PHARMACEUTICAL COMPOSITIONS FOR PROMOTING THE HEALING OF WOUNDS

Abstract: The invention relates to pharmaceutical compositions in the form of semi-solid aqueous gels for use in wound alimentation by application to a wound during healing. The compositions contain in solution each of the essential and semi-essential amino acids and malic acid and have a pH in the range 6.5 to 8.

Description: "pharmaceutical compositions for promoting the healing of wounds". The present invention relates to pharmaceutical compositions for promoting the healing of wounds. Patients with multiple injuries, especially those with large third degree burns and those undergoing major surgical operations, frequently need intravenous feeding. The nutrients can reach the reparative area if that area is well vascularised, but if adequate vascularisation is lacking, the only way for nutrients to reach the site under repair is by diffusion from neighbouring vascularised regions. If the areas to be repaired are large, the regenerative capacity of the patient may be exceeded, resulting in poorly granulating; easily infected surfaces. When large infected wounds do not respond to intensive nursing and medical care, the distress to both patient and nursing attendants is very great. It has been found that wound healing can be promoted by application of nutrients directly to the site concerned. The theoretical basis for such uptake of nutrients directly by the growing cells is not, however, well understood. Previous proposals of this kind have required application of a solution of nutrients, principally amino acids and carbohydrates, by infusion onto the surface, preferably using a dressing to maintain a body of liquid in contact with the wound. We have now found that a particuluar type of nutrient solution in the form of an aqueous semi-solid gel is especially suitable for the promotion of wound healiL-r by direct alimentation. By the term "semi-solid gel" we mean a gel which is spreadable or smearable, having the consistency of an ointment or cream. This term is intended to include colloidal dispersions of such materials as carboxymethyl cellulose, agarose etc., which have little or no resilience or elasticity but are of a gel-like nature. Compositions of such a consistency are particularly beneficial in releasing nutrients into the wound, as compared with solid or rigidly gelatinous nutrient formulations. We have found that the pH of such a composition is advantageously neutral or slightly alkaline, i.e. in the range 6.5 to 8.0. This is in contrast to a number of intravenous nutrient solutions which have generally previously been acidic. According to the present invention we provide a semisolid aqueous gel composition for wound alimentation containing in solution each of the essential and semi-essential amino acids and malic acid, the pH of the composition being in the range 6.5 to 8. According to a further aspect of the present invention we provide a method of manufacturing a semi-solid aqueous gel composition for wound alimentation which method comprises mixing each of the essential and semi-essential amino acids together with malic acid and adjustinq the pH of the composition to within the range 6.5 to 8. According to a yet further aspect of the present invention we provide a method of wound alimentation wherein a composition according to the present invention is applied to the wound during healing. In general, the total weight of amino acids should be in the range 3-17%. However, the overall quantity of amino acid material partly depends on the nature of the individual amino acids. In many intravenous nutrient solutions, the total nitrogen supplied is predominantly in the form of simple amino acids such as glycine, alanine and glutamic acid. The body is capable of using these amino acids to synthesise a number of the non-essential amino acids present in human tissue. In general, however, this approach is less efficient than using a mixture of amino acids which approximates relatively closely to the proportions of the amino acids found in human tissues. It seems likely that the mechanisms available to the body for synthesis of other amino acids from glycine, alanine and glutamic acid may not be effective at the site of granulation of new tissue. For that reason, the amino acids are, in one embodiment of the invention, preferably substantially in the proportions found in human tissue and in that it is not intended that the quantities of glycine, alanine and glutamic acid should be high enough to provide significant levels of other amino acids, the overall concentration of amino acids in the gel according to the invention is preferably in the range 3 to 6% by weight. It should be noted, however, that although the primary task of wound healing may be to regenerate skin, which consists largely of fibrous tissue, crude amino acid preparations derived by hydrolysis of collagen or elastin, which may be relatively inexpensive, do not contain all the essential amino acids and may contain peptide materials giving rise to reactions at the site of application. When the gel is hypertonic, due to relatively high concentrations of amino acids, the wound healing process may be promoted due to increased absorption of liquid secretion into the gel and increased movement of amino acids out of the gel. On the other hand, where the gel is substantially isotonic, it is more compatible with the granulating tissue. The amino acids used in the gel formulations of the invention are preferably present in the following quantities in g/kg gel. L-Isoleucine 1.3 - 5.7 L-Leucine 2.1 - 8.8 L-Lysine HC1 3.1 - 8.5 L-Methionine 1.8 - 7.5 L-Phenylalanine 3.2 - 7.5 L-Threonine 1.0 - 4.0 L-Tryptophane 0.5 - 1.7 L-Valine 1.6 - 6.7 L-Arginine 2.1 - 9.7 L-Histidine 1.1 - 5.8 L-Alanine 2.9 -15.6 L-Glutamic acid 1.9 -21.6 EMI4.1 <tb> <SEP> Essential <tb> <SEP> amino <SEP> acids <tb> X <SEP> Semi-essential <tb> J <SEP> amino <SEP> acids <tb> Glycine 2.0 -25.0 L-Proline 2.0 -15.0 L-Ornithine - L-Aspartate 1.0 - 8.5 L-Serine 1.6 - 7.3 As indicates above, it is important that all the essential and semi-essential amino acids are present in the gel. A preferred range of amino acid concentrations in g/kg gel is as follows: L-Isoleucine 1.8 - 5.4 L-Leucine 2.7 - 8.3 L-Lysine HC1 3.2. - 9.6 L-Methionine 2.2 - 6.8 L-Phenylalanine 3.2 - 9.8 L-Threonine 1.5 - 4.5 L-Tryptophane 0.6 - 2.0 L-Valine 2.1 - 6.3 L-Arginine 4.3 - 12.9 L-Histidine 1.0 - 3.2 L-Alanine 4.7 - 14.1 L-Glutamic acid 0.9 - 2.9 Glycine 2.0 - 6.2 L-Proline 5.6 - 16.9 L-Ornithine - L-Aspartate 0.9 - 2.9 L-Serine 1.1 - 3.5 The nutrient composition of the invention should also contain essential trace of minerals, in particular sodium, potassium, magnesium, chloride and acetate ions. A particularly important component in the nutrient gel according to the invention is malic acid. This is directly beneficial in the regenerative process. The concentration of malic acid in the medium is preferably in the range 2-6% by weight. The pH of the medium is preferably approximately neutral, i.e. in the range 6.5-8, preferably 7.0-7.5. It will be apsreciated that in this pH range, many of the amino acids and the malic acid will be present partially in the form of salts, e.g. alkali metal salts such as sodium salts. The gel-forming agent may be of a type conventional in the pharmaceutical art. Sodium carboxymethylcellulose is particularly suitable. Other cellulose derivatives such as microcrystalline cellulose are also suitable, as well as polysaccharides such as alginate, agarose, tragacanth, etc, andpolyvinylpyrrolidone. A surprising finding is that the compositions of the invention are resistant to bacterial and fungal infection in spite of the relatively high concentrations of nutrient material present. This is contrary to previous experience in handling nutrient materials. In some cases actual antibacterial activity has been observed. Thus, our tests have shorn thn compositions according to the invention to inhibit growth of Candida albicans, Clostridium sporogenes, Pseudomonas aerogenes and Escherischia coli and to be bactericidal with respect to Staphylococcus aureus. The new compositions are intended for application to the surface to be treated at relatively long intervals, for example, every 12 hours. Such a regime is similar to that proposed when using liquid solutions of amino acids by a continuous infusion technique and it is surprising that the gel can contain sufficient amino acid material to sustain increased granulation over such a long period. It will be appreciated that it is a significant advance in such treatment that it is possible to dispense with the container for liquid nutrient and its necessary suort system and tubing as previously used with the proposed infusion technique. In view of the significant danger of infection of large wound areas, it is often desirable to interpose a wound-disinfection treatment between applications of the gel material according to the invention. Particularly suitable antibactcrial substances for this purpose are Noxythioline, Taurolidine, iodine-providone, chlorhexidine and antibiotics suitable for local administration such as amfomycin, bacitracin, neomycin, tyrothricin, ploymycin, as well as tetracyclines and amino glycosides. The following example is given by way of illustration. EXAMPLE 1.0 kg of gel contains g Sodium-carboxy-methylcellulose 13,000 Glycerol BP 10,000 Propylenglycol 10,000 L-Isoleucine 3,586 L-Leucine 5,444 L-Lysine HCl 6,382* L-Methionine 4,506 L-Phenylalanine 6,459 L-Threonine 2,998 L-Tryptophane 1,315 L-Valine 4,206 L-Arginine 8,635 L-Histidine 2,060 L-Alanine 9,380 L-Glutamic acid 1,876 Glycine 4,129 L-Proline 11,265 L-Ornithine - L-Aspartate 1,876 L-Serine 2,253 mmol 59,100 Sodium ions Na + 32,87 Potassium ions K + 28,04 Magnesium ions Mg ++ 2,34 Chloride ions Cl - 63,04 Acetate ions Ac - 4,68 Malic acid 4,318 Aqua dest. ad 1000,000 * (Base 5.016) The glycerol and propylene glycol are added to the sodium carboxymethylcellulose and mixed to produce a smooth dispersion. The amino. acids,trace minerals and malic acid are dissolved in most of the water and ttepH is adjusted to 7.2 withsodium hydroxide. The above dispersion is added to the amino acid solution with continuous stirring, until free from undispersed solids and entrained air. The remaining water is then added to make up to the final volume. The resulting transparent, semi-solid gel is then autoclaved at 1150-1180C for at least 30 minutes. The consistency at 200C is about 20,000 cps (by Brook field Viscometer).

Claims: CLAIMS: 1. A semi-solid aqueous gel composition for wound alimentation containing in solution each of the essential and semi-essential amino acids and malic acid,the pH of the composition being in the range 6.5 to 8. 2. A composition as claimed in claim 1 containing the amino acids L-isoleucine, L-leucine, L-lycine, L-methionine, L-phenylalamine, L-threonine, L-tryptophane, L-valine,L-arginine, L-histidine L--alanine, L-glutamic acid, glycine, L-proline, L-serine, L-ornithine and L-aspartic acid. 3. A composition as claimed in claim 1 or claim 2 in which the gel is free from proteins or peptides. 4. A composition as claimed in claim 3 containing as a gel-forming agent, carboxymethyl celluldse, microcrystalline cellulose, alginate, agarose, tragacanth or polyvinylpyrrolidone. 5. A composition as claimed in any of the preceeding claims having a pH in the range 7.0 7.5. 6. A composition as claimed in any of the preceeding claims in which the concentration of amino acids is 3 to 6% by weight. 7. A composition as claimed in any of the preceeding claims in which the concentration of malic acid is 2 to 6% by weight. 8. A method of manufacturing a semi-solid aqueous gel composition for wound alimentation which method comprises mixing each of the essential and semi-essential amino acids together with malic acid and adjusting the pH cf the composition to within the range 6.5 to 8.

Inventors: CALVER, RICHARD FREDERICK, COTTIER, DAVID, STANLEY, JOHN KNOWLES
Applicants: ED. GEISTLICH SOHNE A.G. FUR CHEMISCHE INDUSTRIE
Application year: 1981
Main classification: A61K9
IPC codes: A61K47, A61L26, A61K31, A61K9