GB1604020A - Sterilizing compositions - Google Patents

Description

(54) STERILIZING COMPOSITIONS (71) We, SMITH & NEPHEW PHARMACEUTICALS LIMITED, a British Company of Bessemer Road, Welwyn Garden City, Hertfordshire, 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 is concerned with improvements in and relating to sterilizing compositions and, more particularly, is concerned with an improvement in or modification of the invention described in our co-pending Application No.

49354/74 (Serial No. 1,534,853).

In Application No. 49354/74 (Serial No. 1,534,853) we have disclosed a method of sterilizing an article which comprises contacting the article with an aqueous solution of an iodophor also containing sufficient of an organic aldehydic reducing agent to reduce the available iodine level of the solution to substantially zero within a period of from 30 minutes to 8 hours; the reaction products of the iodophor and the reducing agent being non-toxic and non-irritant.

As disclosed in Application No. 49354/74 (Serial No. 1,534,853) by employing the method thereof it has been found that it is not necessary to remove any adherent sterilizing solution from the sterilizing article even if the article is to be brought into contact, directly or indirectly, with human tissue. Further the sterilizing capacity or effectiveness of a sterilizing solution containing 'available iodine as sterilizing agent is not adversely impaired by the presence of a reducing agent for reducing the level of available iodine provided that the reducing agent does not react with the iodine too fast, i.e. does not reduce the available iodine level to substantially zero in less than 15 minutes. The method disclosed in Application No. 49354/74 (Serial No. 1,534,853) is particularly well adapted for the sterilization of articles made of hydrophilic polymers, especially contact lenses.

The present invention is concerned with compositions for the production of sterilizing solutions for use in the method disclosed in Application No. 49354/74 (Serial No. 1,534,853). Various methods of, and compositions for, producing sterilizing solutions for use in accordance with the method thereof are described in the said application, e.g. compositions comprising a solid dosage unit form containing an iodophor for addition to an aqueous solution of reducing agent or a solid dosage unit form containing a reducing agent for addition to a solution of iodophor.

It has now been found, in accordance with the present invention, that the iodophor and reducing agent may be put up together in a single solid dosage unit form which may subsequently be added to water to provide a sterilizing solution for use in accordance with the method described in Application No. 49354/74 (Serial No. 1,534,853).

Accordingly, one aspect of the present invention provides a sterilizing composition in solid dosage unit form comprising (a) a solid iodophor and (b) a solid organic aldehydic reducing agent (as hereinafter defined); components (a) and (b) being such that on dissolution in water the solid dosage unit form yields an aqueous solution of the iodophor containing sufficient of the organic aldehydic reducing agent to reduce the available iodine level of the solution to substantially zero within a period of from 15 minutes to 8 hours at ambient temperature.

The term "iodophor" as used herein is intended to refer to a water-soluble complex of iodine with an organic complexing agent which complex, on dissolution in water, yields available (i.e. titratable) iodine. Suitable complexing agents include hydrophilic water soluble polymers and surface active agents. A particularly suitable iodophor for use in the compositions of the invention is a polyvinyl pyrrolidone/iodine complex (so-called "Povidone Iodine", hereinafter simply referred to as PVP/I2 complex).

As discussed in Application No. 49354/74 (Serial No. 1,534,853), the iodophor should be present in the sterilizing solution in an amount sufficient to give a sterilizing level of available iodine bearing in mind the fact that the solution will also contain a reducing agent which will act to reduce the level of available iodine.

Thus, provided the available iodine level is at least 5 ppm for a period of at least 15 minutes effective sterilization will be achieved. Accordingly, the iodophor will generally be present in the solution to give an initial available iodine level (i.e. the level of available iodine as determined by titration before the addition of or reaction with the reducing agent or contact with the article to be sterilized) of at least 10 ppm, preferably at least 20 ppm. The initial available iodine level will ordinarily not need to be above 300 ppm and is preferably from 25 to 100 ppm and most preferably is about 50 ppm. Clearly, the amount of iodophor in the dosage unit forms of the invention will depend upon the quantity of water to which the dosage unit form is to be added. However, in general terms the dosage unit forms of the invention may suitably contain from as little as 2 mg of iodophor to 5 g of iodophor. As will be discussed more fully hereinafter, the dosage unit forms of the invention for use in sterilizing contact lenses will generally contain from 2 to 30 mg of an iodophor. Dosage unit forms of the invention intended for more general sterilization of articles the compositions of the invention may contain from 200 mg to 2.5 g, preferably from 200 to 1000 mg of iodophor, such a composition being suitable for addition to, say, 1 litre of water to produce an effective sterilizing solution for use in the method described in Application No. 49354/74 (Serial No.

1,534,853).

The reducing agent employed in the dosage unit forms of the invention is an organic aldehydic reducing agent and this term is intended to refer to a compound containing a group -CHO or one which evolves groups containing such a grouping on dissolution in water (e.g. hexamine). Preferred aldehydic reducing agents for use in accordance with the invention include solid reducing carboxylic acids or alkali metal salts thereof and reducing sugars such as glucose and arabinose. A particularly preferred reducing agent is sodium formate. The sterilizing solution formed by dissolution of the dosage unit form in water must contain sufficient of the reducing agent to reduce the available iodine level of the solution to substantially zero (i.e. an available iodine level of 1 ppm or less, i.e. a level virtually undetectable by conventional analytical techniques) at commonly encountered ambient temperatures (e.g. 5 40 C, preferably 15 to 250C). Accordingly, the reducing agent must be present in molar excess over the available iodine (calculated as I) in the solution and in the composition. The actual molar excess of reducing agent will depend upon the nature of the iodophor and the reducing agent. Thus, for example, in the case of sodium formate it is preferred that the reducing agent be present in an amount of at least 10 times the weight of the available iodine in the iodophor, more preferably in an amount of from 25 to 100 times the weight of available iodine. Thus, taking sodium formate as an example of.

a reducing agent this is suitably present in an amount of from 20 mg to 50 g in the compositions of the invention.

As indicated above, the dosage unit forms of the invention may be used in the formulation of sterilizing solutions for so-called "soft" contact lenses or other articles made of similar hydrophilic polymers. Such hydrophilic polymers are lightly cross-linked polymers or copolymers of hydrophilic monomers such as hydroxyalkyl acrylates or methacrylates (e.g. hydroxyethylmethacrylates) or vinyl pyrrolidone. Such polymers are in the form of hydrogels and contain substantial amounts of water. Accordingly, the lenses themselves may absorb the available iodine and it is therefore necessary to reduce, by means of the reducing agent, the iodine in the lenses to substantially zero for two reasons. Firstly, the presence of available iodine in the lens may cause a short or long term irritancy on the wearers' eyes if the iodine is not substantially removed. Secondly, the lens on absorbing iodine acquires a yellowish/amber colouration and obviously the lens must be clear before it is worn and hence the iodine must be substantially removed. The problem is exacerberated by the fact that it appears that in many cases the available iodine may preferentially concentrate in the lens as opposed to the sterilizing solution. In order for the reducing agent to reduce the iodine in the lens it appears that it is necessary for the reducing agent to pass from the sterilizing solution into the water contained in the lens hydrogel since otherwise an unduly long period of time (i.e.

considerably in excess of 8 hours) may be required to clear the lens of iodine. This is believed to be due to the fact that if the reducing agent cannot enter the lens hydrogel it can only react with available iodine at the surface of the lens and that the iodine from the body of the lens is only slowly liberated at the lens surface.

Accordingly, the reducing agent employed in the sterilization of a lens should be one capable of entering the water of the lens hydrogel and not all reducing agents are apparently capable of so doing or if so are unduly irritant to the ocular tissue.

However, it has been found that alkali metal formates do meet the necessary criteria. Further, the iodophor should be non-irritant to ocular tissue and it has been found that iodophors derived from hydrophilic polymers or nonionic surface active agents are not so irritant and are thus suitable for use in the steriliation of lenses.

The pH of any residual liquid in contact with the soft lens should be from 5.0 to 8.0, preferably 6.5 to 7.5 and hence it is desirable that a pH adjuster, generally a buffer system, be incorporated in the sterilization solution to bring the pH of the final liquid to the desired level.

Such a buffer may be incorporated in the dosage unit form of the invention itself, or, alternatively, may be incorporated in the water to which the dosage unit form is added.

It is also desirable that the tonicity of the final solution, after reaction with the reducing agent, be approximately equal to that of the eye fluids, and, hence, it is most desirable that a tonicity adjusting agent, generally sodium chloride, be incorporated in the sterilization solution. Such tonicity adjusting agents may also be incorporated in the dosage unit forms of the invention or in the water to which they are intended to be a ded.

The buffers are suitably present in amounts to give from 100 to 10,000 ppm of buffer in the sterilization solution when used in the treatment of 50 ppm available iodine solutions. The tonicity adjusting agents should be present in the solutions in an amount to render the solution approximately isotonic with human tears.

When calculating the amount of a sterilizing agent, reducing agent, buffering agent, and/or tonicity adjusting agent to be present in the dosage unit form of the invention, account must be taken of the strength of the eye sterilization solution produced and the amount of liquid to be treated.

A 50 ppm available iodine solution has been found to be very suitable for sterilizing soft contact lenses. Generally the lenses will be brought into contact with the sterilization solution in a so-called lens case having a capacity of from 5 to 25 ml, preferably about 10 ml. Accordingly, dosage unit forms in accordance with the invention for use in sterilizing soft contact lenses preferably contain from 2-30 mg (preferably from 2-10 mg) of a solid iodophor which is a complex of hydrophilic polymer or a nonionic surface active agent and from 20--300 mg (preferably from 20 to 100 mg) of an alkali metal formate. These dosage unit forms may also contain, as indicated above, buffering agents and tonicity adjusting agents. Alternatively, however, these may be contained in the water to which the composition of the invention is intended to be added in appropriate concentrations.

Where the dosage unit forms of the invention are to be employed in the sterilization of soft contact lenses the water to which they are added should be distilled or deionised water in order to avoid the presence of extraneous ions or dissolved salts which may unfavourably affect the final tonicity of the-sterilizing solution. The water should also, desirably, itself be sterile and to this end may be put up as single dosage units containing appropriate amounts (e.g. 10 ml) of sterile water; such dosage units may, for example, take the form of metal foil/plastics sachets. Alternatively, the water may be present in a multidose container, in which case, the water should be sterilized, e.g. by the action of beta or gamma radiation, and also contain a bactericide or preservijg agent. Since many of the known preservatives, unfortunately, concentrate in soft lenses thereby giving rise to possible problems of damage of the eye it is necessary to select one which does not and in this regard sorbic acid has been found not to concentrate in soft lenses.

Accordingly, the invention also provides, in accordance with another aspect thereof, a two-part pack, one part comprising a solid dosage unit form as described above and the other part comprising a container containing sterile water, optionally also containing buffering agent and/or tonicity adjusting agent.

In the two-part packs of the invention the solid dosage unit form will always contain the solid iodophor and solid aldehydic reducing agent and the water container will always contain sterile water but each or either may also contain buffering agents and/or tonicity adjusting agents as discussed above. Thus the components of each part of the two-part pack may be as listed below.

Solid Dosage Unit Form Aqueous Component Solid iodophor (essential) Sterile water (essential) Solid aldehydic reducing agent Tonicity adjusting agent (essential) (optional) Tonicity adjusting agent Buffering agent (optional) (optional) Buffering agent (optional) Preservative (for multidose containers) As indicated above where the solid dosage unit forms of the invention are used in the sterilization of soft contact lenses the water to which they are added should be distilled or deionised water and should, preferably, be sterile. It is not however, essential that the water be sterile since the solid dosage unit forms of the invention have, of course, a sterilizing ability and thus it is possible for a user to produce a sterilizing solution by adding a dosage unit form of the invention to distilled or deionized water which has not been sterilized.

Where the dosage unit forms of the invention are employed in the sterilization of articles where the tonicity and/or pH of the final sterilizing solution is not of such importance as in the sterilizing of soft contact lenses, e.g. in the sterilizing of surgical instruments, no buffenng agent and/or tonicity adjusting agent need be included in the dosage unit form and/or water to which it is added. Further in this case it is not essential that the water be distilled or deionized or be sterile, although sterile water will be preferred. In accordance with another aspect of the invention the dosage unit form of the invention may be used to sterilize water itself.

The compositions of the invention are dry solid dosage units and may, thus, comprise tablets or a mixture of the dry constituents contained in a suitable container such as a hard or soft gelatin capsule. However, having regard to the fact that it is generally desirable that no extraneous, unwanted matter be introduced into a soft lens sterilizing solution it isreferred that the dosage unit form contain no extraneous material and thus it preferably takes the form of a solid tablet comprising only the active ingredients or, possibly, water-soluble non-irritant excipients such as boric acid or a polyethylene glycol. Such tablets may comprise a mixture of the active ingredients (iodophor and reducing agent) together with possible excipients or may take the form of two layer tablets, one layer comprising the iodophor and the other layer comprising the reducing agent. Where the tablet is intended for purposes other than sterilizing soft lenses the tablet may contain ingredients containing materials which might prove essential in the sterilization of soft lenses, e.g. converted tablet excipients, lubricants and disintegrating agents.

Alternatively the dosage unit forms of the invention for use in sterilizing soft contact lenses may comprise a two-part capsule (e.g. a two-part hard or soft gelatine capsule) containing a mixture of the powdered ingredients, the user separating the two-parts of the capsule and introducing the powder into the water to be sterilized. This presentation has the advantage that no excipients are introduced into the sterilizing solution.

In order that the invention may be well understood, the following Examples are given by way of illustration only.

Example I Tablets having the formulation given below are prepared as follows.

PVP/I2 5 mg per tablet Sodium formate 50 mg per tablet Sodium chloride 29.8 mg per tablet Boric acid 13.5 mg per tablet Total 98.3 PVP/I2 complex powder is sieved through a No.60 (British Standard) sieve and dried at 600C overnight.

Sodium formate and sodium chloride are dried at 60"C and then sieved, the material passing through a No. 40 (British Standard) sieve but being retained on a No. 60 sieve being retained for use.

Appropriate quantities of the dried and sieved PVP/I2 complex, sodium formate and sodium chloride are mixed together and finely powdered boric acid is added to the mixture as lubricant. The mixture is then tabletted using 1/4 inch punches.

These tablets are suitable for use with 10 ml lots of solution having the following formulation: Anhydrous sodium dihydrogen phosphate 0.023% Anhydrous disodium hydrogen phosphate 0. lOovo Distilled water ad 100.000 /O This solution is packed as 10 ml lots into single dose containers (metal foil/plastic sachets) and sterilized.

A solution suitable for the sterilization of soft contact lenses is prepared by adding one of the above tablets to one 10 ml lot of the solution. It will be seen that in this example the tonicity adjusting agent (sodium chloride) is included in the solid dosage form and the buffering agent in the water.

Example 2 Tablets having the following formulation are made PVP/I2 5 mg per tablet Sodium formate 50 mg per tablet Sodium chloride 30 mg per tablet Boric acid 8.5 mg per tablet These tablets may be used with 10 ml lots of the aqueous solution described in Example 1 in the manner described in Example 1.

Example 3 Tablets having the following formulation are made.

PVP/I2 5.0 mg per tablet Sodium formate 50.0 mg per tablet Sodium dihydrogen phosphate 2.3 mg per tablet Disodium hydrogen phosphate 10.0 mg per tablet Sodium chloride ' 30.0 mg per tablet Boric acid 8.5 mg per tablet These tablets are suitable for use in the sterilization of soft contact lenses by the addition of one tablet to 10 ml of sterile distilled water.

Examples 46 Two-part hard gelatine capsules are filled with the powdered ingredients listed in the table below.

Amounts of Component in mg Per Capsule Component Example 4 5 6 PVP/I2 complex 5 5 5 Sodium formate 50 50 50 Sodium chloride 29.8 30.0 30.8 Sodium dihydrogen - - 2.3 phosphate Disodium hydrogen - - 10.0 phosphate ~ The capsules of Examples 4 and 5 may be used with 10 ml lots of the sterile buffered solution described in Example I and the capsule of Example 6 with 10 ml lots of sterile distilled water.

Claims (16)

WHAT WE CLAIM IS:

1. A sterilizing composition in solid dosage unit form comprising (a) a solid iodophor and (b) a sofid organic aldehydic reducing agent (as hereinbefore defined); components (a) and (b) being such that on dissolution in water the solid dosage unit form yields an aqueous solution of the iodophor containing sufficient of the organic aldehydic reducing agent to reduce the available iodine level of the solution to substantially zero within a period of from 15 minutes to 8 hours at ambient temperature.

2. A solid dosage unit form as claimed in Claim 1 in which the iodophor comprises a water-soluble complex of iodine with a hydrophilic water-soluble polymer or a surface active agent.

3. A solid dosage unit form as claimed in Claim 2 in which the iodophor is a polyvinyl pyrrolidone/iodine complex.

4. A solid dosage unit form as claimed in any one of the preceding claims containing from 2 to 30 milligrams of iodophor.

5. A solid dosage unit form as claimed in any one of Claims 1--3 containing from 200 milligrams to 2.5 grams of iodophor.

6. A solid dosage unit form as claimed in any one of the preceding claims in which the aldehydic reducing agent is a solid reducing carboxylic acid or an alkali metal salt thereof or a reducing sugar.

7. A solid dosage unit form as claimed in Claim 6 in which the reducing agent is an alkali metal salt of formic acid.

8. A solid dosage unit form as claimed in Claim 7 in which the reducing agent is present in an amount of at least 10 times the weight of the available iodine in the lodophor.

9. A solid dosage unit form as claimed in Claim 8, in which the reducing agent is present in an amount of from 25 to 100 times the weight of available iodine in the iodophor.

10. A solid dosage unit form as claimed in any one of the preceding claims also containing a buffer system and/or a tonicity adjusting agent.

11. A solid dosage unit form as claimed in any one of the preceding claims in which the solid dosage unit form comprises a tablet.

12. A solid dosage unit form as claimed in any one of Claims 1--11 comprising a mixture of the dry constituents contained in a hard or soft gelatin capsule.

13. A solid dosage unit form as claimed in Claim 1 substantially as hereinbefore described with reference to the Examples.

14. A two-part pack for the preparation of a sterilizing solution comprising, in the first part, a solid dosage unit form as claimed in any one of the preceding claims and in the second part sterile water.

15. A two-part pack as claimed in Claim 14 in which the water also contains a preservative to maintain its sterility.

16. A two-part pack as claimed in Claim 14 substantially as hereinbefore described.