Sterile gel compositions for wound treatment

Abstract: The invention provides aqueous gel compositions for use as wound dressings and comprising from 2% to 10% w/v of alginate and from 25% to 40% w/v of polyhydric alcohol, said compositions being substantially sterile. The alginate is preferably sodium alginate and/or potassium alginate. the polyhydric alcohol is preferably propylene glycol or hexylene glycol. Also provided is a process of making such gel compositions comprising the steps of: providing an aqueous gel having the above composition and sterilising the aqueous gel. Preferably, the aqueous gel is sterilised by heating.

Description: The present invention relates to sterile gel compositions for application to the surface of wounds, such as decubitus ulcers and burns. The present invention also relates to a method of making such sterile gel compositions. Aqueous gel compositions for application to the surface of wounds to assist healing are known. The purpose of applying the gels is to form a wound-friendly and humectant wound contact layer between the wound surface and conventional wound dressing layers. This also helps to reduce the adherence of conventional wound dressings, such as bandages or gauzes, to the wound surface. The aqueous gel can also serve as a vehicle for pharmaceutically active agents such as antiseptics or antibiotics. US-A-4393048 describes protective gel compositions for wounds comprising about 0.5 to 3% by weight alkali metal alginate, about 8 to 12% by weight glycerol and about 82 to 90% by weight water. Medicaments in an amount of 0.01 to 10% by weight may optionally be included in the compositions. The resulting gel is brushed over the surface of the wound and dries in air to form a non-toxic, flexible and stretchable film covering the wound. A drawback of the gel compositions described in US-A-4393048 is that they cannot readily be prepared in a sterile form suitable for medical applications. This is because the usual methods of sterilisation, namely gamma-ray irradiation or autoclaving, result in hydrolysis of the alginate and consequent drastic reduction in the gel viscosity. This rules out sterilisation of the alginate gel after it has been manufactured and filled into packages. In fact, the only way to manufacture an alginate gel of this type that is sterile would be to sterilise all the ingredients dry and then mix and package them under aseptic conditions. This method of manufacture would be prohibitively expensive for WO84/00111 describes heat sterilisable pharmaceutical gel compositions for the treatment of burns, cuts, wounds or abrasions. The gel compositions comprise a pharmaceutically acceptable glycol and a cellulose derivative which is heat sterilizable. The preferred glycol is propylene glycol, preferably in an amount of 20-30% w/v. The preferred cellulose derivative is hydroxy ethyl cellulose, preferably in an amount of 1-4% w/v. The gel compositions optionally contain medicaments and/or dissolved physiologically acceptable salts. The use of hydroxy ethyl cellulose gives a gel that is heat sterilisable. That is to say, the gel regains its consistency and does not break down into a liquid when it is sterilised in an autoclave. A drawback of the gel compositions described in WO84/00111 is that the heat sterilisable cellulose derivatives are inherently less effective in promoting wound healing than natural biopolymers such as alginates. Accordingly, it is an object of the present invention to provide a heat sterilisable alginate gel for use in the treatment of burns, cuts, wounds, ulcers or abrasions. EP-A-0532275 describes web dressings formed by casting an aqueous gel of a polysaccharide such as an alginate, water and a humectant such as propylene glycol onto a mold, followed by drying and sterilization by gamma irradiation. US-A-4393048 describes water-soluble hydrogels for the treatment of wounds comprising alkali metal alginates and glycerol. The present invention provides a process to prepare a substantially sterile gel for use as a wound dressing, the process comprising the steps of; providing an aqueous gel comprising from 2% to 10% w/v of alginic acid or an alginate, from 15% to 40% of one or more polyhydric alcohols, and from 55% to 83% w/v of water; inserting the aqueous gel into a package; and heat sterilising the packaged aqueous gel to provide said substantially sterile gel for use as a wound dressing, wherein said packaged sterile aqueous gel has a viscosity of at least 10 Ns/m 2 (10,000 cps) at 20 °C. Surprisingly, it has been found that the inclusion of relatively large amounts of polyhydric alcohol (more than 15% w/v) results in an alginate gel that is stabilised against hydrolysis and consequent loss of viscosity during sterilisation. Sterilisation can be carried out by autoclaving using standard conditions. Compositions containing more than 40% w/v of polyhydric alcohol tend to separate on autoclaving. Such compositions can also cause discomfort or stinging when applied to a wound. The alginate may consist of one or more of alginic acid and its salts. Preferably, a soluble alginate salt is used to produce a gel that is fully water soluble both before and after sterilization. Preferably, the alginate consists of sodium alginate and/or potassium alginate. Preferably, the gel compositions comprise 3% to 6% w/v of the alginate. Preferably, the molecular weight of the alginate is in the range of 50,000 to 500,000. The polyhydric alcohol preferably comprises one or more C 3 -C 6 dihydric or trihydric alcohols, more preferably C 3 -C 6 dihydric alcohols and most preferably propylene glycol or hexylene glycol. Other preferred polyhydric alcohol include ethylene glycol, butylene glycol, glycerol, diethylene glycol, dipropylene glycol, polyethylene glycol and polypropylene glycol. Preferably, the composition contains a total of 20% to 35% w/v of the one or more polyhydric alcohols. The gel compositions may consist only of the said alginate, polyhydric alcohol and water. However, preferably, the gel compositions also contain 0.01% to 10% w/v of one or more pharmaceutically active compounds, more preferably 0.1% to 5% w/v of such compounds. Preferred pharmaceutically active compounds are selected from: antiseptics such as chlorhexidine or silver sulphadiazine; antibiotics such as pencillins or tetracyclines; analgesics such as aspirin, paracetamol, ibuprofen or naproxen; steroids; glycosaminoglycans such as hyaluronic acid and its salts, chondroitin sulfate or heparan sulfate; vitamins such as vitamins A and E; haemostats; cytokines; antibodies; enzymes; inflammatory agents; anti-inflammatory agents, and growth factors. The total water content of the aqueous gel is preferably from 55% to 79% w/v. The alginate gel may also contain up to 3% w/w, preferably less than 2% w/w of one or more cellulose derivatives, such as carboxymethyl cellulose or hydroxyethyl cellulose. The aqueous gel preferably further comprises from 0.1% to 5% w/v of dissolved salts. The salts are preferably selected from the chlorides, iodides, sulfates, phosphates, bromides, carbonates, bicarbonates and hydroxides of sodium, potassium, ammonium, zinc, silver and calcium. The dissolved salts preferably comprise sodium chloride, since it has been found that the presence of small amounts of sodium chloride can significantly affect the change in viscosity of the gel on sterilisation. The sodium chloride content thus provides a further parameter with which to control the viscosity of the sterile gel compositions. Also preferably, the gel compositions comprise phosphate salts or other suitable buffers to regulate the pH of the gel. As noted above the gels according to the present invention retain useful viscosity of at least 10 Ns/m 2 (10,000 cps) at 20°C after sterilisation. Preferably, the step of sterilising is carried out by heating at a temperature of for a period sufficient to give a sterility measure of FO 4 , more preferably FO 8 , and most preferably FO 12 . These FO values are standard measurements of the cumulative lethal effect of heating at a specified temperature for a specified time. Heating at 121°C (250°F) for 2.45 minutes corresponds to FO 12 , since it is understood to achieve a 10 12 - fold reduction in viable CL. Botulinum spores in phosphate buffer. Details of the FO measurement may be found in Principles and Practice of Disinfection. Preservation and Sterilization, 2nd edition, edited by A.D. Russell, W.B. Hugo and G.A.J. Ayliffe (Blackwell Scientific Publications), pages 521-524. Preferably, this step of heat-sterilising is carried out under pressure in an autoclave. The process according to the present invention further comprises the step of inserting the aqueous gel into a package prior to carrying out the step of sterilising. Preferably, the package is a tube, can or sachet. This procedure is advantageous because it enables the aqueous gels to be made under non-sterile conditions, packaged and then sterilised, thereby providing a relatively low-cost route to packaged sterile alginate gels. In order for the aqueous gel to be easily packaged prior to sterilisation, it is preferable for the viscosity of the aqueous gel (as determined by a spindle viscometer at ambient temperature) before sterilisation to be less than 150,000 cps, preferably less than 100 Ns/m 2 (100,000 cps). After sterilization, the viscosity at ambient temperature is preferably in the range 70-180 Ns/m 2 (70,000-180,000 cps). Preferably, the change in viscosity on autoclaving is no more than ± 20%. Specific embodiments of the processes according to the present invention will now be described further in and by the following Examples:- Example 1 The effect of propylene glycol (PG) content on the heat sterilisability of aqueous alginate gels is determined as follows. A number of aqueous alginate gels is made up according to the following proportions. The sodium alginate (Protanal® LF 10/60) has a stated molecular weight in the range 70,000 to 200,000. The potassium alginate has a molecular weight range of 300,000 to 350,000. Each gel is then sterilised in an autoclave to give a sterility measure of FO 12 . The viscosity in centipoise (cps) at 20°C is measured before and after sterilisation for each of the gels. 1 cps = 0.001 Ns/m 2 . The viscosity measurements are carried out with a rotating spindle, dial reading mechanical viscometer manufactured by Brookfield Viscometers Ltd. Brookfield Spindle No. 7 is used at a speed of 10 revolutions per minute. The sample is held in a cylindrical container measuring at least 50mm in diameter and holding sample to a depth of at least 70mm. The results are as follows (* denotes a comparative example). a) 4% w/v Sodium Alginate PG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 5* 2000 100 10* 2200 100 15* 4300 130 20* 9000 190 25* 7480 270 30 2700 13600 35 200 30000 40 50 17600 b) 5% w/v Sodium Alginate PG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 5* 4000 200 10* 6000 220 15* 12300 320 20* 19800 490 25 16200 21400 30 5780 53000 35 1400 34000 40* 50 Separated c) 6% w/v Sodium Alginate PG Conùc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 5* 7200 440 10* 17600 460 15* 29920 740 20* 38000 2200 25 28000 27000 30 10600 104000 35 4000 139000 40* 70 Separated d) 3% w/v Potassium Alginate PG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 5* 8400 180 10* 12000 190 15* 14000 400 20* 24200 440 25* 30200 700 30* 44000 1100 35* 35200 1760 40 12400 30000 e) 4% w/v Potassium Alginate PG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 5* 33000 900 10* 32000 1200 15* 42600 1700 20* 61200 1940 25* 78000 3460 30* 87200 4100 35 67200 30000 40 28000 122000 f) 5% w/v Potassium Alginate PG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 20* 141000 5400 25* 129000 7600 30 154000 36400 35 114000 172000 40 26400 126000 These results demonstrate clearly that, by optimising the level of alginate and propylene glycol, it is possible to produce an alginate gel which maintains, or even increases, its viscosity on autoclaving. Example 2 The procedure of Example 1 is followed for the following compositions, in which the propylene glycol (PG) of Example 1 has been replaced by hexylene glycol (HG). The results are as follows (* denotes a comparative example). 1 cps = 0.001 Ns/m 2 . a) 3% w/v Sodium Alginate HG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 5* 400 4 10* 980 14 15* 2900 40 20* 1200 60 25 80 10000 30* 20 Separated b) 4% w/v Sodium Alginate HG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 5* 2200 50 10* 4400 104 15* 9700 156 20* 2900 2100 25 25 10000 30* 10 Separated c) 5% w/v Sodium Alginate HG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 5* 4980 190 10* 14200 236 15* 17400 360 20 6600 32000 25 300 20600 30* 20 Separated d) 6% w/v Sodium Alginate HG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 5* 9850 100 10* 28700 100 15 30300 24400 20 13400 39600 25 1000 78000 30* Separated Separated These results demonstrate that hexylene glycol can also be used to form autoclave-stable alginate gels. It appears that less hexylene glycol than propylene glycol is needed to achieve equivalent stabilisation. Example 3 The effect of adding 0.6% w/v of sodium chloride to a 3% sodium alginate gel is illustrated by the following data (* denotes a comparative example). 1 cps = 0.001 Ns/m 2 . PG Conc. % w/v Unsterile Viscosity (cps) Sterile Viscosity (cps) 2.5* 1000 105 5.0* 1100 145 10.0* 4010 135 15.0* 2950 170 20.0* 584 2000 25.0 44 12000 40.0* 13 260 It can be seen that the addition of 0.6% w/v sodium chloride to the aqueous alginate gel at 25% w/v PG content results in a gel having substantially increased viscosity after autoclaving. Example 4 A heat-sterilizable alginate gel composition is manufactured as follows:- Component Trade Name % w / w in Formulation Sodium Alginate Protanal ®LF 10/60 3.00 Carboxymethyl Cellulose Aquasorb ® A250 7.00 Hydroxyethyl Cellulose Natrosol ® 250HX 0.35 Sodium Chloride - 0.30 Propylene Glycol Mono-PG USP 25.00 Purified Water - 70.35 The components are mixed thoroughly and then heat - sterilized to FO 12 . The resulting clear, sterile gel has a dynamic viscosity at 21°C of 150 Ns/m 2 (150,000 cps). The above embodiments have been described by way of example only. Many other embodiments falling within the scope of the accompanying claims will be apparent to the skilled reader.

Claims: A process to prepare a substantially sterile gel for use as a wound dressing, the process comprising the steps of; providing an aqueous gel comprising from 2% to 10% w/v of alginic acid or an alginate, from 15% to 40% of one or more polyhydric alcohols, and from 55% to 83% w/v of water; inserting the aqueous gel into a package; and heat sterilising the packaged aqueous gel to provide said substantially sterile gel for use as a wound dressing, wherein said packaged sterile aqueous gel has a viscosity of at least 10 Ns/m 2 (10,000 cps) at 20 °C. A process according to claim 1, wherein the aqueous gel comprises from 3% to 6% w/v of the alginate. A process according to claim 1 or 2, wherein the alginate is selected from the group consisting of sodium alginate and potassium alginate. A process according to claim 1, 2, or 3, wherein the aqueous gel contains 20% to 35% w/v of the polyhydric alcohol. A process according to any preceding claim, wherein the polyhydric alcohol comprises one or more C 3 -C 6 dihydric alcohols. A process according to claim 5, wherein the C 3 -C 6 dihydric alcohol comprises propylene glycol or hexylene glycol. A process according to any preceding claim, wherein the water content of said aqueous gel is from 55% to 79% w/v. A process according to any preceding claim wherein said aqueous gel, further comprises from 0.01% to 10% w/v of pharmaceutically active compounds. A process according to claim 8 wherein said aqueous gel comprises from 0.1% to 5% w/v of the pharmaceutically active compounds. A process according to claim 8 or 9, wherein the pharmaceutically active compounds comprise an antiseptic, an antibiotic, an analgesic, a glycosaminoglycan, a vitamin, an antibody, an enzyme, a haemostat, a cytokine, an inflammatory agent, an anti-inflammatory agent, a steroid or a growth factor. A process according to any preceding claim wherein said aqueous gel further comprises from 0.1% to 5% of dissolved salts. A process according to claim 11, wherein the dissolved salts comprise sodium chloride or phosphate salts. A process according to any preceding claim, wherein the step of heat sterilising is carried out by heating at a temperature and for a time sufficient to give a sterility measure of FO 4 . A process according to any preceding claim, wherein the step of heat sterilising is carried out under pressure in an autoclave. A process according to any preceding claim, wherein the package is a tube, can or sachet.

Inventors: FINDLAY CHARLOTTE MARIA, HARDY CRAIG JULIAN, FINDLAY, CHARLOTTE MARIA, HARDY, CRAIG JULIAN
Applicants: JOHNSON & JOHNSON MEDICAL, JOHNSON & JOHNSON MEDICAL, INC.
Application year: 1995
Main classification: A61L15
IPC codes: A61L2, A61L26, A61F13, A61K9, A61L15