JPH0354084B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to topical pharmaceutical compositions for the treatment of diseases of the skin or mucous membranes characterized by irritation or inflammation. More particularly, the invention consists of treating such diseases by applying selected acylaminophenols in suitable vehicles topically to the affected area. There are many steroid drugs that are suitable for the treatment of certain sensitive skin diseases. They have a wide range of applicable biological activities, such as cell membrane stabilization, vasoconstrictor neuroactivity, antimitotic effects, DNA repression and protein synthesis. However, steroids often exhibit undesirable local and systemic side effects when used over long periods of time. They produce localized skin atrophy symptoms or, in the most severe cases, adrenal atrophy. moreover,
Their use is accompanied by a reduction in host defense mechanisms against infection. Besides possible unwanted side effects, steroids do not interact with the full biological spectrum of inflammation. For example, erythema caused by ultraviolet light does not respond to treatment with steroid anti-inflammatory drugs. Initial changes caused by UV radiation in the skin, such as vasodilation, can occur from arachidonic acid to E prostaglandins or, for example, to HETE (12L-hydroxyn-5,
8,10,14-eicosatetraenoic acid) or endoperoxide, the latter being vasoactive and causing hyperproliferative epidermal activity, such as triggering hyperproliferative epidermal activity. Believed to have skin actives. For example, Bem,
JL and Greaves, MW1974, Prostoglandin E ₁ effect on epidermal cell growth in vitro, Arch.Derm.Forsch. 251 :35-41; Snyder, DS and Eaglstein, WH1974. , Topical Indomethacin and Burns, Brit. J. Derm. 90:90-93; Snyder, DS and Eaglestein, WH1974, Intradermal Anti-Prostaglandin Agents and Burns, J. Invest.
Derm.62.47−50; and Goldyne,
ME et al. 1973, Prostaglandin activity in human skin inflammation: radioimmunological examination,
See Prostaglandins 4:737-749. Also,
Hsia, SL; Ziboh, VA and Snyder, DS1974, natural production and synthesis inhibitor of cutaneous prostaglandin synthase;
Prostaglandin Synthetase Inhibitors353〜361
See also Although not fully understood, these effects on prostaglandin biosynthesis are an important component of many dermatologies, and as a result drugs that interfere with this biosynthesis should be useful in the clinical treatment of diseases. be. There are many non-steroidal compounds or agents that have anti-inflammatory effects. Many of these are believed to act by blocking the prostaglandin synthase complex of enzymes that are present in normal skin and are necessary for the biosynthetic steps mentioned above.
Furthermore, as a general principle, these drugs are relatively free of undesirable side effects. Examples of such non-steroidal anti-inflammatory compounds include aspirin, indomethacin, suprofen, cryprofen and 5-p-chlorobenzyl-1,4-dimethylpyrrole-2-ethyl acetate. Although many acylaminophenols, including the compounds used in the treatment of the present invention, have been reported in the literature and used for various purposes, to the best of our knowledge they are useful as topical anti-inflammatory agents. It has not been reported that. A review of the Chemical Abstracts reveals the pharmaceutical activity of related aminophenols, as well as the pharmaceutical and non-pharmaceutical properties of the substituted aminophenols identified below that are useful in the topical compositions and methods of the present invention. The following literature regarding activity was found. CA 57 16492 (1962) contains reports of antirheumatic activity for N-nicotinyl-p-aminophenol and N-succinyl-p-aminophenol, and Austrian patent 222,647
(1962). Dutch patent application 6,
505, 431, p-aminophenolamide of whale head oil acid and whale fat oil acid is reported in CA 64 14137 (1966). U.S. Patent No. 3,081,321 CA 60 2833
(1964), who disclose the analgesic activity of the aliphatic monocarboxylic acid p-aminophenolamide. CA 76 on French Patent M7624 (1970) to Laboratories J. Benchel
153384x (1972), analgesic, antipyretic and anti-inflammatory activity was achieved by dipropylacetylamide of p-aminophenol, and Portelli, Renzi, Cervato and Frigeni, Farmaco, Ed. Sci.31(11)767~
CA 86 107003f (1977) which is a paper abstract of 775 (1976)
The same activity was reported for cysteine derivatives of p-aminophenol. CA 86 43215s
(1977), Belgian patent 834,304 has the formula It has been reported that arylamides of omega-aminoalkanoic acids having the formula: [where n is 4, 5, 6, or 8] inhibit platelet aggregation. CA 89 108193s (1978) is a Belgian patent 1,498,996 which is clearly similar to the above Belgian patent.
The same report was made while referring to . CA88
585682 (1978) is Japanese Patent Publication (Publication 77-110,
(835) discloses that certain benzanilide derivatives (but none of them are 4-acylaminophenols) exhibit anti-inflammatory activity when administered orally or by intraperitoneal injection to rats. It is reported that they are doing so. Structural formula Salicylaminophenol [4'-hydroxysalicylanilide; also called N-(p-hydroxyphenyl) salicylamide and N-salicoyl aminophenol] has choleretic activity [Merck Index, 9th edition]. , 6724, p. 894]; in vitro viricidal activity [CA 71 , 69577b, (1969)];
Suppressive activity of allergic reactions or inflammation in rats upon oral or intraperitoneal administration [CA 88 ,
58568z, (1978)], molluscicide and cercariocidal activity [CA 89 192405t, (1978)]; photosensitizing effect in guinea pigs [CA 83 , 37501d, (1975)];
Anthelmintic activity [CA 80 , 133081a, (1974)] and usefulness as an antioxidant for unsaturated rubbers [CA 91 ,
6227e (1979)]. formula wherein n is an integer from 5 to 11; 11], the following activities have been reported: n=2 Analgesic [CA 74 , 123508g, (1971)] n=2 or 3 Anti-inflammatory, anti-edema, antipyretic and sedative-enzyme When combined with muramidase and amylase [CA 71 , 42305z (1969)
- concerning French patent M5,575]; n=3 Increased biodegradability of polyolefins [CA
83, 194578b (1975) - U.S. Pat.
] n=7 Local anesthetic [CA 50 , 9424, Bull.Soc.
Regarding Chim.France (1955) 1603-9] n=8, 11 Polyester stabilizer [CA 76 ,
154779s (1972), German Publication Specification 2,036,
Regarding 712] n=3, 8, 11 Polyacetal stabilizer [CA 66 ,
29609d (1967) - Relating to U.S. Patent 3,288,885] n=9 Desensitizer of thermoregulatory reflex in guinea pigs [CA 72 , 76596f (1970) - J.Physiol, (London) 206 (3) 495-507 (1970)] n=11 Heat stabilizer in resin [CA 86 , 107522z
(1977) - Relating to U.S. Patent 4,002,701] n=15.2-15 Antioxidant [CA 58 , 14257e
(1963) - French Patent 1,309,355; CA 48 ,
1714i (1954) - Relating to U.S. Pat. No. 2,654,722. While working with experimentally induced inflammation, we discovered that treatment with certain acylaminophenols resulted in unexpectedly improved suppression of inflammation. They have local anesthetic properties, especially when applied mucosally, and have low toxicity in standard tests. The treatment of the present invention can also be used in the therapeutic treatment of a wide variety of skin and mucosal diseases in which inflammation is a symptom. Examples of these diseases are psoriasis, eczema, contact dermatitis, atopic dermatitis, etc. Inflammation with thermal or chemical burns, e.g. burns, as well as decubitus dermatitis,
Insect stings, sore throat and eye irritations, pruritus, poison ivy irritation, hemorrhoids, and inflammation caused by mouth adhesives, orthopedic castings, etc. are other areas of application for the treatment of the present invention. Also, follicular diseases, particularly those characterized by stratum spinosum atrophy, and other herpes conditions appear to be particularly sensitive to this treatment. According to the invention, the dermal or Topical compositions for the treatment of mucosal inflammatory conditions are provided. n, which is the active ingredient in the compositions and treatments of the invention;
-The structural formula of aliphatic N-acylaminophenol is shown in the following formula (); where n is 6 to 12. The present invention also provides for administering to the affected area a pharmaceutically acceptable topical composition containing an effective amount of an acylaminophenol selected from a compound of formula Also provided is a method of treating inflammatory skin conditions comprising topical application. The concentration of active ingredient in the composition depends both on the particular compound and on the excipients used. The excipient used is propylene glycol/ethanol (30:
70% by weight), the concentration of active ingredient is approximately
It should be between 0.01 and 10.0%, preferably between about 0.05 and about 5.0%. As noted above, lower or higher concentrations may also be suitable for various drugs and various excipients or administration systems. In addition to liquid vehicles, which also include sprays and nasal, ear, and eye drops, topical vehicles can be creams, lotions, gels, or other forms acceptable for topical use. Generally, treatment is carried out by applying the composition to the affected area from one to about four times per day until inflammation is reduced. The length of treatment varies depending on the severity of symptoms. Typical Preparations (All amounts are by weight throughout this specification, unless otherwise specified) A. Topical creams (oil-in-water emulsion) [Table] [Table] These oil-in-water emulsion creams It is also possible to replace all or part of the cetyl alcohol with other fats and waxes, such as stearyl alcohol, glyceryl monostearate, spermaceti, white petrolatum, and the like. Other emollients that can be used in place of or in addition to mineral oil and isopropyl myristate include isopropyl palmitate, squalene and hexadecyl alcohol.
Surfactants other than polyoxyethylene (20) stearate include other polyoxyethylene derivatives,
Included are sorbitan monoesters, polysorbates with appropriate HLB values, and other pharmaceutically acceptable surfactants known in the art. Other cosolvents that can be used in place of or in combination with propylene glycol include glycerin,
Includes 1,2,6-hexa-triol and liquid polyethylene glycol (300, 400). Preservatives other than benzoic acid include parabens (methyl, propyl or combinations thereof) and sorbic acid. Antioxidants other than butylated hydroxyanisole include butylated hydroxytoluene, citric acid and propyl gallate, and tierants other than sodium edetate include calcium disodium edetate and ethylenediaminetetraacetic acid (EDTA). is included. The following is a typical method for making the topical cream described above. Oil Phase Mineral oil is dispersed in isopropyl myristate in a suitable vessel (glass or stainless steel) heated to 80-90°C, followed by oil-soluble components such as butylated hydroxyanisole and surfactants. Add a portion of and the fat or wax from the general formula. Continue heating with stirring until a homogeneous solution/melt is obtained. Aqueous Phase In a separate suitable container, heat water to 80°-90°C. Then dissolve the benzoic acid and add propylene glycol and the remainder of the surfactant with good mixing. Emulsification Step Add the aqueous phase to the oil phase at 80°-90°C and stir for a sufficient time to ensure mixing is complete. Cool to freezing point and add enough water to make the correct weight. Addition of active ingredient The acylaminophenol is added in finely divided powder form and dissolved in one of the excipient ingredients. B Solution A liquid preparation for topical administration in which the acylaminophenol is present in solution form is prepared using a pharmaceutically acceptable solvent. Other pharmaceutically acceptable excipients may also be included if acceptable, including stabilizing systems to preserve the chemical properties of the acylaminophenol. The following common formulations are exemplified: Ingredients Concentration range (by weight) Acylaminophenol 0.01-10.0 Adjuvant(s) 0.0-0.2 Solvent Sufficient amount to make 100 Solvent system localized It may contain one or more solvents suitable for administration, such as lower alcohols (ethanol, isopropanol), glycols such as propylene, ethylene and polyethylene glycols (liquid at room temperature), other organic solvents,
For example selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, 1,2,6-hexanetriol, butanediol and other liquids which are completely or partially miscible with water. The method for preparing these anti-inflammatory agents in solution form is generally (as is known in the art) by dissolving the solid ingredients in the main solvent using a suitable container (glass or stainless steel lined) and a mixer. be. The resulting solution is then filtered to remove excess material,
The co-solvent and/or main solvent are then brought to the final weight, taking general precautions to minimize loss of solvent through evaporation. C. Gels The above solutions can be made into semi-solid (gel) preparations by using gelling agents such as hydroxypropyl cellulose, hydroxyethyl cellulose, carbomel polymers and combinations of the above, according to the formulation and process described below. can. Ingredients Concentration range (by weight) Acylaminophenol 0.01-10.0 Alcohol 10.0-70.0 Co-solvent 0-80.0 Gelling agent 0.5-5.0 Purified water Sufficient amount to make 100 Gelling agent (e.g. hydroxypropyl cellulose) Solution of acylaminophenol in its solvent system using a glass-lined or stainless steel container, avoiding agglomeration or excessive air loading.
Add while stirring. D Ointment The ointment (water-immiscible or water-miscible) of the composition of the present invention is represented by the following general formulation. Ingredients Concentration range (by weight) Acylaminophenol 0.01-10.0% Surfactant 0-5.0% Solvent 1.0-20% White petrolatum Sufficient amount to make 100% Typically in a suitable container (glass or stainless steel) The ointment is prepared by heating white petrolatum in a steel plate until fluid and adding the active ingredient in the following form to solubilize the acylaminophenols: b) for example alone or 1,2, 6
- in combination with hexanetriol, propylene carbonate or other such solvents,
Propylene glycol, polyethylene glycol
300, polyethylene glycol 400 or polyethylene glycol 1540. Suitable oil-soluble surfactants, such as hydroxylated lanolin, ethoxylated lanolin derivatives or polyoxyethylene esters, can be added to petrolatum to produce water-miscible ointments, or the surfactant can be omitted to produce water-immiscible ointments. Can produce sex ointment. E Powder The following are representative powder formulations containing acylaminophenols according to the present invention. Ingredients Concentration range (by weight) Acylaminophenol 0.01-10.0 Talcum powder 0-99.99 Cornstarch 0-99.99 Glaze the talcum powder and/or cornstarch, preferably in a geometric progression, until the entire mixture is evenly incorporated. Alternatively, the acylaminophenol is mixed with the talcum powder and/or cornstarch by addition using a stainless steel container and suitable mixing equipment. A particle size distribution of the acylaminophenol within the range of 5 to 25 microns is preferred for a homogeneous mixture. F Aerosols According to the invention, many types of aerosol formulations can be used as excipients for the acylaminophenols. These can vary depending on the type of propellant and concentrate used during manufacture, as known to those skilled in the art. The example below is a general formulation for a fast-breaking alcohol foam. Table: Acylaminophenol is dissolved or dispersed in an ethanol/water solvent system together with cetyl alcohol and a lanolin derivative. If it is permissible,
Preservatives (eg Hyamine 1622) can also be added. The concentrate is then mixed with the propellant according to known manufacturing methods, either by cold filling or by pressure filling. G Impregnated tape RCV Robinson et al. 1972 1
Patent No. 3,632,740 (“Topical device for the therapeutic treatment of skin lesions with steroids”) issued on May 4th.
The acylaminophenol-impregnated adhesive tape of the present invention is manufactured using the techniques and instructions described in . The acylaminophenol can be added in solution in a suitable organic solvent. As mentioned above, the acylaminophenol compounds used in the compositions and treatments of the present invention are known compounds. Methods suitable for their production are e.g. Helvetica Chimica Acta 22 :82~
112 (1939), more particularly on pages 89-93. Generally, p-aminophenol is reacted with a suitable acid anhydride or chloride. H Throat Lozenge Candy Base Finely Powdered Acylaminophenol 0.01-0.2 gm Candy Base Enough amount to make 2.0 mg Candy Base is made from sucrose and corn syrup solids,
Consists of food coloring and flavoring agents. Manufacturing method 1 345 pounds (46 gallons) of liquid sugar No. 1 and
The candy base is prepared by metering 230 pounds of 43° Baumecorn syrup into a kettle surrounded by steam, known as a premelter. 2. Heat the material to 238°C under atmospheric pressure, then pump it into a storage container and add it to the National Equipment continuous cooker. As the syrup passes through the coil in the cooking chamber, where it is surrounded by high-pressure steam, it reaches a temperature of 290-300°C. 3. Transfer the batch to a stainless steel receiver kettle maintained at a 28-29 inch vacuum using a multi-stage steam vacuum evacuator for 7 minutes. The vacuum acts to remove excess moisture without using extra heat. 4 At this stage, the candy base consists of approximately 64.77% sugar solids, 34.63% corn syrup solids, and 0.6% water. 5 Next, add 300 pounds of candy base (each
(150 lbs each) into two stainless steel mixing kettles. One is referred to as the "A" portion of the batch and the other as the "B" portion. 6 Add sufficient amount of approved food coloring agent to “A”
Divide into two equal parts for mixing with part and "B" part. A sufficient amount of fragrance compound is added to part “A” and part “B”
Divide into two equal parts to mix with the parts. The finely divided acylaminophenol to give 0.5-10% of the lozenge is divided into two equal parts for mixing with the "A" part and the "B" part. 7. The batch is then placed into an automatic batch roller for feeding into a Hansela molding machine which punches holes in the lozenges. The lozenges are fed into a cooling and curing conveyor in a dehumidification chamber. They are then sent to a machine for individual packaging. I Acylaminophenol - lozenge, sucrose-based acylaminophenol 0.02-0.06gm Pluronic F68 0.40-0.60gm Sucrose 2gm Binder solution Sufficient fragrance Sufficient lubricant Sufficient amount Production method 1 Melt acylaminophenol into Pluronic
Dissolve in F68. The solution is cooled to a solid state and then ground and sieved through a #40 mesh screen. 2. Grind the sucrose and pass it through a #40 mesh screen. 3 Mix #1 and #2 and then granulate with a suitable aqueous binder solution such as gum tragacantha, gum arabic or methylcellulose or other binders known in the art. 4. Add and mix flavors, such as peppermint oil and menthol or cherry flavor. 5 Dry the wet granules in a hot air oven. 6 Add a suitable lubricant such as talc or magnesium stearate or stearic acid to the dry granules and mix. 7. Compress the granules in a tablet machine to produce tablets that melt easily in the mouth. Instead of the above (wet granulation) method, “pounding”
Alternatively, a dry granulation method using chilsonating may be substituted. J Acylaminophenol pastilles Acylaminophenol 0.01-0.2 gm Pastille base Enough to make 2.0 gm Base from glycogelatin or other suitable preparation containing gelatin and glycerin or a mixture of gum arabic and sucrose. It's summery. Glycerin in the base can be replaced with propylene glycol. K. Acylaminophenol throat liniment Acylaminophenol (0.5-10%) is dissolved in propylene glycol or glycerin. The final concentration in glycerin or propylene glycol constitutes a saturated solution of the acylaminophenol, which will vary according to the solubility of the particular acylaminophenol selected, but will range from 0.5 to 10% in the final solution. It gives concentration. L Acylaminophenol Throat Spray Acylaminophenol 0.5-10% Fragrance Sufficient Satucharin Sodium Sufficient Alcohol 50% Sufficient to make 100 Propellant Sufficient Propellant is available as known in the art Propellant, e.g. chlorofluorocarbon (Propellant 114 or Propellant 12 or mixtures thereof), CO ₂ , suitable head space
space). The 50% alcohol can also be replaced with propylene glycol, glycerin or a mixture of alcohol, glycerin and propylene glycol to provide a 0.50-10% solution of the particular acylaminophenol selected. Example 1 The effect of selected compositions on skin inflammation caused by topical application of arachidonic acid (AA) was evaluated. In addition to inflammation, the proliferative response of the epidermis treated with arachidonic acid and the composition was also evaluated. 14 kinds of acylaminophenols were studied. The drug propylene glycol and ethanol (30:
70) and used at 1% concentration unless otherwise stated. 5 guinea pigs each
Fourteen groups were used as experimental subjects. Apply 25μ AA to the dorsal skin of both ears once a day for 4 days.
Propylene glycol/ethanol (30/70)
treated with a 1% solution in medium. Immediately after this application, one ear of each guinea pig was randomly selected to receive 25μ of test compound, while the contralateral ear received vehicle only. During the 4-day experimental period, the synthesized DNA was treated with continuous administration of the radioactive precursor ^3H -thymidine (3 intraperitoneal injections/day;
10 μci each) and labeled. On the fifth day, the animals were killed and a 6 mm diameter circular sample of dorsal skin from the central part of the treatment area was taken and
Dissolved in NCS solubilizer. The tissue solution was acidified and pure fluorite (diphenyloxazole in toluene) was added for measurement of radioactivity by a liquid scintillation counter. Radioactivity, expressed in degrees per minute (cpm), was related to the amount of proliferative activity in the epidermis. The amount of DNA synthesized is estimated by the British Journal of Dermatology.
British Journal of Dermatology” Volume 98, 209
(1978) in the paper entitled "Animal models for assessing the local and systematic effects of locally administered corticosteroids on epidermal DNA synthesis". It was done. The degree of proliferative activity is determined by the amount of DNA synthesized during the test.
and proliferative activity can be a measure of anti-inflammatory effect. Erythema appearance corresponding to local AA was measured daily with a subjective sensitivity of 0-3. Total erythema was determined by plotting the average daily erythema rating (0=none, 1=mild, 2=moderate, 3=severe) for each day of the 5-day study period. The horizontal axis represents "day" and the vertical axis represents the daily average erythema evaluation value. A curve was drawn through the plotted daily erythema evaluation values. The area under the obtained curve is measured with a planometer,
A total erythema evaluation value was obtained. Results It was found that topical application of acetamidophenol (acetaminophen) had no substantial effect on AA-induced erythema or proliferation. 4-propionylaminophenol, 4-
Application of n-tetradecanoylphenol or 4-n-hexadecanoylaminophenol also had no substantial effect. Benzoylaminophenol, an example of an aromatic acid 4-acylaminophenol, was also inactive in this model. 4-n-butyroylaminophenol is AA-
It was found that it substantially inhibited induced epidermal proliferation but was not effective against erythema. Acylaminophenols with straight chain aliphatic hydrocarbon groups ranging from 6 to 12 carbon atoms showed good activity against both AA-induced erythema and proliferation. These include 4-n-hexanoylaminophenol, 4-n-decanoylaminophenol, 4-n-undecanoylaminophenol and 4-n-dodecanoylaminophenol,
-n-heptanoylaminophenol, 4-n-
Includes octanoylaminophenol and 4-n-nonanoylaminophenol. Furthermore, 4-acylaminophenol of salicylic acid (4-salicylaminophenol) showed activity against both erythema and proliferation. These data are summarized in Table 1. [Table] [Table]

Claims (1)

[Scope of Claims] 1. An anti-inflammatory agent selected from the group consisting of N-acylaminophenols having a straight chain aliphatic hydrocarbon group having 6 to 12 carbon atoms in an amount sufficient to suppress inflammatory symptoms. A composition for the topical treatment of inflammatory conditions, comprising a pharmaceutically acceptable topical excipient containing: 2 The acylaminophenol is 4-n-hexanoylaminophenol, 4-n-heptanoylaminophenol, 4-n-octanoylaminophenol, 4-n-nonanoylaminophenol, 4-n-decanoylaminophenol , 4-
n-undecanoylaminophenol and 4-n
-dodecanoylaminophenol. 3. the acylaminophenol is in the excipient,
The composition of claim 1, wherein the composition is present in an amount of about 0.01 to about 10.0% by weight. 4. the excipient consists of propylene glycol;
A composition according to claim 1. 5. The composition of claim 4, wherein said excipient further comprises a member selected from the group consisting of ethanol and dimethyl sulfoxide.