CA1166573A - Treatment of inflammatory viral infections, acne, dermatitis and arthritis conditions - Google Patents

Abstract

ABSTRACT

There is disclosed a method and composition of matter for treating mammalian inflammatory viral infections, acne, dermatitis, and arthritic conditions comprising the application of 3,3-Bis(p-hydroxyphenyl)-phthalide (phenolphthalein) by itself, or in combination with a carrier, or in a mixture with a bicarbonate salt of Group I of the Periodic Table, or in combination with both a carrier and bicarbonate salt. These mixtures can be anhydrous or aqueous solutions and can be applied either by injection, ingestion, or topically.

Description

TREATMENT OF INFLAMMATORY VIRAL INFECTIONS, ACNE~ D~RMATITIS AND ARTHRITIS CONDITION5 This invention relates to the discovery that 3,3-Bis (p-hydroxyphenyl)phthalide is an effective treatment for certain inflammatory skin conditions, especially those of a viral origin~ arthritis, rheumatism, and rheumatoid arthritis.
Phenolphthalein has long been known as one of a group of primary diphenylmethane catharticsO The cathar-tic effect of phenolphthalein was reportedly discovered in 1902 and since that time it has been widely employed 10 in laxative formulas. It is also reported that phenol-phthalein is relatively non-toxic. Goodman & Gillman, Pharmacolo~ical Basis of Therapeutics (4 Ed. 1977) "Cathartic and Laxatives" pp. 1021 and 1022. Phenol-~ phthalein is also used as an indicator in titrations of '~ mineral and organic acids and most alkalies.
Although inflammatory viral infections may becaused in humans, mammals, and other animals by a wide variety of viruses, a common virus which produces per-sistently hard to treat conditions is the Herpes Simplex 20 virus. In humans Type I normally produces above-waist infections while Type II produces lesions below the waist, in the genital region. Common manifestations of viral infection, including Herpes Simplex I infections are labialis (cold sores, fever blisters, etc.) pharyn-gitis, keratitis, skin infections (herpetic whitlow), encephalitis, and chronic ulcerative stomatitis. Herpes ~; Simplex Type II may cause progenitalis oropharyngeal :

infections, meningitis and encephalitis. Other mani-festations of inflammatory viral infections are canker sores, sun blisters and other such skin lesions and ulcerous conditions. In mammals, such as cows, bulls, and sheep, both Types I and II infect eyes, ears, mouth, and upper respiratory systems. Birds, such as parrots, are virally infected in their diyestive tracts among other regions, by what is known as New Castle disease.
Inflammatory viral infections have proven very 10 difficult to treat and in many instances are allowed to run their course with symptomatic treatment such as ointments, local anesthetics and the like. Treatment for Herpes Simplex infections includes dusting with bismu~h formic iodide, application of camphor spirit;
epinephrine, idoxuridine, adenine arabinoside, large `dose~ of steroids and x-ray or grenz ray therapy.
; Infla~matory skin conditions (dermatitis) which occur frequently include photodermatitis and actinic dermatitis such as sunburn, actinic keratosis and the 20 like, eczema pruritus, acute and chronic lesions, burn-ing, swelling and blistering. These conditions are also `: ~
~- difficult to treat with moisturizing creams, lotions and other topical agents being employed.
Acne is a disease of the pilosebaceous unit which includes the hair follicle and its sebaceous gland~
They are most numerous on the face but also are found in abundance on the back, chest and upper arms. ~L.
Kaminester, "Acne,'l Journal of the American Medical Association, May 19, 1978, Volume 239, No. 20, pages 30 2171-72). Normally the sebaceous glands secrete an oily ` `~

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material called sebum which rises to the top of the hair follicle and ~hen flows out onto the skin surface. Acne occurs when the canals throuyh which the oily sebum flows become plugged up. Bacteria, chiefly Corynebacterium acnes, li~e in the hair follicles and break down complex fats into triglycerides and free fatty acids.
The plugged hair follicle, or comedo, often ruptures into the lower skin areas and dumps free fatty acids, horn, fat, hair and bacterial products into the dermis, 10 creating a toxic foreign body response which can cause scarring. Recently recommended treatment of acne in-cludes oral antibiotics that effectively decrease the bacterial count of C acnesO These include tetracycline and erythromycin which selectively concentrate around the hair follicles, thus reducing the C acnes count and subsequent inflammation. Those antibiotics may also ; be applied in topical application. Kaminester reports that topical applications of antibiotics are inferior to ; orally administered antibiotics and should not be used in 20 severe cases of inflammatory acne. Topical tretinoin and benzoyl peroxide preparations have also had beneficial effects.
-~ Arthritis is the inflammation of a joint usually accompanied by pain. It can result from a number of ~-~ conditions including infection, trauma, and degenerative :
-~ joint diseases~
Rheumatism is an acute or chronic condition charac-teri~ed by soreness and stifness of muscles, and pain in joints and associated structures.
Rheumatoid arthritis is a systemic disease charac-; -3-~ ~' .

terized by inflammatory changes in joints and related structures. It tends to be chronic. There is no speci-fic cure for it and physical therapy and orthopedic measures are often utilized in its treatment. Various special methods of treatment have been tried with diverse degrees of effectiveness.
It is well known that phenolphthalein is highly insoluble in water. When phenolphthalein is ingested into the human body less than 1~% of the active drug in solution is absorbed into the blood stream. The rest of the drug is excreted in the feces.
It is an object of this invention to provide a methodology for rendering phenolphthalein readily soluble in either hot or cold water. This solubility not only enhances its ingestibility by and injectability into the human organism or other mammals but also allows for topical applications using aqueous media, or the prepara-:
tion of capsules or tablets for ingestion by the mam-malian organism.
It is an object of the present invention to provide a fast acting, efective treatment of inflammatory viral infections and skin conditions.
It is a further object to provide a topical agent to arrest dermatitis conditions.
It is a further object of this invention to pro-~ i ~ vide a fast, acting, effective treatment of arthritis, : ':
rheumatism, and rheumatoid arthritis, and its pain and symptoms.
It is yet a further object of the invention to 30 provide a topical agent which helps prevent and aids in ~, o ~

curing acne.
The method of the invention provides for the treat-ment of inflammatory viral infections, acne and arthri-tis, rheumatism, and rheumatoid arthritis~ by the appli-cation of 3,3-Bis(p~hydroxyphenyl)-phthalide (hereafter phenolphthalein) by itself, or in combination with a ;carrier, or in a mixture with a bicarbonate salt of Group I of the periodic ta~le. These mixtures can be anhydrous or solutions in water, and treatment can be by injection, 10 ingestion, or topical application to the infected area.
These mixtures can be prepared in tablet, capsule, or similar form for use by ingestion.
These mixtures can also be applied as a topical agent within the scope of ~he invention to relieve or cure Herpes Labialis, cold sores, sun blisters, canker sores, photodermatitis, actinic dermatitis, actinic ~`~ keratosis and dermatitis manifested as pruritus, acute and chronic lesions, burning, swelling, and blistering.
When applied as a topical agent phenolphthalein can be ;20 mixed with a suitable carrier and can be formulated to provide a moisturizing cream with anti-viral action.
,~
Alternatively, it can be mixed with a bicarbonate salt to Eorm either an aqueous solution or anhydrous mixture.
In a topical preparation including antibiotics, phenolphthalein may be applied ~o effectively treat acne. In such applications the suitable carrier will be ~` selected to avoid comedogenic agents.
~ In an informal clinical study 41 patients with ;~ symptoms of ~erpes Labialis were treated with oral 30 dosages of phenolphthalein. The patients were treated at .
~ ~ -5-' `~
.
. ~ . . . -different times over a period of about two months. The initial dosaye was one hundred milligrams administered every 8 hours for the first day and every 12 hours thereafter. Due to complaints related to the laxative effect of the phenolphthalein, the dosage was reduced to 30 milligrams in the early stages of the testing. Of the 41 patients treated, 39 made complete recovery within ~wo days without any noticeable development of the cold sore. The other two patients made complete recovery with 10 no swelling or visible evidence of the cold sore remain-ing after three days. A control group of 24 patients with Herpes Labialis history were selected at random from clinical files as a control group. Of the 24 patients, 5 were excluded because of the total absence of early ~; indications of infection. The other 19 patients were treated conventionally over a 10 day period. Only 4 experienced even partial relief from developing cold sores and 15 developed active cold sores and blisters which lasted up to 4 weeks.
~; 20 Follow-up observations on the 41 patients treated with phenolphthalein disclosed no development of Herpes Labialis. The results of this informal study indicate that phenolphthalein is a very effective drug for pre-venting and arresting the development of cold sores and ~` blisters at the time of initial appearance in patients.
Oral dosages of phenolphthalein have been success-fully administered to victims of Herpes Simplex infec-tions, including cold sores~ fever blisters and Herpes Genitalis. Oral dosages have also proved effective to 30 relieve and cure canker sores within a matter of hours.
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,~ -6-, Phenolphthalein has successfully been combined with agents to relieve other cold and flu symptoms often associated with inflammatory viral infections. Tablets were prepared for this purpose having the ingredients listed in Table 1. In some formulations th~ phenol-phthalein content was one hundred milligrams but this amount was reduced to thirty milligrams because of complaints of the laxative effect. Other formulations comprising antihistamines~ decongestants, analgesics and 10 antipyretics will be readily apparent to those skilled in the ar~ and may be selected for specific conditions to be treated~
TABLE I
Nominal Analyzed Ingredient Amount Amount Phenolphthalein30 mg. 27.6 mg.
Acetaminophen325 mg. 316.0 mg.
;~ Caffeine 33 mg. 36.1 mg.
Chlorpheniramine Maleate 2 mg. 1.9 mg.
20 Phenylephrine ~Cl10 mg. 9~7 mg.
The inventor has been contacted by more than 20 ~ men and women who indicated they were ~erpes Simplex - sufferers and that they received relief from cold sores and other Herpes Simplex inflammations by taking the tablets. The recommended dosage is one tablet every eight hours for the first day followed ~y one tablet every twelve hours until sypmtoms disappear. One person reported that she was a cold sore sufferer for years and - that her ingestion of tablets, having either 30 or 100 30 milligrams of phenolphthalein with the remainder of the -7- ; ~

:

ingredients as set forth in Table 1, provided satisfac-tory results in combating cold sores.
A male who used tablets having the composition set forth in Table 1 reported that he had suffered fro~
diagnosed Herpes Simplex II since 1972. ~e reported he took the recommended dosages and that the development of Herpes 5implex II was halted.
Phenolphthalein has also been prepared for topical application by formulating it at a concentration of 250 mg. per ounce with Natural Callagen Protein with pro-vitamin D-panthenol, lecithin and allantoin. The topical formulation provided a moisturizing cream which was effective in treating dermatitis conditions including photoderma~itis, actinic dermatitis, actinic keratosis, eczema, pruritus, acute and chronic lesions, burning, swelling, blistering and acne.
i Phenolphthalein was formulated at the same concen~
tration in a topical ointment with benzoyl peroxide and ~-~ calamine base and demonstrated to be effective in provid-20 ing relief from acne vulgaris and acne conglobate.
In treating dermatitis condi~ivns one formulation ~; included 500 milligrams of phenolphthalein combined with 2 ounces of a moisturi~ing skin cream containing purified water ~USP~, Vitamin E, polyoxyethylene monostearate, ~`~ glycerol monostearate, propylene glycol, ethyl alcohol, stearyl alcohol and parabens. That topical preparation `~ was effective in promo~ing quick healing and growth of ., -new skin in the treatment of rashes, blemishes and skin lesions commonly associated with old age.
As will be readily appreciated by those skilled in ~'"
.
:: -the art, phenolphthalein for oral application may be formulated with a variety of other agents to treat disease conditions associated with the disease for which phenolphthalein is selected. While orally administered phenolphthalein is effective in dosa~es at least up to 100 milligrams, the preferred dosage is from about 15-30 milligrams in order to avoid the objectionable laxative effect. The oral dosage may be administered in tablet, suspension or solution form.
10In preparing topical applications for the treatment of external conditions, such as dermatitis and acne as well as arthritis, rheumatism, and related conditions, it is within the scope of the invention to formulate phenol-phthalein with suitable carriers and bases to aid in ` the application to, or absorption into, the target or affected area. One group of carries is the oil-based carriers for external application this group includes dimethyl sulfoxide (DMSO~, petrolatum, mineral oil, and anhydrous lanolin. In most topical applications the 20 concentration of the phenolphthalein in the carrier may vary widely~ For example 500 milligrams in 2 ounces of carxier is effective against acne. It is believed that a concentration of at least about 250 milligrams per ounce of carrier will be effective.
Another carrier useful in external application is the mixture of 10~ methyl salicylate and lanolin, with 20% phenolphthalein. Triethanolamine salicylate can be substituted for methyl salicylate. A mixture of poly-ethylene glycol as a carrier with phenolphthalein is also 30 effective in external applications.

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For external eyedrop applications the mixture of 0.1~ phenolphthalein with the carrier solution of 1.4%
polyvinyl alcohol, and .004% benzalkonium chloride as a preservative, with sodium chloride and edetate disodium as maintainers of the i50tonicity oE the solution is useful. Another solution for external eyedrop applica-tion can be prepared with phenyl mercuric nitrate, benzalkonium chloride, and boric acid as the carrier solution, with phenolphthalein in an effective dosage amount. The above examples are not meant to be limiting, and the scope of the invention includes all effective concentrations of phenolphthalein in carriers.
Topical applications were prepared for the treatment of the external conditions, di~eases and symptoms of arthritis, rheumatism, and rheumatoid ar~hritis or similar conditions. Phenolphthalein was formulated with a topical carrier of dimethyl sulfoxide (DMSO) to aid in the application of phenolphthalein to, and i~s absorption into, the a~fected area for the relief of pain and the treatment of the area. It has been discovered that DMSO
is an especially effective solvent for phenolph~halein.
As little as one milliliter of liquid DMSO will dissolve two-hundred milligrams of phenolphthalein, or powders containing phenolphthalein. This factor coupled with the known ability of DMSO to penetrate organic tissue are believed to allow smaller dosages of phenolphthalein to be used in both oral and topical applications as well as in preparation of injectable solutions. For example the DMSO/phenolphthalein solution can be formulated into topical ~arriers which should enhance the penetration of 1 0~

phenolphthalein into the skin, or ingested.
In preparing the mixture of phenolphthalein and DM~SO, one effective mixture is 150 milligrams phenol-phthalein in 1 milliliter DMSO. This concentration is not viewed as a lower limit as the maximum solubility of phenolphthalein in DMSO has not been determined. Another effective mixture requires mixing DMSO with phenolphtha-lein (already in aqueous solution), and then the further combination of this resulting solution with any suitable 10 base cream, ointment or other carrier, such as lanolin or petrolatum.
In order to provide for greater mammalian systemic activation, absorption~ and circulation of the phenol-phthalein at a strength greater than 15% of the dosage administered, penetration of the stomach and small intestinal walls for absorption into the blood stream is required. Since the human body and mammalian circulatory systems and body fluids are aqueous based, water solu-bility of phenolphthalein enhances its efficacy.
In preparing water soluble preparations for the treatment of all of the above conditions the following is within the scope of the invention. By preparation of a mixture of phenolphthalein and a bicarbonate salt the efficacy by absorption of phenolphthalein can be increased from the 15% of the dosage, noted above. While the actual increase has not been determined, in view of the subsequent examples, it is believed that phenolphtha-; lein can be rendered virtually completely water soluble.
Thus a greater amount of the dissolved phenolphthalein 30 will pa~ through the intestinal walls in an oral appli-; -11-' ;

: -cation. This absorption will greatly enhance the ability of phenolphthalein to treat viral infections such as those of Herpes Simplex Types I and II. As stated above, the preferred dosage is between 15 and 30 milligrams of phenolphthalein in an oral application to avoid laxative eff2cts. At a 15% maximum absorption, only approximately 2 to 5 milligrams would actually be absorbed in mammalian systems. However, with the exceptional increase of water solubility of this inventionr virtually the entire dosage 10 of phenolphthalein is beiieved able to pass through the intestinal walls. This allows the dosage size to be substantially decreased.
This aspect of the invention involves the mixing of ,~ phenolphthalein and sodium bicarbonate with water, the formation of a moist paste, the heating of this paste to a point less than the boiling point of water, the evaporation of substantially all the water in the paste thus forming a substantially anhydrous mixture, grinding ~; this resultant mixture into a powder, dissolving this 20 powdered mixture into water either hot or cold, utilizing stirring if necessary, whereby a solution of phenolphtha-lein is formed. The resultant solution can be applied to the afflicted human, mammal, or other animal, hypoder-mically, intramuscularly, intravenously, subcutaneously, topically, or by ingestion.
By way of example bu~ in no way limiting on the scope of the claims or the invention are the following examples:
EXAMPLE I
Phenolphthalein (a N.F. purified grade of 3,3-Bis '~

;f~ 3 (p-hydroxyphenyl)-phthalide) and sodium bicarbonate (Na~CO3), both in powdered form were mi~ed in the ratio of four parts by weight of the phenolphthalein with one part by weight of the bicarbonate. The powdered mixture was mixed thoroughly and then mois~ened lightly with distilled water to form a mixture with a paste consis-tency. Within a very short period of time, less than 5 minutes thereafter/ this mixture was then heated to approximately 80 Centigrade for about 30 minutes. At 10 the end of this period substantially all the moisture had evaporated~ Thereafter the resulting mixture was crushed to a powder consistency. Then, 200 milligrams powder was completely dissolved in four ounces of hot water (in the range ~f 120 to 170 Fahrenheit) to form a solution.
The resulting solution was ready for applieation either by injection, topically, or direc~ ingestion.
EXAMPLE II
I'he dry powder prepared according to Example I was dissolved in cold water while stirring. After about 5 ~`~ 20 minutes a stable solution was formed. The solution was ready for appllcation by injection, topically, or by ingestion.
- _AMPLE III
After the formation of the dry powder according to Example I, the mixture can be made into tablets, or , placed into gelatinous capsules for application by oral ingestion.

EXAMPLE IV

In carrying out the methods of Example I~ the paste 30 mixture was heated to approximately 93 degrees Centi-.~ ' ~:

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3~i5'~'3 grade. This shortened the time for evaporation of the water to less than 30 minutes.
EXAMPLE V
After mixing the powdered phenolphthalein and bicarbonate compounds as described in Example I, the resulting powdered mixture was mixed wi~h hot water (between 120 and 170 Fahrenheit) by stirring, in a ratio of 200 milligrams of powder per four ounces of water. All of the phenolphthalein did not dissolve into 10 the alkaline solution of sodium bicarbonate, Instead a suspension of phenolphthalein was formed, Within approximately three minutes, about 50% of the phenol-phthalein settled out of solution.
EXAMPLE VI
Fifty (50) milligrams of sodium bicarbona~e was ;~ placed in hot water with stirring until ~he sodium ~' bicarbonate was dissolved. Thereafter, 200 milligrams of phenolphthalein was added to this solution and s-tirring took place for approximately 15 minutes. The phenol-20 phthalein settled out of the solution very rapidly after stirring ceased. ~pproximately 50% of phenolphthalein settled out in less than about five minutes.
EXAMPLE VII
. ~
; Phenolphthalein powder was moistened with water and thereater heated and dehydrated. The product was a dry ,~, phenolphthalein powder. Sodium bicarbonate powder was moistened to paste consis~ency with water and heated to ,~ dryness. The sodium bicarbonate thus prepared was dissolved in hot water, The previously treated phenol-30 phthalein was added to this solution. The phenolphtha-'~
~' .;

lein required approximately 10 to 15 minutes of stirring to form a suspension. Within 5 minutes after stirring ceased, the phenolphthalein started to settle out.
EXAMPLE VI I I
The method of preparation of the mix~ure for treat-ment of antiviral infection as described in Example I was modified by changing the ratio of components to anywhere from one part phenolphthalein to one part sodium bicar-bonate (a 1:1 ratio), to ten parts phenolphthalein to one 10 part sodium bicarbonate (a 10:1 ratio). Each of these preparations was water soluble as described in Example I.
EXAMPLE IX
It was also found that the method of Example I could ~;~ be modified by using a ratio of as little as 1 part of phenolphthalein to 2 parts sodium bicarbonate (1:2 -~ ratio). There was no recorded detrimental effect on the ;`` solubility of phenolphthalein in water.
While specific formulations have been given above, 20 it is not intended that they limit the scope of the invention. The invention is limited only by the scope of the appended claims set forth below.
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Claims (26)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A medicament useful notably for treating the condition, disease or symptom of inflammatory viral infection such as Herpes Simplex viral infection, cold sores, sun blisters, canker sores, photodermatitis, actinic dermatitis, actinic keratosis, dermatitis, acne, pain of arthritis, rheumatism, and rheumatoid arthritis in mammals and in particular in humans characterized in that is comprises an effective amount of 3,3-Bis (p-hydroxyphenyl)-phthalide and a topical carrier or a Group I bicarbonate salt.

2. The medicament of claim 1, wherein the Group I bicarbonate salt is sodium bicarbonate.

3, The medicament of claim 2 wherein a mixture of 3,3-Bis (p-hydroxy-phenyl)-phthalide and a sodium bicarbonate is dispersed in a topical carrier, an aqueous solution dispersed in a topical carrier, or is a solution addi-tionally comprising water.

4. The medicament of claim 1 or 3 wherein the topical carrier is selected from the group consisting of dimethyl sulfoxide, petrolatum, mineral oil, anhydrous lanolin, polyethylene glycol, methyl salicylate, triethanol-amine salicylate, polyvinyl alcohol, benzalkonium chloride, phenyl mercuric nitrate, sodium chloride, boric acid, and edetate disorium, and combinations thereof.

5. The medicament of claim 2 wherein a mixture of 3,3-Bis (p-hydroxy-phenyl)-phthalide and sodium bicarbonate is under a form to be applied by injection or ingestion.

6, A method of forming a 3,3-Bis(p-hydroxyphenyl)-phthalide compound, sùitable for the topical treatment of mammals afflicted with the condition, disease, or symptoms of inflammatory viral infection, cold sores, sun blisters, canker sores, photodermatitis, actinic dermatitis, actinic keratosis, derma-titis acne, pain of arthritis, rheumatism, or rheumatoid arthritis, which method comprises making a mixture of 3,3-Bis(p-hydroxyphenyl)-phthalide and a topical carrier.

7. A method of forming a water soluble 3,3-Bis-(p-hydroxyphenyl)-phthalide compound, suitable for treating mammals afflicted with the condition, disease, or symptom of inflammatory viral infections, cold sores, sun blisters, canker sores, photodermatitis, actinic dermatitis, actinic keratosis, dermatitis, acne, pain of arthritis, rheumatism, or rheumatoid arthritis, which method comprises:
(a) making a mixture of 3,3-Bis(p-hydroxyphenyl)-phthalide and a Group I bicarbonate salt;
(b) adding water to the mixture to yield a paste;
(c) heating the paste to less than the boiling point of water for a time sufficient to evaporate substantially all water, forming a substantially dry compound.

8. The method of claim 7 including the addition of a topical carrier.

9. The method as claimed in either claim 6 or 8 wherein the compound is comprised of a ratio of about 150 to 250 milligrams of 3,3-Bis(p-hydroxy-phenyl)-phthalide per ounce of topical carrier.

10. The method as claimed in claim 6 or 8, including selecting the topical carrier from the group consisting of petrolatum, mineral oil, anhydrous lanolin, polyethylene glycol, methyl salicylate, triethanolamine salicylate, polyvinyl alcohol, benzalkonium chloride, phenyl mercuric nitrate, sodium chloride, boric acid, and edetate disodium, and combinations thereof.

11. The method as claimed in claim 6, 7 or 8, including the addition of dimethyl sulfoxide.

12. The method of claim 7 including the additiion of agents to relieve cold and flu symptons.

13. The method of claim 7 wherein the Group I bicarbonate salt is sodium bicarbonate.

14. The method as claimed in either claims 7 or 13 including dissolving the mixture in water.

15. The method as claimed in claim 7 comprising making a mixture in a ratio of about four parts by weight of 3,3-Bis(p-hydroxyphenyl)-phthalide to about one part by weight of Group I bicarbonate salt.

16. The method as claimed in clalm 15 including the dissolving of the mixture in water in a ratio of about two hundred milligrams mixture per four ounces of water.

17. The method as claimed in claim 7 including the combination of the compound with a carrier suitable for ingestion.

18, A composition of matter which is soluble in water comprising of 3,3-Bis(p-hydroxyphenyl)-phthalide and a Group I bicarbonate salt or a topical carrier.

19. The composition of claim 18, wherein a mixture of the phthalide and the bicarbonate is suspended in a carrier,

20. The composition of claim 18 or 19, wherein the Group I bicarbonate salt is sodium bicarbonate.

21. The composition of matter as in claim 18 which also comprises water.

22. The composition of matter as in claim 21, which is suspended in a carrier.

23. The composition of matter as in claim 18 comprising about four parts by weight of 3,3-Bis(p-hydroxyphenyl)-phthalide and about one part by weight of Group I bicarbonate salt.

24. The composition of matter as in claim 21 which comprises four ounces of water per 200 milligrams of mixture.

25. A composition of mattar comprising 3,3-Bis-(p-hydroxyphenyl)-phthalide and a topical carrier in a ratio of about 150 to 250 milligrams of 3,3-Bis(p-hydroxyphenyl)-phthalide per ounce of topical carrier.

26. The composition of matter as claimed in claim 18 or 25 wherein the topical carrier is selected from the group consisting of dimethyl sulfoxide, petrolatum, mineral oil, anhydrous lanolin, polethylene glycol, methyl salicylate, triethanolamine salicylate, polyvinyl alcohol, benzalkonium chloride, phenyl mercuric nitrate, sodium chloride, boric acid, and edetate disodium, and combinations thereof.