WO2011124895A2

WO2011124895A2 - Phospholipid-containing pharmaceutical and nutraceutical compositions

Info

Publication number: WO2011124895A2
Application number: PCT/GB2011/000548
Authority: WO
Inventors: Kurt Ingar Draget; Ingvild Haug; Anne-Ma H. Carlsen; Tore Seternes
Original assignee: Probio Asa; Cockbain, Julian
Priority date: 2010-04-09
Filing date: 2011-04-08
Publication date: 2011-10-13
Also published as: WO2011124895A3; GB201006012D0

Abstract

This invention provides a pharmaceutical composition comprising a physiologically tolerable phospholipid selected from the group consisting of marine phospholipids and lecithin and said physiologically tolerable phospholipid having dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent phospholipid having lipophilic, structure disrupting agent.

Description

Phospholipid-containinq pharmaceutical and nutraceutical compositions

This invention relates to pharmaceutical and nutraceutical compositions containing phospholipids, and to methods for preparing them.

Many nutraceuticals and pharmaceuticals (both hereinafter simply referred to as pharmaceuticals) contain essential fatty acids, for example polyunsaturated fatty acids (PUFAs) such as omega-3 acids like eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA). These are presented as esters, for example lower alkyl esters, triglycerides, diglycerides, monoglycerides and phospholipids. Such PUFAs may be administered as powders, simple liquids (e.g. cod liver oil), dispersions in water, dispersions in a gelled aqueous phase, and as encapsulated liquids, e.g. in soft gelatin capsules. For use as nutraceuticals, the most common forms of presentation are as simple liquid triglycerides and as gelatin-encapsulated liquids. Gelatin-encapsulation is particularly preferred as the recipient is shielded from the taste and odour of the lipid.

The use of phospholipids, in particular marine phospholipids, for example

phospholipids derived from fish roe, is becoming increasingly important.

We have now surprisingly found that the bioavailability of orally ingested

phospholipids may be enhanced if the lipid is intimately mixed with a low molecular weight, lipophilic, structure disrupting agent, i.e. an agent which promotes randomisation of the phospholipid molecules in the lipid phase, e.g. inhibits formation of structured phospholipid aggregates, such as liquid crystalline structures or the like. This randomisation or inhibition is evidenced by improved dispersion of the phospholipid in an aqueous phase, e.g. artificial gastric juice.

Thus viewed from one aspect the invention provides a pharmaceutical (i.e.

pharmaceutical or nutraceutical) composition comprising a physiologically tolerable phospholipid selected from the group consisting of marine phospholipids and lecithin and said physiologically tolerable phospholipid having dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent.

Viewed from a further aspect the invention provides a pharmaceutical (i.e.

pharmaceutical or nutraceutical) composition comprising a physiologically tolerable phospholipid having dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent, said structure disrupting agent being selected from the group consisting of 1 ,2-propanediol, propanoic acid, butanoic acid, castor oil, ethyl acetate, Polysorbate 80, sorbitan monooleate, sorbitan trioleate, sorbitan laurate, and polyglycolpolyricinoleate (PGPR), especially from the group consisting of butanoic acid, propionic acid and 1 ,2-propanediol.

The compositions of the invention may for example take the form of liquids, gels, emulsions or dispersions, optionally, but preferably, disposed within a physiologically tolerable coat, preferably a capsule shell, particularly preferably a soft gelatin capsule. (The term "soft gelatin capsule" is a standard term within the pharmaceutical and nutraceutical fields). Especially preferably the compositions comprise a continuous lipid phase disposed within a capsule.

Lipid encapsulation, for example in soft gelatin capsules, is a well known technique in the pharmaceutical and nutraceutical industry and need not be described further here.

The lipid phase of the compositions of the invention may contain other components beside the phospholipid and the structure disrupting agent. In particular they may contain other fatty acid esters, particularly PUFA esters, e.g. lower alkyl (d-6, preferably C,_₄, especially ethyl) esters, and mono, di and triglycerides. They may also contain dissolved lipophilic drugs and lipophilic vitamins. Additionally they may contain further components in a dispersed phase, e.g. a solid dispersed phase or an aqueous dispersed phase. Such further components may for example be non- lipophilic drugs and vitamins and minerals, e.g. calcium salts. The use of statins and analgesics as drug compounds in the compositions of the invention is especially preferred. The proportion of the fatty acid compounds present in the lipid phase which is phospholipid is preferably 5 to 100%wt, especially 10-90%wt, particularly 20- 80%wt.

The phospholipid in the compositions of the invention may be a single phospholipid compound; however preferably it will be a phospholipid mixture, e.g. of plant or land animal origin, e.g. a lecithin, but more preferably of marine origin, e.g. fish, cephalopod or crustacean phospholipids. Such phospholipids are widely available commercially. The phospholipid used should be synthetic or derived by extraction from organic material, i.e. it should not simply be provided by cells as such. The phospholipid moreover is preferably a high viscosity material, e.g. having a shear viscosity at 20°C and a shear rate of 0.1 sec^"1 of at least 0.5 Pa.s, especially at least 5 Pa.s, more particularly at- least 10 Pa.s, more especially at least 45 Pa.s, and preferably below 1000 Pa.s, particularly below 300 Pa.s.

The structure disrupting agent is a lipophilic, in particular an amphiphilic, compound preferably with a molecular weight below 1500 Da, especially below 1000 Da, particularly below 600 Da, more particularly below 100 Da, and preferably above 35 Da, particularly above 65 Da. It may for example be an alcohol, acid, ester, ether or hydrocarbon, especially a C_2-i₀ compound. Where it contains heteroatoms, preferably it contains more carbons than heteroatoms. Particularly preferably it is other than an amine, especially other than trimethylammonia. Examples of preferred disrupting agents include 1,2-propanediol, propanoic acid, butanoic acid, castor oil, ethanol, ethyl acetate, Polysorbate 80, sorbitan monooleate, sorbitan trioleate, sorbitan laurate, and polyglycolpolyricinoleate (PGPR), especially ethanol, propanoic acid, butanoic acid and 1 ,2-propanediol.

Examples of other materials that may be considered as disrupting agents include: p- hydroxybenzoates (e.g. methyl, ethyl and propyl p-hydroxybenzoates); benzoic acid; sorbic acid; gallic acid esters; o-phenyl-phenol; tocopherol; adipic acid; 1 ,3- butanediol; and astaxanthin.

The structure disrupting agent will preferably be included in the lipid phase at a concentration capable of increasing the dispersion of the lipid phase in an aqueous phase such as artificial gastric fluid (e.g. measured by light transmission or, more preferably, light scattering, at 37°C after a period of contact with the artificial gastric fluid of 4 minutes). Thus, we have found that light transmission at 500nm after 4 minutes is almost twice as high using a viscous phospholipid treated with 1 ,2- propanediol than with the untreated phospholipid. Typically the content of the disrupting agent, relative to the fatty acid lipid content, will be 0.1 to 20%wt, preferably 0.5 to 15%wt, especially 1-10%wt, more especially 4 to 6 %wt.

The compositions of the invention may be prepared in ways convention for the manufacture of fatty acid-containing pharmaceuticals by adding the structure disrupting agent to at least one of the fatty acids being used, e.g. the phospholipid and/or a triglyceride. Thus viewed from a further aspect the invention provides a process for the preparation of a composition according to the invention which process comprises dispersing a physiologically tolerable, lipophilic, structure disrupting agent in a physiologically tolerable fatty acid material, and if said material does not comprise a phospholipid adding a physiologically tolerable phospholipid, and optionally encapsulating the lipid and disrupting agent mixture.

Viewed from a further aspect, the invention provides a method of producing an encapsulated composition according to the invention, said method comprising encapsulating in a physiologically tolerable capsule, e.g. a soft gelatin capsule, a mixture of a physiologically tolerable phospholipid and a physiologically tolerable, lipophilic, structure disrupting agent according to the invention.

Desirably, the lipid will be degassed and placed under an oxygen depleted atmosphere before or, less preferably, after addition of the disrupting agent.

Where the composition is to contain further components, e.g. water, gelling agents, colors, flavours, drug substances, vitamins, minerals, dispersants, anti-oxidants, pH regulators, etc., these may be added as, when and how required to produce the desired composition, e.g. a dispersion, gelled emulsion, etc. This may be done in conventional fashion.

The invention is also applicable to animal feeds, e.g. land animal or more particularly marine animal feeds comprising lipid, protein and carbohydrate.

Thus viewed from a further aspect the invention comprises an animal feed, preferably in pellet form, comprising lipid, protein and carbohydrate, characterized in that said feed comprises a physiologically tolerable phospholipid with dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent.

Such animal feeds may be prepared in conventional fashion, e.g. by extruding an aqueous mixture of lipid, protein and carbohydrate, or by extruding and peiletising an aqueous mixture of protein and carbohydrate and subsequently impregnating the pellets with lipid.

Such animal feeds may contain lipid, protein and carbohydrate in conventional quantities. A further unexpected benefit from the addition of the disrupting agent to the phospholipid, especially where it is a marine phospholipid, is that the viscosity of the lipid is significantly reduced, thereby facilitating its encapsulation, e.g. allowing encapsulation at lower temperatures.

Thus viewed from a further aspect the invention provides the use of a physiologically tolerable, lipophilic, structure disrupting agent in a physiologically tolerable phospholipid to reduce the viscosity thereof.

Viewed from a further aspect the invention provides a composition comprising (a) a drug substance, and (b) a physiologically tolerable phospholipid having dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent, for use in medicine.

Viewed from another aspect the invention provides the use of a physiologically tolerable, lipophilic, structure disrupting agent for the manufacture of a medicament containing a physiologically tolerable phospholipid and a drug substance for use in the treatment of ailments responsive to said drug substance.

Viewed from still another aspect the invention provides a method of treatment of a human or non-human (preferably mammalian, avian or piscine) animal to combat a condition responsive to a drug substance, said method comprising orally administering to said animal an effective amount of said drug substance in a pharmaceutical composition according to the invention.

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.

The invention will now be illustrated further by reference to the following non-limiting examples, and the accompanying drawings in which:

Figure 1 is a graph showing absorbance of light at 500nm by a dispersion of phospholipid, with and without added disrupting agent, in artificial gastic fluid as a function of time; and Figure 2 is a graph plotting viscosity over time for samples of phospholipid containing increasing contents of added disrupting agent.

Example 1

Preparation of disrupting agent-containing phospholipid

A high viscosity marine phospholipid (MPL), derived from fish roe, and a structure disrupting agent were added to a beaker at ambient temperature. The solutions contained 4% wt. structure disrupting agent and 96 % wt..MPL The solutions were thoroughly stirred/mixed at ambient temperature, heated to 6Q°C for 2-5 minutes, and then stored at ambient temperature overnight prior to analysis and observation at 20°C. The solutions containing MPL and a structure disrupting agent immediately became less viscous after mixing at ambient temperature, but heating at 60°C was included to obtain and secure homogeneous solutions.

Table 1 below describes the visually observed reduction in viscosity.

Table 1

xx - large effect x - small effect.

Example 2

Preparation of encapsulated compositions

Phospholipid compositions (for example the compositions described in Example ) are encapsulated in soft gelatin capsules using conventional encapsulation techniques. Prior to encapsulation, the phospholipid is mixed with 4-6 % wt. of the disrupting agent (preferably 1 ,2-propanediol), heated to 40-60 °C for 15-30 minutes, and cooled to ambient temperature.

Example 3

Dispersion experiments

1 g of the 1 ,2-propanediol-containing solution of Example 1 was added to 200 mL of artificial gastric juice (1 L gastric juice was prepared according to European Pharmacopoeia containing 2g NaCI and 80 mL 1 M HCI) at about 37 °C with gentle stirring (magnetic stirrer about 40-80 rpm). After 4, 7, 1 1 and 13 minutes, samples were taken (1.5 mL) and the light transmittance at 500nm was measured with a spectrophotometer.

By comparison, 1 g of the unmodified marine phospholipid used in Example 1 was similarly dispersed and the light transmittance was similarly measured.

Figure 1 shows the transmittance at 500 nm recorded as a function of time for the phospholipid, with (solid diamonds) or without (solid squares) 1 ,2-propanediol (PG), dispersed in gastric juice. Less transmittance indicates a higher degree of dispersion taking place.

Example 3

Viscosity reduction

The marine phospholipid used in Example 1 was used to prepare, in analogous fashion, solutions of phospholipid containing 0, 1 , 2, 2.5, 3, 4, 8 and 12%wt. 1 ,2- propanediol (PG). For each solution, the viscosity as function of shear rate was determined at 20 °C using a Rheologica Stress-Tech Rheometer.

Figure 2 shows the viscosities determined. The PG content values shown in the graph are in the same vertical order as those shown in the explanation box. It can be seen that at 4%wt. PG, the phospholipid behaves in a Newtonian fashion with a zero shear viscosity almost 2 orders of magnitude lower than that of the PG-free sample.

Claims

Claims:

1. A pharmaceutical composition comprising a physiologically tolerable phospholipid selected from the group consisting of marine phospholipids and lecithin and said physiologically tolerable phospholipid having dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent.

2. A composition as claimed in claim 1 wherein said physiologically tolerable phospholipid comprises a marine phospholipid.

3. A composition as claimed in claim 1 wherein said physiologically tolerable phospholipid comprises a crustacean phospholipid.

4. A composition as claimed in any one of claims 1 to 3 wherein said disrupting agent is a lipophilic compound with a molecular weight below 500 Da, selected from C_2-io alcohols, esters, ethers and hydrocarbons.

5. A pharmaceutical composition comprising a physiologically tolerable phospholipid a pharmaceutical composition comprising a physiologically tolerable phospholipid having dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent, said structure disrupting agent being selected from the group consisting of

1 ,2-propanediol, propanoic acid, butanoic acid, castor oil, ethyl acetate, Polysorbate 80, sorbitan monooleate, sorbitan trioleate, sorbitan laurate, and

polyglycolpolyricinoleate (PGPR), having dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent.

6. A composition as claimed in claim 5 wherein said structure disrupting agent is selected from the group consisting of butanoic acid, propionic acid, and 1,2- propanediol.

7. A composition as claimed in any of claims 1 to 6 wherein said disrupting agent is 1 ,2-propanediol.

8. A process for the preparation of a composition according to any use of claims 1 to 6, which process comprises dispersing a said physiologically tolerable, lipophilic, structure disrupting agent in a physiologically tolerable fatty acid material, and if said material does not comprise a said phospholipid adding a said physiologically tolerable phospholipid, and optionally encapsulating the lipid and disrupting agent mixture.

9. A method of producing an encapsulated composition according to any use of claims 1 to 6, said method comprising encapsulating in a physiologically tolerable capsule a mixture of a said physiologically tolerable phospholipid and a said physiologically tolerable, lipophilic, structure disrupting agent.

10. An animal feed comprising lipid, protein and carbohydrate, characterized in that said feed comprises a physiologically tolerable phospholipid with dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent, wherein the combination of said phospholipid and disrupting agent is in accordance with any one of claims 1 to 6.

1 1. The use of a physiologically tolerable, lipophilic, structure disrupting agent in a physiologically tolerable phospholipid to reduce the viscosity thereof.

12. A composition comprising (a) a drug substance, and (b) a physiologically tolerable phospholipid having dispersed therein a physiologically tolerable, lipophilic, structure disrupting agent in accordance with any one of claims 1 to 6, for use in medicine.

13. The use of a physiologically tolerable, lipophilic, structure disrupting agent for the manufacture of a medicament containing a physiologically tolerable phospholipid and a drug substance according to claim 12 for use in the treatment of ailments responsive to said drug substance.

14. A method of treatment of a human or non-human animal to combat a condition responsive to a drug substance, said method comprising orally administering to said animal a effective amount of said drug substance in a pharmaceutical composition according to any one of claims 1 to 6.