ZA200300639B - Pharmaceuticals and nutritional supplements. - Google Patents
Pharmaceuticals and nutritional supplements. Download PDFInfo
- Publication number
- ZA200300639B ZA200300639B ZA200300639A ZA200300639A ZA200300639B ZA 200300639 B ZA200300639 B ZA 200300639B ZA 200300639 A ZA200300639 A ZA 200300639A ZA 200300639 A ZA200300639 A ZA 200300639A ZA 200300639 B ZA200300639 B ZA 200300639B
- Authority
- ZA
- South Africa
- Prior art keywords
- chitosan
- acid
- complex
- salt
- carnitine
- Prior art date
Links
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Landscapes
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Description
. . &8003/¢
THIS invention relates to pharmacologically acceptable salts of chitosan, or mixtures of salts of chitosan, and their use as pharmaceuticals or nutritional supplements. :
Chitin is a water insoluble non-uniform mixture of various lengths of linear polymer chains of mainly N-acetyl-D-glucosamine and some D- glucosamine; the ratio of N-acetyl groups to free amino groups is relatively high. In chitosan, which is derived from chitin by deacetylation, free amino- groups predominate. The extent of deacetylation (or percentage of free amino-groups) depends on the method and conditions of deacetylation employed. Chitosan is insoluble in water and most other solvents. The solubility of chitosan in aqueous acid is determined by several factors which include average polymer chain length, degree of deacetylation, nature and concentration of the acid or acids employed, temperature, presence of other solutes and the like.
oe a 0037/0630
Aqueous solutions of chitosan salts are disclosed in US 2,040,879. The chitosan salts are readily prepared as non-hygroscopic free flowing : particles by treatment of a suspension of powdered chitosan in an appropriate solvent with a chosen acid. US 4,574,150 discloses the use of mainly non-hydroxylic organic solvents containing varying quantities of water. In US 5,061,792 dry free-flowing chitosan salts are prepared in aqueous monohydric alkanol mixtures of which the dielectric constant is required to be between 30 and 40 using acids having a first pK, in water of less than 5; these two criteria are considered critical for obtaining dry free- flowing chitosan salts.
It is known that water soluble salts, or mixtures of salts of chitosan, can be produced by neutralization of the basic amino groups of chitosan with one or more acids chosen from the following: nitric acid, phosphoric acid, phosphorous acid, phosphonic acids, sulphuric acid, sulphonic acids, mono-, di- or tricarboxylic acids, or polycarboxylic acids.
Whilst neutralization of a large number of the free amino-groups of chitosan by an appropriate mineral acid or a carboxylic acid with a pKa of less than 5 will often produce water soluble salts, weak acids (pKa above 5) cannot protonate free amino-groups quantitatively, or in stoichiometric proportions.
According to the invention a pharmacologically acceptable chitosan salt comprises a complex of a weak acid, a quaternary ammonium inner salt and chitosan.
The invention extends to a pharmaceutical or nutritional composition comprising a chitosan salt complex as defined above, or a pharmacologically acceptable salt or mixture of salts thereof, in a pharmacologically acceptable carrier.
The invention also extends to the use of a chitosan salt complex of the invention for optimising athletic performance, for facilitating muscle tissue repair for assisting the body in returning to normal physiological and metabolic status after exertion, as a nutritional composition in weight loss and maintenance diets, in geriatric tonics and as an immune system stimulant.
A further aspect of the invention comprises a method of producing a chitosan salt complex of the invention by contacting a weak acid with a quaternary ammonium inner salt to form a complex having an acid group sufficiently strong to complex with chitosan, and contacting the complex so produced with chitosan to produce a chitosan salt complex. This aspect extends to enhancing the ability of a weak acid to react with chitosan fo form a chitosan salt, comprising contacting the weak acid with a quaternary ammonium inner salt to form a complex having an acid group sufficiently strong to complex with chitosan. In order for the weak acid to bind quantitatively to chitosan (to form a water soluble salt) it is necessary to contact the weak acid with the inner salt in an equimolar ratio. The resulting complex will be bound to chitosan quantitatively and the complex so produced will typically contain 5% to 30% (by mass) thereof. oo The preferred weak acids of the invention include monobasic salts of the dicarboxylic acids malonic acid, succinic acid, glutaric acid, maleic acid, malic acid, citramalic acid (2-hydroxy-2-methylsuccinic acid) and especially the dibasic and complex salts of calcium, magnesium, iron and zinc with tricarboxylic acids including citric acid (2-hydroxy-1,2,3-propanetricarboxylic acid) and ftricarballylic acid (1,2,3-propanetricarboxylic acid) and further including complexes of iron with choline and citric acid described in US 2,865,938 and US 2,575,611.
Typical quaternary ammonium inner salts of the invention are betaine (carboxymethyltrimethylammonium), carnitine (both isomers and racemate) and O-acyl carnitine derivatives such as O-pyruvoyl-L-carnitine and the like,
I BR003/0639 , A choline-O-phosphate (phosphocholine) and phosphatidyicholine and its derivatives.
Particularly preferred chitosan complex salts of the invention are L-carnitine magnesium citrate chitosan salt, alkanoyl-L-camnitine magnesium citrate chitosan salt, L-carnitine magnesium pyruvate chitosan salt and alkanoy!-L- carnitine magnesium pyruvate chitosan salt.
It has surprisingly been found that the complex salt resulting from the reaction of a quaternary ammonium inner salt and a weak acid will result in a complex that possesses an acid group sufficiently strong to form a further complex salt with chitosan. Thus, for example, it has been found that L- carnitine reacts with magnesium citrate to form a complex salt, L-carnitine magnesium citrate, which can be used without isolation in a further reaction with chitosan.
OH CH,c02 :
Me CC) ® © S) | © (CH,);NCH,CHCH,CO + CHyCO; ———— = HOCCO, oo | E -Camitine repos vig OO CH,CO; hil
CH,CO% CH,
Magnesium citrate lL con "FORMULA 1 f ‘ [1 [f= -5-
The acidic complex salt of formula 1 reacts readily with the free amino groups of the chitosan to produce a chitosan complex salt. The structure of the complex (formula 2) may be depicted as follows:
H
7 0
H 0 —" . eo .
Js T
OH HOC——COP
VICE
CH,COP
FORMULA 2
The reaction between the complex salt of formula 1 and chitosan is quantitative. If a stoichiometric quantity of a complex salt of a quaternary ammonium inner salt such as betaine, for example, and a weak acid is reacted with chitosan according to the method of this invention, a quantitative yield of a free-flowing chitosan-betaine-weak acid complex can be isolated.
Similar reactions have been found to occur with alkanoyl-L-carnitine magnesium citrate.
Water soluble free flowing complex salts of chitosan of the invention have been prepared by the treatment of chitosan (base) with a bridging betaine - (or inner salts in general) and weak carboxylic acids (pK, above 5) as well as mixtures of these salts so produced in combination with “solubilizing” acids (pK; below 5). These “solubilizing” acids are stronger acids and may be added to the weak acid-inner salt-chitosan complex. This added strong acid can aid in improving water solubility of the resulting complex. The total quantity of acid that may be added to chitosan, in terms of the sum of the proton acid equivalents of the weak acid—-inner salt and the strong acid, should not exceed the amount of free amino-groups of chitosan, in equivalents —NH, per unit mass, available for salt formation.
It has been found that the water soluble dry, pharmaceutically acceptable salts of chitosan produced by the treatment of chitosan with weak acids (pKa above 5) and with betaine substances according to the invention, are excellent for use as pharmaceuticals or nutritional supplements, especially as components of nutritional compositions in the form of a dry powder to be taken as a mixture in water for optimising athletic performance requiring strenuous muscular activity and to facilitate muscle tissue repair and a rapid return of the body to normal physiological and metabolic status after exertion. Other applications of the invention include nutritional compositions useful in weight loss and maintenance diets, in geriatric tonics and as immune system stimulants.
Chitosan complexes of the invention, especially in combination with carnitine and pyruvic acid, help to prevent the occurrence of muscle fatigue and alleviate muscle pain. Chitosan itself is an immune stimulant and aids in the prevention of post-exercise respiratory irritation and infections. The complexes also have beneficial cardiovascular effects. The components of the preferred complex are: ¢ Chitosan, which is a poly-D-glucosamine of natural origin and is a known immune stimulant that is also capable of binding fat. It serves as a metabolic source of D-glucosamine. e L-Carnitine, which is essential for fatty acid metabolism and the transport of fatty acids between cell compartments. It helps to reduce serum glycerides and to increase blood high-density lipoprotein (HDL, or “good fat”) levels.
e Magnesium and Pyruvate, which promote fat metabolism, enhance glucose transport into muscle and assist in the maintenance of the water balance of cells. o Citrate, which is a member of the oxidative energy cycle (Krebs cycle).
Further, chitosan is known to be used in conjunction with vaccines for the purpose of immunostimulation. The use of chitosan linked to a phospholipid to stimulate the immune response to an antigen or to a vaccine in a host is described in US 5,785,975. In US 5,980,912 immunopotentiation induced by chitosan administered orally is described.
Additionally, the essential role of L-carnitine in fat metabolism is well established: a) It features prominently in the p-oxidation of fatty acids in mitrochondria of muscle tissue. b) lt is involved in the elimination and detoxification of selected fatty acids. c) Itassists in the translocation of fatty acids in cell compartments. d It modulates the ratio of free coenzyme A (CoA) and acylCoA.
It is known that L-carnitine is produced in human tissue from L-lysine and methionine and it is not considered to be an essential nutrient in the diet of adults. However, little evidence is available to indicate that humans can synthesize sufficient quantities to meet all metabolic requirements under all circumstances. Some studies suggest that for some individuals synthesis of endogenous carnitine may be inadequate. The precise daily requirement of the body for camitine is unknown. It is known that the L-form is the natural metabolite and is well tolerated by oral intake even in large doses.
In general animal tissues (beef and lamb) and dairy products contain relatively high levels of carnitine. Avocado has the highest carnitine concentration among vegetable foods. Low meat or vegetarian diets are low in L-carnitine. Weight loss diets provide very little carnitine.
Furthermore, the carnitine concentration in muscle is reduced by exercise.
Some clinical conditions present as primary or secondary carnitine deficiencies.
It has been demonstrated that under certain conditions oral administration of L-camitine can assist in reducing serum triglyceride (fat) levels, increasing blood high density lipoprotein (HDL) or “good fat” levels, and in relieving muscle pains.
The use of L-carnitine, acetyl-L-carnitine and propionyl-L-carnitine as basic active ingredients in a nutritional supplement for use in strenuous exercise and counteracting fatigue has been described in US 6,245,378.
Supplementation of L-carnitine in weight-loss diets or in high activity (sports) diets and in special nutritional compositions may therefore be justified, especially in combination with other nutritional supplements and adjuvants, such as those in the present invention.
Pyruvic acid, another ingredient that can be used in the Chitosan complex of the invention, (2-oxopropanoic acid, Merck Index 12" Edition, 8205) is a rapidly available source of energy in muscle. The medical uses of pyruvates are summarized in US 6,086,789.
Finally, acyl-muramic acid derivatives, especially peptide derivatives such as N-acetyl muramyl-L-alanyl-D-glutamic acid (MDP) are described in
US 4,186,194 as immunological adjuvants for stimulating in the host an immune response to various antigens, notably vaccines, and thus also form an important ingredient in certain of the pharmacological and nutritional supplements of the invention. :
A preferred but non-limiting embodiment of the invention, in the form of a nutritional composition for strenuous exercise and sport, consists of the following components:
0- 1. Carbohydrates in the form of a mixture of monosaccharides, such as glucose and fructose, to provide a rapidly absorbed and readily available source of energy and a mixture of polysaccharides, preferably in the form of acid modified high amylose starch with an average molecular mass of about 5000 to 30000, which is water soluble to a degree and which is readily digestible to provide a sustained source of energy over a period of time, thereby avoiding a sudden and undesirable increase in blood insulin levels. The mixture of carbohydrates allows the maintenance of optimum levels of blood glucose and stable levels of insulin, without the fluctuations associated with large doses of rapidly absorbed monosaccharides.
Constant near normal insulin levels ensure minimum lipogenesis (fat formation), prevent calcium depletion and enhance the rate of restoration of glycogen in muscle tissue. 2. Protein: sufficient protein in relation to carbohydrate in the mixture provides a source of amino acids essential for synthesis of proteins, such as muscle fibres, structural and functional proteins, enzymes and the like, and for muscle hydration repair and recovery and also to help balance gastric effects associated with high sugar intake. 3. Amino acids: added free amino acids aid in cell repair and regeneration of muscle and serve as building materials for the production of proteins and essential metabolites in cells: 3.1 L-Arginine: stimulates insulin release. 3.2 L-Glutamine: improves water absorption in the small intestine, assists in reducing muscle stress and stimulates the immune system. 3.3 L-lsoleucine and L-Leucine: contain branched hydrocarbon side-chains to serve as possible alternative sources of energy. 4, Vitamins: all vitamins are incorporated in the mixture at levels that will provide the recommended daily allowance per portion.
5. Minerals maintain and regulate the hydration status and integrity of cells. They are also essential structural components of many enzymes (biochemical catalysts). Electrolytes are lost through. perspiration and should be replaced continuously during exercise in order to perform at an optimum. Included in the mixture are sodium chloride, potassium phosphate, calcium, magnesium and zinc in absorbable pharmaceutically acceptable form. 6. Chitosan/L-Carnitine/Magnesium/Citrate-Pyruvate complex of the invention. 7. Antioxidants. The mixture contains several natural antioxidants that serve to deactivate free radicals, thus preventing them from destroying cell components. Antioxidants also provide exceptional long-term health benefits in preventing genetic mutations and other metabolic disturbances. They contribute to the prevention of cancer, coronary heart disease and delay certain processes of ageing.
Admixed antioxidants are: Vitamins A, C and E, soya isoflavones (diadzein and genestein) polyphenols (resveratrol and grape seed extract) and ubiquinone (co-enzyme Q10). 8. B-Sitosterol: the mixture of the invention contains B-sitosterol, which is a known immune stimulant that also reduces blood cholesterol levels and the absorption of cholesterol. 9. Other metabolic aids of the mixture include glutathione, o-lipoic acid and inositol. These substances are involved in cellular energy metabolism. 10. Flavourants, colourants and artificial sweeteners generally approved by pharmaceutical and food registration authorities. : ! The following non-restrictive examples illustrate the invention:
EXAMPLE 1
L-Carnitine magnesium citrate chitosan salt
To a stirred solution of 52.5g (0.25 mol) of citric acid monohydrate in 200ml of water at ambient temperature was added 10.08g (0.25mol) of magnesium oxide to produce a clear solution of magnesium citrate. To this solution was added 40.3g (0.25 mol) of L-carnitine. The clear solution of L- carnitine magnesium citrate is added to a rapidly stirred suspension of 50g of powdered chitosan in 1500ml of 2-propanol at 40-50°C. (The chitosan had a degree of deacetylation of 80+%, and therefore the 50g chitosan contained at least 0.25 mol equivalents of free amino-groups). The mixture was stirred at 40°C for 6 hours. The solid was collected on a filter, washed with 400ml of 2-propanol followed by 200ml of hexane. The solid was dried at 50°C. Yield: 96g of off-white free flowing powder. The product was soluble in water.
EXAMPLE 2
L-Carnitine pyruvate chitosan salt
A solution of 40.3g (0.25 mol) of L-carnitine and 22.0g (0.25 mol) of pyruvic acid in 200ml of water was added to 50g (0.25+ mol of free amino-groups) of chitosan vigorously stirred in 1500ml of 2-propanol at 40°C. After 6 hours of stirring the solid was collected and washed according to the procedure of example 1. The yield was 104g of light yellow free-flowing powder that was water soluble.
EXAMPLE 3
L-Carnitine magnesium citrate/pyruvate chitosan salt
The mixed salt was prepared by addition of 200ml of an aqueous solution of 0.125 mol of L-carnitine magnesium citrate and 0.125 mol of L-carnitine pyruvate to 50g (at least 0.5 mol of free amino groups) of chitosan in 1500ml of 2-propanol according to the previous examples. The yield of mixed salt was nearly quantitative.
EXAMPLE 4
A fraction of the total equivalents of acid used in example 3 was replaced with MDP to give a more complex chitosan salt.
The products were tested and found to be useful in weight reduction diets and as nutritional supplements for sportsmen.
EXAMPLE 5
A particular nutritional composition of the invention in which the chitosan, magnesium citrate, L-carnitine and pyruvic acid are added in the form of the complex salt of Example 3 comprises the following components:
Starch, modified high amylose 40.00 g °ROPGEN ©
Soya protein extract 16.00 g
Aumosens. oo...
L-Arginine hydrochloride 125¢
L-Glutamine 1.00¢g
[i Veneasem | om
EE
ROE a ES
Claims (13)
1. A chitosan salt comprising a complex of a weak acid, a quaternary ammonium inner salt and chitosan.
2. A chitosan salt according to claim 1, wherein the weak acid has a pK, value above 5.
3. A chitosan salt according to claim 2, wherein the weak acid is selected from the group comprising monobasic salts of the dicarboxylic acids malonic acid, succinic acid, glutaric acid, maleic acid, malic acid and citramalic acid, the dibasic and complex salts of calcium, magnesium, iron and zinc with the tricarboxylic acids citric acid and tricarballylic acid, and of iron with choline and citric acid.
4. A chitosan salt according to any one of claims 1 to 3, wherein the quaternary ammonium inner salt is selected from the group comprising betaine, carnitine and O-acyl carnitine derivatives.
5. A chitosan salt according to claim 4, wherein the O-acyl carnitine derivatives are selected from the group comprising O-pyruvoyl-L- carnitine, choline-O-phosphate (phosphocholine), and phosphatidylcholine and its derivatives.
6. A chitosan salt according to claim 1, which is L-carnitine magnesium citrate chitosan salt, alkanoyl-L-carnitine magnesium citrate chitosan salt, L-carnitine magnesium pyruvate chitosan salt, or alkanoyl-L-carnitine magnesium pyruvate chitosan salt.
7. A pharmaceutical or nutritional composition comprising a chitosan salt complex as defined in any one of the preceding claims, or a pharmacologically acceptable salt or mixture of salts thereof, in a pharmacologically acceptable carrier.
w | 8200370639
:
8. The use of a chitosan salt complex as defined in any one of claims 1 to 6 in a method for optimising athletic performance, for facilitating muscle tissue repair for assisting the body in returning to normal physiological and metabolic status after exertion, as a nutritional composition in weight loss and maintenance diets, in geriatric tonics or as an immune system stimulant.
9. A method of producing a chitosan salt complex, comprising the steps of contacting a weak acid with a quaternary ammonium inner salt to form a complex having an acid group sufficiently strong to complex with chitosan, and contacting the complex so produced with chitosan to produce a chitosan salt complex.
10. A method of enhancing the ability of a weak acid to react with chitosan to form a chitosan salt, comprising contacting the weak acid with a quaternary ammonium inner salt to form a complex having an acid group sufficiently strong to complex with chitosan.
11. A chitosan salt according to claim 1, substantially as herein described with reference to any one of the illustrative Examples.
12. A nutritional composition substantially as herein described with reference to Example 5.
13. A method of producing a chitosan salt complex substantially as herein described with reference to any one of the illustrative Examples. DATED THIS 23RD DAY OF JANUARY 2003
Hy . APPLICANTS PATENT ATTORNEYS
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200300639A ZA200300639B (en) | 2002-02-08 | 2003-01-23 | Pharmaceuticals and nutritional supplements. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200201116 | 2002-02-08 | ||
| ZA200300639A ZA200300639B (en) | 2002-02-08 | 2003-01-23 | Pharmaceuticals and nutritional supplements. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200300639B true ZA200300639B (en) | 2003-08-20 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200300639A ZA200300639B (en) | 2002-02-08 | 2003-01-23 | Pharmaceuticals and nutritional supplements. |
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| Country | Link |
|---|---|
| ZA (1) | ZA200300639B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017187033A1 (en) * | 2016-04-27 | 2017-11-02 | Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic | Method for evaluating the ability of a composition to prevent muscle damage and fatigue; food supplement and drug |
-
2003
- 2003-01-23 ZA ZA200300639A patent/ZA200300639B/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017187033A1 (en) * | 2016-04-27 | 2017-11-02 | Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic | Method for evaluating the ability of a composition to prevent muscle damage and fatigue; food supplement and drug |
| CN109073636A (en) * | 2016-04-27 | 2018-12-21 | 化工产品开发公司Seppic | Method for assessing the ability of composition prevention muscle damage and fatigue；Food supplement and drug |
| EP3583952A1 (en) * | 2016-04-27 | 2019-12-25 | Société d'Exploitation de Produits pour les Industries Chimiques SEPPIC | Method for assessing the capacity of a composition for preventing muscle fatigue and damage; novel food supplement and drug |
| US11246853B2 (en) | 2016-04-27 | 2022-02-15 | Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic | Method for evaluating the ability of a composition to prevent muscle damage and fatigue; food supplement and drug |
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