Method and composition having enhanced alpha-hydroxy acid skin permeation and retention

Methods of enhancing skin permeation and skin retention of .alpha.-hydroxy acids for the treatment of dermatological disorders by applying a composition containing an amphoteric salt of an .alpha.-hydroxy acid, such as lactic, glycolic, citric, tartaric or malic acid and an amino acid, dipepdide, polypeptide or proteins, in a dermatologically acceptable carrier which contains 0.5 to 8% glycerol monocaprylate, 0 to 80% petrolatum and 0 to 30% isopropyl myristrate, the pH of the composition being from 3 to 9, 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 and to 
compositions employed for such administration. More particularly, it 
relates to topical administration of therapeutically effective amounts of 
amphoteric salts of .alpha.-hydroxy acids, such as lactic acid salts of 
amino acids, in topical compositions that contain selected amounts of 
glyceryl monocaprylate (GMC) and have a selected pH range. The 
compositions provide enhanced permeation of the lactic acid into the skin 
and substantial retention therein. 
BRIEF DESCRIPTION OF THE PRIOR ART 
The topical use of .alpha.-hydroxy acids and .alpha.-keto acids for 
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 various 
.alpha.-hydroxyacids, .alpha.-ketoacids and their derivatives, in the form 
of various salts, particularly amphoteric salts obtained by reaction of 
the hydroxy acids or ketoacids with amines, especially amphoteric amines 
such as 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.-hydroxy acid, lactic acid. 
The patent also describes the use of ammonium salts of .alpha.-hydroxy 
acids such as ammonium lactate, stating that the composition, while 
retaining some of its effects for certain cosmetic conditions, has lost 
most of its potency for other dermatological disorders. Patentees conclude 
ammonium lactate exhibits less skin permeation of lactic acid than the 
other amphoteric salts of lactic acid described in the patent. 
Despite this adverse teaching, the art has utilized topical ammonium 
lactate compositions for various therapeutic purposes. One reason for this 
acceptance is that, contrary to the teaching of U.S. Pat. No. 5,091,171, 
ammonium lactate does, in fact, have a high permeation profile for lactic 
acid. Moreover, it has been surprisingly found that the amphoteric salts 
of .alpha.-hydroxy acid and amino acid, have a poor skin permeation 
profile for .alpha.-hydroxy acid as compared to the corresponding ammonium 
salts. 
A problem associated with the use of ammonium lactate is that it is a skin 
irritant to a degree which many patients find unacceptable. Amino acids 
are known to have moisturizing effects on mammalian skin. Amphoteric 
.alpha.-hydroxy acid amino acid salts, therefore, should afford less skin 
irritation than the corresponding ammonium salts. However, as stated, they 
exhibit substantially poorer skin permeation of .alpha.-hydroxy acid than 
the corresponding ammonium salts. 
There is need for amino acid salts of .alpha.-hydroxy acids that have skin 
permeation of the .alpha.-hydroxy acid comparable to that observed with 
ammonium salts of such acids while having less skin irritation than such 
ammonium salts. The present invention teaches compositions and methods 
which enhance skin permeation and skin retention of .alpha.-hydroxy acids, 
particularly lactic acid in the form of amphoteric salts. In essence, the 
present invention is the discovery that selected amphoteric amino acid 
salts of .alpha.-hydroxy acids, particularly lactic acid, offer equal, or 
even better, skin permeation than the corresponding ammonium salts when 
incorporated in the dermatologically acceptable compositions described 
herein. 
SUMMARY OF THE INVENTION 
Novel compositions for the treatment of dermatological disorders have now 
been discovered. They comprise compositions for topical administration to 
patients in need of such treatment, the compositions containing a 
dermatologically effective amount of an amphoteric salt of an 
.alpha.-hydroxy acid in a dermatologically acceptable pharmaceutical 
carrier containing from about 0.5% to 8% of GMC. The compositions are 
further characterized by a pH range of from about 3 to 9, preferably 3.5 
to 6.5 and most preferably 3.8 to 5. Within this pH range, the 
.alpha.-hydroxy acid forms an amphoteric salt with the selected base. The 
optimum pH for the formation of a specific salt will depend upon the 
basicity of the selected salt forming reagent, i.e. its pK value. These 
novel compositions manifest a degree of skin permeation and retention of 
.alpha.-hydroxy acid which is, surprisingly, substantially equivalent to, 
and in some instances better than, the ammonium salt of such acid. 
The skin permeation of .alpha.-hydroxy acids, present in the compositions 
of the invention as the .alpha.-hydroxy acid amphoteric salts, is even 
further improved by addition to such compositions of selected amounts of 
isopropyl myristrate (IPM) and/or petrolatum (PET).

DETAILED DESCRIPTION OF THE INVENTION 
The compositions employed in this invention are useful for all known 
utilities for topical administration of .alpha.-hydroxyacids. These 
include, for example treatment of dry skin, xerosis, ichthyosis, dandruff, 
acne, keratoses, psoriasis, wrinkles, warts, blemished skin, 
hyperpigmented skin, inflammatory dermatoses, eczema, pruritis, 
hyperkerotic skin, lentigines, melasma, age spots, laxity, leathery 
texture, roughness, sallow complexion, scaling, telangiectasia, mottled 
pigmentation, skin atrophy caused by steroids, and skin changes associated 
with intrinsic aging and photodamage. 
The term "dermatological disorders", as used herein, refers to any of those 
cited above as well as other conditions treated by cosmetologists or 
dermatologists with .alpha.-hydroxy acids or salts thereof, in particular 
amphoteric amino acid salts of such acids. It includes skin conditions the 
treatment of which might usually be regarded as cosmetic, such as the 
treatment of hyperpigmented skin areas, as well as more serious skin 
conditions, such as chronic or acute psoriasis. 
In addition to the .alpha.-hydroxy acid amphoteric salt, the compositions 
of the invention may contain any of a large number of additional cosmetic 
and pharmaceutical agents, provided that such additional agents are inert 
with respect to the formation, stability and activity of the 
.alpha.-hydroxy acid salts of the invention, i.e., they are reaction 
inert. 
Cosmetic and pharmaceutical agents include those that improve or eradicate 
age spots, keratoses and wrinkles; analgesics; anesthetics; antiacne 
agents; antibacterials; antiyeast agents; antifungal agents; antiviral 
agents, antidandruff agents; antidermatitis agents; antipruritic agents; 
antiinflammatory agents; antihyperkeratolytic agents; antidryskin agents; 
antiperspirants; antipsoriatic agents; antiseborrheic agents; hair 
conditioners and hair treatment agents; antiaging and antiwrinkle agents; 
antiphotoaging agents; antiasthmatic agents and bronchodilators; sunscreen 
agents; antihistamine agents; skin lightening agents; depigmenting agents; 
vitamins; corticosteroids; tanning agents; hormones; retinoids; and 
topical cardiovascular agents. 
Examples of cosmetic and pharmaceutical agents are clotrimazole, 
ketoconazole, miconazole, griseofulvin, hydroxyzine, diphenhydramine, 
pramozine, lidocaine, procaine, monobenzone, erythromycin, tetracycline, 
clindamycin, meclocycline, hydroquinone, 4-hydroxyanisole, minocycline, 
naproxen, ibuprofen, theophylline, cromolyn, albuterol, all trans retinoic 
acid, 13-cis retinoic acid, hydrocortisone, hydrocortisone 21-acetate, 
hydrocortisone 17-valerate, hydrocortisone 17-butyrate, betamethasone 
valerate, betamethasone dipropionate, triamcinolone acetonide, 
fluocinonide, clobetasol propionate, halobetasol propionate, benzoyl 
peroxide, crotamiton, propranolol, promethazine, vitamin A palmitate, 
vitamin E acetate and calcipotriene. 
The salts of this invention may be employed with any of a variety of 
dermatologically acceptable carriers or excipients normally employed in 
compositions for topical administration, These are well known to the 
skilled artisan and include, for example, surfactants, emulsifiers, 
stabilizers, preservatives, antiseptics, emollients, thickeners, 
lubricants, humectants, chelating agents, fragrances and skin permeation 
enhancers. 
The compositions may be in the form of solutions, emulsions, suspensions, 
lotions, creams, gels, sticks, ointments, liposomes, aerosol sprays, 
polymeric gels, plasters, patches, films or tapes, the preparation of 
which are well known to those skilled in the art of topical pharmaceutical 
formulation. 
Examples of suitable emulsifiers include, steareth-2, steareth-21, 
polyoxyethylene-4-lauryl ether, polyethylene glycol-23-lauryl ether, 
sorbitan monostearate and polyoxyethylene-20-sorbitan monostearate. 
Examples of preservatives include, methyl paraben, propyl paraben, sorbic 
acid, potassium sorbate, benzyl alcohol, diazolidinyl urea, 
methylisothiazolinone and methylchloroiosothiazolinone. 
Examples of emollients include, silicone oils, mineral oil, cocoa butter, 
hexyl laurate, diisopropyl adipate, dibutyl adipate, glyceryl stearate, 
beeswax, lanolin, sperm wax, cetyl palmitate, isopropyl myristate, 
isopropyl palmitate, isopropyl isostearate and propylene glycol 
dioctanoate. 
Among the thickening agents there may be mentioned by way of example, 
xanthan gum brine tolerant, xanthan gum, and gum acacia, which are 
excellent as emulsion stabilizers and gelling agents. 
Acceptable humectants include, for example, propylene glycol, glycerin, 
butylene glycol and polyethylene glycols. 
As will be recognized by the skilled artisan, the term "effective amount" 
relates to the condition under treatment. Some conditions may require 
treatment with large amounts of .alpha.-hydroxy acid salts. Others may be 
effectively treated with smaller amounts. The treatment may require one or 
multiple dosage units applied all at once or over a period of time. 
Generally, the dosage requirements will be of the order of magnitude 
normally employed with similar treatments using .alpha.-hydroxy acid 
salts. However, because of the rapid onset of permeation and higher 
permeation concentration achieved, it is often possible to use lesser 
amounts of .alpha.-hydroxy acid salts, in accordance with the procedures 
of the present invention. In any event, the skilled artisan will have no 
difficulty in determining an "effective amount" for the treatment of a 
specific condition, by the application of the routine test procedures 
normally employed. 
The advantages of this invention will be readily apparent from the 
following description taken together with the results illustrated in the 
figures. 
The results to be described were based on skin permeation and skin 
retention tests, since a principal object of the invention is that the 
lactic acid permeate into the skin but that a sufficient amount of it be 
retained therein to be therapeutically effective. 
The skin permeation test was conducted by the following 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 test formulations with 
L-lactic acid salts and DL-lactic acid salts were spiked and mixed 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 
microcurie per ml. 
Franz Diffusion Cell Study at Finite Dose 
For each formulation, skin sections were mounted on three or four flat 
flange Franz diffusion cells (FDC 400) with a diffusional cross-section 
area of 1.2cm.sup.2. About 60 to 100 mg of test formulation were 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 for a 
period of 68 hours. Fifteen ml of scintillation fluid (INSTA-GEL XF 
KARD) were added directly to the scintillation vials 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. 
Preparation of Epidermis and Dermis for Analysis 
After the skin permeation study, the stratum corneum surface of the skin 
was washed three times with 0.5 ml of water. Cotton swabs were used during 
the rinsing procedure to recover the remaining surface dose. A circular 
incision was made in the skin exposed to the formulation. The epidermis at 
the circular edge was slowly lifted using a pointed flat spatula, and then 
separated from the dermis using forceps. The epidermis and dermis were 
transferred to previously weighed teflon tape and dried in a desiccator 
for 72 hours until a constant weight was obtained. Known weights of 
epidermis and dermis were transferred to scintillation vials, 2 ml of 
SOLUENE-350 were added, and the vials were shaken at 40.degree. C. until 
the skin samples were completely dissolved. The samples were then 
decolorized by adding 0.2 ml of H.sub.2 O.sub.2 (30% solution) and 
refrigerated for two hours, Fifteen ml of HIONIC FLUOR solution were then 
added to the vials and they were then stored in complete darkness at 
5.degree. C. for 12 hours before counting. Refrigeration in darkness was 
necessary to avoid any chemiluminescence. 
As indicated above, a principal object of this invention is to achieve a 
skin permeation and skin retention profile of lactic acid from amphoteric 
amino acid lactates comparable to that of lactic acid from ammonium 
lactate. As noted earlier, contrary to the teaching in U.S. Pat. No. 
5,091,171, ammonium lactate has excellent lactic acid skin permeation and 
skin retention profiles and is very effective for treating dermatological 
disorders such as those mentioned above. As noted earlier, it has also 
been found, contrary to the teaching of U.S. Pat. No. 5,091,171, that 
amphoteric salts of .alpha.-hydroxy acid, such as amino acid salts of 
.alpha.-hydroxy acid, do not have advantageous .alpha.-hydroxy acid skin 
permeation profiles as compared with the ammonium salts of the 
corresponding .alpha.-hydroxy acid. In point of fact, the amphoteric amino 
acid salts of .alpha.-hydroxy acids have much poorer .alpha.-hydroxy acid 
skin permeation profiles than the ammonium salts of such .alpha.-hydroxy 
acids. 
It has now been found, unexpectedly, that it is possible to obtain improved 
.alpha.-hydroxy acid skin permeation and retention profiles with lysine 
lactate and other amphoteric amino acid salts of .alpha.-hydroxy acids by 
incorporating such salts in compositions having a specific pH range and 
containing defined quantities of GMC. 
The specific pH range of operability for the compositions of this invention 
is from about 3 to 9, preferably about 3.5 to 6.5, and most preferably 
about 3.8 to 5. 
The specific concentration range of GMC for the compositions of this 
invention is from about 0.5 to 8%, preferably about 1 to 7%, and most 
preferably about 2 to 5%. 
It has been observed that, when operating within these defined ranges, it 
is possible to effect a degree of lactic acid skin permeation and 
retention which is comparable to that obtained with ammonium lactate. 
Within the ranges and at constant pH, it is possible to increase lactic 
acid skin permeation and retention by increasing the GMC content of the 
compositions. It is similarly possible to increase lactic acid skin 
retention and skin permeation by decreasing the pH while maintaining a 
constant GMC content. 
Some variation from the defined ranges is possible. However, appreciable 
variation from the defined pH values may cause skin irritation with some 
patients. If the GMC content is too low, the desired results are not 
achieved. If it is too high, the cost of the compositions may be too high 
in relation to the improved results. Generally, for optimum results, it is 
preferred to operate towards the higher end of the defined range of GMC. 
As recognized in U.S. Pat. Nos. 5,041,437, 5,059,427 and 5,073,369, GMC is 
known to assist the skin permeation of several therapeutic agents. There 
is, however, no predictability as to whether permeation enhancers such as 
GMC will assist in the permeation of a particular therapeutic agent. As 
shown in U.S. Pat. No. 4,732,892, valine is another material that is known 
to enhance skin permeation. However, in the absence of GMC, valine does 
not enhance skin permeation of lactic acid from a composition containing 
lysine lactate. It is, in fact well recognized by those skilled in the art 
that skin permeation enhancers that are useful with one therapeutic agent 
are not predictably useful with another agent. Moreover, GMC has been used 
principally to achieve complete permeation of the therapeutic agent 
through the skin for systemic distribution thereof. There has been no 
prior recognition of the presently discovered relationship between GMC 
content and pH or that this relationship pertains to both skin permeation 
and skin retention of .alpha.-hydroxy acids from their amphoteric salts, 
particularly the amino acid salts. For the treatment of dermatological 
disorders with .alpha.-hydroxy acids, the desidiratum is not systemic 
distribution. Rather, it is that the .alpha.-hydroxy acid permeate into 
the skin and be retained there. 
Typical compositions of this invention will contain a salt of a 
DL-.alpha.-hydroxy acid, such as DL-lactic acid, and a L-amino acid, such 
as L-lysine, because lactic acid is commercially available as the racemic 
mixture and lysine is commercially available as the L-enantiomer. However, 
either of the enantiomers of the selected acids can be used to form the 
salt. The salt can also be formed from a racemic mixture of the selected 
amino acid. Lysine in the L-form is the presently preferred amino acid for 
use in this invention, although other amino acids, both natural and 
synthetic, are also useful. Typically useful amino acids include, lysine, 
histidine, arginine, ornithine and 4-amino butyric acid. 
The reactants used to form the useful salts of this invention may be pure 
enantiomers, either D or L, or they may be mixtures of enantiomers, 
including racemic mixtures. 
This invention, for purposes of illustration, has been described 
principally as applicable to .alpha.-hydroxy acid salts of amino acids, 
such as the preferred embodiment, lysine lactate. It is, however, 
applicable to salts of other dermatologically useful .alpha.-hydroxy 
acids, such as lactic acid, glycolic acid, citric acid tartaric acid and 
malic acid. It is applicable not only to natural and synthetic amino 
acids, but also to other amphoteric organic compounds which will form 
salts with such .alpha.-hydroxy acids, particularly nitrogen containing 
amphoteric organic compounds particularly amino group containing compounds 
which also contain an available reactive carbonyl group. These include 
dipeptides, polypeptides and proteins which contain at least one basic 
group, such as the amino group, or others including, for example imino, 
guanidino, imidazolino, imidazolyl or other basic groups which permit the 
formation of amphoteric salts with selected .alpha.-hydroxy acids. 
Typically useful .alpha.-hydroxy acids include, alkyl .alpha.-hydroxy 
acids, aralkyl and aryl .alpha.-hydroxy acids, polyhydroxy .alpha.-hydroxy 
acids and polycarboxylic .alpha.-hydroxy acids. Acids which may be 
mentioned by way of example, include, methyllactic acid, 
2-hydroxypentanoic acid, .alpha.-hydroxylauric acid, 
.alpha.-hydroxystearic acid, mandelic acid, benzilic acid, 
3-hydroxy-4-methoxymandelic acid, glyceric acid and saccharic acid. 
Preferred for most applications are lactic acid, glycolic acid, citric 
acid, tartaric acid and malic acid. More preferred acids are lactic acid 
and glycolic acid. They are readily available and give consistently good 
results, most preferred is lactic acid. 
The useful salts of this invention may be formed, for example, from 
lecithin and related types including, for example, phosphatidyl 
ethanolamine, phosphatidyl serine and sphingomyaline and other bases, such 
as carnosine (alanylhistidine), 4-aminobutanoic acid and citrulline 
(.alpha.-amino-.alpha.-ureidovaleric acid). 
Representative amino acids that can be used to form salts of 
.alpha.-hydroxy acids, such as lactic acid include for example, glycine, 
alanine, valine, leucine, isoleucine, serine, threonine, cysteine, 
cystine, ornithine and tryptophan. Preferred salts of the invention are 
.alpha.-hydroxy salts of the basic amino acids lysine, histidine and 
arginine with lactic acid or glycolic acid. 
It should be noted that unless otherwise indicated, when reference is made 
to percent by weight, in the description of this invention and in the 
claims that follow, it means percent by weight based on the total weight 
of the composition. 
Table 1 shows the compositions of four lysine lactate 12% test lotions 
containing a number of ingredients, the most important of which, for 
purposes of this description, are lysine lactate, petrolatum (PET), 
propylene glycol dioctanoate (PGD), isopropyl myristrate (IPM) and 
glyceryl monocaprylate (GMC). It will be noted that all of the 
compositions contain the same amount of GMC and all have a pH of 4.6, but 
they differ in the amount of petrolatum and the amount of emollients 
isopropyl myristate and propylene glycol dioctanoate. 
General Description of Preparing Amino Acid Lactate Emulsified Lotion 
Formulations 
1) In a first vessel, disperse xanthan gum BT in propylene glycol. 
2) In a second vessel, disperse magnesium aluminum silicate (VEEGUM K) in 
water and then, while mixing, slowly add step 1 xanthan gum BT mixture 
while maintaining the temperature at 65.degree.-70.degree. C. 
3) In a third vessel, heat the oil components, such as petrolatum, glyceryl 
monocaprylate, isopropyl myristate, PG-dioctanoate, dimethicone, 
steareth-2, steareth-21, cetyl alcohol and stearyl alcohol, to 65.degree. 
to 70.degree. C. and mix until uniform. 
4) In a fourth vessel heat lysine lactate solution to 35.degree.-40.degree. 
C., and then, with rapid mixing, slowly disperse titanium dioxide in it. 
5) With rapid mixing, add step 3) oil phase slowly to step 2) water phase. 
Mix for about 5 to 10 minutes and then cool to 50.degree.-55.degree. C. 
Then, while mixing, add sorbic acid and begin cooling to 
48.degree.-50.degree. C. 
6) To step 5) mixture at 48.degree.-50.degree. C., with rapid mixing, add 
slowly the step 4) lysine lactate mixture. Mix while permitting the 
temperature to fall below 35.degree. C. 
It should be noted that the aforementioned process is preferred as it 
assists in appropriate incorporation of lysine lactate and xantham gum BT. 
The xanthan gum BT is an excellent emulsion stabilizer. 
TABLE 1 
______________________________________ 
Composition of experimental lotions containing lysine 
lactate equivalent to 12% wt of lactic acid 
EXAM- EXAM- EXAM- EXAM- 
Ingredients % w/w 
PLE 1 PLE 2 PLE 3 PLE 4 
______________________________________ 
Lysine Lactate* 
50.00 50.00 50.00 50.00 
Titanium Dioxide 
0.15 0.15 0.15 0.15 
Petrolatum 3.0 3.0 3.0 5.5 
PG Dioctanoate 
5.0 3.0 -- 2.0 
Steareth-2 2.0 2.0 2.0 2.0 
Steareth-21 3.0 3.0 3.0 3.0 
Cetyl Alcohol 
0.5 0.5 0.5 0.5 
Stearyl Alcohol 
5.0 5.0 5.0 5.0 
Dimethicone 200 
1.0 1.0 1.0 1.0 
Isopropyl Myristate 
-- 3.0 5.0 2.5 
Glyceryl 3.0 3.0 3.0 3.0 
Monocaprylate 
Propylene Glycol 
5.0 5.0 5.0 5.0 
Xanthan Gum BT 
0.4 0.4 0.4 0.4 
VEEGUM K 0.3 0.3 0.3 0.3 
Water 21.45 20.45 21.45 20.45 
Sorbic Acid 0.2 0.2 0.2 0.2 
pH 4.6 4.56 4.6 4.60 
______________________________________ 
*A solution containing 27.27 grams of lactic acid (88% active), 32.3 gram 
of lysine monohydrate, water QS 100 grams, the monomer content of the 
lactic acid being at least 91%. 
FIG. 1 shows the permeation profile of the four compositions of Table 1 
compared to that of ammonium lactate commercially available from 
Westwood-Squibb as LAC-HYDRIN 12% lotion. It will be noted that during the 
entire period of the test the permeation of lactic acid from ammonium 
lactate was appreciably higher from ammonium lactate than from lysine 
lactate contained in any of the four test compositions. 
FIG. 2 is a scaled up version of FIG. 1 showing on the abscissa the lactic 
acid skin permeation range from 0 to 30% instead of the 0 to 100% range of 
FIG. 1. The enlarged scale shows that there are, in fact, differences in 
skin permeation of lactic acid from compositions all of which are at a pH 
of 4.6 and contain 3% percent by weight GMC. These differences may be 
attributed to variations in the amounts of other components in the 
compositions, such as PET, IPM and PGD. 
FIG. 3 shows the results of lactic acid skin retention studies on the same 
compositions shown in FIG. 1. From the graphs it will be seen that there 
is excellent skin retention of lactic acid from the compositions 
containing ammonium lactate. It will be seen, also, that at constant GMC 
content and pH, there is variation in skin retention which, again, may be 
attributed to variation in the amounts of PET, IPM and PGD in the 
compositions. Under the conditions of the test, it is clear that increased 
PET content markedly increases both skin permeation and skin retention of 
lactic acid from lysine lactate. 
Of the formulations tested, the composition of Example 4 was the best in 
both skin permeation and skin retention of lactic acid. It is also 
apparent that IPM is a better skin permeation enhancer for lactic acid 
than PGD. 
The data of Table 2, which follows, demonstrates that the lactic acid 
permeation from the composition of Example 4 can be improved by decreasing 
pH or by increasing GMC concentration. 
TABLE 2 
______________________________________ 
Compositions of experimental lysine lactate lotions 
containing lysine lactate equivalent to 12% lactic acid 
Ingredients % w/w 
EXAMPLE 5 EXAMPLE 6 
______________________________________ 
Lysine Lactate 40.0 -- 
Solution A* 
Lysine Lactate -- 40.0 
Solution B** 
Titanium Dioxide 0.15 0.15 
Petrolatum 5.5 5.5 
Isopropyl Myristate 
2.5 2.5 
PG-Dioctanoate 2.0 2.0 
Steareth-2 2.0 2.0 
Steareth-21 3.0 3.0 
Stearyl Alcohol 4.0 4.0 
Dimethicone 200 1.0 1.0 
Glyceryl Monocaprylate 
3.0 4.0 
Cetyl Alcohol 0.5 0.5 
Propylene Glycol 5.0 4.0 
Xanthan Gum BT 0.4 0.4 
VEEGUM K 0.3 0.3 
Water 30.45 30.45 
Sorbic Acid 0.2 0.2 
pH 4.0 4.6 
______________________________________ 
*A solution containing: 
lactic acid (88%) 34.0 gm 
lysine monohydrate 27.0 gm 
water qs 100 gm 
The monomer content of the lactic acid being at least 91% 
**A solution containing: 
lactic acid (88%) 34.0 gm 
lysine monohydrate 40.37 gm 
water qs to 100 gm 
The monomer content of the lactic acid being at least 91% 
It is evident from a comparison of Tables 1 and 2 that the composition of 
Example 5 is substantially the same as that of Example 4, except for the 
decreased pH (which is achieved by changing the lactic acid to lysine 
ratio), and that the composition of Example 6 is substantially the same as 
that of Example 4, except for the increase in GMC content from 3% to 4%. 
FIG. 4 shows that a decrease in pH, while maintaining the GMC content at a 
constant value, remarkably increases the skin permeation of lactic acid to 
a value higher than that for ammonium lactate lotion and that increasing 
the GMC content at the same pH produces compositions which have 
substantially the same permeation profile as ammonium lactate (LAC-HYDRIN 
12% lotion). 
FIG. 5 is similar to FIG. 4 but on an enlarged scale with respect to the 
abscissa. It further confirms the conclusions reached concerning increased 
GMC content at constant pH and concerning decreasing the pH of the 
composition at constant GMC content. 
FIG. 6 shows the results of a skin retention test on the same compositions 
studied to produce the skin permeation results shown in FIGS. 4 and 5. 
Although LAC-HYDRIN is best for skin retention, it is evident that a 
reduction in pH and an increase in GMC content improves skin retention of 
lactic acid. 
FIGS. 7 through 11 record the results of similar studies which further 
support the unexpected finding of the relationship between GMC content and 
pH, the discovery of which permits control of both skin retention and skin 
permeation of lactic acid. 
The first group of compositions studied are shown in Table 3. 
TABLE 3 
______________________________________ 
Composition of solution formulations containing 
L-lysine and L-histidine salts of 
12% DL- and L-lactic acid. 
EXAM- EXAM- EXAM- EXAM- 
Ingredients % w/w 
PLE 7 PLE 8 PLE 9 PLE 10 
______________________________________ 
DL-Lactic Acid (88%) 
13.6 13.6 -- -- 
L-Lactic Acid (88%) 
-- -- 13.6 13.6 
L-Histidine 16.52 -- 16.52 -- 
L-Lysine H.sub.2 O 
-- 16.14 -- 16.14 
Water QS 100.00 100.00 100.00 100.00 
pH 4.76 4.63 4.81 4.69 
______________________________________ 
Method: Mix lactic acid, amino acid and water until uniform. Heat to 
60-65.degree. C. and mix for 25 minutes, then mix while cooling to room 
temperature, QS with water and measure the pH. 
FIG. 7 shows the lactic acid skin permeation profiles of the compositions 
of Table 3 and of 12% DL-ammonium lactate solution. From the figure and 
the table, it will be apparent that permeation of lactic acid from 
ammonium lactate is significantly higher than from the amino acid salts of 
lactic acid. 
FIG. 8 shows a similar result with respect to lactic acid skin retention of 
the four compositions of Examples 7 through 10. 
In summary, FIGS. 7 and 8 show that skin permeation of lactic acid from 
amphoteric amino acid lactate is 7 to 10 fold less than from ammonium 
lactate and that lactic acid epidermal retention is five fold less with 
amphoteric amino acid lactate as compared to ammonium lactate. 
Table 4 shows the formulations of the next compositions studied. The study 
was designed to evaluate the influence of GMC and pH on skin retention of 
lactic acid from amino acid lactates. It will be noted that the pH 
increases from the composition of Example 11 to those of Examples 13 and 
.sup.14, but that the pH of the compositions of Examples 13 and .sup.14 
remains constant. The compositions of Examples 11, 12 and 13 are free of 
GMC, whereas the composition of Example 14 contains 2.5% by weight of GMC. 
The increase in pH is accomplished by increasing the concentration of 
lysine in the composition. All these solution compositions were heated at 
60.degree. C. for 5 days to hydrolyze lactalate esters of lactic acid so 
that the final composition has a lactic acid monomer content greater than 
91% of total lactic acid. 
TABLE 4 
______________________________________ 
Compositions of solutions containing lysine 
lactate equivalent to 12% DL-lactic acid 
Ingredients 
EXAM- EXAM- EXAM- 
% w/w PLE 11 PLE 12 PLE 13 EXAMPLE 14 
______________________________________ 
DL-Lactic 13.6 13.6 13.6 13.6 
Acid (88%) 
L-Lysine H.sub.2 O 
4.3 16.14 20.0 20.0 
Glyceryl -- -- -- 2.5 
monocaprylate 
Water qs 100.00 100.00 100.00 100.00 
pH 3.0 4.2 5.0 5.0 
______________________________________ 
Method: Mix DLlactic acid, LLysine-H.sub.2 O in water until uniform. Then 
heat in closed container for 5 days at 60.degree. C. Cool to room 
temperature, then add glyceryl monocaprylate and mix well. 
FIG. 9 shows the skin retention of lactic acid for the compositions of 
Examples 11 through .sup.14 of Table 4 and for 12% ammonium lactate 
solution. It will be seen that ammonium lactate at pH 4.7 is the best 
composition for lactic acid skin retention. It is also apparent that skin 
retention of lactic acid from lysine lactate solution is increased by 
5-fold when the pH of the composition is decreased from pH 5 (Example 13) 
to pH 3 (Example 11). At constant pH 5, the retention of lactic acid from 
lysine lactate was increased about 2.5 fold by the addition of GMC 
(Example 14). 
The compositions of Table 5 were prepared to study the effect of decreasing 
pH at a fixed GMC content. 
TABLE 5 
______________________________________ 
Solution compositions containing lysine 
lactate equivalent to 12% tactic acid 
EXAM- EXAM- 
Ingredients % w/w 
PLE 15 PLE 16 EXAMPLE 17 
______________________________________ 
DL-Lactic Acid (88%) 
13.6 13.6 13.6 
L-Lysine H.sub.2 O 
4.8 16.14 20.0 
Glyceryl Monocaprylate 
2.5 2.5 2.5 
Water QS 100.00 100.00 100.00 
pH 3.2 4.2 5.0 
______________________________________ 
Method: Mix DLlactic acid and Llysine H.sub.2 O with water until uniform. 
Then heat in a closed container at 60.degree. C. for 5 days. Cool to room 
temperature, then add glyceryl monostearate and mix well. 
FIG. 10 shows the skin permeation profile of the compositions of Table 5 
and for 12% ammonium lactate solution. It will be seen that at a fixed GMC 
content of 2.5% by weight, the skin permeation profile was increased by 
3.5 fold when the pH was decreased from 5 (Example 17) to 3.2 (Example 
15). Most important of all, the lactic acid skin permeation profile of the 
composition of Example 15 at pH 3.2 was during the entire period of the 
study, better during the entire period of the study than the lactic acid 
skin permeation profile of ammonium lactate. 
FIG. 11 shows exactly the same profile for skin retention; i.e., skin 
retention of lactic acid from lysine lactate solutions was increased by 
2.5 fold when the pH was decreased from 5 to 3.2 at a constant GMC content 
of 2.5%. The skin retention of lactic acid from the lysine lactate pH 3.2 
composition was equivalent to that from the ammonium lactate composition. 
From the results of the studies described herein, it is apparent that it is 
possible to optimize skin permeation and skin retention of lactic acid 
from compositions containing amino acid salts of lactic acids by 
manipulation of pH and GMC content within defined ranges. It is further 
evident that it is possible to achieve skin permeation and retention 
values for lactic acid that are at least comparable to and with some 
compositions even better than can be achieved with the use of ammonium 
lactate. Similar results are achieved with other compositions of the 
invention. 
It is also clear that increasing the IPM content and/or the PET content of 
the compositions further improves lactic acid skin permeation and lactic 
acid skin retention. Petrolatum is an occlusive agent and is known to 
hydrate the skin and enhance permeation of highly oil soluble compounds. 
With water soluble compounds like methanol and ethanol, permeation is 
unaltered by hydration. With a compound such as propranolol hydration 
decreases the permeation rate by two fold. Thus petrolatum's enhancement 
of the permeation of lactic acid and other .alpha.-hydroxy acids from 
their highly water soluble amphoteric salts, expecially their amino acid 
salts, is surprising. 
The amounts of PET and IPM which will be effective to further enhance the 
skin permeation and skin retention of .alpha.-hydroxy acids from specific 
compositions of this invention may be readily determined by a few simple 
observations by one skilled in the formulation art. With PET, the amount 
is typically from about 0 to 80%, preferably 1 to 20%, most preferably 3 
to 10%. For IPM, the amount is typically from about 0 to 30%, preferably 
0.5 to 15%, most preferably 2 to 10%. Mixtures of PET and IPM can be 
employed.