Use of certain anionic amino acid based surfactants to enhance antimicrobial effectiveness of topically administrable pharmaceutical compositions

Anionic amino acid based surfactants are used to enhance antimicrobial effectiveness in topically administrable pharmaceutical compositions containing at least one active ingredient, a cationic preservative and an anionic polyelectrolyte, such as carboxyvinyl polymers, xanthan gum, polystyrene sulfonic acid polymers and cationic exchange resins.

BACKGROUND OF THE INVENTION 
The present invention relates generally to the preservation of 
pharmaceutical compositions. In particular, the present invention relates 
to the use of anionic surfactants, particularly amino acid based 
surfactants, to prevent or to reduce binding of the antimicrobial 
components of topically administrable pharmaceutical compositions to other 
components contained therein, thereby improving the antimicrobial efficacy 
of such compositions. 
In recent years, a number of ophthalmic compositions have been introduced 
that contain a variety of components, such as carboxyvinyl polymers (e.g., 
Carbopol.RTM.), ion exchange resins (e.g., Amberlite.RTM.), or other large 
polyelectrolytes, which provide sustained release of the ophthalmic 
agent(s), as well as increased patient comfort. Such compositions are 
described, for example, in U.S. Pat. No. 4,911,920 (Jani et al.). Although 
these compositions are comfortable and have sustained release 
characteristics, cationic antimicrobials, such as benzalkonium chloride 
(BAC), which are often added as preservatives to such compositions, tend 
to bind to the anionic polyelectrolytes present in the formulations, 
resulting in loss of antimicrobial effectiveness. 
Sarcosinate surfactants are composed of acylated sarcosines. Sarcosine 
(CH.sub.3 --NH--CH.sub.2 --COOH), an amino acid normally found in starfish 
and sea urchins, is chemically related to glycine (NH.sub.2 --CH.sub.2 
--COOH), a basic amino acid in mammals. Common fatty acids and their 
derivatives utilized in the manufacture of sarcosinate surfactants are 
lauric, oleic, and myristic acids and their esters and halides. Because of 
their mildness, sarcosinate surfactants have been utilized in shampoos, 
mouthwashes, skin cleansers, sunscreens, aerosol shaving lathers and other 
personal care products. To date, the main applications of these types of 
surfactants have been in the cosmetic industry. For example, European 
Patent Application No. 0 194 097 (Schmidt et al.), assigned to Procter & 
Gamble, mentions sodium lauroyl sarcosinate as the mild anionic surfactant 
utilized in an aerosol skin-cleansing and moisturizer mousse. 
U.S. Pat. No. 5,520,920 (Castillo, et al.) discloses the use of certain 
modified sarcosinates and lactylates to enhance antimicrobial 
effectiveness of ophthalmic compositions, particularly in the case where 
cationic preservatives otherwise bind to anionic polyelectrolytes. The 
modified sarcosinates have the formula: 
##STR1## 
wherein: R.sup.1 =C.sub.4 -C.sub.27 saturated or unsaturated hydrocarbon; 
M=H or a pharmaceutically acceptable salt; and 
n=1, 2 or 3. 
Representative modified sarcosinates include those sold under the 
Hamposyl.RTM. trade name, such as lauroyl sarcosine (Hamposyl.RTM. L), 
oleoyl sarcosine (Hamposyl.RTM. O), myristoyl sarcosine (Hamposyl.RTM. M), 
cocoyl sarcosine (Hamposyl.RTM. C), stearoyl sarcosine (Hamposyl.RTM. S), 
and pelargodoyl sarcosine (Hamposyl.RTM. P). Representative lactylates 
include sodium capryl lactylate (Pationic.RTM. 122A). 
Additional solutions to the problem of cationic preservative--anionic 
polyelectrolyte binding problem in topically administrable pharmaceutical 
compositions are desirable. 
Anionic amino acid surfactants other than the Hamposyl.RTM. surfactants are 
known and include, for example, those surfactants sold under the 
Amilite.TM. and Amisoft.TM. trade names (Ajinomoto Co., Inc., Tokyo, 
Japan). According to its product brochure, one such surfactant, 
Amilite.TM. GCK-12, is used as a detergent, a foaming agent, an 
emulsifier, a solubilizer and a dispersing agent. Examples of applications 
of Amilite.TM. GCK-12 include cosmetics and toiletries (hair shampoo and 
body wash), face wash (facial washing foam, facial washing creme, facial 
washing liquid and make-up remover), facial soap, toothpaste, bath soap, 
contact lens cleaners and household cleaners. Amisoft.TM. surfactants are 
described as gentle cleansers for the skin and hair. Major applications of 
Amisoft.TM. surfactants include facial and body cleansers, hair shampoos, 
syndet bars, body care and dermatological products. 
SUMMARY OF THE INVENTION 
The present invention provides a method of enhancing the preservative 
efficacy of topically administrable pharmaceutical compositions containing 
an anionic polyelectrolyte and a cationic preservative. According to the 
method of the present invention, an anionic amino acid based surfactant is 
added to the topically administrable pharmaceutical composition. The 
anionic amino acid based surfactant has the formula: 
##STR2## 
wherein: R=C.sub.8 -C.sub.24 saturated or unsaturated hydrocarbon; Y=H, 
(CH.sub.2).sub.4 NH.sub.2 or (CH.sub.2).sub.3 NHC(NH.sub.2)=N.sup.+H.sub.2 
; and 
M.sup.+=H or a pharmaceutically acceptable salt. 
Although the Applicants do not wish to be bound to a particular theory, it 
is believed that the addition of these anionic surfactants to the 
compositions results in the release of the bound cationic preservative 
from the anionic polyelectrolyte by the formation of a loose and 
reversible surfactant-preservative complex. The surfactant-preservative 
complex has antimicrobial effectiveness. Alternatively, the anionic 
surfactants of formula I may themselves possess antimicrobial activity. 
Regardless of the mechanism, the anionic surfactants of the present 
invention improve the preservative efficacy of topically administrable 
pharmaceutical compositions. Accordingly, the present invention also 
relates to topically administrable pharmaceutical compositions containing 
one or more pharmaceutically active agents, an anionic polyelectrolyte, a 
cationic preservative, and one or more of the anionic amino acid based 
surfactants of formula I. 
DETAILED DESCRIPTION OF THE INVENTION 
Unless indicated otherwise, all amounts of composition ingredients 
expressed in percentage terms are expressed as weight/weight. 
The anionic amino acid based surfactants of the present invention can be 
made by known methods and, in some cases, are commercially available. For 
example, Amilite.TM. GCK-12 is commercially available from Ajinomoto Co., 
Inc. (Tokyo, Japan). Amilite.TM. GCK-12 is described by formula I above 
when R is selected to be cocoyl, a coconut oil fatty acid residue; and 
M.sup.+ is K.sup.+ (i.e., potassium cocoyl glycinate). 
Preferred surfactants of formula I include those where R is C.sub.12 
-C.sub.18 saturated or unsaturated hydrocarbon; Y is H; and M.sup.+ is 
selected from the group consisting of H.sup.+ ; Na.sup.+ ; K.sup.+ ; and 
triethanolamine. 
In general, the amount of anionic amino acid based surfactant present in 
the compositions of the present invention is from about 0.001 to about 1%, 
preferably from about 0.01 to about 0.2%. For topical ophthalmic 
preparations, the concentration of the anionic amino acid based surfactant 
should be adjusted, usually in the 0.01 -0.1% range, to minimize patient 
discomfort. 
The compositions of the present invention contain cationic antimicrobials 
and anionic polyelectrolytes. Cationic antimicrobials include quaternary 
ammonium compounds, such as benzalkonium chloride and polyquaternium-1. 
Anionic polyelectrolytes include high molecular weight, anionic 
mucomimetic polymers (e.g., carboxyvinyl polymers such as Carbopol.RTM.), 
polystyrene sulfonic acid polymers, cationic exchange resins (e.g., 
Amberlite.RTM. or Dowex.RTM.), and the like. 
High molecular weight, anionic mucomimetic polymers have a molecular weight 
between about 50,000 and 6 million. The polymers are characterized as 
having carboxylic acid functional groups and preferably contain between 2 
and 7 carbon atoms per functional group. Suitable high molecular weight, 
anionic polymers are carboxyvinyl polymers, preferably those called 
Carbomers, e.g., Carbopol.RTM. (B.F. Goodrich Co., Cleveland, Ohio). 
Specifically preferred are Carbopol.RTM. 934P, Carbopol.RTM. 974P and 
Carbopol.RTM. 940. Other suitable high molecular weight, anionic polymers 
include: alginates, carrageenans, natural gums (xanthan, karaya and 
tragacanth) and carboxy methyl cellulose. Such polymers will typically be 
employed in an amount between about 0.05 and about 6%, depending on the 
desired viscosity of the composition. Pourable liquid compositions 
generally comprise an amount of the polymer between about 0.05 and about 
2%. 
Cation exchange resins are characterized as either strongly acidic, such as 
those having sulfonic acid or sulfuric acid functionality, or weakly 
acidic, such as those having carboxylic acid functionality. Such resins 
are readily available, for example, from Rohm & Haas (Philadelphia, Pa.) 
under the name Amberlite.RTM. and from Dow Chemical Co. (Midland, Mich.) 
under the name Dowex.RTM.. The average particle size of the commercially 
available forms of the resins is about 40 to 150 microns. The particle 
size of the resin is critical for topically administrable ophthalmic 
compositions. Accordingly, for topically administrable ophthalmic 
compositions, commercially available resin particles are reduced by known 
techniques, including ball milling, to a particle size of about 20 .mu.m 
or less such that the average particle size is.ltoreq.10 .mu.m, and are 
preferably reduced to a particle size of about 10 .mu.m or less. Ion 
exchange resins are typically used in an amount from about 0.05 to about 
10%. 
Anionic mucomimetic polymers and cation exchange resins are discussed in 
greater detail in U.S. Pat. No. 4,911,920 issued Mar. 27, 1990, the entire 
contents of which are hereby incorporated by reference herein. 
The polystyrene sulfonic acid polymers (and their salts) useful in the 
compositions of the present invention comprise the following repeating 
unit: 
##STR3## 
wherein: W=H or CH.sub.3 ; and x=an integer such that the molecular weight 
of the polystyrene sulfonic acid polymer is from about 10,000 to 1.6 
million. 
In the preferred polystyrene sulfonic acid polymers of formula I, W=H and 
the molecular weight is between about 500,000 to about 1,000,000, 
preferably about 600,000. If present in the compositions of the present 
invention, the polystyrene sulfonic acid polymers of formula I comprise 
less than about 8%, preferably less than about 5%. 
The active ingredient or ingredients that can be included in the 
compositions of the present invention include all ophthalmic, 
dermatological, otic or nasal agents that can be topically applied. For 
example, such ophthalmic agents include (but are not limited to): 
anti-glaucoma agents, such as beta-blockers (e.g., betaxolol and timolol), 
muscarinics (e.g., pilocarpine), prostaglandins, carbonic anhydrase 
inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide), 
dopaminergic agonists and antagonists, and alpha adrenergic receptor 
agonists, such as para-amino clonidine (also known as apraclonidine) and 
brimonidine; anti-infectives, such as ciprofloxacin; non-steroidal and 
steroidal anti-inflammatories, such as suprofen, ketorolac, dexamethasone, 
rimexolone and tetrahydrocortisol; proteins; growth factors, such as EGF; 
and anti-allergic agents, such as cromolyn sodium, emedastine and 
olopatadine. Compositions of the present invention may also include 
combinations of active ingredients. Most preferred are topically 
administrable ophthalmic compositions. 
The compositions of the present invention can also include other 
components, for example, pharmaceutically acceptable buffers; tonicity 
agents; comfort-enhancing agents; solubilizing aids; pH adjusting agents; 
antioxidants; and stabilizing agents. The compositions may also contain 
additional preservatives (in conjunction with the cationic preservatives 
addressed above). As will be appreciated by those skilled in the art, the 
compositions may be formulated in various dosage forms suitable for 
topical delivery, including solutions, suspensions, emulsions, and gels.