GB1593954A

GB1593954A - Xanthan gum or locust bean gum topical therapeutic compositions

Info

Publication number: GB1593954A
Application number: GB334978A
Authority: GB
Original assignee: American Home Products Corp
Current assignee: Wyeth LLC
Priority date: 1977-01-31
Filing date: 1978-01-27
Publication date: 1981-07-22
Also published as: CA1093467A

Description

(54) XANTHAN GUM OR LOCUST BEAN GUM TOPICAL THERAPEUTIC COMPOSITIONS (71) We, AMERICAN HOME PRODUCTS CORPORATION, a corporation organized and existing under the laws of the State of Delaware, United States of America, of 685, Third Avenue, New York 10017, New York, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to therapeutic compositions comprising gums and more particularly to the use of naturally derived gums as adjuvants in topical therapeutic compositions, especially ophthalmic compositions, to potentiate the miotic response of cholinergic agents, (tor example, echothiophate iodide which is used in treatment of glaucoma). This allows the administration of lower, more effective dosages of said cholinergic agents, thereby alleviating side effects. In a further aspect this invention relates to a drug delivery system that is a gel and is useful for topical applications.

In this application the term "adjuvant" is defined as found in Stedman Medical Dictionary, 22nd Edition as "that which aids or assists; denoting a remedy that is added to a prescription to assist or increase the action of the main ingredient".

The prior art discloses a variety of gums and polymers used as adjuvants in ophthalmic compositions.

For example, C. Rosenblum et al in Arch Ophthal, 77: 234237, 1967, discloses the use of hydroxyethyl cellulose to increase the systemic absorption by ocular tissues of dexamethasone. With drugs such as erythromycin propionate and sulfapyridazine sodium, Y. F. Maichuk, Am. J. Ophthal, 74: 694, 1972 taught the use of polyvinyl alcohol to potentiate their pharmacological response.

Similarly guar gum was found to increase the corneal absorption of tripicamide as reported by Lee et al, J. Pharm. Sci. 63: 721, 1974.

In accordance with the present invention, xanthan gum or locust bean gum is incorporated in topical therapeutic compositions, particularly ophthalmic compositions, to enhance the drug's therapeutic activity thereby allowing a reduction in dosage and a concomitant reduction in toxicity. Compositions containing cholinergic agents, e.g. echothiophate iodide, are particularly preferred.

Accordingly this invention provides a composition for topical administration comprising a topically active drug, a pharmaceutically acceptable liquid vehicle and a naturally derived gum consisting essentially of xanthan gum or locust bean gum in an amount sufficient to potentiate the pharmacological response of the drug, with the proviso that the drug is other than tretinoin when xanthan gum is present.

This invention also provides a composition comprising an ophthalmic drug and a naturally derived gum consisting essentially of 0.01% to 2.5% weight/volume of xanthan gum or locust bean gum in a pharmaceutically acceptable liquid vehicle.

The xanthan gum or locust bean gum, incorporated in the therapeutic compositions, such as ophthalmic solutions of echothiophate iodide, acts as an adjuvant and thus promotes the activity of the drug. The xanthan gum or locust bean gum adjuvant is prepared by dissolving the gum in the solution, i.e. the pharmaceutically acceptable liquid vehicle, followed by dissolution of the echothiophate iodide.

Echothiophate iodide is described in U.S. Patent 2,911,430.

In this application "xanthan gum" means Xanthomonas hydrophilic colloid produced by bacteria of the genus Xanthomonas. Illustrative of such a colloid is the xanthan gum sold under the Keltrol trademark (Kelco Co., Clark, N.Y.). It may be described as a high molecular weight natural carbohydrate, or more specifically polysaccharide. The generic term xanthan gum defines exocellular biopolysaccharides which are produced in a pure culture fermentation process by the microorganism Xanthomonas campestris. Three different monosaccharides are found in the basic structure-mannose, glucose and glucuronic acid (as mixed potassium, sodium and calcium salt). Each repeating block within the polymer contains sixteen sugar units. The linear portion consists of five p, I-m4-linked D glucose units, four p, I,, ,4-linked D-mannose units and four p, I , ) l2-linked D- glucuronic acid units. At C-3 of two glucose units there are mannose branches and at some other position, as yet undetermined, in the repeating unit is a side chain derived from pyruvic acid and glucose i.e. 4,6-O-(carboxyethylidene)-D-glucose.

Each repeating unit contains an average of 3.4 acetyl groups which are believed to be connected at C6 of mannose.

Locust bean gum is a high molecular weight polysaccharide derived from ceratonia siliqua. Chemically, locust bean gum is a galactomannan best illustrated with galactose units located on every fourth man nose unit, with smaller amounts of pentoglycan, protein, cellulose and ash. A detailed description of the composition, physical and chemical properties, preparation, etc. of locust bean gum is given in Industrial Gums (Polysaccharides and Their Derivatives), Academic Press, (1959) at pp. 361-376.

In the compositions of this invention the concentration of xanthan gum or locust bean gum is preferably from 0.01% to 2.5% weight by volume. It will be appreciated that as the concentration of the gum is increased, it is accompanied by an increase in viscosity. Thus, at concentrations of gum above 1.0% and up to 2.5%, a gel like consistency is attained. This gel like consistency permits various topical applications of drug such that the drug is maintained at the site of administration over a longer period than is possible by a liquid composition. By a gel it is meant a colloid in which the disperse phase has combined with the continuous phase to produce a semi-solid such as a jelly. By "gelling agent" is meant an agent which would produce a gel like consistency if used in sufficient quantity. However, the concentration of naturally derived gum used in the composition of this invention need not be such as to produce a gel.

The preferred concentration of xanthan gum or locust bean gum for dropwise ophthalmic applications is from 0.02% to 1.0% weight/volume. When echothiophate iodide, a drug used in the treatment of glaucoma, is the ophthalmic drug incorporated in said gum composition, its concentration can vary from 0.005 to 0.25% weight/volume. An advantage of this invention is that the systemic side effects observed at higher concentrations of echothiophate iodide may be reduced due to the potentiation of the drug's pharmacological response by xanthan gum or locust bean gum thereby permitting the administration of reduced concentrations of drug. Illustratively, it was observed that a composition containing 0.03% echothiophate iodide and 0.2% xanthan gum or locust bean gum potentiated a greater pharmacological response than one containing 0.25, ó echothiophate iodide and no gum.

Potentiation of pharmacologic response was observed to increase with increasing concentrations of xanthan gum or locust bean gum. Also, required or preferred concentrations of gum needed to achieve optimum results will vary from drug to drug. Thus, while with echothiophate iodide a concentration of xanthan gum or locust bean gum from 0.02% to 1.0% is preferred; with the aldose reductase inhibitor, 1,3 - dioxo - 1 - H - benz[de]isoquinoline - 2(3H) - acetic acid a concentration of xanthan gum or locust bean gum from 0.5% to 1.5% is preferred. The xanthan gum or locust bean gum composition has also been found suitable as a vehicle for widely varied concentrations of drug. For example, these compositions have been found suitable for delivering as little as 0.005 weight/volume of echothiophate iodide or as much as 12.0% of Alrestatin. The choice is usually limited only by the desire to incorporate a therapeutically effective dosage of drug within the compositions of this invention.

An advantage of the herein disclosed invention is its superiority as an adjuvant over such previously art known adjuvants as polyvinyl alcohol, hydroxyethyl cellulose, and ethylene oxide polymer as demonstrated in tests conducted with echothiophate iodide. Also, while the compositions of this invention may be prepared inan aqueous solvent, these compositions are also feasible in liquid vehicles containing water and water miscible solvents; thus, it will be appreciated that these compositions are equally well adapted to the delivery of drugs with varying degrees of solubility. By way of illustration, the xanthan gum compositions are stable in the presence of such non-aqueous solvents as ethanol, propylene glycol, 1,3-butanediol, glycerin, sorbitol and the like when such solvents compose up to about 1/2 by volume of the carrier system, i.e. the liquid vehicle comprises 50-100% water. The locust bean gum compositions are stable in the presence of such non-aqueous solvents as ethanol up to 6% volume/volume, propylene glycol up to 25% volume/volume and the like when such solvents are incorporated within the carrier system, i.e. the pharmaceutically acceptable liquid vehicle comprises 75100% water.

The compositions of this invention can be designed by first selecting the drug to be used and the pharmacological response desired. A composition can then be designed to produce that pharmacological response comprising the xanthan gum or locust bean gum adjuvant and the selected drug in a pharmaceutically acceptable liquid vehicle.

Any of the drugs used to treat the eye and surrounding tissues can be incorporated in the ophthalmic compositions of this invention.

Although the use of the xanthan gum or locust bean gum adjuvant has principally been described with respect to drug delivery systems for the administration of ophthalmic drugs, it will be appreciated that each gum may be employed as well in a wide variety of topical bioerodable compositions for administering drugs to the other areas of the body. Thus, the pharmaceutical delivery systems of this invention may be employed to advantage in external and internal erodable topical drug delivery compositions such as, for example, oral cavity, (e.g. buccal) and intranasal preparations. In each instance, the composition employs xanthan gum or locust bean gum in combination with the selected drug and is of a shape or form appropriate for implantation or insertion in the described body tissue or cavities respectively or for application to a particular body area. LH-RH may be administered intranasally.

Accordingly this invention also provides a topical therapeutic composition comprising a naturally derived gum consisting essentially of about 0.01% to about 2.5% weight/volume of locust bean gum or xantahn gum and a therapeutically effective dosage of a drug in a pharmaceutically acceptable liquid vehicle, with the proviso that the drug is other than tretinoin when xanthan gum'is present.

Suitable drugs for use in therapy with the compositions of the invention include antibacterials, such as, bacitracin, chloramphenicol, gentamycin, gramicidin, polymyxin, sulfacetamide, sulfisoxazole, and tetracycline; antiglaucomatous agents, such as acetazolamide, epinephrine and echothiophate iodide; sympathomimetic agents, such as, epinephrine, phenylephrine, cocaine, and ephedrine; parasympatholytics, such as, atropine, homatropine, scopolamine, tropicamide and cyclopentolate; parasympathomimetics, such as carbachol, echothiophate, pilocarpine, and isoflurophate; sympatholytics, such as, dibenamine and tolazoline; anti-inflammatory agents, such as, cortisone, hydrocortisone, prednisolone, prednisone, and dexamethasone, and others, such as antipyrine, antizoline, LH-RH, LH-FSH, and 1,3 - dioxo - lH benz[delisoquinoline - 2(3H) - acetic acid.

The term "drug" as used herein is intended to be interpreted in its broadest sense as including any composition or substance that will produce a pharmacologic response, either at the site of application or at a site remote therefrom.

Additionally, the compositions of the invention may include a variety of additives including preservatives, buffers, electrolytes, antioxidants, stabilisers and pharmaceutically acceptable liquid vehicles as described earlier.

The invention may be illustrated in part through the following examples.

EXAMPLE I Ingredients A B C D E F G H Echothiophate lodide 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g 2.5 g 0.3 g Xanthan Gum - 2.0 g 5.0 g 0.4 g 0.2 g 2.0 g - - Locust Bean Gum - - - g - - - 2.0g Boric Acid, Reagent Grade 0.6 g 0.6 g 0.6 g 0.6 g 06g - 0.6 g Sodium Phosphate Dried 0.26 g 0.26 g 0.26 g 0.26 g 0.26 g - 0.26 g Mannitol l2.Og l2.Og l2.0g 12.0 g 12.0g - 12.0g Chlorbutanol Anhydrous 5.0 g 5.0 g 5.0 g 5.0 g 5.Og g 5.0 g Potassium Acetate 8.0 g 8.0 g 8.0 g 8.0 g 8.0 g - 8.0 g Phenylethyl Alcohol - - - - - 5.0 ml - 5.0 ml Hydrochloric Acid, INq.s.topH3 - - # # # # - # Distilled Water q.s. to IL IL 1L IL IL 1L IL IL These formulations were prepared by dissolving sodium phosphate, boric acid, mannitol, chlorobutanol or phenylethyl alcohol in distilled water; dispersing the gum in the solution; autoclaving the solution at 121 C for 60 minutes; adjusting the solution's pH to 3 where noted and filtering. Then, dissolve echothiophate iodide to prepare the test solution.

Rabbits' eyes were treated with 2 drops of the test solutions of example I and pupillary diameters were measured with a cathetometer. The miotic response intensity was computed by taking the difference in pupillary diameters at zero time and time "T" (i.e. hours after installation) and dividing it by the pupillary diameter at zero time. The table below illustrates the average miotic response for all eyes as a function of hours after installation.

*AMI at the Following Hours After Installation 1 2 3 7 24 25 hour hours hours hours hours hours A 0.02 0.02 0.06 0.04 0.14 0.19 B 0.27 0.37 0.53 0.52 0.25 0.25 C 0.47 0.68 0.74 0.54 0.30 0.32 D 0.17 0.35 0.37 0.27 0.25 0.25 E 0.11 0.16 0.17 0.13 0.19 0.17 F 0.66 0.68 0.69 0.60 0.32 0.33 G 0.19 0.39 0.34 0.24 0.19 0.19 H 0.44 0.53 0.57 0.39 0.28 0.26 By comparing formulations B-E and H with formulation A and G, it is clear that the former group potentiated significantly higher miotic response intensities than those formulations not having xanthan gum or locust bean gum. Thus, it was observed that the dosage level of gum containing formulations can be reduced. It was also observed that the gum containing formulations could be used to deliver a sustained and controlled dosage regimen of echothiophate iodide over a 24 hour period.

EXAMPLE 2 Ingredients I J K L M N Echothiophate Iodide 0.10g 0.10g 0.10g 0.30g 0.30g 0.30g Locust Bean Gum - 2.0 g 5.Og - 3.0 g 5.0 g Boric Acid, Reagent Grade 0.60g - - 0.60g 0.60g 0.60g Sodium Phosphate, Dried 0.26g - - 0.26g 0.26g 0.26g Mannitol l2.Og - - 12.0 g 12.0 g 12.0 g Chlorobutanol, Anhydrous 5.Og g - 5.0 g 5.0 g 5.0 g Potassium Acetate 2.80 g - - 8.0 g - Phenylethyl Alcohol - 5.0 ml 5.0 ml - - - Hydrochloric Acid, 1N q.s. to pH 3 '/, - Distilled Water q.s. to IL 1L 1L IL IL IL Formulations D-G were prepared and evaluated as in Example 1. The table below illustrates the average miotie response intensity for all eyes as a function of hours after instillation.

AMI at the Following Hours After Installation 2 2 3 7 24 25 Hour Hours Hours Hours Hours Hours I 0.03 0.09 0.04 0.02 0.08 0.08 J 0.19 0.33 0.37 0.32 0.17 0.16 K 0.50 0.64 0.58 0.32 0.16 0.05 L 0.01 0.02 0.06 0.05 0.13 0.18 M 0.08 0.18 0.25 0.28 0.17 0.13 N 0.47 0.68 0.73 0.54 0.30 0.32 The tests on formulations I-K were done simultaneously but separately from the tests on formulations L-N which were also run simultaneously. These results indicate, as in Example 1, that locust bean gum containing formulations potentiate significantly higher miotic response intensities than those formulations not having the gum adjuvant. It was observed that as the concentration of gum adjuvant increases, the degree of potentiation also increases. Thus, it was observed that lower concentrations of the drug may be administered and that a sustained and controlled dosage of echothiophate iodide over a 24 hour period is feasible with the use of the gum containing formulation.

EXAMPLE 3 Ingredients O P Q R Pilocarpine Hydrochloride 0.01 g 0.01 g 0.05 g 0.01 g Xanthan Gum - 0.50 g Locust Bean Gum - 0.05 g Boric Acid 1.24 g 1.24 g 1.24 g 1.24 g Potassium Chloride 0.04 g 0.04 g 0.04 g 0.04 g Phenylethyl Alcohol - 0.50 ml 0.50 ml 0.50 ml Sodium Carbonate 2.12% solution in water or 0.lNHCI, q.s. to pH 5.3 V V V V Distilled Water q.s. to 100 ml 100 ml 100 ml 100 ml *Avg. Miotic Response Intensity Formulations containing pilocarpine hydrochloride were prepared as in Example 1.

Rabbits' eyes were treated and tested as in Example 1 and the results are listed in the following table.

AMI at the Following Hours After Installation 0.3 0.7 0.8 1 2 Hours Hours Hours Hours Hours 0 - 0.01 0.01 0.01 - P 0.01 0.09 0.09 0.09 - Q 0.12 0.2 0.19 0.18 0.15 R - 0.01 0.02 0.04 0.03 These results indicated that xanthan gum or locust bean gum potentiates the miotic response of pilocarpine hydrochloride. It therefore appears that the dose of pilocarpine can be reduced when used in combination with xanthan gum or locust bean gum.

EXAMPLE 4 Formulations containing the aldose reductase inhibitor, 1,3 - dioxo - IH bznz(delisoquinoline - 2(3H) - acetic acid, Alrestatin were prepared as in example 1: S T U Alrestatin l2.0g 12.0 g 12.0 g Potassium Hydroxide 3.25 g 3.40 g 3.30 g Xanthan Gum 1.0 g Locust Bean Gum 1.0 Benzalkonium Chloride 17% 0.06 ml 0.06 ml 0.06 ml EDTA acid 0.10g 0.10g 0.10g Potassium Hydroxide q.s. to pH 6 V V V Phenylethyl Alcohol - 1.0 ml 1.0 ml Distilled Water q.s. to 100 ml 100 ml 100 ml Potentiation of the reductase inhibitor was demonstrated by measuring its ocular penetration following installation in the eyes of unanesthesized rabbits, see below: Ocular Penetration of Alrestatin S T U Aqueous Humor (mcg/ml) 8.5 14.2 10.8 Cornea(mcg/ml) 78 173 142 Lens (mcg/ml) 0.5 0.6 0.4 These results illustrate increased ocular penetration in formulations containing xanthan gum or locust bean gum in combination with aldose reductase inhibitor.

EXAMPLE 5 Manufactured as described in Example 1, formulations containing carbachol, 2 - [(Aminocarbonyl)oxy] - N,N,N - trimethylethananinium chloride were prepared.

Formula per 50 ml V W X Carbachol 0.50 g 1.50 g 1.50 g Xanthan Gum 0.25 g 0.25 g Locust Bean Gum - - 0.25 g Phenylethyl alcohol 0.125 ml 0.125 ml 0.125 ml Distilled Water q.s. to 50 ml 50 ml 50 ml The stability of carbachol containing formulations was evaluated and found to be satisfactory.

EXAMPLE 6 A formulation containing polypeptide, gonadorelin also known as luteinizing hormone-releasing hormone (LH-RH) was prepared as in Example I for intranasal application.

LH-RH 1.0 g Locust Bean Gum 0.5 g Phenylethyl Alcohol 0.5 ml Distilled Water q.s. to 100 ml The stability of this LH-RH formulation was evaluated over a one year period and found to be satisfactory.

WHAT WE CLAIM IS: 1. A composition for topical application comprising a topically active drug, a pharmaceutically acceptable liquid vehicle and a naturally derived gum consisting essentially of xanthan gum or locust bean gum in an amount sufficient to potentiate the pharmacological response of the drug, with the proviso that the drug is other than tretinoin when xanthan gum is present.

2. A composition as claimed in Claim 1 wherein the drug is an ophthalmic drug.

3. A therapeutic composition as claimed in Claim I comprising a naturally derived gum consisting essentially of 0.01% to 2.5% weight/volume of locust bean gum or xanthan gum and a therapeutically effective dosage of a drug in a

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. EXAMPLE 4 Formulations containing the aldose reductase inhibitor, 1,3 - dioxo - IH bznz(delisoquinoline - 2(3H) - acetic acid, Alrestatin were prepared as in example 1: S T U Alrestatin l2.0g 12.0 g 12.0 g Potassium Hydroxide 3.25 g 3.40 g 3.30 g Xanthan Gum 1.0 g Locust Bean Gum 1.0 Benzalkonium Chloride 17% 0.06 ml 0.06 ml 0.06 ml EDTA acid 0.10g 0.10g 0.10g Potassium Hydroxide q.s. to pH 6 V V V Phenylethyl Alcohol - 1.0 ml 1.0 ml Distilled Water q.s. to 100 ml 100 ml 100 ml Potentiation of the reductase inhibitor was demonstrated by measuring its ocular penetration following installation in the eyes of unanesthesized rabbits, see below: Ocular Penetration of Alrestatin S T U Aqueous Humor (mcg/ml) 8.5 14.2 10.8 Cornea(mcg/ml) 78 173 142 Lens (mcg/ml) 0.5 0.6 0.4 These results illustrate increased ocular penetration in formulations containing xanthan gum or locust bean gum in combination with aldose reductase inhibitor. EXAMPLE 5 Manufactured as described in Example 1, formulations containing carbachol, 2 - [(Aminocarbonyl)oxy] - N,N,N - trimethylethananinium chloride were prepared. Formula per 50 ml V W X Carbachol 0.50 g 1.50 g 1.50 g Xanthan Gum 0.25 g 0.25 g Locust Bean Gum - - 0.25 g Phenylethyl alcohol 0.125 ml 0.125 ml 0.125 ml Distilled Water q.s. to 50 ml 50 ml 50 ml The stability of carbachol containing formulations was evaluated and found to be satisfactory. EXAMPLE 6 A formulation containing polypeptide, gonadorelin also known as luteinizing hormone-releasing hormone (LH-RH) was prepared as in Example I for intranasal application. LH-RH 1.0 g Locust Bean Gum 0.5 g Phenylethyl Alcohol 0.5 ml Distilled Water q.s. to 100 ml The stability of this LH-RH formulation was evaluated over a one year period and found to be satisfactory. WHAT WE CLAIM IS:

1. A composition for topical application comprising a topically active drug, a pharmaceutically acceptable liquid vehicle and a naturally derived gum consisting essentially of xanthan gum or locust bean gum in an amount sufficient to potentiate the pharmacological response of the drug, with the proviso that the drug is other than tretinoin when xanthan gum is present.

2. A composition as claimed in Claim 1 wherein the drug is an ophthalmic drug.

pharmaceutically acceptable liquid vehicle, with the proviso that the drug is other than tretinoin when xanthan gum is present.

4. A therapeutic composition as claimed in Claim 3 wherein the drug is luteinizing hormone-releasing hormone and the gum is locust bean gum.

5. A gel composition for topical application as claimed in Claim I comprising a naturally derived gum consisting essentially of 1.0% to 2.5% weight/volume of xanthan gum or locust bean gum and a drug in a pharmaceutically acceptable liquid vehicle; said percentage expressed as weight per volume, with the proviso that the drug is other than tretinoin when xanthan gum is present.

6. A composition comprising an ophthalmic drug and a naturally derived gum consisting essentially of 0.01% to 2.5% weight/volume of xanthan gum or locust bean gum in a pharmaceutically acceptable liquid vehicle.

7. A composition according to Claim 6 wherein the concentration of said gum is from 0.02% to 1.0%, said percentages expressed as weight per volume.

8. A composition according to Claim 6 or Claim 7 wherein said ophthalmic drug is echothiophate iodide.

9. A composition according to Claim 6 or Claim 7 wherein said ophthalmic drug is pilocarpine hydrochloride.

10. A composition according to Claim 6 or Claim 7 wherein said ophthalmic drug is carbachol.

11. A composition according to Claim 6 or Claim 7 wherein the ophthalmic drug is 1,3 - dioxo - 1H - benz[d,e]isoquinoline - 2(3H) - acetic acid.

12. An ophthalmic composition for the treatment of glaucoma comprising 0.005% to 0.25% echothiophate iodide and a naturally derived gum consisting essentially of 0.02% to 1% of xanthan gum or locust bean gum in a pharmaceutically acceptable liquid vehicle; said percentages expressed as weight per vorume.

13. An ophthalmic composition according to Claim 12 wherein the concentration of said echothiophate iodide is 0.03% to 0.25% and wherein the concentration of said gum is from 0.1% to 0.5%.

14. An ophthalmic composition comprising 0.01% to 0.05% of pilocarpine hydrochloride and a naturally derived gum consisting essentially of 0.02% to 1.0% of xanthan gum or locust bean gum in a pharmaceutically acceptable liquid vehicle; said percentages expressed as weight per volume.

15. An ophthalmic composition comprising 1,3 - dioxo - 1H benz[d,elisoquinoline - 2(3H) - acetic acid and a naturally derived gum consisting essentially of 0.5% to 1.5% of xanthan gum or locust bean gum in a pharmaceutically acceptable liquid vehicle and wherein said percentages are expressed as weight per volume.

16. An ophthalmic composition comprising a naturally derived gum consisting essentially of 0.02% to 1.0% weight/volume of xanthan gum or locust bean gum and a therapeutically effective dosage of carbachol in a pharmaceutically acceptable liquid vehicle.

17. A method for potentiating the pharmacological response of drugs used in treating the eye of a mammalian patient which consists essentially of incorporating as an adjuvant a naturally derived gum consisting essentially of xanthan gum or locust bean gum into liquid compositions of said drug.

18. A composition according to any one of Claims 1 to 16 wherein the pharmaceutically acceptable liquid consists essentially of water.

19. A composition according to Claim 1 substantially as hereinbefore described with reference to any one of Examples 1B to 1E, 1H, 2J, 2M, 2N, 3P, 3R, 4T, 4U and 5V to 5X.

20. A composition according to Claim 3 substantially as hereinbefore described with reference to Example 6.

21. A composition as claimed in any one of Claims 6 to 17 wherein the naturally derived gum is xanthan gum.

22. A composition as claimed in any one of Claims 6 to 17 wherein the naturally derived gum is locust bean gum.

23. A composition as claimed in any one of Claims I to 3 and 5 wherein the naturally derived gum is xanthan gum.

24. A composition as claimed in any one of Claims 1 to 3 and 5 wherein the naturally derived gum is locust bean gum.