IE58858B1 - Saliva replacement formulations - Google Patents

Abstract

A liquid saliva replacement formulation comprises an aqueous solution of carboxymethylcellulose having a viscosity in the range 170-230 centipoise, a preservative which consists either of a mixture of methyl, ethyl and propyl p-hydroxybenzoate or 2-bromo-2-nitropropane 1,3-diol and a mixture of salts present in normal saliva in a buffer medium which is sufficient to maintain the formulation at a pH in the range 5.8-6.2. The formulation is especially suitable for delivery to the mouth via an atomiser.

Description

This invention relates to saliva replacement formulations. More particularly, the invention relates to saliva replacement formulations which can be delivered via an atomiser.

Reduced salivary flow leading to xerostomia 'dry mouth' is an uncomfortable and often a distressful condition. In many cases the intraoral mucosa is cracked, bleeding and sore and hence swallowing and speech can be difficult. The reduced flow also gives rise to a higher incidence of dental caries due to the lack of the mechanical washing effect of saliva in clearing the mouth of cariogenic sweet foods and also due to the lack of the normal buffering action of the saliva in maintaining pH levels in the tooth environment at the correct level. A further reason for the higher incidence of caries in persons suffering from dry mouth is that in order to make eating more comfortable, they often change to soft diets usually with a high sugar content.

Dry mouth is a fairly common condition and is associated with a number of conditions such as Sjogren's syndrome and sarcoidosis and also with treatments such as therapeutic radiotherapy in the head and neck and prolonged medication with salivary depressant drugs.

A variety of mouth lubricants and saliva substitutes are available for prescribing by physicians and dentists. However, the action of most of these products is concerned with the substitution of the physical lubricating action of saliva and does not take into account the increased susceptibility of affected persons to dental caries (Kidd, E.A.M. and Joyston-Bechal, S. Research (1984) 18 , P 155.

A further disadvantage of known saliva replacement formulations is that they are extremely thick and sticky and consequently are difficult to administer.

Furthermore, the preservatives used do not always comply with the requirements of the National Drugs Advisory Board (NDAB).

One artificial saliva formulation currently in use is that sold under the Trade Name Oralube. The effective ingredient of Oralube for combating xerostomia is sodium carboxymethylcellulose of unspecified grade and viscosity. The preservative used is methyl £hydroxybenzoate. The remainder of Oralube is made up of various salts required to simulate normal saliva, flavouring agents and other additives and distilled water. Oralube is an ad lib medication which the patient administers by placing a few drops on the tip of the tongue as required. However, this form of administration, necessitated by the sticky nature of Oralube, leads to problems of bacterial contamination.

The preservative used in Oralube - methyl £hydroxybenzoate - has not been found to be effective in preventing bacterial contamination. Furthermore use of methyl £-hydroxybenzoate does not meet the requirements set down by the NDAB for an artifical saliva.

It is an object of the present invention to provide an improved saliva replacement formulation which can be readily administered and which has good bactericidal activity.

Accordingly, the invention provides a liquid saliva replacement formulation comprising a carboxymethylcellulose having a viscosity in the range 170-230 centipoise (mPas), a preservative selected from a mixture of methyl, ethyl and propyl p-hydroxybenzoate and 2bromo-2-nitropropane 1,3-diol in association with a buffer medium sufficient to maintain the formulation at a pH in the range 5.8 - 6.2 and containing a mixture of salts present in normal saliva.

Preferably, the carboxymethylcellulose used is sodium carboxymethylcellulose. A particularly preferred form of sodium carboxymethylcellulose for use in the formulation according to the invention is a form sold under the Trade Mark 7H3SF. The carboxymethylcellulose is preferably used at a concentration in the range 0.57.5% w/v.

A preferred mixture of methyl, ethyl and propyl phydroxybenzoate for use as the preservative is that sold under the Trade Mark Nipasept Sodium. 2-Bromo-2nitropropane 1,3-diol which can also be used as the preservative in the formulation according to the invention is sold under the Trade Mark Bronopol.

The preservative is preferably used at a concentration in the range 0.15-0.22% w/v.

The formulation according to the invention will preferably have a pH of 6.0.

The formulation according to the invention preferably contains fluoride in an amount effective to combat the formation of dental caries. Accordingly, a fluoride-containing formulation according to the invention will increase the resistance of the teeth to dental caries. Hence, as well as alleviating the pain and discomfort associated with xerostomia such a formulation will prevent the development of dental caries which invariably adds to the distress of xerostomia.

The liquid formulations of the invention can be administered by an atomiser because of their low viscosity. Thus they are easy to administer and economical to use. Administering the formulation according to the invention via an atomiser reduces the problems of bacterial contamination. Suitably, the formulation according to the invention will be filled into plastics containers of 60ml capacity fitted with a conventional atomiser.

It is found that the preservatives specified for use in the formulation according to the invention provide enhanced resistance to bacterial contamination.

The formulation may also include various additives, such as flavouring agents, colouring agents and non-sugar sweetening agents. An example of a non-sugar sweetening agent is sorbitol.

A typical formulation of the invention is as follows.

Ingredients Quantity per batch Nipasept Sodium Sodium carboxymethylcellulose B.P. Potassium chloride B.P.

Magnesium chloride B.P.

Calcium chloride B.P.

Dipotassium hydrogen phosphate U.S.P. Potassium Dihydrogen phosphate N.F. Sodium fluoride B.P.

Orange Flavour I.F.F. XV-1997 Carmosine C.I. 14720 Sorbitol B.P. 70% (non-crystallising grade ) Purified Water B.P. to produce 1.8 .85 562.5 52.92 149.58 723.42 329.58 3.87 900 38.52 900 kg . kg . g· g· g· g· g· g· ml. g· kg. litres Batch Size: 900 litres Approximately 500 litres of the purified water were placed in a calibrated plastics tank. The water was heated with slow but continuous stirring to 60°C. The various ingredients were added slowly with continuous stirring, beginning with the Nipasept Sodium. Finally, the volume was brought to 900 litres by adding the remaining purified water.

The formulation as prepared was filled into 60ml plastics containers fitted with a conventional atomiser. The plastics containers contain instructions for use, the patient being advised simply to spray the formulation directly into the mouth as required.

The remineralising capacity of the above formulation was compared with that of two commercially available saliva substitutes for patients with xerostomia. The commercial solutions tested were Glandosane (Trade Mark) (Dylade), which is based on carboxymethylcellulose and Saliva Orthana (Trade Mark) (Nyegaard) based on porcine mucin. Each of the formulations tested contained calcium and phosphate ions but only the formulation of the invention and Saliva Orthana contained fluoride. Laboratory made artificial saliva (Birkland, J.M., Caries Res. 2 1973) was used as a control. Artificial caries-like lesions were created on sound buccal surfaces of 10 extracted premolar teeth. Four longitudinal ground sections, 100 tun thick, were prepared through each lesion and examined histologically in polarized light, qualitatively and quantitatively. Each section was then varnished to expose only the outer surface of the lesion One section from each tooth was placed in each solution for 48 hours, solutions being changed once after 24 hours. Histological examination at the end of the experiment showed significant remineralisation with Saliva Orthana and the formulation of the invention throughout the lesion, while the laboratory artifical saliva only remineralised the surface. However, with Glandosane the deeper parts of the lesion showed significant demineralisation due possibly to the CO2 propellant in this spray.

Claims (5)

CLAIMS : 1. ,3-diol. to any one of Claims 1 to 2-bromo-2-nitropropane 6. A formulation according to any preceding claim, wherein the preservative is used at a concentration in the range 0.15 - 0.22% w/v. 7. A formulation according to any preceding claim, which has a pH of 6.0. 8. A formulation according to any preceding claim which contains fluoride in an amount effective to combat the formation of dental caries. 9. A formulation according to any preceding claim which contains one or more additional components selected from a flavouring agent, a colouring agent, and a nonsugar sweetening agent.

1. A liquid saliva replacement formulation comprising a carboxymethylcellulose having a viscosity in the range 170-230 centipoise (mPas), a preservative selected from a mixture of methyl, ethyl and propyl £-hydroxybenzoate and 2-bromo-2-nitropropane 1,3-diol in association with a buffer medium sufficient to maintain the formulation at a pH in the range 5.8 - 6.2 and containing a mixture of salts present in normal saliva.

2. A formulation according to Claim 1, which contains the carboxymethylcellulose at a concentration in the range 0.5 - 7.5% w/v.

3. A formulation according to Claim 1 or 2, which contains a sodium salt of carboxymethylcellulose.

4. A formulation according 3, wherein the preservative is and propyl £-hydroxybenzoate. to any one of Claims 1 to a mixture of methyl, ethyl 5. A formulation according 3, wherein the preservative is

5. 10. A formulation according to Claim 1, substantially as hereinbefore described with particular reference to the accompanying Formulation Example.