ENGELSEN, Steinar Johan (Ayanda AS, Fridtjof Nansens plass 6, Tromsø, N-9008, NO)
SETERNES, Tore (Ayanda AS, Fridtjof Nansens plass 6, Tromsø, N-9008, NO)
DRAGET, Kurt Ingar (Ayanda AS, Fridtjof Nansens plass 6, Tromsø, N-9008, NO)
ENGELSEN, Steinar Johan (Ayanda AS, Fridtjof Nansens plass 6, Tromsø, N-9008, NO)
SETERNES, Tore (Ayanda AS, Fridtjof Nansens plass 6, Tromsø, N-9008, NO)
COCKBAIN, Julian (45 Souothmoor Road, Oxford OX2 6RD, GB)
| Claims: 1. A method of nutritional supplementation of a human subject having a condition causing impaired essential fatty acid uptake, said method comprising administering orally to said subject a pharmaceutical or nutraceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion wherein the oil phase comprises an essential fatty acid or ester or salt thereof. 2. A pharmaceutical or nutraceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion wherein the oil phase comprises an essential fatty acid, characterised in that at least part of the essential fatty acid is present as a free fatty acid, a physiologically tolerable salt of a free fatty acid, or a monoacylglyceride. 3. A drug substance-containing physiologically tolerable gelled oil-in-water emulsion wherein the oil phase comprises an essential fatty acid, at least part of which is present as a free fatty acid, a physiologically tolerable salt of a free fatty acid, or a monoacylglyceride, for use in medicine. 4. The use of a drug substance for the manufacture of a medicament in the form of a drug substance-containing physiologically tolerable gelled oil-in-water emulsion wherein the oil phase comprises an essential fatty acid, at least part of which is present as a free fatty acid, a physiologically tolerable salt of a free fatty acid, or a monoacylglyceride, for use in treatment by oral administration of said composition of a condition responsive to said drug substance. |
The present invention relates to pharmaceutical and nutraceutical compositions suitable for oral administration to patients having impaired ability to absorb essential fatty acids from the gut, and to methods of treatment of such patients to enhance their nutrition.
Several disease conditions are associated with a diminished ability to absorb essential fatty acids (i.e. omega-3, omega-6 and omega-9 fatty acids) from normal foodstuffs, for example due to inflammation in the gut, reduced gut surface area, impaired secretion of digestion enzymes or bile, etc.
Examples of such conditions include coeliac disease, tropical sprue, Crohn's disease, short bowel syndrome, bowel cancer, cystic fibrosis, Shwachman- Diamond syndrome, Johanson-Blizzard syndrome, Pearson syndrome, pancreatic disorders, liver and biliary tract disorders, etc.
In the healthy human, the essential fatty acids are present in the diet as
triglycerides or phospholipids, e.g. of marine, plant or animal origin. Essential fatty acid supplementations of the diet for healthy humans normally take the form of marine or plant oils, administered in gelatin capsules or as a simple liquid.
We have now surprisingly found that essential fatty acid uptake from the gut is enhanced when the essential fatty acid is administered orally in or as the oil phase of a gelled oil-in-water emulsion. Such gelled emulsions are thus eminently suited for the nutritional enhancement of patients with impaired essential fatty acid uptake from the gut, e.g. patients suffering from one or more of the conditions listed above. Since impaired fatty acid uptake is also frequently associated with impaired uptake of lipid-soluble vitamins, the emulsions are also particularly suitable for use as a delivery vehicle for such vitamins.
Thus viewed from one aspect the invention provides a method of nutritional supplementation of a human subject having a condition causing impaired essential fatty acid uptake, said method comprising administering orally to said subject a pharmaceutical or nutraceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion wherein the oil phase comprises an essential fatty acid or ester or salt thereof.
In the gelled emulsion used according to the invention, the essential fatty acid may be present as the free fatty acid or a salt thereof with a physiologically tolerable counterion (e.g. sodium, potassium, calcium, magnesium, ammonium, etc.) or as an ester, e.g. a lower alkyl (e.g. C 1-6 alkyl, especially ethyl) ester, a triglyceride, diglyceride, monoglyceride or phospholipid.
Since the patient may have impaired essential fatty acid uptake due to reduced secretion of digestive enzymes capable of triglyceride or phospholipid cleavage (e.g. pancreatic lipase), it is especially preferred that at least part of the essential fatty acid is presented as a monoglyceride or as the free fatty acid or salt. Gelled emulsions containing the essential fatty acid in this form are new and form a further aspect of the present invention.
Thus viewed from this aspect the invention provides a pharmaceutical or nutraceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion wherein the oil phase comprises an essential fatty acid, characterised in that at least part of the essential fatty acid is present as a free fatty acid, a physiologically tolerable salt of a free fatty acid, or a monoacylglyceride.
The compositions of and used in the method of the invention may be nutraceuticals or pharmaceuticals, in the former case containing only nutrients (e.g. fatty acids, proteins, carbohydrates, vitamins and minerals) and carriers and excipients, and in the latter also containing physiologically active drug substances, e.g. anticancer agents, antibiotics, analgesics, etc.
The essential fatty acid may, as mentioned above, be an omega-3, omega-6 or omega-9 acid or a mixture thereof.
Examples of omega-3 acids include a-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA),
tetracosapentaenoic acid and tetracosahexaenoic acid. Examples of omega-6 T/GB2011/000556
- 3 - acids include linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo- gamma-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid, docosapentaenoic acid, and calendic acid. Examples of omega-9 acids include oleic acid, eicosenoic acid, mead acid, erucic acid and nervonic acid.
Omega-3 acids are especially preferred, particularly EPA and DHA.
The essential fatty acids may form part or the whole of the oil phase in the gelled emulsion, preferably at least 10% wt, more especially at least 50% wt, particularly at least 80% wt. of that phase. They may be used as single compounds or as compound mixtures, e.g. plant or marine oils. The free fatty acids, the monoacyl glycerides and diacylglycerides may be prepared by full or partial hydrolysis of triacylglycerides, for example acid, base, or enzyme-catalysed hydrolysis, e.g. using lipases such as pancreatic lipases and/or lipases which may be produced from bacteria as fermentation products.
AlkyI esters of essential fatty acids may be prepared by transesterification using the appropriate alkanol or by esterification of the free fatty acid with that alkanol.
Where a free fatty acid is used, this may be in acid form or salt form (e.g. wholly or partially in salt form), and preferably constitutes 5 to 75% wt, especially 10 to 35% wt. of the essential fatty acid in the oil phase. Salt forms may be preferred. Quite surprisingly, the soapy taste of the free fatty acid is masked by presentation in the gelled oil-in-water emulsion form. Where free fatty acids or salts thereof are used, it is particularly preferable to use these in conjunction with monoacylglycerides or diacylglycerides such that the molar ratio of free fatty acid to monoacylglyceride is about 2:1 , e.g. 1.9:1 to 2.1 :1 , or free fatty acid to diacylglyceride is about 1 :1 , e.g. 0.9:1 to 1.1:1.
Besides the essential fatty acid, the lipid phase of the gelled emulsion may contain other lipids or lipid-soluble materials, e.g. saturated fatty acid esters, lipid-soluble vitamins, lipid soluble drug substances, flavours, colorants, antioxidants, etc., as desired. It may also be preferred to include lipases, in particular pancreatic lipases within the compositions of the invention to further enhance fatty acid uptake, especially if the oil phase includes triglycerides or phospholipids. The oil phase of the oil-in-water emulsion may also contain solubilisers in order to increase the solubility of the drug substance in the oil phase. Suitable solubilisers would be known to a person skilled in the art and include Chremophor EL™, castor oil, Tween 80™, Solutol™ HS15, Lutrol™ and Olestra.
It is particularly preferred that the compositions according to the invention contain a citrus flavour (e.g. orange or lemon oil) in order to mask any remaining oil taste on chewing. It is also particularly preferred that the compositions according to the invention contain xylitol, e.g. as 0.5 to 50% wt., preferably 1 to 40% wt., e.g. 15 to 40% wt., in order to mask both taste and mouth feel. These may be in the aqueous phase or the oil phase (e.g. as a water-in-oil-in water emulsion), or both; however inclusion in the aqueous phase will generally be sufficient.
The aqueous phase of the gelled emulsion will contain water and a physiologically tolerable gelling agent, e.g. a hydrocolloid such as gelatin, alginate, carrageenan or a pectin. Such gelling agents and their gel-forming properties are well known. See for example Phillips GO and Williams PA (Eds.) Handbook of hydrocolloids, Woodhead Publishing, Cambridge (2000). The use of gelatin is especially preferred. Besides water and the gelling agent, the aqueous phase of the gelled emulsion may contain other water-soluble components, e.g. vitamins, minerals, pH modifiers, viscosity modifiers, antioxidants, colorants, flavours, water-soluble drug substances, etc. as desired.
Particularly preferably the gelled emulsions contain vitamins and optionally also minerals. Examples of such components include calcium, folic acid, iron, vitamin B12 and other B vitamin complexes, and vitamins A, D, E, K, and retinyl palmitate. Desirably these should be included at 10 to 100% of the recommended daily dose.
The weight ratio of the lipid phase to the aqueous phase in the gelled emulsions is preferably 1 :19 to 3:1 , especially 35:65 to 1 :1 , particularly 2:3 to 1 :1 .
The gelled emulsion is preferably in dose units of 50 to 5000 mg, especially 100 to 3000 mg, particularly 400 to 2000 mg, more particularly 600 to 1500 mg. Such dose units may be coated, e.g. with a capsule shell, however preferably they are uncoated. Dose units are preferably individually packed, e.g. in foil wrappers or in the blisters of a blister pack.
The dose units of the gelled emulsion may be formed for example by moulding, extrusion or cutting or the like. For adult use, the dose units are preferably in tablet or lozenge form; however for child use they may conveniently be presented in child- friendly form, e.g. geometric shapes such as rods, strips and tubes, or animal, doll, or vehicle shapes, for example the shape of a popular cartoon character.
Dose units may be coated if desired, e.g. as described in WO2007/085835. The use of gelatin coatings is preferred.
If desired, the compositions may be double emulsions, e.g. water-in-oil-in-water emulsions or oil-in-water emulsions containing two different oil phases. These may be prepared conventionally, e.g. by mixing two oil-in-water emulsions before gelling begins or by emulsifying a water-in-oil emulsion into a gelling agent containing aqueous phase.
Emulsion formation may be effected by conventional techniques; however emulsification under a non-oxidising gas, e.g. nitrogen, is preferred. Likewise, the components of the emulsion are preferably degassed before emulsification and handling and packaging of the set emulsion is preferably performed under such a gas.
The gelled emulsions of and used according to the invention may be produced as described in WO 2007/085835 and WO 2007/085840 and PCT/GB2009/002404 and PCT/GB2009/002406 (copies of which are annexed to the description of this application as Annexes A and B) the contents of which are hereby incorporated by reference.
Viewed from a further aspect the invention provides a drug substance-containing physiologically tolerable gelled oil-in-water emulsion wherein the oil phase comprises an essential fatty acid, at least part of which is present as a free fatty acid, a physiologically tolerable salt of a free fatty acid, or a monoacyiglyceride, for use in medicine. The drug substance used may be any drug substance capable of functioning following oral administration, e.g. an analgesic, antibiotic or anticancer agent. The drug substance may typically be administered at or near its conventional oral dosage amount.
Viewed from another aspect the invention provides the use of a drug substance for the manufacture of a medicament in the form of a drug substance-containing physiologically tolerable gelled oil-in-water emulsion wherein the oil phase comprises an essential fatty acid, at least part of which is present as a free fatty acid, a physiologically tolerable salt of a free fatty acid, or a monoacylglyceride, for use in treatment by oral administration of said composition of a condition
responsive to said drug substance
The invention will now be described further with reference to the following non- limiting examples:
Example 1
Free fatty acid tablet
Components (% bv weiqht)
Gelatin 5.6 %
Gum arabicum 3.7 %
Sorbitol 10.3 %
Xylitol 24.0 %
Citric acid 0.6 %
Flavour 1.2 %
Colour 0.7 %
Free fatty acids 10 - 40 %
Water to 100 %
Free fatty acids (e.g. omega-3 acids, in particular a mixture of DHA and EPA) are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet. Example 2
Combined free fatty acid/triglyceride tablet
Components (% bv weight)
Gelatin 5.6 %
Gum arabicum 3.7 %
Sorbitol 10.3 %
Xylitol 24.0 %
Citric acid 0.6 %
Flavour 1.2 %
Colour 0.7 %
Free fatty acids * 10 - 30 %
Triglycerides * 10 - 30 %
Water to 100 %
* The sum not to exceed 40%
Free fatty acids (e.g. omega-3 acids, in particular a mixture of DHA and EPA) and triacylglycerides of poly and mono unsaturated fatty acids are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.
Example 3
Combined free fatty acid/fatty acid ethyl esters tablet
Components (% by weight)
Gelatin 5.6 %
Gum arabicum 3.7 %
Sorbitol 10.3 %
Xylitol 24.0 %
Citric acid 0.6 %
Flavour 1.2 % Colour 0.7 %
Free fatty acids * 10 - 30 %
Ethyl esters of free fatty acids * 10 - 30 %
Water to 100 %
* The sum not to exceed 40%
Free fatty acids (e.g. omega-3 acids, in particular a mixture of DHA and EPA) and ethyl esters of poly and mono unsaturated fatty acids are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.
Example 4
Combined free fatty acids/monoacylglycerides tablet
Components (% bv weiqht)
Gelatin 5.6 %
Gum arabicum 3.7 %
Sorbitol 10.3 %
Xylitol 24.0 %
Citric acid 0.6 %
Flavour 1.2 %
Colour 0.7 %
Free fatty acids * 10 - 30 %
Monoacylglycendes * 10 - 30 %
Water to 100 %
* The sum not to exceed 40%
Free fatty acids (e.g. omega-3 acids, in particular a mixture of DHA and EPA) and monoacylglycendes of poly and mono unsaturated fatty acids (e.g. Omacor (Trade Mark)) are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.
Example 5
Gelled tablet with fat soluble vitamins
Components (% by weight)
Gelatin 5.6 %
Gum arabicum 3.7 %
Sorbitol 10.3 %
Xylitol 24.0 %
Citric acid 0.6 %
Flavour 1 .2 %
Colour 0.7 %
Free fatty acids* 0 - 40 %
Monoacylglycerides* 0 - 40 %
Triglycerides* 0 - 40 %
Ethyl esters of free fatty acids* 0 - 40 %
Lipid soluble vitamins 0.001 - 0.5 %
Water to 100 %
* The sum not to exceed 40%
Free fatty acids (e.g. omega-3 acids, in particular a mixture of DHA and EPA), ethyl esters, triacylglycerides and/or monoacylglycerides of poly and mono unsaturated fatty acids are emulsified together with the lipid-soluble vitamins into the aqueous phase and the emulsion is poured in aliquots of 1 .5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.
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