TW200418516A - Droplet dispersed ointment - Google Patents

Abstract

Ointments comprising pirfenidone that is superior in skin irritation, stability of the drug, and permeability to skin are provided. The invention relates to ointments which comprise pirfenidone and a ointment base, in which droplets containing pirfenidone dissolved in a solvent are dispersed in the ointment base.

Description

发明. Description of the invention: I: The technical field of the inventor's office 3 Field of the invention The present invention relates to a topical preparation for treating skin fibrous diseases. 3 Previous Background of the Invention Generally, an oily ointment called an ointment can be classified into a crystalline dispersion type ointment in which an active ingredient microcrystal is uniformly dispersed in an oily base, and a dissolution type in which an active ingredient is dissolved in an oily base An ointment and a droplet-dispersing softener that dissolves an active ingredient into fine droplets and disperses them in an oily base. The crystalline dispersion type ointment has the advantage of simple preparation, but the solid components cause irritation to the skin, and therefore have the disadvantages of poor drug absorption and uniform content. Dissolved ointments have the disadvantage of poor storage stability. It is known that the effective ingredients of the droplet type ointment are superior in percutaneous absorption compared to the crystalline dispersion type ointment. Solubilizers for external use usually cause skin irritation. For the treatment of burns and keloids in skin fibrotic patients, attention must be paid to the choice and amount of such dissolving agents. 5-methyl-1-phenyl-2- (1Η) -α-pyridone has antifiber effect, and is a well-known drug known as Pirfenidone (referred to as this publication No. 21-215719). ). Japanese Gazette No. 215719 describes that pirfenidone preparations include capsules, creams, ointments, etc. Ointments include hydrophilic ointments containing 5-10% pirfenidone, but do not describe droplet dispersion type Ointment. The so-called anti-fibrillation and quasi-chemical means pulmonary fibrosis, arteriosclerosis, and skin fibrotic diseases. 200418516 For example, the repair and normalization of fibrotic tissue of keloid disease. This publication 2002-526447 (W000 / 16775) contains a pirfenidone external preparation for treating skin fibrous diseases, including a gel and a right θ W cream, but not a droplet dispersion type. Ointment. It contains the pirfenidone ointment described in 5 here, and does not describe the characteristics of good storage stability. 0 Japanese Patent Publication 8-51025l (W094 / 26249) describes that it contains 5-10% of pirfenidone, but No droplet dispersion type ointment is described.

In 5,310,562, it is described that the pirfenidone preparation is a capsule, a tablet, a cream, an ointment, a hydrophilic ointment, and the like, but no droplet-dispersion type ointment is described.

A night-drop dispersing softener, in which the active ingredient is dexamethasone acetate, the base is white petrolatum and flowing paraffin, the dispersant is sorbitan sorbate, and the solvent is ethanol, benzyl alcohol, propylene glycol or 15 of these mixed liquids are described in 1) Pharmacology, Volume 50, No. 3, 279-285, 1990, 2) Pharmacology, Volume 50, No. 3, 286-291, 1990, and 3) Pharmacy Science, Volume 54, No. 1, 35-41, 1994, but no pirfenidone is recorded.

Chem.Pharm.Bull.47 (5), 647_65l (l999), describes the droplet dispersion type of the drug is mometasone furoate and the solvent is ethyleneglycol salicylate 20 The main reason for the effect of the drug release in the ointment, but pirfenib g is not documented. I: Summary of the invention 3 Summary of the invention In general, when pharmaceuticals are formulated for external use, ointments 6 200418516, external liquids, creams, lotions, plasters, and other types can be selected, but the ointments are It is made into a semi-solid external preparation with appropriate viscosity and uniform quality, and is a useful preparation that can be applied to diseased skin in various states and can be directly applied to diseased skin in various areas. 5 Therefore, compared with the conventional external preparations, choose ointment as the σ ratio

It is a topical preparation for pirfenidone, which is a topical study on skin irritation, drug stability, and transfer to the skin. It was found that by selecting an appropriate dissolving agent for dissolving pirfenidone, a droplet-dispersing ointment containing pirfenidone was successfully prepared, and its skin irritation, drug stability, and transfer to the skin Excellent. That is, the present invention is (1) a droplet-dispersing ointment which dissolves 5-fluorenyl-1-phenyl-2 (1Η) -pyridone or its pharmaceutically acceptable salt as an active ingredient in a dissolving agent The droplets are formed by dispersing in an ointment base. 15 (2) The droplet-dispersing ointment of (1) above, wherein the dissolving agent is benzyl alcohol,

N-methyl-2-pyrrolidone, ethylene glycol salicylate, 1-butanediol, hexanediol, propylene glycol, propylene carbonate, dipropylene glycol, or a mixture thereof. (3) The droplet-dispersing ointment of (2) above, wherein the dissolving agent is benzyl alcohol, N-fluorenyl-2-pyrrolidone, ethylene glycol salicylate, hexanediol, propylene glycol, propylene carbonate 20 or Its mixed liquid. (4) The droplet-dispersing ointment according to any one of the above (1) to (3), wherein the concentration of the dissolving agent is 1 to 15 W / W% with respect to the entire ointment. (5) The droplet-dispersed ointment according to any one of the above (1) to (4), wherein the concentration of the effective ingredient is 1 to 15 W / W% with respect to the entire ointment. 7 (6) The droplet-dispersing ointment of (1) above, wherein the ointment base contains sorbitan sestearate relative to the entire ointment in an amount of 5 to sW / W%. (7) The droplet-dispersing ointment according to any one of (1) to (6) above, wherein the ointment base comprises a flowing stone sacrifice, white vaseline, or a mixture thereof. (8) Regarding the droplet-dispersing ointment of (1) above, the active ingredient concentration is O.UW / W% with respect to the entire ointment; the concentration of the dissolving agent component is 1 to 15 W / W%; The sugar alcohol anhydride concentration is 0.5 to 8 W / W%. In the present invention, since the pirfenidone is dissolved in the dissolving agent and dispersed in the ointment as compared with the crystalline dispersion type ointment, the drug absorbability is good. In addition, it has excellent drug stability and content uniformity. In addition, since there is no solid matter, it has a hot, rough feeling and excellent use feeling, and does not cause skin irritation. Compared with a gel containing a carboxyvinyl polymer (CVP), the present invention has good skin absorption even with a small amount of a dissolving agent. In addition, the skin can efficiently absorb even a small amount of fun. Simple illustration

Fig. 1 is a graph showing changes in pirfenidone concentration in rat plasma. [Embodiment J The best form for implementing the present invention The droplet-dispersing ointment of the present invention refers to a dissolving agent of the active ingredient of the dissolving agent as a drop of money and uniformly dispersed in the ointment base mixed with it. Formulation 'Specifically, the aforementioned ointment is a dispersion of 5-methyl-1-phenyl-2 (ΐΗ) -pyridone or a pharmaceutically acceptable salt thereof, which is an active ingredient, in a dissolving agent and dispersed in an ointment base. Forming agents. The liquid droplet-dispersing soft lean agent of the present invention-such as a liquid droplet containing material with effective age and a fine ointment, 200418516, but the ointment base may also contain active ingredients. The droplet dispersion type ointment can be confirmed by observing the dispersion of the droplets in the ointment base with an optical microscope or the like, and the crystal dispersion type ointment and the dissolution type ointment can be distinguished by this. The droplet size is preferably less than 50 // m, and more preferably 5 is less than 20 // m. The droplet-dispersing ointment of the present invention containing pirfenidone as an active ingredient is useful for the treatment of skin fibrous diseases, such as keloids, hypertrophic keloids, fibrotic lesions, contact warts, and contact dermatitis. And post-operative burns are effective. 10 15

The active ingredient contained in the ointment of the present invention, methyl-bubenzyl-2 (1H) -oripoxanone, is prepared according to the method described in Japanese Laid-Open Gazette 7 and is used to prepare "salts allowed by Bibinisaki." Examples can include: amino acids and their salts, seeders (wind, hydrogen / stinky acid, dish acid, rock acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, Fumar Acid, tartaric acid, p-toluene acid, etc.) and their salts. Relative to the whole soft agent, the concentration of the active ingredient is preferably 0.1 to 5%, and more preferably 0.1 to 3%.

The dissolving agent constituting the liquid droplets of the soft lean agent of the present invention is a solvent which is excellent in the solubility of pirfenib steel, and can be used to hold the fenifepine in a residual state, and can maintain the dispersed state of the stable droplets. . The dissolving agent is preferably one having low compatibility with ointment bases of white petroleum jelly and flowing stone, and can form droplets in the ointment base by means of dispersants. In addition, a solvent that promotes transdermal absorption and a solvent that minimizes skin irritation are preferred. An ideal solution: N-N-m-Lang, salicylic acid, 13-butanol, hexanediol, propylene glycol, propylene carbonate, dipropylene glycol 9 200418516

Alcohol or a mixture thereof. More preferred are benzyl alcohol, N-methyl-2-pyrrolidone, ethylene glycol salicylate, hexanediol, propylene glycol, propylene carbonate, or a mixture thereof. The ideal composition and ideal concentration of the aforementioned mixed solution are: 1) benzyl alcohol 1 to 5% + salicylic acid ethylene glycol 1 to 7%, 2) benzyl alcohol 1 to 5% + hexanediol 1 to 7%, 3) Benzyl alcohol 1 to 5% + propanediol 1 to 7%, 4) Benzyl alcohol 1 to 5% + propylene carbonate 1 to 7%, 5) N-methyl-2-pyrrolidone 1 to 5% + salicylic acid Acid glycol 1 ~ 7%, 6) N-methyl-2-pyrrolidone 1 ~ 5% + hexanediol 1 ~ 7%, 7) N-methyl-2-pyrrolidone 1 ~ 5% + propylene glycol 1 ~ 7%, 8) N-methyl-2-pyrrolidone 1 ~ 5 ° / 〇 + propylene carbonate 1 ~ 7%. The amount of dissolving agent used should be as small as possible. Preferably, it contains 1 to 15% of the whole ointment, and more preferably 2 to 12%, and 4 to 8 ° /. For the best. The ointment base contained in the ointment of the present invention is suitable for use, for example, flowing paraffin, white petrolatum, white wax, ramie oil paraffin, or a mixture thereof.

The ointment base of the ointment of the present invention contains a dispersant for the purpose of stably dispersing the droplets of the dissolving agent. As the dispersant, one or more types of sorbitan 15 alkyd fatty acid esters and polyoxy fatty acid sorbitan fatty acid esters can be used. The ideal dispersant is sorbitan fatty acid esters, and the more preferred dispersant is sorbitan fatty acid sorbitan. The amount used is preferably 0.5 to 8 W / W% relative to the entire ointment, and more preferably 2 to 6 W / W%. The typical prescription and typical ratio of the ointment of the present invention (W / W% relative to the entire ointment 20) are as follows. Table 10 200418516 Pirfenidone 0.1 ~ 5W / W% Solvent 1 ~ 15W / W% Dispersant 0.5 ~ 8W / W% Flowing paraffin 2 ~ 10W / W% White vaseline 62 ~ 96.4W / W% 5 Suitable formulations of the present invention can be inferred from the drug stability results at 40 ° C for 2 months or 60 ° C for 1 week as described in Table 4 below: even after storage at room temperature for more than 6 months after manufacture, It contains pirfenidone stably, does not syneresize, does not precipitate crystals, and maintains a homogeneous droplet dispersion state. 10 The liquid droplet dispersion type ointment of the present invention is prepared by first mixing the ointment base and the dispersant after heating and cooling, and then adding a dissolving agent to dissolve pirfenidone, and it is easily prepared by mixing with a blender. The prepared ointment can be visually confirmed with a light microscope to disperse the droplets. The ointment of the present invention may further contain an antioxidant and the like. 15 Examples The following examples and test examples illustrate the present invention in more detail, but the present invention is not limited thereto. Test Example 1 Selection of Dissolving Agent 20 Pirfenidone 200 mg and 1.2 dissolving agent prepared by the method described in Japanese Laid-Open Patent Publication No. 49-87677 were placed in a test tube, and after shaking sufficiently, the dissolved state was visually confirmed. 11 200418516 Table 2 Dissolving state of the dissolving agent Diisopropyl adipate is incompletely dissolved Cetyl isostearate is not completely dissolved 5 Diethyl sebacate is not completely dissolved η-butyl acetate is not completely dissolved Isopropyl myristate incompletely dissolves isostearyl alcohol Incompletely dissolves octyldodecanol Incompletely dissolved 10 oleyl alcohol incompletely dissolves hexyldodecyl alcohol Incompletely dissolved benzyl alcohol completely dissolves 2-ethyl-1, 3-Hexanediol incompletely dissolved 1,3-butanediol completely dissolved 15 Hexanediol completely dissolved propylene glycol Completely dissolved 1,2,6-hexanetriol Incompletely dissolved ethylene glycol salicylate Completely dissolved propylene carbonate Completely dissolved Dissolve 20 N-methyl-2-pyrrolidone Completely dissolve polypropylene glycol 2000 Incompletely dissolve polypropylene glycol 400 Incompletely dissolve dipropylene glycol Completely dissolve It can be clearly known from Table 2 that the appropriate dissolution of pirfenidone The agents include 12 418516 methanol, 1,3-butanediol, hexanediol, propylene glycol, ethylene glycol salicylate, propylene carbonate, N-methyl-2 · pyrrolidone, and dipropylene glycol. There is no coloring in these solvents. From this, it can be seen that by selecting a dissolving agent suitable for pirfenidone, a droplet-dispersing ointment having excellent drug stability and no precipitation, such as precipitation, and excellent content uniformity can be obtained. Example 1 For the eight dissolving agents tested in Test 1, the following table composition (W / w%) was used to prepare a droplet dispersion type ointment. 10 That is, a predetermined amount of white petroleum jelly, flowing paraffin, and sorbitan sestearate are heated and melted at 80 ° C to a liquid state to prepare an ointment base. Next, it is cooled to 45 to 55 ° C, and a predetermined amount of pirfenidone is dissolved in various dissolving agents, and then added to the ointment base and stirred to a temperature of 30 to 37 ° C. After defoaming under reduced pressure, it was filled into a 5 g test tube. 15 Table 3 ^ Example ingredients 1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9 pirfenidone 1 1 1 1 1 1 1 1 1 benzyl alcohol 4 6 1,3-butanediol 6 Hexanediol 6 Propylene glycol 6 Ethylene glycol salicylate 6 N-fluorenyl-2-pyrrolidone 6 Propylene carbonate 6 Dipropylene glycol 6 Sorbitan sorbitan 4 4 4 4 4 4 4 4 4 flowing white soil 5 5 5 5 5 5 5 5 5 white petroleum jelly 86 84 84 84 84 84 84 84 84 Comparative Example 13 200418516 Modified by 1W / W% pirfenidone, 5W / W% flowing Paraffin wax, 94W / W% white petroleum jelly is a crystalline dispersion ointment. That is, a predetermined amount of flowing paraffin and white petroleum jelly are heated and melted at 80 ° C to a liquid state to prepare an ointment base. Next, it is cooled to 45 to 55 ° C, and the regular amount of pirfenidone is dissolved in various dissolving agents, and then added to the ointment base and stirred to a temperature of 30 to 37 ° C. After defoaming under reduced pressure, it was filled into a 5g test tube. Test 2 The ointments produced in Example 4 and Comparative Example 1 were stored at 40 ° C for 2 months, 10 or 60 ° c for 1 week, and then the pirfenidone content was measured by HPLC (internal standard method). Table 4 Formulation Soluble Agent 60 ° C for 1 week Example 1-1 Benzyl alcohol 102.0% Example 1-2 Benzyl alcohol 95.3% 15 Example 1-3 1,3-butanediol 97.1% Example 1-4 hexane Glycol 100.5% Example 1-5 Propylene Glycol 98.4% Example 1 -6 Ethylene glycol salicylate 98.5% Example 1-7 Propylene carbonate 91.7% 20 Example 1-8 N-methyl-2-pyrrolidone 95.3 % Example 1-9 Dipropylene glycol 97.6% No control example 87.9% The results shown in Table 4 show that the droplet-dispersed ointment of the present invention has stability equal to or higher than that of the crystal-dispersed ointment. In addition, the results stored in 60 14 200418516 c are presumed to have stability at room temperature for more than 6 months. Moreover, in any of the examples, 'there was no precipitation of crystals or syneresis after long-term storage. Example 2 A mixed dissolving agent of methanol and ethylene glycol salicylate was prepared in the same manner as in Example 1 and prepared in the following table (W / W%) to prepare a droplet dispersion type ointment. Brother 5 shows the composition of the examples --- 2-1-σ bifenib _ 1 3 benzyl alcohol 4 4 salicyl sulphonate _ ferment 4 4 times harder sour sorbitan 4 4 flowing white wax 5 5 White Vaseline 82 80 Comparative Example 2 A crystalline dispersion ointment formed by 3W / W% pirfenidone, 5W / W% flowing paraffin, 92W / W% 10 white Vaseline. Comparative Example 3 was prepared from 5W / W% fluorfenidone, 1.7W / W% carboxyvinyl polymer (CVP), 15W / W% isopropyl glycol, 25W / W% propylene glycol, 12.5WAV% polyethylene glycol 400, A gelling agent formed by 1.0 W / W% triisopropanolamine and 39.8 W / W% pure water. Test Example 3 The ointment of Example 1-1, Example 1-4, Example 1-8, Example, Example 2-2, and Comparative Example 3, and the gel of Comparative Example 3, respectively, 15 200418516 300 mg of the drug was injected into the abdomen of rats, and the amount of flesh transfer after 6 hours was measured. In the administration, a glass liquid tank was connected to the atmospheric abdomen from which body hair had been removed by a razor, and the preparation was placed in the aforementioned liquid tank to administer a certain area. The dosing method involves closed administration 5 that covers the upper part of the glass tank with a lid that is ground and bonded, and open administration that removes the lid. Chloroform was used to remove the formulation remaining at the administration site. Next, the skin at the administration site was collected and minced, and pirfenidone 10 in the skin was extracted with vinyl acetate and quantified by HPLC.

The results obtained are shown in Table 6. Table 6_ 15 Formulation t 1 Bifenidone W / W% Soluble agent intradermal distribution 2) Closed administration open system Example 1-1 1.0 Benzyl alcohol 16.2 ± 4.0 10.1 ± 4.8 Example 1-4 1.0 Hexanediol 12.9 ± 1.1 Example 1 -8 1.0 N-methyl-2-3 ratio σ each ketone 14.0 ± 4.7 Example 2 -1 1.0 Mixed solvent 16.9 ± 4.3 Example 2-2 3.0 Mixed solvent 31.3 ± 7.4 13 5 ± 4.8 Comparative Example 2 3.0 None (Crystal-dispersed paste) 9.2 ± 2.4 Table 6 shows that compared with the crystalline-dispersed ointment, the liquid 20-drop dispersion-type ointment of the present invention has a small drug content. In the case of intradermal distribution, σ than fenidone can be easily transferred into the skin. Test Example 4 The ointment of Example 1-8 and Example 2-2 and the gel of Comparative Example 3 were administered to the abdomen of a rat at 200 mg, and the plasma concentration was measured after 8 hours. 16 200418516 Quantitative radioactive agents using pirfenidone. The results obtained are shown in Figure 1.

Figure 1 shows that although the pirfenidone content in the formulations of Examples 1-8 is low, the drug can be quickly transferred into the skin. This indicates that N-methyl-2-pyrrolidone 5one is suitable as a solubilizing agent for pirfenidone, which has an absorption-promoting effect. In addition, compared with the preparation of Comparative Example 4, the preparation of Example 2_2 also showed that although the σ was lower than that of fenidone, the drug could be quickly transferred into the skin. Compared to any of the gelling agents of Comparative Example 3 (isopropyl alcohol, propylene glycol, and polyethylene glycol 400 as dissolving agents), these preparations preferably have a low dissolving agent content and are less irritating to the skin. Test Example 5 The ointments of Examples 1-8 and 2-2 were applied to the skin of the back of white rabbits once a day and repeatedly for 14 days to perform a skin irritation test. Neither formulation is substantially irritating to the skin. 15 Test example 6

The ointments of Examples 1-1, 1-8, and 2-2 were stored at -20, 5, 40, and 60 ° C for 3 months without crystallization after long-term storage. Precipitation. Industrial Applicability 20 According to the present invention, a pirfenidone effective for repairing and normalizing fibrotic tissues of pulmonary fibrosis, arteriosclerosis, and skin fibrotic diseases such as keloid disease is provided. A formulation that is excellent in skin irritation, drug stability, and transfer to the skin. 17 200418516 Brief description of the L pattern 3 Figure 1: A graph showing changes in pirfenidone concentration in rat plasma. [Schematic symbol list of main elements] (none) 18

Claims (1)

200418516 < Scope of patent application: L A droplet-dispersing ointment, which disperses the 5-methyl microbenzyl-2 ⑽ ㈣, which is an active ingredient, or a pharmaceutically acceptable salt thereof in a dissolving agent, and disperses it in Formed in ointment base. 5 2 · The droplet-dispersing ointment of item 1 in the scope of application in May, where the aforementioned dissolving agent is alcohol, N-methyl_2, each ketone, salicylic acid glycol, 1: 3- Butanol, hexanediol, propylene glycol, propylene carbonate, dipropylene glycol or a mixture thereof. 3. If you apply for the liquid soft palate of item 2, where the aforementioned 10 solvents are narrow alcohol, N-methyl_2 ketone, salicylic acid ethylene glycol, hexanediol, propylene glycol, carbonic acid Acrylic ester or a mixture thereof. 4. = Application #Patent Supplement No. 1-Drop Dispersion Ointment ^ The concentration of the alysing agent in A described in 相对 above is 1 ~ 15W / W% relative to the whole ointment 〇15 5. Ruzhong May Patent液 The droplet-dispersed ointment according to item 丨, wherein the effective effective knife / chen degree is huw / w% with respect to the entire ointment. 6. The droplet-dispersed ointment according to item 丨 of the patent application, wherein the soft beta base contains 0.5 to 8 W / W% of sorbitan stearate relative to the whole of the ointment. 207. The droplet-dispersing ointment according to item 1 of the application, wherein the aforementioned soft lean base agent comprises flowing paraffin, white petrolatum or a mixture thereof. 8. If the liquid droplet dispersion type ointment according to item 1 of the patent application scope, the concentration of the aforementioned active ingredient is 0.1 to 5 W / W%, and the concentration of the aforementioned dissolving agent ingredient is ^ MW / W%. The concentration of sorbitan stearate 15 is 0.5 to 8 W / W%. 19