US2484035A - Trichomonadicidal therapeutic composition - Google Patents

Description

Patented Oct. 11, 1949 TRICHOMONADICIDAL .THERAPEUTIC COMPOSITION J'GarthJohnson, Bound Brook"; Ni J5, assignorto OrthoTharmaceuticaI Corporation; a corporation of-New Jersey No Drawing. Application JunedLJMGi: Serial No. 676,103

9-*Claims.- (Cl. 167 586 ofzthe Bartholinsglands-of the female, as well as thezurethra, bladder,- and-possibly the prostate of the :malet.

Conservative; estimates :have placed the incidencezof the infestation in thefemale at about 20 to lO. percent in the unselected population-the world over, with a somewhat higher incidence in the colored race; Irrthemale, the incidenceof Trichomonasinfestation is estimated to heap,- proximatelylS. per cent of the unselected population with an incidence of aboutBi-per cent in cases ;of non specific prostatitis.

Oneof the major problems -in the control of Trichomonas vaginaZis'vaginit-is arises from the recurrence of infectionfollowing apparent clinical cure.-; Thesezrecurrencesdn the femal'e may be duewto 'reinfestationfrom the" female urinary tractafrom 'dllCtSfOf theassociatedvaginal glands or from contact with an infected sexualvpartnerl The clinical control of the infection therefore includes topical medicatib'nofthe vagina per se I and; treatment of theurethra and bladderf'in bothseXual-partners, aswell as medication of the ducts of the associated vaginal glands.

Various medicaments: and methods of treatment-have heretofore been employed inth'e treatmentof Trichomonas vwg'inalis vaginitis, but all of these have been subject to numerous limitations and disadvantages. Thus, for example, the commonly used organic acids such as acetic, lactic, and citric acids, are characterized by very low. trichomonadicida'l action, and in many instances they fail 'satisfactorilyto clear up the infestation, even when the therapy is continued fonzlongv :periods of time; Other agents such as silver picrate have high trichomonadicidal propi erties but are objectionable for the reason that they give rise to severe'sensitizations, argyria and the like, and also because they produce aesthetically inacceptablelstainsb The phenyl mercuric compounds, such as the nitrate or acetate, .are

likewise, exceedingly, active trichomonadicidal compounds, but theyare reported to be unstable except-at a .limitedpli range (7.4 to 7.6) which difiers considerably I from that/likely ,to be encountered in. an infested vagina. Still other 2* preparationsnsingvariousagents in the powdered form formedicationf *byf-tlre' insuflation' technique (e:g., borica'cid} diiod'oquinonezlactose, and dex troselas welP'a's silver picrate) are'open to serious criticismbntl'iebasis #of numerous air embolisms resultingiin death following "insufliation of preg na'nt"'womer1'.' For these? and"other' reasons, a more? satisfactory t'r'ichomona'dicide has long been desired:

The object of the present invention is 'to pro-' vide a new andfirnprovedtherapeutic preparation and technique for" the treatment of Tric'h'omonas vaginalis infestations, twitl'ia' View to" obviating the disadvantages "of. the medicaments and modes oftreatmentiheretofoi eemployed? A more particular objectdstlie provision of a therapeutic composition cl'iaract'e'r'ized'- by 'high trich'or'n'onadicidal' pewer and capable ofeffecting the rapid destruction of the parasites "without causing irritation of 'the human tissue including the vaginal mucosa.

Still another "object. istheprovision of a composition ofv the characterdescribedwhich is free of any..adverse side! reactions upon the patient; issatelfdr home use: by the patient-- following oiiice treatment.bythe-physician; is characterized by a high degree-0L efiqcacm in the treatment of l-Trichomonas paginalzs vaginitis'; and is free of unaesthetic staining-tendencies when used for the=purposeintended.-,-- I

Other objects and advantages of the invention willtbecomee apparent as? the description progressess- The foregoingsobjects may, be attained in accordance-with the: present: invention which" is basedvin pare upon:- two' correlative discoveries; namely (-1)'- that bromoacetic acid 1 and its watersoluble: sa lts -(hereinaftercollectively referred to as bromoacetic acid: compounds) are charac terizedciby-isan extraordinarilyxhigh' trichom'onadi cidal: action thatt isz many'ztimes' greater than-that ofit the organic'cacids; heretofore most commonly empl'oyede ins the: treatment-1 of Triohomonas var/malts infestations? and (2) that, although 'bromoacetic acid: ompounds in concentrated form I are vesicant to hunian' tissiie, nevertheless, because I of theirextremely potent trichom'onadi cida-T action, they m'ay' be employed as effective tric'hom'on'adi'cid'e's by incorporating them in a suitable *tlierap'euticveliicle an concentrations so low"thatthe-resultiiig compositions are essentially non-irritant to the-most sensitive human tissues including-the vaginal -mucdsa. The-'trichomonadicidal' compositions --of-'--the' present invention therefore'"'comprises one or'mo're bromoacetic acid compounds;- uniformly distributed throughout a suitable pharmaceutical vehicle, the acid compound beingpresentin thevehicl'ein a proportion sufficient" t0imparttrichomonadicidal properties to the composition, but insufilcient to render the composition irritant to sensitiv human tissue.

The trichomonadicidal potency of bromoacetic acid and its soluble salts was established by extensive investigations which demonstrated that they constitute highly effective agents even used in concentrations far below 1 part of acid compound in 1000 parts of vehicle} Indeed, the preparations to be described in detail hereinafter have efiective dilutions ranging from apsolvents, the resulting solution being employed as a vaginal douche. For several reasons, however, it is much more desirable to employ water 'dispersible liquid or semi-liquid vehicles that are colloidal in nature, particularly those that are viscous and/or mucilaginous in character. This preference is based in part upon the fact that,

in the topical treatment of infestations of the vagina and external genitalia, a preparation that proximately 1:l0,000 to 1245,000, the efiective dilution being defined as the maximum dilution (expressed in terms of the eifective agent) at v which the composition is capable of destroying Trichomonas in 10 minutes, but not in 5, in the presence of per. cent human serum, when tested in vitro by the standard procedure described by Johnson and Trussell, Proceedings of The Society for Experimental Biology and Medicine, vol. 54, pp. 245-249, 1943. This extremely high activity of bromoacetic acid and its salts is to be compared with that of acetic acid, for example, which has an effective dilution of only 1 part in 256, or with that of lactic acid, which has an effective dilution of only 1 part in 213. In other words, under the conditions of the Johnson and Trussell test, the trichomonadicides of this invention are'roughly to 200 times as active as the agents heretofore most commonly used in the treatment of Trichomonas vaginalis.

The non-irritancy of bromoacetic acid at effective concentrations was established by rigorous tests which demonstrated that'this acid, when used in a suitable chemotherapeutic vehicle in concentrations as high as'l part by Weight of acid to 700 parts by weight of vehicle, produces no objective signs of local tissue irritation of the human vaginal mucosa, except in an exceedingly small percentage of cases of special drug sensitivity. The acid can probably be used without irritancy at significantlyhigher levels of concentration; however concentrations above l-part in 1000 are not required for effective trichomonadicidal potency, and I prefer to use the bromoacetic acid compound in concentrations ranging from about 1:1000 to about 1:10,000 although, as previously indicated, concentrations from about 1:700 to about 1:100,000 are useful and effective under certain conditions.

In employing thetrichomonadicides in the present invention for the treatment of vaginal infestations, one or more of the active agents are uniformly distributed in a suitable chemotherapeutic vehicle that-is chemically compatible with the particular trichomonadicide selected, non-inhibiting with respect to-the action of thc effective agent upon the parasite, and essentially non-injurious to the vaginal mucosa under the conditions of use.- Since it is desirable to avoid the previously mentioned hazards arising from the insufiation of powdered materials, the vehicle is preferably of a liquid or semi-liquid type. Furthermore, since the final preparation should be readily miscible with the vaginal fluids, the vehicles, whether hydrous or anhydrous in character, should nevertheless be of the watermiscible or water-dispersible type.

The foregoing criteria may be met by a large number of liquid or semi-liquid chemotherapeutic vehicles that are well known in the art. Thus for example, the vehicle may consist merely of a simple, non-injurous water-miscible solvent, such as water itself, or any of the various watersoluble glycols, such as propylene glycol, for example; or it may comprise a mixture of such ment and the parasite.

is gelatinous or mucilaginous in character will afiord prolonged contact between the medica- A further and possibly even more important reason for the preference mentioned is based upon the discovery that the trichomonadicidal potency of a given bromoacetic acid compound, when dispersed in all the colloidal vehicles investigated, is substantially greater than the potency of the same agent when used in the same concentrations in solution in non-colloidal vehicle such as water. Accordingly, by employing a colloidal vehicle, concentrations far below the irritant level for bromoacetic acid and its compounds may be used. I

Of the various types of water-dispersible, viscous colloidal gels or emulsions that may be used as suitable colloidal vehicles for the trichomonadicides of the present invention, particular mention may be made of the well known oil-in-water types of emulsions or creams as well as the equally well known aqueous jells such as those prepared with the aid of various jelling agents, for example, acacia, tragacanth, bentonite, alginic acid and the like. The preferred vehicle, however, comprises a viscous, aqueous jell containing pectin as a jelling agent, inasmuch as the presence of pectin in the finished composition, for reasons at present not understood, appears to enhance the trichomonadicidal potency of bromoacetic acid compounds to an outstanding degree.

In order more clearly to disclose the nature of the present invention, several specific examples will hereinafter be described in considerable detail. It should be understood that these are presented solely for purposes of illustration and not with the object of either delineating the scope of the invention or restricting the breadth of the appended claims.

EXAMPLE I This example is illustrative of one of the preferred embodiments of the inventionnamely, a water-dispersible aqueous gel containing pectin and bromoacetic acid, the latter at a 11000 dilution. The complete formulation is as follows:

Per cent (A) Pectin powder N. F.VII 6.5 (3) Methyl cellulose (Dow Methocel) 1500 cps 0.75 (C) Propylp-hydroxy benzoate 0.05 (D) Bromoacetic acid 0.1 (E) Deionized water to The gel may be prepared by either of the following two methods:

Method A H Iv. when solution n i cfo'oledto 125, c.,;jedd jtrie pectin powder, slowly and with constant agiffion' 3" NU. I V. Add to the pectin-containing mixture IV;,the for mo'acetic acid solution II, then 'stir for 30 minutes; let it stand forlz hours, andfinally mix for minutes before packaging the gel in any suitable container such as a collapsible tube.

Method B Heat ji t t about 0. e l5?f 'p' h'ydroxy ben'zoate and mix until dissolved.

II. Remove 50 of the solution from the mixing vefssel (portion A). Cool the 50% of the solutipn remaining, in the mixing ,vessel (portion jB) to "T ',C., add thepectin powder with agitation and stir until dissolved.v 4 p ,LIII. 10.40% of withdrawn portion A, "at 90 to '05 C add the nie'thyl cellulose and'stir rorfio "fiiiflutes. V I p. ,I.V. "Add 40% of withdrawn portion *Agcbold to m III.

N 31.1mm 11 and IV for minutes, with continuagitation. v Dissolvebromoaceticacid in 20% of portion Wand-add to V; 'st ir for30 minutes, let it stand I01 12 hoursfand finally mix for 10 minutes before packaging in "any suitable container.

The product produced by either of the above gadrnirably adapted ior th'e topical treatment of infestations of the vagina and external genitalia.

EXAMPLE 'II illustrates'a forrnulation j ingbromoacetic acid in an, aqueous-base cream- .l lge veliicle The composition of the finished cream is as follows:

v 'Prcent )(A) Glycerylmonosterate ;9'.0 1(3) Stearic acid 6.0 ":(C) Peanut oil 5.0

(D) Glycerin 510 (E) Triethanol'amine "0.5

(F) Bromoacetic acid "0.0125 (G) Distilled water, to make 100.0000

'Thecre'am' may be prepared as follows:

.4 .=1a. h oleaginous in ients A. .B-, and C) "in a suitable vessel, heat the contents untira'u the ingredients are melted, mix thoroughly, and adjust the temperature to about 70 C.,

"II. Then slowly and with 'rapidagitation" (iii the resulting mixture to'all butasmall propo tion of the water to be used, warmedto about? C., continue the agitationior absur /21mm, until a crearn-Iike emulsionis form'edandc'o'ol the emulsion to about 50 C. Y

III. Then add the bromoacetic acid (F), dissolved in about 5% of the total water to be used,

'jfto the cream-like emulsion at ab 9 d 'a gitate continuously until a uniform composition obtained. Cool the product to about room'temrature and package it in suitable containers. 'Iheproduct is a smooth, water-dispersibleemuls'ion resembling'cold' cream in consistency.

EXAMPLE III This-formulation is a cream'similar to thatbf Exa'm'ple II, except as regards the particular bromo'active acid compounds employed; 'inthis f case, the sodium salt is used instead of the free acid. -The 'vehicle is the same as that'usedin Example II.

The-composition of the finished cream is as folethods is a clear, smooth, viscous gel thatis (E) Cholesterol concentrat (Amerchol) 12.0 "The g'eImay be prparedfas renews;

IC Melt the chlesterolcohcentrate (stems in anfabsorption ase) an polyethylene glycol woarbtwagn fat'abbut 70 c.

1:. Add the irie'thyl cellulose to I and stir'tl'ie mixture for about 20 minutes, the temperature at this stage being ab'c'iut 50 WC. v

"III. Dissqlve the bron'ioacetic acid in the prolene glycolf'ata temperature of about 40 'C.

"and add" meresmung solution to the above mix- "IV; Heat 'tlie'hiixture III to about 50 C. and pass it throug h'n canola mill. The resultin product is a viscous. water-dispersible colloidal gel.

EXAMPLE V This; 5e t2 l;-i:1f)l='e-illustrates a formulation similar 50 t o that'of "Example IV except for variations. in

the formula andthe method of preparation.

h The composiuonbf the finished gel is as follows:

' g Percent 1A) Methyl cellulose (Dow) 25' cps 2.5 (BY'Propyleife'glycol'N. F. VII 64.4

(C) Polyethylene glycol (Carbowax) 4000 .;;;i: i 21.0 .(D)..:. 2,h0lesterol concentrate (Amerchol) 12.0 (E) ";Bromoaceti'c acid '0.1

Theg el may beprepared as follows: I."'Dissolv'e the methylcellulose (A) in about (50% ct thepropyleneglycol (B). with a vigoragltanbn. I

j LII. Heat the polyethylene glycol (C) with the cholesterol --concntrate (D) on water bath till both are melted. I

' III. Add the melted'polyethylene glycol-choles- 270 terol mixture *to the propylene glycol-methyl icellulosamixture. Continue stirring till a uni- I form"dis;per sion is obtained.

IV. At C. add the bromoacetic acid (E) 'nissolvedt the" balance rofthe propylene glycol lamest Percent (A) Water-soluble polyvinyl alcohol (med.

. visc.) 0.5 (B) Polyethylene glycol (Carbowax) 4000 25.0 (C) Polyethylene glycol (300) 66.40 (D). Cholesterol concentrate 8.0 (E) Bromoacetic acid 0.1

The gel may be prepared as follows:

I. Heat the polyethylglycol 4000 and cholesterol concentrate together, and adjust the temperature to about 60 C.

II. Heat about 99% of the polyethylene glycol 300 to about 60 C., then add'the polyvinyl alcohol and stir until the latter swells.

III. Mix I and II for about 20 minutes, the cool to about 25 C.

IV. Add the bromoacetic, acid, dissolved in about 1% of the polyethylene glycol 300, to H1.

V. Pass the resulting composition through a colloid mill twice. The resulting composition is a viscous, water-dispersible colloidal gel.

EXAIVIPLE VII This example illustrates a formulation con- III. Add Iand II and mix thoroughly.

IV. Add the polyethylene glycol 300 andthe 'bromoacetic acid, dissolved in the remaining 25% of; propylene glycol, to III.

V. Pass the resulting mixture through a colloid mill twice. The resulting product is a viscous,

.water-dispersible colloidal gel.

EXAMPLE VIII This example illustrates a formulation using ,a bentonite water cream as the vehicle. The composition of the finished cream is as follows: i Per cent (A) Micronized bentonite 15 (B) Bromoacetic acid 0.1

(0) Deionized water to 100.00

The cream may be prepared'by adding the bentonite slowly to water and then thoroughly homogenizing' the mixture to form a gel or cream. Thebromoacetic acid, dissolved in a small proportion of the water, is then thoroughly mixed in the bentonite gel. The resulting productis a viscous, colloidal cream having an effective'dilution of about 1 :20,000, or more than twice that of asimple aqueous solution of the same concentration with respect to bromoacetic acid.

Trichomonadicidal potency Table I summarizes the results of tests carried out in accordance with the standard procedure of Johnson and Trussell (loc. cit.), in orderto determine the eifective dilution of certain trichomonadicidal preparations in accordance with the present invention. In this table, the dilution figures given in the fourth column are representative of the sensitivity of the Trussell strain of Trichomonas vaginalis to the various test preparations, the composition ofwhich is inditaining bromoacetic acid in an anhydrous base prepared from propylene glycol, thickened-with both low and high molecular weight polyethylene glycol (mol. wt. about 300 and 4000respectively) polyvinyl alcohol and cholesterol concentrate.

cated'in the second and third columns. From the data given in this table, the enhanced trichomonadicidal potency of the colloidal compositions, compared to that of a simple aqueous solution of the same concentration, will be apparent. 7 w

Table --I Cone. of Bromoace tic No Acid Oomp'd in Test Type of Vehicle used in Test Composition Effective Dilution Composition 0.01% (acid) water alone 1:7500 .d pectin-containing aqueous el as 1n Example I 115,000 to 135,000

0.0125% (acid). 0.025% (sod. salt). 0.01% (acid).

oil-in-water emulsion or cream, asin Example II 1. same as'in O, and Example III 112,000 to 1:20,000 anhydrous jell as in Example IV. 1120,000

The composition is as follows:

Mode of application Per cent 00 The chemotherapeutic compositions in accord- (A) Water-soluble polyvinyl alcohol (med.

visc.) 0.5 (B) Polyethylene glycol4000 ("Carbo- Wax) 21.0 (C) Cholesterol concentrate (Amerchol") 12.0 (D) Propylene glycol, N. F. VII 10.0 (E) Polyethylene glycol (300) 51.4 (F) Glycerin, C. P. 5.0 (G) Bromoacetic acid 0.1

The gel may be prepared as follows:

I. Mix the polyvinyl alcohol and the glycerin until evenly dispersed. Then add about 75% of the propylene glycol.

II. Melt the polyethylene glycol 4000 and cholesterol concentrate at about 70 C. i

ance with the present invention are preferably applied to the vagina by means of a vaginal applicator of the type commonly used for contraceptive preparations. Approximately 5 cc. of the material is placed within the vagina per application, and a small amount is topically applied to the external genitalia. Two applications daily, morning and evening, are recommended with P continuous medication for a period of four weeks,

including, if possible, the menstrual period. The

1 results observed are the immediate disappear- 'ance of clinical symptoms with complete eradication of the parasites from the vagina :follow- 'ing the first 15 to 30 days of treatment.

It will be apparent to those skilled in the. art

that numerous variations, modifications, and extensions of the principles involved may be made without departing from the spirit and scope of the invention. Thus, for example, the pharmaceutical vehicles employed in the various examples are merely illustrative and it will be apparent that many other colloidal pharmaceutical vehicles may be used in place of those illustrated in the examples. Likewise, water-soluble bromoacetic acid compounds other than those specifically mentioned may be used either singly or in combination. All such variations, modifications, and extensions are to be understood as included within the ambit of the appended claims.

I claim as my invention:

1. A therapeutic composition adapted for the treatment of Trichomonas vaginalis vaginitis comprising a member of the group consisting of bromoacetic acid and its water-soluble salts as the efiective trichomonadicidal agent, uniformly distributed in a water-dispersible, colloidal therapeutic vehicle that is compatible with said bromoacetic acid compound and essentially nonirritating to human tissue, said bromoacetic acid compound being present in said composition to the extent of not more than about 1 part by weight to 700 parts by weight of said vehicle.

2. The composition of claim 1 wherein said vehicle comprises an anhydrous colloid.

3. The composition of claim 1 wherein said vehicle comprises a cream-like aqueous oleaginous emulsion.

4. The coin-position of claim 1 wherein said vehicle comprises a gelatinous colloid.

5. A therapeutic composition adapted for the treatment of Trichomonas vaqinalis vaginitis comprising a member of the group consisting of bromoacetic acid and its water-soluble salts as the effective trichomonadicidal agent uniformly distributed in a water-dispersible, pectin-containing, gelatinous, colloidal gel, said bromoacetic acid compound being present in the said composition to the extent of not more than about one part by weight to 700 parts by weight of said vehicle.

6. A therapeutic composition adapted for the treatment of Trichomonas vaginalz's vaginitis, comprising a member of the group consisting of bromoacetic acid and its water-soluble salts as the efiective trichomonaclicidal agent, uniformly distributed in a water-dispersible, gelatinous therapeutic vehicle containing pectin and a Waterdispersible, gel-stifiening agent adapted to increase the mucilaginous character of said vehicle, said bromoacetic acid compound being present in said composition to the extent of not more than about one part by weight to 700 parts by weight of said vehicle.

7. The composition of claim 6 wherein said gelstiifening agent comprises water-soluble methyl cellulose.

8. The composition of claim 6 wherein said gel-stifiening agent comprises polyvinyl alcohol.

9. The composition of claim 6 wherein said composition also contains a small proportion of a fungicidal agent.

J GARTH JOHNSON.

REFERENCES CITED The following references are of record in the file of this patent:

Allen et al., American Journal of Obstetrics and Gynecology, vol. 45, No. 2, Feb. 1943, pages 246- 253.

Journal of Amer. Med. Assoc, vol 123, No. 8,