U.S. patent number 3,711,602 [Application Number 05/085,697] was granted by the patent office on 1973-01-16 for compositions for topical application for enhancing tissue penetration of physiologically active agents with dmso.
This patent grant is currently assigned to Crown Zellerbach Corporation. Invention is credited to Robert John Herschler.
United States Patent |
3,711,602 |
Herschler |
* January 16, 1973 |
COMPOSITIONS FOR TOPICAL APPLICATION FOR ENHANCING TISSUE
PENETRATION OF PHYSIOLOGICALLY ACTIVE AGENTS WITH DMSO
Abstract
Compositions for topical application for enhancing tissue
penetration of physiologically active agents with dimethyl
sulfoxide (DMSO). Such agents include physiologically active
steroids, antineoplastic agents, antigens, antihistaminic agents,
neuropharmacologic agents, antiinflammatory agents, anticoagulants,
vasodilators, ultra-violet screening agents and nutrients. Such
compositions, which may be in the form of lotions, ointments and
suppositories, include the physiologically active agent, at least
10% by weight of DMSO and a pharmaceutically acceptable thickening
agent. Liquid formulations for topical application of DMSO and the
physiologically active agent in spray containers are also
provided.
Inventors: |
Herschler; Robert John (Camas,
WA) |
Assignee: |
Crown Zellerbach Corporation
(San Francisco, CA)
|
[*] Notice: |
The portion of the term of this patent
subsequent to December 28, 1987 has been disclaimed. |
Family
ID: |
22193359 |
Appl.
No.: |
05/085,697 |
Filed: |
October 30, 1970 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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753231 |
Aug 16, 1968 |
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329151 |
Dec 9, 1963 |
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Current U.S.
Class: |
424/45;
514/711 |
Current CPC
Class: |
A61K
9/0014 (20130101); A61K 47/20 (20130101) |
Current International
Class: |
A61K
47/20 (20060101); A61k 009/00 () |
Field of
Search: |
;424/45,337 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Marson Bull. Chimicofarm 102:109-124 February 1963. .
Fitzpatrick D&CI 96(2):254 February 1965..
|
Primary Examiner: Rose; Shep K.
Parent Case Text
CROSS REFERENCES TO RELATED APPLICATION
This is a continuation-in-part of co-pending application Ser. No.
753,231, filed Aug. 16, 1968, now abandoned, which is, in turn, a
continuation in part of application Ser. No. 329,151, filed Dec. 9,
1963, now abandoned.
Claims
What I claim is:
1. A composition suitable for topical application to external
membranes of a human or animal subject for enhanced penetration of
a physiologically active agent in said composition which comprises
an amount of a physiologically active agent effective to produce
the desired physiological effect on topical application of the
composition to an external membrane of the subject, said agent
being selected from the group consisting of physiologically active
steroids, antineoplastic agents, antigens, antihistaminic agents,
neuropharmacologic agents, antiinflammatory agents, anticoagulants,
vasodilators, ultra-violet screening agents and nutrients, an
amount of DMSO effective to enhance external membrane penetration
of said agent and comprising at least about 10 percent by weight of
said composition, and a pharmaceutically acceptable thickening
agent in an amount sufficient to materially increase the viscosity
of said composition, whereby to facilitate controlled topical
application thereof.
2. A composition as in claim 1 for dermal application and wherein
said DMSO comprises at least about 50 percent by weight of said
composition.
3. A composition as in claim 2 and wherein said agent is selected
from the group consisting of physiologically active steroids,
antineoplastic agents, antigens, antihistaminic agents, analgesics,
local anaesthetics and antiinflammatory agents.
4. A composition as in claim 1 and wherein said composition is in
the form of a lotion.
5. A composition as in claim 1 and wherein said composition is in
the form of an ointment.
6. A composition as in claim 1 and wherein said composition is in
the form of a suppository.
7. A container provided with liquid spray dispensing means and
containing a fluid, sprayable composition which comprises an amount
of a physiologically active agent effective to produce the desired
physiological effect on topical application of the composition to
an external membrane of a human or animal, said agent being
selected from the group consisting of physiologically active
steroids, antineoplastic agents, antigens, antihistaminic agents,
neuropharmacologic agents, antiinflammatory agents, anticoagulants,
vasodilators, ultra-violet screening agents and nutrients, and an
amount of DMSO effective to enhance external membrane penetration
of said agent and comprising at least about 10 percent by weight of
said composition.
8. A container as in claim 7 and wherein said DMSO in the
composition charged therein comprises at least about 50 percent by
weight of said composition.
9. A container as in claim 7 and wherein said container is an
aerosol bomb containing a halocarbon propellant.
10. A container as in claim 7 and wherein said container is a
squeeze bottle.
11. A container as in claim 7 and wherein the composition therein
contains a substantial amount of water as a diluent.
Description
BACKGROUND OF THE INVENTION
A predominant and limiting problem in the development and use of
physiologically active agents is the inability to administer them
as effectively as is desired. In particular, there is often a
limitation as to the routes of administration because of the
following factors:
1. Some agents are inactivated in the gastrointestinal tract or
they are absorbed poorly into the body from the tract. Also,
undesirable side effects may result which prevent effective oral
administration.
2. In every case where injection must be resorted to, there is a
risk of needle injury, infection, and other trauma (including the
emotional trauma inevitably associated with injections).
3. Few agents are absorbed through the skin or mucous membranes in
effective quantities and the rate of absorption is less than would
be desirable for those that do.
4. A local concentration for a local effect is often desired but a
larger systemic dose must be given to achieve an effective
concentration at the local area when the agent can only be injected
or given orally, (but not topically). This higher dose often causes
undesirable side effects, since dosage related side effects are
very prevalent for many agents.
Animal tissues comprise various membranes which are selectively
permeable and which allow some substances to pass freely, while
rejecting others or permitting only slight passage. Such membranes
comprise the body coverings and externally communicating cavities,
including the skin and mucous membranes of the body cavities, e.g.
alimentary tract, respiratory tract, genitourinary tract, oral
cavity, eyes, etc. (collectively defined herein as external
membranes). They also include internal membranes such as the
linings of the various organs and other internal body structures,
e.g., peritoneum and pleura, and the membranes surrounding cellular
and intracellular structures. It is desirable in overcoming the
aforementioned problems in drug administration, to increase the
passage or penetration of agents across such membranes and further
to enhance their intercellular and intracellular diffusion in order
for them to reach their situs of activity more rapidly to achieve
the desired response more quickly and often more effectively. It is
exceptionally desirable to do this in a reversible manner, by which
is meant penetration of the agents into tissue without adversely
affecting or impairing the function or structure of the tissue. It
is known that certain substances will penetrate tissue only after
the tissue has been irreversibly damaged which is certainly
undesirable. Certain agents, such as surfactants, have been known
previously for increasing penetration of various agents. However,
again, such penetration was effected only through irreversible
damage of the tissue.
It has been a major rule in medicine that the "vehicles" or
"carriers" have relatively little effect on the penetration rate
for a given agent and this rule generally still holds true. Thus,
with conventional carriers for medicines, such as alcohol,
carbowax, water, etc., few agents will adequately penetrate such
formidable external membrane barriers as the intact skin or mucous
membrane. It is to be expected that this would be true of all
potential "vehicles" or materials combined with physiologically
active agents. However, surprisingly, it has been discovered that
dimethyl sulfoxide (DMSO) has the unusual ability to greatly
enhance the penetration of agents when they are applied to such
membrane barriers along with dimethyl sulfoxide. The penetration of
agents which previously have not penetrated these membranes to an
effective degree may be enhanced sufficiently so that a useful
result may be obtained. The penetration of agents which have been
known to penetrate to a limited degree in conventional vehicles may
be significantly enhanced. New and convenient routes of
administration, often with a decrease in side effects of the
agents, better localized concentration and a more sustained
activity, may thereby be created for many agents.
In my co-pending application (Ser. No. 615,377 filed Feb. 13, 1967)
is disclosed my related discovery that DMSO enhances the
penetration of plant-active agents (pesticides, dyes, nutrients,
hormones, herbicides, and the like) into plant tissue in a highly
unusual manner.
Dimethyl sulfoxide (DMSO) is a water-white liquid at room
temperature having a freezing point of approximately 18.5.degree.C
and a specific gravity of approximately 1.1. Dimethyl sulfoxide is
a well known industrial solvent and it has been available in
commercial quantities for at least a decade (from Crown Zellerbach
Corporation, San Francisco, Calif.). DMSO was originally
synthesized in 1866 and since that time it has been extensively
investigated for possible industrial and biological utility and a
considerable amount of literature has developed on its properties
and uses. Over the last 25 years it has found widespread use as a
solvent in industry and in the laboratory.
DMSO has been investigated in the past for various biochemical
uses, for example as a reaction solvent for preparing derivatives
of various proteins, and antibiotics, as an extraction solvent for
various proteins, as an analytical solvent and as a solvent for
various other laboratory uses. It has also been suggested as a
solvent for certain pesticides.
DMSO has been investigated as a preservative agent for in vitro
storage of chilled or frozen tissue and it has also been determined
to have a protective effect in experimental animals subjected to
X-irradiation following injection of DMSO into such animals.
In connection with topical application of the antifungal
griseofulvin, DMSO has been listed along with various inert
materials as "bland, high boiling fluids" to be used as carriers
for the griseofulvin in applying it to the skin to control fungus
growth in the skin. DMSO has been employed as a solvent for
preparation of certain injectable formulations, namely
chloramphenicol and an anthelminic preparation.
Despite the employment of DMSO as a solvent for these purposes and
despite general experimentation with DMSO in the medical field, the
unique ability of DMSO to alter membrane permeability and to
thereby enhance penetration of physiologically active agents was
neither suggested nor discovered. Although DMSO has been a well
known and widely investigated solvent for many years, its unique
ability to enhance penetration of external and internal membrane
barriers as contemplated in the present invention has been totally
unrecognized.
SUMMARY OF THE INVENTION
By a mechanism or mechanisms not yet fully understood, DMSO, when
applied to animal tissue, increases the permeability of the tissue
in a reversible manner to cause a much greater penetration rate for
conjointly applied physiologically active agents. Although the mode
of activity is still unclear, it is definitely not that of the
simple "vehicle" or "carrier" since the effect may be obtained to
some extent even when the DMSO is applied to the tissue separately
and the enhanced penetrability of the tissue may last for as much
as three hours after the DMSO treatment.
When applied to the intact skin along with dimethyl sulfoxide,
particularly at a DMSO concentration of 50 percent by weight and
above, or to skin pretreated with the dimethyl sulfoxide, an agent
such as a steroid, may penetrate rapidly to and saturate the
stratum corneum (the highly resistant "horny layer" of the skin
which is the major barrier to penetration). The steroid continues
to penetrate through the skin from this "reservoir" in the stratum
corneum to the underlying tissue and into the circulatory
system.
Similarly, penetration into underlying tissues and into the
circulatory system may be obtained from topical application to the
mucous membranes of the body cavities as in the case of intraoral,
conjuctival sac, rectal, vaginal, and bladder instillation
administration, particularly where the DMSO is utilized at a
concentration of 10 percent by weight and above. It is thus seen
that a particularly important aspect of this invention is that
penetration of agents may be effectively enhanced following topical
administration. As used in this connection herein, the term
"topical" is intended to include application to all external
membrane barriers including the cutaneous or epidermis regions and
the mucous membranes including the gastrointestinal tract, the
respiratory tract and the genitourinary tract.
As previously indicated, the mechanisms of penetration enhancement
are as yet not fully elucidated. Accordingly, it is not intended to
be bound to one specific theory of operation. However, it is
believed that DMSO acts by several mechanisms in enhancing
penetration. DMSO is believed to act directly on tissue to alter
the general permeability of the tissue membrane. More specifically,
DMSO when applied thereto, is believed to decrease the natural
resistance of tissue membranes to penetration by foreign agents.
DMSO is also believed to promote penetration by a direct transport
effect, perhaps by the mechanism of complexing with the agent. This
mechanism is believed more applicable to cationic and anionic
agents.
By the present invention compositions are provided which are
uniquely suitable for the purpose of utilizing the penetration
enhancement of DMSO, which compositions include the physiologically
active agent, an amount of DMSO effective to enhance topical
penetration of such agent and a pharmaceutically acceptable
thickening agent. For application to mucous membranes, the DMSO
concentration may be 10 percent by weight and higher. For
application to the intact skin DMSO concentrations of 50 percent or
higher are suitable. The thickened composition forms of this
invention permit more sustained contact of the composition with the
treated surface and more accurate and controlled dosing. Accidental
spilling, run off and undesired contact with the composition can
also be minimized. Pharmaceutically acceptable hydrophillic
diluents, particularly water, may also be employed in these
compositions to lessen the tissue irritation affects which may
result from application of higher concentrations of DMSO.
Liquid formulations for topical application comprising at least 10
percent by weight DMSO, the physiologically active agent and,
optionally, diluents, thickening agents, etc. in spray containers
are also provided. Such dosage forms are useful for topical
application to prevent accidental spilling and undesired contact
with the composition. They are particularly suitable for
application to mucous membranes of various body orifices. They are
also advantageous in providing a more uniform application to both
dermal and mucous membrane surfaces.
GENERAL DESCRIPTION OF THE INVENTION
This invention is applicable to the tissue or organisms of all
animal phyla, DMSO having differing degrees of influence on
penetration of various tissue types of a given animal. Animals of
particular importance in the practice of the invention are the
mammalians, especially man and veterinary animals. However, the
invention may also be practiced with other vertebrates, as for
example the amphibians, fishes, reptiles, etc., and with the lower
species comprising the non-vertebrates.
Penetration enhancement is generally non-selective in terms of the
type of physiological effect or effects of agents to be transported
across membrane barriers. The extent of penetration enhancement
will depend upon many factors, the predominant factors being the
relative natural permeability of the particular membrane, the
concentration of DMSO applied, the extent of solubility of the
agent in DMSO and the chemical and physical properties of the
agent.
The thickened dosage forms of this invention for topical
application include lotions, ointments (including creams and gels)
and suppositories. These compositions comprise the physiologically
active agent combined with the DMSO and a base comprising a
thickening agent for the composition and such pharmaceutical
diluents as may be indicated.
Lotions and ointments may contain the usual ingredients to provide
the thickening base, as for example cetyl alcohol, an emulsifier
such as lauryl sulfate and water. Another base may be formulated by
combining equal weight amounts of stearic acid, cetyl alcohol,
triethanolamine and glycerol monostearate with water. Still other
thickening bases may utilize polyethylene glycols of different
viscosities, depending upon the desired consistency. DMSO may be
added to the lotion or ointment base in varying amounts as desired,
generally up to around 50 percent by weight or higher.
A suppository form may be made from a high viscosity polyethylene
glycol 4,000, water and DMSO, which may be present in an amount of
about 20 percent by weight.
The spraying and misting dosage forms of the invention constitute
nasal spray bottles, aspirators, misting devices, aerosol bombs and
other dispensing containers having liquid spray or mist dispensing
means, which containers are charged with fluid formulations
comprising the physiologically active agent, at least 10 percent by
weight DMSO and, optionally, water or diluent, thickening agents
and the like. The compositions for this purpose are sufficiently
fluid to permit dispensing by spray or mist from the container.
Normally the DMSO component will provide adequate fluidity.
However, the usual liquid diluents may be provided where desired to
enhance sprayability.
The term "physiologically active" in describing the agents
contemplated herein is used in a broad sense to comprehend not only
agents having a direct pharmacological effect on the host but also
those having an indirect or observable effect which is useful in
the medical arts, e.g., the screening of U.V. radiation from the
tissues, etc., Agents, penetration of which across external
membrane barriers may be beneficially enhanced upon direct
application of the compositions of this invention include:
physiologically active steroids, antineoplastic agents, antigens,
antihistaminic agents, neuropharmacologic agents, antiinflammatory
agents, anticoagulants, vasodilators, ultra-violet screening agents
and nutrients.
The concentration of physiologically active agent in the various
dosage forms is, of course, commensurate with that normally
utilized for the particular agent in conventional formulations for
effective results for the intended route. Both the amount of
physiologically active agent and the amount of DMSO will be
influenced by the type of effect desired. If a more localized
effect is required, lower amounts of physiologically active agents
and lower concentrations of DMSO may be called for. Where deeper
penetration is desired, as in the case of local anaesthesia, a
higher concentration of DMSO may be desirable to promote adequate
penetration. Where general systemic concentration of an agent is
desired for a topical preparation, generally higher concentrations
of DMSO are desirable and the amount of agent as, for example, a
steroid, may be included in the composition sufficient to provide
the blood level desired.
The concentration of the DMSO in the compositions to enhance
penetration may vary over wide limits. The concentration selected
is desirably related to the route of administration to be employed.
For cutaneous application, compositions including at least about 50
percent by weight DMSO are preferable in that they have been found
to increase percutaneous penetration in a highly significant
manner. Maximum cutaneous penetration is generally attained with
DMSO concentrations closely approaching 100 percent (excluding the
agent), but with concentrations much above 90 percent by weight the
incremental increase in penetration rate over that achieved at 90
percent often is relatively small. On the other hand, above a 90
percent concentration of dimethyl sulfoxide the side effects of a
burning sensation and erythema increase significantly. Accordingly,
for topical use, it may be desirable, consistent with physical
stability of the composition, to formulate the DMSO in compositions
containing a DMSO concentration of between about 50 and 90 percent
by weight and containing water, preferably 10 percent by weight or
greater.
Application to mucous membranes follows generally the procedure for
cutaneous administration. However, lower concentrations of DMSO in
the compositions, for example as low as 10 percent by weight, may
be preferred since penetration of mucous membrane is more easily
affected.
The usual pharmaceutical compounding agents, diluents or carriers,
especially water, may be included in the compositions of this
invention as desirable for the particular route of administration
and dosage form. As discussed previously in relation to the
concentration of DMSO in the formulations, the amount and type of
diluent or carrier used should, of course, be consistent with the
compatability of the agent in DMSO and the diluent. A cosolvent or
other standard adjuvant, such as a surfactant, may be called for to
maintain the agent in solution or suspension at the desired
concentration. Where stability of the agent in the presence of DMSO
at the desired concentration is a problem, it may be desirable to
prepare the formulation immediately before administration.
The various pharmaceutical forms are desirably provided in
determined amounts, as in containers of a given volume. Cotton
tipped stick applicators, squeeze tubes may all be utilized for
topical application of the thickened formulations.
The amount of the composition, and thus of the physiologically
active agent therein, to be administered will obviously be an
effective amount for the desired result expected therefrom. This,
of course, will be ascertained by the ordinary skill of the
practitioner. Due to enhanced activity which may be achieved
through better penetration, the dosage of agent may often be
decreased from that generally applicable. In accordance with the
usual prudent formulating practices, a dosage near the lower end of
the useful range of the particular agent may be employed initially
and the dosage increased as indicated from the observed response,
as in the routine procedure of the physician.
The examples which follow illustrate the compositions of the
present invention. For an additional discussion of the various
physiologically active agents and exemplification of the
compositions of this invention, reference is made to copending
application Ser. No. 753,231, filed Aug. 16, 1968, the disclosure
of which is incorporated herein by reference.
EXAMPLE 1
The following lotion formulation may be prepared containing about
0.01 to 1.0 percent, with preferably 0.1 percent fluocinolone
acetonide:
Gm. Fluocinolone acetonide 0.1-1.0 Cetyl alcohol 200 Propylene
glycol 100 Sodium lauryl sulfate 15 DMSO 300 Water q.s. 1000
cc.
The steroid is dissolved in the DMSO and added to a stirred,
cooling melt of the other ingredients. The preparation is
particularly useful for the treatment of inflammed dermatoses by
topical application to the affected skin area. The amount and
frequency of application is in accordance with standard practice
for topical application of this steroid. Penetration of the steroid
into the inflammed tissue is enhanced and a therapeutic level is
achieved more rapidly than when the steroid is applied in
conventional formulations.
EXAMPLE 2
The following ointment (gel) formulation may be prepared containing
about 0.2 to 1.0 percent, and preferably 0.6 percent triamcinilone
acetonide:
Gm. Triamcinilone acetonide 0.2-10 Polyethylene glycol 400 400
Dimethyl sulfoxide 598 Carboxy vinyl polymer powder 1
Triethanolamine 0.4
The corticosteroid is dissolved in a mixture of the first two
ingredients, and the carboxy vinyl polymer gelling agent is
sprinkled on the surface of the combined liquids and stirred until
all the particles have been wetted and dispersed. The
triethanolamine is then added dropwise to the mixture until it has
gelled, care being taken to minimize the air entrapment. This gel
is particularly effective in the treatment of seborrhea and other
scalp and hair inflammatory conditions and may be applied in amount
and frequency conventionally used for topical application of this
steroid. Better penetration and thereby an increased
anti-inflammatory active is obtained for the amount of steroid
applied than results from its application in conventional
formulations.
EXAMPLE 3
The following ointment formulations may be prepared containing
about 0.1 to 1.0 percent prednisone and preferably 0.5 percent:
Prednisone gm 0.1-10 Glyceryl monostearate, acid type gm 180
Stearyl alcohol gm 50 Polysorbate 80 cc 20 Water cc 450 Dimethyl
sulfoxide cc 300
The product is prepared as described in Example 1. The ointment is
a valuable base for application of the corticosteroid to
inflammatory dermatological areas, particularly when they require
inunction. Application is in accordance with that usual for topical
application of this steroid in conventional bases.
EXAMPLE 4
The following cream formulations may be prepared containing about
0.1 to 1 percent 16a-methyl prednisolone and preferably 0.5
percent:
Gm. 16a-methyl prednisolone 0.1-10 Stearic acid 200 Glyceryl
monostearate, acid type 200 Sodium lauryl sulfate 20 Dimethyl
sulfoxide 200 Water q.s. 1000 cc.
As above, the product is prepared as directed in Example 1 and is
useful in severe dermatoses requiring inunction.
EXAMPLE 5
The following ointment formulation may be prepared containing about
0.5 to 2.5 percent preferably 1.0 percent, desoxycorticosterone
acetate:
Desoxycorticosterone acetate gm 5-25 Stearic acid gm 300 Cetyl
alcohol gm 100 Polysorbate 20 cc 20 Sorbital 70% cc 100 Dimethyl
sulfoxide cc 300 Water, q.s. 1000 cc.
The product is prepared as specified in Example 1. The product may
be employed in treatment of pigmentation in Addison's disease by
topical application to the affected area. Penetration may be
increased sufficiently so that effective results may be obtained.
In conventional bases this steroid has had very limited
effectiveness topically and injection usually must be resorted
to.
EXAMPLE 6
A suppository formulation may be prepared as follows containing
about 1 to 5 percent, preferably 2 percent, testosterone
propionate:
Testosterone propionate gm 10-50 Polyethylene glycol 4000 gm 400
Propylene glycol monostearate gm 100 Dimethyl sulfoxide cc 500
The solid constituents are melted, added to the solution of the
steroid in DMSO and poured into an appropriate mold. The product is
recommended for rectal application as replacement therapy.
EXAMPLE 7
A suppository formulation may be prepared as follows containing
about 1 to 5 percent, preferably 2 percent, 17-methyl
testosterone:
17-Methyl testosterone gm 10-50 Hydrogenated castor oil gm 400
Stearic acid gm 100 Dimethyl sulfoxide cc 500
The product is prepared as noted in Example 5 and used in a similar
manner.
EXAMPLE 8
A cream formulation may be prepared as follows containing about 1
to 10 percent, preferably 3 percent,
17a-ethyl-19-nortestosterone:
17a-ethyl-19-nortestosterone gm 10-100 Cetyl alcohol gm 250 Stearyl
alcohol gm 200 Polysorbate 80 cc 20 Water cc 250 Dimethyl
sulfoxide, q.s. cc 1000
This cream may be prepared as noted in Example 1. It may be applied
topically for stimulation of epithelization and connective tissue
regeneration.
EXAMPLE 9
The following cream may be formulated with the following
composition containing about 1 to 10 percent, and preferably 3%,
2a-methyl-dihydrotestosterone propionate (metholone):
Metholone gm 10-100 Stearyl acid gm 200 Glycerol monostearates,
acid type gm 200 Sodium lauryl sulfate cc 20 Water cc 400 Dimethyl
sulfoxide cc 200
The cream is prepared as directed in Example 1. The product is
useful in the treatment of muscle wasting and weakness followed
breast cancer surgery and may be applied topically to the affected
area. Penetration of the steroid is greatly improved over that
obtained in conventional formulations.
EXAMPLE 10
The following ointment (gel) may be formulated containing about 1
to 5 percent, preferably 2 percent, steroid:
2-hydroxymethylene-17a-methyl-dihydrotestosterone gm 10-50
Propylene glycol cc 500 Dimethyl sulfoxide cc 498 Carboxy vinyl
polymer powder gm 1 Triethanolamine gm 0.5
The product is prepared as specified in Example 2. The product is
useful in topical anabolic treatment, particularly in preventing
thinning of the skin and in inducing blood vessel thickening.
EXAMPLE 11
The following lotion may be formulated as follows containing about
0.1 to 1.0 percent, preferably 0.4 percent, estradiol valerate:
Estradiol valerate gm 1-10 Cetyl alcohol gm 200 Propylene glycol gm
100 Sodium lauryl sulfate gm 15 Water cc 400 Dimethyl sulfoxide cc
300
This product is prepared as noted in Example 1. The product is
designed as a means of establishing systemic replacement therapy
for estrogens during menopause by simple topical application to the
skin or mucous membrane. The DMSO enhances penetration of the
estrogen sufficiently to obtain a systemic effect. This has not
been possible in conventional formulations.
EXAMPLE 12
A suppository may be formulated as follows to contain 0.1 to 1.0
percent, preferably 0.5 percent, of 3-methyl ether of
ethynylestradiol:
3-methyl ether of ethynylestradiol gm 10-100 Polyethylene glycol
4000 gm 400 Propylene glycol monostearate gm 100 Dimethyl sulfoxide
(DMSO) cc 500
The suppositories are prepared as noted in Example 7. The product
is used in estrogenic replacement therapy and may be used by rectal
or vaginal application.
EXAMPLE 13
The following ointment (gel) may be formulated containing 0.1
percent diethylstilbesterol:
Diethylstilbesterol gm 1 Propylene glycol cc 500 Dimethyl sulfoxide
cc 498 Carboxy vinyl polymer powder gm 1 Triethanolamine gm 0.5
This gel is prepared as detailed in Example 2. The preparation is
particularly suitable for topical application in the treatment of
adolescent acne.
EXAMPLE 14
A cream may be formulated as follows to contain about 0.72 percent
norethynodrel and about 0.0286 percent mestranol:
Norethynodrel gm 10.5 Mestranol gm 0.42 Cetyl alcohol gm 100
Stearyl alcohol gm 100 Polysorbate 80 cc 20 Water cc 250 Dimethyl
sulfoxide, q.s. cc 1000
This cream is prepared as noted in Example 1. This formulation is
to be used as a contraceptive agent applied cutaneously twice
monthly at a dosage of 10 grams.
EXAMPLE 15
A suppository formulation may be prepared as follows:
Chlormadinone mg 5 Stilbesterol mg 1 Polyethylene glycol 4000 gm
400 Propylene glycol monostearate gm 100 Dimethyl sulfoxide cc
500
The suppositories are formed as in Example 7. The product may be
employed for treatment of irregular or prolonged bleeding.
EXAMPLE 16
The following ophthalmic formulation may be prepared containing
about 0.1 to 0.75 percent, preferably 0.3 percent,
spironolactone:
Spironolactone gm 1-7.5 Polyethylene glycol 4000 cc 200 Dimethyl
sulfoxide cc 200 Water, q.s. 1000 cc.
The formulation is prepared by melting the polyethylene glycol
4000, dissolving the steroid in the DMSO, mixing the two liquids
together and diluting to volume with water while stirring. The
preparation is applied topically to the eye by eye dropper, or
similar applicator, for treatment of glaucoma.
EXAMPLE 17
A 5-fluorouracil formulation may be prepared by blending the
following:
5-fluorouracil 10 grams DMSO 80 grams Water 10 grams Carboxymethyl
cellulose 0.25 grams
The formulation is particularly useful in topical treatment of skin
tumors or other localized superficial tumors. A typical dose is 5
grams. It is also useful in treating viral disorders such as
warts.
EXAMPLE 18
A suppository formulation may be prepared by melting together the
following:
Gm. Estradiol valerate 2.75 Guiacol glycerol stearate 100 DMSO 300
Diglycol laurate 150
The melted blend is poured into a suppository mold to provide 10
gm. suppositories for treatment of prostatic cancer.
EXAMPLE 19
A cyclizine hydrochloride mist formulation may be prepared and
charged into an aerosol container to provide fifty 100 mg. doses
which may be administered intranasally for treatment of allergy
states and motion sickness, etc. Five grams of cyclizine
hydrochloride are incorporated in a halocarbon propellant
formulation base containing 4 percent by volume DMSO.
EXAMPLE 20
A topical ointment formulation of tripelennamine base particularly
suitable for treatment of itching dermatoses (applied to the
affected area several times daily), may be formulated as
follows:
Percent Tripelennamine base percent 2 DMSO 70 Sodium
carboxymethylcellulose 4 Water 24
EXAMPLE 21
A chloral hydrate suppository formulation may be prepared by
blending together:
Gms. Chloral hydrate 10 DMSO 4.7 Stearic acid 1 Water 0.5
The melt is poured into a suppository mold and cooled to form 10
suppositories each supplying a 1 gram dose. One or two
suppositories, as indicated, may be administered as a general
sedative.
EXAMPLE 22
A unit dose suppository form of imipramine can be prepared by
melting together:
Imipramine base mg. 50 DMSO gm 4.5 Sodium stearate gm 1.0 Glycerine
gm 4.5 Water 1.0
and cooling the melt in a suppository mold. This dosage may be
administered rectally T.I.D. to relieve depression.
EXAMPLE 23
The following formulation may be melted together, placed in a
suppository mold and cooled to form a unit dose for rectal
application as a monoamine oxidase inhibitor for treatment of
depressive states:
N-benzyl-N-methyl-2-propynylamine mg 100 DMSO gm 4 Diglycol laurate
gm 1.5 Carbopol 934 gm 0.25 Triethanolamine gm 0.01
EXAMPLE 24
Mecamylamine is representative of agents having a site of activity
at the autonomic ganglia (ganglionic stimulating and blocking
agents). It may be formulated as follows to provide a single dose
in suppository form for rectal application in treatment of
hypertension:
Mecamylamine base mg 15 Propylene glycol stearate gm 4.5 DMSO gm
4.5 Triethanol amine gm 0.3 Stearic acid gm 1.5
Melt ingredients together and pour into cooled suppository
mold.
EXAMPLE 25
A glycerol trinitrate ointment may be prepared by blending the
following ingredients:
Gms. Glycerol trinitrate 2 DMSO 70 Ethanol 8 Carbowax 1500 20
A typical dosage of 10 mg. of glycerol trinitrate is provided with
one-half gram of this ointment. The dosage may be applied topically
as, for example, to the intact skin of the upper arm, or
sublingually.
EXAMPLE 26
A male subject had a skin markedly sensitive to ultraviolet light.
A test solution was made containing 1 percent ultraviolet absorber
in 100 percent dimethyl sulfoxide. A control solution was made
containing the ultraviolet absorber in 100 percent ethanol, and
both solutions were similarly thickened with Carbowax 4000 to
provide lotion forms. The ultraviolet absorber was
2,2'-dihydroxy-4,4'-dimethoxy benzophenone. The two lotions were
applied to different sides of the subject's face. After one day of
severe sun exposure, the subject was examined. The side with the
control application showed marked redness. The side with the test
application showed only slight redness. Two days later, the control
side was blistered, whereas the test side was normal and free of
redness.
EXAMPLE 27
An ointment base may be prepared from the following:
Parts by wt. Lanolin 90 DMSO 10 Isopropyl myistate 5
to which is added 1,800 U.S.P. units of Vitamin A and 300 U.S.P.
units of Vitamin D.sub.3 per gram of ointment base. This ointment
is applied topically for the treatment of burns, skin irritation,
diaper rash and pruritis.
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