KR100439204B1 - Composition for transdermal delivery of methotrexate - Google Patents

Abstract

The present invention relates to a composition for transdermal administration containing methotrexate as an active ingredient. More specifically, the present invention relates to methotrexate, which exhibits pharmacological activity in the treatment of rheumatoid arthritis, as an active ingredient. By using a polyhydric alcohol having a solubility of 20 mg / g or more as a solvent, a sufficient amount of the drug is used in the transdermal composition, and fatty acids or fatty alcohols are included as skin permeation accelerators, thereby significantly improving the skin permeability of the drug. It relates to a composition for transdermal administration that can be usefully used for the treatment of rheumatoid arthritis.

Description

Composition for transdermal administration containing methotrexate as an active ingredient {Composition for transdermal delivery of methotrexate}

The present invention relates to a composition for transdermal administration containing methotrexate as an active ingredient.

Rheumatoid arthritis is a chronic systemic inflammatory disease that begins with inflammation in the synovial joints of the joints, chronic hypertrophy of the synovial membranes, destroys the cartilage and surrounding tissues, and causes stiffness and deformation of the joints as symptoms progress. Immune disease that can not move. Rheumatoid arthritis, unlike degenerative arthritis due to aging of the joints, is present throughout all age groups, especially between the 30s and 50s, and occurs 2-3 times more frequently in women than in men. The causes of rheumatoid arthritis include hereditary, infectious, and autoimmune hypotheses, but there are no known mechanisms.In general, they appear in the hands, feet, or peripheral joints and gradually move to larger joints. Appears as a pattern. Therefore, plaster formulations for topical treatment are inadequate for the alleviation and treatment of rheumatoid arthritis, a systemic disease. Arthritis is divided into two stages according to the severity of the disease. Drugs used in the first stage of treatment include nonsteroidal anti-inflammatory drugs and steroids. Nonsteroidal anti-inflammatory drugs are prescribed for the treatment of mild arthritis with mild edema, fever or pain. These drugs include naproxen, diclofenac, ketoprofen, pyroxicam, and other side effects such as gastrointestinal disorders or liver toxicity when administered orally orally. Plaster or gel formulations may also be applied topically to minimize this.

However, in the case of patch for topical application, the drug has a limited effect only on a specific site, and thus is not suitable for treating pain in systemic joints, which is a common feature of rheumatoid arthritis. In addition, when a patch or the like is to be applied to the curved portion due to the shape characteristic of the joint, there is a problem in that adhesion is poor. Severe arthritis, which is poorly treated as a nonsteroidal anti-inflammatory drug, has side effects such as joint stiffness, swelling, and frequent pain. In this case, steroids (Steroids) drugs may be temporarily prescribed. Examples of effective drugs include dexamethasone, predisolone, or betamethasone. However, steroid drugs prescribed orally for the treatment of arthritis are effective for short-term treatment, but due to the strong anti-inflammatory action of the drugs, they cause weakening of the skin, muscles, and bones, and severe systemic effects such as weight gain, cataracts, diabetes mellitus, and osteoporosis. It is difficult to take long-term because it has side effects.

Therefore, in the treatment of stage 2 malignant advanced arthritis, which is impossible or inadequate with stage 1 drugs, methotrexate, an immunosuppressant, or gold, an anti-rheumatic agent, is prescribed. Methotrexate, when taken orally, should take 2.5 mg of the active drug three times every 12 hours at weekly intervals. It has the disadvantages of severe liver toxicity, gastrointestinal disorders, kidney and hematopoietic organ damage. In addition, in the case of injection formulations should be repeatedly administered to the patient in the same way is accompanied by the fear and discomfort that the patient feels.

In order to overcome such drawbacks, U. S. Patent No. 5,318, 960 proposes a transdermal composition consisting of surfactant / Co-solubilizer alcohol / water and the like. However, the transdermal composition of this patent is difficult to use because it does not exhibit sufficient drug skin penetration for systemic treatment of rheumatoid arthritis. In addition, in the case of caster oil, sorbitan (Ethoxylated sorbitan) or fatty acid ester derivatives, the surfactant proposed in the patent, the solubility in methotrexate is 2.5 mg / g or less, so the drug required for treatment is contained in the transdermal composition. There is a drawback that cannot be answered enough.

SUMMARY OF THE INVENTION An object of the present invention is to provide a transdermal composition comprising a methotrexate, which minimizes the side effects of drugs occurring when applied as a conventional oral or injectable agent, and which has a simple method of administration and high patient compliance.

Another object of the present invention can be applied to a flat body part, unlike the local action patch that must be applied directly to the curved joint, can be applied to any part of the human body, the risk of detachment by movement or daily activity of the joint. It is to provide a composition for transdermal administration.

Still another object of the present invention is to provide a transdermal composition containing methotrexate having an excellent skin permeability using a specific solvent having sufficient solubility in a drug as an active ingredient.

In the present invention, 0.1 to 20% by weight of methotrexate as a pharmacologically active ingredient, 50 to 98% by weight of a polyhydric alcohol having a solubility in the active ingredient of 20 mg / g or more, and 0.1 to 30% by weight of a fatty acid or fatty alcohol as a skin permeation accelerator It is characterized by the composition for transdermal administration containing the methotrexate contained as an active ingredient.

The present invention will be described in more detail as follows.

The present invention relates to the composition of the Reservoir type patch for the percutaneous delivery of pharmacologically active methotrexate in the treatment of rheumatoid arthritis, the solubility of the pharmacologically active ingredient in the composition of more than 20 mg / g The present invention relates to a composition for transdermal administration in which a sufficient amount of a drug is used in the transdermal administration composition using an alcohol as a solvent, and the skin permeability of the drug is improved by using a skin absorption accelerator.

The content of methotrexate used as the pharmacologically active ingredient in the present invention is 0.1 to 20% by weight, preferably 1.5 to 8% by weight based on the total composition. If the content is less than the above range, there is a problem in that the content of the drug required for treatment cannot be sufficiently contained in the composition. If the above content is exceeded, there is a risk of drug precipitation in the composition due to the excessive amount of the drug. Here, the methotrexate includes a free acid form or a pharmaceutically acceptable salt form.

In general, the solvent supporting the drug used in the leisure composition does not cause skin irritation for a long time application for more than 24 hours and at the same time should have the ability to support a sufficient amount of the drug required for skin permeation, in the present invention, ethylene glycol, It was found that the solvents of diethylene glycol and triethylene glycol correspond to the above conditions. These polyhydric alcohols have a solubility in the drug of 20 mg / g or more as a solvent, and the solubility in methotrexate is large enough to support a sufficient amount of drug in the composition required for delivery of the drug through the skin.

As a solvent for supporting the effective drug commonly used in the composition of the Reservoir patch, there are water, ethanol, glycerin, propylene glycol, polyethylene glycol, etc., but these are the solubility of the present invention as in the case of Comparative Examples 2-5 Is up to 100 times or more in the skin penetration rate of the drug compared to the composition using a polyhydric alcohol of 20 mg / g or more. Therefore, the present invention improves the skin penetration rate of the drug by using one or two or more selected from ethylene glycol, diethylene glycol and triethylene glycol mentioned above. The content of the polyhydric alcohol is used in 50 to 98% by weight, preferably 65 to 95% by weight based on the total composition. At this time, if the content is less than 50% by weight, there is a problem in that a sufficient amount of the drug cannot be supported in the composition, and if it exceeds 98% by weight, the skin permeation accelerator and drug added are low so that the skin permeability is low. there is a problem.

In addition, the composition of the present invention essentially contains fatty acids or fatty alcohols as a skin permeation accelerator in order to continuously permeate the drug in the transdermal composition to the effective blood concentration or higher. Among them, fatty acids show particularly good skin permeation promoting effect. Fatty acids include hexanoic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, Neodecanoic acid, Undecanoic acid, Lauric aid, Palmitic acid, Linoleic acid and Oleic acid Among them, 0.1 to 10% by weight, preferably 0.5 to 6% by weight, based on the total composition is used. At this time, if the content is less than 0.1% by weight, there is a problem in that it does not act as a skin permeation accelerator, and when it exceeds 10% by weight, the skin permeability is improved but the skin irritation is severe and difficult to apply to the patient. The fatty alcohols may be selected from octanol, nonanol, decyl alcohol, n-decyl alcohol, undecanol, and lauryl alcohol. 0.1 to 10% by weight, preferably 0.5 to 6% by weight, based on the total composition.

In addition, the present invention can be used as an additional skin permeation accelerator in addition to the fatty acids or fatty alcohols to promote the absorption of the drug. Such skin permeation accelerators are broadly divided into one or two selected from terpenes, 2-pyrrolidones, sulfoxides, surfactants, and solvents. Mixtures of species or more may be used. Terpenes used in the present invention are thymol, carvacrol, menthol, l-Menthol, l-Menthone, carbon (1-Carvone), eugenol and Among the eucalyptol (Eucalyptol) is used 0.1 to 10% by weight based on the total composition, in particular carbacrol and thymol exhibits excellent skin permeability in the range of 0.5 to 5% by weight relative to the total composition. The pyrrolidones used in the present invention are N-methyl-2-pyrrolidone (N-Methyl-2-pyrrolidone), 1- (2-hydroxyethyl) pyrrolidinone (1- (2-Hydroxyethyl) pyrrolidinone) and poly (N-vinylpyrrolidone) (Poly (N-vinylpyrrolidone)) are used. The sulfoxides may be selected from dimethyl sulfoxide and decyl methyl sulfoxide. Among these skin permeation promoters, the skin permeation promoting effect is remarkable in pyrrolidones and terepenes. Pyrrolidones or sulfoxides are used in an amount of 0.1 to 10% by weight based on the total composition, preferably 2 to 8% by weight. The surfactants are bridge 30 (Brij30), bridge 56 (Brij56), bridge 72 (Brij72), bridge 96 (Brij96), sorbitan monolaurate (Sorbitanmonolaurate), sorbitan monooleate (Sorbitan monooleate), glyceryl Glyceryl monolaurate, Glyceryl monooleate, Span20, Span40, Span80, Span80, Tween20, Tween40, Tween60 Tween60, Tween80, Tween85, Isopropyl myristate, Isopropyl isostearate, Isopropyl linoleate and Sodium lauryl sulfate Sodium lauryl sulfate) is used in an amount of 0.1 to 10% by weight based on the total composition, preferably 0.2 to 5% by weight.

In addition, the composition of the present invention may additionally use a gelling polymer, which serves as a thickener for imparting an appropriate viscosity to the composition. Examples of the thickener include hydroxy propyl cellulose, hydroxy methyl cellulose, hydroxy ethyl cellulose, polyvinyl prrolidone, and carbomer. It is preferable to use the selected one at 0.1 to 10% by weight based on the whole composition.

Preferred compositions of the composition according to the present invention as described above include (1) 0.1 to 20% by weight of methotrexate as an active ingredient pharmacologically active, (2) 50 to 98% by weight of polyhydric alcohol having a solubility of 20 mg / g or more in an active ingredient, (3) essentially containing 0.1 to 8% by weight of fatty acids or fatty alcohols, and optionally (4) one or two or more skins selected from pyrrolidone terephene compounds, sulfoxide compounds, surfactants and solvents It is good to add 0.1-20 weight% of permeation accelerators, and (5) 0.1-10 weight% of gelling polymers as a thickener.

Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited by the examples.

Skin penetration test example

In order to measure the skin permeation rate of the drug, it was measured by the following method using a Franz diffusion cell (Crown glass Co. Model FDC-400, USA). Donor compartment with the stratum corneum facing towards the donor department of human cadaver skin (IIAM, USA) or 6-week-old hairless mouse (Charlse River, USA) It is located between and the receptor department. At this time, the effective area of the skin in contact with the receptor solution and used for direct drug permeation was 0.636 cm 2. 5 ml of 0.05M pH 7.4 phosphate was used as the receptor solution, the stirring speed of the receptor solution was fixed at 600 rpm, and the temperature of the receptor solution was maintained at 32 ± 0.5 ° C. using a constant temperature circulation pump. After removing the bubble from the receptor solution, the drug-containing composition is placed in the donor compartment, and the drug solution is sealed to prevent volatilization, and then the receptor solution is collected at 4, 8, 16, 24, 36 and 48 hours from the sampling site. It was. The collected sample was analyzed by 1100 HPLC of Hewlett-Packard Corporation.

Example 1 Preparation of Methotrexate Transdermal Composition

After adding 3% by weight of methotrexate and 90% by weight of ethylene glycol to the light-shielded brown sample bottle, the mixture was stirred from side to side for 4 hours at a rate of 250 motion / min until the drug was completely dissolved in the ethylene glycol solution. In the next step, 1% by weight of capric acid was added and stirred for 1 hour at a speed of 120 motion / min, and left for 30 minutes. 6 wt% of hydrocipropyl cellulose was added to the solution prepared through the above procedure for 10 minutes. After adding hydrocipropyl cellulose, a transdermal composition containing methotrexate was prepared by stirring at a speed of 300 rpm using a mechanical stirrer (Heidon, Japan) for 24 hours. . The skin permeation rate (Js) was measured for the transdermal administration composition prepared above using the human skin skin in the same manner as in the skin permeation experiment. Skin permeation rate was calculated by the following equation 1 to express the amount of drug that penetrated the skin of the unit area per unit time as a function of time, the results are shown in Table 1 below.

In Equation 1: Js is the skin penetration rate of the drug in equilibrium (mcg / ㎠ / hr), A is the effective area of the skin used for drug penetration (cm 2), (dQ / dt) _ss is equilibrium The amount of drug that penetrates the skin per unit time in the condition (mcg / hr).

Examples 2-4 Preparation of the composition for methotrexate transdermal administration

Prepared in the same manner as in Example 1, but the methotrexate transdermal composition was prepared in the composition shown in Table 1, by measuring the skin permeation rate (Js) using the human Cordeber skin in the same manner as in the skin permeation experiment example The results are shown in Table 1 below.

Comparative Example 1

It was prepared in the same manner as in Example 1, but the methotrexate transdermal composition was prepared without capric acid, and then the skin permeation rate (Js) was measured using human Cordeber skin in the same manner as in the skin permeation experiment. The results are shown in Table 1 below.

Examples 5-9

Prepared in the same manner as in Example 1, but after the transdermal administration composition was prepared by adding ethylene pyrrolidone as a skin permeation accelerator, as shown in the composition ratio of the following Table 2, Human Cordeber in the same manner as in the skin permeation experiment Skin penetration rate (Js) was measured using the skin.

Comparative Examples 2 to 5

Prepared in the same manner as in Example 1, except for changing the type of solvent used as the composition ratio of the following Table 3 and by adding the ethylene pyrrolidone as a skin permeation accelerator to prepare a transdermal administration composition, skin permeation experiment The skin penetration rate (Js) was measured using human Cordeber skin in the same manner as in Example.

Examples 10-14

Prepared in the same manner as in Example 1, but after the percutaneous administration composition was prepared by adding ethylene pyrrolidone, carbacrorol as a skin permeation accelerator in the composition ratio of the following Table 4, human in the same manner as in the skin permeation experiment example Skin permeation rate (Js) was measured using Curdaver skin.

Examples 15-19

Prepared in the same manner as in Example 1, but using the decyl alcohol as fatty alcohol instead of fatty acids in the composition ratio of the following Table 5 and by adding thymol and ethanol as a skin permeation accelerator to prepare a transdermal administration composition, in the skin permeation experiment example The skin penetration rate (Js) was measured using human Cordeber skin in the same manner as described above.

As described above, the transdermal administration composition according to the present invention contains a methotrexate or methotrexate sodium salt as a pharmacologically active ingredient, and a sufficient amount using a polyhydric alcohol having a solubility in the pharmacologically active ingredient as a solvent of 20 mg / g or more. The drug can be supported in the transdermal administration composition, and because it contains a skin absorption accelerator, it can significantly improve the skin permeability of the drug can be useful for the treatment of rheumatoid arthritis.

Claims (8)

0.1-20 wt% of methotrexate as a pharmacologically active ingredient, 50 to 98% by weight of one or two or more polyhydric alcohols selected from ethylene glycol, diethylene glycol and triethylene glycol having a solubility in the active ingredient of 20 mg / g or more as a solvent, and As skin permeation accelerator, fatty acid or fatty alcohol 0.1-30% by weight A transdermal administration composition containing methotrexate having excellent skin permeability as an active ingredient, characterized in that it is contained. The method of claim 1, wherein the methotrexate is a transdermal composition, characterized in that the free acid form or in the form of a pharmaceutically acceptable salt. delete The method of claim 1, wherein the fatty acids are hexanoic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, neodecanoic acid, undecanoic acid, lauric acid, palmitic acid, Transdermal administration composition, characterized in that selected from linoleic acid and oleic acid. The transdermal administration of claim 1, wherein the fatty alcohols are selected from octanol, nonanol, decyl alcohol, undecanol, and lauryl alcohol. Composition. The composition according to claim 1, wherein the composition further comprises 0.1 to 20% by weight of one or two or more skin permeation promoters selected from pyrrolidone compounds, terephen compounds, sulfoxide compounds, surfactants and solvents, and 0.1 to thickeners. A composition for transdermal administration, characterized in that it contains 10% by weight. 7. The transdermal composition according to claim 6, wherein the pyrrolidone compound is selected from N-methyl pyrrolidone, hydroxyethyl pyrrolidinone and polyvinyl pyrrolidone. 7. The transdermal composition according to claim 6, wherein the terepene compound is selected from carbacrolol, thymol and menthol.