WO2010035013A1

WO2010035013A1 - Krill oil powder and krill oil tablets

Info

Publication number: WO2010035013A1
Application number: PCT/GB2009/002311
Authority: WO
Inventors: Jo Klaveness
Original assignee: Omegatri AS
Current assignee: Golden Omega Norway AS
Priority date: 2008-09-26
Filing date: 2009-09-28
Publication date: 2010-04-01
Anticipated expiration: 2011-03-26
Also published as: GB0817701D0

Abstract

A pharmaceutical or nutraceutical composition in solid form, e.g. powder or tablet form comprising krill oil and carbohydrate.

Description

KRILL OIL POWDER AND KRILL OIL TABLETS

This invention relates to pharmaceutical and nutraceutical products in solid form, especially in the form of powder and tablets comprising krill oil and at least one carbohydrate optionally together with vitamins, minerals and/or pharmaceuticals, and the use of such tablets in the treatment or prophylaxis of disorders related to the cardiovascular system, skin and bone. In particular, the invention concerns the use of tablets comprising high concentrations and high doses of omega- 3 phospholipids in form of krill oil in the treatment or prevention of hypertriglyceridemia and cardiac infarction.

Omega-3 and omega-6 fatty acids are fatty acids essential to human health but ones which cannot be manufactured by the body. For this reason, omega-3 fatty acids must be obtained from food sources and can be found in fish and certain plant oils. It is important to maintain an appropriate balance of omega-3 and omega-6 (another essential fatty acid) in the diet as these two substances work together to promote health. Omega-3 and omega-6 fatty acids play a crucial role in brain function as well as normal growth and development for example.

There are three major types of unsaturated fatty acids that are ingested in foods and used by the body: the omega-6 fatty acid alpha-linolenic acid (ALA), and the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Once eaten, the body converts ALA to EPA and DHA, the two types of omega-3 fatty acids more readily used by the body. Extensive research indicates that omega-3 fatty acids reduce inflammation and help prevent certain chronic diseases such as heart disease and arthritis. These essential fatty acids are highly concentrated in the brain and appear to be particularly important for cognitive and behavioural function. In fact, infants who do not get enough omega-3 fatty acids from their mothers during pregnancy are at risk for developing vision and nerve problems.

As mentioned previously, it is very important to maintain a balance between omega-3 and omega-6 fatty acids in the diet. For example, omega-3 fatty acids help reduce inflammation whereas most omega-6 fatty acids tend to promote inflammation. An inappropriate balance of these essential fatty acids contributes to the development of disease while a proper balance helps maintain and even improve health. A healthy diet should consist of roughly one to four times more omega-6 fatty acids than omega-3 fatty acids.

With the development of convenience foods and a general decline in the consumption of healthy foodstuffs such as fresh fish, fruit and vegetables, the typical American diet tends to contain 1 1 to 30 times more omega-6 fatty acids than omega- 3 fatty acids and many researchers believe this imbalance is a significant factor in the rising rate of inflammatory disorders in the United States.

In contrast, however, the Mediterranean diet consists of a healthier balance between omega-3 and omega-6 fatty acids and many studies have shown that people who follow this diet are less likely to develop heart disease. The Mediterranean diet does not include much meat (which is high in omega-6 fatty acids) and emphasizes foods rich in omega-3 fatty acids including whole grains, fresh fruits and vegetables, fish, olive oil, garlic, as well as moderate wine consumption.

Thus, since their discovery in the 1970s, and the finding that the ratio of omega-3 to omega-6 acids is imbalanced in the diets of many individuals, omega-3 fatty acids or their derivatives have been made available to consumers as dietary supplements to try to restore the desired omega-3 to omega-6 balance. Omega-3 fatty acids or derivatives thereof are thus now taken routinely by many hundreds of thousands of individuals to prevent a variety of illnesses such as arthritis, cardiac infarction and stroke.

Omega-3 fatty acids are often provided to consumers in their naturally occurring triglyceride form. The Omega-3 fatty acid triglyceride or the free fatty acid itself are generally sourced from natural oils such as marine oils. Since it is difficult to isolate the omega-3 acids in high purity from marine oils, omega-3 supplements often possess an unpleasant fishy after taste which the consumer dislikes. It is also a major problem for many individuals, such as the elderly and children, to swallow the gelatine capsules used today to contain the omega-3 material. Capsules are also expensive to produce.

In addition to triglycerides and free fatty acids, omega-3 fatty acids might be in the form of esters (e.g. ethyl esters) and phospholipids. Omega-3 comprising phospholipids is present in relative high concentrations in krill oil and the phospholipid form of omega-3 fatty acids is claimed to have higher bioavailability than other omega-3 fatty acid derivatives. There is today an increasing interest in the market for krill oil as nutraceuticals and there are several capsule formulations of krill oil on the nutraceutical market. Some of these capsule formulations comprise of a mixture of fish oil and krill oil, while others are pure krill oil. One such product comprising pure krill oil is capsules from Swanson Health products in US (Swanson EFAs comprising Antarctic pure Neptune Krill oil). Each capsule comprises of 500 mg krill oil.

Krill are small shrimp-like animals living in the sea in Antarctic and Arctic regions. The total biomass of krill is huge, and over the last few years there has been an increasing interest in harvesting krill, especially from the Antarctic region. Companies like Neptune Technologies and Aker Biomarine ASA in Oslo, Norway are companies focusing on krill harvesting, krill processing and marketing of krill based products.

There are several species of krill. The most popular species for use in krill products seems to be E. superba. The size and the composition of krill vary a lot from species to species. The composition of the krill also varies during the year.

The lipid composition of krill oil is very different from the lipid composition in fish oil. Krill oil comprises of large quantities of phospholipids in addition to triglycerides and other lipophilic substances. Krill oil typically comprise of 40-50% phospholipids, typically phosphatidylcholines and phosphatidylethanolamines. Krill oil also contains astaxantin which is a natural antioxidant. Due to the content of astaxantin, the oil from krill is deep red in colour. The chemical composition of krill oil is thus more complex than fish oil.

There are many scientific publications and patent applications describing various aspects of krill technology. Several recently published patent applications suggest new methods for harvesting krill, new methods for processing krill, new compositions comprising krill and krill-based components and compounds. There are also several new patent applications describing new uses of krill and krill-based component and compounds. These uses include medical and nutraceutical use. US20080166418, US20080166419 and US20080166420 (all Sones) describe various krill compositions for treatment and preventing of cardiovascular diseases. US2007080515 (Aker Biomarine) describes antithrombotic krill extracts. WO2008060163 (Pronova) describes a process for preparation of omega-3-rich marine phospholipids from krill. WO2008050219 (Krill) describes methods and equipment for extraction of lipid fractions from marine and aquatic animals. US2006/0078625(Rockway) describes a composition including krill extracts and conjugated linoleic acid. WO2008/006607 (Nattopharma) describes pharmaceutical and nutraceutical products comprising Vitamin K2 and krill oil. WO2008/048107 (Aker Biomarine) describes floating trawl and methods for harvesting krill.

Other patent documents suggesting medical and/or nutraceutical use of krill or krill-based components or compounds are JP2568833, WO85/04809,

WO2007/044659, US2006078625, JP2004065152, WO2002/ 102394, WO93/24142, WO96/24371,WO95/33471, WO95/33470, EP170115 and JP54119011.

All krill oil compositions on the market are however capsule formulations. Capsule formulations are not mechanically resistant formulations and have the potential for leakage of krill oil from the capsule. This could result in discoloration of the environment (e.g. clothes, bags) due to the astaxantin present in the oil. Capsules are also a dosage form which many individuals are reluctant to swallow in view of their size and shape.

A further problem with capsule formulations of krill oil is their stability. Capsule formulations of krill oil have only limited stability, therefore. A further issue is that the amount of omega-3 which needs to be administered to achieve a clinical does is quite high. This means the capsules on the market are large making them even harder to swallow and also means that they contain high levels of krill oil and hence a strong, unpleasant fishy aftertaste. Alternatively, it means that the consumer has to take multiple smaller tablets which causes issues of repeated swallowing/after taste and expense.

The current solution to the problems of krill oil formulation is therefore the use of a capsule which contains a considerable amount of oily liquid and therefore delivers a sufficient dose. As noted above however, capsules are expensive, leave a bad "fishy" taste in the mouth of the consumer and are susceptible to oxidation. It would be therefore be useful if krill oil could be offered in alternative dosage forms, in particular tablets. In general, the most popular oral dosage form is a tablet, and it would be advantageous if a krill oil containing tablet could be made available which does not suffer from the problems of taste, oxidation, expense and the need for multiple/oversize dosage forms. None of the patent documents describes above enable krill oil tablets. Krill oil based products are used in high doses all over the world e.g. as nutraceutical products, and there is a need for new cheap and stable one-dose formulations, especially tablets, comprising a high dose of fatty acid or derivatives thereof. There is also a need for stable krill oil powder.

Surprisingly, we have now found that krill oil in the form of complexes or mixtures with carbohydrates can be prepared as stable solid materials, e.g. in form of a powder. These solid materials, especially powders can easily be transformed into tablets with high concentration of krill oil in the tablet. The present inventors have realised that ideal dosage forms for these compounds are tablets and these are readily swallowed and are cheap to manufacture. In particular, the inventors have found that tablets containing complexes or mixtures of krill oil with carbohydrates can be prepared by direct compression and moreover they can be prepared having a high concentration of the desired krill oil.

Thus, viewed from one aspect the invention provides a solid, preferably a powder, comprising krill oil and at least one carbohydrate. Preferably said solid is pharmaceutically or nutraceutically acceptable. Viewed from another aspect the invention provides a solid, preferably a powder, consisting of krill oil and at least one carbohydrate.

Viewed from another aspect the invention provides a pharmaceutical or nutraceutical composition in the form of a tablet for oral administration comprising krill oil and at least one carbohydrate. Said tablet is preferably formed from said pharmaceutically or nutraceutically acceptable powder.

Viewed from another aspect the invention provides a pharmaceutical tablet as hereinbefore described for use in the treatment or prophylaxis of disorders related to the cardiovascular system, metabolic system, skin and bone. Viewed from another aspect the invention provides the use of krill oil and at least one carbohydrate in the manufacture of a medicament in the form of a solid, e.g. a powder or tablet, for use in the treatment or prophylaxis of disorders related to the cardiovascular system, metabolic system, skin and bone.

Viewed from another aspect the invention provides a method of treatment or prophylaxis of disorders related to the cardiovascular system, metabolic system, skin and bone comprising administering to a patient a pharmaceutical tablet as hereinbefore described.

By nutraceutical is meant a composition comprising a food extract that provides medical or health benefits, including the prevention and treatment of disease. The solid composition, especially powders and tablets of the invention comprise a mixture krill oil and at least one carbohydrate. That mixture is preferably in the form of a complex. The term "complex" is used herein to designate that the krill oil, or at least some of the components in the krill oil, is associated with the carbohydrate through some form of intermolecular interaction involving non-covalent bonds. These bonds include relative weak bonds like hydrophobic interactions, ion-ion interactions, ion-dipole interactions, dipole-dipole interactions, hydrogen bonds or other weak chemical bonds. Without wishing to be limited by theory, it is the inventors opinion that these bonds are the basis for the observed transformation of the oil to a solid, in particular a dry powder. This unexpected observation forms part of the basis for this invention.

Moreover, it is believed that this behaviour is specific to krill oil over other marine oils such as fish oils. Fish oils contain much lower amounts of phospholipids and are not believed to form powders with carbohydrates readily. At the same concentration of carbohydrate to oil, it is believed that where powder krill oil/carbohydrate complexes will form, fish oil/carbohydrate complexes will not. It is only krill oil with its high phospholipid content that enables powder formation through non covalent molecular interactions as discussed above.

The krill oil used in the invention can be purchased from commercial sources such as Neptune Krill oil. The krill oil of the invention preferably contains at least 20 wt%, e.g. at least 25 %, preferably at least 35 wt%, especially at least 40 wt% unsaturated fatty acid phospholipids, typically phosphatidylcholines and phosphatidylethanolamines. Ideally the krill oil of the invention may contain at least 20 wt%, especially at least 25% omega-3 phospholipids. The krill oil used in the invention may also contain astaxantin. It is within the scope of the invention for a mixture of different krill oils to be used.

The at least one carbohydrate used in the invention can be any carbohydrate including monosaccharides, disaccharides, oligosaccharides and polysaccharides and mixtures thereof.

The most preferred monosaccharide is lactose. The most preferred disaccharide is sucrose. The most preferred oligosaccharides are dextrins or cyclodextrins. The most preferred polysaccharides are alginates, cellulose, starch, pectin, chitin and chitosan and derivatives of these compounds.

Lactose is available in different forms such as alpha-lactose, beta-lactose and spray dried lactose from various suppliers. All these lactose forms can be used in the present invention.

Various cyclodextrins and derivatives of cyclodextrins are available. Cyclodextrins with different cavity size can optionally be substituted. The preferred substituent include alkyl groups, hydroxyalkyl groups, acyl groups For reviews on pharmaceutical acceptable cyclodextrin derivatives see: K.Uekama et al in J. Inclution Phenomena and Macrocyclic Chemistry (2006) 56:page 3-8,T.Loftsson et al. in Am. J.Drug Deliv. (2004)2:page 261-275 and J.Szejtli in J. Inclution Phenomena and Macrocyclic Chemistry (2005)52:1-11.

The most preferred cyclodextrin to be used together with krill oil to form powder or tablet of krill oil are alpha-cyclodextrin, beta-cyclodextrin and gamma- cyclodextrin, in particular unsubstituted alpha-, beta- or gamma-cyclodextrins and methyl or hydroxypropyl derivatives thereof. The most highly preferred cyclodextrins are beta-cyclodextrin and hydroxypropyl-cyclodextrin.

If cyclodextrins are used, it is believed that some of the compounds in the krill oil will form non covalent bonds to the inner part of the cyclodextrins.

In one embodiment of the invention the carbohydrate used is not a cyclodextrin.

The polysaccharides to be used to form krill oil powder can be charged or non-charged. The molecular weight and the viscosity grade of the polysaccharide to be used according to the present invention can vary over a wide range. The most preferred polysaccharides are alginates including salts and derivatives thereof, e.g. alginic acid, dextrins, cellulose specially including commercial grades of microcrystalline cellulose, methylcellulose, ethylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose (e.g. its sodium salt), carboxymethylhydroxyethylcellulose, starch and alkylated starch, chitin and chitosan. One of the most preferred celluloses which can be used according to the present invention is microcrystalline cellulose like for example Avicel®. As an alternative to the use of the carbohydrate or optionally as well as their use, the invention covers the use of calixarenes to form complexes with the fatty acid compounds. Calixarenes are macrocyclic compounds capable of assuming a basket (or "calix") shaped conformation. They are formed from p-hydrocarbyl phenols and formaldehyde and the term applies to a variety of compounds derived by substitution of the hydrocarbon cyclo{oligo[(l,3-phenylene) methylene]}.

A discussion of the use of calixarenes in complexation of amphiphilic molecules can be found in Nannelli et al, Molecular Crystals and Liquid Crystals (2001), 367 621-630.

Viewed from another aspect therefore the invention provides a pharmaceutical or nutraceutical composition in the form of a solid, preferably powder or tablet for oral administration comprising krill oil and at least one calixarene, e.g. at least 10 wt% krill oil.

The pharmaceutical or nutraceutical solid, powder or tablet of the invention may comprise more than 10 wt%, e.g. more than 15 wt%, e.g. more than 20 wt%, especially more than 25 wt% of a complex or mixture comprising krill oil and at least one carbohydrate.

The solids, powders or tablets of the invention may contain at least 10 wt% krill oil e.g. at least 15 wt% or at least 20 wt% or at least 25 wt% krill oil.

The solids, powders or tablets of the invention may contain at least 10 wt% total oil content, e.g. at least 15 wt% or at least 20 wt% or at least 25 wt% krill oil

The weight ratio between krill oil (or oils total) and carbohydrate can vary over wide limits. The weight ratio may be in the range of 1 : 10 to 10:1 (between the krill oil (or oils in total) and carbohydrate), such as 1 :5 to 5: 1 , preferably 1 :4 to 4: 1.

It is preferred if the carbohyrate(s) is in excess.

The tablets of the invention preferably comprise krill oil/carbohydrate powder complex or mixture where the powder weight is more than 10% of the tablet weight , e.g. more than 20 %, preferably more than 30%, such as greater than 40%.

In some embodiments, the complex can form more than 70% of the tablet weight, preferably more than 80% of the tablet weight most preferably more than 90% of the tablet weight.

The tablets of the invention preferably contain at least 100 mg, e.g. at least 125 mg, preferably at least 150 mg, such as at least 200 mg, e.g. at least 300 mg of krill oil or krill oil in combination with at least one other oil, preferably at least 400 mg, more preferably at least 500 mg, especially at least 600 mg.

The pharmaceutical or nutraceutical solid composition, e.g. powder or tablet of the invention can contain other components in addition to krill oil and the at least one carbohydrate. In particular, the composition of the invention can comprise at least one other oil, especially an oil containing omega-3 compounds, e.g. a marine oil such as a fish oil.

Crude marine oils contain a variety of fatty acids or derivatives thereof (e.g. esters thereof, in particular triglycerides) having differing carbon chain lengths and differing levels of unsaturation.

The crude marine oil used as an additional component in the powders and tablets of the invention can be derived from any marine source such as fish, especially seawater fish such as tuna, sardines, salmon, mackerel, herring, trout, halibut, cod, haddock, catfish, sole etc. The use of oily fish is preferred. Ideally however, the crude marine oil will derive from marine mammals such as seals, walrus or sea lions, preferably seals. Seal oil has been found to be especially rich in omega-3 compounds, e.g. of the order of 20-25 wt% and therefore forms an ideal additional oil for the powders and tablets of the invention. Seal oils are available from a variety of commercial sources. A particularly preferred solid composition of the invention comprises a krill oil, another marine oil (e.g. a fish oil), and a cyclodextrin. It will be appreciated that the composition of the invention must still be in solid (ideally powder or tablet) form even when there is an additional oil present.

The pharmaceutical or nutraceutical tablet for oral administration preferably comprises more than 100 mg, e.g. at least 200 mg more preferably at least 300 mg, most preferably at least 400 mg of the mixture/complex of krill oil and at least one carbohydrate.

In a further preferred aspect of the invention, the solid composition, e.g. powders and tablets of the invention comprising krill oil can be formulated together with one or more other active agents. Active agents which could be combined with the complexes of the invention include pharmaceuticals, nutraceuticals, vitamins, minerals and other health supplementing compounds. Combination with drugs is highly preferable.

The most preferred drugs to be formulated together with fatty acid compounds in tablets according to the present invention are drugs for treatment and/or prophylaxis of diseases in the cardiovascular system, the metabolic system and in bone. Typical such drugs include ACE-inhibitors, like for example enalapril, angiotensin II receptor antagonists like losartan, beta-blockers like propranolol, plasma cholesterol reducing compounds like statins, typically simvastatin or atorvastatin, and bisphosphonates like for example alendronate. Other favourable drugs include glucosamine.

Highly preferred additional components in the compositions of the invention also include simvastatin, atorvastatin, glucosamine, vitamins and/or minerals in particular calcium, e.g. in the form of calcium carbonate.

Another preferred aspect of the present invention relates to tablets comprising krill oil together with these nutraceutical or pharmaceutical ingredients. Typical nutraceutical ingredients can be calcium, e.g. calcium carbonate, iron or other minerals, water-soluble vitamins like Vitamin B or Vitamin C, lipid-soluble vitamins like Vitamin A, D, K or E and ingredients present in the nature like for example herbs and extracts thereof. It is preferred if compositions of the invention are free of vitamin K, especially vitamin K2.

Viewed from another aspect the invention provides a pharmaceutical tablet for oral administration comprising krill oil and at least one carbohydrate and at least one drug compound selected among drugs for treatment or prophylactic treatment of metabolic disorder.

Typical methods for preparation of the krill oil carbohydrate powder complex or mixture include for example, formation of the complex/mixture in water, in mixture of water and organic solvent(s) or water- free organic solvents at ambient temperatures. Typical organic solvents include preferably methanol, ethanol and isopropanol but can also include acetone, DMSO, DMF and acetonitrile. The ratio between carbohydrate and krill oil should preferably be so that the formed powder has good flowing and tabletting properties. The powder complex or mixture with krill oil is isolated by filtration, evaporation, spray drying or freeze drying.

In a preferred embodiment, the krill oil is in the form of an oil when combined with the carbohydrate. One preferred option is to use a solvent to prepare the powder. If a solvent is used the solvent is subsequently removed.

Preferred solvents are water and alcohols and mixtures of these solvents. Preferred methods for removal of solvents when preparing the powder include freeze drying, evaporation and spray drying.

The mixture or complex of krill oil with carbohydrate is forms as a solid, preferably as a powder. In a highly preferred embodiment, the material is a crystalline solid. It should not be an oily material. It will be appreciated that sometimes to achieve a powder a solid may need to be ground. In a further preferred embodiment therefore the mixture or complex of krill oil and at least one carbohydrate complex will be suitable for grinding to form a powder.

The formation of solid mixtures or complexes of krill oil and carbohydrates is new and these solids form intermediates in the preparation of the tablets of the invention.

The invention therefore provides a process for converting a krill oil into a solid comprising contacting the krill oil with a carbohydrate to form a complex or mixture thereof and optionally drying to form a solid, preferably a powder.

Drying of the complex can be carried out by any known means. The material can be vacuum dried or simply left to dry in ambient air. It could be gently heated to encourage drying. Preferred drying methods include freeze drying and spray drying however. Spray drying techniques are disclosed in "Spray Drying Handbook", K. Masters, 5th edition, Longman Scientific Technical UK, 1991, the disclosure of which is hereby incorporated by reference at least for its teaching of spray drying methods.

It will be appreciated that krill oil comprises very many different phospholipids and other lipid compounds and hence there can be more than one complex formed.

In order to form tablets it is highly preferred if the krill oil is in the form of a solid, especially a powder, especially a crystalline solid. This can be achieved through complex formation as described above or achieved by spray drying of a krill emulsion.

The tablets of the invention may be produced by compression or compaction of a formulation containing krill oil and certain excipients, typically selected to aid in the processing and to improve the properties of the tablet. The tablets of the invention may be coated or uncoated and can be made from powdered, crystalline materials. Tablets may be plain, film or sugar coated, bisected, embossed, layered, or sustained release. Any film coating preferably comprise of a physiologically acceptable water-soluble organic polymer. They can be made in a variety of sizes, shapes and colours.

Excipients which may be present include diluents, binders, disintegrants, lubricants, glidants, anti-oxidants and in many cases, colorants. The excipients used are classified according to the function they perform. For example, a glidant may be used to improve the flow of powder blend in the hopper and into the tablet die.

Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1 % by weight. The most commonly used lubricants are magnesium stearate, stearic acid, hydrogenated oil, and sodium stearyl fumarate.

Tablets often contain diluents, such as lactose, which are added to increase the bulk weight of the blend resulting in a practical size for compression. This is often necessary where the dose of the drug is relatively small so the use of diluents is favoured in this invention where high doses of the fatty acid compounds are required. Typical diluents include for example dicalcium phosphate, calcium sulphate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and other sugars. The cellulose can preferably be microcrystalline cellulose (Avicel).

Binders are agents which impart cohesive qualities to the powdered material. Commonly used binders include starch, gelatin, sugars such as sucrose, glucose, dextrose, and lactose, natural and synthetic gums, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, ethyl cellulose and waxes..

Disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. Typical disintegrants include starch derivatives, crospovidone, croscaramelose and salts of carboxymethylcellulose. Some binders, such as starch and cellulose, are also excellent disintegrants.

Krill oil contains astaxanthin, a natural antioxidant, so the use of additional anti-oxidants may not be required. It is possible however to add conventional antioxidants such as vitamin C, vitamin E and BHT to any tablet of the invention. Other desirable characteristics of excipients include high compressibility to allow strong tablets to be made at low compression forces, good flow properties that can improve the flow of other excipients in the formula and cohesiveness (to prevent tablet from crumbling during processing, shipping and handling). The skilled man knows the type of excipients appropriate for tablet formulation. It is preferred if the total weight of excipients in a tablet of the invention is no more than 20 wt% of that tablet, preferably less than 15 wt% of the tablet, especially less than 10 wt% of the tablet.

The three processes for making compressed tablets are wet granulation, direct compression, and dry granulation (slugging or roller compaction). Whilst all three methods can be used to form the tablets of the invention, it is preferred if direct compression is employed.

Viewed form another aspect therefore the invention provides a process for the preparation of a tablet comprising krill oil and at least one carbohyrate comprising the direct compression of a mixture, preferably a complex thereof. Dry granulation consists of blending, slugging the ingredients, dry screening, lubrication, and compression. The wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tableting. The procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation. The damp mass is then screened through a suitable screen and dried by tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill. The overall process includes: weighing, dry powder blending, wet granulating, drying, milling, blending lubrication and compression.

Direct compression is a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug. The fatty acid compound, direct compression excipients and any other auxiliary substances, such as a glidant and lubricant are blended, e.g. in a twin shell blender or similar low shear apparatus before being compressed into tablets.

The advantages of direct compression include uniformity of blend, few manufacturing steps involved, (i.e. the overall process involves weighing of powders, blending and compression, hence less cost), elimination of heat and moisture, prime particle dissociation, and physical stability.

However, direct compression is usually limited to those situations where the drug or active ingredient has a crystalline structure and physical characteristics required to form pharmaceutically acceptable tablets. Since the fatty acid compounds of the invention typically present as oils, the use of direct compression to form oral dosage forms of fatty acid compounds is not reported. Moreover, since excipients need to be added to a direct compression formulation to allow the compression process to take place manufacturers are often limited to using the direct compression method in formulations containing a low dose of the active ingredient per compressed tablet as otherwise tablet sizes become to large for swallowing.

A solid dosage form containing a high dose drug (i.e. where the drug itself comprises a substantial portion of the total compressed tablet weight) can only be directly compressed if the drug itself has sufficient physical characteristics (e.g. cohesiveness) for the ingredients to be directly compressed. Surprisingly, the inventors have found that fatty acid mixtures and complexes of the invention possess the necessary physical characteristics. The fatty acid compounds and complexes of the invention have unexpectedly good flow and compression characteristics. The material, optionally mixed with excipients as described above, for example microcrystalline cellulose and magnesium stearate, is free-flowing and sufficiently cohesive to act as a binder.

It is surprisingly found therefore that krill oil which can be presented in solid form as carbohydrate complexes or mixtures, especially solid forms comprising high amounts of krill oil, can be tabletted without prior granulation (i.e. by direct compression). The most preferred method of production of tablets of the invention is therefore by direct compression.

The size of the tablets, according to the present invention can vary. The tablet diameter can vary from 6 mm to 20 mm, preferably 8 to 14 mm. The tablet weight can vary from 100 mg to 3 grams. The most preferred tablets have tablet weights between 200 mg and 2 grams with a diameter from 8 to 12 mm.

The tablets are for oral administration either by direct swallowing thereof or by any other known means, e.g. chewable tablets, dissolution or suspension of the tablet in a drinkable liquid and so on.

Whilst the tablets are primarily for use with human consumers, tablets might also be administered to animals, especially mammals, e.g. higher mammals.

The health benefits of the fatty acid compounds of the invention have been confirmed in many studies. Polyunsaturated fatty acids have been found to keep serum cholesterol levels low, stabilise irregular heartbeat, reduce blood pressure, improve autoimmune disease, improve depression disorders, treat psoriasis, treat rheumatoid arthritis, and to prevent colon cancer. They are generally applied in cardiovascular disorders and for the treatment of bone disorders. The tablets of the invention are of particular interest in the treatment or prevention of hypertriglyceridemia and cardiac infarction. Hypertriglyceridemia is a medical condition characterized by increased plasma concentration of triglycerides.

The invention is further illustrated by the following non-limiting examples: Example 1-16

Preparation of krill oil powder based on carbohydrates

General Experimental Protocols

Carbohydrates and water were mixed in a mortar using a pestle for 10 minutes. Krill oil from Neptune was added and mixed for 15 minutes. The mixture was freeze dried for 3-5 hours.^'

Example Carbohydrate(CH) CH weight Water Krill oil Characterization

No. mg mg mg of the product

1 Beta-cyclodextrin 1500 1500 500 pale orange powder

2 Carboxymethylcellulose(Na) 1500 1500 500 orange solid material

3 Alginic acid (Na) 1500 1500 500 orange solid material

4 Pectin 1500 1500 500 orange solid material

5 Methylcellulose 1500 1500 500 orange solid material

6 Hydroxyethylcellulose 1500 1500 500 orange solid material

7 Ethylcellulose 1500 1500 500 orange solid material

8 Dextrin 1500 1500 500 orange solid material

9 Chitosan 1500 1500 500 orange powder

10 Starch 1500 1500 500 orange solid material (1)

11 Microcrystalline cellulose 1500 1500 500 very pale red powder

12 Alpha-cyclodextrin 1500 1500 500 very pale red powder

13 Gamma-cyclodextrin 1500 1500 500 orange powder

14 Microcrystalline cellulose 1000 1000 500 very pale red powder

15 Microcrystalline cellulose 2000 2000 500 very pale red powder

16 Microcrystalline cellulose 3000 3000 500 very pale red powder

(1) somewhat sticky Example 17

Tablet prepared from krill oil/microcrystalline cellulose powder

Krill oil/microcrystalline cellulose powder (from Example 16) 500 mg Microcrystalline cellulose 100 mg

Crosscaramellose(Na) (AcDiSoI) 20 mg

Stearic acid 20 mg

All ingredients were blended. A tablet was compressed. Tablet diameter 13 mm Tablet weight : 640 mg. Krill oil content: 71 mg.

Example 18

Tablet prepared from krill oil/microcrystalline cellulose powder

Krill oil/microcrystalline cellulose powder (from Example 15) 800 mg

Microcrystalline cellulose 100 mg

Crosscaramellose(Na) (AcDiSoI) 20 mg

Stearic acid 20 mg

All ingredients were blended. A tablet was compressed, Tablet diameter 13 mm Tablet weight: 940 mg. Krill oil content: 160 mg.

Example 19

Tablet prepared from krill oil/microcrystalline cellulose powder

Krill oil/microcrystalline cellulose powder (from Example 14) 800 mg ■ Microcrystalline cellulose 200 mg

Crosscaramellose(Na) (AcDiSoI) 20 mg

Stearic acid 20 mg

All ingredients were blended. A tablet was compressed, Tablet diameter 13 mm

Tablet weight: 1040 mg. Krill oil content: 267 mg. Example 20

Tablet prepared from krill oil/alpha-cyclodextrin powder

Krill oil/alpha-cyclodextrin powder (from Example 12) 800 mg

Microcrystalline cellulose 100 mg

Crosscaramellose(Na) (AcDiSoI) 20 mg

Stearic acid 20 mg

All ingredients were blended. A tablet was compressed, Tablet diameter 13 mm Tablet weight: 940 mg. Krill oil content: 200 mg.

Claims

1. A solid composition, preferably a powder, comprising krill oil and at least one carbohydrate.

2. A solid composition, preferably a powder, as claimed in claim 1 consisting of krill oil and at least one carbohydrate.

3. A solid composition as claimed in claim 1 or 2 in the form of a complex.

4. A solid composition as claimed in any preceding claim wherein said carbohydrate is a monosaccaride, oligosaccharide or polysaccharide, e.g. microcrystalline cellulose.

5. A solid composition as claimed in any preceding claim wherein the weight ratio between the krill oil and carbohydrate is 1 :4 to 4: 1.

6. A pharmaceutical or nutraceutical composition in the form of a tablet for oral administration comprising krill oil and at least one carbohydrate.

7. A pharmaceutical or nutraceutical composition as claimed in claim 6 comprising a solid composition as claimed in claim 1 to 5

8.. A composition as claimed in claim 6 or 7 wherein the content of said krill oil in said composition is 10 wt% or more.

9. A pharmaceutical or nutraceutical composition of claim 6 to 8 wherein the composition comprises more than 15 wt%, e.g. more than 20 wt%, especially more than 25 wt% of a complex consisting of krill oil and at least one carbohydrate.

10. A composition as claimed in any one of claims 6 to 9 comprising more than 100 mg, e.g. at least 200 mg of krill oil and at least one carbohydrate.

11. A composition as claimed in any one of claims 6 to 10 additionally comprising another different marine omega-3 containing oil and cyclodextrin.

12. A composition as claimed in any one of claims 6 to 11 comprising an additional active agent.

13. A composition as claimed in claim 12 wherein said active agent is a pharmaceutical, nutraceutical, vitamin, mineral or other health supplementing compound.

14. A composition as claimed in claim 13 wherein the active agent is selected from a calcium salt, simvastatin, atorvastatin, glucosamine, at least one vitamin, and folic acid.

15. A composition in the form of a tablet according to any one of claims 6 to 14 prepared by direct compression.

16. A process for the preparation of a solid composition as claimed in claims 1 to 5 comprising mixing a carbohydrate and krill oil in a solvent, preferably water and drying.

17. A pharmaceutical tablet as claimed in any one of claims 6 to 14 for use in the treatment or prophylaxis of disorders related to the cardiovascular system, metabolic system, skin and bone.

18. Use of krill oil and at least one carbohydrate in the manufacture of a medicament in the form of a solid, e.g. a powder or tablet, for use in the treatment or prophylaxis of disorders related to the cardiovascular system, metabolic system, skin and bone.

19. A method of treatment or prophylaxis of disorders related to the cardiovascular system, metabolic system, skin and bone comprising administering to a patient a pharmaceutical tablet as claimed in any one of claims 6 to 14 .

20. A method for preparation of tablets as claimed in any one of claims 6 to 14 comprising directly compressing a complex of krill oil and at least one carbohydrate.