WO2004073713A1

WO2004073713A1 - Pirfenidone gel preparation

Info

Publication number: WO2004073713A1
Application number: PCT/JP2004/001968
Authority: WO
Inventors: Kaori Ikeda; Yuichi Takasu; Kazumasa Morimoto
Original assignee: Shionogi & Co., Ltd.
Priority date: 2003-02-21
Filing date: 2004-02-20
Publication date: 2004-09-02
Also published as: TW200501952A

Abstract

A gel preparation containing denatured HPMC together with 5-methyl-1-phenyl-2-(1H)-pyridone or a pharmaceutically acceptable salt or ester thereof as the active ingredient. Thus, a gel preparation for treating fibrous skin diseases which is excellent in stable shape retention, spread properties and skin migration of a drug is provided.

Description

Description Genolating agent for pinorefenidone Technical field

The present invention relates to gels for treating fibrotic diseases of the skin. Background art

5-Methyl-11-phenyl-1- (1H) -pyridone is a drug known as Pirfenidone, which has an antifibrotic action (Japanese Patent Laid-Open No. 2-215719). Here, the formulation of pirfenidone includes capsules, tablets, tablets, ointments and the like. As an ointment, “Hydrophilic ointment containing 5 to 10% of pirfenidone” is mentioned, but no specific composition is described. Anti-fiber means pulmonary fibrosis, arteriosclerosis, skin fibrosis 'I', and the repair or normalization of pathological fibrotic tissue in keloids.

U.S. Pat.No. 5,310,562 describes the possibility of topical application of pirfenidone, and describes capsules, tablets, creams, ointments, hydrophilic ointments, etc. as pirfenidone preparations. The specific composition is not described. JP-T-Hei 2002-526447 (W000 / 16775) describes gels, ointments and creams as external preparations for treating fibrotic diseases of the skin. The gel described in JP-T-Hei 2002-526447 uses carboxybutyl polymer (CVP> as a gel-forming agent. This gel is contained in the ionic component of the preparation and the biological component at the administration site. Since the viscosity of the gel changes due to the influence of the ON component, it is necessary to add some additives and adjust the pH of the whole preparation to obtain stable shape retention and spreadability of the preparation. In this gel, CVP reacts with the active ingredient and additives, and there is a concern that the coloring of the formulation and the stability of the active ingredient may be reduced.

W094 / 26249 (Tokuhyo Hei 8-510251) describes capsules, tablets, creams, ointments and the like as preparations containing N-substituted 2- (1H) pyridone as an active ingredient. The description of the ointment "Hydrophilic ointment containing 5- 10% pyreuyudon" A certain composition is not described.

JP-A-3-151339 discloses a nonionic water-soluble cellulose ether (such as partially hydrophobized hydroxypropylmethylcellulose (HM-HPMC)) treated with a modifying agent having an alkyl group having 6 to 26 carbon atoms. Gels containing are described. It is described as a stable gel that has less interaction with drugs and does not require a neutralizing base compared to carboxybutyl polymer (CVP). Not listed. Here, tetracycline hydrochloride, kanamycin and gentamicin sulfate are described as active ingredients, and modified cellulose ether, ethanol, isopropanol, glycerin, polyethylene glycol 400, and propylene glycol are described as solvent components.

Pharmacology, Vol. 52, No. 4, 272-279, 1992 states that HM-H PMCs are less susceptible to changes in pH and less susceptible to salt formation with drugs than CVP. In addition, water / "ethanol, water isopropanol, benzyl alcohol, and dimethyl sulfoxide are described as solvents with high solubility of HM-HPMC. Gel pill phenodon is not described.

Pharmaceutical Sciences, Vol. 52, No. 4, 280-287, 1992 states that gels using HM-H PMC are more effective than gels using CVP in terms of properties, drug stability, drug release, and transdermal drug delivery. Although there was no significant difference in absorbency, it describes the features of preventing the precipitation of crystals and stabilizing the drug for some drugs. Gentamycin sulfate, dexamethasone acetate, and indomethacin are described as active ingredients, but no mention is made of gels of pirfenodon. As the solvent component, ethanol, isopropanol, polyethylene glycol, polyethylene glycol 400, polyethylene glycol monooleate, and glycerin are described. Used. Disclosure of the invention

Therefore, in order to obtain a genole agent that is stable and has excellent shape transferability and excellent skin transferability of a drug, we focused on the gel-forming agent and the solvent component instead of devising additives, and conducted intensive studies. As a result, the type and amount of non-ionic gel-forming agent It has been found that the desired gel agent can be easily prepared by appropriately selecting a solvent composition which is excellent in solubility and stable in a solution state.

That is, the present invention

(1) A gel preparation containing 5-methyl-1-phenyl-2- (1H) -pyridone or a pharmaceutically acceptable salt thereof as an active ingredient together with partially hydrophobized hydroxypropylmethylcellulose,

(2) The gel according to (1), further comprising a solvent component,

(3) The gel according to the above (2), wherein the solvent component is propylene glycol, isopropanol, polyethylene glycol, N-methyl-2-pyrrolidone, benzyl alcohol or a mixture thereof.

(4) The gel according to (3), wherein the solvent component is polyethylene glycol having a weight average molecular weight of 380 to 420.

(5) The gel according to any one of (2) above, wherein the concentration of the solvent component is 5 to ⁷⁰ W /

(6) The concentration of the active ingredient is 0:! ~ 15W // based on the whole gel. The gel according to any one of claims (1) to (5),

(7) The gel according to any one of the above (1) to (6), wherein the concentration of the partially hydrophobized hydroxypropylmethylcellulose is 0.5 to 5 W / W% based on the entire gel.

(8) The concentration of the active ingredient is 0 .; 15 to 15 W / W%, the concentration of partially hydrophobic hydroxypropylmethylcellulose is 0.5 to 5 W / W%, and the concentration of the solvent component is 5 to

The gel according to the above (1), which is 70 W / W%.

According to the present invention, by selecting a solvent having excellent skin irritation, drug stability and transferability to the skin, the shape retention and spreadability of the preparation are not affected by ions or pH, and A preparation excellent in transferability to the skin is obtained.

Also, compared to carboxybutyl polymer (CVP) gels, it is less likely to interact with pirfueudon and other additives, and has excellent stability. Furthermore, it is not affected by biological components (such as ions) at the administration site.

Furthermore, in the present invention, since the range of the solvent content can be set broadly by appropriately selecting the type and amount of the nonionic gelling agent, the concentration range of pirufenidone can be broadly adjusted. The solvent composition can be selected in consideration of skin irritation and skin absorption as well as possible. In addition, a gel in which the drug is dissolved in a solvent that is miscible with water at an arbitrary ratio without causing phase separation is formed stably, so that a preparation with excellent drug uniformity can be obtained. BRIEF DESCRIPTION OF THE FIGURES

Figure 1: is a graph showing the viscosity changes with respect to _P H gels.

Figure 2: Graph showing the inhibition of granulation formation by the gel in the rat; BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, a gel means a preparation in which a drug solution comprising a solvent that is miscible with water at an arbitrary ratio is imparted with shape retention and spreadability by a gelling agent.

The gel of the present invention containing pirfenidone as an active ingredient treats fibrotic diseases of the skin, for example, keloids, hypertrophic scars, fibrotic lesion tissues, contact warts, contact dermatitis and postoperative burns Useful to do.

"5-Methyl-1-phenyl-2- (1H) -pyridone (pinolephenidone)" as an active ingredient contained in the gel preparation of the present invention is disclosed in Japanese Patent Application Laid-Open No. 49-876777. Prepared by the method described. Examples of the salt of pyrfuedone include salts with amino acids, inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.), and organic acids (acetic acid, cunic acid, maleic acid, fumaric acid, benzenesulfonic acid) , P-toluenesulfonic acid and the like). The concentration of the active ingredient is preferably from 0.1 to 15 WZW%, more preferably from 0.1 to 5 W / W%.

The `` partially hydrophobized hydroxypropylmethyl cellulose '' contained in the gel of the present invention is an external gel base also referred to as modified HPMC, in which a hydroxy group in the molecule is substituted with an alkyl group having 6 to 26 carbon atoms. Means a non-crosslinked nonionic water-soluble cellulose ether substituted with a halide, monoepoxide or monoisocyanate. The details are described in B Patent No. 2610052.

Non-ionic water-soluble cellulose ethers include hydroxypropyl methyl cellulose. Hydroxypropyl methylcellulose is a cellulose hydride A compound in which a loxy group is substituted by a methyl group or a hydroxypropyl group, and is derived to a methoxy group or a hydroxypropoxyl group, respectively. Preferably, the substitution rate of the methyl group is 10% to 35%, and the substitution rate of the hydroxypropoxyl group is 2% to 15%. More preferably, a compound having a methyl group substitution rate of 18% to 25% and a hydroxypropoxyl group substitution rate of 3% to 13%, and a methyl group substitution rate of 26% to 32%. A compound having a hydroxypropoxyl group substitution rate of 5% to 9%, or a methyl group substitution rate of 26% to 32% and a hydroxypropoxyl group substitution rate of 6 ° / ₀ to: L 3% compound. For example, hydroxypropylmethylcellulose 2208, 2906, or 2910, the 13th Revised Japanese Pharmacopoeia.

By introducing an alkyl group having 6 to 26 carbon atoms into the remaining hydroxy group to such a substituted hydroxymethyl cellulose, the partially hydrophobized hydroxypropyl methylcellulose (modified HPMC) used in the present invention can be obtained. Is obtained.

By changing the introduction ratio of the alkyl group having 6 to 26 carbon atoms to the substituted hydroxymethylcellulose, a modified HPMC can be obtained in which the range of the solvent amount can be variously changed. For example, by reducing the introduction rate in the modified HPMC such as 0.1 to 0.7%, the amount of solvent required in the gel can be reduced. On the other hand, by increasing the introduction rate as high as 2.6 to 2%, the solvent content can be set high, and a formulation in which pirfenidone is dissolved at a high concentration can be obtained. In addition, by setting the introduction rate to 0.9 to 2.2%, a drug product with characteristics intermediate between the two can be obtained.

Modified HPMC is readily prepared by the method described in Japanese Patent No. 2610052. Alternatively, it is commercially available from Daido Kasei under the trade name Sangelose. The concentration of the partially hydrophobized hydroxypropylmethyl cellulose is preferably 0.5 to 5 W / W%, more preferably 1 to 2 W / W% based on the whole gel.

The solvent component that can be contained in the gel preparation of the present invention is also used for reducing the skin irritation and improving skin transferability used for dissolving pirfenidone.

The preferred solvent component in the present invention is propylene glycol, isopropanol, polyethylene glycol, N-methyl-1-pyrrolidone, benzyl alcohol or a mixture thereof. Coal 400 (polyethylene glycol with a weight average molecular weight of 380 to 420) is preferred.

Preferred combinations with preferred concentration in the case of mixture, the 1) I isopropanol 5 ~15W / W ^_0/0 + propylene glycol 5~15WZW ^_0/0, 2) isopropanol Lumpur 5~ 15WZW% + benzyl alcohol 1 5W / W%, 3) Isopropanol 5 to 15WZW% + N-methyl-2-pyridone 1 to 5WZW%, 4) Propylene glycol 5 to 15W ^/ W% + Polyethylene glycol 400 power S5 to 10W / W%, 5) Propylene glycol 5-15 /% + benzyl alcohol 1-5W / W%, 6) Propylene glycol 5-15WZW% + N-methyl-1-pyridone 1-5WZW%, 7) Isopropanol 5- 15W / W% + 5 to 15WZW% for propylene glycol + 5 to 10WZ W% for polyethylene glycol 400, 8) 5 to 15W / W% for isopropanol + 5 to 15W / W% for propylene glycol + 1 for benzyl alcohol ~ 5 W / W%, 9) Isopropanol 5-15 W / W% + propylene glycol 5-15 WZW% + N-methyl-2-pyridone 1-5W / W%, 10) Isopropanol 5-15WZWQ / 0 + propylene glycol 5-15 WZW ⁰ / o + polyethylene glycol 400 5-10W / W W ^o / ₀ + benzyl alcohol 1 to 5 W / W%, 11) isopropanol 5 to 15 W / W% + propylene glycol 5 to 15 WZW% + polyethylene glycol 400 5 to 10 WZW ⁰ / o + N-methyl 2-Pyridone is 1 to 5 W / W%.

Typical formulations and typical ratios (W / W% based on the whole formulation) of the present invention are as follows.

table 1

Pilfudon 0.1 ~ 15 W / W ° / o

Solvent component 5-70 W / W ° / o

Denatured HPMC 0.5-5 W / W%

Deionized water 10 to 94.4 W / W In the process of dispersing the denatured HPMC in heated deionized water and then cooling, add the pyrphenidone dissolved in the solvent component and stir. Easy to do Is prepared.

The gel of the present invention can further contain an antioxidant, a preservative, and the like. Example

The present invention is described in more detail by the following examples. However, the present invention is not limited to this. Example 1

Preparation of Genorai U

Add an appropriate amount of deionized water to a beaker, heat to 80 ° C, and disperse uniformly:! ~ 1.5 g of each grade of denatured HPMC Sangelose, then transfer the beaker to an ice-water bath. And cooled. Separately, dissolve l to 15 g of pirfenidone in 5 to 70 g of solvent, add to the beaker in the middle of cooling, and finally add an appropriate amount of deionized water to make the total amount 100 g, and mix uniformly with a stirrer. A gel was prepared by dissolving all components. Table 2 shows the composition of each formulation. Table 2

Example 2

A gel was prepared in the same manner as in Example 1 with the composition shown in the following table (W / W ° / o), and filled in a 5 g tube. Table 3

Test example 1

Example 2-3, Example 2-4, Example 2-5, Example 2-6, Example 2-7, Example 2-8, Example 2-9, Example 2-10, Example The gels prepared in 2-11 and Example 2-12 were stored at 40 ° C for 3 months, and the content of pirfenidone was measured by HPLC (absolute calibration method).

Table 4 shows the obtained results.

Table 4

Formulation 40 ° C for 3 months

Example 2-3 99.5%

Example 2-4 100.9%

Example 2-5 103.80%

Example 2 = -6 103.10%

Example 2-7 1 10.40%

Example 2-8 106.90%

Example 2-9 104.20%

Example 2-10 105.50%

Example 2- "105.40%

Example 2-12 103.70% The results shown in Table 4 were obtained by using denatured HPMC (San Jellose 90L) as the gelling agent. This shows that the gel has good stability. Note that no precipitation of crystals was observed after storage over time in any of the examples. Test example 2

The gels of Example 2-1, Example 2-2, Example 2-3, Example 2-8, Example 2-11, and Example 2-12 were administered to the rat abdomen at 300 mg each, The amount of intradermal transfer after time was measured. The administration was performed by attaching a glass cell to the abdomen of the rat, from which the hair had been removed using a razor, and placing the preparation in the cell to keep the administration area constant. As the administration method, occlusion administration in which the top of the glass cell was covered with a rubbed lid, and open administration in which the lid was removed were performed.

The formulation remaining at the administration site was removed with ethanol. Next, the skin at the administration site was collected and, after shredding, pirfenidone in the skin was extracted with ethyl acetate and quantified by HPLC, and the results obtained are shown in Table 5.

Table 5

Intradermal distribution (g)

Formulation Pirfenidone W / W%

Occlusion administration Open system

Example 2-1 50.8 ± 13.9 16.0 ± 2.3

Example 2-2 28.8 ± 7.7

Example 2-3 58.5 ± 25.7

Example 2-8 1 19.2 ± 38.2

Example 2-11 53.83 ± 13.85

Example 2-12

64.9 ± 31.1 Table 5 shows that gels using denatured HPMC (Sangelose 90L) as a gelling agent have good intradermal distribution and can easily transfer pirueyudon into the skin. Is shown. It is also possible to increase the amount of intradermal distribution by changing the solvent composition as shown in Table 5, and it is possible to increase the amount of pirufenidone as in Examples 2-11 and 2-12. Sufficient intradermal distribution can be maintained. Example 3

A gel was prepared with the composition (W / W%) shown in the table below and filled in a 5 g tube.

Table 6 [w / w%]

Example 4

Preparation of a gel was attempted with the composition (W / W) shown in the table below. Table 7

〇: Uniform gel preparation is possible

X: Crystal precipitation, gel preparation not possible In the case of the composition using carboxyvinyl polymer (CVP) (Control Example 4-1, Control Example 4-2, Control Example 4-3, Control Example 4-4), cloudiness or drug crystals precipitated, It was not possible to prepare a uniform gel. However, even with these compositions, uniform gels could be prepared by changing the gel-forming agent to denatured HPMC (Sangelose 90L) (Examples 4-1, 4-1 and 4- 3, Example 4-4). Example 5

A gel was prepared with the composition (W / W%) in the table below _c

Table 8

[W / W%]

Control 1

A gel was prepared with the composition (WM) shown in the table below.

Table 9

Test example 3

Gels of Example 5-1, Example 5-2, Example 5-3, Example 5-4, Control example 1-1, Control example 1-2, Control example 1-3, Control example 1-4 Was measured with an E-type viscometer.

The results are shown in Table 10, which is graphed in FIG.

Table 10

PH CVP denatured HPMC

2. 3 28365

3. 8 32768

4. 1 11468. 8

5. 3 76288

5. 9 33 280

9.2 76390. 4

10. 2 31232

10.8 73728 1, gels with denaturing HPMC gelling agent relative to that maintain _P H2. 3 to 10. Stable viscosity 2 was used Karubokishibi two Ruporima (CVP) Gel This indicates that the viscosity of the agent is greatly reduced on the acid generation side. When denatured HPMC (Sangelose 90L) is used as the gelling agent, a pH stable gel can be prepared. Test example 4

The gel was tested for its ability to inhibit granulation formation according to the method described in Jpn Pharmacology Journal 99, 241-246 (1992).

8-week-old male Wistar (Wi star) 0. Rats 5% / c- force Ragenin (逗child Chemical) osmotic minipumps filled with saline solution (Alzet ® (a 1 _Z et®), Model 2002) pent the It was implanted subcutaneously in the back under parbital anesthesia. In other words, after shaving and disinfection, an incision was made about 1 cm in the center between the scapulae, and a pocket for mounting a pump was made subcutaneously from the incision to the tail. The pump was implanted with the outflow part of the drug first, the incision part was sewn at one or two places, and then glued with a medical adhesive. From the next day, Example 3-1, Example 2-3 and Control A were applied once a day for 14 days. On the day after the final administration, all cases were euthanized with over anesthesia, the granulation tissue around the mini-pump was excised including the pump, the granulation was incised, the pump was removed, and the weight of the granulation tissue after 145 was measured. The significant difference test with control A was performed by Dunnett's test. In addition, 5 animals were used for each group.

Control A had 25% w / w of propylene dalicol, polyethylene glycolone 4

It is a gel agent that does not contain the active ingredient pirfenidone, which consists of 00 12.5 W / W%, Sangelose 90 L 1.3 W / W% _N and deionized water 61.2 WZW%.

The result is shown in figure 2. Granulation formation was significantly suppressed by applying the gel of the present invention. Individuals available for industrial use

According to the present invention, a preparation having excellent drug stability and skin transfer properties can be obtained by selecting a solvent component suitable for pirfenidone. Also, by selecting the type of denatured HPMC, gels with various amounts of solvent are formed, the range of concentration of pirufenidone is widened, and the amount of solvent is reduced to obtain a formulation with less skin irritation.

Claims

The scope of the claims

1. A gel preparation containing, as an active ingredient, 5-methyl-1-phenyl-2- (1H) -pyridone or a pharmaceutically acceptable salt thereof together with partially hydrophobized hydroxypropylmethylcellulose.

2. The gel preparation according to claim 1, further comprising a solvent component.

3. The gel preparation according to claim 2, wherein the solvent component is propylene glycol, isopropanol, polyethylene daricol, N-methyl-1-pyrrolidone, benzyl alcohol or a mixture thereof.

4. The gel preparation according to claim 3, wherein the solvent component is polyethylene glycol having a weight average molecular weight of 380 to 420.

5. The gel preparation according to any one of claims 2 to 4, wherein the concentration of the solvent component is 5 to 70 W / W% based on the whole gel preparation.

6. The gel preparation according to any one of claims 1 to 4, wherein the concentration of the active ingredient is 0.1 to 15 W / W% based on the whole gel preparation.

7. The concentration of partially hydrophobized hydroxypropyl methylcellulose is 0.5 to 5 W / W for the whole gel. /. The gel according to claim 1, which is:

8. The concentration of the active ingredient is 0.1-15 W / W%, the concentration of partially hydrophobized hydroxypropylmethylcellulose is 0.5-5 W / W%, and the concentration of the solvent component is 5-70 W / W. The gel according to claim 1, which is W%.