Method for enhancing the rate of skin permeation of lactic acid through use of the L-enantiomer

Methods of increasing the rate of lactic acid permeation in skin for the treatment of dermatological disorders by applying a composition containing an inorganic or organic salt of lactic acid in a dermatologically acceptable composition wherein at least 70% of the lactic acid moiety in the salt is L-lactic acid, and compositions for practicing such methods.

FIELD OF THE INVENTION 
This invention relates to topical administration of therapeutic 
compositions for the treatment of determatological disorders, to 
compositions employed for such administration and to methods of preparing 
such compositions. More particularly, it relates to topical administration 
of therapeutically effective amounts of L-lactic acid salts under 
conditions such that there is rapid and higher skin permeation of the 
L-lactic acid. 
BRIEF DESCRIPTION OF THE PRIOR ART 
The topical use of .alpha.-hydroxy acids and .alpha.-keto acids for the 
treatment of various skin conditions is well known in the art. It is 
described, for example in U.S. Pat. Nos. 3,879,537, 4,105,783 and 
4,363,815. 
U.S. Pat. No. 5,091,171 describes the employment of salts of various 
.alpha.-hydroxyacids and .alpha.-keto acids with amines, especially 
amphoteric amines, including amino acids, dipeptides, polypeptides and 
proteins. Typical therapeutically useful salts described in the patent 
include, for example, lysine lactate, a salt obtained by reaction between 
lysine and the .alpha.-hydroxyacid, lactic acid. Other salts include 
aliphatic, aromatic and heterocyclic amino acids; dibasic and diacidic 
amino acids; substituted and unsubstituted amino acids as well as 
synthetic and natural amino acids. The prior art recognizes that 
.alpha.-hydroxy acids exist in enantiomeric forms and racemic mixtures, 
but there is no recognition of a distinction between the skin permeation 
and, hence, the therapeutic efficacy of the enantiomers and racemic 
mixtures. More specifically, there is no recognition in the prior art of 
the discovery described and claimed herein, namely that the L-form of 
lactic acid is more efficient for permeating mammalian skin than is the 
D-form.

DETAILED DESCRIPTION OF THE INVENTION 
The advantages of this invention will be readily apparent from the 
following description taken together with the results illustrated in the 
figures. 
The compositions tested are shown in the following Table 1. The 
formulations in this table and subsequent tables are represented by 
capital letters. Those represented by the same letter in different tables 
are identical formulations. 
The compositions were prepared by mixing the identified forms of the lactic 
acid and the selected amino acid together with water until uniform. The 
mixture was heated to a temperature of 60.degree.-65.degree. C. with 
mixing for 25 minutes. Mixing was continued while cooling to room 
temperature and the necessary amount of water was added. The pH was then 
measured. 
TABLE 1 
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Composition of solution formulations containing L-lysine and L- 
histidine salts of 12% DL and L-lactic acid. 
Ingredients A B C D 
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DL-Lactic Acid (88%) 
13.6 13.6 -- -- 
L-Lactic Acid (88%) 
-- -- 13.6 13.6 
L-Histidine 16.52 -- 16.52 -- 
L-Lysine Monohydrate 
-- 16.14 -- 16.14 
Water QS 100.00 100.00 100.00 100.00 
pH 4.75 4.63 4.81 4.69 
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The capacity of the various compositions to penetrate the epidermis was 
tested by the following standard procedure. 
In-vitro Skin Permeation Study 
.sup.14 C-L-lactic acid sodium salt and .sup.14 C-DL-lactic acid sodium 
salt were used in the skin permeation study. The formulations with 
L-lactic acid salts and DL-lactic acid salts were spiked with .sup.14 
C-L-lactic acid sodium salt and .sup.14 C-DL-lactic acid sodium salt, 
respectively, to result in a radioactive concentration of 6 micro curie 
per ml. 
Skin Preparation 
Excised human cadaver skin samples obtained from the New York Firefighters 
Skin Bank were used. The skin was supplied as sterile, split-thickness 
skin with most of the underlying dermis already removed. The skin samples 
were thawed for 15 minutes at room temperature and then transferred and 
rinsed in normal saline for 30 minutes. Appropriate size specimens were 
sectioned into squares to fit the diffusion cells. 
Franz Diffusion Cell Study at Finite Dose 
For each formulation, the skin section was mounted on three or four flat 
flange Franz diffusion cells (FDC 400) with a diffusional cross-section 
area of 1.2 cm.sup.2. A 100 micro liter sample of test formulation was 
placed on the stratum corneum surface of the skin in the donor compartment 
and the receptor compartment was filled with about 11 ml of normal saline. 
The receptor fluid was well stirred throughout the experiment and the 
temperature was maintained by circulating water at 37.degree. C. through 
the water jacket of the diffusion cells. Precisely 500 .mu.l of receptor 
fluid was collected in a scintillation vial at appropriate intervals over 
a period of about 73 hours. Fifteen ml of scintillation fluid (INSTA-GEL 
XF, KARD) were added directly to the scintillation vial and the lactic 
acid content was determined on a Beckman LS 3801 scintillation counter. 
The receptor fluid was replenished after each withdrawal. All the receptor 
fluid and replenished fluids were filtered using a 0.22 .mu.m filter and 
thoroughly degassed before use. 
FIG. 1 shows the results of a skin permeation study comparing compositions 
containing: 
12% solution of the L-histidine salt of DL-lactic acid 
12% solution of the L-lysine salt of DL-lactic acid 
12% solution of the L-lysine salt of L-lactic acid 
It will be seen that over the course of about 70 hours, the permeation of 
DL-lactic acid (DL-LA), whether as a salt with L-histidine (L-His) or with 
L-lysine (L-Lys), was essentially the same. In contrast, over the complete 
course of the study, the degree of permeation of L-lactic acid (L-LA) as a 
salt with L-lysine was rapid in onset and much higher than with the other 
compositions. 
Table 2 summarizes the results shown in FIG. 1. From the table, it is clear 
that at 4 hours and 73 hours, the skin permeation of L-lactic acid (as the 
L-lysine salt) is about 7.5 fold and 2 fold higher than that of the 
corresponding DL-lactic acid salt. It is also clear that L-lactic acid 
permeated faster and to a higher level than DL-lactic acid from their 
respective L-lysine salt solutions and that there is practically no 
difference in the permeation profile of the DL-lactic acid from either the 
L-lysine or L-histidine lactate solutions. 
TABLE 2 
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In vitro skin permeation of L-lactic acid and DL-lactic acid from 
different formulations. 
Amount Permeated 
Amount permeated relative 
(mcg/cm.sup.2) 
to DL-LA-L-Lysine control 
Formulation 
4 Hours 73 Hours 4 Hours 73 Hours 
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B 21 119 1.0 1.0 
D 158 223 7.5 1.9 
A 18 143 0.9 1.2 
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Similar results are achieved if the L-lactic acid salts are prepared from 
either enantiomer of histidine or lysine or from racemic mixtures of these 
amino acids. The essence of the invention is the L-lactic acid anion not 
the geometric arrangement of the atoms in the cation. 
FIG. 2 shows the results of a further study comparing: 
12% solution of the L-Histidine salt of DL-lactic acid 
12% solution of the L-Histidine salt of L-lactic acid 
12% solution of the L-Lysine salt of L-lactic acid. 
It is again seen that there is a rapid onset of permeation and a 
consistently higher degree of permeation for the L-lactic acid as a salt 
of L-histidine compared to DL-lactic acid as a salt of L-histidine. 
Table 3 summarizes the results shown in FIG. 2. From the table, it is clear 
that at 4 hours and 73 hours, the skin permeation of L-lactic acid (as the 
L-histidine salt) is about 10.3 fold and 2.1 fold higher than that of the 
corresponding DL-lactic acid salt. Overall the rank order of skin 
permeation is L-LA-L-His&gt;L-LA-L-Lys&gt;DL-LA-L-His. In each instance, the 
L-lactic acid salt has higher degree of permeation and more rapid onset 
than DL-lactic acid salt. 
The permeation of L-lactic acid can be further improved in comparison to 
DL-lactic acid by selecting appropriate cations. The NH.sub.4.sup.+, 
Na.sup.+, K.sup.+, cations are preferred over L-lysine and L-histidine, 
because of their small molecular weight compared to amino acids, because 
they are more readily available and because they provide consistently good 
results. 
TABLE 3 
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In vitro skin permeation of L-lactic acid and DL-lactic acid from 
different formulations 
Amount Permeated 
Amount permeated relative 
(mcg/cm.sup.2) 
to DL-LA-L-His control 
Formulation 
4 Hours 73 Hours 4 Hours 73 Hour 
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A 23 631 1.0 1.0 
C 237 1309 10.3 2.1 
D 293 994 12.7 1.6 
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It will be noted by a comparison of the second columns in Tables 2 and 3 
that there are appreciable differences in the amounts of permeated 
products under what appear to be identical conditions. This apparent 
anomaly arises because different skin samples were employed in the tests. 
The skilled artisan will know that there are large variations in skin 
porosity and that tests of the nature employed herein are only valid when, 
as here, identical skin samples are compared. 
The salts of this invention may be obtained by standard procedures by 
reaction between L-lactic acid and any of variety of inorganic alkali and 
organic bases. 
Any of a wide variety of inorganic alkali bases or organic bases may be 
employed to form the inorganic and organic salts of this invention, and 
such salts will be prepared by simple acid/base reactions using procedures 
well known to the skilled artisan. Alkali and alkaline earth metal salts, 
such as Na, K, Ca, Mg and Li hydroxides, oxides, carbonates, bicarbonates 
and others may be utilized. Ammonium salts, particularly ammonium 
hydroxide, are useful as are quaternary ammonium compounds such as 
tri-alkylammonium hydroxide. Organic nitrogen bases, including both 
natural and synthetic amino acids, peptides, polypeptides, and proteins, 
are useful. Other nitrogen containing bases which may be employed to 
produce the salts include, organic bases with imino, guanidino, 
imidazolino, imidazolyl, or other equivalent functionality. Various 
primary, secondary and tertiary amines, particularly those substituted 
with C.sub.1-8 alkyl or aryl groups, may be utilized. Preferred amines 
include, alkanolamines mono-, di- and tri-substituted amines such as 
propyl and dipropyl amine, aniline, methyl aniline and propyl aniline, 
pyridine, dialkanolamines, alkylalkanolamines, rialkylamines and 
trialkanolamines. 
The useful salts of the invention also include amphoteric salts of L-lactic 
acid, such as, lecithin, phosphotidyl ethanolamine, phosphatidyl serine 
and sphingomyelin salts. They also include salts prepared from ornithine, 
arginine, carnosine (alanyl- histidine), 4-aminobutanoic acid and 
citrulline (.alpha.-amino .alpha.-ureidovaleric acid). 
Representative amino acid salts of lactic acid include, for example, 
glycine, alanine, valine, leucine, isoleucine, serine, threonine, 
cysteine, cystine and tryptophan. The most preferred are salts of the 
basic amino acids lysine, histidine and arginine. 
The important criterion in selecting the counter ion of the salts of the 
invention is that the base from which they are formed have a low PK.sub.b 
value. The base must be a sufficiently strong to counteract the acidity of 
lactic acid. Lactic acid is a weak acid. A 1M aqueous solution of lactic 
acid has a pH of 1.9. As stated above, the pH of the compositions of this 
invention is such as to ensure salt formation. Generally, it is from about 
2.5 to 9. Preferably it is from 3.5 to 7 and most preferably it is from 4 
to 5.5. 
The concentration of L-lactic acid salt in the enantiomer mixtures of the 
invention is at least about 70%. Preferably it is 85%. Most preferably, it 
is about 100%, i.e. the compositions are substantially free of D-lactic 
acid salts. 
The crux of this invention is the unexpected discovery that L-lactic acid, 
as the sole lactic acid component, or in a mixture containing both 
L-lactic acid and D-lactic acid, when in the form of selected salts of 
either enantiomer, permeates mammalian skin at a higher rate than D-lactic 
acid. Thus, when a topical mixture containing a major portion of an 
L-lactic acid and a minor portion of a D-lactic acid is applied to human 
skin, the L-lactic acid salt permeates the skin at a higher rate than the 
D-lactic acid salt. As a result the proportion of L-lactic acid salt in 
the skin compared to the D-lactic acid salt will be higher than the 
proportion of these enantiomers in the form of their salts in the 
composition. 
The most preferred compositions of this invention will contain 100% of the 
selected lactic acid salt in the L-form. However, there is a tendency for 
pure L-lactic acid to spontaneously racemize with time to form an 
equilibrium mixture containing about 85% of the L-enantiomer and about 15% 
of the D-enantioner. Such mixtures are useful to form the compositions of 
this invention. 
At the present time, lactic acid is commercially available in solutions 
containing 85 to 90% lactic acid in the D-form, or in the L-form or as a 
racemic mixture. It is most convenient to use these solutions for the 
preparation of compositions of this invention. The solutions can be mixed 
in accordance with procedures readily apparent to the skilled artisan to 
produce lactic acid solutions with a preselected proportion of L-lactic 
acid and then converted to the selected salt. Thus, for example, an 
L-lactic acid solution can be mixed with a DL-lactic acid solution to 
prepare a solution containing 70% L-lactic acid and 30% D-lactic acid. 
These mixtures are useful for the formation of the compositions of the 
invention. They can be used directly or can be converted by well known 
means to dermatological compositions of the invention such as lotions, 
creams, ointments and the like, for topical administration to patients in 
need of treatment for dermatological disorders.