Note: Descriptions are shown in the official language in which they were submitted.
The present lnventlon relates to a method o~
treatlng a skin condition wlth an e~rective medication by
applying it with ultrasonlc vlbrations through a coupling
agent such as oll. More particularly, the present lnvent-
ion relates.to a method ror applylng an efrective antiviral
drug to Herpes Simplex lesions by ultrasound and to t~e com-
posltions thereof. It also relates to a method for applying
an errective medlcation to demidox mites by ultrasound and
to the composition thereor.
Herpes Simplex is an ~nrectious disease having
two ma~or serotypes of the causative virus. As a general
rule, Type 1 virus is responslble ror oral herpes and other
skin lesions above the waist.- Type 2 virus, on the other
hand, is usually responsible ror genital herpes~ other skin
lesions below the waist and ~or neonatal herpes.
The two serotypes difrer in thelr cytopathic ef~ect
on cells in tissue culture, virulence ~or laboratory animals,
behavior on embryonated chicken eggs and, as mentioned above,
their usual site on the body. Both types, however, can occur
outside of its usual loca~ion and with changing mores, more and
more cases Or genital herpes are caused by Type 1 virus. Oc-
casionally, neonatal herpes is also caused by Type 1 virus. The
occurrence Gr genital herpes is on the riseg particularly among
young people. The disease is classified as venereal and is re-
garded as a serious medical problem.
The clinical manirestations of oral and genital
herpes vary rrom individual to individual but the disease
usually appears as a series Or veslcles. In the case Or oral
herpes, the disease may mani~est itself as fever blisters or
as lesions on the lip~ or ~ace. The lesions are self-limiting
and usually heal in about 7 to 14 days but are troublesome
.
~1
~ 33~4~
Io the patient causlng ltchlng and burning and are somewhat
.~ 1 S ri guring.
Genltal herpes is more serious and can be ver~
pain~ul, especially in women. In remales, genital herpes
can be dif~use and involve the entire vulva~ oriflce Or
the vagina, cervix and cervical end Or the vagina. B1-
lateral inguinal lymphadenopathy ls the rule. When the
vesicles are diffuse, the ma~ority Or women have systemlc
manifestations such as chill, fever and general aching.
Dysuria and dyspareunia are common. Occasionally, there
is acute urinary retention due to rerlex spasm of the
urethral sphincter.
In males, genital herpes usually consists o~
vesicles on the glans o~ the penis or on the penis~ The
lesions may be painrul but systemic mani~estations are un-
common.
In most patients overt recurrent Herpes Simplex
lesions do not appear but in other individuals, recurrences -
~are common. The duration and rrequency Or reactivatlon of the
infection varies considerably, but the course o~ the disease
tends to remaln rairly constant ln any given individual~
These recurrences may be provoked by excitants, such as re- -
~ver, sunshlne, gastrointestinal upsets, mechanical trauma,
allergy, repressed anxiety or hostility or menstrual periods
and are known to be more common during pregnancy. Frequent
recurrences are distresslng to the patient, and for women
~enital herpes take~ on additional slgnificance because Or --
the suspected association of Type 2 Herpes Simplex and
carcinoma Or the cervix and because Or the serious nature
of neonatal herpes transmitted rrom mother to inrant during --
~ate pregnancy and dellvery.
~ .
3~
In the past, ultrasound has been used to re-
lieve symptoms Or musculoskeletal disorders and to clean
and treat open wounds. Numerous treatments ror Herpes
Simplex les~ons have been tried. In the case Or genital
herpes, one Or the more common methods involves painting
inrected areas with acridine dyes and then exposing them
to llght. This treatment has been crlticised as a potent
ial danger in itself because the inactivated viruses may
still be able to transrorm normal mammalian cells into
cells with new inheritable characteristics and with loss
Or contact inhibition, which characteristics are orten as-
soclated wlth a malignant potential.
In view of the above, among the several ob~ects
Or the present invention is the provision o~ a method ~or
treating a skin condition with an efrective medication by
applying it with ultrasonic vibrations through a coupling
agent such as oil~ More specifically, the ob~ect o~ the
present invention is the provision of a method for treat-
ing Herpes Simplex involving the application Or an effect-
ive antiviral drug such as urea to the afrected area by
ultrasound, said method facilitating the administration o~
the antiviral drug intracellularly. Other obJects and fea-
tures will be in part apparent and in part pointed out here-
inarter .
The invention accordingly comprises the methods
and compositions hereinafter described, the scope of the
inventlon being indicated in the following claims.
In accordance with the present invention, skin
conditions in man or other animals are treated with an ef-
fective medication which is applied to the afrected area
33~
and then directly mlcromassaged thereln by ultrasonic
vibrations through a coupling agent such as oil.
More particularly, lesions caused by Herpes
Simplex are treated with an antiviral drug which is er-
fective against Herpes Simplex and directly applied wlth
ultrasonic vlbrations.
Suitable antiviral-drugs effective for the pre-
sent purpose include urea, idoxuridine, amantadine, meth-
isazone~ cytarabine, interrerons or the like. In the pre-
ferred rorm, a medicament containing an effective amount
of the antiv~ral drug is flrst made up. In general, the
medicament contains ~rom about 5 to about 40 percent by
welght o~ the antiviral drug. In treating Herpes Simplex~
urea is often selected as the antiviral drug because it is
also erfective against cancer. When the drug is urea and
the medicament is ror treatment of oral herpes, it gener-
ally contains ~rom about 10 percent by welght to about
30 percent by weight Or urea, and when it is for treat-
ment of genital herpes, it contains from about 10 percent
~20 by weight to about 40 percent by weight Or urea.
More preferred medlcaments ~or treatment Or oral
Herpes Simplex contain rrom about 20 percent to about 30
percent by weight Or urea and ~or treatment of genital Her-
pes Simplex contain from about 30 percent by weight to about
40 percent by weight. Especially preferred are medicaments
containing about 30 percent by weight Or urea for treatment
Or oral herpes or genital herpes.
Usually, the medicament includes other materials
to accelerate or otherwise promote healing. W~en the medi-
cament is ror oral application, such materials lnclude zinc
3~4~
oxlde, tannic acid~ menthol) ethyl alcohol or the like .
For this purpose, the zinc oxide ls present in an amount
rrom about 0.5 percent by weight to about 3 percent by
weight 3 pre~erably from about 1 percent by weight to -
about 3 percent by weight and more pre~erably from about
1.5 percent by weight to about 2 percent by weight.
Zinc compounds such as zinc oxide are included
because zinc amplifies the mechanical efrects Or the ultra-
sonic vibrations to break the viral membranes so that the
0 antlviral drug is administered intracellularly. More- ;
over, zinc oxide functions as an astringent, as a corro-
sive to promote healing and as a mild antiseptic.
Tannic acid is included because it is an astrin-
gent and precipitates protein with heavy metal ions such
as zinc. Since Herpes Simplex viruses are protein, the
combined ef~ect o~ zinc oxide and tannic acid is to kill
the virus.
Menthol is added to the lip ~ormulation because
it gives a cool feeling and relie~es itching. Ethyl alco-
hol is included as a mild antiseptic because patients orten
scratch their blisters and cause secondary ~nrection there-
in.
The tannic acid is present in an amount from about
0.5 percent by we~ght to about 2 percent by weight, pre~er-
ably ~rom about 0.5 percent by weight to about 1.5 percent
; by weight and more preferably from about 1 percent by weight
to about 1.5 percent by weight.
The menthol is present in an amount ~rom about 0.25
percent by weight to about 1 percent by weight, preferably
3 from about 0.25 percent by weight to about 0.75 percent by
~ 836~
welght and more preferably ~rom about 0.30 percent by weight
to about 0.50 percent by welght.
The ethyl alcohol is present in an amount ~rom
about n . 30 percent by weight to about 1.0 percent by weight,
prererably ~rom about 0.30 percent by weight to about 0.75
percent by weight and more prererably ~rom about 0.30 per-
cent by weight to about 0O50 percent by weight.
When the medlcament is ~or genital application, the
materials to accelerate or otherwise promote healing are the
same as for oral application except that menthol and ethyl
alcohol are eliminated. In this case, the zinc oxide is
present in an amount rrom about 1 percent by weight to about
5 percent by weight, preferably from about 2 percent by weight
to about ~ percent by weight and more preferably rrom about
.. .
2.5 percent by weight to about 3 percent by weight.
The tannic acid is present in an amount from about
1 percent by weight to about 5 percent by weight~ preferably
rrom about 2 percent by weight to about 4 percent by weight
and more prererably rrom about 3 percent by welght to about
4 percent.
Since ultrasound does not transmit through air,
the me~icament must provide a coupling between the ultra-
sonic applicator and the skin to be treated. IFor this purpose,
the medicament usually contalns oil or similar material so
?5 there are no air gaps between the applicator and the under-
lying skin~
The particular coupling agent selected is preferably
non-stainlng, non-irritating and slow drying. The nature and
amount of coupling agent is selected so that the~resultant paste
or gel is not so ~luid at body temperature that is ~lows from
.
-- 7 --
. ' .
~3~4~
between khe ultrasonic applicator and the skin resulting ln
poor or no ultrasonic coupling.
Suitable coupling agents lnclude mlxtures o~ mineral
oil and glycerln or the like b~t the prererred coupling a~ent
,.,.,, ,~ .
~i is HEB cream sold by Barnes Hind Company. This material is a
mixture of cetyl alcohol, stearyl alcohol, white petrolatum9
mineral oil and propylene glycol. When the medicamenk is for
oral application and the coupling agent is HEB cream, the coupl-
ing agent is present in an amount from about 65 to about 70,
pre~erably from about 65 to about 67 and more preferably rrom
about 65 to 66 percent by weight. When the medicament is for
genital application and the coupling agent is HEB cream, the
coupling agent is present in an amount ~rom about 60 per-
cent to about 7G percent by weight, preferably ~rom about 60
to about 68 and more prererably ~rom about 60 to 65. Other
formulations based on other coupling agents can be readily
determined by one skilled in the art given the properties re-
quired thereo~ as descrlbed above. -- - -
The medicament is made up by combining the above-
rnentioned materials_in the amounts described and by blending
them until a paste or gel is rormed. Since the medicament is
shel~ stable, it-may be prepared in advance and skored.
l~en the medicament is ready for use, the patient
is com~ortably positioned and his lesions examined. An amount
~5 Or medicament ls rubbed onto the area to be treated in an
amount su~icient to assure good coupling between the ultra-
sonic applicator and the skin to be treated.
.
~ ~r~e ~har3(
~ -
- 8 -
3~
The medicament is then micromassaged lnto the
arrected area by ultrasonic vibrations. For this purpose,
an ultrasonlc applicator is slowly moved back and rorth
over the leslons, either in a rotary or transverse direction,
in order to reduce the concentration of energy at any given
point. The pressure applied through the applicator is light
but is rirm enough to maintain good coupling. In treating
patients having lesions which are particularly pain~ul and
sensitive to heat, the ultrasonic applicator, which includes a
transducer within an applicator houslng, is preferably water
cooled.
The length Or the treatment, output frequency Or
the ultrasonic generator coupled to the applicator and power
level at the applicator surface will vary in the individual
case and is up to the physician. Preferably, however, the
output rrequency Or the generator is about 1000 KHZ and the
power level at the applicator head is about 1.0 to 3.0 watts
per sq. cm~ A suitable ultrasonic generator for this purpose
is manufactured by Whitewater Electronics, Inc. and has a
20 _= .. =frequency of 1100 XHZ + 10 KHZ, a continuous power output Or
0 to 32 watts and an erfective power level at the applicator
head Or 3.0 watts per sq. cm.
The rrequency and number Or treatments is deter-
mined individually at the discretion Or the physician. Orten
to begin with, treatments are given daily ~or 2 to 3 minutes
and then reduced in rrequency when desired efrects are ob-
tained. It is not unusual, however~ that only one treatment
is necessary berore beneficial efrects become a~parent.
The rollowing examples illustrate the invention~
: ~ _ 9 _
~ .
~ 3~ ~
- EXAMPLE 1
An e~recti~e medicament (HERPIGON LOTION I) ror
the treatment Or Herpes Slmplex Type 1 lesions by ultra-
sound was prepared by blending the following materials:
.
In~redient Percent by Weight
Urea . 3
Zinc oxide 2
Tannic acid
Menthol .5
HEB cream 66
Ethyl alcohol . qs
.
EXAMPLE Z
.To demonstrate that ultrasonic vibrations cause
HERPIGON LOTION I to penetrate tissues through the skin,
sixty rats were chosen, their backs shaved and treated as
rOllOws: - -
: Ten rats were selected ~or each o~ three tests
in Group A. In each tes~, radioactive HERPIGON LOTION I
was rubbed onto the shaved backs o~ the rats. As shown in
Table A, in Test 1 the radioactive component o~ the HERPIGON
LOTION I was tannic acid, ln Test ~ it was urea and in Test
3 it was a combination Or tannic acid and ureaO Otherwlse9
the HERPIGON LOTION I used in these tests was prepared as
in Example 1~
'
TABLE A
Rad~oactive Component
Test 1, Test 4 Tannic acid (H3)
Test 2, Test 5 Urea (C14)
Test 3, Test 6 Tannic acid (H3) and Urea (C14
--10--
. . .
~ j l
~33~D4~
Ten rats were selected for each o~ three tests
in Group B. In each test, radioactive HERPIGON LOTION I
was rubbed ~nto the shaved backs o~ the rats and micro-
massaged therein with ultrasound ror about 5 minukes. An
ultrasonlc generator with a f'requency of 1100 KHZ ~ 10KHZ -
was coupled to an ultrasonic applicator. The applicator
head measured 2.5 sq. cm. and had an efrectlve power level
of 1 watt per sq. cm. As shown in Table A, the radioactive
components of the HERPIGON LOTION I in Tests 4, 5 and 6
were the same as in Tests 1, 2 and 3, respectively.
All Or the rats in Groups A and B were sacrificed
and vertical sections 1 inch thick including the skin were
taken rrom their back muscles. Slices were then made, ~ixed
; and analyzed by autoradiographic localization ror penetration
Or the radioactive drugs. The results show that both radio-
- active urea and tannic acid are caused to enter the muscle
_to a depth Or from about 1/2 inch to about 1 inch when they
are applled with ultrasonic vibrations. When they are ap-
plied without vibrations, they remain on the surface o~ the
skin and do not penetrate the muscle.
EXAMPLE 3 ---
Ten sub~ects su~fering oral herpes were chosen on
the basis Or visible evidence of active lesions on the lips,
inside Or the lips or mouth. Each had 3 or 4 vesicles and
came in for treatment between 12 and 24 hours after appearance
of the blisters. A sample was taken by cotton swab rrom the
inrected area Or each sub~ect and preserved in a special media
for virus culture. The virus h~as identified as Herpes Simplex
; 3o Type 1 by culture and by electron microscopy.
Five of the subJects were selected for a control
group. They were treated by rubblng an ultrasonic applicator ;
-- 11 --
r ~3~
head as described in Example 2 over the infected area
for two minutes~ The control patients reported that
itching continued ror 4 to 7 days and that the blisters
took rrom 7 to 12 days to disappear.
me other five sub~ects were selected for an
active treatment group acsording to the present lnvent-
ionO An amount o~ HERPIGON LOTION I as prepared ~n Ex-
ample 1 was applied to the lesions and the sub~ects
were treated with ultrasound as described above. The
blisters were treated on two consecutive days. The active
treatment patients reported that itching stopped after 4
to 6 hours. Blisters were reported as having a healing
crust after 12 to 18 hours and as disappeared arter about
4 days.
EXAMPLE 4 -
An effective medicament (HERPIGON LOTION II3
.. .. .
for the treatment of Herpes Simplex Type 2 lesions by
ultrasound was prepared by blending the following mater-
~; 20 ials: `
IngredientPercent by Weight
Urea 3
Zinc oxide 3
Tannic ac~d 2
HEB cream 65
, '
EXAI~PLE 5
Twenty female subJects sufrering from recurrent
geni~al herpes at least three tlmes in the preceding year
were chosen. Each patient came in for treatment about 12
-12-
~83~
- to 24 hours a~ter appearance o~ the blisters as veslcles
on the vulva and orirlce Or the vaglna. A sample was taken
by cotton swab from the infected area of each subJect both
be~ore and after treatment and preserved in a speclal medla
for virus culture. The virus was ident~fied as Herpes
Simplex Type 2 by culture and by electron microscopy.
Five Or the sub~ects were selected for a control
group. Members of this group had 20 to 50 blisters and
were treated by rubbing an ultrasonic applicator over the
infected areas ~or three minutes. The particular applicator
selected depended on the size Or the infected area. Probe
A measured 5 sq . cm., Probe B 2.5 sq . cm. and Probe C 1.5
sq. cm. Probe A was used if the blisters covered a wide
area. In smaller areas9 Probe B was used and in hidden
areas such as beneath the clitorls or labia minora, Probe
C was used. The ultrasonic generator coupled to the ap-
plicator had an output ~requency of 1100 KHZ ~ 10 KHZ and
. .~
the power output was selected so that the e~rective power
level a~ the applicator head3 regardless o~ whlch one was
selected, was 0 watts per sq. cm~- The control "treatment"
was applied once daily for three consecutive days. The
control patients reported that itching and pain lasted ~or
about a week to 10 days and that the blisters took 3 to
4 weeks to disappear. All o~ the sub~ects experienced re-
current inrections withln three months.
Another five sub~ects were selected as a group
for treatment with ultrasound alone. Members o~ this
group had 7 to 50 vesicular lesions and were treated as de-
scrlbed above except that the power level at the applicator head
, .
-13-
was 1 watt per sq. cm.~ once daily ror three consecutlve
days~ On the third day Or treatment 3 60 percent Or the
vlrus had been killed ~s evidenced by the sample taken
on the cotton swab. The ultrasound treatment group re-
ported that itching and pain lasted about 4 days and that
the bllsters disappeared after about 18 to 20 days.
Five more of the sub~ects were selected for
treatment with HERPIGON LOTION II alon~. Members o~ this
group had 10 to 50 vesicular lesions and were treated by
rubbing HERPIGON LOTION II onto the infected areas twice
a day for three daysO On the third day Or treatment, 65
percent of the virus had been killed. The HERPIGON LOTION
II treatment group reported that itching lasted about 3
days and that the blisters disappeared after about 15 to
17 days.
The other five subJects were treated as follows.
, = = ~ .
Members of this group had 10 to 50 vesicular lesions and
. _ . . . .......... . .
were treated by rubbing HERPIGON LOTION II onto the infected
areas and immediately micromassaging it therein with the
~20 probes described for the con~rol group except that the power-
level at the applicator head was 1 watt per sq. cm. This
treatment was applied once daily for three minutes on each o~
three consecutive days. On the third day of treatment~ 100
percent Or the vlrus had been killed at the site Or the
lesions. This treatment group reported itching stopped
after 12 to 24 hours and blister disappearance after 5 to
- -
7 days.
All t~enty sub~ects were followed after treatment,
As ~entioned above, all of the control group had recurrent
; :
.
- 14 - ,
.
.
3~
genital herpes ln~ections wlthin three monthsr ~i~ty
percent o~ the subJects treated with ultrasound alone had.
recurrent lnfections within 5 months, 45 percent o~ the
sub~ects treated with HERPIGON LOTION II alone had recur-
rent infections within 6 months but 100 percent Or the
sub~ects treated with HERPIGON LOTION II and ultrasound
were stlll ~ree ~rom recurrent infections after one year.
EXAMPLE 6
Ten male sub~ects suf~ering genital herpes were
o chosen. Each had 2 to 6 vesicles on the glans o~ the penis
or on the penis. No bllsters were noted on the scrotum with
the exception of one patient who had two blisters.. A sample - .
was taken by cotton swab from the inrected areas Or each~
; sub~ect and preserved in a special media ~or virus culture.
; The virus was identified as Herpes Simplex Typë II by cul-
ture and by electron microscopy.
- Five of the sub~ects were selected-for a control~~
group. They were treated by rubbing an ultrasonic applicator
~ L; :. head such as Probe A or Probe B o~ Example 4 over.the in-. ~r~
0 ~ected areas for three minutes. The power level~at the-:--~--- ----
applicator head was set for O watts per sq. cm. The control
patlents seldom reported itching but those who did said
that lt lasted about 3 days. Blisters took 2 weeks to dis-
appear. : .
The other rlve sub~ects were selected--ror an actlve
treatment group according to the present invention~ An
amount Or HERPIGON LOTION II was applied to the lesions and
the sub~ects were treated as described for the control group
aboYe except that the effective power level at the appli-
3 cator head was 1 watt per sq. cm. These patients reported
.
.
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:
3~
that itching (if initially pr~ opp~d within 4 ko
8 hours and that the blisters disappeared within 5 to
7 days,
EXAMPLE 7
An effective medicament (DEMIDOX SHAMPOO~ for
the treatment o~ demidox mites in dogs when applied with
ultrasound was prepared by blending the following mater-
ials~
In~redient Percent by Weight
Urea 20
: ' Dimethyl sulfoxide 10
C:lyFerol ' qs '' ,',,,,, ,,,,,, ,,, ~,
- In general~ effective DEMIDOX SHAMPOOS conta~n =~. .. .
rrom about 10 to about 50 percent by weight of urea and
from about 1 to about 20 percent by weight. of-dimethyl. ..... _ .
-., ........ sulfoxide with the balance being made up by gly.cerol. _
l~en these shampoos are micromassaged into the infected
... areas with ultrasound as described for treatment.o~ Herpes
- - . ~
- - Simplex Type 1 or 2 lesions, the urea.and.dime~hy.l.,,sul-..~
2~ foxide penetrate the tissues ancl kill the mite e&gs. The
; glycerol acts as an ultrasound coupling agent and as a
lubricant.
. ' .
EXAMPLE 8 -
Seven dogs suffering with demidox were treated--'''
by rubbing an ~mount Or DEMIDOX SHAMPOO as prepared in ~-
Example 7 onto the infected areas. These areas were then
rubbed with an ultrasonic applicator for 5 to 7 minutes.
An ultrasonic generator as described in Example 2 was
'`, ' `,.
.
.~ '".
set so that the efrectlve power level at the appllcator
head was rrom about 1 to about 1.5 watts per sq. cm. The
dogs were treated every other day ror 20 days. All seven
Or the dogs were cured after 10 treatments.
In view Or the above~ lt will be seen that the
several ob~ects Or the inventlon are achieved and other
advantageous results attainedO
As various changes could be made in the above
methods and compositions wlthout departing rrom the
scope of the invention, it is intended that all matter
contained in the above description shall be interpreted
as illustrative and not in a limiting sense.
