Note: Descriptions are shown in the official language in which they were submitted.
I`his inven-tion relates to topical pharmaceu-tical
compositions and their use in -the -treatmen t of lesions of -the skin
and mucous membranes.
The oral and parenteral administration of lithium and
in particular lithium salts such as lithium carbonate, has found
widespread application in the treatmen t of manic-depressive
psychosis. Lithium treatment has been reported as being particu-
larly effective in the treatment of the manic phase of this
illness and also in the prophylaxis of both manic and depressive
10 relapses.
It has been reported (Lieb, N.Eng.J.Med. 301(1979), 942)
that the oral administration of lithium salts in the treatment of
manic-depressive illness has been accompanied by the remission of
recurrent herpes infection in a patient additionally suffering
from labial herpes and in a patient also having genital herpes.
United States Patent Specification No. 3639625 (issued
February 1972 to Sherwin) describes therapeutic compositions
containing lithium succinate for treating dermatitis and for pro-
ducing an antipruritic effect, the compositions thus being suitable
2 n for topical application.
Our copending United States Patent Serial No. 4,328,243
filed 7 April 1981, describes a method for the treatment of the
side-effects of lithium treatment in a subject suffering from
manic-depressive psychosis and undergoing lithium treatment by
orally administering to the subject an effective amount of dihomo-
~-linolenic acid and/or ~r-linolenic acid or linoleic acid.
, `t~
-
-- 2 --
We now propose that the conjoint topical administra-
tion of lithium with one or more substances selected
Erom substances capable o~ selectively increasing
the in vivo level of E-series prostaglandins, substances
capable of inhibiting cyclooxygenase en~yme, substances
capable of inhibiting the ln vlvo formation oE lipoxygenase
products, and lysine will be effective in the treatment
of lesions of the skin and mucous membranes.
Thus, in one aspect, the invention provides
a pharmaceutical composition for topical administration
which comprises at least one physiologically acceptable
lithium salt together with at least one substance
selected from substances capable of selectively increasing
the in vivo level of E-series prostaglandins, substances
capable of inhibiting cyclooxygenase enzyme, substances
capable of inhibiting the formation of lipoxygenase
products, and lysine.
Lesions of the skin and of mucous membranes
are generally associated with an inflammatory response,
and, in turn, inflammation is believed to be due in
part to excessive and/or d-efec-tive production of certain
prostaglandins and related substances. Prostaglandins
and related substances are biosynthesised in the body
from two main substances, dihomo-~-linolenic acid
and arachidonic acid. In general, prostaglandins
o~ the E-series e~hibit a beneficial anti-inflammatory
activity, and while minor amounts of such prostaglandins
are formed from arachidonic acid, most of the prostaglandin
products derived from arachidonic acid show an inflammatory
action. The principal prostaglandin product derived
from dihomo-~-linolenic acid is prostaglandin El
which exhibits the anti-inflammatory activity. Concomitant
with the production of prostaglandins and related
substances from dihomo-~-linolenic acid and arachidonic
acid by the cyclo-oxygenase enzyme, other bioproducts
are formed from these acids as a result of the action
of the enzyme, lipoxygenase. These lipoxygenase products
also exhibit an inflammatory action.
~g~3
3 --
Dihomo-~-linolenic acid and arachidonic acid
for metabolism in the body to prostaglandins and lipoxy-
genase products are usually available either from
endogenous stores of these acids or from food sources.
For example, dihomo-~-linolenic acid may be biosynthesised
from dietary sources of its precursor substances ~-
linolenic acid and linoleic acid. In animals arachidonic
acid may readily be biosynthesised from dihomo~-linolenic
acid, but in adult humans such a mechanism is not
particularly effective so that the ma~or source of
arachidonic acid for prostaglandin synthesis may be
from ingestion of the acid ~ se.
We now believe that the previously noted activity
of lithium succinate for treating dermatitis and for
producing an antipuritic effect is due to the ability
of lithium to block the release of dihomo-~-linolenic
acid and arachidonic acid from endogenous stores of
these compounds, so that the availability of the compounds
for conversion to the inflammatory prostaglandins
and lipoxygenase products is reduced.
However, as indicated above~ E-series prostaglandins
are believed to be benefical in the treatment of skin
and mucous membrane lesions due to their anti-inflammatory
activity, so that in one embodiment, the compositions
according to the invention incorporate one or more
substances which are capable of selectively increasing
the ln vivo level of E-series prostaglandins.
For example, the in vivo level of E series prostagl-
andins and especially prostaglandin El may be increased
by incorporating dihomo-~-linolenic acid and~or its
bioprecursors such as ~-linolenic acid and linoleic
acid into the compositions, conveniently in an amount
of from 0.01 to 80, preferably from 1 to 15, per cent
by weight. If desired, the level of E-series prostag-
landins may be increased by including a substancewhich acts to mobilise the endogenous stores o~ dihomo-
~-linolenic acid and examples of such substances include
physiologically acceptable zinc salts, conveniently
in an amount suficient to provide from 0.01 to 10,
preferably 0.1 to 5 per cent by weight of zinc ions.
This object may also be achieved by including in the
composition a substances which is capable of activating
the bioconversion of dihomo-~-linolenic acid to E
series prostaglandins such as, for example, ascorbic
acid (e.g. in an amount of from 0.01 to 20, preferably
0.1 to 5 per cent by weight), ethanol (e.g. in an amo-.nt
of form 0.01 to 80, preferably 0.1 to 10% per cent,
by weight) and spironolactone, (e.g~ in an amount
of from 0.01 to 20, preferably 0.1 to 5, per cent
by weight).
In the body, E-series prostaglandins may themselves
act as bioprecursors for other prostaglandins. For
example, prostaglandin El may be converted to prostaglandin
Fl~, which does not show the desired anti-inflammatory
action. The level of E-series prostaglandins may
therefore be increased by incorporating a substance
which is capable of blocking their bioconversion to
other prostaglandins. Examples of such substances
are rutin and other bioflavanoids. Rutin may
conveniently be incorporated into the compositions
in an amount of from 0.01 to 20, preferably 0.1 to
10 per cent by weight.
As indicated above, prostaglandins of the E-
series form only a minor proporation of the prostaglandin
products of the metabolism of arachidonic acid. As
the major proportion of the prostaglandin products
from arachidonic acid do not provide an anti-inflammatory
action, it may theref~r be desirable -to incorporate
into the compositions of the invention a substance
which is capable of selectively promoting the formation
of E-series prostaglandins in the bioconversion of
arachidonic acid. An e~ample of a substance which
may be used for this purpose is glutathione, conveniently
in an amount of 0.01 to 20, preferably 0.1 to 5, per
cent by weight of the composition~ It may also be
desired to include in the composition a substance
which is capable of blocking the conversion of arachidonic
-- 5 --
acid ~o any prostaglandin. On such substance which
may be used is (20:5n3) eicosapentaenoic acid and
this may conveniently be present in an amount of from
0.01 to 20, preferably 0.1 to 5, per cent by weight.
As indicated the biosynthesis of prostaglandins
from dihomo-~-lino~enic acid and arachidonic acid
by the cyclo-oxygenase enæyme is also associated with
the formation of lipoxygenase products which themselves
exhibit inflammatory activity. Thus it has been found
that the biosynthesis of the prostaglandins ma~ be
inhibited or blocked by substances which are able
to inhibit the cyclo-oxygenase enzyme. It has also
been found that the formation of lipoxygenase products
may be inhibited or blocked e.g.in the presence of
vitamin E and related tocopherols. Thus, in one embodiment,
the compositions according to the invention may contain
one or more substances which are capable of inhibiting
the cyclo-oxygenase enzyme and/or one or more substances
which are capable of inhibiting the formation of lip-
oxygenase products optionally in addition to one ormore substances which are capable of selectiely increasing
the in vivo level of E-series prostaglandins. Substances
which are capable of inhibiting the cyclo-oxygenase
enzyme include, for example, acetylsalicylic acid,
indomethacin, mefenamic acid, ketoprofen, ibuprofen
and paracetamol. The formation of lipoxygenase products
may be inhibited by, for example, vitamin E and/or
related tocopherols, or any other physiologically
acceptable lipoxygenase inhibitorO
Where the compositions according to the invention
are to be used for topical application to lesions
associated with viral infections, it may be desirable
to incorporate lysine, which may be capable of inhibiting
viral replication, into the compositions, optionally
together with the substance capable of selectively
increasing the in vivo level of E-series prostaglandins,
the substance capable of inhibiting cyclooxygenase
enzyme and/or the substance capable of inhibiting
~3
the formation of lipoxygenase products. Lysine m~y
conveniently be present in the compositions in an
amount of from 0.01 to ~0, preferably 0.1 to 5, per
cent by weight.
If oedema is present, this may limit the access
of therapeutic agents to cells which are inflammed
or infected. It may therefore be advantageous to
administer the composition of the invention in a form
which is capable of reducing local oedema and which
will aid the penetration of the other components of
the co~position to the affected cells. This may be
achieved by additionally incorporating one or more
high molecular weight polysaccharides into the compositions.
Examples of such polysaccharides include dextrans,
such as dextran sulphate.
The compositions according to the invention
are in a form suitable for topical administration.
Examples of such forms include creams, ointments,
solutions, suspensions, emulsions, lotions, gels and
sprays. Such forms may be prepared with pharmaceutical
carriers and excipients conventionally used for such
purposes. The compositions of the invention are preferably
in the form of ointments, which may conveniently be
formulted using an appropriate base such as, for example,
lanolin, paraffin or cetyl alcohol.
The compositions according to the invention
may be used for the treatment of disorders of the
skin and mucous membranes e.g. oral, nasal, ocular,
aural, genital or gastrointestinal membranes. In
particular, the compositions may be used in the treatment of
pruritis, lesions arising from inflammatory disorders such
as eczema and psoriasis and the lesions due to allergic
reactions such as to poison ivy as well as having
a soothing and analgesic effect on such lesions.
In addition, the compositions may be used in the treatment
of lesions resulting from viral infections, for example
the lesions due to infection with herpes viruses such
as herpes simplex or herpes zoster, e.g. in herpes
labialis and genitalis, and shingles; as well as lesions
arising from superficial wounds, burns, and local
poisoning e.g. as a result of insect bites and stings.
Thus, in a further aspect, the invention provides
a method for the treatment of lesions of the skin
or mucous membranes of a subject, which method comprises
topically administering to said lesions an effective
amount therefor of a composition according ~o the
invention.
The lithium salts employed according to the
invention will be physiologically acceptable, and
examples of such salts include lithium carbonate,
chloride, sulphate, citrate, succinate, salicylate
and acetylsalicylate.
When the compositions according to the invention
contain dihomo-~-linolenic acid this may, if desired,
be replaced, at least in part, by an equivalent amount
of a biosynthetic precursor thereof such as the above-
mentioned ~-linolenic acid or linoleic acid. If desired,
these substances may be used in admixture. These
substances may also be used in the form of physiologically
acceptable functional derivatives thereof such as,
for example, their Cl - C4 alkyl (e.g. methyl and
ethyl) esters and the triglycerides of the acids.
Convenient sources of linoleic acid for use according
to the invention are the many vegetable oils of which
it forms a major constituent. Examples of such oils
include cotton-seed, soyabean, peanut, corn/ sunflower
seed, safflower, poppy seed, linseed and perilla oils,
where the linoleic acid occurs in the form of its
triglyceride, and the vegetable oils may be used as
such i.e. without any treatment to isolate the linoleic
acid therefrom.
At the present time known sources of oils having
a high ~-linolenic acid content are few. One source
currently available is the seed of the Evening Primrose
or Oenothera biennis L, the oil extract therefrom
containing ~-linolenic acid and linoleic acid in the
-- 8 --
form of their trigl~cerides. Another source Of d-
linolenic acid is the seed of Borago officinalis which
provides a richer source of ~-linolenic acid with
smaller amounts of linoleic acid. Agaill, these seed
oil extracts may be used as such or may, if desired,
be fractionated to yield an oil composition enriched
in the desired ~-linolenic and/or linoleic acids.
Dihomo-~-linolenic acid for use according to
the invention may be prepared from ~-linolenic acid
according to known methods.
If convenient, it may be appropriate to utilise
the lithium in the form of a salt with the above mentioned
acids, that is with dihomo-~-linolenic, ~~linolenic
or linoleic acid.
The bioconversion of linoleic acid to ~-linolenic
acid, which is itself subsequently converted to dihomo-
~-linolenic acid, is promoted in the presence of zinc.
We have found that the conversion of dihomo-~-linolenic
acid to prostaglandin El is also enhanced by zinc.
Thus, as indicated above, the compositions according
to the invention may i desired contain a ph~siologically
acceptable zinc salt such as, for example, zinc sulphate
or gluconate. The use of a zinc salt in compositions
of the invention may be beneficial independent of
its effects on fatty acid and prostaglandin metabolism,
as it may have healing properties of its own.
Compositions according to the invention conveniently
contain an amount of lithium salt sufficient to provide
from 0.01 to 25, preferably 1 to 5, per cent by weight
of lithium ions in the compositions. When the composition
contains vitamin E and/or related tocopherols, these
are conveniently present in an amount of 0.01 to 25,
preferably 1 to 10, per cent by weight.
Under certain circumstances, it may be desirable
to limit the formation of all cyclo-oxygenase and
lipoxygenase products from both dihomo-~-linolenic
acid and arachidonic acid. In this situation it may
be appropriate to use a combination of a lithium salt
~%~
and a tocopherol which is capable of inhibiting the
formation of lipoxygenase products without conjointly
adminstering dihomo-~-linolenic acid or its precursors.
The following Examples serve to illustrate the invention:
-
2~
-- 10 --
Example 1
Ointment
% by weight
Lithium citrate 8
5 Vitamin E
Oil of Evening Primrose 8
Zinc sulphate 2
Dextran sulphate 2
The above components are formulated with an appropriate
ointment base, such as a base containing one or morecetyl alcohols with non-irritant emulsifiers or a
lanolin base.
Examples 2-8
Ointments
The following components are formulated in the amounts
- shown in Table I with an appropriate ointment base,
such as those described in Example 1,-
TABLE I
Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 Ex 7 Ex 8
% by weight
Lithium succinate 6 8 - - - 8 8
Lithium citrate - - - 8 8
Lithium acetyl - - 5 - - - -
salicylate
25 Vitamin E
Oil of Evening 4 - - 8 5 5
Primrose
Zinc sulphate 2 - - 2 - - 2
Dextran sulphate 2 2 3 - - - 2
Examples 9-11
Ointments
The following components are formulated in the per
~2~3
cent by weight amounts shown in Table II with an appropriate
ointment base r such as those descr ibed in Example
35 1:-
TABLE II
Ex.9 Ex.10 Ex.ll
Lithium succinate 8
Lithium citrate - 6 5
Vitamin E - 1 2
Indomethacin 1 - 2
Mefenamic acid - 2
Examples 1~-25-
Ointments
The following components are formulated in the per
cent by weight amounts shown in Table III with an
appropriate ointment base, such as those described
in Example 1:-
--12 ~
TABLE m
Ex. 12Ex. 13Ex. 14Ex. 15Ex. 16Ex. 17
Lithium succinate 8 4 - - 5
Lithium citrate - - 6 8 - 6
Lithium ac:et~yl-
salicyLate
Dndomethacin ~ 0.5 L0 - - -
Vitam~n E 1.0 0.5 O.S 1.0 0.5 1.0
Evening primrose 2.0 1.0 - 2.0
oil
Dihomo~inclenic - - 2.0 - - 3.0
acid
Zmc s~lphate 0.05 0.1 0.2 - 0.05
Dextran s~?hate 2.0 2.0 3.0 - - L0
Spironc~ctone L0 1.0 0.5 - 0.5
Ascorbic Acif~L0 L0 2.0 - - 2.0
Ethancl 5.0 5.0 4.0 - 3.0
~ir~ent~en~i~ L0 1.0 L0 - - 5.0
acid
Glul~ e L0 L0 0.5 - L0 0.5
Rutin 0.5 1.0 0.5
Ly~;ine 0.5 L0 2.0 - - 2.0
- 13 -
TABLE :m: (cont.)
Ex. 18EX. 19 Ex. 20Ex. 21 Ex. 22Ex. 23 E~s. 24 Ex. 25
Li~um succinate - - 8.0 ~ - 6.0 - 7.0
Lithium citrate - ~ - 4.0 - - 5.0
Lithium acetyl-
salicy~te 5.0 10.0 - - 4.0 - - -
hldome~acin - - 1.0
Vi~amin E 1.0 Lû
Evening primrase 3.0 - - 2.û - - - -
oil
Dihom~l;n~lPni~
acid
Zinc ~~ hate - 0.5
Dextean sulphate
Spiron~actone ~ - L0
Ascorbic Acid - L0
Ethanc~ 5.0 - - - - - - -
1 cten~ 2.0
acid
ne L0 2.0 - - - - 2.0
Ru~n 0.5
Lysine 1.0 0.5 - - - - L0
