AU671374B2 - Use of certain anionic surfactants to enhance antimicrobial effectiveness of ophthalmic compositions - Google Patents

Description

AUSTRALIA

Patents Act 1990 Alcon Laboratories, Inc.

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Invention Title: "Use of certain anionic surfactants to enhance antimicrobial effectiveness of ophthalmic compositions" The following statement is a full description of this invention including the best method of performing it known to us:-

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s Backaround of the Invention The present invention relates generally to ophthalmic compositions. In particular, the present invention relates to the use of certain anionic surfactants, particularly modified sarcosinates and lactylates, to prevent or to reduce binding of the antimicrobial components of ophthalmic compositions to oth6r components contained therein, thereby improving the antimicrobial efficacy of such compositions.

In recent years, a number of ophthalmic compositions have been introduced which contain a variety of components, such as carboxyvinyl polymers Carbopol®), ion exchange resins Amberlite"), or other large polyelectrolytes, is which provide sustained release of the ophthalmic agent(s), as well as increased patient comfort. Such compositions are described, for example, in US 4,911,920 (Jani et 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 molecules present in the formulations, resulting in loss of antimicrobial effectiveness.

Sarcosinate surfactants are composed of acylated sarcosines. Sarcosine

(CH

3

-NH-CH

2 -COOH) is an amino acid derivative produced in ith body for the synthesis of glycine (NH,-CH 2 -COOH), a basic amino acid. 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 f their I_ _I 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, U.S. Patent Application Serial No. 07/707,308 s filed March 1, 1985 (Schmidt et assigned to Procter Gamble, mentions sodium lauroyl sarcosinate as the mild anionic surfactant utilized in an aerosol skincleansing and moisturizer mousse. Applicants are not aware of any ophthalmic use of these types of surfactants.

Summary of the Invention It has now surprisingly been found that the inclusion of certain anionic S surfactants, particularly modified sarcosinates and lactylates, in the comfortable, sustained release compositions described above significantly reduces the abovecited binding problem. That is, addition of certain anionic surfactants to some commonly utilized ophthalmic compositions substantially enhances the antimicrobial efficacy of such compositions. 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 result in the release of the bound preservative by the formation of a loose and reversible surfactant-preservative complex, which has antimicrobial effectiveness.

The compositions of the present invention have improved preservative efficacy but retain the desired characteristics of comfort and sustained release of the active ingredient(s). In preferred embodiments, the comfortable, sLstained release compositions of the present invention comprise one or more modified sarcosinates or lactylates, an ophthalmic agent ("active"), a preservative and an ophthalmically acceptable carrier, which may include one or more polyelectrolytes.

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Detailod Description of the Invention Anionic surfactants of the prestmt invention are certain modified sarc'osinates having the following goneric structure- R 1-C-NW-C wherein:- R' ('4.-C27 saturated or unsaturated hydrocarbon: M 11I or a pharmaceutically acceptable salt: and n 2 or 3, In general. in amount of omw or mnore sarcosinates of Structure I are usedl in the compositions of the present invention in an amount between about 0.005 andl about 0,5 percent 1w weight (w(116), preferably between about 0,01 and about 0.2 It is most preferred to use between about 0,03 mid about 0.12 wtl% of one or more of these sarcosinates.

20 Also are coertain lactvlates liuving the following generic structure.

0 H-j 0 0

M

25 C11 CH3 :wherein: R' C 4

-C

27 saturated or unsaturatecd hydrocarbon; N1 1-I or a pharmaceutically acceptable sal'.; and n 2or 3.

Iii op structures I and II, when ji= 1 and NM Na+, R1 is not lauroyl, 111ritolcocoyl orstearoyl anoR S 1t C 4 -CIR alkyl.

VT 0 ~-_I__IC--C111 In general, one or more lactylates of Structure II may be used in the compositions in an amount between about 0.1 and about 5.0 wt%, It is preferred to use an amount between about 0.1 and about 2.0 wt%, and it is most preferred to use about 0.5 wt% of a lactylate of Structure II.

For purposes of this specification, the term "Surfactant" or "Surfactants" shall refer to the compounds of Structure I and/or II, except as otherwise indicated. The preferred Surfactants are sold under the HamposylI Grace), Sarkosyl® and Medialan" (Ciba-Geigy) labels. Especially preferred are: lauroyl sarcosine (Hamposyl" oleoyl sarcosine (Hamposyl® myrstoyl sarcosine (Hamposyl® M), cocoyl sarcosine (Hamposqy1 stearoyl sarcosine (Hamposyl® pelargodoyl sarcosine (Hamposyl P) and sodium capryl lactylate (Pationic® 122A).

The Surfactants can be used in any ophthalmic compositions containing cationic antimicrobials which also contain polyelectrolytes such as high molecular S weight, anionic mucomimetic polymers carboxyvinyl polymers such as Carbopol"), polystyrene sulfonic acid polymers, cationic exchange resins Amberlite" or Dowex®), or the like. Examples of suitable polyelectrolytes are detailed below.

The high molecular weight, anionic mucomimetic polymers useful in the present invention 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. The gels which form during preparation of ophthalmic polymer dispersions have a viscosity between about 1,000 to about 300,000 centipoise (cps). Suitable polymers are carboxyvinyl polymers, preferably those called Carbomers, Carbopol" (B.F.

Goodrich Co., Cleveland, Ohio). Specifically preferred are Carbopol® 934P, Carbopol® 974P and Carbopol" 940. Other suitable gelling polymers include: alginates, carrageenan, natural gumar (xanthan, karaya and tragacanth) and carboxy methyl cellulose. Such polymers will typically be employed in an amount between about 0.05 and about 8.0 wt%, depending on the desired viscosity of the composition. Pourable liquid compositions generally comprise an amount of the polymer between about 0.05 and about 2.0 wt%.

The cation exchange resins useful in the present invention are characterized s 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, Pennsylvania) under the name Amberlite® and from Dow Chemical Co. (Midland, Michigan) under the name Dowex®. The average particle size of the commercially available forms of the resins is about 40 to 150 microns. ,As the'particle size of the resin is critical, such commercially available particles are most conveniently reduced to a particle size range of about 1.0 to 25 microns by ball milling, according to known techniques. At least 95% of the resulting spheroidal particles must have a diameter less than 20 microns. The ion exchange resins will typically is be present in an amount between about 0.05 to about 10,0 wt% and will have an average particle size diameter between about 1 to about 20 microns.

These anionic mucomimetic polymers and cation exchange resins are discussed in greater detail in U.S. 4,911,920 issued March 27, 1990. The entire contents of that patent are hereby incorporated by reference herein.

ftS ~I I I I- The polystyrene sulfonic acid polymers (and their salts) useful in the compositions of the present invention have the following formula:

R

H

2

C-C

Si I so, I- xII

III

wherein: R H or CH 3 and X an integer such that the molecular weight of the polystyrene sulfonic acid polymer may vary from about 10,000 to 1.6 million.

n the preferred polystyrene sulfonic acids of Structure III, R H and the molecular weight is between about 500,000 to about 1,000,000, preferably about 600,000.

The polystyrene sulfonic acid polymers of Structure III are used in the compositions of the present invention at a concentration less than about 8.0 by weight preferably less than about 5.0 wt%.

The active ingredient or ingredients which can be included in the compositions of the present invention include all ophthalmic agents which can be topically applied. Such ophthalmic agents include (but are not limited to): glaucoma agents, such as beta-blockers betaxolol and timolol), muscarinics pilocarpine) and carbonic anhydrase inhibitors acetazolamide, methazolamide and ethoxzolamide); dopaminergic agonists and antagonists; post-surgical ,-2 agonists, such as para-amino clonidine (aiso known as apraclonidine); antiinfectives, such as ciprofloxacin; non-steroidal and steroidal anti-inflammatories, such as suprofen, ketorolac and tetrahydrocortisol; prostaglandins; proteins; growth 6 factors, such as EGF; and anti-allergics. Compositions of the present invention may also include combinations of ophthalmic agents.

The compositions of the present invention can also include other components, for example, ophthalmically acceptable buffers, preservatives, and s tonicity agents. As will be appreciated by those skilled in the art, the compositions may be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, gels and erodible solid ocular inserts.

The following examples are presented to illustrate further various aspects of S' the present invention, but are not intended to limit the scope of the invention in any respect.

EXAMPLE I Ingredient Betaxolol HCI Amberlite® IRP-69 Carbopol" 934P Hamposyl' L Boric Acid Mannitol

EDTA

BAC

NaOH and/or HCI Purified Water Percent (w/w) 0.28 5% xs 0.25 0.2 0.03 0.6 0.01 0.01 10% xs q.s. to pH 6.6 q.s. to 100 Preparation: To a solution of 0.29 grams of betaxolol HCI in 50 milliliters of purified water was added 0.250 g of Amberlite® IRP-69. The suspension was stirred for 12 hrs, at which time 10 ml of 2% Carbopol® 934P slurry, 4.5 g of ~eslc~ mannitol, 0.6 g of boric acid, 0.01 g of EDTA and 1.1 ml of 1% BAC solution were added with continuous stirring. Batch weight was brought to 70 g with purified water and pH was adjusted to 7.6 0.2 with sodium hydroxide.

The suspension was autoclaved for 30 minutes, and .hen 3 ml of 1% sterile s filtered Hamposyl® L solution was added aseptically. Formulation batch weight was then brought to 100 g with sterile purified water and final pH was adjusted to 7.6, as necessary.

EXAMPLE 2 Ingredient Percent (w/w) .p Timolol Maleate 0.34 Amberlite® IRP-69 0.25 Carbopol® 934P 0.2 Mannitol SHamposyl" L 0.09 EDTA 0.01 BAC 0.01 NaOH and/or HCI q.s. to pH Purified Water q.s. to 100 Preparation: To a solution of 0.34 g of timolol maleate in 50 g of purified water was added 0.25 g of Amberlite® IRP-69. The suspension was stirred for 12 hrs, at which time 10 ml of 2% Carbopol" 934P slurry, 4.5 g of mannitol, 1.0 ml of 1% EDTA solution and 1.1 ml of 1% BAC solution were added with continuous stirring.

Batch weight was brought to 80 g with purified water and pH was adjusted to with sodium hydroxide and the suspension was autoclaved for 30 minutes. At that time, 9 ml of 1% sterile filtered Hamposyl® L solution was added aseptically.

Formulation batch weight was then brought to 100 g with sterile purified water and pH was adjusted, if needed, to EXAMPLE 3

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Ingredient Betaxolol HCI Pilocarpine HCI Amberlite® IRP-69 Carbopol® 934 P Boric Acid Mannitol Hamposyl® L

EDTA

BAC

NaOH and/or HCI Purified Water Percent (w/w) 0.28 1.75 0.25 0.4 0.08 1.76 0.03 0.01 0.01 q.s. to pH q.s.to 100 Preparation: A) Betaxolol Suspension: To a solution of 0.294 g of betaxolol HCI in 20 ml of purified water was added 0.250 g of Amberlite IRP-69. The suspension was stirred for a minimum of 12 hrs, at which time 20.0 g of Carbopol" 934P slurry, 1.76 g of mannitol, 0.08 g of boric acid, 0.01 g of EDTA, and 1.1 g of 1% BAC solution were added with continuous stirring. Batch weight was adjusted to 65 g with purified water and pH was adjusted to 8.0 0.2 with sodium hydroxide. The formulation was autoclaved for 30 minutes, and the suspension was allowed to cool to room temperature under stirring. Final batch weight was brought to 80 g with purified water under aseptic conditions and pH was adjusted to 8.0, as necessary.

B) Pilocarpine Solution: In another container, 1.838 g of pilocarpine HCI was dissolved in 10 ml of purified water and pH of the solution was.adjusted to

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0.2 with sodium hydroxide. This solution was sterile filtered through a 0.2p filter and 3 ml of 1% sterile filtered Hamposyl® L solution was added aseptically to the pilocarpine solution. Batch weight of the final formulation was brought to 20 g and pH was adjusted to 5.0, as necessary.

s When reconstituted together, Parts A and B provide the composition of Example 3.

EXAMPLE 4 10 *o o Ingredient Betaxolol HCI Dipivefrin HCI Amberlite® IRP-69 Carbopol® 934P Boric Acid Mannitol Hamposyl® L

EDTA

Sodium Metabisulfite

BAC

NaOH and/or HCI Purified Water Percent (w/w) 0.28 0.1 0.25 0.35 1.25 0.06 0.01 0.04 0.01 q.s. to pH q.s. to 100 Preparation: A) Betaxolol Susension: To a solution of 0.28 g of betaxolol HCI in 20 ml of purified water was added 0.250 g of Amberlite" IRP-69 under continuous stirring for a minimum of 12 hours. Carbopol® 934P slurry (0.35 g) was added and stirred well, then 0.5 g of mannitol, 0.01 g of EDTA and 1.1 g of 1% BAC solution were added with continuous stirring. Boric acid (1.25 g) was then added with stirring until dissolved. Batch weight was brought to 40 g with purified water and pH was ~II~RII~l 1 adjusted to 7.0 with sodium hydroxide, and the formulation was autoclaved for minutes. The Hamposyl" L sterile solution) was then added to the solution with continuous stirring. Batch weight was brought to 50 g with purified water and pH was adjusted, if needed, to B) Dipivefrin Solution: To a solution of 0.11 g of dipivefrin HCI in 30 ml of purified water was added 0.04 g of sodium metabisulfite with continuous stirring.

The formulation pH was adjusted to 3.2 0.2 with sodium hydroxide, the batch weight was brought to 50 g with sterile purified water, and the formulation sterile filtered.

When reconstituted together, Parts A and B provide the composition of Example 4.

EXAMPLE Ingredient Percent (w/w) Pilocarpine HCI 4.0 Carbopol" 940P EDTA 0.01 Hamposyl L 0.12 BAC 0.008 NaOH and/or HCI q.s. to pH 4.8 Purified Water q.s. to 100 Preparation: To a solution of 4.4 g of pilocarpine HCI in 15 ml of purified water were added 0.01 g of EDTA and 0.88 g of 1% BAC solution with continuous stirring.

The solution was then sterile filtered, 17.5 g of 2% Carbopol" 940P slurry added and the pH adjusted to 4.8 with sterile sodium hydroxide. At that time, 4 g of 3% sterile Hamposyl" L solution was added with continuous stirring. Batch weight was then brought to 100 g with sterile purified water and pH was adjusted to 4.8, as necessary.

EXAMPLE 6 .io'.

.1g e o go0• Ingredient Ciprofloxacin HCI Polystyrene Sulfonic Acid Hamposyl L Mannitol

BAC

NaOH and/or HCI Purified Water Percent (wlw) 0.35 0.03 3.9 0.01 q.s. to pH q.s. to 100 20 Preparation: To a solution of 0.35 g of ciprofloxacin HCI in 25 ml of purified water was added 40 ml of 5% PSSA (Mw 500,000) solution with stirring. At that time, 3.9 g of mannitol, and 1 ml of 1% BAC solution were added and the pH adjusted to with sodium hydroxide. The solution was then autoclaved for 30 minutes. After autoclaving, 3 ml of 1% sterile filtered Hamposyl® L solution was added, the batch weight brought to 100 g with sterile filtered water, and the final pH was adjusted to 6.0, as necessary.

I_ EXAMPLE 7 s *o10 2 o e* o el i. 20 Ingredient Apraclonidine HCI Amberliteo IRP-69 Carbopol® 934P Mannitol Hamposyl® L

EDTA

BAC

NaOH and/or HCI Purified Water Percent (w/w) 0,293 0.25 0.2 0.18 0.01 0.01 10% xs q.s. to pH 7.4 q.s. to 100 Preparation: To a solution of 0.293 g of apraclonidine in 30 ml of purified water was added 0.25 g of Amberlite® IRP-69. The suspension was stirred for a minimum of 12 hrs, then 10 g of 2% Carbopol® 934P slurry, 4.0 g of mannitol, 0.01 g of EDTA and 1.1 ml of 1% BAC solution were added to the suspension with continuous stirring. Batch weight was brought to 65 g with purified water, and the pH adjusted to 7.4 0.2 with sodium hydroxide. The suspension was autoclaved for minutes, and then allowed to cool to room temperature with stirring. Upon cooling, 6 ml of 3% sterile filtered Hamposyl® L solution was added to the suspension, the final weight brought to 100 g with sterile filtered purified water, and the final pH adjusted to 7.4 0.2, as necessaiy.

-I EXAMPLE 8 :4 Ingredient Betaxolol HCI Amberliteo IRP-69 Carbopol® 974P Hamposyl 0 Mannitol Boric Acid Edetate Disodium Benzalkonium Chloride NaOH and/or HCI Purified Water Percent 0.28 5% xs 0.25 0.2 0.03 0.6 0.01 0.01 10% xs q,s. to pH 6.6 q.s. to 100% Preparation: The equivalent of 1.250 g of Amberlite® was weighed into a suitable 500 ml container, about 100 ml of purified water was added and the mixture stirred.

Betaxolol HCI (1.47 g) was added to the Amberlite" suspension, and the mixture stirred for 12 hours. A 2% Carbopol" 974P slurry (50 ml) and 20 g of mannitol were dissolved in about 150 ml of purified water, and the mixture filtered through a 0.2 micron filter. Then 3.0 g of boric acid and 0.05 g of EDTA were added under constant stirring. The batch weight was brought to about 400 g with purified water S and the pH was adjusted to 6.6 with sodium hydroxide.

The suspension formulation was autociaved for 45 minutes, then 5 g of a sterile filtered 3% Hamposyl® O solution was aseptically added to the suspension.

After stirring the suspension for 3 hours, 5.5 g of a sterile filtered 1% benzalkonium chloride solution were added, the batch was brought to 500 g with purified water and the final pH was adjusted to 6.6.

The invention in its broader aspects is not limited to the specific details shown and described above. Departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention and without sacrificing its advantages.

Claims (17)

1. 4. The method of claim 3, wherein the final composition concentration of said surfactant is between 0.005 and 0.5 wt%. The method of claim 4, wherein the final composition concentration of said surfactant is between 0.01 and 0.2 wt%.
2. 6. The method of claim 5, wherein the final composition concentration of said surfactant is between 0.03 and 0,12 wt%.
3. 7. The method of claim 2, wherein the surfactant comprises a compound of formula II.
4. 8. The method of claim 7, wherein the final composition concentration of said surfactant is between 0.1 and 5.0 wt%.
5. 9. The method of claim 8, wherein the final composition concentration of said surfactant is between 0,1 and 2.0 wt%. The method of claim 9, wherein the final composition concentration 20 of said surfactant is about 0,5 wt%.
6. 11. The method of claim 1, wherein said surfactant is selected from the group consisting of lauroyl sarcosine, oleoyl sarcosine, myrstoyl sarcosine, c' cocoyl sarcosine, stearoyl sarcosine, pelargodoyl sarcosine and sodium 25 capryl lactylate. i 12. The method of claim 1, wherein said cationic antimicrobial comprises benzalkonium chloride, 30 13. The method of claim 1, wherein said polyelectrolyte is selected from the group consisting of: carboxyvinyl polymers, polystyrene sulfonic acid polymers and finely divided cationic exchange resins. ~b-
7. 14. The method of claim 13, wherein said polyelectrolyte comprises a carboxyvinyl polymer. The method of claim 13, wherein said polyelectrolyte comprises a polystyrene sulfonic acid polymer of formula: R H C-C- 2C so; x Ill wherein: R H or CH 3 and X an integer such that the molecular weight c, :he polystyrene sufonic acid polymer ma%' from S10,000 to 1.6 million.
8. 16. The method of claim 13, wherein said polyelectrolyte comprises a 1O finely divided cationic exchange resin. 19
9. 17. An ophthalmic composition having enhanced or improved antimicrobial efficacy, said composition comprising a cationic antimicrobial. a polyelectrolyte and an anionic surfactant, wherein said anionic surfactant is selected from the group consisting of: a) a compound of formula: RI-C-N-Cf-C M n wherein: R' C 4 -C,7 saturated or unsaturated hydrocarbon: NI H or a pharmaceutically acceptable salt; and n 1, 2 or 3: and b) a compound of formula: -n o H 0 H 0 1 M CH 3 CH 3 II wherein: R 2 C 4 -C"7 saturated or unsaturated hydrocarbon: M H or a pharmaceutically acceptable salt; and 25 n 1, 2 or 3; provided that in a) and b) when n 1 and M Na RI is not lauroyl, myristoyl. cocoyl or stearoyl and R2 is not C 4 -CI8 alkyl.
10. 18. The composition of claim 17, wherein the final composition concentration of said surfactant is between 0.005 and 5.0 wt%,
11. 19. The composition of claim 17, wherein said surfactant comprises a compound of formula 1,
12. 20. The composition of claim 19. wherein the final composition concentration of said surfactant is between 0,01 and 0.5 wt%. W M I
13. 21. The composition of claim 17, wherein said surfactant comprises a compound of formula II.
14. 22. The composition of claim 21, wherein the final composition concentration of said surfactant is between abot 0.1 and 5.0 wt%.
15. 23. The composition of claim 17, wherein said surfactant is selected from the group consisting of lauroyl sarcosine, oleoyl sarcosine, myrstoyl sarcosine, cocoyl sarcosine, stearoyl sarcosine, pelargodoyl sarcosine and sodium capryl lactylate.
16. 24. The composition of claim 17, wherein the active ingredient comprises 10 a beta-blocker. The composition of claim 24, wherein the beta-blocker is selected from the group consisting of betaxolol and timolol.
17. 26. The composition of claim 17, wherein said polyelectrolyte is selected from the group consisting of: carboxyvinyl polymers, polystyrene sulfonic acid polymers and finely divided cationic exchange resins. DATED THIS 15 day of July 1994 Alcon Laboratories, Inc Patent Attorneys for the Applicant: F B RICE CO -I Abstract of the Disclosure Certain anionic surfactants are used to enhance antimicrobial effectiveness in comfortable, sustained release ophthalmic compositions containing polyelectrolytes, such as carboxyvinyl polymers, polystyrene sulfonic acid polymers and cationic exchange resins, as well as at least one active ingredient. S a *g i b- I