Note: Descriptions are shown in the official language in which they were submitted.
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
- 1 -
:
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
` `~
-2-
' ' ' ' .
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
~,
-4-
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.
'~
,~ -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
-8-
~'"
.
:: -
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.
_g_
;
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
-12-
'~
;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-
-13-
.~ '
~:
~:::
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.
~'
~`';''
``'~,
'~,`
~ -15-
-
