polystyrene, Or more of the pressure-sensitive adhesive composition of the present invention. The percutaneous absorption preparation according to claim 8, wherein the pressure-sensitive adhesive is an acrylate pressure-sensitive adhesive containing no functional group. 10. The percutaneous absorption preparation according to any one of claims 5 to 9, further comprising at least one acid selected from the group consisting of acetic acid, methanesulfonic acid, oxalic acid, phosphoric acid, and lactic acid as a drug release modifier . 11. The transdermal absorption formulation according to claim 10, wherein the acid is present in the range of 0.01 to 2 equivalents based on 1 equivalent of the ribastigmine free base. 6. The method of claim 5, further comprising: 18 mg of ribastigmine free base per unit patch; 0.2 to 20 mg of allantoin; 4.3 mg of acetic acid, and 171.2 mg of an acrylate pressure-sensitive adhesive. The method of claim 1, wherein the ligand is selected from the group consisting of ribastigmine free base; Allantoin; gelatin; Carboxymethylcellulose sodium; And kaolin. &Lt; RTI ID = 0.0 &gt; 8. &lt; / RTI &gt; The method of claim 1, wherein the ligand is selected from the group consisting of ribastigmine free base; Allantoin; Hydrophilic polymers; And a gel formulation containing ethanol or an aqueous ethanol solution. The method of claim 1, wherein the ligand is selected from the group consisting of ribastigmine free base; Allantoin; Cetanol; Stearyl alcohol; And propylene glycol. &Lt; RTI ID = 0.0 &gt; 8. &lt; / RTI &gt; The method of claim 1, wherein the ligand is selected from the group consisting of ribastigmine free base; Allantoin; And an ointment formulation comprising cetanol.

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