GB2512098A - An oral dosage form - Google Patents

Abstract

An oral dosage form comprises a therapeutically active composition containing at least one omega-3-polyunsaturated fatty acid (PUFA), which oral dosage form has an outer surface comprising medicated print, where the medicated print comprises a hypolipidaemic drug. Preferably, the hypolipidaemic drug is a statin, such as atorvastatin, or a fibrate. The fatty acid may comprise 5,8,11,14,17-eicosapentaenoic acid (EPA) and 4,7,10,13,16,19-docosahexaenoic acid (DHA). The dosage form may be used in the treatment or prevention of cardiovascular disease, or in the prevention or treatment of hyperlipidaemia. The medicated print may be a medicated ink printed onto an outer surface of the oral dosage by inkject printing.

Description

AN ORAL DOSAGE FORM

The present invention relates to an oral dosage form, specifically an oral dosage form that comprises a therapeutically active composition, and an additional medicament.

It is often necessary to treat a particular indication with at least two different pharmaceutically active agents. Often these agents are administered in separate oral dosage forms. However, such administration can lead to the patient having to take regularly a large number of oral dosage forms which can in turn lead to a reduction in patient compliance, either deliberately or inadvertently. Obviously, if the patient is under-medicating, then there is a substantial risk that the indication will not be treated properly. A reduction in the number of oral dosage forms that needs to be taken by a patient usually results in an increase in compliance. Therefore, there is a need for new ways of incorporating more than one pharmaceutically active agent in a single oral dosage form.

Where two or more pharmaceutically active agents are physically and chemically compatible with each other, they can usually be combined in direct contact with each other within the same oral dosage form. For example, certain pharmaceutically active agents may be dissolved, suspended or emulsified within certain therapeutically active liquid components. However, there are many combinations of active agents in which the active agents, whilst being therapeutically compatible with each other, are not physically and/or chemically compatible. These active agents cannot be combined in direct contact with each other since they will interact with each other, perhaps causing a reduction in the bioavailability or efficacy of at least one, or perhaps all, of the active agents. Such interaction may reduce the stability and/or shelf life of the oral dosage form, and could potentially cause regulatory problems, particularly if the composition of the authorised product changes significantly overtime. Therefore, there is also a need for new ways of incorporating incompatible pharmaceutically active agents within the same oral dosage form whilst maintaining the bioavailability and efficacy of the active agents to produce a stable product.

Different pharmaceutically active agents may also need to be released at different locations along the gastrointestinal (GI") tract in order to maximise absorption, and hence efficacy, of the active agents. For example, it may be desirable for at least one of the active agents to be absorbed in the stomach, but other active agent(s) to be absorbed in the small intestine. Thus, oral dosage forms that combine physically and/or chemically incompatible active agents within the same dosage form should ideally also provide for different release profiles for the active agents as appropriate.

Certain polyunsaturated fatty acids (PUFAs), particularly the omega-3 PUFAs 5, 8, 11, 14, 1 7-eicospentenoic acid (EPA) and 4, 7, 10, 13, 16, 19-docosahexaenoic acid (DHA), are known to regulate lipid metabolism. PUFA5 have been found to have beneficial effects on the risk factors for cardiovascular diseases, including mild hypertension and hypertriglyceridaemia. There is evidence that PUFAs lower serum triglyceride levels, increase serum high density lipid (HDL)-cholesterol, lower systolic and diastolic blood pressure, and lower pulse rate.

Statins are examples of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, and are used extensively to treat risk factors for cardiovascular events, including hyperlipidaemia. Statins are used to control the levels of serum cholesterol by inhibiting HMG-CoA reductase (which is an enzyme controlling the rate of cholesterol production in the body), and by increasing the ability of the liver to remove low density lipid (LDL)-cholesterol from the blood. Thus, the principle effect of statins is to lower serum LDL-cholesterol levels.

W020061096806A provides a discussion of studies that have examined the effects of PUFA and statin co-therapy in the treatment of dyslipidaemia, hyperlipidaemia, hypertriglyceridaemia, hypercholesteraemia and other risk factors for cardiovascular diseases.

Previously attempts at combining PUFAs and statins in the same oral dosage form include dissolving the statin in a solvent system comprising PUFAs (see W02006/096806A & W02006/062748A); and applying a coating comprising a statin to a capsule containing PUFAs (see W02007/103557A). In this connection, the Inventor notes that oils comprising PUFAs in free acid form are aggressive and highly reactive, and that some statins, e.g. atorvastatin, fluvasatin, pravastatin and pitavaststin, are acid labile. Therefore, a solution or suspension of an acid labile statin in an oil comprising PUFAs in free acid form may not have sufficient stability over time for the commercial product to be authorised. In addition, not all oral dosage forms require a coating. In such embodiments, applying a coating complising a statin requires the addition of a step to an existing process which incurs additional capital and operating costs. In addition, where the coating is functional, e.g. for providing delayed release, the characteristics of the coating, e.g. thickness, are determined by the function of the coating. Since the concentration of the active in the coating solution has to be carefully controlled to ensure that the correct amount of active is present in the finished coating, embodiments requiring different amounts of active would require different coating solutions. The process is therefore quite inflexible when producing different formulations comprising different amounts of the active in the coating. With the foregoing in mind, there are drawbacks with these prior examples of attempts to combine omega-3 PUFA5 and statins in the same oral dosage form. Thus, there is a particular need for an oral dosage form that provides a safe and effective combination of PUFAs in free acid form with an acid labile statin.

There are examples in the prior art of printing a non-medicated ink onto an edible substrate, e.g. an oral dosage form such as a tablet or a capsule.

W02004/003089A discloses a fat and/or wax-based edible ink for inkjet printing onto edible substrates. The edible substrates are primarily chocolate sweets but it is disclosed that the substrates may include pharmaceutical pills and tablets.

W02005/004797A discloses oral dosage forms (e.g. tablets) having printed ink markings thereon to identify/authenticate oral dosage forms or the drugs contained therein. The markings include bar codes and 20 matrix codes.

US2007/0026064A discloses oral dosage forms such as tablets having unique identification markings similar to water marks. The ink used is similar in colour to the colour of the film coating applied to the oral dosage form.

W02005/113693A discloses food grade ink jet inks for use in printing on edible substrates. The inks generally contain food grade pigments, such as food grade lakes; a carrier which typically includes food grade lower alcohol(s) and/or food grade glycol(s), such as 1,2-propanediol; and a resin component! such as shellac.

W02007/102903A discloses a consumable inkjet ink for use in inkjet printing on to a pharmaceutical tablet, pill or capsule. The ink comprises an aqueous inkjet vehicle comprising at least one consumable water soluble organic solvent selected from C1 to C6 alcohols, and a colorant.

There are also examples in the prior art of the use of medicated inks generally.

US2004/0219109A discloses applying a medicated ink to a non-medicated chewing gum, candy or other edible product. This reference also discloses applying non-medicated inks to pharmaceutical products.

EP1640421A discloses applying medicated inks to edible wafers. This refeience also discloses the application of non-medicated inks to oral dosage forms such as

tablets.

US2004/0253185A discloses the application of medicated inks onto medical devices such as stents. This reference discloses that the ink could contain statins.

US2004/0253281A discloses the application of medicated inks diiectly onto the tissue of patients to control release of the medication into the tissue. Statins are disclosed as active substances suitable for incorporation into the inks.

US51 1 0599A discloses a process for producing and administration and/or dosage form for medicament active substances using a pad printing process. The process has particular application for preparing transdermal patches although an oral dosage foim is exemplified. The exemplified oral dosage form is a tablet having a layered core containing an active substance, and a sugar coating. The layered core is produced using the pad printing process.

It is a objective of piefeiied embodiments of the piesent invention to piovide a new oral dosage form containing more than one pharmaceutically active agents that overcomes at least one, and preferably all, of the above mentioned drawbacks in the

prior art.

The Inventor has discoveied that PUFAs in free acid foim and statins (including acid labile statins) may be combined in the same oral dosage form without the above mentioned difficulties if the PUFAs are encapsulated within a capsule having a delayed ielease coating, and the statin(s) is contained in an ink used to punt information on to the coated capsule. The Inventor believes that application of the discovery is not limited to PUFAs/statin combinations, but in contrast embraces combinations of PUFAs with any hypolipidaemic drugs.

According to a first aspect of the present invention, there is provided an oral dosage form comprising a therapeutically active composition comprising at least one omega- 3 PUFA, said oral dosage form having an outer surface comprising medicated print thereon, wheiein said medicated print comprises at least one hypolipidaemic drug.

As described above, certain omega-3 PUFAs are known to have hypolipidaemic properties. Howevei, the or each hypolipidaemic drug in the medicated punt on the oral dosage form of the present invention is not a PUFA. The hypolipidaemic drugs in the medicated print may therefore be described as non-PUFA hypolipidaemic drugs.

The term "medicated print" means dried ink marking(s) containing a medication in the form of at least one hypolipidaemic drug. The marking(s) may be random, or arranged in some way, such as in the form of text and/or a design. e.g. for the purpose of providing information regarding the oral dosage form, e.g. identity of the active agents, dosages, name of manufacturer, batch number, date of manufacture, etc. The marking(s) may be in the form of plain text and/or a design such as a bar code, 2D matrix code and/or logo. The marking(s) may also encode information for the purpose of preventing counterfeiting of the pharmaceutical composition. The marking(s) may be visible to the naked eye, or may be invisible unless viewed, for example, using wavelength(s) of light outside the visible spectrum, e.g. using ultraviolet or infrared light.

The medicated print may be mucoadhesive, e.g. may comprise at least one mucoadhesive polymer in an amount sufficient to enable mucoadhesion the gastrointestinal (01) mucosa, to enable release of the hypolipidaemic drug(s) in different parts of the 01 tract.

The medicated print typically comprises at least one hypolipidaemic drug for absorption at any location along the GI tract, for example in the mouth, in the stomach and in the small intestine. However, the medicated print preferably complises a hypolipidaemic agent for absorption in the stomach.

The medicated print may contain further pharmaceutically and/or nutraceutically active agents. A "pharmaceutically active agent" is a drug, usually (although not exclusively) synthetic, that has a therapeutic effect on the human or animal body in the treatment or prevention of a condition. A "nutraceutically active agent" is a compound derived from a natural origin (animal or vegetable) that has a beneficial and/or therapeutic effect on the human or animal body. Such compounds may be regarded as nutrients. Suitable nutraceutically active agents may be natural products extracted from animals or vegetables.

The active agent(s) in the medicated print may be any drug having a local effect or, in preferred embodiments, a systemic effect.

The non-PUFA hypolipidaemic drugs may be selected from HMG CoA reductase inhibitors, e.g. statins; cholesterol absorption inhibitors, e.g. ezetimibe and MD-0727; niacin and derivatives thereof, e.g. nicotinamide, possibly in combination with a flushing inhibitor e.g. Laropiprant; PPAR agonists and/or antagonists; FPAR-alpha agonists including fibrates, e.g. fenofibrate, bezafibrate, clofibrate, gemfibrozil and TriLipixTM (ABT-335); PPAR-gamma agonists including thiazolidinediones, e.g. pioglitazone and rosiglitazone; dual alpha/gamma PPAR agonists including non-thiazolidinediones, e.g. tesaglitazar, naviglitazar and muraglitazar; partial PFAR gamma agonists/antagonists, e.g. metaglidasen; bile acid sequestrants, e.g. cholestyramine, colestipol and colesevelam; MTP inhibitors, e.g. implitapide; liver X receptors (LXR) agonists and/or antagonists; isotropic agents; R-blockers; calcium antagonists; organic nitrates; anti-arrhythmic agents; ACE inhibitors; angiotensin II (=AT1) antagonists; diuretics; cholesterol lowering drugs; clot-busters; anti- coagulants; anti-platelet drugs; aldosterone receptor blockers; combined a-and R-blockers; calcium channel blockers such as dihydropyridine calcium channel blockers, e.g. Bay K 8644, amlodipine, felodipine; lacidipine; lercanidipine; nicardipine; nifedipine, nimodipine, nisoldipine, nitrendipine and isradipine; and cholesteryl ester transfer protein (CETP) inhibitors, e.g. anacetrapib and R1658; squalene synthase inhibitors, e.g. lapaquistat; antisense RNA agonists, e.g. PCSK9 and mipomersen; acetyl Co-A cholesterol acyl transferase inhibitors, e.g. avasimibe; farnesoid X receptor activators, e.g. gugglesterone; sulfonyl urea derivatives, e.g. glimepiride and glipizide; and metformin.

In some embodiments, the hypolipidaemic drug in the medicated print is a statin.

Suitable statins include atorvastatin; cerivastatin; fluvastatin; lovastatin; mevastatin; pitavastatin; pravastatin; rosuvastatin; and simvastatin. The statin may be an acid labile statin. In other embodiments, the hypolipidaemic drug in the medicated print is a fibrate.

In some embodiments, the outer surface of the oral dosage form comprises more than one medicated print. i.e. two or more medicated prints comprising different active agent(s). In one such embodiment, the oral dosage form comprising a first medicated print comprising a statin, and a second medicated print comprising a fibrate.

The pharmaceutically or nutraceutically active agent(s) may be present in the medicated print in micronized form. The fibrates in particular may be in micronized form.

The medicated print typically comprises a therapeutically effective amount of the or, in embodiments where there are more than one, each active agent. The therapeutically effective amount may be from about 0.1 mg to about 200 mg, e.g. from about 0.5 mg to about 100 mg, per oral dosage form, depending on the identity of the active agent(s). In embodiments where a single oral dosage form is administered per day, the entire daily dosage of the active agent(s) is contained within the medicated print on the single oral dosage form. In embodiments where more than one oral dosage form is administered per day, the entire daily dosage of the active agent(s) may be contained within the medicated print of one of the dosage forms, or the medicated print on each oral dosage form may contain a portion of the daily dosage of the active agent(s) and sufficient oral dosage forms are taken to provide the required daily dosage.

For example, the average daily dosage of a statin depends on the identity of the statin but is usually from about 20 mg to about 60 mg per day, e.g. about 40 mg per day. In embodiments where a single oral dosage form is administered per day, the medicated print contains the entire daily dosage, e.g. from about 20 mg to about 60 mg. In embodiments where two oral dosage forms are administered per day, the medicated print on each oral dosage form may contain about half the daily dosage, e.g. from about 10 to about 30 mg per dosage form. In embodiments where four oral dosage forms are administered per day, the medicated print on each oral dosage form may contain about a quarter of the daily dosage, e.g. from about 5 to about 15 mg per dosage form.

The oral dosage form may be a lozenge, pellet, tablet or capsule. The lozenge, pellet, tablet or capsule may be uncoated in which case the outer surface of the oral dosage form is the surface of the uncoated lozenge, pellet, tablet or capsule itself, and the medicated print is provided directly on to the outer uncoated surface.

Alternatively, the lozenge, pellet, tablet or capsule may be coated in which case the outer surface of the oral dosage form is the outer surface of the coating, and the medicated print is provided directly on top of the coating. The function of the coating may be to improve the appearance of the oral dosage form; and/or seal the oral dosage form to the ingress of water; and/or to mask the taste and/or odour of an oral dosage form to be swallowed; and/or protect the oral dosage form from light. The coating may be a delayed, pieferably post-gastric, release coating, e.g. an enteric coating to delay release of the therapeutically active component from the oral dosage form until the oral dosage form is in the small intestine. Alternatively, the delayed release coating may be a time-mediated release coating.

Whether the medicated print is applied directly to the surface of an uncoated oral dosage form, or directly on top of the coating of a coated oral dosage form, the oral dosage form may comprise a protective outer coating provided on said outer surface thereof over said medicated print. The protective outer coating may be opaque, for example in embodiments where the medicated print is present solely as a carrier for the drug and does not provide information. However, in embodiments where the medicated print provides information, the protective outer coating should be at least sufficiently transparent for the medicated print to be "visible" through the outer protective coating, either to the naked eye or by using an appropriate device to read the information. The function of the protective outer coating may be to prevent removal of the medicated print by abrasion; and/or to prevent damage to an inner coating. However, the protective outer coating may have one or more other functions. For example, the protective outer coating may improve the appearance of the oral dosage form; and/or seal an otherwise uncoated oral dosage form to the ingress of water; and/or to mask the taste and/or of a coated or uncoated oral dosage form intended for swallowing.

The protective outer coating may dissolve in the stomach. A suitable protective outer coating that dissolves in the stomach would be the cationic polymer with dimethyl-aminoethyl methacrylate as a functional group manufactured and sold under the trade mark, EudragitTM E, by Evonik Industries AG of Essen, Germany.

The protective outer coating may also be gastro-resistant, e.g. may be a delayed release coating, such as an enteric coating, if it is desired to delay release of the pharmaceutically active agent(s) in the medicated print until after passage through the stomach.

Thus, in some embodiments, there may be an inner delayed release coating on the oral dosage form on top of which is applied the medicated print, and an outer protective delayed release coating provided on the outer surface of the oral dosage form over the medicated print. Careful selection of different coating materials from which to form the different delayed release coatings can result in a beneficial staggered release of the medication from the medicated print, and the therapeutically active component along the GI tract.

Delayed release coating materials that may be suitable for an inner and/or an outer delayed release coating include pH sensitive coating materials (such as cellulose acetate phthalate ("CAP"): cellulose acetate trimellitate ("CAT"); hydroxypropyl methylcellulose ("HPMC"); and anionic co-polymeis of (meth)acrylic acid and methyl(meth)acrylate including EudragitTM L, Eudragit S and EudragitTM ES! all of Evonik Industries AG): time dependent release coating materials (such as neutral polyaciylates including EudragitTM NE 30D and EudragitTM NM 30D, both of Evonik Industries AG); and coatings that are susceptible to colonic bacteria such as coating complising glucose-based polysaccharides including starch, amylose and/or amylopectin; and mixtures thereof. In one embodiment where release of the therapeutically active component in the small intestine is desiied, the capsules may be coated with a mixture of a pH sensitive coating (such as EudragitTM L) with a time dependent release coating (such as EudragitTM NE 30D), preferably in a ratio of 2:1.

The "therapeutically active composition" is a composition that has a therapeutic effect on the human or animal body in the treatment or prevention of a condition. The therapeutically active composition may consist essentially of one or more omega-3 PUFA, oi may comprise one or moie of such active agents and at least one pharmacologically acceptable excipients. The identity of suitable excipients would be determined by, for example the form of the therapeutically active composition, and the nature of the oral dosage form.

In view of the unpleasant taste of omega-3 PUFAs and the potential foi "fishy bieath" after oral ingestion, the therapeutically active composition is typically for absorption in the small intestine.

The therapeutically active composition may be in the form of a liquid. The term "liquid" is intended to cover not only liquids per se (such as oils; solutions; suspensions including micro-suspensions; and emulsions including micro-emulsions) but also semi-liquids (such as syrups; and gels). In preferred embodiments, the therapeutically active composition is in the form of an oil.

A suitable therapeutically active composition in liquid form may consist essentially of one or moie omega-3 PUFA in liquid foim or may be a composition of one oi more of said fatty acids dissolved, suspended or emulsified in a pharmacologically acceptable vehicle. Suitable vehicles may comprise, for example, one or more pharmacologically acceptable carriers and/or excipients such as solvents: surfactants; preseivatives; antioxidants; stabilisers; and fuither processing aids.

Preferably, the therapeutically active composition is in the form of an oil comprising at least one omega-3 PUFA. The fatty acid(s) may be present in free acid form or the form of pharmacologically acceptable derivatives, e.g. esters (such as triglyceride or ethyl esters); amides; complexes (such as with bile salts, cholesterol or chitosan); salts (such as alkali metal salts, e.g. lithium, sodium or potassium salts); and mixtures thereof. The therapeutically active composition preferably consists essentially of a fatty acid composition in the form of an oil.

Suitable omega-3 PUFAs include EPA and DHA. EPA may be present in the therapeutically active composition in an amount of at least about 30 wt % and, preferably, from about 40 wt % to about 90 wt %, e.g. from about 40 wt % to about 65 wt %, based on the total weight of the composition although it may also be desirable to have EPA present in an amount of at least about 90 wt % and may be up to 100 wt % for certain applications and/or to minimise the number of capsules needed to be taken to provide a therapeutically active dose. DHA may be present in the oil in an amount of between from about 10 wt % to about 35 wt %. The remainder of the component is typically formed of other fatty acids.

The therapeutically active composition may be a fish oil such as cod liver oil.

However, in preferred embodiments, the therapeutically active composition is a fatty acid composition comprising EPA and OHA, e.g. a highly concentrated fish oil product comprises a total amount of EPA/DHA of at least 50 wt %, e.g. at least 60 wt %, and preferably at least 70 wt %. The EPA:DHA ratio preferably ranges from about 1:1 to about 5:1.

In a particularly preferred embodiment, the product comprising from about 40 wt % to about 65 wt % EPA and from about 15 wt % to about 35 wt % DHA, based on the total weight of the oil. Both the EPA and DHA may be in the form of esters such as triglyceride esters or alkyl esters, e.g. ethyl esters. However, in preferred embodiments, the EPA and DHA are in free acid form.

Suitable concentrated fish oil products for use in the present invention include Incromega 3F60 and Incromega F2250 (Croda Universal Limited, UK) and the fatty acid compositions disclosed in EP0825858; US5502077; US5656667; US5698594; and W02010/093634, the disclosures of which are incorporated herein by reference.

The fish oil product usually comprises additives such as an antioxidant, e.g. a-tocopherol.

Oral dosage forms according to the present invention are suitable for the oral administration of two or more active agents. The or each active agent in the therapeutically active composition is usually present in each oral dosage form in a therapeutically effective amount although, in some embodiments, the amount of the active(s) per oral dosage form may be less than a therapeutically effective amount in which case more than one oral dosage form may be administered to achieve the desired therapeutic effect. The therapeutically effective amount of the therapeutically active composition may be from about 0.1 mg to about 2000 mg.

Preferred oral dosage forms are capsules. Capsules may be of any suitable size and may contain from about 200 to about 2000 mg, preferably from about 500 to 1500 mg, and more preferably from about 750 to about 1250 mg of the therapeutically active component, e.g. in the form of a free fatty acid oil. Piefeired capsules may weigh from about 500 to about 2000 mg after drying.

The daily therapeutic dosage of the preferred free fatty acid oils may be from 500 mg to 8000 mg. e.g. from about 1500 mg to about 4500 mg. For example! where each capsule contains about 1000 mg of the free fatty acid oil, from 1 to 8 capsules and prefeiably from 2 to 4 capsules are typically administered per day.

Capsules according to these embodiments of the present invention may be hard capsules or soft capsules and the capsule shell may be made from any pharmacologically acceptable mateiial suitable foi capsule manufacture. Examples of suitable materials for the manufacture of hard capsule shells according to the present invention include polysacchaiides, e.g. pullulan and staiches; cellulose based polymers, e.g. methyl cellulose, hydroxypropyl methylcellulose and carboxymethyl cellulose; and pioteinaceous hydrocolloid materials such as gelatins.

Examples of suitable materials for the manufacture of soft capsule shells according to the present invention include polyethylene oxides (PEOs); polyvinyl alcohol; polysaccharides such as starches, carrageenan, alginate, agar, locust bean gum, guar gum, tamarind seed polysaccharide, pectin, xanthan gum, glucomannan, chitin material, pullulan and cyclodextrin; graft polymers containing starch and/or polyvinyl alcohol; and proteinaceous hydrocolloid materials such as gelatins. The soft capsules (and/or pellets) may be made from the polysaccharide-based hydrocolloid materials disclosed in JP63-164858A. In preferred embodiments, the capsules are hard or soft gelatin capsules. In the most preferred embodiments, the capsules are soft gelatin capsules.

Any type of gelatin may be used for the capsule shell of the hard or soft capsules such as Type A gelatin; Type B gelatin; or mixtures thereof. The gelatin may come from any suitable collagen source such as porcine collagen; bovine collagen; or piscine collagen and may be in its native form or chemically modified by reaction with diprotic carboxylic acids such as succinic acid. The gelatin may have any Bloom strength suitable for capsule manufacture. Type A gelatin, preferably from a porcine source, is preferred for use in embodiments in which the therapeutically active component is a free fatty acid oil.

In embodiments in which a soft gelatin capsule encapsulates a pharmaceutical formulation comprising EPA in free acid form in an amount from about 25 wt % to about 99 wt % of the formulation, and DHA in free acid form in an amount from about 1 wt % to 75 wt % of the formulation, the capsule shell preferably comprises a gelatin component made up of porcine Type A gelatin and at least one other gelatin, said porcine Type A gelatin being present in an amount of no more than about 75 wt %, preferably no more than about 50 wt %, of said gelatin component. The porcine Type A gelatin is usually present in an amount of no less than about 10 wt %, preferably no less than about 25 wt %, of said gelatin component.

The capsules shells may contain other components such as components conventionally used in the art. For example, the shell of a soft gelatin capsule may also comprise water; a plasticiser (such as glycerol or sorbitol); dyes; pigments; stabilizers; aromas, etc. Different therapeutically active agents can interact chemically or physically with each other when provided in contact with each other in situ within an oral dosage form, for example in solution, in a suspension or in an emulsion. For example, therapeutically active agents comprising carboxylic acid groups, e.g. omega-3 PUFAs in free acid form, may react with other therapeutically active agents comprising primary or secondary alcohol groups, e.g. statins, to form esters or may undergo acid-base reactions with other therapeutic active agents comprising amine groups. In addition, therapeutically active agents comprising esters groups, e.g. ethyl or triglyceride esters of omega-3 PUFA5, may react with other therapeutically active agents comprising primary or secondary alcohol groups, e.g. statins, or amide groups to form transesterification products or amides respectively. Further, therapeutically active agents comprising carbon-carbon double bonds, e.g. omega-3 PUFAs, may be sensitive to addition reactions across the double bonds or to oxidation.

The solution proposed by preferred embodiments of the present invention is to at least reduce and preferably minimise or even eliminate such unwanted interactions by physically separating the active agents in question.

The active agent(s) is/are selected on the basis of the condition to be treated and may be locally or systemically active. However, the Inventor envisages that the present invention will have particular application in the administration of therapeutically active agent(s) to treat cardiovascular disease and/or metabolic disease. In this connection, specific dosage forms within the scope of the present invention may be formulated for regulation, e.g. lowering, of lipid levels or to treat or prevent hyperlipidaemia; hypertriglyceridaemia; hypercholesteraemia; mixed dyslipidaemia; coronary heart disease; heart failure; cardiac arrhythmias; ischemic dementia; hypertension; coagulation related disorders; nephropathy; retinopathy; cognative disorders; autoimmune diseases; inflammatory diseases; metabolic syndrome; vascular disease; atherosclerotic disease and related conditions; and obesity. Other specific dosage forms may be formulated for the prevention or reduction of cardiovascular and vascular events; reduction of insulin resistance, adjustment of fasting glucose levels; adjustment of postprandial glucose levels; and the reduction of incidence and/or delay of onset of diabetes (including Type 2 diabetes).

According to a second aspect of the present invention, there is provided a coated capsule for oral administration, said coated capsule comprising a capsule shell encapsulating a free fatty acid composition comprising EPA and DHA in free acid form; and a delayed release coating for providing post gastric release of said free fatty acid composition, said coated capsule having an outer surface comprising medicated print thereon, said medicated print comprising a hypolipidaemic drug.

In a particularly preferred embodiment, the capsule is a soft gelatin capsule containing a concentrated fish oil product comprising from about 40 wt % to about 65 wt % EPA and from about 15 wt % to about 35 wt % DHA based on the total weight of the oil. The EPA and DHA may be in triglyceride or ester form although are preferably in free acid form. The capsule may comprise from about 500 mg to about 1500 mg, preferably about 1000 mg, of the concentrated fish oil product. In such embodiments, the medicated print comprises from about 1 mg to about 100 mg of a statin or a fibrate. Where two 1000 mg capsules are administered per day, the medicated print typically contains from about 10 to about 30 mg statin or fibrate per capsule. Where four 1000 mg capsules are administered per day, the medicated print typically contains from about 5 to 15 mg statin or fibrate per capsule. Such a capsule formulation is stable with regard to interaction between the active agents, and would have a lipid lowering effect. On this basis, the capsule formulation may be used to treat or prevent cardiovascular disease and/or hyperlipidaemia.

The oral dosage form according to the first aspect of the present invention, and specifically the coated capsule of the second aspect, has particular application for use in the treatment or prevention of cardiovascular disease and/or hyperlipidaemia.

Advantages of the oral dosage form aspects of the present invention include a potentiation of clinical effect of the omega-3 PUFA(s) and/or the active agent(s) in the medicated print, thereby enabling a possible reduction in dosage of at least one of the active agents; providing a simple and cost effective solution to the problem of combining more than one active agent, including active agents that are physically and/or chemically incompatible with each other and/or that need to be released at different locations in the GI tract, in the same oral dosage form, thereby reducing the number of oral dosage forms to be taken by the patient and reducing the risk of under-medication. In addition, the use of printing, and inkjet printing in particular, increases the flexibility of the manufacturing process since, if higher unit doses of the active(s) in the medicated print are required, then more ink can be simply applied to the oral dosage form, rather than having to coat a fresh batch of dosage forms with a different coating solution having a different concentration of the active(s). Further, the release profile of the active agent in the medicated print can be adjusted to optimise absorption, to reduce degradation and/or to minimise the side effect profile, simply by selecting a different composition for the ink base.

In one embodiment of this aspect of the invention, there is provided an oral dosage form comprising a therapeutically active composition comprising at least one omega- 3 PUFA, together with a mucoadhesive medicated print comprising at least one fibrate in micron ized form.

In another embodiment of this aspect of the present invention, there is provided an oral dosage form providing the combination of at least one omega-3 PUFA with an anti-sense drug to prevent expression of selected enzymes, with benefits in lipidology and other conditions.

According to a third aspect of the present invention, there is provided a process for producing an oral dosage form according to the first aspect, said process comprising: providing an oral dosage form comprising a therapeutically active composition comprising at least one omega-3 PUFA, said oral dosage form having an outer surface; printing a medicated ink comprising at least one hypolipidaemic drug on to the outer surface of the oral dosage form; and drying said ink to form medicated print comprising said hypolipidaemic drug(s).

According to a fourth aspect of the present invention, there is provided a process for producing a coated capsule according to the second aspect, said process comprising: encapsulating a free fatty acid composition comprising EPA and DHA in free acid form within a capsule shell to produce a capsule; coating said capsule to produce a coated capsule having an outer surface; printing a medicated ink comprising at least one hypolipidaemic drug on to the outer surface of the coated capsule; and drying said ink to form medicated print comprising said hypolipidaemic drug(s).

An ink" is a liquid that typically comprises a pigment, colorant and/or dye for used for colouring a surface to produce print, e.g. an image, text, or design. Inks are typically formed using a pigment to impart colour; a resin binder! or equivalent, to form the finished ink and carry the pigment; and a solvent. Once applied, the ink dries by solvent evaporation to form print. Since medicated print of the present invention is to be ingested, the components of the ink must be pharmacologically acceptable and, preferably, one of more of the components of the ink are of the type "generally recognised as safe" (GRAS) by the US Food and Drug Administration ("FDA").

The term "medicated ink" is intended to mean ink that containing a medication comprising at least one pharmaceutically or nutraceutically active agent.

The medicated ink may be printed on to the outer surface of the oral dosage form by any suitable printing method such as rotogravure, flexographic and pad printing although inkjet printing, e.g. from a piezoelectric print head, is preferred. In some embodiments, the ink typically has a viscosity of no more than about 100 centipoise (cps), preferably from about 5 cps about 20 cps, to at 25°C. The other embodiments, the ink has a surface tension from about 20 to about 60 dynes/cm at 25°C. Such viscosities and surface tensions are particularly suitable for inkjet inks.

A suitable ink composition for use as a base to form a medicated ink in accordance with the present invention is disclosed in W02005/113693A, the disclosure of which is incorporated herein by reference.

Such an ink base comprises from about 25 wt % to about 50 wt % of a food grade glycol. e.g. 1,2-propanediol; from about 20 wt % to about 50 wt % of one or more food grade lower, e.g. C to 06, alcohol, preferably selected from n-butanol, ethanol and isopropanol; from about 0.1 to about 10 wt % food grade pigment; and from about 5 wt % to about 25 wt % shellac resin solids. The ink typically has a low water content, e.g. no more than 5 wt %.

A further suitable ink composition for use as a base to form a medicated ink in accordance with the present invention is disclosed in W02007/102903A, the disclosure of which is incorporated herein by reference.

The ink base may typically contain an aqueous vehicle; at least one colorant, such as dyes or pigments or a combination thereof, such as isoprenol derivatives, tetrapyrrol derivatives, benzopyran derivatives, and FD&C colorants; and at least one water soluble organic solvent, such as methanol, ethanol, 2-propanol, n-butanol, sorbitol, propylene glycol, glycerine, polyethylene glycol and combinations thereof (e.g. a 5:95 mixture of methanol:ethanol). Various types of additives may be employed in the inks to enhance or optimise the properties of the ink. Examples of such additives include resins, binders, surfactants, buffers, humectants, preservatives, anti-foaming agents, chelating agents, flavouring agents, and viscosity modifiers.

A further suitable ink base composition comprises water (from about 30 wt % to about 98 wt %, e.g. about 60 to about 95 wt %); water soluble organic solvent (each from about 0.01 wt % to about 80 wt %, e.g. about 1 wt % to about 25 wt %); colorant (from about 0.05 wt % to about 20 wt %); buffer additive (from 0 to about 5 wt %); surfactant (from 0 to about 5 wt %); viscosity modifier (from 0 to about 10 wt %); antioxidant (from 0 to about 5 wt %); antimicrobial (from 0 to about 5 wt %); chelating agent (from 0 to about 5 wt %); and flavouring (from 0 to about 5 wt %).

The or each pharmaceutically active agent and/or nutraceutically active agent is added to the ink base in an amount sufficient to ensure an appropriate amount is present in the medicated print after printing. The or each active agent may be added to the ink base in an amount sufficient such that the medicated ink comprises from about 0.1 wt % to about 10 wt % active agent(s).

The medicated ink composition may be prepared by combining the solvent(s), additive(s), colorant(s) and the active agent(s). The ink vehicle may be formed by combining the solvents to form a solution. Additives may be added at this point. The colorant is added next, followed by the active agent(s) to form the medicated ink in the form of a solution/suspension depending on the solubility of the colorant(s) and active agent(s) in the solvent vehicle. The composition is typically stirred throughout the method.

The ink composition typically (but not exclusively) contains a pigment so that the medicated print may be viewed by the naked eye. Different ink compositions may contain different pigments so that different medicated prints may be differentiated from each other. In this connection, the medicated inks may be colour coded to identify different actives, or to identify different dosages of a given active.

The ink composition may further comprise ferro-magnetic particles to aid differentiation of authentic products from counterfeit products; and/or absorption enhancers, e.g. surfactants, to facilitate absorption of the active agent(s) from the medicated print into the body.

An advantage of the process aspects of the present invention is that existing printing equipment used to apply non-medicated ink to pharmaceutical dosage forms should also be appropriate for applying medicated inks. Thus, there should be no need for additional investment in developing, installing and running new printing equipment.

The invention will now be described by way of example only with reference to Fig. 1 which is a diagrammatic partial cross-sectional view of a soft gelatin capsule according to the present invention.

A soft gelatin capsule 10 has a gelatin shell 12 coated with a delayed release coating 14 (such as a pH sensitive coating, a time dependent release coating or a combined pH sensitive and time dependent release coating) to provide release in the small intestine. The capsule 10 contains about 1000 mg of a free fatty acid oil 16 complising about 55 wt % EPA and about 20 wt % DHA, both in free acid form. The remainder of the oil is composed essentially of other fatty acids.

Medicated print 18 in the form of plain text and a bar code is on the outer surface of the delayed release coating 14 of the soft gelatin capsule 10. The print 18 contains 20 mg of atorvastatin. The capsule is coated with a transparent protective outer coating (not shown).

EXAMPLE

A medicated ink according to the present invention has the following composition.

Polysorbate 80 0.2 wt %; 2-propanol 17 wt %; n-butanol 3 wt %; propylene glycol 3 wt %; atorvastatin 5 wt %; pigment (carbon black) 2 wt %; and water 69.8wt%.

The ink is prepared by mixing the water with the 2-propanol, n-butanol and propylene glycol to form the solvent vehicle. The polysorbate 80 is then added to the solvent vehicle, together with the colorant and the active agent. The mixture is stirred at room temperature until mixing is complete.

The medicated ink composition is printed on to a coated soft gelatin capsule using an inkjet printer system.

It will be appreciated that the invention is not restricted to the details described above with reference to the preferred embodiments but that numerous modifications and variations can be made without departing form the spirit or scope of the invention as defined in the following claims.

Claims (18)

1. CLAIMS1. An oral dosage form comprising a therapeutically active composition containing at least one omega-3 polyunsaturated fatty acid (PUFA), said oral dosage form having an outer surface comprising medicated print thereon, wherein said medicated print comprises a hypolipidaemic drug.
2. 2. An oral dosage form as claimed in Claim 1, wherein said hypolipidaemic drug is for absorption in the stomach.
3. 3. An oral dosage form as claimed in Claim 1, wherein said medicated print is mucoadhesive.
4. 4. An oral dosage form as claimed in any of Claims 1 to 3, wherein said hypolipidaemic drug is a statin or a fibrate.
5. 5. An oral dosage form as claimed in any of the preceding claims comprising a delayed release coating for providing post-gastric release of said therapeutically active composition, said medicated print being on top of said coating.
6. 6. An oral dosage form as claimed in any of the preceding claims, comprising a protective coating on said outer surface thereof over said medicated print.
7. 7. An oral dosage form as claimed in any of the preceding claims, wherein said therapeutically active composition is a fatty acid composition comprising 5, 8, 11, 14, 17-eicosapentaenoic acid (EPA) and 4, 7, 10, 13, 16, 19-docosahexaenoic acid (DHA).
8. 8. An oral dosage form as claimed in any of the preceding claims for use in the treatment or prevention of cardiovascular disease.
9. 9. An oral dosage form as claimed in any of the preceding claims for use in the treatment or prevention of hyperlipidaemia.
10. 10. A coated capsule for oral administration, said coated capsule comprising a capsule shell encapsulating a free fatty acid composition comprising EPA and DHA in free acid form; and a delayed release coating for providing post gastric release of said free fatty acid composition, said coated capsule having an outer surface comprising thereon medicated print comprising a hypolipidaemic drug.
11. 11. A coated capsule as claimed in Claim 10 for use in the treatment or prevention of cardiovascular disease.
12. 12. A coated capsule as claimed in Claim 10 or Claim 11 for use in the treatment or prevention of hyperlipidaemia.
13. 13. A process for producing an oral dosage form as defined in Claim 1, said process comprising: providing an oral dosage form comprising a therapeutically active composition comprising at least one omega-3 PUFA, said oral dosage form having an outer surface; printing a medicated ink comprising a hypolipidaemic drug onto the outer surface of the oral dosage form; and drying said ink to form medicated print comprising said hypolipidaemic drug.
14. 14. A process for producing a coated capsule as defined in Claim 10, said process comprising: encapsulating a free fatty acid composition comprising EPA and DHA in free acid form within a capsule shell to produce a capsule; coating said capsule to produce a coated capsule having an outer surface; printing a medicated ink comprising a hypolipidaemic drug on to the outer surface of the coated capsule; and drying said ink to form medicated print comprising said hypolipidaemic drug.
15. 15. A process as claimed in Claim 13 or Claim 14, wherein said medicated ink is printed onto said outer surface of said oral dosage form by inkjet printing.
16. 16. A pharmaceutical composition substantially as hereinbefore described with reference to the accompanying drawing and/or example.
17. 17. A capsule substantially as hereinbefore described with reference to the accompanying drawing and/or example.
18. 18. A process substantially as hereinbefore described with reference to the accompanying example.