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Publication numberUS3346451 A
Publication typeGrant
Publication dateOct 10, 1967
Filing dateJan 27, 1965
Priority dateJan 27, 1965
Publication numberUS 3346451 A, US 3346451A, US-A-3346451, US3346451 A, US3346451A
InventorsButt Oscar L, Collins Galen F
Original AssigneeS E Massengill Company
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Concentrated liquid lactic acid douche preparation containing aromatics
US 3346451 A
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Description  (OCR text may contain errors)

United States Patent 3,346,451 CON CENTRATED LIQUID LACTIC ACID DOUCHE PREiARATION CONTAINING AROMATICS Galen F. Collins and Oscar L. Butt, Bristol, Tenn., as-

signors to The S. E. Massengill Company, Bristol,

Tenn., a corporation of Tennessee No Drawing. Filed Jan. 27, 1965, Ser. No. 428,566

5 Claims. (Cl. 167-58) This invention in one of its aspects pertains to liquid douche compositions. In one of its more particular aspects the invention relates to liquid douche compositions which, although in aqueous phase, nevertheless contain aromatics. The term aromatics as used in connection with douches in powder form is well known and is understood to encompass one or more of menthol, thymol, oil of eucalyptus, methyl salicylate, and the like, all of which are virtually insoluble in water. See Modern Drug Encyclopedia and Therapeutic Index, Drug Publications, Inc.

A study of textbooks on gynecology reveals divergent views on douching. Some physicians advocate acid douches; some prefer alkaline douches; and there are those who advocate no douching. It is generally believed, however, that while many vaginal symptoms can be cleared up only by the removal of deep-seated causes, the therapeutic vaginal douche serves as an important adjuvant in the treatment of such conditions. In addition a surprising number of minor infections appear to be cured by the use of acid douche preparations.

It has been reported that alkaline douches have no application in therapy of vaginitis. Vaginal therapy for irichomonas vaginalis vaginitis depends upon the restoration of the vaginal pH to a normal range of 3.5 to 5. Treatment for vaginalis vaginitis and for nonspecific vaginitis consists of acid douching. The selection of a suitable douche is, therefore, a matter of great importance to the clinician.

This invention is concerned with acid douche preparations used to restore and maintain an acid pH corresponding to that of the normal lactobacillary flora of the vaginal tract. These are liquid preparations used as adjuncts in the management of vaginal and cervical infections due to trichomonas and other vagino-cervicitis in- 3,346,451 Patented Oct. 10, 1967 since the product does not require any significant stirring for preparation for use. A liquid also lends itself to measuring devices such as bottle caps which find better consumer acceptance.

In spite of the advantages of liquid douche preparations they have not been as widely accepted as powder douche products. One reason for this is believed to be that liquid douche preparations do not include the effective aromatics. Experience has shown that combinations have excellent acceptance by users of powder douche products which contain menthol, oil of eucalyptus, methyl salicylate and thymol, and various mixtures of these. These aromatics have such low solubility in water they have heretofore been used only in powders. Powder douche preparations are highly diluted with water; this permits solution of the aromatics.

One possible method for incorporating aromatics in a liquid douche preparation would be to dissolve the aromatics in a water-soluble alcohol and dissolve this alcohol solution of aromatics in water. However in the case of an acid douche, an alcohol-acid reaction is possible. Desirable acid douches should provide a pH between 3.5 and 5 with good buifer capacity. The acidalcohol reaction and accompanying ester formation will raise the pH and reduce the butter capacity of the douche reparation. It is therefore not possible to maintain the desired pH if a reaction occurs between the acidic material and the alcohol. In addition esters introduce unexpected odors or a foreign substance undesirable from a psychological standpoint.

In accordance with one aspect of this invention is has been found that the combination of lactic acid and ethyl alcohol can be used in a liquid douche preparation with essentially no reaction of alcohol with acid. An indication of the alcohol-acid reaction is the percent titratible acidity. This percent acidity is determined from cubic centimeters of standard sodium hydroxide, titrating with 0.1 N sodium hydroxide using a phenolphthalein end point. The percent acidity decreases with increasing alcoholacid reaction. Acetic acid has a dissociation constant of 1.75 X l0 whereas lactic acid has a dissociation constant of 8.4' l0-*. It would be expected therefore that lactic acid would form esters at about the same rate as acetic acid. 'The following data show that this is not the case.

TABLE I.-ESTERIFICATION TEST Composition A Composition B Acetic Acid,

gm Ethyl Alcohol 95%, ml Sodium Hydroxide, gm Water, q.s., ml pH, approximately Lactic Acid, gm Ethyl Alcohol m1. Sodium Hydroxide, gm Water, q.s., m1 pH, approximately ACID ITY Percent Acidity Ingredient Time Elapsed CRT 40 C. 50 0.

Composition:

Acetic Acid in 30% Ethanol 1 month.-. 9 months" Initial 1 month--- 9 months Lactic Acid in 30% Ehtanol fections. There are certain advantages to the use of liquid douche preparations for feminine hygiene. A liquid preparation has all of the active ingredients dissolved. This eliminates possible irritations that may occur in the case of powder douche preparations due to the fact that all of the solid materials or oils are not in solution prior to use. Moreover a liquid preparation is easier to use The foregoing data show that in the case of acetic acid, commonly employed in douche preparations, there is a drop in the percent acidity at controlled room temperature (CRT) from 12.33 to 10.18 in 9 months. In the lactic acid preparation the acidity change for the same period and temperature is 11.12 to 11.34. (The slight increase is believed due to the presence of anhydride.) At 40 C with the acetic acid preparation, the acidity is 10.92, at the end of the first month and 9.32 at the end of 9 months. With the composition of this invention the percent acidity changed from 11.73 at the end of one month to 10.89 at-the end of 9 months. It can be seen, therefore, that very little reaction occurs between ethyl alcohol and lactic acid. Such is not the case with ethyl alcohol and acetic acid.

In accordance with another aspect of this invention the combination of lactic acid and isopropanol, although less desirably, will also function as a vehicle for the introduction of aromatics into the douche composition. The

dropped from 12.33 to 11.91 in one month at room temperature, whereas the lactic acid composition C, at room temperature exhibited no appreciable change.

Now consider citric acid which is also frequently used in douche preparations. This acid has dissociation constants of 8.4X10- 1.8 10 and 4.0X- Citric acid likewise would be expected to be similar to lactic acid in its reaction with ethyl alcohol. Rather, a reaction occurs as in the case of acetic acid, rendering it unsuitable for a liquid douche preparation containing aromatics. The esterification of citric acid by reaction with the ethanol is shown in the following table.

TABLE III.ESTERIFICATION TEST Composition D:

data in the following table show that ester formation also is not a significant factor in this combination. The use of this combination is hampered only by the odor of the alcohol which requires difierent proportions of the various aromatics.

TABLE IL-ESTERIFICATION TEST Composition 0:

Lactic acid 85%, e

The data in Table 111 show a significant reduction in percent titratible acidity, indicating considerable reaction between the citric acid and the ethanol. Citric acid, like acetic acid, is unsuitable for liquid douche preparations containing ethyl alcohol.

Isopropyl alcohol 30%, gm. Sodium hydroxide, Q'm Water, q.s., m

5 w re 9 2" con-ea pH, approximately 3. 5.

ACIDITY Percent Acidity Ingredient Time Elapsed CRT 40 C. C.

Composition: Tn flail 9, 03

1 month--. 10.1 10. 7 10. 5 C Lactic Acid in 30% IsopropanoL- 2 months-. 10. 5 10.9 10. 5 3 months 10.7 10.4 9. 9 5 months.. 10.7 1 9.8 Tnii'ial 12, 33 A Acetic Acid in 30% Ethanol-- {1 month--- 11. 91 10. 92 9.95 9 months.- 10.18 9. 32 8. 99

Here again very little change in percent acdity, which would indicate ester formation, is noted compared to the acetic acid-ethanol combination. Thus, acetic acid-ethanol It has been pointed out that in addition to providing a pH of 3.5 to 5 an eifective liquid douche should have good buiier capacity. Buffer capacities can best be dis- TABLE IV.BUFFER INDEX Butler Index Time Elapsed Ingredient Composition:

Acetic Acid in 30% Ethanol 9 months.. Initial--- 1 month... 2 months- 3 months.. 5 months.. Initial.. 1 month..- 2 months. 3 months-. 5 months- Lactic Acid in 30% Ethanol-. {I mont Lactic Acid in 30% Isopropanol Citric Acid in 30% Ethanol.

cussed in terms of the buifer index. Buffer index is the increment of base required to produce an increment in the pH value of the solution. Butter index as used herein is the amount of standard sodium hydroxide, expressed in millimoles, necessary to produce an increase from the original pH to pH 6.0.

Calculation: BuiI'er index: Millimoles of NaOH=ml. of NaOI-I addedx normality of NaOH.

It can be seen from Table IV that the two acids A and D, widely used in liquid douches devoid of alcohol, do not have the buffer capacity which compositions B and C of this invention possess. There is a marked drop in butter index in the tests conducted with compositions A and D whereas there is little or no drop in buffer index in the case of compositions B and C.

Lactic acid thus lends itself admirably to concentrated liquid douche preparations wherein C alcohols, and to a lesser extent, C alcohols are employed as the vehicle for the introduction of the aromatics. According to an aspect of this invention therefore, a liquid douche preparation containing aromatics is provided, which is water dilutable, to form an aqueous douche for restoring and maintaining a normal vaginal pH. The douche preparation is a buffered aqueous solution of lactic acid having a pH of 3.5 to 5. It contains (1) a surfactant or wetting agent, and, (2) dissolved therein, a C or C alcohol solution of aromatics, the lactic acid permitting solution with essentially no reaction of alcohol with lactic acid to raise the pH. i

The douche preparation of this invention desirably is diluted 100 to 1000 parts to 1 by volume and will usually be sold with a device dispensing an amount to which a quart of water should be added. A douche preparation must, of course, not be harsh or irritating if used in stronger dilution since experience has shown that exact dilutions will not be used due to carelessness. The preparation of this invention can be so used.

This first aspect of the invention thus provides a liquid lactic acid douche preparation containing aromatics for use in the restoration of the vaginal pH to a normal range of 3.5 to 5, this aqueous douche composition containing 96 to 74 Weight percent lactic acid as an active ingredient; 2 to 14 weight percent of a surfactant; and 2 to 12 weight percent aromatics, the total being 100 percent. The buffer ing is well known, sufiicient alkali being used to adjust the pH in the 3.5 to 5 range. Other ingredients such as known astringents, colorants and the like can, of course, be added. The percentages of theforcgoing essential ingredients will not change regardless of the quantity of alcohol, water or other ingredients added. The alcohol employed in the concentrated composition generally will be sufficient to dissolve the aromatics up to fifty percent of the water in the concentrate.

In the preparation of the douche compositions of this invention the aromatics can be dissolved in the ethanol and the water-soluble ingredients dissolved in water. The two solutions are then combined. Another method is illustrated in the following example. In use, ml. of the preparation is added to a quart (approximately 1000 ml.) of water. Accordingly, the examples herein are based on 10 ml. doses.

EXAMPLE A (Per 10 ml. dose) Lactic acid (USP. 85%) gm 1.5 Sodium hydroxide gm 0.30 Tartrazine F. D. and C. Yellow No. 5 mg 0.25 Quinoline yellow, water soluble D. and C. Yellow No. 10 mg 1.50 Alcohol (U.S.P. 95%) cc 3.15

6 EXAMPLE AContinued Octylphenoxy polyethoxy ethanol Triton The lactic acid and sodium hydroxide are dissolved in half of the water (5 1111.). In the other half of the water the quinoline and tartrazine colorants are dissolved. The two 5 ml. moieties are then combined and the alcohol, Triton X- and aromatics are added to the solution. The composition can be filtered if necessary. When 10 ml. of the liq id is added to 1 quart of water, a pH of about 3.6 results with a surface tension of about 30 dynes. The solution has a buffer index of about 10. Sodium hydroxide is not a buffering agent as such, but when it reacts with lactic acid, it forms sodium lactate, and sodium lactatelactic acid is the buffering agent. Potassium hydroxide can be used as a replacement for the sodium hydroxide.

In the formulation of Example A the No. 10 and No. 5 colorants, the surfactant and the solution of aromatics are conventional. It is obvious that changes in these ingredients can be made without affecting the therapeutic objective. Thus other colorants such as Rhodamine B Hydrochloride (D. and C. Red No. 19) and Brilliant Blue PCP (F. D. and C. Blue No. l) as well as other nonionic and anionic surfactants such as sodium lauryl sulfate, lauryl amide polyether, nonylphenoxy polyether ethanols and octylphenoxy polyether ethanols With three to thirty oxyethylene groups, and the like can be used. The sodium hydroxide, on the other hand, is used to provide the desired hydrogen ion concentration. Potassium hydroxide and other inorganic bases can be substituted therefor.

Douche preparations formulated according to the aspect of this invention which has been described are excellent for use by physicians who prefer a lactic acid douche physician and the patient. It maintains the normal vaginal pH. It has cleansing and antiseptic properties due to the surfactant. It is safe, and it contains the aromatics which experience has shown are in greater demand.

Many physicians, however, prefer that a douche preparation also have mild astringent properties. One of the features of this invention is that mildly astringent compounds such as aluminum lactate and aluminum phenol sulfonate can be included in the formulation, frequently in lieu of sodium hydroxide. Potassium and ammonium alum, which are often used in douche products for their astringency, cannot be employed in the liquid lactic acid douche preparations of this invention because of their poor solubility in the alcohol which is required for solution of the aromatic constituents. Likewise boric acid and citric acid cannot be used in liquid preparations with aluminum salts, since both aluminum borate and aluminum citrate are relatively insoluble. In another of its aspects this invention provides a unique combination of astringents which overcome this solubility problem. Moreover, in accordance With the practice of this aspect of the invention novel astringents have been found which in combination with lactic acid produce the normal vaginal pH. This aspect of the invention contemplates the use of an aluminum chlorhydroxide complex [Al (OH) C-1] wherein x is one to ten, and aluminum chloride in combination with lactic acid to provide a douche preparation with astringent properties. The following example illustrates the preparation of a liquid douche product of this aspect of the invention.

7 EXAMPLE B (Per 10 ml. dose) Lactic acid (USP. 85%) mg 500 Aluminum chlorhydroxide complex mg 225 Aluminum chloride, hydrous (U.S.P.) mg 350 Quinoline yellow, water soluble D. and C. Yellow No. mg 1.5 Tartrazine F. D. and C. Yellow No. 5 mg. 0.25 Aromatics mg 60.0 10 Octylphenoxy polyethoxy ethanol Triton X100 mg 150.0 Ethyl alcohol (USP. 95%) ml 3.15 Water, q.s. ml 10.0

Aromatics: Gm. Menthol 29.6 Thymol 29.6 Oil eucalyptus 38.6 Methyl salicylate 2.2

To make the douche preparation the water is separated into two moieties. In one portion the lactic acid, aluminum chlorhydroxide complex, aluminum chloride, quinoline and tartrazine are dissolved in the amounts shown above for each 5 ml. quantity in the moiety. In the other moiety the alcohol, aromatics and surfactant are dissolved in the quantities shown per 5 ml. of moiety.

Clinical data Clinical evaluation of the composition of Example B was completed with 59 subjects. The patients used the medication 3 to 7 times weekly for 24 doses. It was used as a cleansing douche and as adjunct for other vaginal therapy. The patients were instructed to add 10 ml. (a measuring device was provided) to 1 quart of water, and then douche.

Results: Irritation, burning, undesirable side eifects, none; prefer to douche powders, 57.

The product was described by the patients as soothing, refreshing, excellent, easy to prepare, and convenient. In addition, as is known to those skilled in the art, aluminum salts confer the desired astringency on the compositions. The unique combination of water-soluble astringents employed herein were found particularly effective in the clinical evaluation.

The example which follows illustrates the invention when isopropyl alcohol is used, the method of preparation being the same as in Example B.

Combinations of an aluminum chlorhydroxide complex and aluminum chloride have not, to our knowledge, been employed as astringents for the vaginal tract. In addition it was not realized that their use in combination with lactic acid would provide a composition possessing the buffer capacity of the douche preparation of this invention. When used in a weight ratio in the range of 1 aluminum chlorhydroxide complex:1.5 aluminum chloride:2 lactic acid, to 1 aluminum chlorhydroxide complex:2 aluminum chloride:3 lactic acid resulting in a pH of 3.5 to 5, a douche product with good buffer capacity results. Using the foregoing ratios the ingredients are employed in ranges set forth hereinbefore. The aluminum chlorhydroxide complex and aluminum chloride are the buffer ingredients, constituting 1.5 to 20 pehcent of the composition.

Thus this invention provides not only a liquid douche preparation containing aromatics, but a liquid douche preparation containing new and unique astringents. All of the advantages of lactic acid douches are attained by the preparations of the invention. Obviously changes in the other ingredients can be made. For example several combinations of aromatics can be employed, and these can be varied depending on the alcohol employed. These and other obvious ramifications and variations are, of course, within the scope of this invention.

What is claimed is:

1. A concentrated liquid douche preparation containing aromatics, said preparation being water dilutable to form an aqueous douche for restoring and maintaining a normal vaginal pH, said preparation being a buffered aqueous solution of lactic acid having a pH of 3.5 to 5 and containing a Wetting agent selected from the group consisting of nonionic surfactants and sodium lauryl sulfate, and, dissolved therein, an alcohol solution of aromatics selected from the group consisting of menthol, thymol, oil of eucalyptus, methyl salicylate and mixtures thereof, the alcohol permitting solution of the aromatics in the buffered aqueous acid solution, the alcohol being selected from the group consisting of ethyl and isopropyl alcohols, essentially no reaction of these alcohols with lactic acid occurring to raise the pH, the solution containing 96 to 74 Weight percent lactic acid, 2 to 14 percent wetting agent, 2 to 12 Weight percent aromatics, the total being percent, and at least suflicient alcohol to dissolve the aromatics.

2. A concentrated liquid douche preparation containing aromatics, said preparation being water dilutahle to form an aqueous douche for restoring and maintaining a normal vaginal pH, said preparation being a buttered aqueous solution of lactic acid having a pH of 3.5 to 5 and containing a nonionic surfactant, and, dissolved therein, an ethanol solution of aromatics selected from the group consisting of menthol, thymol, oil of eucalyptus, methyl salicylate and mixtures thereof, the ethanol permitting solution of the aromatics in the buffered aqueous acid solution, essentially no reaction of ethanol with lactic acid occurring to raise the pH, the solution containing 96 to 75 weight percent lactic acid, 2 to 14 percent surfactant, 2 to 12 weight percent aromatics, the total being 100 percent, and at least suflicient ethanol to dissolve the aromatics.

3. The douche preparation of claim 2 wherein the surfactant is an octylphenoxy polyether ethanol having three to thirty oxyethylene groups.

4. A concentrated douche preparation, said preparation being water dilutable to form an aqueous douche for restoring and maintaining a normal vaginal pH, said preparation containing in aqueous solution 96 to 74 weight percent lactic acid as an active ingredient,

2 to 14 weight percent of a nonionic surfactant,

2 to 12 weight percent aromatics selected from the group consisting of menthol, thymol, oil of eucalyptus, methyl salicylate and mixtures thereof,

the total being 100 percent,

aluminum chlorhydroxide and aluminum chloride as astringents and buffer ingredients to maintain a pH of 3.5 to 5,

the Weight ratio of aluminum chlorhydroxide to aluminum chloride to lactic acid being in the range of 1:1.5:2 to 1:2:3, and

ethanol,

the ethanol having the aromatics dissolved therein permitting solution of the aromatics in the aqueous lactic acid solution with essentially no reaction with lactic acid raising the pH, the volume of ethanol being from sufficient to dissolve the aromatics to 50 percent of the aqueous solution in volume.

5. A concentrated douche preparation, said preparation being Water dilutable to form an aqueous douche for restoring and maintaining a normal vaginal pH, said preparation containing in aqueous solution 96 to 74 Weight percent lactic acid as an active ingredient,

2 to 14 Weight percent of a nonionic surfactant,

2 to 12 Weight percent aromatics selected from the group consisting of menthol, thymol, oil of eucalyptus, methyl salicylate and mixtures thereof,

the total being 100 percent,

aluminum chlorhydroxide and aluminum chloride as astringents and buffer ingredients to maintain a pH of 3.5 to 5,

the Weight ratio of aluminum chlorhydroxide to aluminum chloride to lactic acid being in the range of 1:1.5:2 to 1:2:3, and

isopropanol,

the isopropanol having the aromatics dissolved therein permitting solution of the aromatics in the aqueous lactic acid solution with essentially no reaction With lactic acid raising the pH, the volume of isopropanol being from sufiicient to dissolve the aromatics to 50 percent of the aqueous solution in volume.

References Cited UNITED STATES PATENTS 2,556,567 6/1951 Wright et al. 167-58 2,649,398 8/1953 Wright et al 167-58 2,904,468 9/1959 Davis et al. 167-58 3,026,247 3/ 1962 Hill 167-22 FOREIGN PATENTS 1,306,648 9/1962 France.

ALBERT T, MEYERS, Primary Examiner. I. S. LEVITT, Examiner V. C. CLARKE, Assistant Examiner

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2556567 *Apr 1, 1949Jun 12, 1951Tampax IncDouche composition
US2649398 *Apr 1, 1949Aug 18, 1953Tampax IncDouche composition
US2904468 *Apr 13, 1954Sep 15, 1959Carlen CorpSkin disinfectant containing polyoxyethylene alkyl phenol, calcium chelating agent and either an organic sulfate or sulfonate salt
US3026247 *Dec 17, 1957Mar 20, 1962Towner Hill RobertPharmaceutical preparation
FR1306648A * Title not available
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Classifications
U.S. Classification424/682, 514/159, 424/685, 424/742
International ClassificationA61K8/30, A61K8/19, A61K36/61, A61K8/37, A61K8/34, A61K8/26, A61Q15/00, A61K36/185, A61K8/365, A61K8/39, A61K31/16
Cooperative ClassificationA61K8/365, A61K8/26, A61K8/39, A61Q15/00, A61K8/37, A61K8/347, A61K8/34
European ClassificationA61K8/39, A61K8/34, A61Q15/00, A61K8/26, A61K8/37, A61K8/365, A61K8/34F