JPS61229824A - Percutaneous absorption type steroid external agent - Google Patents

Abstract

PURPOSE:The titled external agent containing a specific anti-inflammatory steroid. CONSTITUTION:A percutaneous absorption type steroid external agent containing 0.1-5wt%, preferably 0.5-2.5wt%, anti-inflammatory steroid in which the OH group at the 21-position is substituted by a group expressed by the formula -OCO(R)nCOOH (R is -CH2-; n is an integer 0-7) or farnesyl group or a salt thereof. The agent is in the form of an acid (-COOH) under acidic conditions (3.5-6.5pH), and is easily passed through the skin, and becomes COO<-> at about 7.4pH under the skin to provides easy migration in the body. Examples of the above-mentioned anti-inflammatory steroid include prednisone, dexameth asone, betamethasone, etc. The dosage form includes ointment, cream or jelly. The agent is applicable to chronic articular rheumatism, arthritis accompanied by collagen disease, deformed arthrosis, gout, lumbago, frozen shoulder, etc.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a transdermal topical steroid preparation.

[Problems to be solved by conventional technology and invention]

Anti-inflammatory steroids such as dexamethacin and prednisone are known to have physiological activities such as anti-inflammatory, anti-allergic and immunosuppressive effects and have been widely used.

However, in the treatment of rheumatoid arthritis, osteoarthritis, frozen shoulder, pedislenitis, etc., these anti-inflammatory steroids are used internally or by injection, and are highly effective; however, these anti-inflammatory steroids are used as external agents. Nothing has been done. This seems to be because even if these drugs are applied to the affected area in the form of external preparations such as ointments or creams, they hardly penetrate into the skin and do not reach the affected area (and thus cannot be effective. The conventional administration methods of oral administration or injection tend to cause side effects of the anti-inflammatory steroid itself.

The present inventors have investigated drugs that can be used for treatment by penetrating into the skin while avoiding the oral and injection forms of administration that tend to cause side effects of these anti-inflammatory steroids.
The present invention has been discovered.

[Means for solving problems]

That is, in the present invention, the OH group at position 21 has the formula -〇〇〇(El)n
Transdermal absorption type containing an anti-inflammatory steroid substituted with a COOE group (wherein R is 10H2- and n is an integer from 0 to 7) or a 7-arnesyl group or a pharmaceutically acceptable salt thereof Regarding topical steroids.

The external preparation of the present invention is acidic (PH3.5-6.5) and acidic (PH3.5-6.5).
- Because it is in the form of COOE ( ), it easily passes through the skin. Subcutaneously, since - in the living body is around 7.4, it becomes COO-, becomes water-soluble, and is easily transferred into the body. In addition, squalene itself has good membrane permeability and internalization.

The anti-inflammatory steroid used in the present invention may be any steroid that has physiological activities such as anti-inflammatory and analgesic effects (for example, prednisolone, dexamethacin, betamethacin, and triamcinolo7). A steroid whose OH group at position 21 is substituted with 1000 (R)nCOOH group or farnesyl group or a pharmaceutically acceptable salt thereof is used. In the formula, R is 10H2- and n is 0 to is an integer of 7.n is 0
It is an integer of 7 to 7, preferably 1 to 4, most preferably 2. Examples of these esters include L, oxalic acid esters, malon powder esters, moss acid esters, glutaric acid esters, adipic acid esters, etc. Pharmaceutically acceptable salts include sodium salts, potassium salts, tartrate salts, etc. , citrate, maleate, fumarate, etc. These substituted anti-inflammatory steroids used in the present invention can be obtained by conventional methods such as esterification reaction.

Taking prednisone as an example, the cap replacement anti-inflammatory steroid used in the present invention is represented by the following formula.

A method for producing prednisolone sodium succinate is also shown in German Patent No. 1,045,400 (Pfizer).

The external preparation of the present invention contains about 0.0% of the above anti-inflammatory steroid.
It contains 1 to 5% by weight, preferably about 0.5 to 2.5% by weight.

The external preparation of the present invention can be manufactured according to conventional ointment, cream, or jelly manufacturing methods.

For example, an effective amount of the above anti-inflammatory steroid may be added to an anhydrous base (oleaginous base, water-soluble base), emulsion base (oil-in-water emulsion base, water-in-oil emulsion base), It is manufactured by mixing it into a suspending base. Examples of raw materials used for the base include oily substances such as liquid rough fin, vaseline, silicone oil, aliphatic lower or higher alcohols, higher fatty acids, fatty acid esters, vegetable oil, castor oil, lanolin and its derivatives, squalane, squalene, etc. ; Emulsifiers/dispersants such as nonionic surfactants (polyhydric alcohol ester, polyoxyethylene, anionic, etc.), rubbers, lecithin, etc.; Wetting agents such as glycerin, ethylene glycol, propylene glycol, Nrubit, amino acids, etc.; stabilizers such as antioxidants, preservatives, etc.; and polyethylene glycol, polyethylene, suspending agents such as carboxymethyl cellulose, cellulose gel, polyvinyl alcohol, etc. Taking a hydrophilic ointment as an example, the oil phase components include appropriate amounts of white petrolatum, stearyl alcohol, etc., and the water phase components include appropriate amounts of propylene glycol, sodium lauryl sulfate, preservatives, etc.
Using water or the like, add the above-mentioned anti-inflammatory steroid to the oil phase component, heat and melt, and add the water phase component little by little to the oil phase component while heating and stirring, and gradually cool to prepare an external preparation. The gel ointment contains the above-mentioned anti-inflammatory steroids and lower-hydric alcohols,
It is prepared by mixing glycol with a gelling agent if necessary.

The external preparation of the present invention is applied in an appropriate amount to the affected area several times a day depending on the symptoms.

Indications include rheumatoid arthritis, arthritis associated with collagen disease, osteoarthritis, gout, low back pain, glenohumeral periarthritis, trap/key joint inflammation, peripeditis, humeral epicondylitis (tennis elbow). Such),
Examples include muscle pain, swelling and pain after trauma.

〔Example〕· Next, examples will be shown.

Example 1 Prednisolone moss (acid monoester 1.5% by weight Ethanol 401 Polyethylene glycol 15 1 Gelling agent 2I Add water to make 100% by weight) The above-mentioned components were mixed to obtain a gel ointment.

Example 2 A gel ointment was obtained in the same manner as in Example 1, except that prednisolone moss (prednisolone in which the DH group at position 21 was substituted with a farnesyl group instead of the acid monoester) was used.

〔effect〕

Next, the effects of the external preparation of the present invention will be shown.

The gel ointment obtained in Example 1 was used to treat rheumatoid arthritis (RA).
) or used in patients with poditis. The results are shown in Table 1.

1st table P engineer P umbrella 2 middle ○ Kei D female, 39 FLA right No. 2.3
N'/1 day Effective MCP Mocking 3 Sugi○Riki○ Female, 62 FLA Left 3.4
4? /3 days Effective IP 4 Fu0 Shun○ Female, 46 RA Right hand joint 6
T/7 days Effective 5 Ike○Ei○ Male, 39 Chronitis Right joint 1V day Effective/cured 6 Red○Ru○ Female, 54
RA right hand joint 4? /day Effective 8 Standing O Bun○ Female, 66 RA Left wrist joint 4″15 days Effective 9 Saka○Yu○ Female, 53 RA Right ankle joint t5
Day P/10: PIP with significant effect Proximal phalangeal joint Nakamoto MCP Metacarpophalangeal joint Next, the gel ointment obtained in Example 2 was used and tested in the same manner. The results are shown in Table 2.

1 K, N, Female, 39 RA Right 2.3M
CP 4177 days Valid 2 K, S, Female, 62
RA Left 1st place 6 r/10th Effect 3 Y
, S, Female, 53 RA Right 4th PIF 6
9/14 Effective 4 K, T, Female, 48 RA
Right 2nd PIP 1t/day Slightly effective 5T,
A, Female, 54 RA Left wrist joint 4 days Slightly effective 6 F, T, Female, 63 RA Right hand joint 11 days Slightly effective 7 Y, Female, 51
RA Right No. 3.4 PIF 41 days valid” PI
F Proximal phalangeal joint axis MCP The effect of the topical preparation on the metacarpophalangeal joint was observed from around the 3rd day and lasted for 3 to 4 days.

In addition, in the same case, the existing Linden ointment (betamethasone valerate 0.11) was applied to the same area to see if it was effective, but it was completely ineffective.

Patent applicant Yutaka Mizushima Procedural amendment (voluntary) Procedural amendment (voluntary) July 1985 Director General of the Japan Patent Office 1987 rij July 1986: i -5! ]
Submission 1, display of potato matter 1985 patent kIA No. 7239
No. 0 No. 2, Name of the invention Transdermal absorbent topical steroid agent 5 Relationship with the case of the person making the amendment Patent applicant 4 Detailed explanation of the invention in the specification subject to the amendment 5, Contents of the amendment (1) Details "Squalene" on page 5, line 12 of the book
is corrected to "compound having a farnesyl group."

[Incidentally, AZONE was used as the base [1-Dob 1985 r month λ day 1, case description 1985 patent application No. 72390 2
, Name of the invention Transdermal topical steroid preparation 38 Amendment case Relationship to the case Patent applicant address 4-25-20 Daita, Setagaya-ku, Tokyo (155
) 4. Detailed explanation of the invention column 5 of the specification subject to amendment, Contents of the amendment (1) "Manufactured" on page 7, line 8 of the specification Silhexahydro-2H-azepin-2-one ] can bring about excellent effects. "that's all

Claims (1)

[Claims] Antibiotics in which the OH group at position 21 is substituted with the formula -OCO(R)_nCOOH group (wherein R is -CH_2- and n is an integer from 0 to 7) or a farnesyl group or a pharmaceutically acceptable salt thereof. A transdermal topical steroid containing inflammatory steroids.