EP0472575A1

EP0472575A1 - Improvements in or relating to pharmaceutical preparations

Info

Publication number: EP0472575A1
Application number: EP19900907317
Authority: EP
Inventors: Jean Vilain
Original assignee: Individual
Current assignee: Individual
Priority date: 1989-05-16
Filing date: 1990-05-15
Publication date: 1992-03-04
Also published as: GB8911177D0; AU5561690A; WO1990014110A1; JPH04505267A

Abstract

Une préparation pharmaceutique se compose d'une suspension stable d'un alginate insoluble dans l'eau, destinée à une application externe sur un patient. Une suspension colloïdale d'alginate de calcium est bien stabilisée au moyen d'une gomme de xantham, et/ou une gomme de gellam, et/ou une gomme de fève locuste, qui agissent comme agents de suspension ou de gélification. La préparation peut revêtir une diversité de formes physiques, qui vont d'un gel fin et coulant qui peut être appliqué directement sur la surface du corps humain, en passant par un gel épais, à une plaque, pastille ou rondelle autoporteuse de taille, forme et épaisseur désirées qui peuvent être maintenues en place au moyen d'un pansement chirurgical. La préparation peut également se présenter sous forme d'un pansement chirurgical qui, par exemple, en est imprégné ou qui contient une plaque ou une rondelle de cette préparation. L'alginate est hémostatique, il a aussi des propriétés curatives et de regranulation. Par conséquent, la préparation peut être utilisée pour traiter les plaies ouvertes et les lésions, et les blessures non ouvertes comme les brûlures, les ulcères et autres affections similaires.A pharmaceutical preparation consists of a stable suspension of a water-insoluble alginate, intended for external application on a patient. A colloidal suspension of calcium alginate is well stabilized by means of a xantham gum, and / or a gellam gum, and / or a locust bean gum, which act as suspending or gelling agents. The preparation can take a variety of physical forms, which range from a thin, flowing gel which can be applied directly to the surface of the human body, passing through a thick gel, to a plate, pellet or self-supporting washer of size, shape and thickness desired which can be held in place with a surgical dressing. The preparation can also be in the form of a surgical dressing which, for example, is impregnated therewith or which contains a plate or a washer of this preparation. Alginate is hemostatic, it also has healing and regranulation properties. Therefore, the preparation can be used to treat open wounds and lesions, and unopened wounds such as burns, ulcers and other similar conditions.

Description

Title; Improvements in or relating to Pharmaceutical Preparations

Filed of invention

This invention relates to pharmaceutical preparations.

Background to the invention

Alginates are known to have haemostatic properties, acting to promote clotting of blood, and it is known to use alginates such as calcium alginate in surgical dressings. For example, a non-woven wound dressing comprising calcium alginate fibres is available from BritCair Limited, UK under the Trade Mark KALTOSTAT. See also EP 0243069 and GB 1329693.

The present invention is based on a novel presentation of alginates for use as pharmaceutical preparations.

Summary of the invention

In one aspect the present invention provides a pharmaceutical preparation comprising a stable suspension of a water insoluble alginate suitable for external application to a patient.

By having the alginate in the form of a stable suspension, the preparation is much more versatile than conventional products and can be produced in a variety of different physical forms, as will be described below, suitable for use in treating a range of different conditions.

A stable suspension is conveniently obtained by incorporating a suspending (or stabilising) agent in a colloidal suspension of the alginate in water. The suspending agent acts to maintain the insoluble alginate in suspension, ensuring long term stability of the preparation: without a suspending agent the alginate would be "rejected" by the aqueous medium, thus destabilising the preparation.

The presently preferred suspending agent is xantham gum (a water soluble polymer). The unique rheology and stability of this polysaccharide molecule render it ideal as a suspending and gelling agent for alginate to be used as a pharmaceutical product, imparting an elastic structure to the aqueous suspension which consequently forms a pourable viscous suspension or gel. Xantham gum is approved for use in foods and is widely incorporated into foods as a suspending agent. Xantham gum is also used in consumable pharmaceutical preparations such as cough syrups and is incorporated in a number of cosmetics. Xantham gum may be used alone or mixed with equal quantities (by weight) of locust bean gum (a high molecular weight polysaccharide). Alternative suspending agents include gellam gum (eg produced by Kelco International Limited), which is also a high molecular weight polysaccharide, sodium alginate, carboxymethyl cellulose and carmellose sodium (the sodium salt of the polymer of carboxymethyl cellulose). The suspending agent is typically present in an amount in the range 0.25 to 2.5% by weight, e.g. 1% by weight, although other amounts can be used in some cases.

A suitable and pharmaceutically acceptable gelling agent may also be included in the preparation, in an appropriat amount to give a suitable viscosity to the product. The greater the amount of gelling agent, the greater the viscosity of the product. Thus, by varying the proportio of gelling agent, the physical form of the end product ma be varied within limits. Physical properties may also be affected by reaction conditions. In this way it is possible to produce a variety of products ranging from a thin, runny gel capable of direct application to the body surface, through a thick gel, to a self-supporting slab, pad or wafer (of desired size, shape and thickness) which .may be held in place with a suitable dressing. Runny forms of the preparation may also be used to impregnate surgical dressings. It will thus be seen that preparations in accordance with the invention are considerably more versatile than the known alginate dressings.

The suspending agents mentioned above additionally function as gelling agents and so perform a dual function. Xantham gum is particularly suitable as a gelling agent for a reagent to be applied to open wounds as its production and quality can be closely controlled. Other suitable gelling agents may alternatively be used.

The alginate is conveniently in the form of calcium alginate. This may be obtained by chemical conversion of water soluble pharmaceutical grade sodium alginate. Alternatively, commercially available calcium alginate can be used. Calcium alginate is commercially available in a range of grain sizes, and good results have been achieved using a grade having 95% of grains smaller than 106 microns in diameter. This is apparently close to the lower limit of grain size able to be manufactured, and it is thought that a larger grain size would be more resistant to suspension. The alginate is typically present in an amount in the range of 5 to 12% by weight, e.g. 10% by weight.

A preservative may optionally be included in the preparation. Suitable preservatives may be selected bearing in mind factors including the intended use of the preparation, the pH of the preparation, compatibility with other components, partition coefficient with other ingredients and with proposed containers or packaging. The currently preferred antimicrobial preservative is methylhydroxybenzoate, e.g. in the form of NIPAGIN M (Trade Mark) produced by 'Nipper Laboratories, which is typically present at a concentration of up to 1% by weight, e.g. 0.1%.

An anti-inflammatory agent may additionally or alternatively optionally be included in the preparation. Suitable reagents may be selected bearing in mind factors as discussed above in relation to preservatives.

The preparation desirably also includes iodine, e.g. as povidone iodine or pyrollidone iodine (a polymer of iodine). Iodine has desirable antiseptic properties and also acts to reduce considerably the allergenicity of the preparation and to prevent bacterial pollinisation of wounds.

The preferred concentration of iodine at manufacturing level would be about 2.5% per weight, giving a concentration of approximately 1% available iodine. However, a reduced dosage, to avoid potential sensitivity or allergic reactions to iodine itself, would be 0.25% at manufacturing level, potentially reducing the available iodine to 0.1%.

The preparation is conveniently supplied in sealed containers, e.g. bottles, tubes or sachets for runny gel forms and packs for slab, pad or wafer forms. The containers are preferably of single-use size, say containing 10ml or 20ml of gel.

The preparation is preferably sterilized before and/or after packaging. Optional intermediate chemical sterilization of the preparation may be effected prior to packaging to reduce the bio-burden to a minimum and facilitate final sterilization. In addition, sealed packs containing the preparation may be sterilized e.g. by exposure to nuclear E beams or by heat treatment.

In use, the preparation is applied externally to the desired region of a patient (human or animal) to be treated, in suitable manner depending on the nature of the preparation and area to be treated. Typically the preparation is applied to the body surface of a patient, including use in treatment of deep wounds e.g. deep intractable wounds and abscesses such as those in the anal area. Runny gel forms can be applied by being rubbed or massaged into the skin surface, even on anatomically complex regions. If appropriate, a conventional surgical dressing, such as those sold under the Trade Name MELOLIN, may be applied over the preparation. The preparation may also be impregnated into a surgical dressing such as a gauze type dressing for application. Slab, pad or wafer forms may be held in place with suitable dressings, although they may be sufficiently flexible to mould themselves onto the skins surface and be self-adhesive to a certain extent. In many cases, no particular skill is required for application, and the preparation can be easily used either by medical personnel or the patient himself. The slab or wafer forms may also be applied onto a plastics backing to form an integral surgical dressing, with the gel either exposed or covered with a gauze.

In use, the preparation has various beneficial effects. The alginate is haemostatic and so can be used to stop bleeding from many types of injuries or wounds, whether traumatic or surgical, including situations such as nose bleeds. The preparation also has healing and regranulation properties and so can be used with advantage in the treatment of non-bleeding wounds including burns, ulcers, such as skin ulcers, decubitus ulcers, venous or varicose ulcers, and other exudating ulcers, pressure sores, abrasions, abscesses, skin donor sites, and also in the treatment of some dermatological conditions.

It is envisaged the preparation will have wide application in hospitals, surgeries and in the home, e.g. for first aid use on cuts and burns.

One typical use involving application of a runny gel form of the preparation to an open wound (or lesion) will now be considered in greater detail.

Prior to application, the suspended alginate particles absorb water up to saturation point. The gel is applied e.g. with fingers to the lesion and surrounding skin and can be massaged in lightly around the lesion if so indicated. Once the gel has been applied on the lesion, the alginate has a rapid haemostatic effect by catalysing the clotting cascade, while the water evaporates from the layer of aqueous medium and from the alginate particles it contains. Simultaneously, the exchange of sodium ions between the blood and exudate against calcium ions in the gel increases the proportion of sodium alginate in the gel and forms sodium calcium alginate. As sodium alginate is water soluble and also an excellent film former, a dryish film develops on the external surface of the gel and the partly dehydrated calcium alginate particles present in the gel pump the infected exudate, hence recharging themselves to saturation point.

Together with the strong absorption capacity of the calcium alginate which pumps the infected exudate, the presence of a moist biological gel under the dry external film seems to enhance the capacity of the tissues to recover and reform, hence providing a regranulation process. The film seals off the lesion while permitting an osmotic exchange with ambient atmosphere. Massaging in of the gel around the lesion improves peripheral circulation (as in the so-called "periulcer massaging" technique), thus contributing to cleansing of the wound. In addition, in conjunction with the plasma which exudes from the lesion, the gel should protect the surrounding intact skin against maceration, and therefore promotes healing. The preparation thus acts to create an "environment" which promotes healing and also improves peripheral circulation, hence contributing to the reduction of swelling and to the "cleansing" of the lesion. Further gel is applied as necessary. If required, a conventional secondary wound dressing can be applied over the gel.

When used in the treatment of burns, the preparation has an immediate pain-relieving effect, and functions well to promote healing. In many cases (2nd degree burns, for instance) no scar is left and the tissues appear to recover a normal physiology.

In a further aspect the invention also provides a surgical dressing, wherein the dressing carries, e.g. is impregnated with or contains in slab or wafer form, a pharmaceutical preparation in accordance with the invention.

The invention also includes within its scope a method of treating a patient (human or animal) comprising applying externally to the patient a pharmaceutical preparation or surgical dressing in accordance with the invention.

The invention will be further described, by way of illustration, in the following Examples.

Example 1

A calcium alginate gel of "standard" viscosity and having the following composition was prepared:

Xantham gum 1% by weight

Preservative 1% by weight

Calcium alginate 10% by weight

Water 88% by weight

10gms xantham gum in the form of standard grain size (with 95% of the grains having a diameter less than 177 microns) KELTROL (Trade Mark) obtained from Kelco International Limited or Kelco USA was fully hydrated in 880mls of cold water in a high speed mixer. Although xantham gum is a cold water soluble material, in order to avoid the formation of lumps at this stage the gum is slowly added to the water at the shoulder of the vortex. A homogenous solution is obtained in 10-15 minutes.

10gms of the cold water soluble preservative NIPAGIN M (Trade Mark) produced by Nipper Laboratories was added to the solution thus obtained. An anti-inflammatory agent and/or iodine may optionally be added.

Using an efficient agitator to disperse the calcium alginate dry powder in the solution, 100gms of calcium alginate (of a grade having 95% of grains smaller than 10 microns in diameter obtained from Kelco) was added to the solution standing in a tank as above. A slow, steady addition is required to allow the calcium alginate time to disperse, with constant agitation. This procedure allows proper dispersion of the calcium alginate in the solution, without lump formation, therefore giving a homogeneous gel.

The resulting gel is of "standard" viscosity and is in the form of a fairly runny gel.

The gel is given an intermediate chemical sterilization to reduce the bio-burden to a minimum, and is then packaged into suitable containers such as 10ml or 20ml tubes, bottles or sachets which are sealed and then sterilized by heat treatment.

The "standard" viscosity gel thus produced is particularly suitable for use in treatment of leg ulcers, open superficial wounds and burns, and is used by being applied directly to the affected area. Alternatively, the gel may be used to impregnate a gauze-type surgical dressing. which can then be applied to the area to be treated.

Good results have been obtained in small scale clinical trials of this product on skin ulcers, particularly venous ulcers of the legs and ulcers following abscess drainage where the wound is deep and difficult to dress and clean. The product has been found to be well tolerated by intact surrounding skin, and to be beneficial to healing.

The viscosity of the gel may be varied by varying the amount of xantham gum, a more runny gel being produced by use of less gum and vice versa. Lower viscosity, runnier gels are particularly suitable for use in treatment of intractable ulcers, complex wounds and burns, and wounds and burns located in complex anatomical regions.

Coarser grain size grades of KELTROL (Trade Mark) are available, e.g. having 95% of grains with a diameter of less than 400 microns, or having 95% of grains with a diameter of less than 1000 microns. Use of such coarser grades may be beneficial as lumps are less likely to form on addition to water.

Example 2

A high viscosity preparation in the form of a self- supporting slab or wafer of calcium alginate gel was formed in the following manner.

The required proportion of gellam gum (which is the chemical name of a range of new high molecular weight polysaccharides of various grades manufactured inter alia by Kelco International under the brand name KELCOGEL) was mixed with an appropriate amount of water to make 100% weight of final product, using a mixer as described in Example 1. The preferred concentration of gellam gum is in the range 0.5 to 1% by weight of the final product.

Using an agitator as described in Example 1 , to the resulting suspension were added preservative such as NIPAGIN M (Trade Mark) in an amount to constitute 1% by weight of the final product, and calcium alginate (as specified in Example 1) in an amount to constitute 10% by weight of the final product.

The resulting suspension was then heated to about 90°C to hydrate the gum. The resulting product is then cooled.

In order to induce the gellation mechanism and obtain the required grain, electrolytic salts (calcium, sodium or potassium) are added during the heating phase and/or during the cooling phase; the level of such salts has to be controlled fairly precisely and depends on the gel grain required. As compared to the gel described in the following Example 3, such a gel is fairly hard and brittle, but this feature should not affect the properties of the active ingredients, as in these conditions they should be more readily available.

The heating step also has the advantage of contributing to sterilization of the product.

During the cooling process, the product should be moulded so that when fully cooled it adopts the desired final form or else an intermediate shape which is capable of being reduced to the required size of slab, or wafer, in which the calcium alginate particles are physically immobilized, to be slowly released when in contact with the skin and plasma exudating from a lesion.

The resulting slab or wafer is packed in a sealed container and sterilized, e.g. by heat treatment.

The slab or wafer may be used in treatment of a variety of different conditions. For example, it may be applied to a lesion and held in place with a conventional surgical dressing such as MELOLIN (Trade Mark) dressing. Once applied onto a lesion, the gel will progressively dessicate and, due to its very structure, will absorb fluid exudating from the lesion. Depending on the level of ambient humidity, such a dessication process will take between a few hours and a few days.

The calcium alginate particles present in the gel in the form of a homogeneous suspension will then absorb the exudate. The exudate will penetrate the gel structure, and act to solubilise the calcium alginate, and the reaction therefore intervenes both at the surface of the lesion and within the gel itself.

Example 3

An alternative high viscosity preparation in the form of a self-supporting slab or wafer which is very flexible was formed using a 2 component suspending/gelling agent comprising a mixture of equal weights of xantham gum and locust bean gum.

These two gums are both polysaccharides having a high molecular weight back bone, and the gums interact by hydrogen bonding hence forming a gel. The reaction is straightforward and constitutes a self-gelling system. Both these components are available from Kelco under various grades, either separately or blended in given proportions.

A mixture of equal amounts by weight of xantham gum and locust bean gum was obtained, either in the form of a commercially available blend or by mixing the separate components. The resulting mixture was added to water using a mixer as described in Example 1. Each gum was used in an amount to constitute 0.25 - 0.5% by weight of the final product, with water being added to make up 100% by weight of the final product.

Calcium alginate powder (10% by weight), preservative (1% by weight) and an anti-inflammatory agent if required were added to the resulting mixture using an agitator as described in Example 2.

The suspension thus obtained was mixed, and the gelling/suspending agents were hydrated by heating the suspension to approx. 80-90°C. This produces a homogeneous self-supporting gel. The gel was cooled, being moulded during the cooling process as described in Example 2.

The resulting product is in the form of a very flexible self-supporting slab or wafer of desired size, shape and thickness. The slab or wafer is packed and sterilized as described in Example 2.

In use, in contact with a lesion, the mechanism is generally similar to that described in Example 2. However, the melting point of this gel is approx.30°C, while that of the gel of Example 2 is 50-60°C with the consequence that this gel should melt to a certain extent once in contact with inflammed skin/lesion. In addition, the degree of absorbancy is affected by this last feature.

The methods of Examples 2 and 3 may be modified by use of hot water soluble preservatives if required.

Being maieable, and their maleability increasing at skin temperature, self-supporting gels (under the form of slabs/wafers) as described in Examples 2 and 3 above should mould themselves on the wound and be self-adhesive to a certain extent. Such slabs or wafers can" therefore be left in situ and replaced at the rate of, say, once or twice a week depending on the stage reached by the lesion/ulcer, with the combined pumping effect of the _xgel structure per se and of the particles of calciurti alginate being particularly important during the intermediate healing phase, after the eschar (scab), if any, has been broken down, and when the lesion gives a considerable amount of exudate.

Claims

Claims :

1. A pharmaceutical preparation comprising a stable suspension of a water insoluble alginate suitable for external application to a patient.

2. A preparation according to claim 1, comprising a suspending agent in a colloidal suspension of alginate in water.

3. A preparation according to claim 2, wherein the suspending agent comprises xantham gum.

4. A preparation according to claim 3, wherein the suspending agent comprises a mixture of equal quantities by weight of xantham gum and locust bean gum.

5. A preparation according to claim 2, wherein the suspending agent comprises gellam gum.

6. A preparation according to any one of claims 2 to 5, wherein the suspending agent is present in an amount in the range 0.25 to 2.5% by weight.

7. A preparation according to any one of claims 1 to 6, additionally comprising a gelling agent.

8. A preparation according to anyone of the preceding claims, in the form of a runny gel.

9. A preparation according to any one of claims 1 to 7 , in the form of a self-supporting pad or wafer.

10. A preparation according to any one of the preceding claims, wherein the alginate is in the form of calcium alginate.

11. A preparation according to any one of the preceding claims, wherein the alginate is present in an amount of about 10% by weight.

12. A preparation according to any one of the preceding claims, further comprising a preservative.

13. A preparation according to claim 12, wherein the preservative comprises methylhydroxybenzoate.

14. A preparation according to claim 12 or 13, wherein the preservative is present at a concentration of up to 1% by weight.

15. A preparation according to any one of the preceding claims, further comprising an anti-inflammatory agent.

16. A preparation according to any one of the preceding claims, further comprising iodine.

17. A preparation according to any one of the preceding claims, packaged in a sealed container.

18. A preparation according to claims 17, wherein the preparation is sterilized before and/or after packaging.

19. A surgical dressing, wherein the dressing carries a pharmaceutical preparation in accordance with any one of the preceding claims.

20 . A method of treating a patient comprising applying externally to the patient a pharmaceutical preparation or surgical dressing in accordance with any one of the preceding claims .