Topical ophthalmic compositions containing one or more retinoids

Topical ophthalmic compositions containing one or more retinoids selected from the group consisting of near and remote analogues and derivatives of retinoic acid are described. Six classes of ophthalmic vehicles suitable as carriers for the retinoids are also described. The compositions are useful in the treatment of dry eye syndrome and related ophthalmic surface disorders and as ocular lubricants. A method of treating dry eye syndrome and related ophthalmic surface disorders and a method of providing topical ocular lubrication using these compositions are also described.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to topical ophthalmic compositions which act 
as ocular lubricants and are useful in the treatment of dry eye syndrome 
and related ophthalmic surface disorders. More particularly, this 
invention relates to ophthalmic compositions having the above-identified 
utility which comprise one or more retinoids selected from the group 
consisting of near and remote analogues and derivatives of retinoic acid, 
and a pharmaceutically acceptable ophthalmic vehicle. 
2. Discussion of Related Art 
The problems associated with dry eye syndrome and related eye ailments 
associated with inadequate lubrication of the eye have been the subject of 
considerable discussion in the scientific and patent literature. For 
example, these problems are discussed in U.S. Pat. Nos. 4,131,651; 
4,039,662; 3,987,163; 3,920,810; and 3,843,782; and Belgian Patient No. 
844,544. The contents of these patents relating to dry eye syndrome and 
related surface disorders are incorporated herein by reference. 
The above-cited patents disclose formulations which are said to relieve the 
symptoms associated with dry eye syndrome. However, none of these prior 
art formulations meet all of the important criteria for an effective and 
long lasting treatment of dry eye syndrome, particularly the moderate to 
serve keratoconjunctivitis sicca (KCS) patient. These prior art attempts 
fall into three categories corresponding to their physical state: liquids, 
anhydrous ointments, and solids. The solids are in the form of ocular 
inserts which slowly dissolve or erode to provide a thickened tear film. 
While these have the potential for providing longer term symptomatic 
relief than liquids, few patients are willing to persist in using them 
since they are difficult to insert and, once in place, tend to be 
uncomfortable, frequently themselves causing the foreign body sensation 
they were meant to treat. Prior liquid and ointment formulations, while 
giving the sensation of relief, are strictly palliatives without long-term 
effect. 
A further description of the physical manifestations associated with dry 
eye disorders is seen in a scientific paper presented by Scheffer 
Chuei-Goong Tseng at the Science Writers Seminar in Ophthalmology, 
sponsored by Research to Prevent Blindness, Inc., held in Washington, 
D.C., Sept. 30 to Oct. 3, 1984: Tseng, "Topical Vitamin A Treatment for 
Dry Eye Disorders", pages 1-6 (1984). The Tseng article describes 
experiments in which an ointment containing Vitamin A is utilized to treat 
dry eye disorders associated with Sjogrens's Syndrome and Stevens-Johnson 
Syndrome. 
Still further description concerning dry eye disorders is presented in 
commonly assigned U.S. patent application Ser. Nos. 700,861 and 695,364 
filed Jan. 23, 1985, which are based on International Applications Nos. 
PCT/US83/00841 and PCT/US83/00840 filed May 25, 1983, respectively; the 
entire contents of these applications are incorporated herein by 
reference. These applications are directed to the use of ophthalmic 
solutions and gels based on polyanionic polymers for the treatment of dry 
eye disorders. The compositions of the present invention differ from the 
solutions and gels described in these related applications in that, inter 
alia, the compositions of the present invention contain one or more 
retinoids. 
Certain retinoids have been previously identified as being useful in the 
treatment of various ophthalmic disorders. For example, U.S. Pat. No. 
3,506,760 discloses oral compositions containing caffeine and 
beta-carotene (10,000 to 100,000 International Units of Vitamin A 
activity), and indicates that oral administration of theses compositions 
provides an effective treatment for night blindness. British patent 
specification No. 1,430,223 discloses topical anti-inflammatory 
preparations which contain a steroid as a principal active ingredient, 
along with other ingredients such as antimicrobial and keratolytic agents; 
retinoic acid is disclosed as a possible keratolytic agent. This patent 
does not provide any teaching concerning the use of retinoids in ocular 
lubricant preparations for treating dry eye syndrome and related 
ophthalmic disorder. British patent specification No. 1,431,841 discloses 
the use of ophthalmic-nutritional preparations for the treatment of 
ophthalmic disorders caused by a Vitamin A deficiency. These preparations 
contain Vitamin A and other vitamins, and are indicated as being useful 
when taken orally or applied topically. This reference does not provide 
any teaching concerning ocular lubricants suitable for the topical 
treatment of dry eye syndrome. European patent application No. EP 0 077 
197 A1 discloses the use of retinoic acid in combination with methotrexate 
to prevent proliferation of remnant lens epithelial cells. 
The use of topically applied retinoic acid in the treatment of 
xerophthalmia, an ophthalmic disorder caused by Vitamin A deficiency and 
characterized by a dryness of the conjunctiva and cornea, is discussed in 
the following articles: Sommer, et al, "Topical Retinoic Acid in the 
Treatment of Corneal Xerophthalmia", American Journal of Ophthalmology, 
Vol. 86, pages 615-617 (1978); Van Horn, et al, "Topical Retinoic Acid in 
the Treatment of Experimental Xerophthalmia in the Rabbit", Archives of 
Ophthalmology, Vol. 99, pages 317-321 (1981); and Pirie, "Effects of 
Locally Applied Retinoic Acid on Corneal Xerophthalmia in the Rat", 
Experimental Eye Research, Vol. 25, pages 297-302 (1977). These articles 
discuss the use of topical retinoic acid therapy in conjunction with 
systemic administration of Vitamin A to treat xerophthalmia. This 
discussion does not indicate that topically applied retinoids alone would 
be effective in the treatment of dry eye disorders and as ocular 
lubricants. 
The use of topically applied retinoids to promote healing of corneal wounds 
is discussed in the following article: Ubels, et al, "Healing of 
Experimental Corneal Wounds Treated with Topically Applied Retinoids", 
American Journal of Ophthalmology, Vol. 95, pages 353-358 (1983). This 
discussion indicates that the retinoids were dissolved in ethanol and then 
combined with corn oil. The final formulations are described as solutions 
which contain "not more than 2% ethanol in corn oil". 
Two recent developments in connection with the use of retinoids in topical 
ophthalmic preparations are described in copending and commonly assigned 
U.S. patent application Ser. Nos. 711,345 and 711,419, both of which were 
filed on Mar. 13, 1985; the entire contents of these copending application 
are incorporated herein by reference. These developments may be more 
particularly described as relating to novel topical ophthalmic 
compositions containing one or more retinoids selected from the group 
consisting of retinol, dehydroretinol, retinal, and retinoic acid and its 
isomers, and to the use of these compositions in the treatment of dry eye 
syndrome and related ophthalmic surface disorders and as ocular 
lubricants. The inventions described and claimed in these copending 
applications differ from the present invention in that, inter alia, the 
compositions of the present invention contain different retinoids which 
are not believed to have been previously utilized in ophthalmic 
preparations. 
Three prior art problems associated with ophthalmic compositions containing 
one or more retinoids have been the poor solubility of retinoids, the 
instability of pharmaceutical compositions containing these compounds, and 
the irritation frequently associated with topical application of these 
compositions to the eye. The present invention is directed to solving 
these and other problems. 
SUMMARY OF THE INVENTION 
A principal object of the present invention is the provision of topical 
ophthalmic compositions which are useful in treating the symptoms 
associated with dry eye syndrome and related ophthalmic surface disorders, 
and which have a topical ocular lubricating effect. 
Another object of the present invention is the provision of a method for 
treating dry eye syndrome and related ophthalmic surface disorders and a 
method of providing topical lubrication to the eye. 
The foregoing objects and other general objects of the present invention 
are satisfied by the provision of topical ophthalmic compositions 
comprising an effective amount of one or more retinoids selected from the 
group consisting of near and remote analogues and functional derivatives 
of retinoic acid which may be biotransformed into an active form, and a 
pharmaceutically acceptable ophthalmic vehicle. The present invention also 
provides a method of treating dry eye syndrome and related ophthalmic 
surface disorders and a method of providing topical lubrication to the eye 
utilizing such compositions. 
DETAILED DESCRIPTION OF THE INVENTION 
The topical ophthalmic compositions of the present invention contain an 
effective amount of one or more retinoids as a principal active 
ingredient. The specific retinoid compounds which may be utilized in the 
ophthalmic compositions of the present invention include near and remote 
analogues and functional derivatives of retinoic acid which may be 
biotransformed into the active form of the retinoid. Such compounds are 
described in the following U.S. Pat. Nos.: 4,395,575; 4,335,248; 
4,299,995; 4,231,944; 4,216,312; and 4,171,318. The contents of these 
patents relating to the structure, synthesis and physical properties of 
these compounds are incorporated herein by reference. Any references to 
the term "retinoid" or variations thereof throughout the remainder of this 
specification are intended to include all such compounds, as well as all 
pharmaceutically acceptable salts of these compounds. 
The preferred retinoids include those of formula: 
##STR1## 
wherein: 
R.sub.1 and R.sub.2 are selected from hydrogen and fluorine, provided that 
if one of R.sub.1 and R.sub.2 is fluorine the other is hydrogen; 
R.sub.3 is selected from formyl, hydroxymethyl, alkoxymethyl, carboxyl, 
alkoxycarbonyl, carbamoyl, mono(lower alkyl)-carbamoyl and di(lower 
alkyl)-carbamoyl; and 
X is selected from 
##STR2## 
wherein: 
at least one of R.sub.4, R.sub.5 and R.sub.7 is halogen and the other are 
hydrogen or lower alkyl; 
R.sub.6 is selected from lower alkyl and lower alkoxy; 
R.sub.8 and R.sub.10 are each lower alkyl; and 
R.sub.9 is selected from hydrogen and lower alkyl, or pharmaceutically 
acceptable salts thereof; and those of formula: 
##STR3## 
wherein: 
A is selected from --CH.sub.2 OH and --CHO; and 
X is selected from 
##STR4## 
wherein: 
at least one of R.sub.4, R.sub.5 and R.sub.7 is halogen and the others are 
hydrogen or lower alkyl; 
R.sub.6 is lower alkyl or lower alkoxy; 
R.sub.8 and R.sub.11 each are lower alkyl; 
R.sub.9 is hydrogen or lower alkyl; and 
R.sub.10 is oxygen or sulphur, or pharmaceutically acceptable salts 
thereof. 
The retinoids are preferably contained in the preparations of the present 
invention in an amount of from about 0.00001% to about 0.01% by weight, 
more preferably in an amount of from about 0.00001% to about 0.001% by 
weight. It has been discovered that even very low concentrations of 
retinoids in these ranges are effective in treating dry eye syndrome and 
providing ocular lubrication. The surprising effectiveness of such low 
concentrations is significant, because at these concentrations the 
incidence of patient complaints of ocular irritation attributable to the 
topical application of retinoids to the eye is expected to be much less. 
The compositions of the present invention comprise one or more retinoids in 
combination with a pharmaceutically acceptable ophthalmic vehicle. 
Suitable ophthalmic vehicles include the following classes of vehicles: 
substantially nonaqueous liquid vehicles; substantially nonaqueous 
semisolid vehicles; solid vehicles and devices; aerosol vehicles; liquid 
and semisolid vehicles containing oil or lipid material and a substantial 
amount of water in the form of a dispersion or mixture; and substantially 
aqueous vehicles. These vehicles are described in greater detail below. 
The first class of vehicles is made up of substantially nonaqueous liquid 
vehicles. These vehicles may contain one or more of the above-described 
retinoids either dissolved or suspended therein, preferably dissolved 
therein. The specific vehicles of this class include: vegetable and 
mineral oils, such as, liquid petrolatum, corn oil, castor oil, sesame 
oil, peanut oil, and so on; triglycerides, such as the capric/caprylic 
triglycerides commonly used in foods and cosmetics; liquid lanolin and 
lanolin derivatives; perfluorohydrocarbons; and combinations of the 
foregoing vehicles. 
The second class of vehicles is made up of substantially nonaqueous 
semisolid vehicles, such as ointments. The retinoids may be suspended or 
dissolved in such vehicles. Specific examples of suitable vehicles in this 
class include: various types of petrolatum, such as white, yellow, red and 
so on; lanolin and lanolin derivatives; gelled mineral oil having a 
hydrocarbon base, such as PLASTIBASE.TM.; petrolatum and ethylene 
carbonate mixtures; petrolatum in combination with surfactants and 
polyglycol, such as polyoxyl 40 stearate and polyethylene glycol; and 
combinations of the foregoing vehicles. These vehicles may be combined 
with oils and/or waxes to vary consistency and enhance retinoid 
solubility. 
The third class of vehicles is made up of solid vehicles or devices. 
Examples of such vehicles include non-erodible devices which are inserted 
into the conjunctival sac of the eye and later removed, such as the 
Alza-type diffusion or osmotic pressure controlled polymer membranes; and 
bioerodible polymers which do not have to be removed from the conjunctival 
sac, such as essentially anhydrous but water soluble polymers and resins 
(e.g., celluloses, polycarboxylic acids, and so on). 
The fourth class of vehicles is made up of aerosols, wherein the retinoids 
are suspended or dissolved in a suitable gas or liquid propellant, such as 
Propellants 11 and 12, and are delivered via a metered-type valve. 
The fifth class of vehicles is made up of liquid and semisolid vehicles 
which comprise oil or lipid material and a substantial amount of water in 
the form of a dispersion or mixture. Examples of such vehicles include: 
phospholipid dispersions, liquid or semisolid water-in-oil emulsions, 
liquid or semisolid oil-in-water emulsions, and mixtures of the above. 
Ophthalmic vehicles containing a phospholipid emulsifying agent are 
described in copending and commonly assigned U.S. patent application Ser. 
No. 711,550, filed Mar. 13, 1985; the entire contents of this copending 
application are incorporated herein by reference. The vehicles described 
in this copending application represent the preferred vehicles of this 
class. 
The sixth class of vehicles is made up of substantially aqueous vehicles. 
The vehicles of this class include: aqueous solutions which optionally 
contain cosolvents such as glycols and surfactants; aqueous solutions of 
the type just described which further comprise viscosity building agents, 
such as methylcellulose, polyvinyl alcohol (PVA), Carbopol, and so on; and 
medium to high viscosity polymer-based gels which increase the ocular 
residence time of the vehicle, such as gels based on Carbopol, 
cellulosics, and combinations thereof. The preferred vehicles of this 
class are based on polyanionic polymers; such vehicles are described in 
greater detail in the above-cited U.S. patent application Ser. Nos. 
700,861 and 695,364, the contents of which have been incorporated herein 
by reference. 
The only limitations with respect to the use of particular ophthalmic 
vehicles are that these vehicles be compatible with the retinoids 
contained therein and facilitate the above-described utility of the 
present formulations in treating dry eye syndrome and related ophthalmic 
surface disorders and providing topical ocular lubrication. 
The stability of the retinoids contained in the compositions of the present 
invention is generally enhanced when antioxidants and/or opaquing agents 
are added to the preparations. It is therefore preferred that such 
stabilizing agents be added to the preparations. The compositions of the 
present invention preferably contain an antioxidant to protect the 
retinoid component of the compositions from oxidative degradation. 
Examples of suitable antioxidants include: propyl gallate, hydroquinone, 
butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl 
palmitate, acetyl cysteine, ascorbic acid, nordihydorguaiaretic acid 
(NDGA), sodium bisulfite, and combinations thereof. The preferred 
antioxidants are propyl gallate, BHA, BHT and hydroquinone, with propyl 
gallate being particularly preferred. Such antioxidants are typically 
employed in an amount of 0.0005% to 1.0% by weight. The compositions of 
the present invention may also require an opaquing agent to protect the 
retinoid component from photolytic deactivation. Examples of suitable 
opaquing agents include: titanium dioxide and silicon dioxide. Such 
opaquing agents are typically employed in an amount of 0.01% to 1.0% by 
weight. 
The compositions of the present invention may also include conventional 
ingredients such as neutralizing agents and tonicity agents, as described 
in more detail below. 
The compositions of the present invention which utilize polyanionic 
polymers as the vehicle preferably also contain a polymer stabilizing 
agent. The preferred stabilizing agents are polyols. These agents are 
utilized in an amount of from about 0.2% to 5% by weight. Representative 
examples of such polyols include: mannitol, sorbitol, glycerol, sucrose, 
related sugars, and the like. An especially preferred stabilizing agent is 
mannitol at a concentration of from 0.2% to 5% by weight. 
Ophthalmic products are packaged in multiple use containers as a general 
rule. Preservatives may be included in the preparations of the present 
invention to prevent contamination of the preparations when they are 
exposed to microorganisms during use. Examples of suitable preservatives 
include: benzalkonium chloride, thimerosal, chlorobutanol, chlorhexidine, 
methylparaben, propylparaben, phenylethyl alcohol, sorbic acid, Onamer M 
(Onamer M is available from Onyx Chemical Company, Jersey City, N.J.), 
other agents known to those skilled in the art, and combinations thereof. 
Such preservatives are typically employed in an amount of from about 
0.0005% to 1.0% by weight. If no preservative is desired, the preparations 
may be sterile packaged in unit-of-use containers. With respect to the use 
of Onamer M, the contents of commonly assigned U.S. Pat. No. 4,407,791 are 
incorporated herein by reference. 
The compositions of the present invention which utilize substantially 
aqueous vehicles may be neutralized to the desired pH with basic chemicals 
such as sodium hydroxide, ammonium hydroxide, ethanolamine, urea, and 
selected amines. Mineral acids such as hydrochloric, phosphoric or 
sulfuric may be used to adjust pH toward acidity. The preferred pH range 
is from 4.5 to 8.5. The tonicity of such compositions can be adjusted to 
either hypotonicity, isotonicity or hypertonicity relative to normal tears 
by use of generally used materials known to the art. Sodium chloride and 
mannitol are preferred tonicity agents. 
The mechanism of action which explains the utility of retinoids in the 
compositions of the present invention is not clear at this time. However, 
it has been found that the retinoids are effective in reversing 
keratinization and enhancing normal reepithelialization of the cornea. 
The compositions of the present invention are useful as ocular lubricants 
and in the treatment of dry eye syndrome and related ophthalmic surface 
disorders. The dosage regimen utilized with the liquid preparations of the 
present invention is typically one or two drops dispensed from a standard 
ophthalmic dropping device, such as, glass or plastic dropping pipets or 
plastic bottles fitted with a dropper orifice. Individual drops are within 
the range of 5 to 75 mg. The drops are placed onto the corneal or sclera 
surface or into the lower conjunctival sac. The dosage regimen utilized 
with the solid and semisolid preparations of the present invention is 
typically 5-75 mg, preferably 25-50 mg, placed into the lower conjunctival 
sac of the affected eye. Frequency of dosing is variably dependent upon 
the severity of the condition, but will typically be one to four times per 
day. 
The compositions of the present invention contain an effective amount of 
retinoid to be dosed only at intervals sufficient to maintain the desired 
therapeutic effect. The dose and frequency will be critical to prevent a 
toxic effect. However, there may be a preferred dosage regimen wherein the 
retinoid provides remission and is no longer required or is only required 
on a periodic prophylactic basis. It may be necessary in some cases to 
provide a separate product to dose the eye in between doses of retinoid so 
as to maintain the corneal epithelium in a hydrated state and provide 
additional lubrication, thereby reducing irritation and discomfort and 
enhancing tear film stability. This adjunctive product must be formulated 
so as to provide these beneficial effects while at the same time 
minimizing any potential toxicity to the somewhat compromised epithelial 
cells which could result from the usual preservatives contained in 
existing artificial tear products. It is therefore preferred to provide an 
adjunctive product in a sterile form but with no preservative. Another 
preferred method of providing the desired adjunctive product would be to 
use a low concentration of a preservative agent which has little or no 
surface activity, for example, a polyquat such as Onamer-M or similar 
polyquats. Onamer-M at a concentration of 0.001 wt. % is an effective 
preservative yet has almost no effect on the corneal epithelial cells. The 
adjunctive product would contain lubricating and mucomimetic polymers such 
as methylcellulose, dextran, polyvinylalcohol, polyvinylpyrrolidone, 
polyethylene glycol, carbomer, polyox, and particularly combinations 
thereof. These products may be dosed as frequently as required without any 
concern for adverse effects. 
The following Examples are intended to further illustrate, but not to 
limit, the compositions of the present invention. The term "Retinoid" in 
these Examples is intended to represent any of the retinoids identified 
above. All percentages are by weight based on the total weight of the 
respective compositions.

EXAMPLE 1 
The following formulation further illustrates the compositions of the 
present invention which utilize substantially nonaqueous liquid vehicles. 
______________________________________ 
Component Wt. % 
______________________________________ 
Retinoid 0.0005 
Methylparaben 0.05 
Propylparaben 0.01 
Propyl Gallate 0.05 
Liquid Lanolin (anhydrous) 
3.0 
Corn Oil q.s. 100 
______________________________________ 
This composition may be prepared as follows. First, the lanolin and corn 
oil are combined and heated to a temperature of 40.degree.-45.degree. C. 
to form a liquid mixture. The remaining components are then dissolved in 
this liquid mixture. The resulting solution, while under nitrogen 
pressure, is then passed through a sterilizing membrane filter which is 
compatible with nonaqueous liquids and has been previously sterilized by 
means of dry heat. The sterilized solution is then collected in a sterile 
container. 
EXAMPLE 2 
The following formulation further illustrates the compositions of the 
present invention which utilize semisolid vehicles. 
______________________________________ 
Component Wt. % 
______________________________________ 
Retinoid 0.005 
Propyl Gallate 0.05 
Methylparaben 0.05 
Propylparaben 0.01 
Anhydrous Lanolin 3.0 
Corn Oil 20.0 
White Petrolatum q.s. 100 
______________________________________ 
This composition may be prepared by dissolving the propyl gallate in the 
corn oil at 90.degree. C. and dissolving the methylparaben and 
propylparaben in the lanolin at 90.degree. C. The two resulting solutions 
are then combined to form a single solution. The retinoid is then 
dissolved in this solution at a temperature of 70.degree. C. or higher. 
The retinoid-containing solution is then combined with the white 
petrolatum at 90.degree. C. to form the final product. Sterilization of 
the product may be achieved by filtration through a sterilizing membrane 
according to known techniques, such as the techniques described in Example 
1 above. 
EXAMPLE 3 
The following formulation further illustrates the compositions of the 
present invention which utilize a bioerodible solid vehicle. 
______________________________________ 
Component Wt. % 
______________________________________ 
Microfine Retinoid Particles 
0.005 
Hydroxyethylcellulose 
49.95 
Carbopol 934P 50.0 
______________________________________ 
This composition may be prepared as follows. The retinoid is first 
sterilized by dissolving it in a suitable solvent, such as diethyl ether, 
and filtering the resulting solution through a solvent-inert sterilizing 
membrane. Sterilized retinoid crystals are then recovered from sterilized 
ethanol. The dried crystals are subjected to an aseptic particle size 
reduction treatment so that 90% or more of the resulting microfine 
particles have a maximum dimension (i.e., diameter) of less than 10 
microns. These microfine retinoid particles are then aseptically mixed 
with a sterile, anhydrous powder consisting of an approximately 50:50 
mixture of hydroexethylcellulose and Carbopol 934P. The resulting powder 
mixture is then compressed using a Carver press to form a rod-shaped 
ocular insert. A small amount of a plasticizer, such as polyethylene 
glycol or polypropylene glycol, may optionally be added to the 
above-described powders to improve cohesion of the powders. 
EXAMPLE 4 
The following formulation further illustrates the compositions of the 
present invention which utilize an aerosol vehicle. 
______________________________________ 
Component Wt. % 
______________________________________ 
Microfine Retinoid Particles 
0.0001 
(at least 90% of which have a 
maximum dimension of 10 microns 
or less) 
Propellant (a mixture of Propellants 
99.9 
11 and 12 in a ratio of 65:35) 
______________________________________ 
This composition may be prepared by placing the above components into a 
Medihaler.TM. dispenser having a Riker metered valve and an eyecup. 
EXAMPLE 5 
The following formulation further illustrates the compositions of the 
present invention which utilize a liquid or semisolid vehicle comprising 
oil or lipid material and a substantial amount of water in the form of a 
dispersion mixture. 
______________________________________ 
Component Wt. % 
______________________________________ 
Retinoid 0.0005 
Corn Oil 20.0 
Phospholipid (purified 
10.0 
lecithin) 
Propyl Gallate 0.05 
Methylparaben 0.05 
Propylparaben 0.01 
Hydroxyethylcellulose 
2.0 
Purified water q.s. 100 
______________________________________ 
This composition may be prepared by heating the corn oil to 
70.degree.-90.degree. C. and then dissolving the retinoid, the parabens 
and the propyl gallate therein. The resulting solution is cooled to about 
40.degree. C., and the powdered lecithin is then dispersed therein to form 
an oil mixture. A 2% (w/v) solution of hydroxyethylcellulose in water is 
then slowly added to this mixture under high shear agitation to form a 
uniform dispersion of the oil mixture in the hydroxyethylcellulose 
solution. This composition must be shaken well before use. 
EXAMPLE 6 
The following formulation further illustrates the compositions of the 
present invention which utilize substantially aqueous vehicles. 
______________________________________ 
Component Wt. % 
______________________________________ 
Retinoid 0.001 
Polyethylene Glycol 300 
15.0 
Polyoxyl 40 Stearate 
5.0 
Chlorobutanol 0.5 
Povidone 3.0 
Purified water q.s. 100 
______________________________________ 
This composition may be prepared by dissolving the povidone in water and 
then dissolving the chlorobutanol in this solution, followed by addition 
of the polyethylene glycol 300 and polyoxyl 40 stearate. The retinoid is 
then dissolved in this solution, and the resulting solution is then 
sterilized by means of appropriate filtration. 
The present invention has been described above in connection with certain 
preferred embodiments. However, as obvious variations thereon will become 
apparent to those skilled in the art, the invention is not to be 
considered as limited thereto.