DE2337333A1 - Triamcinolone acetonide 21-valerate - as antiinflammatory agent for topical use - Google Patents

Abstract

Title cpd. (I) is prepd. by reacting triamincinolone acetomide with valeryl chloride at 50 - 125 degrees C. Medicaments contain 0.01-0.5% (I).

Description

7337333

American Cyanamid Company, Wayne, New Jersey, V.St.A. Sterol acetonides and their uses

It is well known that steroids can be used topically. Their uses in this way have varied Shown success. There is a need for a more topically effective steroid. It has now been found that the Triamcinolone acetonide 21-valerate as the active component in a topical composition is a very effective anti-inflaitimizing agent. This connection is much more effective as a topical anti-inflammatory agent than many after the vasoconstriction attempt Compounds that have been used in the past such as triamcinolone acetonide.

The active component of the invention, triamcinolone acetonide-2 1 -valerate, can be prepared by adding n-valeryl chloride to a cooled, stirred solution Triamcinolone acetonide. The mixture is then heated to reflux temperature and then allowed to return to room temperature cooling down. The mixture is diluted with ice water and extracted with a solvent such as chloroform.

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ORIGINAL INSPECTED

The chloroform extract is treated with water, dilute hydrochloric acid, dilute sodium bicarbonate and finally with saturated saline solution. The chloroform extract is evaporated under reduced pressure. The product is slurried with acetone / n-hexane (1:19). The filtration yields the product, namely 9alpha-fluoro-11beta, 21-dihydroxy-16alpha, 17alpha- (isopropylidenedioxy) -1 _r 4-pregnadiene-3,20-dione 21-valerate, which in the present application as triamcinolone acetonide -21-valerate is called.

This steroid product can be found in a variety of well known pharmaceuticals Formulations giving topical preparations at concentrations of, for example, 0.01% up to 0.50%, can be incorporated into topical ointments in similar concentrations or into lotions.

The compositions containing the active ingredient of the invention can be any pharmaceutical topical Be standard preparations, for example: solutions, suspensions, lotions, ointments, creams, liquid ointments or jelly, sprays, powders, foams, etc. excipients or diluents, as they are in such preparations can be used, buffers such as phosphate, citrate or tartrate buffer, surfactants such as polyoxyethylene (20) sorbltan monooleate (Polysorbate 80), this is a complex mixture of polyoxyethylene ethers mixed partial oleic acid esters of sorbitol anhydrides and oxylated tertiary octylphenol-formaldehyde polymers, an agent that reduces surface tension. Preservatives such as methyl and propyl parabens, i. the methyl and propyl esters of p-hydroxybenzoic acid, potassium sorbate, benzyl alcohol and similar compounds can be used are oils, waxes, fats, etc. as emollients and as raw materials

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for ointments and emulsions are vaseline, wool fat (anhydrous lanolin), squalene, pure whale fat and the like Fabrics useful. Stabilizers such as sebum, clays, vegetable colloids, carboxymethyl cellulose, carboxypolymethylene and similar and perfumes or fragrances such as lavender, lemon, gardenia, etc. are also useful. Such preparations can be filled into pressure vessels, and then a suitable propellant such as trichlorofluoromethane, Dichlorodifluoromethane or 1,2-dichloro-1,1,2,2-tetrafluoroethane add. Means as they are commonly used.

Triamcinoline acetonide 21-valerate has been used with a variety of others Compared to steroids known to be topical have anti-inflammatory activity and using a method in which vasoconstriction is determined. This attempt is described in the following publications: "Topical Activities of Betamethasone Esters in Man ", A. W. McKenzie and R. M. Atkinson, Archives of Dermatology 89, 741-746 (1964). "Method for Comparing Percutaneous Absorption of Steroids," A. W. McKenzie and R. B. Stoughton, Archives of Dermatology, 86: 608-610 (1962). "Percutaneous Absorption of Steroids", A. W. McKenzie, Archieves of Dermatology, 86: 611-614 (1962).

The various compounds are formulated for the investigation by serial dilutions in 95 percent alcohol, using concentrations of 1: 10,000 to 1: 6,250,000 in 5 stunts. Two hundredths One milliliter of each dilution is applied to the palm of the forearm of 10 normal people. Triamcinoline acetonide is applied to the other forearm in the same dilutions. the Application areas are for 16 to 20 hours

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connected or completed and then examined to determine whether vasoconstriction is present or absent, the intensity of the vasoconstruction is not rated.

The results are set out in the present table. In the table are the relative efficacies the steroids listed in comparison with the triamcinolone acetonide.

Tabel

Relative potencies of steroids (based on triamcinolone acetonide) in the human vassoconstriction attempt

Relative potency compound (triamcinolone acetonide = 1.0)

Triamcinolone acetonide 21

valerate 2.6

Triamcinolone 21 valerate 0.105

Triamcinolone 16 acetate

21-valerate 0.01

Triamcinolone 16-valerate 0.021

Triamcinolone-16-acetate-17-

21-methylorthovalerate O, O4O

Triamcinolone-16,17,21-

orthovalerate 0.089

1,2-dihydrotriamcinolone

acetonide-21-valerate 1.6

Triamcinolone acetonide 21

tert-butyl acetate 0.021

Triamcinolone acetonide-21-

tetrahydropyranyl ether 0.72

Triamcinolone-16,71-cyclic
carbonate-21-ethyl carbonate. 0.03

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From this result, it can be seen that compared with triamcinolone acetonide, triamcinolone acetonide 21-valerate was 2.6 times more effective in these experiments is. All other steroids studied have a much lower activity, and only one steroid is more active than txamcinolone acetonide.

The following examples explain the preparation of triamcinolone acetonide-21-valerate and its use in various topical preparations. The parts are by weight unless otherwise specified expressed.

Example i

Preparation of 9alpha-fluoro-11ß-21-dihydroxy-16alpha, 17alpha- (isopropylidenedioxy) -1,4-pregnadiene-3,21-dione-21-valerate

To a stirred solution of 3.0 g (6.9 mmol) of triamine cinolonucetonide in 50 ml of pyridine, which is stirred in an ice / water bath, is added dropwise 1.68 ml (14.1 mmol) u-valeryl chloride. After the addition is complete, the cooling bath becomes removed. The reaction mixture is refluxed for one hour, cooled to room temperature and at room temperature stored overnight. The reaction mixture is poured into approximately 1.5 liters of ice and water with stirring. The aqueous solution is extracted with four 100 ml portions of chloroform. The chloroform extract is mixed with water, dilute hydrochloric acid, dilute sodium bicarbonate and finally treated with saturated saline. The chloroform extract is dried over anhydrous Magnesium sulfate dried overnight and then evaporated under reduced pressure to give a solid.

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The solid is slurried with acetone / n-hexane (1:19), 25 ml. The product is filtered off, 3.03 g (84.5% yield) of a colorless product being obtained. Evaporation of the filtrate gives 0.3-3 g of a second batch (overall yield 93.5%). Crystallization from acetone / n-hexane gave a sample-the following characteristics: Melting point 262.5 ° to 263.5 ⁰ C corrected value on the Koflet-heating stage, DTA, a single endothermic value of 264 ⁰ C, corrected. IR- ^ ^KBr 3390,

1754, 1733, 1672, 1626, 1166 and 1058 cm "¹; / alpha / ^ ⁵ + 93 ° ^max (C = 0.408, CHCl ,, 1 dm); ^ ^CH i ° ^H 238 m, u (£ 16,600) .

j ITlct JC /

The purity, determined by distribution column chromatography, is 99%.

Analysis for C ₂₉ H ₃₉ O ₇ F:

calculated: C, 67.16; H 7.58; F. 3.66 found: C 67.15; H 7.75; F. 3.82.

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ORIGINAL INSPECTED

Example 2

Topical cream formulations that contain different percentages of triamcinolone-acet: onid-21-valerate

Percentage range component (weight / weight)

Triamcinolone acetonide 21-valerate 0.01-0.5

Glycerol monostearate NF 1-5

Sqalan ¹ * 1-5

Polysorbate 6O ²⁾ 1-5

Polysorbate 80 above SP ²⁾ 1-5

Spermacet 5-20

Stearyl alcohol U.S.P. 5-20

Sorbitol solution U.S.P. 1-10

Preservatives 3-5

distilled water made up to 100

'Sqalan = 2,6,10,15,19,23-hexamethyltetracosane

Polysorbate = polyoxyethylene sorbitan monooleate

The ingredients are used in the usual manner as in the manufacture of a pharmaceutical topical cream mixed, whereby a colorless cream is obtained, which depends, for example, on the percentages in which the Ingredients used were containing amounts of steroid of O, O1, 0.025, 0.1 or 0.5%.

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Example 3

Topical ointment formulations containing different percentages of triamcinolone acetonide-21-valerate

Percentage range component (weight / weight)

Triamcinolone acetonide 21-valerate 0.01-0.5 colorless vaseline U.S.P. 100

The ingredients are mixed in the usual way to obtain a colorless topical ointment such as the steroid may contain in percentages of 0.01, 0.025, 0.10 or 0.50%.

If desired, an antibacterial agent such as neomycin can be added to the formulation in amounts ranging from Add 0.1% to 3% (w / w) as sulfate in micronized form.

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Example 4

Topical foam formulation containing triamcinoline acetonide 21-valerate

component

Triamcinolone acetonide-21 ■ valerate

Arlacel ^(R) Myrj 59

(R) 2)

Glycerin Monostearate Cetyl Alcohol Sorbitol 70% Propyl Paraben Methyl Paraben Weight Range (mg per container)

Veegum Neutral

0.5 - 5O 20 - 50 300 - 500 100 - 3OO 70 - 1OO 300 - 400 3 - 5 10 - 15th 15 - 20th

distilled water

Freon ^iR) 12/144 (40/60) ³⁾ 6 - 10 (g per container)

1.3 - 2.0 (g per container)

Arlacel = sorbitan monostearate

2) Myrj

Polyoxyethylene derivative of fat-forming fatty acids

3) dichlorodifluoromethane / 1,2-dichloro-1,1,2,2-tetraflurethane

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The ingredients are mixed in the usual way, filled into containers and then pressurized with Feon.

Example 5

Ophthalmic ointment containing different percentages of triamcinolone acetonide-21-valerate

Percentage range component (weight / weight)

Triamcinolone acetonide 21-valerate 0.01-0.50 mineral oil, light N.F. 1-5

white Vaseline U.S.P. filled up to 100

The ingredients are mixed in the usual way, resulting in an almost colorless eye or ear preparation receives. Neomycin can be used as micronized (= finely ver. split) sulfate salt can be added if an antibacterial agent is desired.

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Example 6

Topical lotion formulations containing different percentages of triamcinolone acetonide-21-valerate

Percentage range component (weight / weight)

Triamcinolone acetonide 21-valerate 0.01-0.5

Polowas PD 34 ^{2) (R)} 3-5

Volpo 20 ^{1) (R)} 0.5-2

Oleyl alcohol 1 - 5

Methyl paraben 0.12-0.2

Propyl paraben 0.02-0.06

Squalane 1-5

Potassium sorbate 0.05-0.25

Sorbitol, 70 percent solution 5-10

distilled water made up to 100

'Volpo 20 = polyoxyethylene ether of oleyl alcohol

Polawax = reaction products of higher fatty alcohols

and ethylene oxide

The ingredients are mixed in the usual way to obtain an opaque, cream-like lotion.

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Example 7 Topical ointment formulation

Percentage range component (weight / weight)

Triamcinolone acetonide-21-valerate 0.01 - O _f 5 Polyethylene glycol 400 USP 5 - 20%

White Vaseline U.S.P. filled up to 100%

The ingredients are mixed together to give a colorless topical color.

If desired, an antibacterial compound such as neomycin can be added to the formulations in the range of amounts add from 0.1% to 3% (weight / weight) as sulfate in micronized form.

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Claims (3)

Claims 1. Process for the preparation of an anti-inflammatory agent, characterized in that 0.01% up to 0.50% of the steroid 9alpha-fluoro-11ß, 21-dihydroxy-10alpha, 17alpha- (isopropylidenoxy) -1,4-pregnadiene-3,20-dione-21-valerate mixed with a pharmaceutically acceptable carrier. 2. Use of the agent according to claim 1 for improving inflammation in mammals, wherein the agent applied topically. 3. Use of the agent according to claim 1 for the treatment of inflammation in mammals, wherein the agent is applied topically. 9alpha-fluoro-11ß, 21-dihydroxy-16alpha, 17alpha- (isopropylidenedioxy) -1,4-pregnadiene-3,20-dione-21-valerate. 509808/0926