United States Patent (19) 1 4,021,572 Van Scott Et Al

United States Patent (19) 1 4,021,572 Van Scott et al. 45 May 3, 1977

(54) PROPHYLACTIC AND THERAPEUTIC 3,549,544 l2/1970 Johnson ...... 252/152 TREATMENT OF ACNE WULGARIS 3,639,623 2/1972 Ritschel et al...... 424/329 UTILIZING LACTAMIDES AND 3,640,883 2/1972 Gotte et al...... 424/320 3,666,863 5/1972 Swanbeck ...... 424/317 QUATERNARY AMMONIUM LACTATES 3,806,593 411974 Swanbeck et al...... 424/31 76 Inventors: Eugene J. Wan Scott, 1138 Sewell Lane, Rydal, Pa. 19046; Ruey J. Yu, OTHER PUBLICATIONS 4400 Dexter St., Philadelphia, Pa. Merck Index, (1968) pp. 848-849. 9.28 Primary Examiner-Norman A. Drezin (22 Filed: July 23, 1975 Attorney, Agent, or Firm-LeBlanc & Shur 21 Appl. No.: 598,224 (57) ABSTRACT 52 U.S. C...... 424/317; 424/320; Preventive as well as therapeutic treatment of acne 424/329 vulgaris (hereafter referred to as acne) consisting of 51 Int. Cl.’...... A61K 31/19; A61 K 31/16; the topical application of a solution, lotion or cream A61K 31/14 containing one or more than one of the lactamides 58 Field of Search ...... 424/317, 320, 329 and/or quaternary ammonium lactates is disclosed. 56 References Cited Topical application to uninvolved or involved skin has UNITED STATES PATENTS been found to achieve respectively a complete preven tion or a substantial remission of acne. 2,717,850 9/1955 Schmitz ...... 424/319 3,068, 145 l2/1962 Glenn ...... 424/320 3,096,244 7/1963 Ehrhart et al...... 424/320 28 Claims, No Drawings 4,021,572 1 2 commonly used antibiotics are tetracycline and eryth PROPHYLACTIC AND THERAPEUTC romycin. TREATMENT OF ACNEWU LGARS UTILIZING Since the cause of acne is still unknown its is difficult LACTAMIDES AND QUATERNARY AMMONUM to prevent the occurrence of acne (prophylactic treat LACTATES 5 ment). Once lesions of acne are developed topical Acne is a skin disorder which affects most people treatment with the foregoing "peeling' or "drying" primarily in the adolescent age range. The principal agents often leads to burning or irritating of the skin. clinical manifestation of the disease is usually a variety Many acne patients discontinue such treatment simply of lesions consisting of comedones, papules, pustules, because they can no longer bear the discomfort from nodules, and cysts. The most frequent site of acne is the 10 those agents. Although the broad spectrum antibiotics face, and to a lesser extent the back, chest and shoul are rather effective in the management of infected acne ders. lesions, long term use of those drugs carries a risk of The basic cause of acne is still unknown. Neverthe systemic side effects. less, considerable data on various factors involved in its It is therefore imperative to develop an efficaceous, 15 non-toxic, non-allergenic and non-irritating substance pathogenesis have been accumulated in recent years. It of physiologic nature for the topical treatment of acne. has been known for some time that acne develops in Lactic acid, CHCHOHCOOH, M.W. 90 is known to the pilosebaceous follicle, specifically the formation of existin D, L, and DL forms. L-Lactic acid occurs in the follicular plugs (comedones). The normal piloseba blood of man and animals (5-40 mg/100 ml). The skin ceous follicle includes a fillicular canal which is open at 20 content of L-lactic acid is reported to be approximately one end to the surface of the skin through a follicular three times higher than that of the blood. Lactic acid orifice and which terminates at its other end in a follic concentration often increases in blood and muscle after ular cul de sac located in the dermal layer of the skin. vigorous exercise. L-lactic acid is also present in liver, Surrounding the neck of the follicular canal are one kidney, thymus gland, human amniotic fluid, and other or more multiacinar holocrine sebaceous glands which 25 organs and body fluids. Biochemically, lactic acid is empty into the lumen of the follicular canal by means one of the key substances in carbohydrate metabolism. of glandular ducts. The acini of the glands have ape DL-lactic acid, also known as ordinary lactic acid, ripheral layer of highly proliferating undifferentiated occurs in sour milk and is produced by the action of basal cells. As these basal cells are displaced from the lactic acid bacteria. It is also found in molasses due to periphery to the center of the acini by the proliferation 30 partial conversion of sugar, and is found in apples and of other basal cells, they mature and differentiate into other fruits, tomato juice, beer, wines opium, ergot, lipid-producing cells. These cells continue to produce a foxglove, and several higher plants. variety of lipids and to store such lipids in their cyto In 1946, Stern suggested in an article appearing in plasm. The Urologic and Cutaneous Review, Volume 50, page As lipids accumulate in the cells, the cytoplasm ap 35 106 that certain dermatoses were related to insufficient pears foamy, the cells enlarge, and the nuclei become acidity in the epidermal surface layer or coat. Accord distorted and disappear. The cells finally rupture, and ingly, certain dermatoses including one reported case the lipids of the cells, along with the cellular debris, of ichthyosis were apparently successfully treated by form the secretory product known as sebum. In the lowering the pH of the patient's skin surface. The treat normal state, the sebum is expelled through the glandu 40 ment included topical application of a 3% buffered lar ducts into the follicular canal thence to the skin lactic acid containing cream. surface. In acne, the normal function of the piloseba Providing an artificial acid coat has, on further inves ceous follicle is disrupted by an unexplained accumula tigation, been disproven as a viable treatment for der tion of lipids and keratinous materials in the mid-por matoses such as ichthyosis. Such wrong concept has tion of the follicular canal, which accumulation ulti 45 also been corrected by our recent article: Control of mately becomes a comedo. keratinization with a-hydroxy acids and related com As more lipids and keratinous materials are depos pounds. I. Topical treatment of ichthyotic disorders. ited onto the comedo, the follicular canal begins to figh of Dermatology, Volume 110, pages 586-590 distend. If the comedo is exposed to the surface of the (1974). skin it is classified as "open'; otherwise, it is referred to 50 In our earlier studies of topical treatment for acne we as "closed". Open comendones generally are not in found that lactic acid in concentrations of more than flammatory while closed comedones may evolve into 2% in a solution could burn or irritate skin involved inflamed pustules, papules, or cysts. with acne. When lactic acid was neutralized with metal Therapeutic regimens for acne include local and alkalis such as sodium hydroxide or potassium hydrox systemic treatments, although the former is necessary 55 ide, the sodium lactate or potassium lactate thus in the vast majority of cases to dislodge comedones. formed did not penetrate the human skin readily. Local treatment currently consists mainly of topical We have now discovered, however, that acne may be application of a variety of chemical agents which vari successfully prevented or treated with lactamides and ously include sulfur, resorcinol, salicylic acid, benzoyl for quaternary ammonium lactate. Generally, the lac peroxide, Vleminckx's solution (comprising sulfur, 60 tamide may be formed from lactic anhydride and am calcium, polysulfide, and calcium thiosulfate) or reti monia or any primary or secondary organic amine. The noic acid (vitamin A acid). All the foregoing topical quaternary ammonium lactate may be formed from agents are known as "peeling" or "drying' agents lactic acid and an organic tertiary amine. which exert their therapeutic effect by causing ery Preferred organic primary amines include any alkyla thema, irritation and desquamation of the skin followed 65 mines such as methylamine and ethylamine; ethanol by loosening and expulsion of the comedones. Oral amines such as monoethanolamine and monoisopropa antibiotics are often administered when microbial in nolamine; diamines such as ethylenediamine and 1,2- fections cause inflammatory papules and pustules. Two diamino propane. 4,021,572 3 4 Preferred organic secondary amines include dialkyla amine, 1,2-diaminopropane, 1-3-diaminopropane and mines such as dimethylamine and diethylamine; dieth N-ethanolethylenediamine. Organic secondary amines anolamine and diisopropanolamine; N-methylethanola may include dialkylamines such as dimethylamine and mine and N-ethylethanolamine. diethylamine; diethanolamine and diisopropanolamine; Preferred organic tertiary amines include trialkyla N-methylethanolamine and N-ethylethanolamine. mines such as trimethylamine and triethylamine; trieth To prepare the quaternary ammonium lactates of this anolamine; N-methyldiethanolamine and triisopropan invention, lactic acid is allowed to react at room tem olamine. It has been established through extensive tests perature with organic tertiary amines in aqueous or on humans having acne that topical application of a alcoholic aqueous solution. The organic tertiary amines solution, lotion or cream containing from 1 to 20% of 10 may include trialkylamines such as trimethylamine and at least one of the lactamides or the quaternary ammo triethylamine; triethanolamine; N-methyldiethanola nium lactates of this invention, and preferably from 2 mine; N,N-diethylethanolamine; N-ethyldiethanola to 10% thereof is therapeutically effective, when ap mine; N,N-dimethylethanolamine; triisopropanolamine plied on a daily basis, to cause, within about 4 weeks' and N,N-dioctylethanolamine. time, a return of the affected areas to a normal skin 15 Generally, the lactamide or quaternary ammonium condition. If two or more than two mixed lactamides lactate formed in the solution needs no isolation proce and/or quaternary ammonium lactates are used in a dure and may be directly incorporated into the thera composition of this invention, the total concentration peutic composition. of the compounds is preferred not to exceed 10% by . The initial concentration of lactic anhydride and/or volume of the composition. 20 lactic acid may range from 1 to 20% by volume of the It has also been found in humans having extremely total composition. The preferred concentration range, oily skin or having frequent occurrence of acne lesions however, is from 2 to 10%. that topical application of the aforementioned compo Ordinarily water is used as a solvent in the prepara sition of the present invention is effective, when ap tion of the composition. To improve the suitability of plied on a daily basis, in preventing development of 25 the composition for topical use on human skin ethanol acne lesions. and propylene glycol may be added to the aqueous Accordingly, it is the object of this invention to pro solution. The ratio of each vehicle may vary; however, vide a cosmetic composition containing at least one of the preferred concentration of ethanol and propylene the lactamides or the quaternary ammonium lactates, glycol should not exceed 70% and 30% respectively. which when topically applied will reliably prevent the 30 Generally, the concentration of ammonia or organic development of acne. amine used for the preparation of lactamine and/or It is another object of this invention to provide a quaternary ammonium lactate may range from 1 to medicinal composition containing at least one of lac 20% by volume of the total composition. The preferred tamide or quaternary ammonium lactate, which when composition range, however, is from 1 to 10%. The pH topically applied will substantially alleviate the symp 35 of the composition may vary from 3 to 8, the preferred toms of acne. pH, however, is from 3.5 to 7.0. It is still another object to provide a method for treat In the methods for formulating compositions of the ing acne with a non-toxic solution, lotion or cream of the present invention. present invention two or more than two different lacta It is still another object to provide a safe and efficient 40 mides or quaternary ammonium lactates may also be method for treating the symptoms of acne through utilized in the composition. regular topical application of a medicinal composition The therapeutic composition may also be prepared in which will promote healing within about 4 weeks. a form of lotions or creams. In these instances, cosmeti It is still another object of this invention to provide a cally acceptable ingredients are incorporated into the method for formulating a cosmetic as well as medicinal 45 formulation and lotions or creams are readily prepared. composition in solution, lotion or cream which when The following are illustrative examples of formula topically applied at least daily to skin prone to lesions tions of compositions according to this invention. Al of acne will prevent the development of acne or result though the examples utilize only representative com in a restoration of normal healthy skin condition. pounds in the interest of clarity, it should be under 50 stood that the following examples are illustrative and PREPARATION OF THE THERAPEUTIC not limited. Therefore, any of the above organic amines COMPOSITIONS may be substituted according to the teachings of this Commercially available lactic acid, USP grade, is a invention in the following formulations. colorless, nearly odorless syrupy liquid consisting of a EXAMPLE 1. mixture of lactic acid (CHO) and lactic anhydride 55 (CHO) equivalent to a total of not less than 85% Lactic acid, USP grade 11 mls was dissolved in 10 and not more than 90% by weight of CHO. This mils of water and the solution admixed with 50 mls of material may be directly used for the preparation of ethanol and 10 mls of propylene glycol. Concentrated lactamides and/or quaternary ammonium lactates in ammonium hydroxide solution (NH 29%), 7 mls was the following compositions. 60 added to the solution. Sufficient water was then added To prepare the lactamides of this invention, lactic to make 100 mls of composition. This composition had anhydride is allowed to react at room temperature with a pH of 6.4. ammonia or organic amines of primary and secondary families in aqueous or alcoholic aqueous solution. The EXAMPLE 2 organic primary amines may include alkylamines such 65 Lactic acid, USP grade 5 mls was dissolved in 10 mls as methylamine, ethylamine, propylamine and butyla of water and the solution admixed with 50 mls of etha mine; ethanolamines such as monoethanolamine and nol and 20 mls of propylene glycol. Ethanolamine 2.5 monoisopropanolamine; diamines such as ethylenedi mls was added to the solution. Sufficient water was 4,021,572 5 6 then added to make 100 mls of composition. This com mice and ICR white mice. The prepared compositions position had a pH of 5. were topically applied to the backs of mice once daily for a period of 1, 2 or 3 weeks. In the case of the ICR EXAMPLE 3 mice, hair was removed by plucking the test site before Lactic acid, USP grade 5 mls was dissolved in 10 mls 5 topical applications of test composition were initiated. of water and the solution admixed with 50 mls of etha Each test preparation was applied to 5 rhino mice and nol and 20 mls of propylene glycol. Diethanolamine 4 10 ICR mice. mls was added to the solution. Sufficient water was At the end of 1, 2, or 3 weeks, biopsy samples of skin then added to make 100 mls of composition. This com were taken from the test sites, fixed in 10% buffered position had a pH of 5.6. O formalin and embedded in paraffin. Histologic sections EXAMPLE 4 were cut at 6p, stained with hematoxyline and eosin Lactic acid, USP grade 5 mls was dissolved in 10 mls and examined for histologic features under a micro of water and the solution admixed with 50 mls of etha scope to determine the effects of topically applied test nol and 20 mls of propylene glycol. Triethanolamine, 5 15 composition on thickness and changes in the epidermis, mls was added to the solution. Sufficient water was the epidermal granular layer and the stratum corneum. then added to make 100 mls of composition. This com In addition, each composition was further treated for position had a pH of 5.2. toxicity by subcutaneous injection of various concen EXAMPLE 5 trations into ICR mice. Ten ICR mice were employed 20 for each test composition. The aforementioned screen ing tests indicated that all compositions listed in the Part A: Ety sorbitan 50 grams above examples were non-toxic. monooleate (hereinafter Tween 80)* A total of 84 patients with acne were divided into 7 Cetyl alcohol 220grams groups of 12 patients each. Each group of 12 patients Sligol : grams 25 was instructed to apply a different one of the prepara ele tions listed in the above examples topically twice daily Part B. S.EE. eeSpy WCO is50 mls on the skin of the face for 4 weeks. Eighty to 100 per Ethanolamine 20 ms cent of the patients tested (at least 10 in each group) Tween 80 is a trademark for a particular brand of poloxyethylene (20) sorbitan showed substantial reduction in the number of acne monooleatc. See Merck Index (1968) pp. 848-849 for a complete description of 30 lesions after 4 weeks of topical treatment. On contin said material. ued use it was also discovered that daily topical appli Heat part A to 70°C and heat Part B to 75°C. Add Part cation of the above preparation could prevent the de B slowly to Part A with agitation. Continue agitation velopment of new acne lesions. until the mixture is congealed. The water-washable 35 Each of the preparations of the present invention was observed, on continued daily topical use, to be nonirri cream thus prepared had a pH of 4.5 tating to the skin, non-allergenic and provocative of no EXAMPLE 6 signs indicative of potential toxicity. Part A: Tween 80 50 grams Cetyl alcohol 150 grams The invention may be embodied in other specific Stearyl alcohol 5g grams 40 forms without departing from the spirit or essential talene grams characteristics thereof. The present embodiments are Part B: Viene lycol 8, E. ene fyWCO 30 mls therefore to be considered in all respects as illustrative Triethanolamine 25 mls and not restrictive, the scope of the invention being Mannitol 20 mls indicated by the appended claims rather than by the 45 foregoing description, and all changes which come within the meaning and range of equivalency of the Heat Part A to 75°C and heat Part B to 80°C. Add Part claims are therefore intended to be embraced therein. B slowly to Part A with agitation. Continue agitation What is claimed and desired to be secured by United until the mixture is congealed. The water-washable States Letters Patent is: cream thus prepared has a pH of 4. 50 1. A non-irritating therapeutic composition for allevi EXAMPLE 7 ating the symptoms of acne in humans and for prevent Part A: Tween 80 50 grams ing the recurrence thereof comprising: as an active Cetyl alcohol 150 grams Steary alchol 50 grams ingredient, a therapeutically effective amount of a aee 5 grams product prepared by reacting, in aqueous or alcoholic lesterol 5 55 aqueous solution at room temperature, lactic acid or Part B: pyleneEvene glycolycol issilsS E. y 40 ms lactic anhydride and a base selected from the group Ethanolamine 20 mis consisting ammonium hydroxide, an organic primary, Mannitol 20 mls secondary, or tertiary alkylamine, alkanol amine, dia 60 mine, dialkylamine, dialkanolamine, alkylalkanol Heat Part A to 75° C. and heat Part B to 80'. Add Part amine, trialkylamine, trialkanol amine, dialkyl alkanol B slowly to Part A with agitation. Continue agitation amine, and alkyl dialkanolamine wherein the alkyl or until the mixture is congealed. The water-washable alkanol substituent has from 1 to 8 carbon atoms, in a cream thus prepared has a pH of 4.6. pharmaceutically acceptable vehicle for topical appli 65 cation. TEST RESULTS 2. The composition of claim 1 wherein the active Each of the aforementioned compositions was ini ingredient is present in a concentration of from 1 up to tially subjected to a series of screening tests on rhino about 20 percent by volume of the total composition. 4,021,572 7 8 3. The composition of claim 1 wherein the active parts by weight, 50 parts polyoxyethylene (20) sorbitan ingredient is present in a concentration of from 2 up to monooleate, 220 parts cetyl alcohol, 4 parts choles about 10 percent by volume of the total composition. terol, and 2 parts squalene; and a liquid comprising, in 4. The composition of claim 1 wherein the active approximate parts by volume, 550 parts water, 100 ingredient comprises a product prepared by reacting 5 parts propylene glycol, admixed with a product pre lactic acid or lactic anhydride and a member selected pared, by reacting, in aqueous or alcoholic aqueous from the group consisting of ammonium hydroxide, solution at room temperature, 50 parts lactic acid and methylamine, ethylamine, monoethanolamine, mono 20 parts ethanolamine, said base and liquid being pre isopropanolamine, ethylenediamine, 1,2-diaminopro sent in a weight-volume ratio of 276 grams of said base pane, dimethylamine, diethanolamine, diisopropanol 10 to 720 mls of said liquid. amine, N-methylethanolamine, N-ethylethanolamine, 13. A non-irritating therapeutic composition for alle trimethylamine, triethylamine, triethanolamine, N viating the symptoms of acne in humans and for pre methyldiethanolamine, and triisopropylamine. venting the recurrence thereof comprising, in admix 5. The composition of claim 1 wherein the active ture: an ointment base comprising, in approximate ingredient comprises a product prepared by reacting 15 parts by weight, 50 parts polyoxyethylene (20) Sorbitan lactic acid or lactic anhydride and a member selected monooleate, 150 parts cetyl alcohol, 50 parts stearyl from the group consisting of ammonium hydroxide, alcohol, 5 parts squalene and 5 parts cholesterol; and a methylamine, ethylamine, propylamine, butylamine, liquid comprising, in approximate parts by volume, 560 monoethanolamine, monoisopropanolamine, ethylene parts water, 20 parts mannitol and 100 parts propylene diamine, 1,2-diaminopropane, 1,3-diaminopropane, 20 glycol, admixed with a product prepared by reacting, in N-ethanolethylenediamine, dimethylamine, diethyl aqueous or alcoholic aqueous solution at room temper amine, diethanolamine, diisopropanolamine, N ature, 40 parts lactic acid, and 20 parts ethanolamine, methylethanolamine, N-ethylethanolamine, trimethyl said base and said liquid present in a weight-volume amine, triethylamine, triethanolamine, N-methyldie ratio of 260 grams base to 740 mls liquid. thanolamine, N,N-diethanolamine, N-ethyldiethanola 25 14. A non-irritating therapeutic composition for mine, N-N-dimethylethanolamine, triisopropanol treatment of the symptoms of acne in humans and for amine, and N-N-dioctylethanolamine. preventing the recurrence thereof comprising, in ad 6. The composition of claim 1 wherein the vehicle is mixture: an ointment base comprising, in approximate at least one member selected from the group consisting parts by weight, 50 parts Tween 80, 150 parts cetyl of water, ethanol, and propylene glycol present therein 30 alcohol, 50 parts stearyl alcohol, 5 parts squalene and 5 in a concentration of up to 99, 70, and 30 percent, parts cholesterol; and a liquid comprising, in approxi respectively. mate parts by volume, 560 parts water, 100 parts pro 7. The composition of claim 1 wherein the pH pylene glycol, 40 parts lactic acid, 20 parts ethanol thereof is from about 3 to about 8. amine, and 20 parts mannitol, said base and said liquid 8. The composition of claim 1 wherein the pH 35 present in a weight-volume ratio of 260 grams base to thereof is from about 3.5 to about 7. 740 mls liquid. 9. A non-irritating therapeutic composition for allevi 15. A non-irritating method for alleviating the symp ating the symptoms of acne in humans and for prevent toms of acne in humans and for preventing the recur ing the recurrence thereof comprising, in approximate rence thereof comprising: topically applying to in parts by volume: a product prepared by reacting, in 40 volved areas of the body and to areas thereof suscepti aqueous or alcoholic aqueous solution at room temper ble to acne lesions, an effective amount of a composi ature, 11 parts lactic acid, and 7 parts concentrated tion comprising: atherapeutically effective amount of a ammonium hydroxide solution admixed with 10 parts product prepared by reacting, in aqueous or alcoholic water, 50 parts ethanol, and 10 parts propylene glycol aqueous solution at room temperature, lactic acid or diluted with sufficient additional water to make 100 45 lactic anhydride and a base selected from the group parts of said composition. consisting of ammonium hydroxide, an organic pri 10. A nonirritating therapeutic composition for alle mary, secondary, or tertiary alkylamine, alkanolamine, viating the symptoms of acne in humans and for pre diamine, dialkylamine, dialkanolamine, alkylalkanola venting the recurrence thereof comprising, in approxi mine, trialkylamine, trialkanol amine, Dialkyl alkanol mate parts by volume: a product prepared by reacting, 50 amine, or alkyl dialkanolamine wherein the alkyl or in aqueous or alcoholic aqueous solution at room tem alkanol substituent has from 1 to 8 carbon atoms, in a perature, 5 parts lactic acid, and 2.5 parts ethanol pharmaceutically acceptable vehicle. amine admixed with 10 parts water, 50 parts ethanol, 16. The method of claim 15 wherein the reaction and 20 parts propylene glycol, diluted with sufficient product is present in a concentration of from 1 up to water to make 100 parts of said composition. 55 about 20 percent by volume of the total composition. 11. A non-irritating composition for alleviating the 17. The method of claim 15 wherein the reaction symptoms of acne in humans and for preventing the product is present in a concentration of from 2 up to recurrence thereof comprising, in approximate parts by about 10 percent by volume of the total composition. volume: a product prepared by reacting, in aqueous or 18. The method of claim 15 wherein the product alcoholic aqueous solution at room temperature, 5 60 comprises a product prepared by reacting lactic acid or parts lactic acid, and 4 parts diethanolamine admixed lactic anhydride and a member selected from the group with 10 parts water, 50 parts ethanol, and 20 parts consisting of ammonium hydroxide, methylamine, eth propylene glycol, diluted with sufficient water to make ylamine, monoethanolamine, monoisopropanolamine, 100 parts of said composition. ethylenediamine, 1,2-diaminopropane, dimethylamine, 12. A non-irritating therapeutic composition for alle 65 diethylamine, diethanolamine, diisopropanolamine, viating the symptoms of acne in humans and for pre N-methylethanolamine, N-ethylethanolamine, triethyl venting the recurrence thereof comprising, in admix amine, triethanolamine, N-methyldiethanolamine, and ture: an ointment base comprising, in approximate triisopropylamine. 4,021,572 10 19. The method of claim 15 wherein the product acid, and 4 parts diethanolamine admixed with 10 parts comprises a product prepared by reacting lactic acid or water, 50 parts ethanol, and 20 parts propylene glycol, lactic anhydride and a member selected from the group diluted with sufficient water to make 100 parts of said consisting of ammonium hydroxide, methylamine, eth composition. ylamine, propylamine, butylamine, monoethanol 26. A non-irritating method for alleviating the symp amine, monoisopropanolamine, ethylenediamine, 1,2- toms of acne in humans and for preventing the recur diaminopropane, 1,3-diaminopropane, N-ethanole rence thereof comprising: topically applying to in thylenediamine, dimethylamine, diethylamine, diethan volved areas of the body and to areas thereof suscepti olamine, diisopropanolamine, N-methylethanolamine, ble to acne lesions an effective amount of a composi N-ethylethanolamine, trimethylamine, triethylamine, 10 tion comprising, in admixture: an ointment base com triethanolamine, N-methyldiethanolamine, N,N-die prising in approximate parts by weight, 50 parts polyox thanolamine, N-ethyldiethanolamine, N-N-dimethyle yethylene (20) sorbitan monooleate, 220 parts cetyl thanolamine, triisopropanolamine, and N,N-dioctyle alcohol, 4 parts cholesterol, and 2 parts squalene; and thanolamine. a liquid comprising in approximate parts by volume, 20. The method of claim 15 wherein the vehicle is at 5 550 parts water, and 1-0 parts propylene glycol, ad least one member selected from the group consisting of mixed with a product prepared by reacting, in aqueous water, ethanol, and propylene glycol present therein in or alcoholic aqueous solution at room temperature, 50 a concentration of up to 99,70, and 30 percent, respec parts lactic acid, and 20 parts ethanolamine, said base tively. and liquid being present in a weight-volume ratio of 21. The method of claim 15 wherein the pH thereof 20 276 grams of said base to 720 mls of said liquid. is from about 3 to about 8. 27. A non-irritating method for alleviating the symp 22. The method of claim 15 wherein the pH thereof toms of acne in humans and for preventing the recur is from about 3.5 to about 7. rence thereof comprising: topically applying to in 23. A non-irritating method for alleviating the symp volved areas of the body and to areas thereof suscepti toms of acne in humans and for preventing the recur 25 ble to acne lesions an effective amount of a composi rence thereof comprising: topically applying to in tion comprising, in admixture: an ointment base com volved areas of the body and to areas thereof suscepti prising, in approximate parts by weight, 50 parts poly ble to acne lesions an effective amount of the composi oxyethylene (20) sorbitan monooleate, 150 parts cetyl tion comprising in approximate parts by volume: a alcohol, 50 parts stearyl alcohol, and 5 parts squalene, product prepared by reacting, in aqueous or alcoholic 30 and a liquid comprising, in approximate parts by vol aqueous solution at room temperature, 11 parts lactic ume, 570 parts water, 20 parts mannitol and 100 parts acid, and 7 parts concentrated ammonium hydroxide propylene glycol, admixed with a product prepared by admixed with 10 parts water, 50 parts ethanol, and 10 reacting, in aqueous or alcoholic aqueous solution at parts propylene glycol, diluted with sufficient addi room temperature, 30 parts lactic acid and 25 parts tional water to make 100 parts of said composition. 35 triethanolamine, said base and said liquid being present 24. A non-irritating method for alleviating the symp in a weight-volume ratio of 255 grams base to 745 mls toms of acne in humans and for preventing the recur liquid. rence thereof comprising: topically applying to in 28. A non-irritating method for alleviating the symp volved areas of the body and to areas thereof suscepti toms of acne in humans and for preventing the recur ble to acne lesions an effective amount of a composi 40 rence thereof comprising: topically applying to in tion comprising in approximate parts by volume: a volved areas of the body and to areas thereof suscepti product prepared by reacting, in aqueous or alcoholic ble to acne lesions an effective amount of a composi aqueous solution at room temperature, 5 parts lactic tion comprising, in admixture, an ointment base com acid, and 2.5 parts ethanolamine admixed with 10 parts prising, in approximate parts by weight, 50 parts poly water, 50 parts ethanol, and 20 parts propylene glycol, 45 oxyethylene (20) sorbitan monooleate, 150 parts cetyl diluted with sufficient water to make 100 parts of said alcohol, 50 parts stearyl alcohol, 5 parts squalene, and composition. 5 parts cholesterol, and a liquid comprising, in approxi 25. A non-irritating method for alleviating the symp mate parts by volume, 560 parts water, 20 parts manni toms of acne in humans and for preventing the recur tol, and 100 parts propylene glycol, admixed with a rence thereof comprising: topically applying to in 50 product prepared by reacting, in aqueous or alcoholic volved areas of the body and to areas thereof suscepti aqueous solution at room temperature, 40 parts lactic ble to acne lesions an effective amount of a composi acid, and 20 parts ethanolamine, said base and liquid tion comprising, in approximate parts by volume: a present in a weight-volume ratio of 260 grams base to product prepared by reacting, in aqueous or alcoholic 740 mls liquid. aqueous solution at room temperature, 5 parts lactic 55 ck k k >k k

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UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 4,021,572 DATED : May 3, 1977 NVENTOR(S) : Eugene J. Van Scott, Ruey J. Yu It is certified that error appears in the above-identified patent and that said Letters Patent are hereby Corrected as shown below:

Column 2, line 3, itS should read -- it--. Column 2, line 31, after 'wines' insert --, --. Column 6, 1ine 17, 'treated' should read -- tested--. eigned and evealed this nineteenth Day of July 1977

Attest.

RUTH C. MASON C. MARSHALL D ANN Attesting Officer Commissioner of Patents and Trademarks