WO2011128631A2

WO2011128631A2 - Vegetarian oral pharmaceutical and nutraceutical compositions

Info

Publication number: WO2011128631A2
Application number: PCT/GB2011/000561
Authority: WO
Inventors: Kurt Ingar Draget; Ingvild Haug; Anne-Ma H Carlsen; Tore Seternes; Steinar Johan Engelsen
Original assignee: PROBIO ASA
Current assignee: PROBIO ASA
Priority date: 2010-04-14
Filing date: 2011-04-11
Publication date: 2011-10-20
Anticipated expiration: 2012-10-14
Also published as: WO2011128631A3; GB201006182D0

Abstract

This invention provides an oral pharmaceutical or nutraceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion containing at least one nutrient or drug substance, characterized in that the aqueous phase of said emulsion contains a pectin gelling agent.

Description

Veqetarian Oral Pharmaceutical and Nutraceutical Compositions

This invention relates to oral pharmaceutical and nutraceutical compositions in the form of physiologically tolerable gelled oil-in-water emulsions containing a polysaccharide gelling agent.

In WO 2007/085835 and WO 2007/085840 were described oral pharmaceutical and nutraceutical compositions in the form of physiologically tolerable gelled oil-in-water emulsions and in which gelatin was used as the gelling agent in the continuous aqueous phase.

Gelatin, as widely used in oral pharmaceutical and nutraceuticals, is generally of animal origin, e.g. from cattle, pigs, or chicken. Accordingly, such compositions may be unacceptable to the patient on the basis of her beliefs or lifestyle. Gelatin moreover is a protein and may interact, e.g. bind to, certain drug substances, for example drugs in ionic form, aldehydes and aldehydic sugars (especially drugs of a tannin-like structure) as well as polyelectrolytes. Accordingly there is a need for oral pharmaceutical and nutraceutical compositions in the form of physiologically tolerable gelled oil-in-water emulsions in which a gelling agent other than gelatin is used.

While many non-proteinaceous gelling agents are known, e.g. alginates, gums and carrageenans, we have now surprisingly found that particularly readily consumable gelled oil-in-water emulsions may be prepared using pectins, plant-derived polysaccharides, as the gelling agent in the aqueous phase.

Thus viewed from one aspect the invention provides an oral pharmaceutical or nutraceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion containing at least one nutrient or drug substance, characterized in that the aqueous phase of said emulsion contains a pectin gelling agent.

Where pectin alone is used as the gelling agent in the aqueous phase, the pectin may be unalkoxylated / unesterified and gelled with Ca²⁺ ions, but is preferably an alkoxylated, e.g. methoxylated or ethoxylated, pectin when a high amount of solids is present and/or at low pH values. Such alkoxylated / esterified pectins, e.g. highly alkoxylated/highly esterified, for example highly methoxylated (HM) or highly ethoxylated (HE) pectins, are available commercially. By highly alkoxylated is meant a degree of esterification of at least 50%. Alternatively, pectins, for example unalkoxylated pectin, may be used in conjunction with a further non-proteinaceous gelling agent not of animal origin, for example a polysaccharide, e.g. an alginate, carrageenan or, preferably, agar.

The oil of the oil phase of the compositions of the invention may be any

physiologically tolerable lipid, e.g. a fatty acid ester such as a mono, di or triglyceride or a phospholipid. While this may be provided by a fish or shellfish triglyceride or phospholipid, for strict vegetarians it is preferably of microbial or plant origin. The lipid preferably comprises so-called essential fatty acids, e.g. the omega-3, omega-6 or omega-9 acids mentioned below. Omega-3 acids are especially preferred. Particularly suitable plant oils include evening primrose oil and borage oil, extra virgin olive oil and rape seed oil.

Where the compositions of the invention are nutraceuticals, the nutrient they contain is preferably at least one of lipids, vitamins, minerals, and folic acid. These may also be present in the pharmaceutical compositions according to the invention which must also contain a drug substance, e.g. an antibiotic, antifungal, analgesic, anticancer agent, etc. The nutrients and drug substances may be contained in the aqueous and/or oil phases of the compositions, e.g. in dissolved or dispersed form. The dosages of these substances may typically be 10 to 100%, especially 50 to 100%, of their recommended daily dosages or their dosages in conventional oral pharmaceutical or nutraceutical compositions.

Besides pectin, nutrients and drug substances, the compositions of the invention may if desired contain further ingredients such as for example antioxidants, pH modifiers, viscosity modifiers, colorants, aromas, and flavours. The compositions moreover may be provided with a physiologically tolerable coating or shell in conventional fashion.

Viewed from a further aspect the invention provides a method of treatment of a mammalian subject (either human or non-human) by oral administration to said subject of an effective amount of composition of the invention, e.g. to supplement nutrition and/or to combat an ailment responsive to the drug substance in the composition.

Viewed from a further aspect the invention provides a composition, comprising a drug substance disposed in a physiologically tolerable gelled oil-in-water emulsion the aqueous phase of which contains a pectin gelling agent, for use in medicine.

Viewed from a further aspect the invention provides a composition, comprising a drug substance disposed in a physiologically tolerable gelled oil-in-water emulsion the aqueous phase of which contains a pectin gelling agent, for use in treatment by oral administration of a condition responsive to said drug substance.

Viewed from a still further aspect the invention provides the use of a drug substance for the manufacture of a medicament, comprising said drug substance disposed in a physiologically tolerable gelled oil-in-water emulsion the aqueous phase of which contains a pectin gelling agent, for use by oral administration in the treatment of a condition responsive to said drug substance.

Examples of nutrients that the compositions of the invention may contain include materials such as lipids, (especially triglycerides and phospholipids, typically of plant or marine, non-mammalian, origin), vitamins, minerals, and folic acid, pH modifiers, viscosity modifiers, flavours, aromas, sweeteners, colorants,

antioxidants, etc.

The gelled emulsion compositions of the invention will preferably be in dose unit form, with each dose unit having a weight of 50 to 3000 mg, especially 100 to 1500 mg, particularly 400 to 1000 mg.

The composition of the invention will preferably be uncoated, i.e. not within a capsule or shell-coating. Accordingly, to avoid water loss during storage, the dose units will conveniently be individually packaged, e.g. in foil wrappers or in the blisters of a blister pack.

The oil phase of the oil-in-water emulsion may be any physiologically tolerable lipid, e.g. fatty acid esters such as triglycerides and phospholipids, for example plant or non-mammalian marine animal oils, especially plant and fish or shellfish oils.

Particularly preferably an oil is used which is high in omega-3, omega-6 or omega-9 essential fatty acids, especially omega-3 essential fatty acids, more especially EPA and DHA. In this way the oil phase itself is a highly bioavailable source of nutrient lipids.

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 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.

Such 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.

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 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. 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.

The aqueous phase of the gelled emulsion will contain Water and a pectin gelling agent, optionally together with one or more other non-proteinaceous gelling agent, e.g. agar, an alginate, or a carrageenan, preferably agar. 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). 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.

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.

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.

The gelled emulsions may if desired be more than Diphasic. Thus a water-in-oil emulsion may be emulsified with an aqueous gelling agent phase to produce a water-in-oil-in-water double emulsion, or two oil-in-water emulsions with different oil phases may be combined and intimately mixed before gelling onset. The invention will now be illustrated further with reference to the following non- limiting Examples.

Example 1

Gels with highly esterifed pectin

Water phase:

Water with 0.021 (w/w)% citric acid (pH about 3.1 ) 21.3 35

Pectin (60% Highly methoxylated-pectin/40% sugar) 1.8 3

Sorbitol 17.0 28

Xylitol 21.9 36

Oil phase:

Corn oil 36.5 60

Lemon flavour 1.5 2.4

Colour (yellow) 0.1 0.2

Total Ϊ00 146.6

The water phase was prepared at about 95°C under stirring (magnetic). The oil phase was heated to about 95°C and then dispersed into the water phase under agitation with a magnetic stirrer. The emulsion was made by mixing the solution with a high speed blender (Ultraturrax).

The emulsion may be filled into the blisters of a blister pack while still ungelled and then sealed in by fusing a foil lid to the blister tray.

Example 2

Combined gels with highly esterified pectin

Component % g

Water 18.66 30.00

Agar 0.75 1.20 Pectin (60% Highly methoxylated-pectin/ 0.12 0.20 40% sugar)

BLG (beta-lactoglobulin) 0.25 0.40

Glycerol 9.95 16.00

Sorbitol 17.41 28.00

Xylitol 17.41 28.00

Citric acid 0.62 1.00

Lemon flavour 1.24 2.00

Colour 0.06 0.10

Corn oil 33.58 54.00

Total 100.06 160.90

Two thirds of the water is mixed with glycerol and agar and kept at 90°C for 15-20 mins. The sorbitol and xylitol are added under shear until dissolved.

The pectin is dissolved in 7.5 mL water at ambient temperature. A stock solution of 16 (w/v)% BLG in water is prepared at ambient temperature by mixing under shear for up to 2 hrs to ensure total protein dissolution. 2.5 mL of 16 (w/v)% BLG is added to the pectin solution which is mixed well at 50°C for 15-20 mins.

The aroma and colour are added to the oil and equilibrated at 50°C for 10-15 mins.

The oil/aroma/colour is mixed with the pectin/BLG solution by applying an

Ultraturrax. The resulting emulsion is placed on a water bath at 50°C for 5-10 mins.

This emulsion (oil/BLG/pectin) is mixed into the agar solution applying an

Ultraturrax until a smooth emulsion is obtained. This emulsion is kept at around 50°C while the citric acid is added in small portions. The emulsion is filled into moulds at ambient temperature, and gel formation occurs after 15-20 mins.

Claims

1. An oral pharmaceutical or nutraceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion containing at least one nutrient or drug substance, characterized in that the aqueous phase of said emulsion contains a pectin gelling agent.

2. A composition, comprising a drug substance disposed in a physiologically tolerable gelled oil-in-water emulsion the aqueous phase of which contains a pectin gelling agent, for use in medicine.

3. A composition, comprising a drug substance disposed in a physiologically tolerable gelled oil-in-water emulsion the aqueous phase of which contains a pectin gelling agent, for use in treatment by oral administration of a condition responsive to said drug substance.

4. A method of treatment of a mammalian subject (either human or non- human) by oral administration to said subject of an effective amount of composition according to any one of claims 1 to 3, e.g. to supplement nutrition and/or to combat an ailment responsive to a drug substance in the composition.

.

5. _ . The use of a drug substance for the manufacture of a medicament, comprising said drug substance disposed in a physiologically tolerable gelled oil-in- water emulsion the aqueous phase of which contains a pectin gelling agent, for use by oral administration in the treatment of a condition responsive to said drug substance.

6. A composition, use or method as claimed in any one of claims 1 to 5 wherein said gelling agent comprises a highly alkoxylated pectin.

7. A composition, use or method as claimed in any one of claims 1 to 6 wherein said composition contains a drug substance which binds to or lyses proteins.